Chronic Kidney Disease (CKD) in Adults: Overview and Recommendations

Chronic kidney disease (CKD) in adults
Overview and Recommendations

Background
Chronic kidney disease is characterized by abnormalities of kidney structure or function

that are present for > 3 months.
It is defined as > 3 months of either a glomerular filtration rate (GFR) < 60 mL/minute/1.73
m2 or other evidence of kidney damage such as albuminuria, abnormal kidney structure
detected by imaging, or a history of a renal transplant.
The most common causes include diabetes, hypertension, and glomerulonephritis.
Complications of CKD can include cardiovascular disease, anemia, bone disease,
nephrogenic systemic fibrosis, electrolyte abnormalities, and uremia.
Evaluation
Staging of chronic kidney disease is based on the cause, the estimated glomerular
filtration rate (GFR) levels, and albumin:creatinine ratio.
GFR can be calculated from patient information such as age, sex, height, and laboratory
values such as serum creatinine and cystatin C. GFR calculators for adults include the
Modification of Diet in Renal Disease (MDRD equation) and the Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI equations).
Other tests recommended for patients with chronic kidney disease include urine
sediment exam, serum electrolytes, and kidney imaging such as ultrasound.
If the GFR is < 60 mL/minute/1.73 m2, test for further complications of CKD, including
anemia, hypoalbuminemia, abnormal calcium, phosphorus, parathyroid hormone, and
vitamin D levels.
Management
Interventions to slow decline in kidney function:

Control blood pressure with goal of < 140/90 mm Hg, or < 130/80 mm Hg if
proteinuria or diabetes present (Strong recommendation).
Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers
(ARBs) are commonly recommended and both may reduce progression of chronic
kidney disease with macroalbuminuria, however, evidence for benefit in CKD stage
1-3 is lacking or limited.
In patients with diabetes, consider a target HbA1c of approximately 7%.
Consider advising patient to limit protein intake to 1.3 g/kg/day if CKD is at risk of
progression and limiting protein intake to 0.8 g/kg/day if GFR < 30 mL/minute/1.73
m2 (GFR categories G4 and G5) (Weak recommendation).
Consider bicarbonate supplementation for patients with severe CKD and metabolic
acidosis (Weak recommendation).
Interventions to prevent and treat comorbidities and complications of decreased kidney
function:
To reduce cardiovascular events:
offer statins to patients with chronic kidney disease who are not on dialysis
consider ACE inhibitors, antiplatelet agents, or fibrates
Consider erythropoiesis-stimulating agent (ESA) to treat anemia with target
hemoglobin levels < 12 g/dL as higher targets increase the risk of stroke (Weak
recommendation).
Monitor serum levels of calcium, phosphorus, parathyroid hormone (PTH), and
alkaline phosphatase activity in adults with CKD stage 3 or higher (Strong
recommendation).
Recommendations for renal replacement therapy:
Educate patients about different modalities of renal replacement therapy when
glomerular filtration rate is < 30 mL/minute/1.73 m2 (stage 4 CKD) (Strong
Recommendation).
Preemptive kidney transplant is the preferred form of renal replacement therapy
(Strong Recommendation).
Consider starting dialysis for uremic symptoms, volume overload, malnutrition, or
inability to control blood pressure.
Related Summaries
Risk factors for chronic kidney disease
Anemia of chronic kidney disease
Chronic kidney disease-mineral and bone disorder (CKD-MBD)
Dialysis for end-stage renal disease
Complications of chronic kidney disease
Diabetic nephropathy
Hypertension
Acute kidney injury
General Information
Description
CKD is characterized by abnormalities of kidney structure or function that are present for
> 3 months and have implications for health(3)
Kidney Disease Improving Global Outcomes (KDIGO) defines CKD as either of the
following for > 3 months(3)
glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2
kidney damage as evidenced by ≥ 1 of
albuminuria
urine sediment abnormalities
electrolyte or other abnormalities due to tubular disorders
abnormal histology
abnormal structure detected by imaging
history of kidney transplant
CKD staging based on cause, GFR category, and albuminuria category (KDIGO Level 1,
Grade B)(3)
cause - assignment based on presence or absence of systemic disease and location in
the kidney of observed or presumed pathologic-anatomic findings
GFR categories
G1 - GFR > 90 mL/minute/1.73 m2 (normal or high)
G2 - GFR 60-89 mL/minute/1.73 m2 (mildly decreased compared to young adult
level)
G3a - GFR 45-59 mL/minute/1.73 m2 (mild-to-moderately decreased)
G3b - GFR 30-44 mL/minute/1.73 m2 (moderate-to-severely decreased)
G4 - GFR 15-29 mL/minute/1.73 m2 (severely decreased)
G5 - GFR < 15 mL/minute/1.73 m2 (kidney failure)
albuminuria categories
A1 - albumin excretion rate (AER) < 30 mg/24 hours, albumin to creatinine
ratio (ACR) < 30 mg/g (3 mg/mmol) (normal to mildly increased)
A2 - AER 30-300 mg/24 hours, ACR 30-300 mg/g (3-30 mg/mmol) (moderately
increased compared to young adult level)
A3 - AER > 300 mg/24 hours, ACR > 300 mg/g (30 mg/mmol) (severely increased
[including nephrotic syndrome])
alternative classification system based on combination of estimated GFR and proteinuria
risk category 0 - if estimated GFR ≥ 60 mL/minute/1.73 m2 and normal proteinuria
risk category 1 - if either
estimated GFR 45-59.9 mL/minute/1.73 m2 and normal proteinuria
estimated GFR ≥ 60 mL/minute/1.73 m2 and mild proteinuria
estimated GFR 45-59.9 mL/minute/1.73 m2 and mild proteinuria present
risk category 3 - if any of the following
estimated GFR ≥ 60 mL/minute/1.73 m2 and heavy proteinuria
estimated GFR 30-44.9 mL/minute/1.73 m2 and mild proteinuria
estimated GFR 15-29.9 mL/minute/1.73 m2 and mild proteinuria
estimated GFR 15-59.9 mL/minute/1.73 m2 and heavy proteinuria
alternative staging system would reclassify some patients to lower stage compared
to standard staging system using estimated GFR alone
Reference - Ann Intern Med 2011 Jan 4;154(1):12, editorial can be found in Ann
Intern Med 2011 Jan 4;154(1):65
Also called
CKD
chronic renal failure (CRF)
chronic renal insufficiency (CRI)
end-stage renal disease (ESRD) - if renal replacement therapy required
Epidemiology
Incidence/Prevalence
prevalence of CKD stratified by stage, gender, and geographical region

based on systematic review of observational studies
systematic review of 100 studies evaluating prevalence of CKD in 112 adult
populations
mean global prevalence of CKD
stages 1-5, 13.4% (95% CI 11.7%-15.1%) in analysis of 44 populations
stages 3-5, 10.6% (95% CI 9.2%-12.2%) in analysis of 68 populations
mean prevalence of CKD by
gender (stages 1-5) in analysis of 51 studies
male 12.8% (95% CI 10.8%-11.9%)
female 14.6% (95% CI 12.7%-16.7%)
geographical region
Prevalence
Region Stages 1-5 Stages 3-5
18.38% (95% CI 11.86% (95% CI
Europe
11.57%-25.2%) 9.93%-13.79%)
17.95% (95% CI 11.68% (95% CI
Iran
7.37%-28.53%) 4.51%-18.84%)
United States and 15.45% (95% CI 14.44% (95% CI
Canada 11.71%-19.2%) 8.52%-20.36%)
14.71% (95% CI 8.14% (95% CI
Australia
11.71%-17.71%) 4.48%-11.79%)
Japan, South Korea, and 13.74% (95% CI 11.73% (95% CI
Oceania 10.75%-16.72%) 5.36%-18.1%)
China, Taiwan, and 13.18% (95% CI 10.06% (95% CI
Mongolia 12.07%-14.3%) 6.63%-13.49%)
13.1% (95% CI 6.76% (95% CI
India and Bangladesh
11.01%-15.19%) 3.68%-9.85%)
South Africa, Senegal, 8.66% (95% CI
7.6% (95% CI 6.1%-9.1%)
and Congo 1.31%-16.01%)
12.1% (95% CI
Chile N/A
11.72%-12.48%)
Abbreviation: N/A, not available.
Reference - PLoS One 2016;11(7):e0158765 full-text
lifetime incidence of chronic kidney disease stages 3-5 in United States in systematic
review
systematic review of data from National Vital Statistics Report, National Health and
Nutrition Examination Survey, United States Renal Data System, and meta-analysis
of cohort studies (> 2 million persons)
overall lifetime incidence of different CKD stages
59.1% with estimated glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2
(stage 3a+)
33.6% with estimated GFR < 45 mL/minute/1.73 m2 (stage 3b+)
11.5% with estimated GFR < 30 mL/minute/1.73 m2 (stage 4+)
3.6% with end-stage renal disease (ESRD)
incidence of CKD increased with age, with approximately 50% of CKD stage 3a+
incidents occurred after age 70 years
Lifetime Incidence of Chronic Kidney Disease by Stage:
Population Stage 3a+ Stage 3b+ Stage 4+ ESRD
White men 53.6% 29% 9.3% 3.3%
White women 64.9% 36.7% 11.4% 2.2%
Black men 51.8% 33.7% 15.8% 8.5%
Black women 3a+ 40.2% 18.5% 7.8%
Abbreviation: ESRD, end-stage renal disease.
Reference - Am J Kidney Dis 2013 Aug;62(2):245 full-text, editorials can be found in
Am J Kidney Dis 2013 Aug;62(2):220, Am J Kidney Dis 2013 Aug;62(2):217
prevalence of CKD and end-stage renal disease in United States
114,813 patients diagnosed with ESRD in United States in 2012 (United States Renal
Data System 2014 Annual Data Report)
prevalence of CKD in United States based on National Health and Nutrition
Examination Survey (NHANES) 2007-2012
13.6% of adults ≥ 20 years old
6.5% with estimated GFR < 60 mL/minute/1.73 m2
9.2% with albumin to creatinine ratio ≥ 30 mg/g
prevalence by age (any stage)
5.7% at age 20-39 years
8.9% at age 40-59 years
33.2% at age ≥ 60 years
Reference - United States Renal Data System 2014 Annual Data Report
6.4%-6.9% prevalence of stages 3 and 4 CKD in 2001-2012 in adults ≥ 20 years old in
United States
based on NHANES
stages 3-4 CDK defined as estimated GFR 15-59 mL/minute/1.73 m2, and
expanded definition of CKD included persons with estimated GFR ≥ 60
mL/minute/1.73 m2 and 1-time urine albumin to creatinine ratio ≥ 30 mg/g
Reference - Ann Intern Med 2016 Oct 4;165(7):473 full-text
more than 50% of patients aged ≥ 80 years in the United States have CKD stage
3a or higher
based on cohort study
971 patients ≥ 80 years old in NHANES study evaluated from 2005 to 2010
51.2% had GFR < 60 mL/minute/1.73 m2
21.7% had GFR < 45 mL/minute/1.73 m2
Reference - JAMA 2013 Sep 25;310(12):1284 full-text
incidence of ESRD in patients with diabetes decreased in United States and
Puerto Rico from 1996 to 2007
based on data from United States Renal Data System and Behavioral Risk
Factor Surveillance System
age-adjusted rate of ESRD in patients with diabetes
304.5 per 100,000 patients with diabetes
199.1 per 100,000 patients with diabetes
Reference - MMWR Morb Mortal Wkly Rep 2010 Oct 29;59(42):1361 full-text
10.8% estimated prevalence of CKD in China
based on cross-sectional study
47,204 adults ≥ 18 years old in China evaluated
CKD defined as estimated GFR < 60 mL/minute/1.73 m2 or presence of albuminuria
overall adjusted prevalence of CKD was 10.8%
adjusted prevalence of estimated GFR < 60 mL/minute/1.73 m2 was 1.7%
adjusted prevalence of albuminuria was 9.4%
Reference - Lancet 2012 Mar 3;379(9818):815, correction can be found in Lancet
2012 Aug 18;380(9842):650, editorial can be found in Lancet 2012 Mar
3;379(9818):783
about 12% prevalence of CKD in Taiwan
462,293 persons > 20 years old who had regular screening from 1994 to 2006 in
Taiwan evaluated
11.9% had chronic kidney disease
higher prevalence of CKD associated with lower socioeconomic status
Reference - Lancet 2008 Jun 28;371(9631):2173, editorial can be found in Lancet 2008
Jun 28;371(9631):2147, commentary can be found in Lancet 2008 Dec
6;372(9654):1949
17.7% prevalence of CKD among acute medical admissions in London
based on retrospective cohort of 6,073 patients admitted to acute medical unit
1,075 patients (17.7%) had GFR < 60 mL/minute/1.73 m2
Reference - QJM 2008 Feb;101(2):91 full-text
3.7/1,000 person-years incidence of chronic kidney disease in patients with acute
myocardial infarction in United States Medicare recipients
127,736 Medicare recipients (mean age 77.1 years) hospitalized with acute
myocardial infarction were evaluated
3.7/1,000 person-years incidence of chronic kidney disease in patients with acute
myocardial infarction
1.7% progressed to end-stage kidney disease (14.9% were African American)
Reference - Am J Kidney Dis 2008 Aug;52(2):251, editorial can be found in Am J
Kidney Dis 2008 Aug;52(2):205
renal dysfunction more common in elderly inpatients than predicted by creatinine
levels
based on prospective cohort study
154 inpatients > 80 years old with urinary catheters and accurate 24-hour urine
collection
of 107 patients (70%) with normal serum creatinine (≤ 1.4 mg/dL [123.8 mcmol/L]),
77 (50%) had creatinine clearance < 60 mL/minute/1.73 m2 (mean creatinine
clearance 45.1 mL/minute/1.73 m2)
prediction of creatinine clearance to within 10% of measured creatinine clearance
occurred in only
9% of patients with Cockcroft formula
9% with Jelliffe formula
17% with Modification of Diet in Renal Disease (MDRD) formula
Reference - QJM 2004 May;97(5):281 full-text
DynaMed commentary -- estimated formulas have higher percent error in
populations with muscle mass at extreme such as elderly or ill patients
impaired kidney function common in elderly persons with normal serum creatinine
based on cross-sectional study
665 community-dwelling persons aged 65-92 years with normal serum creatinine in
Italy evaluated
moderate renal function impairment defined as GFR < 60 mL/minute
prevalence of moderate renal impairment by Cockcroft-Gault equation
18.6% in persons aged 65-74 years
96.8% in persons ≥ 85 years old
prevalence of moderate renal impairment by creatinine clearance calculation
15% in persons aged 65-74 years
58.7% in persons ≥ 85 years old
Reference - J Am Geriatr Soc 2007 Jun;55(6):816 full-text, commentary can be found
in J Am Geriatr Soc 2008 Apr;56(4):774
Risk factors
factors associated with increased risk of chronic kidney disease (CKD) include
older age
diabetes
microalbuminuria or proteinuria
hypertension
acute kidney injury
overweight or obesity
metabolic syndrome
smoking
alcohol, tobacco, or drug abuse
certain nephrotoxic drugs
black race with APOL1 homozygous gene variant
possible risk factors include
kidney stones
nonalcoholic fatty liver disease
hypertensive disorders of pregnancy
sickle cell disease and sickle cell trait
hepatitis C virus infection
low birth weight
ingestion of aristolochic acid
risk prediction
multiple risk scores have been validated to help predict risk of developing CKD,
however, there is insufficient evidence to guide clinical use of CKD risk models
validated risk scores include
8-factor risk score
5-factor risk score
SCORED score
Q kidney score
Taiwan clinical prediction model
Korean risk score
see Risk factors for chronic kidney disease for details
Etiology and Pathogenesis

Causes
glomerular disease leading to renal damage, such as(3, 4)
diabetes mellitus (reported to account for 33% of adult CKD)
immune diseases such as lupus nephritis, minimal change disease,
membranoproliferative glomerulonephritis (MPGN), membranous nephropathy
systemic infection
neoplasia
vascular disease, such as(3, 4)
hypertension (reported to account for 21% of adult CKD)
atherosclerosis
ischemia
vasculitis
thrombotic microangiopathy
cystic and congenital disease(3, 4)
polycystic kidney disease
Alport syndrome
Fabry disease
long-standing obstruction, such as from(4)
nephrolithiasis
benign prostatic hyperplasia (BPH)
toxic exposures, such as(4)
nephrotoxic medications
intravenous contrast dye or gadolinium exposure
renal tubular disorders, such as(3)
renal tubular acidosis (RTA)
nephrogenic diabetes insipidus
renal potassium wasting
renal magnesium wasting
Fanconi syndrome
nonalbumin proteinuria
cystinuria
urinary tract infections including pyelonephritis
kidney transplantation(3)
renal artery stenosis may be responsible for 11%-14% of cases of end-stage renal failure (J
Hypertension 1997 Dec;15(12 Pt 1):1365)
History and Physical

History
Chief concern (CC)
usually asymptomatic in early stages of kidney disease(3)

symptoms of uremia include(1, 2)
sleep disturbances
fatigue
decreased mental acuity
anorexia
nausea
vomiting
weakness
pruritus
seizures
chest pain from pericarditis or pleuritis
History of present illness (HPI)
onset is typically insidious and begins with nonspecific symptoms(1)
Medication history
ask about nephrotoxic medications, including nonprescription medications and herbal

supplements(4)
Past medical history (PMH)
hypertension (one of the earliest manifestations of kidney disease)(1)

anemia(1, 2)
bone disease (renal osteodystrophy) which may manifest as(1, 2)
bone pain
pathologic fractures
metastatic calcifications (advanced)
insulin resistance(1, 2)
blood cell dysfunction (granulocyte, lymphocyte, and platelets)(1, 2)
Family history (FH)
family history of kidney disease
Physical
General physical
hypertension(1, 2)
growth retardation (children)(2)
uremic frost
Uremic frost: Uremic frost presenting as powdery deposits of urea and uric acid salts on
the skin in a patient with untreated chronic kidney disease.
Cardiac
assess for pericarditis(1)
Extremities
Terry's nails (proximal white nail beds with distal pink transverse band) associated with
chronic kidney disease (Am Fam Physician 2004 Jun 15;69(12):2903 full-text)
Beau lines
transverse nail ridging or depressions of nail plates
usually bilateral from temporary cessation of growth during severe systemic illness
signs of calciphylaxis - tender skin lesions of erythema, pallor, ecchymoses, subcutaneous
nodules, or livedo reticularis that evolve into necrosis and ulceration (Semin Dial 2002
May-Jun;15(3):172, Indian J Dermatol 2013 Mar;58(2):87 full-text )
Neuro
possible neurological signs may include(1)

peripheral neuropathy
decreased mental acuity
seizures
Diagnosis
Making the diagnosis
Kidney Disease Improving Global Outcomes (KDIGO) defines CKD as either of the
following for > 3 months(3)
glomerular filtration rate (GFR) < 60 mL/minute/1.73 m2
kidney damage as evidenced by ≥ 1 of
albuminuria
urine sediment abnormalities
electrolyte or other abnormalities due to tubular disorders
abnormal histology
abnormal structure detected by imaging
history of kidney transplant
GFR in adults can be calculated using Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) calculator or Modification of Diet in Renal Disease (MDRD) GFR calculator
available at National Kidney Foundation to estimate GFR from serum creatinine level
GFR can be measured by using exogenous filtration markers
CKD staging based on cause, GFR category, and albuminuria category(3)
GFR categories
normal young adult - GFR approximately 125 mL/minute/1.73 m2
G1 - GFR > 90 mL/minute/1.73 m2 (normal or high)
G2 - GFR 60-89 mL/minute/1.73 m2 (mildly decreased compared to young adult
level)
G3a - GFR 45-59 mL/minute/1.73 m2 (mild-to-moderately decreased)
G3b - GFR 30-44 mL/minute/1.73 m2 (moderate-to-severely decreased)
G4 - GFR 15-29 mL/minute/1.73 m2 (severely decreased)
G5 - GFR < 15 mL/minute/1.73 m2 (kidney failure)
albuminuria categories
normal young adult - albumin excretion rate (AER) < 10 mg/g (1 mg/mmol)
A1 - AER < 30 mg/24 hours, albumin to creatinine ratio (ACR) < 30 mg/g (3
mg/mmol) (normal-to-mildly increased)
A2 - AER 30-300 mg/24 hours, ACR 30-300 mg/g (3-30 mg/mmol) (moderately
increased compared to young adult level)
A3 - AER > 300 mg/24 hours, ACR > 300 mg/g (30 mg/mmol) (severely increased
[including nephrotic syndrome])
Differential diagnosis
acute renal failure (may be superimposed on chronic kidney disease)

medications associated with falsely elevated serum creatinine levels
medications that block tubular secretion of creatinine can elevate serum creatinine
in the absence of reduced glomerular filtration rate
cimetidine
pyrimethamine
trimethoprim
Reference - Arch Intern Med 1998 Dec 7-21;158(22):2509
protein and creatine supplements leading to high-serum creatinine and low reported
estimated glomerular filtration rate in absence of kidney disease in case report (BMJ 2010
Jan 8;340:b5027)
also see differential diagnosis of Proteinuria in adults - approach to the patient
Testing overview
laboratory evaluation of patients with CKD

use serum creatinine to estimate glomerular filtration rate (GFR)
for adults, use Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
calculator (2009) (recommended by Kidney Disease Improving Global
Outcomes [KDIGO]) or Modification of Diet in Renal Disease (MDRD) GFR
calculator or other calculator such as another CKD-EPI equation
creatinine clearance which is calculated by the Cockcroft-Gault formula is
widely used for guidance of drug dosing in patients with CKD
serum cystatin C is another marker of impaired kidney function
may be useful for confirmatory testing, such as in adults with estimated GFR
45-59 mL/minute/1.73 m2 and no markers of kidney damage
if measured, use GFR estimating equation that uses the cystatin C level to
derive the GFR rather than looking at cystatin C concentration alone (such as
CKD-EPI cystatin C calculator)
for initial urine protein measurement, early morning urine always preferred (in
order of preference) (KDIGO Level 2, Grade B)
albumin to creatinine ratio
protein to creatinine ratio
reagent strip urinalysis for total protein with automated reading
reagent strip urinalysis for total protein with over manual reading
urinalysis with urine sediment exam or dipstick for red blood cells and white blood
cells
kidney imaging, usually ultrasound
serum electrolytes (sodium, potassium, chloride, bicarbonate)
if GFR < 60 mL/minute/1.73 m2, further tests should include(4)
hemoglobin
serum albumin (for nutritional status)
ionized calcium
phosphorus
parathyroid hormone
vitamin D
additional tests if hemoglobin ≤ 12.6 g/dL (126 g/L) in men or postmenopausal women or
≤ 11 g/dL (110 g/L) in premenopausal women(4)
complete blood count with red blood cell indices
reticulocyte count
iron
total iron binding capacity
ferritin
transferrin saturation
fecal occult blood test
Blood tests
elevated blood urea nitrogen (BUN) and serum creatinine commonly seen in chronic
kidney disease, but numbers should be used to calculate the estimated glomerular
filtration rate (GFR) rather than basing diagnosis on serum levels alone(3)
13.9% of elderly hospitalized patients with normal serum creatinine reported
to have chronic kidney disease
11,687 elderly hospitalized patients evaluated
13.9% had serum creatinine < 1.2 mg/dL but estimated GFR < 60
mL/minute/1.73 m2 based on Modification of Diet in Renal Disease (MDRD)
formula
normal serum creatinine but decreased GFR associated with increased risk of
adverse drug reactions with hydrosoluble drugs compared to normal serum
creatinine and normal estimated GFR (odds ratio 1.61, 95% CI 1.15-1.25)
Reference - Arch Intern Med 2005 Apr 11;165(7):790
elevated serum cystatin C(3, 4)
serum levels independent of age, sex, or muscle mass
may be useful for confirmatory testing, such as in adults with estimated GFR 45-59
mL/minute/1.73 m2 and no markers of kidney damage
if measured, use GFR estimating equation that uses the cystatin C level to derive the
GFR rather than looking at cystatin C concentration alone (such as CKD-EPI cystatin
C calculator)
common abnormalities include
anemia of chronic kidney disease
secondary hyperparathyroidism
abnormal blood test results may include(2)
hyponatremia (generally late finding)
hyperkalemia (generally late finding)
hyperphosphatemia
hypocalcemia
hyperuricemia
metabolic acidosis
Estimation of GFR
Modification of Diet in Renal Disease (MDRD)
see also MDRD GFR calculator available at National Kidney Foundation or UK version of
4-variable MDRD at United Kingdom CKD guide
4-Variable MDRD Formula (with serum creatinine in mg/dL):
estimated glomerular filtration rate (GFR) [in mL/minute/1.73 m2] = 175 × (serum
creatinine [in mg/dL])-1.154 × (age [in years])-0.203 (× 0.742 if female) (× 1.21 if black)
to use mcmol/L for serum creatinine, replace 175 with 30,849
References
BMJ 2007 Jun 9;334(7605):1198 full-text, commentary can be found in BMJ 2007 Jun
23;334(7607):1287 full-text, BMJ 2007 Jul 21;335(7611):111 full-text
Ann Intern Med 2009 May 5;150(9):604 full-text , commentary can be found in Ann
Intern Med 2009 Dec 15;151(12):892
4-variable MDRD formula may not compensate for physiological differences of age
and sex (level 2 [mid-level] evidence)
based on retrospective cohort study
565 patients (derived from 93,404 outpatients in United Kingdom and 35,572
hospitalized patients in Sweden during 1-year period) for whom GFR had been
measured using Pt-Iohexol (Omnipaque) were included
no significant difference found between MDRD and serum creatinine in ability to
estimate GFR by age and sex
Reference - Int J Med Sci 2008 Jan 5;5(1):9 full-text
4-variable MDRD may be as accurate as 6-variable MDRD for estimating GFR, and
both appear superior to Cockcroft-Gault (level 2 [mid-level] evidence)
based on prospective cohort study without results of MDRD and reference standard
blinded to each other
1,628 patients with CKD were included
GFR reference standard measured via urinary clearance of 125I-iothalamate after
subcutaneous infusion
proportion of GFR estimates within 30% of measured GFR
90% (95% CI 89%-91%) for 4-variable MDRD
91% (95% CI 90%-92%) for 6-variable MDRD
60% (95% CI 58%-62%) for Cockcroft-Gault equation
83% (95% CI 81%-85%) for Cockcroft-Gault equation corrected for bias
Reference - Ann Intern Med 2006 Aug 15;145(4):247, correction can be found in Ann
Intern Med 2007 Feb 20;146(4):316, Ann Intern Med 2008 Oct 7;149(7):519, editorial
can be found in Ann Intern Med 2006 Aug 15;145(4):299, commentary can be found
in Ann Intern Med 2007 Jan 2;146(1):74
4-variable MDRD equation may have higher diagnostic accuracy than Cockcroft-
Gault formula for CKD in elderly patients with diabetes (level 2 [mid-level]
evidence)
based on prospective cohort study without blinding of reference standard and test
under investigation
69 patients with diabetes ≥ 72 years old and serum creatinine ranging from 54 to
367 mcmol/L (0.61-4.15 mg/dL) had comparison of
estimated GFR calculated using 4-variable MDRD and Cockcroft-Gault
equations
actual GFR measured using chromium 51-ethylenediamine tetraacetic acid
(51Cr-EDTA) clearance
formulas using (standard definition of CKD) GFR < 60 mL/minute/1.73 m2 had
98% sensitivity and 61% specificity for MDRD equation
82% sensitivity and 44% specificity for Cockcroft-Gault equation
Reference - J Am Geriatr Soc 2006 Jun;54(6):1007
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equations
CKD-EPI Equations for Estimating GFR in Women:

Serum Cystatin
Serum Creatinine Equation
C
≤ 0.7 mg/dL (≤ 62
GFR = 144 × (Scr/0.7)-0.329 × 0.993Age [× 1.159 if black]
mcmol/L)
Not measured
> 0.7 mg/dL (> 62
mcmol/L)
≤ 0.8 mg/L GFR = 133 × (Scys/0.8)-0.499 × 0.996Age × 0.932
Not measured
> 0.8 mg/L GFR = 133 × (Scys/0.8)-1.328 × 0.996Age × 0.932
≤ 0.7 mg/dL (≤ 62 GFR = 130 × (Scr/0.7)-0.248 × (Scys/0.8)-0.375 × 0.995 Age [×
≤ 0.8 mg/L
mcmol/L) 1.08 if black]
Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR,

glomerular filtration rate [in mL/minute/1.73 m2]; Scr, serum creatinine [in mg/dL]; Scys,
t ti C [i /L]
serum cystatin C [in mg/L].
Serum Cystatin
C
GFR = 130 × (Scr/0.7)-0.248 × (Scys/0.8)-0.711 × 0.995 Age [×
> 0.8 mg/L
1.08 if black]
GFR = 130 × (Scr/0.7)-0.601 × (Scys/0.8)-0.375 × 0.995 Age [×
≤ 0.8 mg/L
> 0.7 mg/dL (> 62 1.08 if black]
mcmol/L) GFR = 130 × (Scr/0.7)-0.601 × (Scys/0.8)-0.711 × 0.995 Age [×
> 0.8 mg/L
1.08 if black]
CKD-EPI Equations for Estimating GFR in Men:
Serum Cystatin
C
≤ 0.9 mg/dL (≤ 80
mcmol/L)
Not measured
> 0.9 mg/dL (> 80
mcmol/L)
≤ 0.8 mg/L GFR = 133 × (Scys/0.8)-0.499 × 0.996Age
Not measured
> 0.8 mg/L GFR = 133 × (Scys/0.8)-1.328 × 0.996Age
GFR = 135 × (Scr/0.9)-0.207 × (Scys/0.8)-0.375 × 0.995 Age
≤ 0.8 mg/L
≤ 0.9 mg/dL (≤ 80 [× 1.08 if black]
mcmol/L) GFR = 135 × (Scr/0.9)-0.207 × (Scys/0.8)-0.711 × 0.995 Age
> 0.8 mg/L
[× 1.08 if black]
GFR = 135 × (Scr/0.9)-0.601 × (Scys/0.8)-0.375 × 0.995 Age
≤ 0.8 mg/L
> 0.9 mg/dL (> 80 [× 1.08 if black]
mcmol/L) GFR = 135 × (Scr/0.9)-0.601 × (Scys/0.8)-0.711 × 0.995 Age
> 0.8 mg/L
[× 1.08 if black]
References
CKD-EPI creatinine equation (Ann Intern Med 2009 May 5;150(9):604 full-text ,
commentary can be found in Ann Intern Med 2009 Dec 15;151(12):892 )
CKD-EPI cystatin C and creatinine-cystatin C equations (N Engl J Med 2012 Jul
5;367(1):20), correction can be found in N Engl J Med 2012 Aug 16;367(7):681, N Engl
J Med 2012 Nov 22;367(21):2060, editorial can be found in N Engl J Med 2012 Jul
5;367(1):75
estimation of GFR using CKD-EPI cystatin C equation or CKD-EPI creatinine-cystatin
C equation improves risk classification compared to CKD-EPI creatinine equation
(level 1 [likely reliable] evidence)
based on validation cohort study
individual patient data from 90,750 patients (from 11 general-population cohorts)
who had standardized measurements of serum creatinine and cystatin C at baseline
were analyzed
estimated GFR calculated for each patient with CKD-EPI equations using serum
cystatin C or creatinine
CKD (estimated GFR < 60 mL/minute/1.73 m2) in 13.7% using cystatin C
equation and 9.7% using creatinine equation
all-cause mortality 13.6% overall in mean follow-up 7.7 years
GFR classification by cystatin C equation was compared to classification by
creatinine equation
21.5% were classified to a lower GFR category (higher stage disease) by cystatin
C equation
classification to lower category by cystatin C equation associated with
significantly increased risk of mortality for each GFR category
hazard ratios for risk of death ranged from 1.36 to 3.04 (p < 0.05 for each
category)
19.3% were classified to a higher GFR category (lower stage disease) by cystatin
C equation
classification to higher category by cystatin C equation associated with
reduction in risk of mortality
hazard ratios for risk of death ranged from 0.44 to 0.88, but were
significant only for estimated GFR categories 45-59 mL/minute/1.73 m2
and 30-44 mL/minute/1.73 m2
net reclassification improvement for cystatin C equation compared to
creatinine equation (assesses relative rates of appropriate and inappropriate
reclassification)
for all-cause mortality 23% (95% CI 18%-28%)
for cardiovascular mortality 17% (95% CI 11%-23%)
for end-stage renal disease (ESRD) 10% (95% CI 0%-21%)
performance of CKD-EPI equation using cystatin C plus creatinine was similar to
equation using cystatin C only
similar results obtained in additional analysis of 5 cohorts with 2,960 patients with
CKD at baseline
Reference - N Engl J Med 2013 Sep 5;369(10):932 full-text , editorial can be found in
N Engl J Med 2013 Sep 5;369(10):974
CKD-EPI creatinine-cystatin C equation may be more accurate than CKD-EPI
creatinine equation for estimating GFR (level 2 [mid-level] evidence)
based on diagnostic cohort study with limited ethnic diversity
CKD-EPI group (which had developed CKD-EPI creatinine equation) developed 2
new equations for estimating GFR based on serum cystatin C alone and combination
of serum creatinine and serum cystatin C
derivation cohort included 5,352 patients from 13 studies and validation cohort
included 1,119 patients from 5 studies that measured GFR
derivation cohort included few nonwhite and nonblack patients, validation cohort
included few nonwhite patients
reference standard for GFR was based on urinary clearance of iothalamate or other
exogenous filtration markers
in analysis of 277 patients in validation cohort with estimated GFR 45-74
mL/minute/1.73 m2 based on CKD-EPI creatinine equation
124 (45%) had measured GFR < 60 mL/minute/1.73 m2
Performance of Specific Equations for Predicting Measured GFR < 60
mL/minute/1.73 m2:
CKD-EPI Creatinine CKD-EPI Creatinine-

Equation Cystatin C Equation
Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration;
GFR l l filt ti t
GFR, glomerular filtration rate.
CKD-EPI Creatinine CKD-EPI Creatinine-

Equation Cystatin C Equation
Sensitivity 83% 89%
Specificity 59% 73%
Positive predictive value 62% 72%
Negative predictive value 81% 89%
Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration;
GFR, glomerular filtration rate.
Reference - N Engl J Med 2012 Jul 5;367(1):20 full-text, correction can be found in N
Engl J Med 2012 Aug 16;367(7):681, N Engl J Med 2012 Nov 22;367(21):2060, editorial
can be found in N Engl J Med 2012 Jul 5;367(1):75
comparison of CKD-EPI formulas to MDRD study equation
CKD-EPI creatinine equation may classify fewer patients as having CKD, but
may more accurately predict likelihood of mortality and end stage renal
disease than MDRD study equation (level 2 [mid-level] evidence)
based on meta-analysis without systematic search
meta-analysis of 40 cohorts (25 general population, 7 at high risk for vascular
disease, 13 with CKD) with 1.1 million adults ≥ 18 years old with 9.4 million
person-years of follow-up
estimated GFR classified into 6 categories by both CKD-EPI creatinine equation
and MDRD study equation
compared with MDRD equation, CKD-EPI creatinine equation
reclassified 24.4% of patients to a higher estimated GFR category
reclassified 0.6% of patients to a lower estimated GFR category
reduced prevalence of CKD stages 3-5 from 8.7% to 6.3%
CKD-EPI equation more accurately categorized the risk for mortality and end-
stage renal disease than the MDRD Study equation
Reference - JAMA 2012 May 9;307(18):1941 full-text, editorial can be found in
JAMA 2012 May 9;307(18):1976
performance of CKD-EPI creatinine and MDRD study equations vary across
populations and GFR ranges (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review comparing performance of CKD-EPI creatinine and MDRD
Study GFR estimating equations, or modifications of these equations with
reference GFR measurement in
12 cross-sectional studies with 12,898 adults in North America, Europe, or
Australia
8 cross-sectional studies in adults outside of North America, Europe, or
Australia
methods of GFR measurement and study populations were heterogeneous
from studies in North American, Europe, and Australia
study populations included
general population in 3 studies
kidney donors (prior to donation) in 1 study
kidney donors (before and after donation) in 1 study
kidney transplant recipients in 3 studies
patients with cancer in 1 study
heterogeneous population in 3 studies
CKD-EPI creatinine equation more accurate than MDRD Study equation in
10 studies, and less accurate in 2 studies
for both accuracy and bias, CKD-EPI equation performed better at higher
GFRs (approximately > 60 mL/minute per 1.73 m2), and MDRD Study
equation performed better at lower GFRs
from studies outside of North America, Europe, and Australia
study populations included
general population in 3 studies
patients with CKD in 3 studies
kidney transplant recipients in 1 study
heterogeneous population in 1 study
unmodified CKD-EPI creatinine and MDRD Study equations less accurate
than in studies in North America, Europe, and Australia
in 6 studies, CKD-EPI creatinine and MDRD Study equations modified by
adding or removing a coefficient to improve performance of equation in
development data set, or new equation developed using same variables
Reference - Ann Intern Med 2012 Jun 5;156(11):785
Cockcroft-Gault formula
see DynaMed calculator for Creatinine Clearance Estimate by Cockcroft-Gault Formula

creatinine clearance [in mL/minute] = {(140 - age [in years]) × (weight [in kg]) (× 0.85 if
female)} / (72 × serum creatinine [in mg/dL])
to use mcmol/L for serum creatinine, replace 72 in denominator with 0.84
widely used for guidance of drug dosing in patients with CKD
drawbacks
derived from small sample (249) of men only
not adjusted for body surface area
formula overestimates kidney function by not accounting for tubular secretion
of creatinine (which varies among individuals and may be inhibited by
medications like trimethoprim)
Reference - N Engl J Med 2006 Jun 8;354(23):2473 , commentary can be found in Rev
Cardiovasc Med 2007 Winter;8(1):46
Estimating GFR in elderly
Berlin Initiative Study equations may be more accurate than other equations for
estimating GFR in elderly patients (level 2 [mid-level] evidence)
based on derivation and validation cohort study without external validation
610 white patients ≥ 70 years old were assessed for serum creatinine and cystatin C,
and iohexol plasma clearance
GFR measured by iohexol plasma clearance was reference standard
570 patients who had valid iohexol plasma clearance measurement were
randomized to derivation cohort vs. internal validation cohort
estimated GFR calculated using
Cockcroft-Gault equation (adjusted for body surface area)
MDRD equation
CKD-EPI equation
CKD-EPI cystatin C equations
2 Berlin Initiative Study (BIS) equations derived in this study
BIS estimated GFR equations based on serum creatinine, cystatin C, age, and sex
were developed in derivation cohort
BIS1:
estimated GFR = 3,736 × creatinine-0.87× age-0.95 (multiply result by 0.82 for female)
BIS2:
estimated GFR = 767 × cystatin C-0.61 × creatinine-0.4 × age-0.57 (multiply result by 0.87
for female)
47% of validation cohort had GFR < 60 mL/minute/1.73 m2 by iohexol plasma
clearance
for detection of GFR < 60 mL/minute/1.73 m2 in validation cohort
BIS1 had sensitivity 85% and 88% specificity 88%
BIS2 had sensitivity 88% and specificity 89%
total misclassification rates (false positives and false negatives) for estimated GFR
equations in validation cohort
17.2% with BIS1 (p < 0.05 vs. MDRD and Cockcroft-Gault equations, not
significant vs. CKD-EPI equation)
20.4% with CKD-EPI
22.8% with Cockcroft-Gault
23.2% with MDRD
11.6% with BIS2 (p < 0.05 vs. CKD-EPI cystatin C equations)
15.1%-20.4% with CKD-EPI cystatin C equations
Reference - Ann Intern Med 2012 Oct 2;157(7):471
various equations for estimating GFR appear equally accurate in elderly patients
(level 2 [mid-level] evidence)
based on diagnostic cohort study with limited ethnic diversity
394 patients aged 74-97 years had GFR estimated using MDRD, CKD-EPI creatinine,
CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C equations
0.7% of patients were black and 1.7% were Asian
reference standard was GFR measured by iohexol plasma clearance
across all 4 equations, no significant differences in overall accuracy (percentage of
estimates within 30% of measured GFR)
CKD-EPI creatinine equation was significantly more accurate than MDRD equation
at GFR > 60 mL/minute/1.73 m2 (p = 0.004)
Reference - Am J Kidney Dis 2013 Jan;61(1):57
serum creatinine alone may be poor indicator of renal insufficiency in patients ≥ 65
years old (level 2 [mid-level] evidence)
854 patients ≥ 65 years old with documented serum creatinine and weight (recorded
within 10 years of each other) in 1 hospital in Canada were included
Cockcroft-Gault formula used to calculate GFR (C-G GFR, reference standard)
renal failure defined as C-G GFR < 50 mL/minute and severe renal failure C-G
GFR < 30 mL/minute
serum creatinine > 1.7 mg/dL (150 mcmol/L) (clinically relevant cutoff value)
compared to C-G GFR had
12.6% sensitivity for renal failure
45.5% sensitivity for severe renal failure
Reference - Arch Intern Med 2003 Feb 10;163(3):356 full-text, commentary can be
found in Arch Intern Med 2003 Oct 13;163(18):2248
Limitations of estimating GFR

MDRD equation may underestimate glomerular filtration rates in patients without
chronic kidney disease (level 2 [mid-level] evidence)
based on 2 cohort studies
900 patients had iothalamate clearance test done and glomerular filtration rate
(GFR) estimated using the MDRD equation
580 patients where healthy kidney donors and 320 patients had CKD
29% of healthy patients had GFR underestimated by MDRD equation
Reference - Ann Intern Med 2004 Dec 21;141(12):929 , editorial can be found at
Ann Intern Med 2004 Dec 21;141(12):959
1,285 outpatients (age ≥ 18 years) had an iothalamate clearance test and estimated
GFR calculated using the MDRD equation and the Cockcroft-Gault formula with
adjustment for body surface area of 1.73 m2
457 patients where healthy kidney donors and 828 had CKD
in the healthy kidney donor group, the MDRD equation significantly
underestimated the measured GFR
Reference - J Am Soc Nephrol 2005 Feb;16(2):459 full-text
using serum cystatin C or creatinine levels to estimate GFR may overestimate renal
function in patients with diabetes (level 2 [mid-level] evidence)
80 patients (40 adults with diabetes and 40 adults without diabetes) were evaluated
for GFR using inulin clearance rates and serum creatinine and/or serum cystatin C
levels
compared to patients without diabetes, patients with diabetes had (p < 0.002 for all)
lower serum cystatin C levels
lower serum creatinine levels
both lower serum cystatin C and creatinine levels
higher estimated GFR based on formulas using cystatin C and/or creatinine
levels
as glycemic control worsened (as measured by hemoglobin a1c or glycated albumin)
the estimated GFR increased
Reference - Diabetes Care 2014 Mar;37(3):596
cystatin C-based formulas and creatinine-based formulas may categorize kidney
disease stages differently in morbidly obese patients (level 2 [mid-level] evidence)
40 morbidly obese patients were evaluated for GFR using formulas based on serum
creatinine or cystatin C levels
mean range of estimated GFR was 85.9-111.1 mL/minute/1.73 m2
categorization of stage 2 or 3 renal disease in
12.5%-17.5% of patients with GFR calculated from serum creatinine-based
formulas
15%-67.5% of patients with GFR calculated serum cystatin C-based formulas
Reference - Adv Med Sci 2013;58(2):376
estimated GFR appears to have relatively consistent performance over 24 months in
adults with estimated GFR < 50 mL/minute/1.73 m2 at baseline but persistent
underestimation with higher baseline estimated GFR (level 2 [mid-level] evidence)
based on cohort analysis of data from randomized trial
155 adults (mean age 54 years) with CKD (stage 3-5) not on dialysis had
radionucleotide-measured GFR compared with estimated GFR derived from 4
equations at baseline, 12, and 24 months
4 equations included 6-variable MDRD (6-MDRD), 4-variable MDRD (4-MDRD),
Cockcroft-Gault (CG), and Cockcroft-Gault equations corrected for body surface area
(CGC)
mean radionucleotide-measured GFR
25.9 mL/minute/1.73 m2 at baseline
23.1 mL/minute/1.73 m2 at 12 months
20.3 mL/minute/1.73 m2 at 24 months
all 4 equations underestimated GFR at higher GFRs and overestimated at lower
GFRs
negative association reduced over 24 months (p < 0.001) largely due to
persistent underestimation of estimated GFR from adults with GFR > 50
mL/minute/1.73 m2 at baseline
GFR < 50 mL/minute/1.73 m2 at baseline had relatively consistent performance over
time, change in bias of any of 4 equations over 24 months ≤ 1.1 mL/minute/1.73 m2
MDRD equations showed sustained advantage in estimating renal function that was
more evident as GFR declined
Reference - Nephrol Dial Transplant 2009 Jan;24(1):109 full-text
Other blood tests
CystC and beta-2-microglobulin concentrations may have strong correlation with

estimated GFR in patients with CKD not on dialysis (level 2 [mid-level] evidence)
95 white adults > 40 years old (mean age 67 years) with CKD (stage 2-5) not on
dialysis were evaluated for associations between different estimated GFR formulae
(creatinine, cystatin C-based, or both) and concentration of low-molecular-weight (<
500 dalton [Da]) proteins (LMWP)
LMWP included parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6),
tumor necrosis factor-alpha (TNF-alpha), leptin, retinol binding protein (RbP),
immunoglobin light chains kappa and lambda, beta-2-microglobulin, and myoglobin
and fibroblast growth factor-23 (FGF-23)
based on CKD-EPI creatinine-cystatin C equation, regression coefficients (R2)
between estimated GFR and LMWP had
strong association (R2 > 0.7) for CystC and beta-2-microglobulin
intermediate association (R2 < 0.2-0.7) for RbP, myoglobin, PTH
weak association (R2 < 0.2) for FGF-23, leptin, IL-6, TNF-alpha, immunoglobin
light chains kappa and lambda
most LMWP had identical R2-values with all estimated GFR-formulae used, except
for weaker associations with creatinine-based compared to CystC-based estimated
GFR for CystC and beta-2-microglobulin
DynaMed commentary -- validation of these findings still needed
Urine studies
Urine protein
for initial urine protein measurement, early morning urine always preferred (in order of
preference) (KDIGO Level 2, Grade B)(3)
albumin to creatinine ratio
protein to creatinine ratio
reagent strip urinalysis for total protein with automated reading
reagent strip urinalysis for total protein with over manual reading
definitions of proteinuria
normal albumin excretion if < 30 mg/24 hours
microalbuminuria is any of
albumin excretion 20-200 mcg/minute
albumin excretion 30-300 mg/24 hours
urine albumin to creatinine ratio 2.5-25 mg/mmol in men
urine albumin to creatinine ratio 2.5-35 mg/mmol in women
macroalbuminuria (overt proteinuria) if > 300 mg/24 hours
nephrotic range proteinuria if > 3 g/24 hours
Reference - BMJ 2002 Jul 13;325(7355):85 full-text
Kidney Disease Improving Global Outcomes (KDIGO) suggests laboratories no longer use
the term "microalbuminuria" and instead use term "moderately increased albuminuria"
(3)
albuminuria categories(3)
normal young adult - albumin excretion rate (AER) < 10 mg/g (1 mg/mmol)
A1 - normal to mildly increased
AER < 30 mg/24 hours
albumin to creatinine ratio (ACR) < 30 mg/g (3 mg/mmol)
A2 - moderately increased compared to young adult level
AER 30-300 mg/24 hours
ACR 30-300 mg/g (3-30 mg/mmol)
A3 - severely increased, including nephrotic syndrome
AER > 300 mg/24 hours
ACR > 300 mg/g (30 mg/mmol)
measurement of protein/creatinine ratio in morning spot urine sample may
correlate with 24-hour proteinuria and may help predict progression of renal
disease in nondiabetic patients (level 2 [mid-level] evidence)
98 patients with nondiabetic chronic renal disease in ramipril efficacy in
nephropathy study were followed prospectively for 5 years after randomization to
ramipril or placebo
single spot protein to creatinine ratio correlated with
24-hour urinary protein excretion (p = 0.0001)
rate of decline in glomerular filtration rate (p < 0.0005)
risk of progression to end-stage renal disease within 12 months (p = 0.04 as
multivariate predictor)
ratio < 1.7 predicted kidney survival > 95%
ratio > 2.7 predicted kidney survival < 80%
Reference - BMJ 1998 Feb 14;316(7130):504 full-text, correction can be found in BMJ
1998 Nov 28;317(7171):1491
to rule out benign orthostatic proteinuria in patients with mild proteinuria, consider
checking spot urine protein to creatinine ratio after the patient has been recumbent
overnight, and also checking after a day of patient being upright
if overnight protein is normal and daytime protein levels are elevated, it is likely
orthostatic proteinuria and benign
Reference - Am Fam Physician 2000 Sep 15;62(6):1333 full-text
if nonalbumin proteinuria suspected, use assays for specific urine proteins such as
monoclonal heavy and light chains, and alpha-1 microglobulin(3)
Urine sediment abnormalities
markers of kidney damage include(3)

isolated microscopic hematuria with abnormal red blood cell morphology
(anisocytosis) in glomerular basement membrane disorders
red blood cell casts in proliferative glomerulonephritis
white blood cell casts in pyelonephritis or interstitial nephritis
oval fat bodies or fat casts in diseases with proteinuria
granular casts and renal tubular epithelial cells in many parenchymal diseases
(nonspecific)
Imaging studies
American College of Radiology recommendations for radiologic investigation of causes of

chronic kidney disease
ultrasound of kidney and bladder is first-line imaging (ACR Rating 9)
can help differentiate between obstructive and intrinsic parenchymal disease
can be used to evaluate for cysts after 3-5 years of dialysis
additional imaging options include
consider magnetic resonance imaging of abdomen without contrast (ACR
Rating 5) to help to detect causes of ureteral obstruction not seen on
ultrasound
consider computed tomography of abdomen without contrast (ACR Rating 5) to
detect calculi or retroperitoneal masses or adenopathy that may be causing
obstruction
consider magnetic resonance angiography (MRA) to evaluate renal arteries
(ACR Rating 4)
may help identify atherosclerotic narrowing of orifice and proximal renal
artery
for patients on dialysis or with estimated GFR rates < 30 mL/minute/1.73
m2, consider MRA without contrast (for example steady-state free
precession using inflow inversion recovery or three-dimensional phase
contrast)
for patients with normal or mildly decreased renal function, consider
MRA with contrast (gadolinium)
assessing for renal artery stenosis
use duplex Doppler ultrasound of kidneys and bladder (ACR Rating 9)
consider contrast computed tomography angiography of abdomen (ACR Rating
4) in patients if nephrotoxicity not a concern
conventional angiography with iodinated contrast might be carefully
considered as there is the ability to treat the stenosis at the time of diagnosis,
this should only be done if high suspicion of renal artery stenosis (RAS),
and taking into account the risk of contrast nephrotoxicity
using carbon dioxide as contrast is option to avoid risk of nephrotoxicity
Reference - American College of Radiology (ACR) appropriateness criteria for renal
failure (ACR 2013 PDF
American College of Cardiology/American Heart Association (ACC/AHA) and European
Society of Cardiology (ESC)
recommend any of the following imaging tests for detection of RAS
duplex ultrasound (ACC/AHA Class I, Level B; ESC Class I, Level B)
computed tomographic angiography (CTA) (in patients with normal renal
function) (ACC/AHA Class I, Level B; ESC Class I, Level B)
magnetic resonance angiography (MRA) (in patients with renal insufficiency,
consider noncontrast MRA techniques) (ACC/AHA Class I, Level B; ESC Class I,
Level B)
invasive catheter angiography considered gold standard for diagnosis and indicated
if high suspicion of disease but inconclusive results from noninvasive tests
(ACC/AHA Class I, Level B; ESC Class I, Level C)
Reference - Circulation. 2006 Mar 21;113(11):e463-654 PDF (focused update can be
found in Circulation 2011 Nov 1;124(18):2020 full-text), Eur Heart J. 2011
Nov;32(22):2851-906 PDF
see Renal artery stenosis for additional information
Biopsy and pathology
percutaneous ultrasound-guided renal biopsy may be used in patients when prerenal and
postrenal causes excluded (ACR Rating 5)
indications include evaluation of proteinuria, microscopic hematuria, renal
manifestations of systemic disease, and unexplained kidney disease
patients > 60 years old, systolic blood pressure > 160 mm Hg, and with acute renal
failure may be at higher risk for complications
Reference - American College of Radiology (ACR) appropriateness criteria for renal
failure (ACR 2013 PDF
Other diagnostic testing
Kidney Disease Improving Global Outcomes (KDIGO) recommended markers to measure

glomerular filtration rate (GFR)
inulin
gold standard, has no side effects
expensive, short supply, and difficult to dissolve and maintain in solution
creatinine
endogenous marker (no need to administer) and assay usually standard in
clinical laboratories
levels vary within patient and between patients
iothalamate
inexpensive and long half life
radioactive (iodine 125) or if nonradioactive used assay is expensive and
excludes patients with allergy to iodine
iohexol
nonradioactive, inexpensive, and sensitive assay for low doses
tubular reabsorption or protein binding possible, nephrotoxic at high doses,
low-dose assay expensive, and excludes patients with allergy to iodine
ethylenediamine tetraacetic acid (EDTA)
widely available in Europe
tubular reabsorption possible and radioactive substance when Chromium 51
(51Cr) tracer used
diethylenetriamine pentaacetic acid (DTPA)
widely available in United States; easy and sensitive assay for contrast
(gadolinium)
99m Technetium tracer used, radioactive, needs standardization, dissociation
and protein binding
Reference - KDIGO 2012 clinical practice guideline for the evaluation and
management of chronic kidney disease (KDIGO 2013 Jan PDF)
renal iothalamate clearance, renal or plasma 51Cr-EDTA clearance, and plasma

iohexol clearance appear sufficiently accurate for measuring glomerular filtration
rate (level 2 [mid-level] evidence)
based on systematic review of mostly moderate-quality trials
systematic review of 88 studies evaluating methods for measuring GFR
renal inulin clearance measured under continuous inulin infusion and urine
collection was reference standard
compared to reference standard, measurement of GFR was sufficiently accurate
using the following methods
renal iothalamate clearance in analysis of 13 studies with 548 patients
renal or plasma chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-
EDTA) clearance in analysis of 14 studies with 324 patients
plasma iohexol clearance in analysis of 5 studies with 172 patients
renal diethylenetriaminepentaacetic acid (DTPA) clearance in analysis of 5
studies with 126 patients
plasma inulin clearance in analysis of 2 studies with 39 patients
Reference - Am J Kidney Dis 2014 Sep;64(3):411, commentary can be found in Am J
Kidney Dis 2015 May;65(5):806
whole-exome sequencing may identify diagnostic mutations in adults with CKD of

unknown cause or suspected inherited kidney disease
based on genetic analysis
92 adults (mean age 42 years) with CKD of unknown cause, suspected inherited
kidney disease, or hypertension had whole-exome sequencing using DNA extracted
from whole blood
23 patients (25%) had diagnostic mutations identified using whole-exome
sequencing
19 patients had diagnostic mutations in known nephropathy-related genes
such as COL4A5, COL4A4, and UMOD
2 patients with tubulointerstitial nephropathy and 1 patient with CKD of
unknown cause had loss-of-function mutations in PARN
1 patient with fibrillary glomerulonephritis had nonsense mutation in BRCA2
Reference - Ann Intern Med 2018 Jan 16;168(2):100
no convincing data to suggest benefit of routinely obtaining bone densitometry for
evaluation of bone metabolism(3)
Treatment
Treatment overview
early referral to nephrologist associated with reduced mortality (level 2 [mid-level]

evidence)
interventions to slow loss of kidney function include
target blood pressure < 140/90 mm Hg, with multiple guidelines suggesting < 130/80
mm Hg if proteinuria or diabetes present
angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular
events in patients with chronic kidney disease (CKD) (level 1 [likely reliable]
evidence), may reduce end-stage renal disease (ESRD) in patients with CKD and
macroalbuminuria (level 2 [mid-level] evidence), but may not reduce ESRD in
patients with nondiabetic stage 1-3 CKD (level 2 [mid-level] evidence)
angiotensin receptor blockers (ARBs) may reduce ESRD in patients with CKD
and macroalbuminuria (level 2 [mid-level] evidence), but limited data in
patients with nondiabetic stage 1-3 CKD
guidelines recommend strict control of diabetes - HbA1c goal of about 7% in most
patients (KDIGO Level 1, Grade A), however evidence suggests
intensive glycemic control in adults with type 2 diabetes may not reduce
mortality or risk for end-stage renal disease (level 2 [mid-level] evidence)
intensive insulin therapy may delay onset of and slow progression of
microalbuminuria and albuminuria (reduced risk of increased serum
creatinine, albuminuria, and hypertension may continue 7-8 years after
intensive therapy) in patients with type 1 diabetes (level 3 [lacking direct]
evidence)
for adults with moderate-to-severe CKD, reduced protein intake may be associated
with reduced risk of death or ESRD (level 2 [mid-level] evidence), however, very
low-protein diet in patients with advanced kidney disease might increase mortality
consider limiting protein intake to 1.3 g/kg/day if CKD at risk of progression
(KDIGO Level 2, Grade C)
consider lower protein intake of 0.8 g/kg/day if CKD and diabetes (KDIGO Level
2, Grade C) or no diabetes (KDIGO Level 2, Grade B) and glomerular filtration
rate (GFR) < 30 mL/minute/1.73 m2 (GFR categories G4 and G5)
bicarbonate supplementation in patients with severe CKD and metabolic acidosis
may slow progression of kidney disease and reduce need for dialysis (level 2 [mid-
level] evidence)
other treatments associated with slowing progression of CKD include
surgical weight loss interventions (level 3 [lacking direct] evidence)
pentoxifylline (level 3 [lacking direct] evidence)
allopurinol (level 3 [lacking direct] evidence)
prevention and treatment of comorbidities and complications of decreased kidney
function
consider erythropoiesis-stimulating agent (ESA) to treat anemia with target
hemoglobin levels < 12 g/dL as higher targets increase the risk of stroke (KDIGO
Level 2, Grade C) (Kidney Disease Improving Global Outcomes [KDIGO] 2012 clinical
practice guideline for anemia in chronic kidney disease [KDIGO (2011) 2012 Aug
PDF])
prevent and treat cardiovascular disease (CVD) - patients with CKD at high risk for
CVD
lipid-lowering therapy with statins reduces major cardiovascular events (level
1 [likely reliable] evidence) and may reduce all-cause mortality and
cardiovascular mortality (level 2 [mid-level] evidence) in patients with chronic
kidney disease not on dialysis
antiplatelet agents may reduce the risk of myocardial infarction but might
increase bleeding risk in patients with chronic kidney disease with stable or no
cardiovascular disease (level 2 [mid-level] evidence)
fibrates may reduce cardiovascular events and improve lipid profile in
patients with CKD (level 2 [mid-level] evidence)
folic acid-based homocysteine lowering does not reduce cardiovascular events
in patients with kidney disease (level 1 [likely reliable] evidence)
vaccinations that may be needed include influenza vaccine, pneumococcal vaccine,
and hepatitis B vaccine
see also Complications section
prepare for kidney replacement therapy
predialysis educational intervention may improve clinical outcomes in patients with
early stages of CKD (level 2 [mid-level] evidence)
educate patients about different modalities of renal replacement therapy when
glomerular filtration rate < 30 mL/minute/1.73 m2 (stage 4 CKD) (NKF Grade A)
preemptive kidney transplant is preferred form of kidney replacement therapy (CST
Grade A)
dialysis may be started for uremic symptoms, volume overload, malnutrition, or
inability to control blood pressure
earlier initiation of dialysis does not appear to increase survival in patients with
CKD (level 2 [mid-level] evidence)
Fluid and electrolytes
Kidney Disease Improving Global Outcomes (KDIGO) suggests giving oral bicarbonate to
patients with chronic kidney disease (CKD) and serum bicarbonate levels < 22 mmol/L to
maintain levels in normal range unless contraindicated (KDIGO Level 2, Grade B)(3)
sodium bicarbonate may reduce need for dialysis in patients with chronic kidney
disease (level 2 [mid-level] evidence)
based on systematic review without adequate reporting of trial quality
systematic review of 6 randomized trials evaluating sodium bicarbonate therapy
compared to standard of care or placebo in 312 patients with chronic kidney disease
all trials were reported as either poor (2 trials), fair (3 trials), or good (1 trial) quality
based on Jadad score
4 trials had follow-up ≥ 2 months including largest study summarized below
in long-term studies, sodium bicarbonate associated with
lower incidence of starting dialysis (risk ratio [RR] 0.21, 95% CI 0.08-0.54) in
analysis of 2 trials with 175 patients
net improvement in glomerular filtration rate (GFR) (increase of 3.2
mL/minute/1.73 m2, 95% CI 1.6-4.7 mL/minute/1.73 m2) in analysis of 3 trials
with 154 patients
no significant differences in initiating or escalating antihypertensive therapy
Reference - Am J Nephrol 2012;35(6):540 full-text
bicarbonate supplementation in patients with severe chronic kidney disease
and metabolic acidosis may slow progression of kidney disease and reduce
need for dialysis (level 2 [mid-level] evidence)
based on randomized trial without blinding
134 patients (mean age 54.8 years) with severe chronic renal impairment
(creatinine clearance [CrCl] 15 to 30 mL/minute/1.73 m2) and metabolic
acidosis (serum bicarbonate 16-20 mmol/L) randomized to supplementation
with sodium bicarbonate 600 mg orally 3 times daily vs. standard care and
followed for 2 years
comparing bicarbonate supplementation vs. standard care
decline in CrCl 1.88 mL/minute/1.73 m2 vs. 5.93 mL/minute/1.73 m2 (p <
0.0001)
rapid progression of CKD in 9% vs. 45% (CrCl loss > 3 mL/minute/1.73 m2,
p < 0.0001, NNT 3)
development of end-stage renal disease (ESRD) requiring dialysis in 6.5%
vs. 33% (p < 0.001, NNT 4)
bicarbonate associated with improvement in dietary protein (p < 0.007)
intake and increased lean body mass (p < 0.03)
increase in caloric intake 297 kcal vs. 72 kcal (p < 0.09)
improved nutritional parameters and increased lean body mass
(metabolic acidosis is hypothesized to contribute to protein-energy
wasting in patients with CKD, p < 0.05 for all)
Reference - J Am Soc Nephrol 2009 Sep;20(9):2075 full-text, editorial can be
found in J Am Soc Nephrol 2009 Sep;20(9):1869
increased fruit and vegetable intake or oral bicarbonate administration may each
slow decrease in glomerular filtration rate in patients with stage 3 chronic kidney
disease with a bicarbonate level of 22-24 mmol/L (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes
108 patients with stage 3 CKD (estimated GFR 30-59 ml/minute per 1.73 m2) due to
hypertensive retinopathy with high urine albumin levels and plasma bicarbonate
levels of 22-24 mmol/L were randomized to 1 of 3 groups and followed for 3 years
oral bicarbonate 0.3 mEq/kg/day
increased fruits and vegetables
usual care
after 3 years, estimated GFR significantly declined for all groups, but estimated GFR
at 3 years for the bicarbonate group and fruits and vegetables group was
significantly higher than the usual care group (p < 0.05)
Reference - Kidney Int 2014 Nov;86(5):1031
increased fruit and vegetable intake may help to prevent decline in kidney function
as effectively as sodium bicarbonate in patients with stage 4 chronic kidney disease
with metabolic acidosis (level 3 [lacking direct] evidence)
76 patients with stage 4 CKD (estimated GFR 15–29 ml/minute per 1.73 m2) due to
hypertensive nephropathy and metabolic acidosis (plasma bicarbonate < 22
mmol//L) were randomized to increased daily fruits and vegetables vs. 1 mEq/kg/day
of oral sodium bicarbonate and followed for 1 year
all patients were receiving angiotensin converting enzyme inhibitors
after 1 year
no significant difference in estimated GFR with sodium bicarbonate vs. fruits
and vegetables
sodium bicarbonate associated with higher plasma bicarbonate levels
compared to fruits and vegetables (p < 0.05)
potassium levels did not increase in either group
Reference - Clin J Am Soc Nephrol 2013 Mar;8(3):371 full-text, editorial can be found
in Clin J Am Soc Nephrol 2013 Mar;8(3):342
Diet
Fluid intake
coaching to drink more water may not slow decline in estimated glomerular
filtration rate (eGFR) in adults with stage 3 CKD (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial with low adherence in
hydration group
631 adults (mean age 65 years, 63% men) from 9 medical centers with stage 3 CKD
were randomized to coaching to increase water intake by 1-1.5 L/day vs. control for
1 year
hydration group contacted via phone once monthly
control group advised to maintain usual intake or decrease intake by 0.25-0.5
L/day if prerandomization 24-hour urine volume > 1.5 L/day and osmolality <
500 mOsm/kg
exclusion criteria included self-reported fluid intake ≥ 10 cups/day, 24-hour urine
volume ≥ 3 L, history of kidney stones in past 5 years, lithium use, or diuretic above
certain dose, or prescribed fluid restriction < 1.5 L/day
predefined minimal clinically important difference (MCID) of 1 mL/minute/1.73 m2
in eGFR
comparing adherence in hydration vs. control
mean 1-year change in 24-hour urine volume +0.6 L/day vs. -0.04 L/day (95% CI
for mean difference 0.5-0.7)
mean 9-month change in self- reported fluid intake +0.7 L/day vs. 0 L/day (95%
CI for mean difference 0.6-0.8)
comparing hydration vs. control at 12 months
mean reduction in eGFR 2.2 mL/minute/1.73 m2 vs. 1.9 mL/minute/1.73 m2
(95% CI for adjusted between group difference -1.8 to 1.2)
mean change in creatinine clearance +0.6 mL/minute/1.73 m2 vs. -3
mL/minute/1.73 m2 (95% CI for between group difference 0.8-6.4)
mean change in plasma copeptin -1.4 pmol/L vs. +0.8 pmol/L (95% CI for
between group difference -3.9 to -0.5)
no significant differences in urine albumin or quality of life
Reference - CKD WIT trial (JAMA 2018 May 8;319(18):1870)
Protein restriction
Kidney Disease Improving Global Outcomes (KDIGO) recommendations(3)

consider limiting protein intake to 1.3 g/kg/day for adults with chronic kidney
disease (CKD) at risk of progression (KDIGO Level 2, Grade C)
consider limiting protein intake to 0.8 g/kg/day for patients with diabetes (KDIGO
Level 2, Grade C) or for patients without diabetes (KDIGO Level 2, Grade B) who
have glomerular filtration rate (GFR) < 30 mL/minute/1.73 m2 (GFR categories G4
and G5)
for adults with moderate-to-severe chronic kidney disease (CKD), reduced protein
intake may be associated with reduced risk of renal death (level 2 [mid-level]
evidence)
based on Cochrane review of trials with methodologic limitations
systematic review of 10 randomized trials comparing different levels of protein
intake (standard intake at ≥ 0.8 g/kg/day vs. moderate-to-severe protein restriction at
0.3-0.6 g/kg/day) in 2,000 nondiabetic adults with moderate-to-severe CKD, followed
for ≥ 1 year
9 trials had unclear allocation concealment; 1 trial with adequate allocation
concealment did not have intention-to-treat analysis
renal death defined as initiation of dialysis, kidney transplant, or patient death
renal death occurred in 113 patients with moderate-to-severe protein restriction vs.
168 patients with standard protein intake (risk ratio [RR] 0.68, 95% CI 0.55-0.84, NNT
2-56 for 1 year)
actual reduction in protein intakes was less than expected
Reference - Cochrane Database Syst Rev 2009 Jul 8;(3):CD001892
very low-protein diet in patients with advanced kidney disease might increase
mortality (level 2 [mid-level] evidence)
based on long-term follow-up of randomized trial with unknown adherence
255 adults (mean age 50.8 years) with CKD and GFR 13-24 mL/minute randomized to
low-protein diet (LPD) (0.58 g/kg/day) vs. very low-protein diet (VLPD) (0.28 g/kg/day
plus mixture of keto/amino acids) for trial period (mean duration 2.2 years) and
followed 7-11 years
average protein intake in VLPD group was 0.25 g/kg/day lower than LPD group
during trial period
dietary protein intake not recorded during follow-up period after trial
termination, but sampling in a subgroup of patients 9 months after study end
showed no significant differences in protein intake between 2 groups
long-term follow up comparing VLPD vs. LPD diets
death in 38.9% vs. 23.3% (p < 0.05, NNH 6)
no significant difference in incidence of progression to end-stage renal disease
(ESRD)
Reference - Modification of Diet in Renal Disease (MDRD) (Group B) trial (Am J
Kidney Dis 2009 Feb;53(2):208 , editorial can be found in Am J Kidney Dis 2009
Feb;53(2):189 )
high-intake of protein (especially nondairy animal protein) may accelerate decline
in renal function for women with mild renal insufficiency (level 2 [mid-level]
evidence)
1,624 women aged 42-68 years followed for 11-year period in Nurses Health Study
sample derived from 121,700 patients in original study who did not have
significant comorbidities or take excessive analgesics, and who provided
adequate blood samples on 2 separate occasions (1989 and 2000)
98% of study patients identified as white
protein intake measured on 2 occasions (1990 and 1994) using semiquantitative
food-frequency questionnaire
protein intake had no significant effect on kidney function in patients with normal
GFR (≥ 80 mL/minute/1.73 m2) at baseline
protein intake associated with accelerated decline in kidney function for patients
with mild renal insufficiency (GFR 55-80 mL/minute/1.73 m2) - for every 10-g
increase in protein intake GFR decreased by
1.69 mL/minute/1.73 m2 (95% CI 0.45-2.93 mL/minute/1.73 m2) in unadjusted
analysis
1.21 mL/minute/1.73 m2 (95% CI 0.33-2.34 mL/minute/1.73 m2) for high intake
of nondairy animal protein
Reference - Ann Intern Med 2003 Mar 18;138(6):460
protein restriction associated with decreased urinary phosphate levels in patients
with chronic kidney disease (level 3 [lacking direct] evidence)
based on post hoc analysis of MDRD randomized trials without clinical outcomes
in study A, 585 patients were randomized to low-protein vs. usual-protein diet
and followed for 3 years
in study B, 255 patients were randomized to very low-protein vs. low-protein
diet and followed for 3 years
mean difference in urine phosphate levels between months 0-4
in study A
-244 mg (95% CI -265 to -223) with low-protein diet
-55 mg (95% CI -76 to -34) with usual-protein diet
in study B
-233 mg (95% CI -264 to -202) with very low-protein diet
- 151 mg (95% CI -181 to -121) with low-protein diet
decreases in urine phosphate levels were sustained throughout the study periods
Reference - Am J Kidney Dis 2013 Jun;61(6):1045
low-protein diet and moderate-protein diet associated with similar mortality and
progression to dialysis in patients with advanced chronic kidney disease (level 2
[mid-level] evidence)
based on randomized trial with low adherence
423 patients (mean age 61 years) with stage 4-5 CKD randomized to low-protein diet
(LPD) (0.55 g/kg/day) vs. moderate-protein diet (MPD) (0.80 g/kg/day) and followed
for mean 32 months
average protein intake per group was 0.73 g/kg/day for LPD vs. 0.9 g/kg/day for
MPD (p < 0.05)
fewer than 30% of patients randomized to LPD strictly adhered to diet
no significant difference between groups in progression to dialysis, overall
mortality, or time to death after initiation of dialysis
Reference - Am J Kidney Dis 2009 Dec;54(6):1052
Dietary electrolyte restriction
KDIGO recommends limiting salt intake to < 2 g (90 mmol) per day of sodium (5 g sodium
chloride) in adult patients unless contraindicated (KDIGO Level 1, Grade C)(3)
sodium intake
lowering salt intake may reduce blood pressure in adults with chronic kidney
disease (level 3 [lacking direct] evidence)
based on nonclinical outcome in Cochrane review
systematic review of 8 randomized trials comparing lower vs. higher salt
intake for ≥ 1 week in 258 adults with chronic kidney disease
trial duration ranged from 1 to 26 weeks
salt intake measured indirectly by 24-hour urine sodium excretion with mean
difference -105.86 mmol/day (-2,433.6 mg/day) between low- and high-salt
groups, equivalent to 6,368.31 mg/day decrease in salt (sodium chloride) intake
low salt intake associated with
decreased systolic blood pressure (mean difference [MD] -8.75 mm Hg,
95% CI -11.33 to -6.16 mm Hg) in analysis of 8 trials with 258 adults
decreased diastolic blood pressure (MD -3.7 mm Hg, 95% CI -5.09 to -2.3
mm Hg) in analysis of 8 trials with 258 adults
increase in reduction in antihypertensive dose (risk ratio [RR] 5.48, 95%
CI 1.27-23.66) in analysis of 2 trials with 52 adults
nonsignificant increase in symptomatic hypotension (RR 5.95, 95% CI
0.74-48.11) in analysis of 2 trials with 72 adults
edema in 15.4% with low salt intake vs. 34.6% with high salt intake (p < 0.05,
NNT 5) in 1 trial with 52 adults
no significant differences in estimated glomerular filtration rate, creatinine
clearance, or serum creatinine
Reference - Cochrane Database Syst Rev 2015 Feb 18;(2):CD010070
tailored low-salt diet may reduce blood pressure compared to dietary advice in
adults with chronic kidney disease and hypertension (level 3 [lacking direct]
evidence)
56 adults with CKD and blood pressure > 130/80 mm Hg or receiving
antihypertensive medication randomized to tailored low-salt diet vs. usual
advice for low-salt diet and followed for 6 months
low-salt diet associated with decreased 24-hour blood pressure (mean
difference -8/-2 mm Hg) and urinary sodium excretion (p < 0.001 for all)
Reference - Heart 2013 Sep;99(17):1256 full-text
addition of low-sodium diet to lisinopril associated with reduced proteinuria
compared to dual blockade with valsartan and lisinopril in patients with
nondiabetic nephropathy (level 3 [lacking direct] evidence)
based on randomized crossover trial without clinical outcomes
52 patients with nondiabetic nephropathy received each of following
treatments for 6 weeks
valsartan 320 mg/day plus low-sodium diet (target 50 mmol of
sodium/day)
valsartan 320 mg/day plus regular sodium diet (target 200 mmol of
sodium/day)
placebo plus low-sodium diet
placebo plus regular-sodium diet
all patients received lisinopril 40 mg/day
comparing low-sodium diet vs. valsartan plus regular-sodium diet
proteinuria reduced by 51% (95% CI 43-58) vs. 21% (95% CI 8-32) (p <
0.001)
systolic blood pressure reduced by 7% vs. 2% (p = 0.003)
no significant difference comparing low-sodium diet with or without valsartan
Reference - BMJ 2011 Jul 26;343:d4366 full-text
low-salt diet associated with increased net endogenous acid production in
patients with chronic kidney disease taking olmesartan (level 3 [lacking direct]
evidence)
based on cohort analysis without clinical outcomes of data from ESPECIAL trial
202 patients (79%) with nondiabetic CKD treated with olmesartan who were
randomized to standard vs. intensive low-salt diet education were assessed at
end of 8-week treatment
compliance with either low-salt diet education group calculated based on 24-
hour urinary sodium reduction ratio (NaRR), with good compliance defined as
NaRR < 50th percentile and poor compliance defined as NaRR ≥ 50th percentile
50% of patients had good compliance and 50% had poor compliance with low-
salt diet
good compliance with low-salt diet associated with increased net endogenous
acid production compared to low compliance group (p = 0.002)
consistent results in analysis adjusted for baseline differences, gender, and
randomized treatment assignment
Reference - Nephron Clin Pract 2014;128(3-4):407
low-sodium diet may reduce blood pressure without affecting estimated
glomerular filtration rate in patients with kidney transplant receiving stable
renin-angiotensin-aldosterone system blockade treatment (level 3 [lacking
direct] evidence)
based on nonclinical outcomes from small randomized crossover trial
23 outpatients (mean age 58 years) with kidney transplant and creatinine
clearance > 30mL/minute, blood pressure ≥ 120/80 mm Hg, and receiving stable
renin-angiotensin-aldosterone system blockade treatment randomized to
regular sodium diet (target 150 mmol/24 hours [3.45 g/24 hours]) vs. low-
sodium diet (target 50 mmol/24 hours [1.15 g/24 hours]) for 6 weeks then
crossed over
86% adherence to sodium diet
comparing regular sodium diet vs. low-sodium diet
mean systolic blood pressure of 140 mm Hg vs. 129 mm Hg (p < 0.001)
mean diastolic blood pressure 86 mm Hg vs. 79 mm Hg (p < 0.001)
mean sodium excretion of 164 mmol/24 hours vs. 87 mmol/24 hours (p <
0.001)
no significant difference in urinary albumin excretion, estimated glomerular
filtration rate (estimated GFR), or creatinine clearance
Reference - Am J Kidney Dis 2016 Jun;67(6):936
increased fibroblast growth factor 23 levels at baseline associated with
reduced antiproteinuric response to low-sodium diet in patients with
nondiabetic nephropathy (level 3 [lacking direct] evidence)
based on cohort analysis of data from randomized crossover trial above
without clinical outcomes
47 patients with nondiabetic nephropathy and residual proteinuria after
treatment were assessed for fibroblast growth factor (FGF) 23 levels at baseline
compared to regular-sodium diet, mean decrease in proteinuria with low-
sodium diet at 6 weeks (no p values reported)
66% in patients in lowest FGF 23 tertile (80-131 relative units/mL)
51% in patients in middle FGF 23 tertile (134-183 relative units/mL)
38% in patients in highest FGF 23 tertile (211-556 relative units/mL)
each 10 relative units/mL-increase in baseline FGF 23 levels associated with
reduced antiproteinuric response to low-sodium diet (p = 0.04)
Reference - Am J Kidney Dis 2015 Feb;65(2):259
phosphate intake
KDIGO recommendations for prevention and treatment of high phosphorus and
abnormal calcium levels in adults with CKD stages 3-5D
consider lowering elevated phosphorus levels toward the normal range
(KDIGO Level 2, Grade C)
consider avoiding hypercalcemia (KDIGO Level 2, Grade C)
consider limiting dietary phosphate intake in treatment of hyperphosphatemia
alone or in combination with other treatments (KDIGO Level 2, Grade D)
it is reasonable to consider phosphate source (for example, animal, vegetable,
additives) when making dietary recommendations (KDIGO Not Graded)
Reference - KDIGO clinical practice guideline on chronic kidney disease–
mineral and bone disorders (CKD-MBD) (KDIGO 2017 Jul PDF ), executive
summary can be found in Kidney Int 2017 Jul;92(1):26 full-text
higher dietary phosphate intake may not be associated with increased
mortality in patients with moderate chronic kidney disease (level 2 [mid-level]
evidence)
1,105 adults with chronic kidney disease in NHANES III study had dietary
phosphate intake assessed by 24-hour dietary recall
average estimated glomerular filtration rate was 49.3 mL/minute/1.73 m2
mean phosphate intake was 1,033 mg/day
54% of patients died during an average 6.5-year follow-up
no significant difference in mortality comparing those in lowest tertile of
phosphate intake to patients in highest tertile of phosphate intake (adjusted
hazard ratio 1.07, 95% CI 0.67-1.7)
Reference - Nephrol Dial Transplant 2012 Mar;27(3):990 full-text
liberal restriction or no restriction of daily dietary phosphate intake might
reduce mortality compared to greater restriction in patients having
hemodialysis (level 2 [mid-level] evidence)
based on cohort analysis of data from HEMO study
1,218 patients with phosphate-restricted diet at baseline were compared to 533
patients with no phosphate restriction
patients with phosphate-restricted diets stratified to 4 groups (about 25% of
patients in each group) by daily dietary phosphate intake (≤ 870 mg, 871-999
mg, 1,000 mg, and 1,001-2,000 mg)
no significant differences among groups in all-cause mortality in unadjusted
analysis
compared to dietary phosphate intake restricted to ≤ 870 mg in adjusted
analyses, reduced mortality with
no phosphate restriction (hazard ratio 0.71, 95% CI 0.55-0.92)
daily dietary phosphate intake restricted to 1,001-2,000 mg (hazard ratio
0.73, 95% CI 0.54-0.97)
Reference - Clin J Am Soc Nephrol 2011 Mar;6(3):620 full-text
education on avoiding phosphorus-containing food additives associated with
decline in serum phosphorus levels in patients with end-stage renal disease
(ESRD) (level 3 [lacking direct] evidence)
based on cluster-randomized trial without clinical outcomes
279 patients with ESRD and elevated serum phosphorus levels (> 5.5 mg/dL
[1.78 mmol/L]) randomized to education on phosphorus-containing food
additives vs. usual care
education included avoiding foods with phosphorus-containing food
additives when grocery shopping or eating at fast food restaurants
all patients receiving hemodialysis
decline in serum phosphorus levels at 3 months 1 mg/dL (0.32 mmol/L) with
education vs. 0.4 mg/dL (0.13 mmol/L) with usual care (p = 0.03)
education associated with increased reading of ingredient list (p < 0.001) and
nutrition fact labels (p = 0.04)
no significant difference in food knowledge scores between groups
Reference - JAMA 2009 Feb 11;301(6):629, commentary can be found in JAMA
2009 Jun 17;301(23):2443
Fruit and vegetable intake
base-producing fruit and vegetable intake may not decrease estimated glomerular
filtration rate compared to sodium bicarbonate in adults with stage 4 CKD and
metabolic acidosis (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial
73 adults with stage 4 CKD and hypertension randomized to base-producing fruit
and vegetable intake dosed to reduce dietary acid by 50% vs. sodium bicarbonate 1
mEq/kg/day orally for 1 year
at baseline all patients had estimated GFR 15-29 mL/minute/1.73 m2, metabolic
acidosis, and were receiving angiotensin-converting enzyme inhibitors
base-producing fruit and vegetables include apples, apricots, oranges, peaches,
pears, raisins, strawberries, carrots, cauliflower, eggplant, lettuce, potatoes, spinach,
tomatoes, and zucchini
no significant difference in estimated GFR between groups
compared to sodium bicarbonate, base-producing fruit and vegetable intake
associated with
lower mean body weight (mean 131.7 kg [290.3 lbs] vs. 136 kg [299.8 lbs], p <
0.01)
decreased plasma total carbon dioxide and systolic blood pressure (p < 0.01 for
each)
Reference - Clin J Am Soc Nephrol 2013 Mar;8(3):371 full-text, editorial can be found
at Clin J Am Soc Nephrol 2013 Mar;8(3):342
Nutrition in patients on dialysis
European Best Practice Guidelines nutritional recommendations for patients on

peritoneal dialysis
give all patients nutritional counseling based on an individualized plan of care
assess nutrition status every 6 months using panel of measures
examples of panel measures include Marckmann’s nutritional index and
Harty’s nutritional index
do not use serum albumin alone as measure of protein/energy nutritional
status in peritoneal dialysis patients
use subjective global assessment, protein intake (as assessed from the protein
equivalent of total nitrogen appearance, or by dietary recall) and an
assessment of protein nutrition (such as anthropometry or dual energy x-ray
absorptiometry [DEXA])
energy needs
in patients with body mass index (BMI) < 27 kg/m2, intake should be 35
kcal/kg/day, adjusted for age and taking energy derived from peritoneal
glucose absorption into account
in malnourished patients, normalize energy and protein intake to the desirable
body weight
target dietary protein intake ≥ 1.2 g/kg ideal body weight per day
target should not be < 0.8 g/kg/day in any patient
achieved protein equivalent of nitrogen appearance (nPNA) should be ≥ 1
g/kg/day, adjusted for patient’s age and physical activity
Reference - Nephrol Dial Transplant 2005 Dec;20 Suppl 9:ix28 full-text
European Best Practice Guidelines nutritional recommendations for patients on
hemodialysis
assess nutrition status
every 6 months in patients < 50 years old
every 3 months in patients ≥ 50 years old or patients who have been on dialysis
for > 5 years
use multiple measures to assess for malnutrition, including
dietary assessment
body mass index
subjective global assessment
normalized protein equivalent of nitrogen appearance
serum albumin and serum prealbumin
cholesterol
tools such as bioimpedancemetry, dual x-ray absorptiometry, near-infrared
reactance
recommended energy intake 30-40 kcal/kg/day, adjusted for age, gender, and
physical activity
restrict sodium intake to ≤ 5 g of sodium chloride (2.0 g or 85 mmol of sodium) to
help control blood pressure
protein intake
target dietary protein ≥ 1.1 g/kg ideal body weight per day
normalized protein nitrogen appearance (nPNA) should be ≥ 1 g/kg ideal body
weight per day
pediatric patients on hemodialysis may need higher protein intake (150% of
recommended intake for age) along with higher dialysis doses to help support
growth (National Kidney Foundation 2006, NKF 2006 Updates Clinical Practice
Guidelines and Recommendations PDF)
recommended phosphate, calcium, and potassium intake
phosphate intake 800-1,000 mg/day
calcium intake ≤ 2,000 mg/day including calcium from phosphate binders
potassium intake 1,950-2,730 mg (50-70 mmol) or 1 mmol/kg ideal body weight
per day if predialysis serum potassium > 6 mmol/L
recommended trace element intake
iron
8 mg/day for men
15 mg/day for women
zinc
8-12 mg/day for men
10-15 mg/day for women
selenium 55 mcg/day
Reference - Nephrol Dial Transplant 2007 May;22 Suppl 2:ii45 full-text , commentary
can be found in Nephrol Dial Transplant 2008 Feb;23(2):772
intradialytic parenteral nutrition may not improve survival in malnourished
hemodialysis patients (level 2 [mid-level] evidence)
based on randomized trial with allocation concealment not stated
186 malnourished hemodialysis patients randomized to intradialytic parenteral
nutrition vs. standard nutrition for 1 year
all patients received oral nutritional supplements
mortality 43% in intradialytic parenteral nutrition vs. 39% for standard nutrition
group at 2 years (not significant)
no significant difference in hospitalization rate, body mass index, or nutritional
status at 2 years
Reference - J Am Soc Nephrol 2007 Sep;18(9):2583 full-text, commentary can be
found in Nefrologia 2008;28 Suppl 2:26
Dietary guidelines
Academy of Nutrition and Dietetics (AND) and National Kidney Foundation (NKF)
guideline for dietitians in nephrology care can be found in J Am Diet Assoc 2009
Sep;109(9):1617
American Society for Parenteral and Enteral Nutrition (ASPEN) clinical guideline on
nutrition support in adult acute and chronic renal failure can be found in JPEN J Parenter
Enteral Nutr 2010 Jul-Aug;34(4):366
Academy of Nutrition and Dietetics (AND) evidence-based nutrition practice guideline on

critical illness can be found at AND Evidence Analysis Library 2012 Sep PDF
Activity
exercise training associated with improvement in physical fitness in adults with

systematic review of 45 randomized trials comparing regular exercise for ≥ 8 weeks
to no exercise in 1,863 adults with chronic kidney disease or kidney transplant
recipients
44 trials had ≥ 1 methodologic limitation including lack of or unclear blinding of
outcome assessors, high dropout rates, lack of attention control, baseline differences
between groups, or unclear allocation concealment
1 high-quality trial not included in meta-analyses of clinical outcomes
types of exercise training included cardiovascular training, resistance training,
cardiovascular plus resistance training, and yoga
3 trials included kidney transplant recipients
regular exercise associated with significant improvement in
aerobic capacity in analysis of 24 trials with 847 patients
walking capacity in analysis of 7 trials with 191 patients
health-related quality of life in 14 of 18 trials and no effect in remaining 4 trials
cardiovascular dimensions including resting diastolic and systolic blood
pressure and pulse
nutritional parameters including albumin, prealbumin, and energy intake
4 trials evaluated depression; longer duration of exercise intervention appeared to
reduce depression
Reference - Cochrane Database Syst Rev 2011 Oct 5;(10):CD003236 , commentary can
be found in Evid Based Nurs 2012 Jul;15(3):95
similar results reported for aerobic and walking capacities with exercise training
(both analyses included same trials in above analyses) in systematic review of 41
randomized trials (Am J Kidney Dis 2014 Sep;64(3):383 , editorial can be found at Am
J Kidney Dis 2014 Sep;64(3):329 )
lifestyle intervention may improve exercise capacity in patients with stage 3-4
based on randomized trial without intention-to-treat analysis
83 patients (mean age 61 years) with stage 3-4 chronic kidney disease and ≥ 1
uncontrolled cardiovascular risk factor were randomized to lifestyle intervention
vs. usual care for 1 year
lifestyle intervention included access to multidisciplinary care, individualized
exercise training, and lifestyle program
exercise training was individualized based on comorbid conditions and
consisted of 8 weeks of supervised aerobic and resistance training followed by
10 months of home-based training
usual care consisted of consultation with nephrologist and lifestyle
modification recommendation without detailed information or education
87% completed trial and were included in analyses
adherence to supervised exercise training was 70%
lifestyle intervention associated with improved exercise capacity and increased 6-
minute walk distance (p < 0.001 for each)
no significant differences in renal function measures, grip strength, blood pressure,
weight, body mass index, or metabolic profile
adverse events included hospitalization, carcinoma, and gastrointestinal problems,
with similar rates between groups
Reference - Am J Kidney Dis 2015 Apr;65(4):583
Counseling
predialysis educational intervention may improve clinical outcomes in patients

with early stages of chronic kidney disease (level 2 [mid-level] evidence)
based on systematic review with heterogeneity
systematic review of 22 randomized trials evaluating effectiveness of educational
interventions in 1,967 patients (mean age 55 years) with CKD followed for 18
months to 20 years
improved clinical, psychological, behavioral, and knowledge based outcomes
reported in 18 studies
psychoeducation associated with improved survival in 1 long term trial
Reference - Am J Kidney Dis 2008 Jun;51(6):933, commentary can be found in Evid
Based Nurs 2009 Jan;12(1):18
cognitive-behavioral therapy (CBT) may be more effective than sleep-hygiene
education alone for improving sleep quality, fatigue, and depression in adults
having hemodialysis and reporting chronic sleep disturbance (level 2 [mid-level]
evidence)
based on randomized trial without blinding
72 adults (mean age 58 years) having hemodialysis and reporting chronic sleep
disturbance (> 6 months) were randomized to 30-minute CBT sessions 3 times
weekly plus sleep hygiene education vs. sleep hygiene education alone for 6 weeks
all patients had Pittsburgh Sleep Quality Index (PSQI) score > 5 at enrollment (PSQI
score range 0-21, with higher scores indicating worse sleep quality)
69.4% of patients used hypnotics at baseline
no significant difference between groups
patients were continued on same doses during trial
comparing CBT vs. sleep hygiene at 6 weeks, improvement in
PSQI score in 86.5% vs. 28.6% (p < 0.001, NNT 2)
Fatigue Severity Scale score in 78.4% vs. 48.6% (p = 0.007, NNT 3)
Beck Depression Inventory in 70.3% vs. 42.9% (p = 0.014, NNT 4)
Reference - Kidney Int 2011 Aug;80(4):415 full-text
insufficient evidence to evaluate effect of education programs on clinical outcomes
in patients with diabetes and chronic kidney disease
based on Cochrane review of quasi-randomized trials
systematic review of 2 quasi-randomized trials comparing education programs plus
routine treatment to routine treatment alone in 207 patients with diabetes and CKD
no data available on cardiovascular events, other adverse events, change in patient
attitudes, or changes in kidney function
education programs associated improvement in
general health knowledge
checking of feet, use of lotion, and appropriate footwear in patients on dialysis
general and specific diet in patients with microalbuminuria
Reference - Cochrane Database Syst Rev 2011 Jun 15;(6):CD007374
Medications
Antihypertensive therapy
target blood pressure (BP) in patients with CKD

current guidelines vary
American College of Cardiology/American Heart Association (ACC/AHA)
recommends < 130/80 mm Hg for adults with chronic kidney disease (ACC/AHA
Class I, Level B-R for SBP; ACC/AHA Class I, Level C-EO for DBP)
Eighth Joint National Committee (JNC 8) recommends < 140/90 mm Hg for
adults with chronic kidney disease (JNC8 Expert opinion)
Kidney Disease: Improving Global Outcomes (KDIGO) recommends
≤ 140/90 mm Hg if urine albumin excretion < 30 mg/24 hours (albumin to
creatinine ratio [ACR] < 30 mg/g) (KDIGO Level 1, Grade B)
≤ 130/80 mm Hg if urine albumin excretion ≥ 30 mg/24 hours (ACR ≥ 30
mg/g) (KDIGO Level 2, Grade D)
European Society of Hypertension/European Society of Cardiology (ESH/ESC)
suggests
systolic blood pressure < 140 mm Hg in patients with nephropathy (ESC
Class IIa, Level B)
systolic blood pressure < 130 mm Hg in patients with overt proteinuria
(ESC Class IIb, Level B)
Hypertension Canada (formerly Canadian Hypertension Education Program
[CHEP]) recommends < 140/90 mm Hg in patients with nondiabetic chronic
kidney disease (Hypertension Canada Grade B)
intensive blood pressure control (< 130/80 mm Hg) associated with reduced risk of
end-stage renal disease (in patients with proteinuria) but no significant differences
in major cardiovascular events compared to standard blood pressure control (<
140/90 mm Hg) in patients with chronic kidney disease (level 2 [mid-level] evidence)
drug selection
guidelines consistently recommend angiotensin-converting enzyme (ACE) inhibitor
or angiotensin receptor blocker (ARB) for blood pressure lowering in patients with
CKD
recommended parameters for stopping ACE inhibitor are
hyperkalemia (serum potassium > 5.6 mmol/L [5.6 mEq/L])
rise in creatinine > 30% above baseline, even for patients with elevated
baseline creatinine > 1.4 mg/dL (123.8 mcmol/L)
ACE inhibitors reduce major cardiovascular events in patients with CKD (level 1
[likely reliable] evidence), may reduce end-stage renal disease (ESRD) in patients
with CKD and macroalbuminuria (level 2 [mid-level] evidence), but may not reduce
ESRD in patients with nondiabetic stage 1-3 CKD (level 2 [mid-level] evidence)
ARBs may reduce ESRD in patients with CKD and macroalbuminuria (level 2 [mid-
level] evidence), but limited data in patients with nondiabetic stage 1-3 CKD
calcium channel blockers might reduce major cardiovascular events in patients
with CKD and appear similar to other antihypertensive medications (level 2 [mid-
level] evidence) but data for add-on efficacy limited and inconsistent
diuretics and beta blockers have similar effect on major cardiovascular events as
ACE inhibitors or calcium channel blockers in patients with chronic kidney disease
(level 1 [likely reliable] evidence)
avoid using the combination of 2 renin-angiotensin system blockers (ACE inhibitors
and ARBs) due to concerns of worsening renal function with use
in patients on dialysis, blood pressure-lowering treatment associated with decreased

cardiovascular events and mortality (level 2 [mid-level] evidence), but evidence for
specific drug selection is limited
see Hypertension treatment in patients with chronic kidney disease for details
Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers

(ARBs) for patients with CKD but not necessarily with hypertension
ACE inhibitors reported to have higher probability to protect against kidney failure,
cardiovascular death, and all-cause death than ARBs in patients with CKD (level 3
[lacking direct] evidence)
based on systematic review and network meta-analysis with indirect comparisons
systematic review of 119 randomized trials evaluating treatment with ACE
inhibitors and ARBs in 64,768 patients with CKD
kidney failure defined as composite of any of either doubling of serum creatinine,
50% decline in glomerular filtration rate (GFR), or end-stage kidney disease
cardiovascular event defined as composite of any of either fatal or nonfatal
myocardial infarction, stroke, and heart failure, or cardiovascular death, or
comparable definitions used by individual authors
comparing ACE inhibitors to placebo in network analysis of 34 trials with 21,491
patients
ACE inhibitors associated with decreased risk of
kidney failure (odds ratio [OR] 0.61, 95% CI 0.47-0.79)
cardiovascular event (OR 0.82, 95% CI 0.71-0.92)
no significant difference in risk of cardiovascular death and all-cause death
comparing ACE inhibitors to active controls in network analysis of 38 trials with
10,628 patients
ACE inhibitors associated with decreased risk of
all-cause death (OR 0.72, 95% CI 0.53- 0.92)
kidney failure (OR 0.65, 95% CI 0.51-0.8)
no significant difference in risk of cardiovascular event or cardiovascular
death
comparing ARBs to placebo in network analysis of 7 trials with 4,854 patients
ARBs associated with decreased risk of
kidney failure (OR 0.7, 95% CI 0.52-0.89)
cardiovascular event (OR 0.76, 95% CI 0.62-0.89)
no significant difference in risk of cardiovascular death or all-cause death
comparing ARBs to active controls in network analysis of 13 trials with 6,505
patients
ARBs associated with decreased risk of kidney failure (OR 0.75, 95% CI 0.54-
0.97)
no significant difference in risk of cardiovascular event, cardiovascular death,
or all-cause death
comparing ACE inhibitors to ARBs in indirect analysis
ACE inhibitors had higher probability to protect against kidney failure,
cardiovascular death, and all-cause death
ARBs had higher probability to protect against cardiovascular event
Reference - Am J Kidney Dis 2016 May;67(5):728, editorial can be found at Am J
Kidney Dis 2016 May;67(5):713
ACE inhibitors may reduce risk for end-stage renal disease in patients with
nondiabetic renal disease if proteinuria ≥ 500 mg/day (level 2 [mid-level] evidence)
based on pooled analysis of individual patient data from randomized trials
pooled analysis of 11 randomized trials comparing antihypertensive regimens with
ACE inhibitors vs. antihypertensive regimens without ACE inhibitors in 1,860
patients with chronic kidney disease without diabetes
94% had hypertension at baseline
studies could include patients with any stage of chronic kidney disease
mean follow-up 2.2 years
no significant difference in protein excretion at baseline
compared to other antihypertensive medications, ACE inhibitors associated with
lower risk of end-stage renal disease (initiation of long-term dialysis) (relative
risk [RR] 0.69, 95% CI 0.51-0.94)
improved mean protein excretion at follow-up (p < 0.001)
benefit was significant only for patients with proteinuria > 1 g/day (RR 0.59, 95% CI
0.37-0.94) in analysis of patients by proteinuria status
benefit was not significant for patients with proteinuria 0.5-1 g/day
no benefit found for patients without proteinuria (< 0.5 g/day)
Reference - Ann Intern Med 2001 Jul 17;135(2):73, correction can be found in Ann
Intern Med 2002 Aug 20;137(4):299, editorial can be found in Ann Intern Med 2001
Jul 17;135(2):138, commentary can be found in ACP J Club 2002 Jan-Feb;136(1):12
subsequent analysis of this data reported benefit (in terms of doubling of baseline
plasma creatinine or need for dialysis) with ACE inhibitor in patients with
proteinuria ≥ 500 mg/day but not in patients with proteinuria < 500 mg/day (J Am
Soc Nephrol 2007 Jun;18(6):1959 full-text), commentary can be found in ACP J Club
2008 Jan-Feb;148(1):12
ARBs may reduce risk of end-stage kidney disease, but may not reduce all-cause
mortality in patients with diabetes and chronic kidney disease (level 3 [lacking
direct] evidence)
based on network meta-analysis with indirect comparisons
systematic review and network meta-analysis of 157 randomized trials evaluating
blood-pressure-lowering medications alone or in combination in 43,256 adults with
diabetes and chronic kidney disease
blood-pressure-lowering medications included ARBs, ACE inhibitors, calcium
channel blockers, beta blockers, alpha blockers, diuretics, renin inhibitors,
aldosterone antagonists, or endothelin inhibitors
most patients had type 2 diabetes
patients who had kidney transplantation or dialysis were excluded
unclear how many patients in included studies had hypertension at baseline
interventions associated with reduced risk of end-stage kidney disease compared to
placebo in analysis of 13 trials with 24,477 patients included
ARB monotherapy (odds ratio 0.77, 95% CI 0.65-0.92)
ARB plus ACE inhibitor (odds ratio 0.62, 95% CI 0.43-0.9)
no significant differences with any blood pressure-lowering medications in
all-cause mortality in analysis of 33 trials with 29,782 patients
risk of acute kidney injury in analysis of 11 trials with 26,960 patients
Reference - Lancet 2015 May 23;385(9982):2047, editorial can be found in Lancet
2015 May 23;385(9982):2018
ACE inhibitors and ARBs may each reduce rate of decline in residual renal function
in patients receiving peritoneal dialysis for end-stage renal disease (level 3 [lacking
direct] evidence)
based on nonclinical outcome in Cochrane review
systematic review of 6 randomized trials evaluating ACE inhibitors or ARBs in 257
patients receiving peritoneal dialysis for end-stage renal disease
comparing ACE inhibitor (ramipril) vs. no treatment in 1 trial with 60 patients
ramipril significantly reduced rate of decline in residual renal function at 1
year (mean difference -0.93 mL/minute/1.73 m2 [95% CI -0.75 to -0.11
mL/minute/1.73 m2])
anuria in 46.7% vs. 73.3% (p < 0.05)
no significant differences in mortality, duration of hospitalization, peritonitis,
and cardiovascular events
comparing ARBs (irbesartan, valsartan) to other antihypertensive drugs (2 trials
having blood pressure goal of < 135/85 mm Hg)
for outcome of residual renal function
no significant difference at ≤ 6 months in 1 trial with 44 patients
ARBs associated with better residual renal function at 12-24 months in
no significant differences in peritonitis, urinary protein excretion, creatinine
clearance, or systolic/diastolic blood pressure
limited evidence to evaluate residual renal function with ACE inhibitors compared
to ARBs
consistent results in systematic review of 11 trials with 1,856 patients evaluating
ACE inhibitors or ARBs on rate of residual renal function decline (reduced) in
patients on dialysis (peritoneal or hemodialysis) (BMC Nephrol 2017 Jun
30;18(1):206 full-text)
while combination treatment with ACE inhibitors and ARBs may be effective for reducing
proteinuria, evidence suggests increased risk for adverse effects compared to
monotherapy, including increased risk for acute kidney injury and hyperkalemia (N Engl
J Med 2013 Nov 14;369(20):1892 full-text, correction can be found in N Engl J Med
2014;158:A7255)
addition of telmisartan to ACE inhibitors increases survival and reduces heart

failure hospital admissions in hemodialysis patients with heart failure (level 1
[likely reliable] evidence)
based on randomized trial
351 adults with chronic heart failure, New York Heart Association (NYHA)
functional class II-III, on hemodialysis, and taking ACE inhibitors were treated with
telmisartan 20 mg/day for 2 weeks during prerandomization run-in phase
332 patients who tolerated run-in phase were randomized to telmisartan (target
dose 80 mg/day) vs. placebo for 3 years
mean follow-up 35.5 months (median 36 months, range 2-40 months)
mean predialysis blood pressure at baseline was 125/81 mm Hg
comparing telmisartan vs. placebo
all-cause mortality 35.1% vs. 54.4% (p < 0.001, NNT 5)
cardiovascular mortality 30.3% vs. 43.7% (p < 0.001, NNT 8)
hospital admission for chronic heart failure in 33.9% vs. 55.1% (p < 0.0001, NNT
5)
improvement in NYHA functional class in 37.4% vs. 32.6% (p < 0.001, NNT 21)
study drug discontinued due to adverse effects in 16.3% vs. 10.7% (p < 0.01,
NNH 17)
Reference - J Am Coll Cardiol 2010 Nov 16;56(21):1701 full-text, commentary can be
found in Ann Intern Med 2011 May 17;154(10):JC5
Aldosterone antagonists in patients with CKD but not necessarily with hypertension
addition of spironolactone to angiotensin-converting enzyme inhibitors and/or

angiotensin receptor blockers may decrease proteinuria and blood pressure (level 3
[lacking direct] evidence), but may increase risk of gynecomastia (level 2 [mid-level]
evidence) and hyperkalemia (level 3 [lacking direct] evidence) in adults with
chronic kidney disease with proteinuria
based on nonclinical outcomes from Cochrane review of trials with methodologic
limitations
systematic review of 27 randomized trials evaluating aldosterone antagonists (alone
or in combination with angiotensin-converting enzyme [ACE] inhibitors,
angiotensin receptor blockers [ARB], or both) in 1,549 adults with chronic kidney
disease and albuminuria or proteinuria
aldosterone antagonists included spironolactone (21 trials) and eplerenone (6 trials)
all trials had unclear allocation concealment and/or lacked blinding of outcome
assessor
only 7 of the 27 trials explicitly included patients with hypertension with some of
the trials explicitly excluding patients with hypertension
comparing spironolactone plus ACE inhibitors and/or ARB to ACE inhibitors and/or
ARB alone
addition of spironolactone to ACE inhibitors and/or ARB associated with
decreased 24-hour protein excretion in analysis of 11 trials with 596
adults, results limited by significant heterogeneity
decreased blood pressure
systolic blood pressure (mean difference [MD] -3.44 mm Hg, 95% CI
-5.05 to -1.83 mm Hg) in analysis of 10 trials with 556 adults
diastolic blood pressure (MD -1.73 mm Hg, 95% CI -2.83 to -0.62 mm
Hg) in analysis of 9 trials with 520 adults
increased gynecomastia in analysis of 4 trials with 281 adults
risk ratio (RR) 5.14 (95% CI 1.14-23.23)
no events of gynecomastia in ACE inhibitors and/or ARB alone group
increased hyperkalemia in analysis of 11 trials with 632 adults
RR 2 (95% CI 1.25-3.2)
NNH 9-80 with hyperkalemia in 5% of ACE inhibitors and/or ARB
alone group
no significant difference in glomerular filtration rate in analysis of 9 trials with
528 adults
insufficient evidence to evaluate for effect on cardiovascular events, end-stage
kidney disease, and mortality
interpretation of results of trials evaluating eplerenone limited because most lacked
statistical comparison between groups
Reference - Cochrane Database Syst Rev 2014 Apr 29;(4):CD007004
consistent results for addition of spironolactone to ACE inhibitors and/or ARB found
in systematic review of 11 trials, including 10 trials in Cochrane review above (Clin J
Am Soc Nephrol 2009 Mar;4(3):542 full-text)
consistent results for addition of mineralocorticoid receptor antagonists to ACE
inhibitors and/or ARB on proteinuria and blood pressure outcomes in systematic
review of 19 trials, including 6 trials in Cochrane review above (BMC Nephrol 2016
Sep 8;17(1):127 full-text)
Neprilysin/angiotensin receptor inhibitors
neprilysin inhibitors increase circulating natriuretic peptides but also cause reflex
activation of renin-angiotensin system and inhibit angiotensin II breakdown, so must be
combined with angiotensin receptor blocker
sacubitril/valsartan and irbesartan may have similar effect on renal function, but
sacubitril/valsartan might further reduce N-terminal prohormone brain natriuretic
peptide (BNP) in adults with chronic kidney disease (level 3 [lacking direct]
evidence)
based on nonclinical outcomes from randomized trial with potential selection bias
566 adults with chronic kidney disease entered 4-7-week run-in with placebo tablets
to washout ACE inhibitor
414 patients (mean age 62 years, 72% male) who adhered to run-in protocol were
randomized to 1 of 2 treatments for 12 months
sacubitril/valsartan 97 mg/103 mg orally twice daily (given once daily for first 2
weeks and increased to twice daily unless potassium or kidney function
precluded dose increase)
irbesartan 300 mg orally once daily (given 150 mg once daily for first 2 weeks
and increased to 300 mg once daily unless potassium or kidney function
precluded dose increase)
3.6% had heart failure and 61% had systolic BP ≥ 140 mm Hg
17% discontinued trial, 100% included in analyses
baseline cardiovascular risk biomarkers in sacubitril/valsartan group and
irbesartan groups
geometric mean troponin I 7.3 ng/L and 7.5 ng/L
geometric mean N-terminal pro-hormone BNP 254.5 ng/L and 250.9 ng/L
comparing sacubitril/valsartan vs. irbesartan at 12 months
geometric mean N-terminal pro-hormone BNP 210.2 ng/L vs. 247.5 ng/L (95% CI
for 12-month difference in percent reduction 2%-26%)
geometric mean troponin 6.3 ng/L vs. 7.1 ng/L (not significant)
no significant differences in mean GFR, ≥ 25% reduction in estimated GFR, or
mean urinary albumin:creatinine ratio at 12 months
adverse events
serious adverse events in 29.5% vs. 28.5% (not significant)
nonserious adverse events in 36.7% vs. 28% (not significant)
potassium ≥ 5.5 mmol/L in 32% vs. 24% (not significant)
symptomatic hypotension in 8.2% vs. 3.4% (p = 0.04, NNH 20)
Reference - UK HARP-IIII (Circulation 2018 Oct 9;138(15):1505)
Lipid management
Recommendations
Kidney Disease Improving Global Outcomes (KDIGO) recommendations for lipid
management in patients with CKD
evaluation in adults with newly identified CKD (including those treated with chronic
dialysis or kidney transplantation)
check lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol,
high-density lipoprotein (HDL) cholesterol, triglycerides) (KDIGO Level 1,
Grade C)
follow-up measurement of lipid levels not required for the majority of patients
(KDIGO Not Graded)
cholesterol-lowering therapy in adults
in adults aged ≥ 50 years with CKD
if estimated GFR ≥ 60 mL/minute/1.73 m2, treat with a statin (KDIGO Level
1, Grade B)
if estimated GFR < 60 mL/minute/1.73 m2, treat with a statin or
statin/ezetimibe combination (KDIGO Level 1, Grade A)
in adults aged 18-49 years with CKD but not treated with chronic dialysis or
kidney transplantation, consider statin therapy in patients with ≥ 1 of the
following (KDIGO Level 2, Grade A)
known coronary disease (myocardial infarction or coronary
revascularization)
diabetes mellitus
prior ischemic stroke
estimated 10-year incidence of coronary death or nonfatal myocardial
infarction > 10%
in adults with CKD on dialysis, consider not starting statins or statin/ezetimibe
(KDIGO Level 2, Grade A)
in patients already receiving statins or statin/ezetimibe combination at the
time of dialysis initiation, consider continuing the medicine (KDIGO Level 2,
Grade C)
in adult kidney transplant recipients, consider treatment with a statin (KDIGO
Level 2, Grade B)
for hypertriglyceridemia in adults and children with CKD, consider advising patient
on therapeutic lifestyle changes (KDIGO Level 2, Grade D)
Reference - KDIGO guideline for lipid management in chronic kidney disease
(KDIGO (2011) 2013 Nov PDF), synopsis can be found at Ann Intern Med 2014 Feb
4;160(3):182
National Kidney Foundation - Kidney Disease Outcomes Quality Initiative
commentary on KDIGO Clinical Practice Guidelines for Lipid Management in
chronic kidney disease can be found in Am J Kidney Dis 2015 Mar;65(3):354
Statins in chronic kidney disease (CKD) patients not on dialysis
lipid-lowering therapy with statins reduces major cardiovascular events (level 1

[likely reliable] evidence) and may reduce all-cause mortality and cardiovascular
mortality (level 2 [mid-level] evidence) in patients with chronic kidney disease not
on dialysis
based on 4 systematic reviews
statins reduce major cardiovascular events (level 1 [likely reliable] evidence)
and may reduce all-cause and cardiovascular mortality (level 2 [mid-level]
evidence) in patients with chronic kidney disease not requiring dialysis
systematic review of 50 randomized or quasi-randomized trials evaluating
statins in 45,285 adults with chronic kidney disease (CKD) not requiring
dialysis
most trials had ≥ 1 limitation including
unclear or inadequate allocation concealment
lack of or unclear blinding
small sample size
comparing statins to placebo or no treatment (control)
statins associated with decreased
major cardiovascular events in analysis of 13 trials with 36,033
adults
risk ratio (RR) 0.72 (95% CI 0.66-0.79)
NNT16-25 with major cardiovascular events in 19% of control
group
analysis includes 2 high-quality trials with results significantly
favoring statins group
all-cause mortality in analysis of 10 trials with 28,276 adults
RR 0.79 (95% CI 0.69-0.91)
NNT 36-124 with all-cause mortality in 9% of control group
cardiovascular mortality in analysis of 7 trials with 19,059 adults
RR 0.77 (95% CI 0.69-0.87)
NNT 54-129 with cardiovascular mortality in 6% of control
group
fatal or nonfatal myocardial infarction in analysis of 8 trials with
9,018 adults
RR 0.55 (95% CI 0.42-0.72)
NNT 56-116 with fatal or nonfatal myocardial infarction in
3.1% of control group
no significant differences in stroke, cancer, and elevated liver enzymes or
creatine kinase levels
significant results for major cardiovascular events, all-cause mortality, and
myocardial infarction also in analyses limited to trials in adults without
cardiovascular disease
Reference - Cochrane Database Syst Rev 2014 May 31;(5):CD007784
similar results found in systematic review of 80 randomized trials evaluating
efficacy of statins vs. no treatment or placebo in 51,099 adults with CKD
followed for ≥ 12 months (Ann Intern Med 2012 Aug 21;157(4):263 full-text ,
commentary can be found in Ann Intern Med 2012 Nov 20;157(10):JC5 )
statins may reduce all-cause mortality and cardiovascular mortality in patients
with chronic kidney disease not on dialysis (level 2 [mid-level] evidence)
based on systematic review without reporting of allocation concealment
systematic review of 31 randomized trials comparing statins vs. placebo or no
treatment (control) for ≥ 6 months in 48,429 patients with chronic kidney
disease
statins included atorvastatin, simvastatin, pravastatin, rosuvastatin,
fluvastatin, and lovastatin
authors stated allocation concealment assessed but did not report it
in patients not on dialysis, statins associated with decreased
all-cause mortality (relative risk [RR] 0.86, 95% CI 0.73-1)
cardiovascular mortality (RR 0.86, 95% CI 0.77-0.96)
coronary events (RR 0.69, 95% CI 0.58-0.83)
stroke (RR 0.61, 95% CI 0.39-0.95)
Reference - Eur Heart J 2013 Jun;34(24):1807 full-text, editorial can be found in
Eur Heart J 2013 Jun;34(24):1772
lipid-lowering therapy may reduce all-cause mortality and cardiac mortality in
patients with chronic kidney disease not on hemodialysis (level 2 [mid-level]
evidence)
based on systematic review with clinical heterogeneity
systematic review of 18 randomized trials evaluating lipid-lowering therapy in
36,529 adults with CKD followed for ≥ 6 months
16 trials compared statins to placebo, usual care, or lower dose of same
statin
2 trials compared statin plus ezetimibe to statin alone or placebo
patient populations varied across studies and included patients with early CKD
and patients receiving dialysis or renal transplant
in patients not on hemodialysis, lipid-lowering therapy with statins associated
with decreased
all-cause mortality (risk ratio [RR] 0.83, 95% CI 0.7-0.98) in analysis of 11
trials with 18,054 patients
cardiac mortality (RR 0.67, 95% CI 0.48-0.94) in analysis of 3 trials with
2,991 patients
cardiovascular events (fatal and nonfatal, including revascularization)
(RR 0.77, 0.71-0.83) in analysis of 9 trials with 16,683 patients
myocardial infarction (RR 0.74, 95% CI 0.65-0.83) in analysis of 8 trials
with 10,279 patients
no significant differences comparing statins vs. control in incidence of end-
stage renal disease in analysis of 3 trials or incidence of stroke in analysis of 7
trials
Reference - Ann Intern Med 2012 Aug 21;157(4):251, commentary can be found
in Am J Kidney Dis 2013 Mar;61(3):371
high-intensity statin therapy may reduce risk of stroke but not all-cause mortality or
myocardial infarction compared to mild-to-moderate statin therapy or usual care in
adults with moderate CKD (level 2 [mid-level] evidence)
systematic review of 6 randomized trials evaluating high-intensity statin therapy in
10,993 adults with CKD
high-intensity statin therapy included atorvastatin 80 mg/day (5 trials) and
rosuvastatin 20 mg/day (1 trial)
controls included mild or moderate statin therapy (atorvastatin 10 mg/day in 2
trials and simvastatin 20-40 mg/day in 1 trial), placebo (2 trials), and usual care
(1 trial)
mean follow-up ranged from 1.9 to 5 years
5 trials enrolled patients with or without CKD and provided subgroup data for
patients with CKD
among trials providing subgroup data
3 trials enrolled patients with coronary heart disease (TNT trial, IDEAL trial,
ALLIANCE trial)
1 trial enrolled patients with prior noncardioembolic stroke or transient
ischemic attack, no known coronary heart disease, and low-density lipoprotein
(LDL) cholesterol 100-190 mg/dL (SPARCL trial)
1 trial enrolled patients with LDL cholesterol < 130 mg/dL and high-sensitivity
C-reactive protein ≥ 2 mg/L (JUPITER trial)
1 trial enrolled patients with type 2 diabetes and early renal disease (PANDA trial)
most patients had moderate CKD
comparing high-intensity statin therapy to control
high-intensity statin therapy associated with
reduced risk of stroke in analysis of 4 trials with 9,274 patients
risk ratio 0.69 (95% CI 0.56-0.85)
NNT 52-152 with stroke in 4.4% of control group
improvement in estimated glomerular filtration rate (mean difference
1.09 mL/minute/1.73 m2, 95% CI 0.35-1.82 mL/minute/1.73 m2) in analysis
of 3 trials with 4,500 patients
no significant differences in
all-cause mortality in analysis of 5 trials with 9,393 patients, results
limited by significant heterogeneity
myocardial infarction in analysis of 3 trials with 6,167 patients, results
limited by significant heterogeneity
heart failure in analysis of 3 trials with 6,007 patients, results limited by
significant heterogeneity
Reference - BMJ Open 2015 May 15;5(5):e006886 full-text
ezetimibe/simvastatin may reduce nonhemorrhagic stroke and revascularization in
patients with chronic kidney disease (level 2 [mid-level] evidence)
based on randomized trial with high discontinuation rate
9,438 patients (mean age 62 years) with advanced or end-stage CKD (32.6% on
dialysis) randomized to ezetimibe 10 mg plus simvastatin 20 mg/day vs. placebo
CKD defined as
plasma creatinine of 150 mcmol/L (1.7 mg/dL) in men
plasma creatinine of 130 mcmol/L (1.5 mg/dL) in women
patients requiring dialysis
median follow-up 4.9 years
study drug discontinuation in 34.5%
98% included in final analysis as randomized to ezetimibe/simvastatin vs. placebo
comparing major atherosclerotic events with ezetimibe/simvastatin combination vs.
placebo
nonhemorrhagic stroke in 2.8% vs. 3.8% (p = 0.01, NNT 100)
revascularization in 6.1% vs. 7.6% (p = 0.0036, NNT 67)
nonfatal myocardial infarction in 2.9% vs. 3.4% (not significant)
coronary heart disease mortality 2% vs. 1.9% (not significant)
in subgroup analysis of patients not on dialysis, ezetimibe/simvastatin treatment
associated with lower risk of major atherosclerotic events compared to placebo (risk
ratio 0.78, 95% CI 0.67-0.91)
Reference - SHARP trial (Lancet 2011 Jun 25;377(9784):2181 full-text), editorial can
be found in Lancet 2011 Jun 25;377(9784):2153
statins may not prevent progression to end-stage renal disease (level 2 [mid-level]
evidence) and do not appear to reduce GFR decline in most patients with chronic
kidney disease (level 3 [lacking direct] evidence)
ezetimibe/simvastatin may not reduce progression to end-stage renal disease in
based on subgroup analysis of SHARP trial with low compliance rate of study
drug
6,245 patients with chronic kidney disease (CKD) (63% had stage 4-5 CKD) not
on dialysis at randomization in SHARP trial were followed for median 4.8
years
end-stage renal disease (ESRD) defined as initiation of maintenance dialysis or
kidney transplantation
study drug compliance at study midpoint was 73%
patients on ezetimibe/simvastatin had mean low-density lipoprotein
cholesterol 0.96 mmol/L lower than placebo group
comparing simvastatin/ezetimibe vs. placebo
ESRD in 33.9% vs. 34.6% (not significant)
ESRD or death in 47.4% vs. 48.3% (not significant)
ESRD or doubling of baseline creatinine in 38.2% vs. 40.2% (p = 0.09)
Reference - J Am Soc Nephrol 2014 Aug;25(8):1825 full-text
pravastatin may not be superior to usual care in preventing end-stage renal
based on post hoc secondary analysis of ALLHAT trial
10,060 patients stratified by estimated glomerular filtration rate (GFR) and
randomized to pravastatin 40 mg/day vs. usual care
through year 6, no significant differences in rates of end-stage renal disease or
rate of change in estimated GFR, but total cholesterol levels decreased more in
pravastatin group and findings consistent across estimated GFR strata
Reference - Am J Kidney Dis 2008 Sep;52(3):412 full-text , editorial can be found
at Am J Kidney Dis 2008 Sep;52(3):391
statin use may slightly increase estimated GFR and might reduce proteinuria in
patients with CKD (level 3 [lacking direct] evidence)
based on systematic review without clinical outcomes
systematic review of 41 randomized trials assessing statin use and renal
function in 88,523 patients
comparing statins to placebo
statin use associated with small but significant improvements in
estimated GFR in analysis of 33 trials with 77,870 patients who
had baseline estimated GFR ≥ 30 mL/minute/1.73 m2
proteinuria in analysis of 18 trials with 3,102 patients who had
baseline urinary protein excretion ≥ 30 mg/day
no significant difference in proteinuria in analysis of 3 trials with
853 patients who had baseline urinary protein excretion < 30
mg/day
comparing high-intensity statins to moderate-intensity statins, high-
intensity statins associated with significant increase in estimated GFR in
analysis of 3 studies with 10,434 patients
Reference - Am J Cardiol 2014 Aug 15;114(4):562
atorvastatin may not reduce decline in estimated GFR in most patients with
chronic kidney disease, but might reduce decline in patients with elevated
inflammatory markers (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes and with high dropout
rate
117 patients with CKD and serum creatinine > 120 mcmol/L (1.4 mg/dL)
randomized to atorvastatin 10 mg orally once daily vs. placebo
at baseline mean estimated GFR 31 mL/minute/1.73 m2
mean follow-up 2.5 years
70% completed trial
no significant difference in rate of decline in estimated GFR in overall analysis
in subgroup analyses of patients with increased levels of inflammatory
markers interleukin (IL)-6/8/10 and/or pentraxin-3 (PTX3), atorvastatin
associated with significantly reduced rate of decline in estimated GFR
Reference - Clin Nephrol 2014 Feb;81(2):75
Statins in dialysis patients
statins may not reduce all-cause mortality or cardiovascular mortality in patients

receiving dialysis (level 2 [mid-level] evidence)
based on 5 systematic reviews of trials with methodologic limitations
statins may not reduce mortality in patients on dialysis (level 2 [mid-level]
evidence)
systematic review of 25 randomized and quasi-randomized trials evaluating
statins in 8,289 patients on hemodialysis or peritoneal dialysis
all trials had ≥ 1 of these methodologic limitations
unclear allocation concealment
unclear or lack of blinding
high dropout rate
comparing statins to placebo or no treatment
no significant difference in
cardiovascular mortality in analysis of 13 trials with 4,627 patients
major cardiovascular events in analysis of 4 trials with 7,084
patients
myocardial infarction in analysis of 3 trials with 4,047 patients
statin associated with nonsignificant increase in stroke (risk ratio 1.29,
95% CI 0.96-1.27) in analysis of 2 trials with 4,018 patients
statin associated with reduced low-density lipoprotein (LDL) cholesterol
level (mean difference -39.99 mg/dL, 95% CI -52.46 to -27.52 mg/dL) in
analysis of 12 trials with 1,747 patients, results limited by significant
heterogeneity
limited data available to compare different statins
Reference - Cochrane Database Syst Rev 2013 Sep 11;(9):CD004289 ,
commentaries can be found in Nephrology (Carlton) 2015 Apr;20(4):302 and
Evid Based Med 2014 Jun;19(3):89
statins may reduce low-density lipoprotein cholesterol (LDL-C) level but not
cardiovascular events in patients having hemodialysis (level 2 [mid-level]
evidence)
based on systematic review without assessment of trial quality
systematic review of 3 trials comparing statins or omega-3 fatty acids vs.
placebo for dyslipidemia with 4,237 patients with end-stage renal disease
(ESRD) requiring hemodialysis
meta-analysis not performed
statins associated with reduced LDL-C levels in 2 trials
no significant difference in cardiovascular events (cardiovascular death,
myocardial infarction, stroke)
Reference - Pharmacotherapy 2010 Aug;30(8):823
statins may not reduce all-cause mortality but may reduce major
atherosclerotic cardiovascular events in patients receiving dialysis (level 2
based on systematic review without reporting of trial quality
systematic review of 3 randomized trials comparing lipid-lowering therapy
(statins) vs. placebo for atherosclerotic cardiovascular events, stroke, and all-
cause mortality in 7,051 patients receiving dialysis
atherosclerotic cardiovascular events included fatal and nonfatal myocardial
infarction, fatal and nonfatal nonhemorrhagic stroke, and arterial
revascularization (excluding dialysis vascular access)
lipid-lowering therapy associated with reduced fatal and nonfatal major
atherosclerotic cardiovascular events in analysis of 3 trials with 7,051 patients
odds ratio 0.89, 95% CI 0.8-0.99
NNT 24-506 with major atherosclerotic cardiovascular events in 27% of
controls
no significant difference in all-cause mortality, cardiovascular mortality,
coronary events, revascularizations, fatal and nonfatal nonhemorrhagic
strokes, all strokes, and fatal and nonfatal hemorrhagic strokes
Reference - Nephron Clin Pract 2013;124(3-4):209 full-text
statins may not be associated with reduced all-cause mortality or
cardiovascular mortality in patients with chronic kidney disease on dialysis
based on systematic review without reporting of allocation concealment
systematic review of 31 randomized trials comparing statins vs. placebo or no
treatment (control) for ≥ 6 months in 48,429 patients with chronic kidney
disease
statins included atorvastatin, simvastatin, pravastatin, rosuvastatin,
fluvastatin, and lovastatin
authors stated allocation concealment assessed but did not report it
in patients on dialysis, statins not associated with significant differences in
all-cause mortality (risk ratio [RR] 0.96, 95% CI 0.9-1.02)
cardiovascular death (RR 0.96, 95% CI 0.86-1.08)
coronary events (RR 0.91, 95% CI 0.81-1.02)
stroke (RR 1.16, 95% CI 0.91-1.47)
Reference - Eur Heart J 2013 Jun;34(24):1807 full-text, editorial can be found in
Eur Heart J 2013 Jun;34(24):1772
statins may not reduce all-cause mortality and cardiovascular events in
patients with chronic kidney disease on dialysis, but might decrease risk of
myocardial infarction (level 2 [mid-level] evidence)
based on systematic review with clinical heterogeneity
systematic review of 18 randomized trials evaluating lipid-lowering therapy in
36,529 adults with chronic kidney disease (CKD) followed for ≥ 6 months
16 trials compared statins to placebo, usual care, or lesser dose of same
statin
2 trials compared statin plus ezetimibe to statin alone or placebo
patient populations varied across studies and included patients with early CKD
and patients receiving dialysis or renal transplant
2 trials assessed patients on hemodialysis and 2 other trials included patients
on dialysis
in patients on hemodialysis
no significant difference comparing lipid-lowering therapy with statins to
placebo or no treatment for
cardiovascular mortality (including cardiac and stroke mortality) in
1 trial with 2,773 patients
cardiovascular events (fatal and nonfatal, including
revascularization) in 1 trial with 2,527 patients
compared to placebo or not treatment, lipid-lowering therapy with statins
associated with decreased
myocardial infarction (risk ratio [RR] 0.72, 95% CI 0.56-0.92) in 1 trial
with 731 patients
cardiac mortality (RR 0.78, 95% CI 0.68-0.89) in analysis of 2 trials
with 2,773 patients
Reference - Ann Intern Med 2012 Aug 21;157(4):251, commentary can be found
in Am J Kidney Dis 2013 Mar;61(3):371
ezetimibe/simvastatin might not reduce major atherosclerotic events in patients
with CKD on dialysis (level 2 [mid-level] evidence)
based on subgroup analysis of randomized trial with high dropout rate
9,438 patients (mean age 62 years) with advanced or end-stage CKD (32.6% on
dialysis) randomized to ezetimibe 10 mg/day plus simvastatin 20 mg/day vs. placebo
per day
CKD defined as
plasma creatinine of 150 mcmol/L (1.7 mg/dL) in men
plasma creatinine of 130 mcmol/L (1.5 mg/dL) in women
patients receiving dialysis
median follow-up 4.9 years
study drug discontinuation in 34.5%
98% included in final analysis as randomized to ezetimibe/simvastatin vs. placebo
comparing ezetimibe/simvastatin combination vs. placebo for major atherosclerotic
events
nonfatal myocardial infarction in 2.9% vs. 3.4% (not significant)
coronary heart disease mortality 2% vs. 1.9% (not significant)
nonhemorrhagic stroke in 2.8% vs. 3.8% (p = 0.01, NNT 100)
revascularization in 6.1% vs. 7.6% (p = 0.0036, NNT 67)
in subgroup analysis of patients on dialysis, no significant difference in major
atherosclerotic events comparing ezetimibe/simvastatin combination vs. placebo
(risk ratio 0.9, 95% CI 0.75-1.08)
Reference - SHARP trial (Lancet 2011 Jun 25;377(9784):2181 full-text), editorial can
be found in Lancet 2011 Jun 25;377(9784):2153
statin use associated with fewer sepsis events in dialysis patients (level 2 [mid-level]
evidence)
based on observational study
prospective cohort study of 1,041 incident dialysis patients at 81 United States
outpatient dialysis clinics followed for mean 3.4 years
303 sepsis events occurred (146 in hospital setting and 157 in other settings)
rates of sepsis events 41 per 1,000 patient-years in statin users vs. 110 per 1,000
patient-years in nonstatin users (p < 0.001)
Reference - JAMA 2007 Apr 4;297(13):1455, correction can be found in JAMA 2008
Feb 20;299(7):765), commentary can be found in JAMA 2007 Jul 18;298(3):284, JAMA
2008 Feb 20;299(7):765
Statins in renal transplant recipients

statins may not reduce all-cause mortality in renal transplant recipients (level 2
based on Cochrane review limited by clinical heterogeneity
systematic review of 22 randomized trials comparing statins vs. placebo, no
treatment, standard care, or another statin in 3,465 adults having kidney transplant
results limited by heterogeneity in intervention and patient population
17 trials compared statins to placebo or no treatment (control)
statins included simvastatin (6 trials), fluvastatin (5 trials), lovastatin (2 trials),
pravastatin (2 trials), rosuvastatin (1 trial), and atorvastatin or cerivastatin (1
trial)
median serum low-density lipoprotein (LDL) cholesterol at baseline 257 mg/dL
(range 159-319 mg/dL)
median statin dose (equivalent to simvastatin) 10 mg (range 5-40 mg)
median follow-up 4 months (range 2-61 months)
most trials had results only for lipid levels
results for most outcomes driven by 1 large trial below
comparing statins to control
end-stage kidney disease in analysis of 6 trials with 2,740 adults
acute allograft rejection in analysis of 4 trials with 582 adults
statins associated with nonsignificant reduction in cardiovascular mortality
(risk ratio 0.68, 95% CI 0.45-1.01) in analysis of 4 trials with 2,322 adults
Reference - Cochrane Database Syst Rev 2014 Jan 28;(1):CD005019 , commentary can
be found in Nephrology (Carlton) 2015 Apr;20(4):304
fluvastatin associated with reduced rate of cardiac death and nonfatal
myocardial infarction in renal transplant recipients (level 2 [mid-level]
evidence)
based on randomized trial with high dropout rate
2,102 renal transplant recipients aged 30-75 years (mean age 50 years, 66%
male) with total cholesterol 4-9 mmol/L (154-350 mg/dL) randomized to
fluvastatin 40 mg/day vs. placebo for 5-6 years
only 62.3% completed randomized trial medication, but 85.1% were included
in follow-up
comparing fluvastatin vs. placebo
cardiac death or definite nonfatal myocardial infarction in 6.7% vs. 9.9%
(p = 0.005, NNT 32)
cardiac death in 3.4% vs. 5.1% (p = 0.031, NNT 59)
no significant difference in major adverse cardiac events, all-cause mortality,
coronary intervention procedures, or cerebrovascular events
Reference - ALERT trial (Lancet 2003 Jun 14;361(9374):2024), commentary can
be found in Am J Transplant 2005 Jun;5(6):1576
Fibrates for cardiovascular protection
fibrates may reduce cardiovascular events and improve lipid profile in patients
with chronic kidney disease (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 8 randomized trials comparing fibrates (gemfibrozil in 3 trials,
fenofibrate in 3, and bezafibrate in 2) vs. placebo in 16,869 patients with chronic
kidney disease or impaired kidney function
all trials had ≥ 1 of the following limitations
unclear allocation concealment
lack of blinding
low adherence
subgroup analysis not prespecified
lack of intention-to-treat analysis
comparing cardiovascular outcomes with fibrates (gemfibrozil and fenofibrate) vs.
placebo
in patients with estimated glomerular filtration rate (GFR) 30-59.9
mL/minute/1.73 m2, fibrates associated with reduced
cardiovascular events in analysis of 2 trials with 918 patients
risk ratio (RR) 0.7 (95% CI 0.54-0.89)
NNT 9-36 with cardiovascular events in 25.7% of controls
cardiovascular death in analysis of 2 trials with 918 patients
RR 0.6 (95% CI 0.38-0.96)
NNT 18-272 with cardiovascular death in 9.2% of controls
fibrates also associated with significant reduction in cardiovascular events and
cardiovascular death in patients with estimated GFR ≥ 60 mL/minute/1.73 m2
in analysis of 2 trials
no significant differences in stroke or all-cause mortality
comparing lipid profile outcomes for fibrates (gemfibrozil and fenofibrate) vs.
placebo in patients with estimated GFR ≤ 60 mL/minute/1.73 m2 in analysis of 3
trials with 484 patients
fibrates associated with
increased high-density lipoprotein cholesterol (p < 0.0001)
nonsignificant reduction in total cholesterol (p = 0.05)
reduced triglycerides (p = 0.03), results limited by significant
heterogeneity
no significant differences in low-density lipoprotein cholesterol
no significant differences in end-stage kidney disease comparing fibrates
(gemfibrozil and fenofibrate) vs. placebo in analysis of 2 trials with 9,852 patients
Reference - J Am Coll Cardiol 2012 Nov 13;60(20):2061 full-text, editorial can be
found in J Am Coll Cardiol 2012 Nov 13;60(20):2072
Glycemic control in patients with CKD and diabetes
in patients with diabetes, aim for target glycated hemoglobin (HbA1c) of approximately
7% (53 mmol/mol) to prevent or delay progression of microvascular complications
(KDIGO Level 1, Grade A)(3)
do not use target HbA1c of < 7% (< 53 mmol/mol) if patient at risk of hypoglycemia
(KDIGO Level 1, Grade B)
consider loosening target HbA1c > 7% (53 mmol/mol) if patient has comorbidities or
limited life expectancy and risk of hypoglycemia (KDIGO Level 2, Grade C)
monitoring blood glucose control in patients with chronic kidney disease

National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF
KDOQI) suggests using HbA1c to measure blood sugar control in patients with CKD
and diabetes (Am J Kidney Dis 2012 Nov;60(5):850 PDF), correction can be found in
Am J Kidney Dis 2013 Jun;61(6):1049
Kidney Disease: Improving Global Outcomes (KDIGO) states HbA1C may not be
reflective of glucose control in people with CKD who have reduced red cell life span,
and thus should be interpreted with caution; reviewing blood sugar daily logs may
be more reliable ( Kidney Int Suppl 2013 Jan;3(1):4 PDF), commentary can be found
in Kidney Int 2013 Sep;84(3):622
albumin corrected fructosamine reported to reliably indicate glycemic control in 30
patients with diabetes and CKD stage 3-4 but HbA1c underestimated glycemic
control (Am J Kidney Dis 2010 May;55(5):867)
glycated albumin reported to more accurately reflect glycemic control compared to
fructosamine and HbA1c in 25 patients with diabetes and CKD stage 4-5 (Nephrology
(Carlton) 2012 Feb;17(2):182)
glycated albumin reported to better estimate glycemic control than HbA1c in 25
patients with diabetes on hemodialysis (Saudi J Kidney Dis Transpl 2013
Mar;24(2):260 full-text, J Am Soc Nephrol 2007 Mar;18(3):896 full-text)
DynaMed commentary -- use of glycated albumin needs validation in larger
cohort
HbA1c and albumin-corrected fructosamine reported to reliably indicate glycemic
control in patients with diabetes on peritoneal dialysis (PLoS One
2013;8(3):e57762 full-text)
intensive glycemic control in adults with type 2 diabetes may not reduce mortality or risk
for end-stage renal disease (level 2 [mid-level] evidence)
see Glycemic goals in patients with type 2 diabetes for details
intensive insulin therapy may delay onset of and slow progression of microalbuminuria
and albuminuria (reduced risk of increased serum creatinine, albuminuria, and
hypertension may continue 7-8 years after intensive therapy) in patients with type 1
diabetes (level 3 [lacking direct] evidence)
see Glycemic goals in patients with type 1 diabetes for details
in patients with CKD and diabetes, other interventions should include lowering blood
pressure and cardiovascular risk(3)
use angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) when indicated
use statins when indicated
use antiplatelet therapy when indicated
see also Diabetic nephropathy
Antiplatelet therapy
antiplatelet agents may reduce the risk of myocardial infarction but might increase
bleeding risk in patients with chronic kidney disease with stable or no
cardiovascular disease (level 2 [mid-level] evidence)
based on 2 systematic reviews of mostly low-quality trials and without significant
differences in high-quality trials
antiplatelet therapy associated with decreased risk of myocardial infarction
but may increase risk of minor bleeding in patients with chronic kidney
disease with stable or no cardiovascular disease (level 2 [mid-level] evidence)
based on systematic review of mostly low-quality trials and post hoc analyses
systematic review of 40 randomized trials evaluating effects of antiplatelet
therapy on cardiovascular events, mortality, and bleeding in 21,670 adults with
chronic kidney disease (CKD)
31 trials evaluated 11,701 patients with stable or no cardiovascular disease and
were classified as "generally low-quality trials"
in patients at risk for or with stable cardiovascular disease, antiplatelet
therapy
associated with decreased risk of fatal or nonfatal myocardial infarction
in analysis of 10 trials with 9,133 patients
relative risk (RR) 0.66 (95% CI 0.51-0.87)
NNT 62-232 with myocardial infarction in 3.3% of patients not
taking antiplatelet therapy
associated with increased risk of minor bleeding in analysis of 8 trials
with 7,202 patients
RR 1.7 (95% CI 1.44-2.02)
NNH 14-33 with minor bleeding in 6.9% of patients not taking
antiplatelet therapy
not associated with significant reduction in fatal or nonfatal stroke, death
due to cardiovascular disease, or all-cause mortality
not associated with significantly increased risk of major bleeding in
analysis of 18 trials with 10,230 patients
Reference - Ann Intern Med 2012 Mar 20;156(6):445 full-text, commentary can
be found in Ann Intern Med 2012 Aug 21;157(4):302
antiplatelet agents may reduce myocardial infarction but may increase risk of
major bleeding in patients with chronic kidney disease (level 2 [mid-level]
evidence)
based on Cochrane review without significant differences in high-quality trials
systematic review of 50 randomized trials evaluating antiplatelet agents in
27,139 patients with chronic kidney disease
2 trials evaluated patients with acute coronary syndrome, 5 trials evaluated
patients with acute or stable coronary artery disease having percutaneous
intervention
follow-up ranged from 1-61 months
comparing antiplatelet agents to placebo or no treatment (control)
antiplatelet agents associated with
decrease in myocardial infarction in analysis of 17 trials with 14,451
patients (including some trials of patients with coronary artery
disease but not patients with acute coronary syndrome)
risk ratio (RR) 0.87 (95% CI 0.76-0.99)
NNT 60-1,429 with myocardial infarction in 7% of control
group
analysis includes 2 high-quality trials with nonsignificant
decrease in antiplatelet agents group
increase in major bleeding in analysis of 26 trials with 15,992
patients (including trial of patients with acute coronary syndrome)
RR 1.35 (95% CI 1.1-1.65)
NNH 53-344 with major bleeding in 2.9% of control group
analysis includes 1 high-quality trial with no significant
difference between groups
decrease in dialysis access failure (thrombosis or loss of patency) in
analysis of 14 trials with 2,608 patients
RR 0.68 (95% CI 0.54-0.84)
NNT 8-21 with dialysis access failure in 30% of control group
results limited by heterogeneity
nonsignificant decrease in failure to attain suitability for dialysis
(RR 0.62, 95% CI 0.33-1.16) in analysis of 5 trials with 1,503 patients
stroke in analysis of 11 trials with 9,544 patients
fatal bleeding in analysis of 16 trials with 7,037 patients
comparing different antiplatelet agents
ticagrelor significantly reduced mortality vs. clopidogrel in subgroup
analysis of 3,237 patients from 1 trial
no significant differences in myocardial infarction and mortality
comparing prasugrel vs. clopidogrel (in subgroup analysis of 1,490
patients from 1 trial) or abciximab vs. tirofiban (in subgroup analysis of
1,192 patients from 1 trial)
Reference - Cochrane Database Syst Rev 2013 Feb 28;(2):CD008834,
commentary can be found in Nat Rev Nephrol 2013 Jun;9(6):314
in patients with chronic kidney disease, antiplatelet therapy (for acute coronary
syndrome or percutaneous coronary intervention) may increase risk for bleeding
and may not reduce myocardial infarction, stroke, or mortality (level 2 [mid-level]
evidence)
based on systematic review of subgroup analyses of randomized trials
systematic review of 40 randomized trials evaluating bleeding risk and mortality
comparing antiplatelet agents vs. placebo in adults with chronic kidney disease
9 trials evaluated 9,696 patients with acute coronary syndrome (ACS) or having
percutaneous coronary intervention (PCI)
for trials of patients with ACS or PCI, trial quality generally high, but all were post
hoc analyses of subgroups with chronic kidney disease
ACS and PCI patients not separately analyzed
antiplatelet agents evaluated included abciximab (4 trials), eptifibatide (2 trials),
tirofiban (1 trial), and clopidogrel (2 trials)
among patients with ACS or having PCI
no significant effect of antiplatelet therapy on
myocardial infarction (relative risk 0.89, 95% CI 0.76-1.05) in analysis of 7
stroke (relative risk 0.51, 95% CI 0.09-2.77) in 1 trial with 411 patients
hemorrhagic stroke (relative risk [RR] 1.08, 95% CI 0.47-2.49) in analysis
of 5 trials with 4,035 patients
all-cause mortality (RR 0.89, 95% CI 0.75-1.05) in analysis of 8 trials with
9,347 patients
cardiovascular mortality (RR 0.96, 95% CI 0.79-1.16) in analysis of 2 trials
with 4,498 patients
antiplatelet therapy associated with increased risk for
major bleeding
RR 1.4 (95% CI 1.05-1.86)
minor bleeding
RR 1.47 (95% CI 1.25-1.72)
both of these analyses (major bleeding and minor bleeding) based on
analysis of 9 trials with 5,776 patients, and limited by heterogeneity
Reference - Ann Intern Med 2012 Mar 20;156(6):445 full-text, commentary can be
found in Ann Intern Med 2012 Aug 21;157(4):302
Pentoxifylline
pentoxifylline may decrease amount of albuminuria and proteinuria in patients

with diabetic kidney disease (level 3 [lacking direct] evidence)
based on nonclinical outcomes from Cochrane review
systematic review of 17 randomized and quasi-randomized trials evaluating
pentoxifylline in 991 patients with diabetic kidney disease
comparing pentoxifylline to placebo in patients receiving routine treatment
pentoxifylline associated with decreased
albuminuria in analysis of 2 trials with 117 patients
overt proteinuria (mean difference [MD] -428.58 g/minute, 95% CI -661.65
g/minute to -195.5 g/minute) in 1 trial with 46 patients
serum creatinine levels (MD -0.1 mg/dL, 95% CI -0.17 mg/dL to -0.03 mg/dL
[-8.84 mcmol/L, 95% CI -15 mcmol/L to -2.65 mcmol/L]) in analysis of 2
diastolic blood pressure (MD -5.75 mm Hg, 95% CI -9.56 mm Hg to -1.94
mm Hg) in analysis of 2 trials with 126 patients
no significant difference in systolic blood pressure in analysis of 2 trials with
126 patients, but results limited by heterogeneity
comparing pentoxifylline plus routine treatment to routine treatment alone
pentoxifylline associated with decrease in
albuminuria in analysis of 4 trials with 220 patients
proteinuria in analysis of 5 trials with 192 patients (MD 0.46 g/24 hours,
95% CI 0.17-0.74 g/24 hours)
serum creatinine levels in analysis of 5 trials with 199 patients
blood pressure in analysis of 5 trials with 240 patients
comparing pentoxifylline to captopril, no significant differences in
serum creatinine in analysis of 2 trials with 166 patients
albuminuria in analysis of 2 trials with 233 patients, but results limited by
heterogeneity
proteinuria in analysis of 2 trials with 145 patients
blood pressure in analysis of 3 trials with 272 patients
adverse effects mild; no serious adverse effects reported
Reference - Cochrane Database Syst Rev 2012 Feb 15;(2):CD006800
addition of pentoxifylline to losartan may decrease proteinuria in patients with

advanced chronic kidney disease (level 3 [lacking direct] evidence)
56 patients with glomerular filtration rate (GFR) 10-60 mL/minute/1.73 m2 and
significant proteinuria (> 500 mg protein/g of creatinine) on losartan 100 mg/day for
> 6 months were randomized to pentoxifylline vs. placebo for 12 months
pentoxifylline dose 400 mg twice daily for GFR 30-60 mL/minute/1.73 m2 or once
daily for GFR 10-29 mL/minute/1.73 m2
proteinuria decreased by median 23.9% in pentoxifylline group vs. median 13.8%
increase in control group (p < 0.001)
Reference - Am J Kidney Dis 2008 Sep;52(3):464
pentoxifylline may slow progression of CKD (level 3 [lacking direct] evidence)

based on small randomized trial without clinical outcomes
40 outpatients with decreased GFR, hypertension, and proteinuria > 1 g/24 hours on
angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or both
were randomized to pentoxifylline 400 mg twice daily vs. placebo
comparing pentoxifylline vs. placebo
mean decrease in GFR at 1 year -1.2 mL/minute/1.73 m2 vs. -7.2 mL/minute/1.73
m2 (p = 0.03)
no significant difference in proteinuria at baseline, 6 months, or 1 year
Reference - Am J Kidney Dis 2009 Apr;53(4):606, commentary can be found in J
Formos Med Assoc 2015 Jan;114(1):94
Allopurinol
allopurinol might slow decline in kidney function in patients with CKD after 1 year
(level 3 [lacking direct] evidence)
based on nonclinical outcomes from systematic review of trials with unclear
allocation concealment or without blinding
systematic review of 4 randomized trials evaluating allopurinol for treatment of
CKD in 267 patients
in 1 trial with 54 patients with CKD and hyperuricemia, 12% of patients on
allopurinol had increase of serum creatinine by > 40% compared to 42% in control
group (p 0.015) at 1 year
compared to controls in 1 trial with 113 patients with CKD summarized below,
allopurinol associated with
nonsignificantly higher estimated glomerular filtration rate (GFR) at 12 months
(mean difference 5.5, 95% CI 0.23-10.77)
significantly higher estimated GFR at 24 months (mean difference 6.3, 95% CI
1.25-11.35)
Reference - Health Technol Assess 2014 Jun;18(40):1 full-text
allopurinol associated with slowed progression of kidney disease (level 3
[lacking direct] evidence) and reduced risk of cardiovascular events (level 2
[mid-level] evidence) in patients with CKD
based on randomized trial with allocation concealment not stated and without
blinding
113 patients with CKD randomized to allopurinol 100 mg/day vs. standard
therapy for 24 months
progression of renal disease defined as a decrease in estimated GFR > 0.2
mL/minute/1.73 m2 per month
comparing allopurinol vs. control
mean change in uric acid levels -1.6 mg/dL vs. +0.3 mg/dL (p < 0.0005)
mean change in estimated GFR 1.3 mL/minute/1.73 m2 vs. -3.3
mL/minute/1.73 m2 (p = 0.018)
adverse cardiovascular events in 12% vs. 27% (p = 0.039, NNT 7)
allopurinol associated with slowed progression of renal disease (p = 0.048)
Reference - Clin J Am Soc Nephrol 2010 Aug;5(8):1388 full-text, commentary
can be found in Nat Rev Nephrol 2010 Oct;6(10):562
Lead chelation
EDTA lead chelation may slow progression of chronic kidney disease in patients
with moderate renal insufficiency and high-normal total body lead burden (level 3
based on 2 randomized trials without clinical outcomes
64 patients > 18 years old without diabetes in Taiwan with serum creatinine 1.5-3.9
mg/dL (132.6-344.8 mcmol/L) and high-normal body lead burden (80-600 mcg) were
randomized to repeated ethylenediamine tetraacetic acid (EDTA) lead chelation vs.
placebo
patients assigned to chelation therapy received 1 treatment during first 3
months and repeated therapy as needed over next 24 months; placebo group
received 5 weekly glucose infusions every 6 months
change in kidney function after initial lead chelation +2.1 mL/minute/1.73 m2
in EDTA group vs. -6.0 mL/minute/1.73 m2 in controls (p < 0.001)
Reference - N Engl J Med 2003 Jan 23;348(4):277 full-text, editorial can be found
in N Engl J Med 2003 Jan 23;348(4):345
32 patients In Taiwan with stable CKD (creatinine 1.5-4 mg/dL [132.6-353.6 mcmol/L]
for 6 months) and mildly elevated lead burden (150-600 mcg as measured by 72-
hour urine collection after EDTA mobilization) were randomized to weekly EDTA
lead chelation vs. no treatment for 2 months and followed for additional 12 months
renal function improved in chelation group after 2 months vs. slight decline in
control group (p = 0.0297)
renal insufficiency progressed more slowly during 12-month follow-up in
chelation group (p = 0.003)
Reference - Ann Intern Med 1999 Jan 5;130(1):7 , commentary can be found in Ann
Intern Med 1999 Nov 2;131(9):716
Vitamins and other supplements for cardiovascular protection and mortality reduction
vitamin D supplementation may not be associated with reduction in all-cause

mortality in adults with chronic kidney disease (level 2 [mid-level] evidence);
inconsistent evidence for cardiovascular mortality reduction
vitamin D supplementation may not be associated with reduction in all-cause
mortality or cardiovascular mortality in adults with chronic kidney disease
systematic review of 13 randomized trials comparing oral vitamin D
supplementation vs. placebo in 1,469 adults with chronic kidney disease
(estimated glomerular filtration rate ≤ 60 mL/minute/1.73 m2)
trials varied in dosing (0.25 mcg/day to 200,000 units/week) and duration (3-104
weeks)
trials were not designed a priori to evaluate mortality or cardiovascular
outcomes
all-cause mortality (relative risk [RR] 0.84, 95% CI 0.46-1.52) in analysis of
13 trials with 1,469 adults
cardiovascular mortality (RR 0.79, 95% CI 0.26-2.28) in analysis of 6 trials
with 937 adults
serious adverse cardiovascular events (RR 1.2, 95% CI 0.48-2.99) in
analysis of 8 trials with 1,217 adults
no significant differences in mortality when data was stratified by stage of
kidney disease, type of vitamin D administered or number of dialysis patients
enrolled
Reference - Clin Kidney J 2015 Feb;8(1):41 full-text
similar mortality results can be found in Cochrane review of 60 randomized
trials with 2,773 patients with CKD requiring dialysis (Cochrane Database Syst
Rev 2009 Oct 7;(4):CD005633) and in Cochrane review of 16 randomized trials
with 894 patients with CKD not requiring dialysis (Cochrane Database Syst Rev
2009 Oct 7;(4):CD008175), commentary can be found in Ann Intern Med 2010
Apr 20;152(8):JC4
vitamin D supplementation might reduce cardiovascular mortality in patients
receiving dialysis (level 2 [mid-level] evidence)
based on systematic review of observational studies and moderate-quality
trials
systematic review of 10 prospective cohort studies and 8 randomized trials
evaluating supplementation with vitamin D, calcium, or both
none of the studies were designed to evaluate cardiovascular outcomes
vitamin D supplementation associated with reduced cardiovascular mortality
in 5 cohorts with 68,426 patients receiving dialysis (no meta-analysis reported)
no significant differences in cardiovascular outcomes in randomized trials (not
specific to dialysis patients) comparing
vitamin D supplementation vs. placebo in analysis of 2 trials with 2,988
patients
calcium supplementation vs. placebo in analysis of 3 trials with 3,861
patients
vitamin D plus calcium vs. placebo in analysis of 2 trials with 36,473
patients
Reference - Ann Intern Med 2010 Mar 2;152(5):315, editorial can be found in
Ann Intern Med 2010 Mar 2;152(5):327, commentary can be found in Ann
Intern Med 2010 Aug 3;153(3):209
vitamin D may not decrease left ventricular mass (level 3 [lacking direct] evidence)
but may decrease hospitalization rate in patients with chronic kidney disease and
left ventricular hypertrophy (level 2 [mid-level] evidence)
based on 2 randomized trial with allocation concealment not stated or without
clinical outcomes
60 patients with stage 3-5 chronic kidney disease and left ventricular hypertrophy
were randomized to activated vitamin D (paricalcitol) 1 mcg orally once daily vs.
placebo for 1 year
no significant differences in left ventricular mass, left ventricular volume, or
left ventricular ejection fraction
hospitalization in 6.7% with vitamin D vs. 33% with placebo (p = 0.02, NNT 4)
Reference - OPERA trial (J Am Soc Nephrol 2014 Jan;25(1):175 full-text)
227 patients (mean age 65 years) with CKD randomized to oral paricalcitol (active
vitamin D compound) 2 mcg/day vs. placebo for 48 weeks
inclusion criteria included
estimated glomerular filtration rate of 15-60 mL/minute/1.73 m2
mild-to-moderate left ventricular hypertrophy without asymmetric septal
hypertrophy or valvular disease
left ventricular ejection fraction > 50%
78.8% completed trial, modified intention-to-treat population included all
patients who took ≥ 1 dose of study drug and completed ≥ 2 endpoint
measurements (86%)
change in left ventricular mass index measured by cardiovascular
magnetic resonance imaging
peak early diastolic lateral mitral annular tissue velocity by
echocardiogram
paricalcitol associated with increased rate of hypercalcemia (p < 0.001)
Reference - PRIMO trial (JAMA 2012 Feb 15;307(7):674), editorial can be found
in JAMA 2012 Feb 15;307(7):722, commentary can be found in Int J Cardiol 2013
Sep 1;167(5):2343
vitamin D supplementation may reduce proteinuria but increase risk of

hypercalcemia in patients with chronic kidney disease not on dialysis (level 3
based on nonclinical outcomes from systematic review with incomplete reporting of
trial quality
systematic review of 18 randomized trial comparing vitamin D supplementation to
placebo or no treatment in patients with chronic kidney disease not on dialysis
quality of individual trials not reported
vitamin D supplementation associated with
increased reduction of proteinuria in analysis of 6 trials with 685 patients
risk ratio 2 (95% CI 1.4-2.8)
NNT 3-11, with reduction of proteinuria in 24% of controls
increased risk of hypercalcemia in analysis of 8 trials with 1,378 patients
risk ratio 4.8 (95% CI 2.2-10.4)
NNH 13-104, with hypercalcemia in 0.8% of controls
glomerular filter rate in analysis of 12 trials with 615 patients
need for dialysis in analysis of 4 trials with 740 patients
overall mortality in analysis of 4 trials with 711 patients
risk of adverse events in analysis of 6 trials with 820 patients
antioxidants do not appear to reduce mortality or cardiovascular disease in

based on Cochrane review limited by clinical heterogeneity
systematic review of 10 randomized trials comparing antioxidants vs. placebo, usual
care, or no treatment in 1,979 adults with chronic kidney disease (CKD)
review limited by heterogeneity in interventions and patient populations
antioxidants included vitamin E, coenzyme Q, N-acetylcysteine, bardoxolone
methyl, recombinant human superoxide dismutase, Omnibionta, curcumin plus
quercetin, and combinations of antioxidants
cardiovascular mortality in analysis of 3 trials with 1,323 adults
cardiovascular disease or coronary heart disease in analysis of 4 trials with
1,550 adults
antioxidants (vitamin E, recombinant human superoxide dismutase) associated with
decreased development of end-stage kidney disease (risk ratio 0.5, 95% CI 0.25-1) in
analysis of 2 trials with 404 adults
Reference - Cochrane Database Syst Rev 2012 Oct 17;(10):CD008176
folic acid-based homocysteine lowering does not reduce cardiovascular events in

patients with kidney disease (level 1 [likely reliable] evidence)
based on systematic review
systematic review of 11 randomized trials comparing folic acid-based homocysteine
lowering to control in 10,951 patients with non-dialysis-dependent chronic kidney
disease (CKD), end-stage kidney disease, or functioning kidney transplant
control included placebo, usual care, reduced dose of folic acid (alone or in
combination with vitamin B6 and B12), or reduced dose of vitamin B6 and B12
composite outcome of cardiovascular events (relative risk [RR] 0.97, 95% CI
0.92-1.03) in analysis of 11 trials with 10,963 patients
cardiovascular-related mortality (RR 0.97, 95% CI 0.82-1.16) in analysis of 7
comparisons from 6 trials with 5,968 patients
all-cause mortality (RR 1.02, 95% CI 0.95-1.1) in analysis of 11 comparisons
from 9 trials with 8,772 patients
myocardial infarction (RR 0.96, 95% CI 0.84-1.1) in analysis of 9 comparisons
from 8 trials with 8,586 patients
stroke (RR 0.95, 95% CI 0.75-1.21) in analysis of 9 comparisons from 8 trials
with 8,586 patients
access thrombosis (RR 0.96, 95% CI 0.83-1.11) in analysis of 3 trials
need for renal replacement therapy in patients with non-dialysis-dependent
CKD (RR 1.05, 95% CI 0.95-1.16 in analysis of 2 trials with 1,543 patients) or
functioning kidney transplant (RR 1.12, 95% CI 0.91-1.37 in 1 trial with 4,110
patients)
Reference - BMJ 2012 Jun 13;344:e3533 full-text, editorial can be found in BMJ 2012
Jun 13;344:e3925
high-dose folic acid, vitamin B6, and vitamin B12 supplement may not reduce
all-cause mortality or cardiovascular events in patients with stable kidney
transplant (level 2 [mid-level] evidence)
based on randomized trial with unclear allocation concealment
4,110 patients aged 35-75 years with stable kidney transplant and elevated
homocysteine levels (≥ 1.49 mg/L for women, ≥ 1.62 mg/L for men) were
randomized to high-dose vs. low-dose vitamin B supplement and assessed once
every 6 months
high-dose vitamin B supplement included folic acid 5 mg, vitamin B6 50
mg, and vitamin B12 1 mg
low-dose vitamin B supplement included vitamin B6 1.4 mg, vitamin B12
2 mcg, and no folic acid
mean follow-up was 4 years (range 0-82 months)
trial stopped early after fourth interim analysis due to futility
> 98% of patients included in analysis
no significant difference between groups in
all-cause mortality
dialysis-dependent kidney failure
hospitalizations
groups also were similar for side effects
high-dose B vitamin supplement significantly reduced homocysteine levels vs.
low-dose B vitamin supplement in convenience sample of 143 patients
Reference - Circulation 2011 Apr 26;123(16):1763 full-text, commentaries can
be found in Am J Kidney Dis 2012 Jun;59(6):754 and Nat Rev Nephrol 2011
Jun;7(6):304
no additional trials found in Cochrane review evaluating homocysteine-
lowering therapy in patients with functioning kidney transplants (Cochrane
Database Syst Rev 2015 May 4;(5):CD007910)
folic acid may not reduce cardiovascular adverse events or mortality in patients
with end-stage renal disease (level 2 [mid-level] evidence)
based on Cochrane review of trials with unclear allocation concealment or unclear
blinding of outcome assessors
systematic review of 6 randomized trials evaluating homocysteine-lowering
therapies in 2,452 patients with end-stage renal disease
all trials assessed folic acid with or without other vitamins (vitamin B6, vitamin B12)
folic acid dose ranged from 5 to 40 mg/day
follow-up duration ranged from 2 to 3.6 years
comparing folic acid to control (placebo, usual care, low-dose folic acid), no
significant differences in
myocardial infarction in analysis of 4 trials with 1,510 patients
coronary revascularization in analysis of 2 trials with 1,160 patients
stroke in analysis of 4 trials with 1,510 patients
adverse events in analysis of 3 trials with 1,248 patients
folic acid plus enalapril may reduce risk of progression of CKD compared to
enalapril alone in patients with hypertension (level 2 [mid-level] evidence)
based on prespecified secondary analysis of CSPPT trial with low adherence
20,702 Chinese adults with hypertension and without history of major
cardiovascular disease were randomized to enalapril/folic acid 10 mg/0.8 mg vs.
enalapril 10 mg alone orally once daily for 5 years
secondary analysis included 15,104 Chinese adults (mean age 60, 61% female) with
estimated GFR ≥ 30 mL/minute/1.73 m2, with baseline folate and total homocysteine
levels similar between groups, followed for median of 4.4 years
primary outcome was progression of CKD, defined as any of
decrease in estimated GFR of ≥ 30% and to < 60 mL/minute/1.73 m2 if baseline
estimated GFR was ≥ 60 mL/minute/1.73 m2
decrease in estimated GFR of ≥ 50% if baseline estimated GFR was < 60
mL/minute/1.73 m2
end-stage renal disease
secondary outcome defined as composite of primary outcome and all-cause death,
rapid decline in renal function (mean decline in estimated GFR of ≥ 5
mL/minute/1.73m2 per year, and annual rate of estimated GFR decline)
in 1,671 adults with chronic kidney disease at baseline, compared to enalapril alone,
enalapril plus folic acid associated with decreased risk of
progression of CKD (odds ratio [OR] 0.44, 95% CI, 0.26-0.75)
decline in renal function (OR 0.67, 95% CI 0.47-0.96)
secondary composite outcome (OR 0.62, 95% CI 0.43-0.9)
in all adults, compared to enalapril alone, enalapril plus folic acid associated with
nonsignificant decrease in progression of CKD (OR 0.79, 95% CI, 0.62-1.00)
Reference - JAMA Intern Med 2016 Oct 1;176(10):1443
vitamin E 800 units/day may reduce incidence of myocardial infarction in

hemodialysis patients with cardiovascular disease, but may not affect all-cause
mortality (level 2 [mid-level] evidence)
based on randomized trial with allocation concealment not stated
196 hemodialysis patients aged 40-75 years with preexisting cardiovascular diseases
randomized to vitamin E 800 units/day vs. placebo for median 519 days
comparing vitamin E vs. placebo
composite endpoint (myocardial infarction, ischemic stroke, peripheral
vascular disease, or unstable angina) in 16% vs. 33% (p = 0.014, NNT 6)
myocardial infarction in 5.1% vs. 17.2% (p = 0.016, NNT 9)
all-cause mortality in 31.2% vs. 29.3% (not significant)
no significant differences in adverse effects reported
2 deaths due to hemorrhage occurred in vitamin E group
Reference - SPACE trial (Lancet 2000 Oct 7;356(9237):1213), commentary can be
found in Lancet 2001 Feb 24;357(9256):632
DynaMed commentary -- study has not been validated in a larger study
Supplements for patients on dialysis
Supplement recommendations
European Best Practice Guideline expert opinion based recommendations for

supplements in patients on hemodialysis
thiamine hydrochloride (vitamin B1) 1.1-1.2 mg/day
riboflavin (vitamin B2) 1.1-1.3 mg/day
niacin (vitamin B3) 14-16 mg/day
pantothenic acid (vitamin B5) 5 mg/day
pyridoxine hydrochloride (vitamin B6) 10 mg/day
biotin (vitamin B8) 30 mcg/day
folic acid (vitamin B9) 1 mg/day
cobalamin (vitamin B12) 2.4 mcg/day
ascorbic acid (vitamin C) 75-90 mg/day
vitamin E 400-800 units/day
vitamin D based on phosphorus and calcium levels
give supplemental iron if patient being treated with erythropoietin-stimulating
agents (ESAs)
consider supplemental zinc 50 mg per day for 3-6 months in patients with
chronically poor protein and energy intake and signs of zinc deficiency
consider supplemental selenium for 3-6 months if patient has symptoms of selenium
deficiency
no supplement for the following
vitamin A - daily intake 700-900 mcg recommended
vitamin K - daily intake 90-120 mcg recommended
Reference - Nephrol Dial Transplant 2007 May;22 Suppl 2:ii45 full-text , commentary
can be found in Nephrol Dial Transplant 2008 Feb;23(2):772
Levocarnitine (L-carnitine)
levocarnitine (Carnitor)
for prevention and treatment of carnitine deficiency in patients on dialysis
Initial dose 10-20 mg/kg of dry body weight administered by slow, direct IV injection
over 2-3 minutes into the venous return line after each dialysis session
L-carnitine might improve muscle cramping but may not improve dialysis-related
hypotension (level 2 [mid-level] evidence)
based on systematic review with significant heterogeneity
systematic review of 7 randomized trials comparing L-carnitine vs. placebo in 193
adults with end-stage renal disease receiving long-term hemodialysis
comparing L-carnitine vs. placebo
decreased cramping with L-carnitine in analysis of 6 trials (odds ratio 0.3, 95%
CI 0.09-1.00, p = 0.05)
no significant difference among groups in dialysis-related hypotension in
analysis of 5 studies
Reference - Am J Kidney Dis 2008 Nov;52(5):962
L-carnitine supplementation may not improve response to recombinant human
erythropoietin in patients having hemodialysis (level 3 [lacking direct] evidence)
92 patients having hemodialysis randomized to L-carnitine 1 g IV vs. placebo after
each dialysis session for 1 year
no significant difference in resistance to recombinant human erythropoietin
Reference - CARNIDIAL trial (Clin J Am Soc Nephrol 2012 Nov;7(11):1836 full-text,
editorial can be found at Clin J Am Soc Nephrol 2012 Nov;7(11):1836 )
Fish oil and omega 3 fatty acids
n-3 polyunsaturated fatty acids may reduce risk for myocardial infarction in
chronic hemodialysis patients (level 2 [mid-level] evidence)
based on secondary endpoint in randomized trial with high dropout rate
206 patients having chronic hemodialysis were randomized to n-3 polyunsaturated
fatty acids vs. control pill with olive oil for 2 years
25% of patients discontinued treatment
comparing n-3 polyunsaturated fatty acids vs. control
cardiovascular event or death in 60.2% vs. 57.3% (not significant)
myocardial infarction in 3.9% vs. 12.6% (p = 0.036, NNT 12)
Reference - Clin J Am Soc Nephrol 2006 Jul;1(4):780 full-text
fish oil supplementation might not reduce the risk of cardiovascular events in
patients with new arteriovenous grafts (level 2 [mid-level] evidence)
based on randomized trial with confidence intervals unable to rule out clinically
meaningful differences
201 adults (mean age 63 years) with stage 5 chronic kidney disease requiring new
arteriovenous graft were randomized to fish oil supplement 1 g vs. placebo 4 times
daily beginning 7 days after synthetic arteriovenous graft creation
comparing fish oil supplement vs. placebo at 1 year
≥ 1 cardiovascular event in 9% vs. 18% (p = 0.1) (relative risk 0.52, 95% CI 0.22-
1.17)
cardiovascular 0.39 events vs. 0.95 events per 1,000 access-days (p = 0.02)
≥ 1 reduction in dose or frequency of antihypertensive medications in 64% vs.
42% (p = 0.004)
Reference - FISH trial (JAMA 2012 May 2;307(17):1809 full-text), editorial can be
found in JAMA 2012 May 2;307(17):1859, commentary can be found in Nat Rev
Nephrol 2012 May 22;8(7):373
Vaccinations
Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommendations(3)
give annual influenza vaccine for adults with CKD (KDIGO Level 1, Grade B)
give polyvalent pneumococcal vaccine for adults with estimated glomerular
filtration rate (GFR) < 30 mL/minute/1.73 m2 and patients at high risk of infection
such as patients with nephrotic syndrome, diabetes, or receiving
immunosuppressants (KDIGO Level 1, Grade B) with revaccination within 5 years
(KDIGO Level 1, Grade B)
hepatitis B vaccine for adults at high risk of progression of CKD and estimated GFR <
30 mL/minute/1.73 m2; confirm response with serologic testing (KDIGO Level 1,
Grade B)
evidence for hepatitis B vaccination
hepatitis B vaccines associated with high levels of hepatitis B antibody
seroconversion in patients with CKD (level 3 [lacking direct] evidence) and
possibly reduction in hepatitis B infection (level 2 [mid-level] evidence)
based on Cochrane review of low-quality trials
systematic review of 7 randomized trials evaluating hepatitis B vaccination for
chronic renal failure in 2,137 patients
in analysis of 3 trials with 1,850 patients, plasma derived vaccine associated
with
higher rate of seroconversion (risk ratio [RR] 23, 95% CI 14.39-36.76)
reduction in active hepatitis B infection reported in 2 trials with 539
patients but not in larger trial with 1,311 patients
comparing recombinant vs. plasma derived hepatitis B vaccine in analysis of 2
no significant difference in rate of seroconversion (RR 0.65, 95% CI 0.28-
1.53)
insufficient evidence to determine if one type of vaccine superior at
preventing hepatitis B infection
comparing reinforced recombinant vaccination series vs. 3 recombinant
vaccine inoculations in analysis of 2 trials with 106 patients
no significant difference in rate of seroconversion
insufficient data to determine if one vaccine superior at preventing
hepatitis B infection
Reference - Cochrane Database Syst Rev 2004;(3):CD003775 (review updated
2008 Nov 9)
administration of combination hepatitis A/hepatitis B vaccine (Twinrix) may
increase seroconversion rates compared to hepatitis B vaccine alone in
hemodialysis patients (level 3 [lacking direct] evidence)
98 patients on hemodialysis who were seronegative to hepatitis B virus (HBV)
were randomized to 1 of 2 groups
hepatitis A/hepatitis B vaccine (containing 20 mcg hepatitis B vaccine)
plus hepatitis B vaccine 20 mcg intramuscularly at 0, 1, and 6 months, and
hepatitis B vaccine 40 mcg at month 2
hepatitis B vaccine 40 mcg intramuscularly at 0, 1, 2, and 6 months
seroconversion to hepatitis B at 7 months occurred in 58% with combination
vaccine vs. 38% with hepatitis B vaccine alone (p = 0.02)
no significant differences in adverse events
Reference - Am J Kidney Dis 2010 Oct;56(4):713
intradermal hepatitis B vaccination associated with higher initial rate of
hepatitis B immunity than intramuscular vaccination in patients with CKD, but
no significant difference at 6-60 months (level 3 [lacking direct] evidence)
meta-analysis of 12 controlled trials comparing intradermal vs. intramuscular
vaccination in 640 CKD patients
intradermal route associated with decreased risk of failure to respond to HBV
vaccine at completion of vaccine protocol (odds ratio [OR] 0.36, 95% CI 0.21-
0.62)
no significant differences over follow-up of 6-60 months (OR 1.1, 95% CI 0.47-
2.5)
Reference - Aliment Pharmacol Ther 2006 Aug 1;24(3):497 full-text
Investigational agents
bardoxolone methyl does not decrease risk of end-stage kidney disease or

cardiovascular death and increases risk of heart failure in adults with type 2
diabetes and advanced chronic kidney disease (level 1 [likely reliable] evidence)
based on randomized trial
2,185 adults (mean age 69 years) with type 2 diabetes and stage 4 chronic kidney
disease (CKD) (estimated glomerular filtration rate [GFR] 15 to < 30 mL/minute/1.73
m2) were randomized to bardoxolone methyl 20 mg/day vs. placebo
all patients also received conventional therapy including renin-angiotensin-
aldosterone system inhibitors, insulin or other hypoglycemic agents, and other
cardiovascular medications
56% had history of cardiovascular disease at baseline
median follow-up 9 months
trial terminated early by independent data and safety monitoring board due to
increased rates of cardiovascular adverse events with bardoxolone methyl
comparing bardoxolone methyl vs. placebo
end-stage kidney disease in 4% vs. 4.6% (not significant)
cardiovascular mortality 2.5% vs. 1.7% (not significant)
hospitalization or death from heart failure in 8.8% vs. 5% (p < 0.001, NNH 26)
nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart
failure, or cardiovascular death in 12.8% vs. 7.8% (p < 0.001, NNH 20)
all-cause death in 4% vs. 2.8% (p = 0.1)
any serious adverse events in 33% vs. 27% (no p value reported)
Reference - BEACON trial (N Engl J Med 2013 Dec 26;369(26):2492 full-text), editorial
can be found in N Engl J Med 2013 Dec 26;369(26):2549
bardoxolone methyl appears to increase estimated GFR in the short term in patients
with CKD and type 2 diabetes, but higher doses appear to also increase the albumin
to creatinine ratio (level 3 [lacking direct] evidence)
227 adults (mean age 67 years) with CKD and type 2 diabetes randomized to
bardoxolone methyl (25 mg once daily vs. 75 mg vs. 150 mg) vs. placebo
CKD defined as estimated GFR 20-45 mL/minute/1.73 m2
bardoxolone methyl at each dose associated with significant increase in mean
estimated GFR compared to placebo at 24 and 52 weeks (p < 0.001)
difference in estimated GFR (in mL/minute/1.73 m2) from placebo group at 24
weeks
+8.2 with bardoxolone methyl 25 mg
difference in estimated GFR (in mL/minute/1.73 m2) from placebo group at 52
weeks
bardoxolone methyl 75 mg and 150 mg associated with significant increase in
albumin to creatinine ratio compared to placebo at 24 and 52 weeks
Reference - N Engl J Med 2011 Jul 28;365(4):327 full-text
no additional trials evaluating bardoxolone methyl for CKD found in Cochrane
review (Cochrane Database Syst Rev 2012 Oct 17;(10):CD008176)
febuxostat may reduce decline in estimated GFR in patients with stage 3 or 4 CKD
and asymptomatic hyperuricemia (level 3 [lacking direct] evidence)
based on nonclinical outcome from randomized trial without intention-to-treat
analysis
108 patients ≤ 65 years old with stage 3 or 4 CKD and asymptomatic hyperuricemia
were randomized to febuxostat 40 mg orally once daily vs. placebo for 6 months
febuxostat is xanthine oxidase inhibitor approved for treatment of
hyperuricemia in patients with gout
all patients received antihypertensive medication unless contraindicated and
diuretics when indicated
86% completed treatment and were included in analysis
comparing febuxostat vs. placebo
≥ 10% decline in estimated GFR in 38% vs. 54% (p = 0.004, NNT 7)
mean change in estimated GFR +3.2 mL/minute/1.73 m2 vs. -4.4 mL/minute/1.73
m2 (p = 0.05)
mean reduction in serum uric acid 3.8 mg/dL vs. 0.4 mg/dL (p < 0.001)
treatment-related adverse events (mild diarrhea) reported in 4.4% with febuxostat
Reference - Am J Kidney Dis 2015 Dec;66(6):945 , editorial can be found in Am J
Kidney Dis 2015 Dec;66(6):933
AST-120 (oral adsorbent)
AST-120 may not reduce risk of end-stage kidney disease in patients with CKD
systematic review of 15 randomized trials evaluating oral adsorbents in 1,590
patients with CKD
oral adsorbents are agents that can adsorb and remove biologically active
substances (including uremic toxins) from gastrointestinal tract
oral adsorbents included AST-120 (spherical microgranules made of high-
purity porous carbon), Ai Xi Te (activated medical charcoal), and Niaoduqing
granules (traditional Chinese medicine)
treatment duration ranged from 1 week to 37 months
all trials had ≥ 1 limitation including
unclear or no blinding
small sample size
comparing AST-120 plus routine treatment to routine treatment alone
end-stage kidney disease in analysis of 3 trials with 504 patients
all-cause mortality and health-related quality of life in 1 trial with
460 patients
AST-120 plus routine treatment associated with increased creatinine
clearance in analysis of 2 trials with 486 patients
inconsistent results comparing adverse effects of AST-120 vs. control
no significant difference in adverse effects comparing AST-120 (2.7-9
g/day) vs. black microcrystalline cellulose (placebo) in 1 trial with 157
patients also receiving routine treatment
adverse effects in 13.5% with AST-120 (6 g/day) plus routine treatment vs.
0% with routine treatment alone (p < 0.05, NNH 7) in 1 trial with 473
patients
comparing Ai Xi Te plus routine treatment to routine treatment alone
Ai Xi Te plus routine treatment associated with
increased creatinine clearance in analysis of 2 trials with 169
patients
increased adverse events in 1 trial with 140 patients
effect on mortality, quality of life, and end-stage kidney disease not
reported
addition of Niaoduqing granules to routine treatment significantly increased
creatinine clearance in 1 trial with 34 patients (adverse events not reported)
most commonly reported adverse events were gastrointestinal symptoms
AST-120 may not slow disease progression or reduce mortality in patients with
moderate to severe chronic kidney disease (level 2 [mid-level] evidence)
based on 2 randomized trials with high dropout rate
2,035 patients (mean age 55 years, 59% men) with moderate to severe chronic
kidney disease had standard therapy and were randomized to AST-120 3 g
orally three times daily vs. placebo
1,020 from the EPPIC-1 trial
1,015 from the EPPIC-2 trial
median treatment duration
in EPPIC-1 trial, 102.1 weeks in AST-120 group and 103.3 weeks in placebo
group
in EPPIC-2 trial, 96.3 weeks in AST-120 group and 91.6 weeks in placebo
group
21% did not complete trial and 98.2% of patients included in analysis
no significant differences between groups in
time to renal disease progression (dialysis initiation, kidney
transplantation, and serum creatinine doubling)
mortality
adverse events
in patients treated with placebo, those who had fast estimated glomerular
filtration rate (eGFR) decline (median > 3.51 mL/minute/1.73 m2/year) had
significantly higher risk of hematuria, higher blood pressure, lower age, male
sex, and lower body mass index than those with eGFR decline ≤ 3.51
mL/minute/1.73 m2/year
Reference - EPPIC-1 and EPPIC-2 trials (J Am Soc Nephrol 2015
Jul;26(7):1732 full-text)
addition of Rheum officinale to routine treatment may decrease serum creatinine
and blood urea nitrogen levels in patients with chronic kidney disease (level 3
based on Cochrane review with nonclinical outcomes from randomized trials with
methodologic limitations
systematic review of 9 randomized trials evaluating R. officinale (Da Huang, type of
rhubarb from family Polygonaceae) in 682 patients with CKD
no trials reported allocation concealment or blinding
comparing R. officinale plus routine treatment vs. routine treatment alone
R. officinale associated with
nonsignificant decrease in end-stage kidney disease (risk ratio 0.53, 95%
CI 0.28-1) in analysis of 2 trials with 124 patients
decreased serum creatinine (mean difference -87.49 mcmol/L [-0.99
mg/dL], p = 0.0009) in analysis of 4 trials with 196 patients
decreased blood urea nitrogen (mean difference -10.83 mmol/L [-30.34
mg/dL], p = 0.014) in analysis of 4 trials with 256 patients
creatinine clearance in 1 trial with 30 patients
proteinuria in analysis of 2 trials with 181 patients
all-cause mortality, adverse events, and quality of life not reported
no significant differences in creatinine clearance, blood urea nitrogen, or patient's
ability to work comparing R. officinale vs. captopril (both as adjunct to routine
treatment)
Reference - Cochrane Database Syst Rev 2012 Jul 11;(7):CD008000
addition of Astragalus to conventional treatment may decrease serum creatinine
and proteinuria in patients with CKD (level 3 [lacking direct] evidence)
based on nonclinical outcomes in Cochrane review
systematic review of 22 randomized trials evaluating Astragalus (traditional Chinese
medicine) in 1,323 patients with CKD
all trials evaluated addition of Astragalus to conventional treatment
conventional treatments included dietary control, symptomatic and supportive
treatment (maintaining water, electrolyte and acid-base balance, controlling blood
pressure, treating anemia, and controlling infection when necessary), and Chinese
herbal medicines (Panax notoginseng saponins and Jinshuibao)
results for serum creatinine, proteinuria, and serum albumin limited by significant
heterogeneity
addition of Astragalus to conventional treatment associated with
decreased serum creatinine (mean difference [MD] -21.39 mcmol/L [-0.24
mg/dL], 95% CI -34.78 to -8 mcmol/L [-0.39 to -0.09 mg/dL]) in analysis of 13
results significant in patients with baseline serum creatinine > 133
mcmol/L (1.5 mg/dL) in analysis of 10 trials with 588 patients
no significant difference in patients with baseline serum creatinine < 133
mcmol/L in analysis of 3 trials with 187 patients
increased creatinine clearance (MD 5.75 mL/minute, 95% CI 3.16-8.34
mL/minute) in analysis of 4 trials with 306 patients
decreased proteinuria (MD -0.53 g/24 hours, 95% CI -0.79 to -0.26 g/24 hours) in
increased serum albumin (MD 3.55 g/L [0.52 mcmol/L], 95% CI 2.33-4.78 g/L
[0.34-0.69 mcmol/L]) in analysis of 9 trials with 522 patients
decreased blood pressure in analyses of 2 trials with 77 patients
systolic blood pressure MD -16.65 mm Hg (95% CI -28.83 to -4.47 mm Hg)
diastolic blood pressure MD -6.02 mm Hg (95% CI -10.59 to -1.46 mm Hg)
increased hemoglobin (MD 9.51 g/L [0.951 g/dL], 95% CI 4.9-14.11 g/L [0.49-1.41
g/dL]) in analysis of 4 trials with 222 patients
no adverse events in 6 trials evaluating this outcome
insufficient evidence to determine if prostaglandin E1 (PGE1) can prevent

progression of diabetic kidney disease
based on Cochrane review
systematic review of 6 randomized and quasi-randomized trials evaluating PGE1 for
preventing progression of diabetic kidney disease in 271 patients
PGE1 significantly reduced proteinuria, albuminuria, and urinary albumin
excretion rate compared to control
no data available for all-cause mortality, end-stage kidney disease, or quality of life
Surgery and procedures
Renal transplant
Canadian Society of Transplantation (CST) consensus guidelines on eligibility for kidney

transplant
general considerations
consider kidney transplant in all patients with end-stage kidney disease (CST
Grade A)
eligibility for kidney transplant should be determined on medical and surgical
grounds and should not be determined on (CST Grade C)
social status
sex
ethnicity
personal or public appeal
patient declined for transplant should be considered for a second opinion (CST
Grade C)
timing of referral
refer patient for evaluation by transplant program when kidney replacement
therapy is expected to be required within next 12 months (CST Grade C)
(DynaMed commentary -- evaluation may begin within 6-12 months and may
depend on complexity and rate of progression of the disease)
patients requiring dialysis should have a transplant evaluation when their
clinical condition stabilizes (CST Grade C)
kidney function
preemptive kidney transplant is preferred form of kidney replacement therapy
(CST Grade A)
preemptive kidney transplant should not proceed unless measured or
calculated glomerular filtration rate (GFR) < 20 mL/minute with progressive
and irreversible deterioration in kidney function present over previous 6-12
months (CST Grade C)
DynaMed commentary -- GFR cutoff for evaluation may vary by transplant
center and may depend on complexity and rate of progression of the disease
age and functional capacity
advanced age is not a contraindication to kidney transplant (CST Grade B)
transplant candidates should have reasonable probability of surviving beyond
current waiting times for transplant, considering resources required to assess
and maintain patients on kidney transplant waiting list (CST Grade C)
very young age and small size are not contraindications for early referral for
transplant evaluation (CST Grade B)
cognitive or neurodevelopmental delay not absolute contraindication to
kidney transplant in children (CST Grade B)
comorbidities
patients should be assessed for presence of ischemic heart disease and left
ventricular dysfunction before kidney transplant (CST Grade A)
patients should be without an active infection of any viral, bacterial, or fungal
origin (CST Grade B)
candidates for transplant with a history of malignancy should be tumor-free
before proceeding with transplant (CST Grade A) and may be required to
undergo a waiting period depending on the type of cancer (CST Grade B)
for additional information about comorbidities see the guideline or refer to the
specific transplant center for guidance
Reference - CST consensus guidelines on eligibility for kidney transplant (CMAJ 2005
Nov 8;173(10):1181 full-text), supporting details can be found in CMAJ 2005 Nov
8;173(10):S1 full-text
HLA-incompatible kidney transplant from live donor may increase survival

compared to waiting list with or without transplant from compatible deceased
donor (level 2 [mid-level] evidence)
1,025 adults (mean age 45 years, 67% women) having perioperative desensitization
therapy and human leukocyte antigen (HLA)-incompatible kidney transplant from
live donors were matched to 2 control groups
5,125 patients who remained on waiting list or received transplant from
deceased donor (45.4%)
5,125 patients who remained on waiting list and did not receive transplant
estimated survival (p < 0.001 for overall survival comparing HLA-incompatible
kidney transplants to each control group)
1 Year 3 Years 5 Years 8 Years
HLA-
incompatible
95% 91.7% 86% 76.5%
kidney
transplants
Waiting-list-or-
transplant 94% 83.6% 74.4% 62.9%
controls
Waiting-list-
89.6% 72.7% 59.2% 43.9%
only controls
Abbreviation: HLA, human leukocyte antigen.
consistent results across all donor-specific antibody levels
Reference - N Engl J Med 2016 Mar 10;374(10):940 full-text , editorial can be found in
N Engl J Med 2016 Mar 10;374(10):982
risk for allograft failure appears highest in kidney transplant recipients aged 14 to
16 years
168,809 first-time kidney transplant recipients up to age 55 years in the Organ
Procurement Transplantation Network Standard Transplant Analysis and Research
Database from October 1987 through October 2010 were followed for mean of 6
years
patients with first kidney transplant at age 14 to 16 years were at highest risk of
graft loss, with inferior outcomes beginning at 1 year and amplifying at 3, 5, and 10
years following transplant
black adolescents had disproportionately high risk of graft failure
variables with significant interaction with recipient age
donor type (deceased vs. living)
insurance type (government vs. private)
having private insurance reduced risk of death across all ages
Reference - JAMA Intern Med 2013 Sep 9;173(16):1524, editorial can be found in
JAMA Intern Med 2013 Sep 9;173(16):1533, commentary can be found in Nat Rev
Nephrol 2013 Oct;9(10):556
presence of 2 apolipoprotein L1 gene (APOL1) nephropathy risk variants in African
American kidney donors associated with decreased graft survival
136 kidney transplants from African American deceased donor kidneys were
evaluated
recipients were followed for a mean 22.5 months
25 renal allograft failures occurred
presence of 2 APOL1 risk variants associated with increased risk for graft failure
(hazard ratio 3.84, p = 0.008) in fully adjusted analysis
Reference - Am J Transplant 2011 May;11(5):1025 full-text, commentary can be
found in Am J Transplant 2011 Oct;11(10):2258
mild hypothermia in organ donors may reduce delayed graft function in kidney
recipients (level 2 [mid-level] evidence)
based on randomized trial with high dropout rate
394 organ donors (mean age 45 years, 63% male) were randomized after declaration
of death according to neurologic criteria to mild hypothermia (34-37 degrees C [93.2-
98.6 degrees F]) vs. normothermia (36.5-37.5 degrees C [97.7-99.6 degrees F]) in
intensive care unit until organ recovery
23.4% were excluded or did not have kidney transplanted
572 patients (mean age 53 years, 60% male) received kidney transplant from
remaining 302 donors, including 11 dual kidney recipients
99% of kidney recipients were included in analysis
trial was terminated early after interim analysis based on predefined stopping rule
for treatment success
delayed graft function in kidney recipients was 28.2% with mild hypothermia
donors vs. 39.2% with normothermia donors (p = 0.008, NNT 9)
mild hypothermia associated with significantly reduced delayed graft function in
subgroup analyses of expanded-criteria donors and dual kidney recipients
Reference - N Engl J Med 2015 Jul 30;373(5):405 full-text , editorial can be found in N
Engl J Med 2015 Jul 30;373(5):477
mycophenolic acid may decrease graft loss and acute rejection but may increase
risk of tissue invasive cytomegalovirus infection compared to azathioprine in
patients having kidney transplantation (level 2 [mid-level] evidence)
systematic review of 23 randomized or quasi-randomized trials comparing
mycophenolic acid vs. azathioprine in 3,301 patients having kidney transplantation
all trials had ≥ 1 limitation including
unclear or no allocation concealment
unclear blinding of outcome assessors
mycophenolic acid associated with decreased risk of
graft loss in analysis of 17 trials with 2,540 patients
risk ratio (RR) 0.78 (95% CI 0.62-0.99)
NNT 24-909 with graft loss in 11% of azathioprine group
acute rejection in analysis of 22 trials with 3,301 patients
RR 0.65 (95% CI 0.57-0.73)
NNT 7-11 with acute rejection in 35% of azathioprine group
Pneumocystis carinii or Pneumocystis jiroveci infection in analysis of 5 trials
with 1,650 patients
RR 0.19 (95% CI 0.05-0.69)
NNT 81-249 with P. carinii or P. jiroveci infection in 1.3% of azathioprine
group
new-onset diabetes in analysis of 4 trials with 445 patients
RR 0.57 (95% CI 0.34-0.95)
NNT 10-125 with new-onset diabetes in 16% of azathioprine group
mycophenolic acid associated with increased risk of
tissue invasive cytomegalovirus infection in analysis of 7 trials with 1,510
patients
RR 1.7 (95% CI 1.1-2.61)
NNH 14-232 with tissue invasive cytomegalovirus infection in 4.3% of
azathioprine group
diarrhea in analysis of 11 trials with 2,638 patients
RR 1.55 (95% CI 1.32-1.83)
NNH 10-26 with diarrhea in 12% of azathioprine group
gastrointestinal bleeding in analysis of 2 trials with 575 patients
RR 3.99 (95% CI 1.07-14.86)
NNH 7-1,428 with gastrointestinal bleeding in 1% of azathioprine group
mortality in analysis of 16 trials with 2,987 patients
malignancy in analysis of 5 trials with 1,735 patients
Reference - Cochrane Database Syst Rev 2015 Dec 3;(12):CD007746
addition of mammalian target of rapamycin inhibitors to calcineurin inhibitors may

not reduce acute rejection or mortality and may increase graft loss compared to
addition of mycophenolic acid in kidney transplant patients (level 2 [mid-level]
evidence)
based on systematic review of trials without blinding
systematic review of 11 randomized trials comparing mammalian target of
rapamycin (mTOR) inhibitors to mycophenolic acid (MPA) as primary
immunosuppressive regimen in combination with calcineurin inhibitors (CNI) in
4,930 kidney transplant patients with no additional organ transplantation
mTOR inhibitors were everolimus and sirolimus; MPA comprised either
mycophenolate mofetil or enteric-coated mycophenolate sodium
CNI were tacrolimus and cyclosporin
follow-up ranged from 6 months to 8.5 years
no significant difference in mortality in analysis of 11 trials with 4,630 patients
no significant difference in risk of biopsy-proven acute rejection at 6 months, 1 year,
2 years, or end of follow-up in analyses of 11 trials with 4,630 patients
mTOR inhibitor associated with increased risk of
graft loss (including death with a functioning graft) in analysis of 11 trials with
4,630 patients
risk ratio 1.2 (95% CI 1.02-1.4)
NNH 13-454 with 11% graft loss in MPA group
inferior graft function assessed by creatinine clearance (mean difference -2.41
mL/min, 95% CI -4.55 to -0.26 mcmol/L) in analysis of 6 trials with 2,177
patients
new-onset diabetes mellitus in analysis of 10 trials with 3,550 patients
risk ratio 1.32 (95% CI 1.07-1.62)
3 trials report increased risk in patients treated with high dose mTOR
inhibitor (compared to low dose)
peripheral edema (risk ratio 1.34, 95% CI 1.08-1.68) in analysis of 5 trials with
2,752 patients
mTOR inhibitor associated with decreased risk of
cytomegalovirus infection (risk ratio 0.43, 95% CI 0.29-0.63) in analysis of 11
malignancy in analysis of 8 trials with 4,250 patients
risk ratio 0.64 (95% CI 0.45-0.91)
NNT 51-309 with 3.6% malignancy in MPA group
no significant differences in diarrhea, anemia, urinary tract infection, polyoma
virus infection, and impaired wound healing
Reference - BMC Nephrol 2015 Jul 1;16:91 full-text
C. sinensis-based and azathioprine-based immunosuppressant therapy associated

with similar acute graft rejection rates and 1-year graft survival in kidney
transplant recipients (level 2 [mid-level] evidence)
based on systematic review of trials with unclear allocation concealment or
blinding
systematic review of 9 randomized trials evaluating fermented preparations of
Cordyceps sinensis (traditional Chinese medicine) in 907 kidney transplant
recipients
C. sinensis dose ranged from 3 to 12 g/day, follow-up ranged from 15 days to 2 years
4 trials compared addition of C. sinensis vs. azathioprine to immunosuppressant
therapy with cyclosporine A and prednisolone
comparing C. sinensis-based vs. azathioprine-based immunosuppressant therapy, no
significant differences in
acute graft rejection rates in analysis of 3 trials with 197 patients
1-year graft survival in analysis of 4 trials with 244 patients
all-cause mortality at 1 year in 1 trial with 34 patients
Reference - Complement Ther Med 2017 Feb;30:84
black race, increased donor age, and delayed graft function may be associated with
adverse two-year outcomes in patients with kidney transplant (level 2 [mid-level]
evidence)
833 de novo kidney transplant patients from randomized trial comparing
everolimus plus reduced cyclosporine vs. mycophenolic acid plus standard
cyclosporine were analyzed
endpoint was composite of biopsy proven acute rejection, graft loss, death, or loss to
follow-up
at 12 months, increased risk of composite endpoint associated with
black race (hazard ratio [HR] 1.68, 95% CI 1.08-2.6)
increasing donor age (HR 1.01, 95% CI 1-1.3)
delayed graft function (HR 2.75, 95% CI 1.82-4.16)
consistent results at 24 months
significantly reduced risk of composite endpoint at 12 months associated with
female gender and < 3 HLA mismatches
Reference - Clin Nephrol 2015 Jun;83(6):338
switching to everolimus from CNI does not appear to improve renal function in
patients with kidney transplant (level 3 [lacking direct] evidence)
based on nonclinical outcomes from randomized trial without blinding
93 patients with kidney transplant taking CNI for maintenance were randomized to
convert to everolimus vs. maintain CNI-based immunosuppression for 1 year
trial had inadequate statistical power for difference in estimated glomerular
filtration rate (GFR) due to early termination for slow recruitment
mean posttransplant time was 83.5 months with everolimus and 70.1 months with
CNI
at 1 year, adjusted estimated GFR was 61.6 mL/minute/1.73 m2with everolimus vs.
58.8 mL/minute/1.73 m2 with CNI (not significant)
discontinuation due to adverse events in 32.6% of patients with everolimus vs.
10.6% with CNI (no p value reported)
Reference - APOLLO trial (Clin Nephrol 2015 Jan;83(1):11)
antiviral treatment before and after kidney transplant from hepatitis C virus (HCV)
positive donor to HCV negative recipient reported to prevent chronic HCV infection
(level 3 [lacking direct] evidence)
based on uncontrolled trial
10 kidney transplant candidates > 50 years old (median age 71 years) without HCV
infection, and no living donors, received kidneys from deceased HCV-positive
donors aged 13-50 years old
all recipients were receiving hemodialysis or peritoneal dialysis or had GFR < 15
mL/min/ 1.73 m2 for ≥ 90 days
immediately before transplantation, all recipients received 1 dose of grazoprevir
100 mg plus elbasvir 50 mg
if donor with genotype 1 infection, recipients continued grazoprevir 100 mg
plus elbasvir 50 mg for 12 weeks
if donor with genotype 2 or 3 infection, recipients had sofosbuvir 400 mg in
addition to grazoprevir 100 mg plus elbasvir 50 mg for 12 weeks
4 recipients had delayed graft function within 7 days of transplantation
at 12 weeks after transplantation
no recipients had detectable HCV RNA
no recipients required reoperation
no recipients had acute rejection
5 recipients had reactive HCV antibody test
Reference - Ann Intern Med 2018 Apr 17;168(8):533
5-year overall survival 74% and 5-year graft survival 84% in case series of 27 HIV-positive
patients on antiretroviral therapy who had kidney transplant from HIV-positive deceased
donors (N Engl J Med 2015 Feb 12;372(7):613 full-text , editorial can be found in N Engl J
Med 2015 Feb 12;372(7):663)
review of preoperative care of patients with kidney disease can be found in Am Fam
Physician 2002 Oct 15;66(8):1471 full-text
Consultation and referral
refer to specialist kidney care services for patients with CKD and any of (KDIGO Level 1,
Grade B)(3)
acute kidney injury or abrupt sustained fall in glomerular filtration rate (GFR)
GFR < 30 mL/minute/1.73 m2 (GFR categories G4 and G5)
consistent evidence of significant albuminuria (albumin to creatinine ratio ≥ 300
mg/g [≥ 30 mg/mmol] or albumin excretion rate ≥ 300 mg/24 hours, approximately
equivalent to protein to creatinine ratio ≥ 500 mg/g [≥ 50 mg/mmol] or protein
excretion rate ≥ 500 mg/24 hours)
progression of CKD
urinary red cell casts, red blood cell > 20 per high power field sustained and not
readily explained
hypertension refractory to treatment with ≥ 4 antihypertensive agents
persistent serum potassium abnormalities
recurrent or extensive nephrolithiasis
hereditary kidney disease
timely referral for renal replacement therapy planning recommended for patients with
progressive chronic kidney disease (CKD) and 1-year risk of kidney failure ≥ 10%-20%
using validated risk prediction tools (KDIGO Level 1, Grade B)(3)
early referral to nephrologist associated with reduced mortality (level 2 [mid-level]
evidence)
based on 2 systematic reviews of cohort studies
early referral to nephrologist may reduce mortality and length of hospital stay
in adults with CKD (level 2 [mid-level] evidence)
based on Cochrane review of observational studies
systematic review of randomized or quasi-randomized trials and cohort
studies comparing early vs. late referral to nephrologist in adults with CKD
40 cohort studies with 63,887 adults met inclusion criteria
early referral defined as first nephrology consultation > 1-6 months prior to
initiation of dialysis and late referral defined as < 1-6 months prior to starting
dialysis
no significant differences between early or late referrals regarding prevalence
of diabetes, ischemic heart disease, peripheral vascular disease, heart failure,
chronic obstructive pulmonary disease, and cerebrovascular disease
early referral to nephrologist associated with
reduced mortality at 1 year in analysis of 16 studies with 23,238 adults
risk ratio 0.65 (95% CI 0.62-0.69)
NNT 11-13 with 25% mortality at 1 year in late referral group
benefits reported regardless of definition of early referral (> 1
month, > 3 months, and > 6 months prior to start of dialysis),
greatest effect size with early referral at > 6 months prior to start of
dialysis
shorter hospital stay (mean difference -9.12 days, 95% CI -10.92 to -7.32
days) in analysis of 6 studies with 1,592 adults
early referral may be associated with improved outcomes in patients with CKD
based on systematic review of cohort studies with heterogeneity and without
clear definitions of "early" and "late" referral
systematic review of 22 cohort studies with 12,018 patients analyzing outcomes
in patients with CKD referred to nephrologist early vs. late (definition of timing
varied from study to study)
comparing early referral vs. late referral
overall mortality 11% vs. 23% (p < 0.0001, NNT 9)
1-year mortality 13% vs. 29% (p = 0.028, NNT 9)
mean hospital stay at initiation of renal replacement therapy 13.5 days vs.
25.3 days (p = 0.0007) in 8 studies with 3,330 patients
Reference - Am J Med 2007 Dec;120(12):1063 , commentary can be found in Am
J Med 2008 Jun;121(6):e17
DynaMed commentary -- authors did not clearly describe and analyze what is
meant by "early" and "late" referral in the cohort studies; authors state
"definition varied from study to study, with late referral < 3 months before
initiation of renal replacement therapy associated with highest cumulative
mortality"
absence of visit with nephrologist > 90 days prior to dialysis initiation associated
increased mortality within 1 year of dialysis initiation (level 2 [mid-level] evidence)
3,014 New Jersey Medicaid and Medicare patients diagnosed with renal disease ≥ 12
months before starting maintenance dialysis were included
absence of visit with nephrologist > 90 days prior to dialysis initiation associated
with risk ratio 1.37 (95% CI 1.22-1.52) for mortality within 1 year of dialysis
initiation
Reference - Arch Intern Med 2002 Sep 23;162(17):2002
consistent outpatient nephrologic care associated with improved survival in
patients with CKD and diabetes (level 2 [mid-level] evidence)
39,031 Veterans Affairs clinic users with stage 3 or 4 CKD and diabetes were
evaluated
compared to patients with 0 nephrologist visits, lower mortality observed in
patients with
2 visits (adjusted hazard ratio [HR] 0.8, 95% CI 0.67-0.97)
3 visits (adjusted HR 0.68, 95% CI 0.55-0.86)
4 visits (adjusted HR 0.45, 95% CI 0.32-0.63)
no significant differences in mortality comparing patients with 1 visit vs. 0 visits
Reference - Arch Intern Med 2008 Jan 14;168(1):55
review of preventing late referral of patients with CKD can be found in Mayo Clin Proc
2006 Nov;81(11):1487, correction can be found in Mayo Clin Proc 2007 Feb;82(2):250,
editorial can be found in Mayo Clin Proc 2006 Nov;81(11):1420, commentary can be found
in Mayo Clin Proc 2007 Feb;82(2):252
reporting of estimated GFR to patient associated with increase in first nephrologist visits
among patients with more severe kidney dysfunction, women, middle-aged, and very
elderly patients, and those with comorbidities (JAMA 2010 Mar 24;303(12):1151),
commentary can be found in JAMA 2010 Mar 24;303(12):1201
Other management
Renal replacement therapy
National Kidney Foundation guidelines on patient preparation for permanent vascular

access
educate patients about different modalities of renal replacement therapy when
glomerular filtration rate < 30 mL/minute/1.73 m2 (stage 4 chronic kidney disease
[CKD]) (NKF Grade A)
in patients with chronic kidney disease stage 4 or 5, avoid venipuncture or placing
IV catheters, subclavian catheters, or peripherally inserted central catheter lines in
forearms or upper-arm veins suitable for vascular access (NKF Grade B)
prior to placing hemodialysis access, perform the following patient evaluations
history and physical exam (NKF Grade B)
duplex ultrasound of upper-extremity arteries and veins (NKF Grade B)
central vein evaluation if patients with pacemaker or prior catheter (NKF
Grade A)
timing
place fistula ≥ 6 months before anticipated start of hemodialysis to allow for
evaluation of access and function of fistula (NKF Grade B), ideal access
parameters include
flow of 600 mL/minute
< 0.6 cm below skin surface
≥ 0.6 cm diameter
place graft ≥ 3-6 weeks before hemodialysis (NKF Grade B)
place peritoneal dialysis catheter ≥ 2 weeks prior to peritoneal dialysis (NKF
Grade B)
Reference - National Kidney Foundation 2006
see also Dialysis for end-stage renal disease

review of preparation for renal replacement therapy can be found in Postgrad Med 2002
Jun;111(6):97
Dialysis
timing of starting dialysis

consider starting dialysis when ≥ 1 of the following occur (usually when estimated
glomerular filtration rate [GFR] 5-10 mL/minute/1.73 m2) (KDIGO Level 2, Grade B)
signs or symptoms of renal failure such as serositis, acid-base disturbances,
electrolyte abnormalities, or pruritus
inability to control volume status
inability to control blood pressure
malnutrition not responsive to dietary interventions
cognitive impairment
earlier initiation of dialysis does not appear to increase survival in adults with
chronic kidney disease (CKD) (level 2 [mid-level] evidence)
early start of dialysis associated with increased mortality in patients without
diabetes or other comorbidities (level 2 [mid-level] evidence)
vascular access may be achieved with arteriovenous fistulas (preferred) or arteriovenous
grafts (catheter should be avoided for hemodialysis if possible)
both surgical procedures create anastomosis between radial artery and neighboring
vein
central venous catheter access associated with increased all-cause mortality and
fatal infection compared to arteriovenous fistula or graft (level 2 [mid-level]
evidence)
arteriovenous graft may have higher mortality and infection rates compared to
arteriovenous fistula (level 2 [mid-level] evidence)
brachiobasilic and brachiocephalic arteriovenous fistulas have similar patency rates
and risk of complications (level 1 [likely reliable] evidence)
early endovascular or surgical treatment of nonmaturing arteriovenous fistulas
associated with high rate of success at producing fistula patency (level 2 [mid-level]
evidence)
antiplatelet therapy may reduce risk of access failure in arteriovenous fistulae and
might reduce risk in arteriovenous grafts (level 2 [mid-level])
hemodialysis dosage and frequency
minimum frequency is 3 times/week for at least 3 hours/session unless patient
retains significant residual kidney function
minimally adequate dose of hemodialysis given 3 times/week to patients with
residual urea clearance < 2 mL/minute/1.73 m2 should be
delivered single-pool Kt/V (spKt/V) (excluding residual kidney function) 1.2 per
dialysis
alternative minimum dose is urea reduction ratio (URR) 65% for treatment
time < 5 hours
hemodialysis 6 times/week may improve control of hypertension and
hyperphosphatemia, improve left ventricular mass, and possibly improve physical
health, but may increase need for vascular access interventions (level 2 [mid-level]
evidence)
preventing infections related to hemodialysis
antibiotics may reduce risk of infections in long-term hemodialysis patients with
central venous catheters (level 2 [mid-level] evidence)
use of antibiotic locking solution may reduce incidence of catheter-related
infections (level 2 [mid-level] evidence)
use of dedicated dialysis machines for hepatitis C virus (HCV) may reduce HCV
transmission (level 2 [mid-level] evidence)
hepatitis B vaccine indicated for persons with end-stage renal disease, including
patients receiving hemodialysis
peritoneal dialysis
dialysate fluid is placed in peritoneal cavity through a catheter and peritoneal
membrane used as semipermeable dialyzing membrane
over time, the peritoneal membrane may become damaged and the efficacy of
peritoneal dialysis may decline
reported benefits of peritoneal dialysis include in-home treatment option with
promotion of patient autonomy and independence, slower decline in residual
kidney function, and lower cost than hemodialysis in most countries
peritoneal dialysis and hemodialysis associated with similar survival for patients
with end-stage renal disease in cohort studies (level 2 [mid-level] evidence), but
insufficient evidence comparing peritoneal dialysis vs. hemodialysis from
randomized trials
dosing for peritoneal dialysis
in patients with residual kidney function (urine volume > 100 mL/day),
minimal delivered dose of total small-solute clearance should be total
(peritoneal and kidney) Kt/V of 1.7 per week
in patients without residual kidney function (urine volume ≤ 100
mL/day), minimal delivered dose of total small-solute clearance should be
a peritoneal Kt/V of 1.7 per week
numerous antibiotic strategies may reduce peritoneal catheter-related exit-site or
tunnel-site infections (level 2 [mid-level] evidence), but efficacy for preventing
peritonitis is uncertain
International Society of Peritoneal Dialysis guideline for treating peritoneal dialysis-
related infections recommends
presuming peritonitis if cloudy effluent; confirm with effluent cell count,
differential and culture
starting empiric antibiotics that cover both gram-positive and gram-negative
organisms as soon as possible
consider both complications of the dialysis procedure itself as well as complications of
end-stage renal disease
see Dialysis for end-stage renal disease for details
Weight loss interventions
surgical and nonsurgical weight loss interventions associated with improvement in

CKD related outcomes (level 3 [lacking direct] evidence)
systematic review of 13 studies evaluating benefits of weight loss intervention (diet,
exercise, and/or obesity agents) in 484 adults with non-dialysis-dependent CKD
mean follow-up 7 months
nonsurgical weight loss (significant decrease in body mass index [BMI]) associated
with decrease in
systolic blood pressure (p < 0.001) in analysis of 3 studies
proteinuria (p = 0.001) in analysis of 4 studies
surgical weight loss (significant decrease in BMI) in morbidly obese patients (BMI ≥
40 kg/m2) with glomerular hyperfiltration (GFR > 125 mL/minute) associated with
decrease in systolic blood pressure (p < 0.001) in analysis of 3 studies
normalization of GFR (p < 0.0001) in analysis of 3 studies
Reference - Clin J Am Soc Nephrol 2009 Oct;4(10):1565 full-text
bariatric surgery may improve estimated glomerular filtration rate in patients with
type 2 diabetes, particularly those with stage 3 chronic kidney disease (level 3
based on retrospective cohort study without clinical outcomes
388 adults with type 2 diabetes evaluated
163 treated with bariatric surgery and followed for mean 3 years (mean age 48
years, mean baseline body mass index [BMI] 50.8 kg/m2)
225 treated with routine care without bariatric surgery and followed for mean
2.5 years (mean age 57 years, mean BMI 33.7 kg/m2)
comparing patients with bariatric surgery vs. usual care
in total study population
mean baseline estimated glomerular filtration rate (eGFR) 86.5 vs. 86.1
mL/minute/1.73 m2 (not significant)
mean study end eGFR 88.8 vs. 81 mL/minute/1.73 m2 (p = 0.001)
mean change in eGFR from baseline 2.3 vs. -5.1 mL/minute/1.73 m2 (p <
0.001)
in subgroup of 56 patients (15 with bariatric surgery, 41 with routine care)
with stage 3 chronic kidney disease characterized by baseline eGFR ≤ 60
mL/minute/1.73 m2
mean baseline eGFR 47.9 vs. 46.9 mL/minute/1.73 m2 (not significant)
mean study end eGFR 60.7 vs. 41.5 mL/minute/1.73 m2 (p < 0.001)
mean change in eGFR from baseline 12.8 vs. -5.2 mL/minute/1.73 m2 (p <
0.001)
Reference - Surg Obes Relat Dis 2016 Dec;12(10):1883
Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding may each
improve estimated glomerular filtration rate, but Roux-en-Y gastric bypass
associated with increased remission of hypertension and diabetes compared to
laparoscopic adjustable gastric banding (level 3 [lacking direct] evidence)
461 patients (mean age 42 years, 79% female) had Roux-en-Y gastric bypass (RYGB)
or laparoscopic adjustable gastric banding (LAGB) and were followed for 5 years
renal impairment defined as creatinine clearance and estimated glomerular
filtration rate (eGFR) < 60 mL/minute/1.73 m2 based on Modification of Diet in
Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration,
and Cockcroft-Gault formulae
hypertension defined as systolic blood pressure ≥ 140 mm Hg and/or diastolic
blood pressure ≥ 90 mm Hg based on European Society of Hypertension and
European Society of Cardiology joint guidelines
diabetes defined as fasting blood glucose ≥ 7.0 mmol/L and HbA1c > 48
mmol/mol based on American Diabetes Association
RYGB group had significantly higher incidence of diabetes, systolic hypertension,
body mass index (BMI), and age at baseline
RYGB and LABG associated with significant improvement in eGFR over 5 years and
creatinine clearance at 1 year from baseline
comparing RYGB vs. LAGB in subgroup analysis of patients with hypertension
remission of hypertension at
1 year in 32% vs. 16% (p = 0.02)
5 years in 23% vs. 11% (p = 0.03)
remission of diabetes at 1 year in 59% vs. 36% (p = 0.006)
Reference - Obes Surg 2017 Mar;27(3):613
dietary weight loss interventions associated with improvements in estimated

glomerular filtration rates in patients with stage III chronic kidney disease (level 3
based on post hoc analysis of DIRECT randomized trial
322 adults (mean age 51 years) with BMI ≥ 27 kg/m2 or with coronary artery disease
or diabetes were randomized to 1 of 3 diets and followed for 2 years
low carbohydrate, restricted calorie diet
Mediterranean, restricted calorie diet
low fat, restricted calorie diet
99 patients had chronic kidney disease stage III at baseline
patients with CKD stage III in all 3 groups had increased estimated glomerular
filtration rate (GFR)
with low carbohydrate diet, change in estimated GFR +5.3% (95% CI 2.1–8.5)
with Mediterranean diet, change in estimated GFR +5.2% (95% CI 3.0–7.4)
with low-fat diet, change in estimated GFR +4% (95% CI 0.9–7.1)
change from baseline was significant in all groups
Reference - Diabetes Care 2013 Aug;36(8):2225 full-text
Follow-up
Kidney Disease Improving Global Outcomes (KDIGO) recommended monitoring
frequency
Monitoring:
Guide to Frequency of Monitoring (number of times per year) by GFR and
Albuminuria Category
Persistent Albuminuria
Categories, Description, and Range
A1 A2 A3
Normal to
Moderately Severely
mildly
increased increased
increased
< 30 mg/g 30-300 mg/g > 300 mg/g
<3 3-30 > 30

mg/mmol mg/mmol mg/mmol
Normal or 1 time per 1 time per 2 times per
G1 ≥ 90
high year if CKD year year
Mildly 1 time per 1 time per 2 times per
G2 60-89
decreased year if CKD year year
Mild to
1 time per 2 times per 3 times per
GFR G3a moderately 45-59
year year year
Categories*, decreased
Description, Moderately
and Range G3b 2 times per 3 times per 3 times per
to severely 30-44
year year year
decreased
Severely 3 times per 3 times per ≥ 4 times
G4 15-29
decreased year year per year
Kidney ≥ 4 times ≥ 4 times ≥ 4 times
G5 < 15
failure per year per year per year
Abbreviation: CKD, chronic kidney disease; GFR, glomerular filtration rate.
* mL/minute/1.73 m2.
used with permission from KDIGO 2012 clinical practice guideline for the evaluation
and management of chronic kidney disease (CKD) (KDIGO (2011) 2013 Jan PDF)
Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for
monitoring for chronic kidney disease–mineral and bone disorder (CKD-MBD)
monitor serum levels of calcium, phosphorus, parathyroid hormone (PTH), and
alkaline phosphatase activity in adults with CKD stage 3 or higher (KDIGO Level 1,
Grade C)
in patients with CKD stages 3-5D, it is reasonable to determine monitoring intervals
for serum calcium, phosphate, and PTH based on the presence and magnitude of
abnormalities, and rate of progression of CKD (KDIGO Not Graded)
options for monitoring intervals for biochemical abnormalities
in stage 3, serum calcium and phosphorus, every 6-12 months and PTH based
on baseline level and CKD progression
in stage 4, serum calcium and phosphorus, every 3-6 months and PTH, every 6-
12 months
in stage 5 including stage 5 on dialysis, serum calcium and phosphorus, every
1-3 months and for PTH, every 3-6 months
in stages 4-stage 5 on dialysis, alkaline phosphatase activity, every 12 months,
or more frequently in the presence of elevated PTH
in stages 3-stage 5 on dialysis, 25-hydroxyvitamin D (25-[OH]D) (calcidiol)
levels might be measured, and repeated testing determined by baseline values
and therapeutic interventions (KDIGO Level 2, Grade C)
monitoring for bone disease
in stage 3-stage 5D, consider, bone biopsy if definitive knowledge of the type of
renal osteodystrophy will impact treatment decisions (KDIGO Not Graded)
in stage 3-stage 5D, consider, measurements of serum PTH or bone-specific
alkaline phosphatase to evaluate bone disease because markedly high or low
values predict underlying bone turnover (KDIGO Level 2, Grade B)
diagnosing vascular calcification
in stage 3-stage 5D, lateral abdominal radiograph can be used to detect
vascular calcification, and echocardiogram can be used to detect valvular
calcification (KDIGO Level 2, Grade C)
in stage 3-stage 5D, patients with vascular and/or valvular calcifications should
be considered highest risk for cardiovascular events (KDIGO Level 2, Grade A)
Reference - KDIGO clinical practice guideline on chronic kidney disease–mineral
and bone disorders (CKD-MBD) (KDIGO 2017 Jul PDF), executive summary can be
found in Kidney Int 2017 Jul;92(1):26 full-text
regularly monitor hemoglobin levels in patients with chronic kidney disease (CKD)
without known anemia
at least annually in patients with CKD grade 3
at least twice per year in patients with CKD grade 4 or grade 5 if not on dialysis
at least every 3 months in patients with CKD grade 5 on either hemodialysis or
peritoneal dialysis
Reference - Blood Rev. 2010 Jan;24(1):39-47, KDIGO 2012 Aug PDF
Complications and Prognosis

Complications
chronic kidney disease (CKD) is associated with dysregulation in many homeostatic

processes, leading to complications such as anemia, bone disease, hypertension and
hypervolemia, acid-base and electrolyte abnormalities, cardiovascular disease,
depression, neurological complications, calciphylaxis, and uremia (Nat Rev Dis Primers.
2017 Nov 23;3:17088)
complications of CKD may include
anemia
approximately 50% prevalence of anemia in patients with chronic kidney
disease (CKD) (prevalence increases with increasing disease stage)
mainly due to erythropoietin deficiency resulting from tubulointerstitial
fibrosis and compromised renal erythropoietin synthesis
other contributing factors may include inhibition of erythropoiesis by uremic
toxins, shortened red blood cell survival, iron deficiency, folate or vitamin B12
deficiency, and severe hyperparathyroidism
associated with poor outcomes, including increased morbidity and mortality
and incidence of cardiovascular disease, higher rates of hospital admission,
reduced quality of life, and cognitive impairment
treatment may include erythropoiesis-stimulating agents (ESAs) and/or iron
therapy
Reference - Nat Rev Dis Primers. 2017 Nov 23;3:17088
mineral and bone disorders
chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic
disorder of mineral and bone metabolism due to CKD
occurs in the majority of untreated patients with CKD stage 3-5 and
almost all patients with CKD stage 5 who require dialysis
manifested as ≥ 1 of the following
abnormalities of calcium, phosphorous, parathyroid hormone, or
vitamin D metabolism
abnormalities of bone turnover, mineralization, volume, linear
growth, or strength
vascular or other soft tissue calcifications
renal osteodystrophy is alteration in bone morphology in patients with CKD
mild increase in bone turnover and normal mineralization
osteitis fibrosa - increased turnover and normal mineralization
mixed renal osteodystrophy - increased turnover and abnormal
mineralization
osteomalacia - decreased bone turnover and abnormal mineralization
adynamic bone - decreased bone turnover and acellularity
types of hyperparathyroidism related to kidney disease
secondary hyperparathyroidism - up to 90% of untreated patients with
CKD reported to develop secondary hyperparathyroidism by the time
dialysis is started
tertiary hyperparathyroidism - most commonly occurs after renal
transplant and in dialysis patients with poorly controlled mineral bone
metabolism
References -
KDIGO 2009 Aug PDF
Surg Clin North Am 2009 Oct;89(5):1227 full-text
hypertension and hypervolemia
hypertension is the most common comorbidity affecting patients with CKD
typically a consequence and not a cause of CKD, though presence of
hypertension may accelerate further kidney injury
can be present in the earliest stages of CKD and contributes to
cardiovascular morbidity and mortality
reported in 67% to 92% of patients with CKD, with increasing prevalence
as kidney function declines
typically results from neurohumoral activation (including the renin
angiotensin aldosterone system), hypervolemia, or corticosteroids or
calcineurin inhibitors used to treat underlying kidney disease
treatment of hypertension is a central component of CKD management to
prevent cardiovascular disease
hypervolemia is increased accumulation of fluid resulting from derangement
of sodium and water handling
can be overt or occult and may become evident at any stage of CKD
may manifest as
arterial hypertension
edema
shortness of breath
risk is increased with defects in urine concentration
References -
Nat Rev Dis Primers. 2017 Nov 23;3:17088
Hypertension 2018 Jun;71(6):e13
acid-base and electrolyte abnormalities
severity and prevalence of metabolic acidosis in patients with CKD reported to
progressively rise with decline in glomerular filtration rate (GFR)
both hyperkalemia and hypokalemia are associated with poor clinical
outcomes in patients with CKD
hyponatremia, hypernatremia, and volume overload increase risk for
mortality and poor outcomes in ambulatory and hospitalized patients with
chronic kidney disease
References -
Adv Chronic Kidney Dis 2017 Sep;24(5):315
Adv Chronic Kidney Dis 2016 Jul;23(4):240
KDIGO (2011). 2013 Jan PDF
cardiovascular disease (CVD)
mild to moderate degrees of renal impairment reported to increase risk of CVD
consider all patients with CKD to be at increased risk for cardiovascular
disease (KDIGO Level 1, Grade A)
cardiovascular complications may include
atherosclerosis (in early stages of CKD G1–G2)
vascular wall degeneration from inflammatory factors and media
calcification (later stages of CKD)
left ventricular hypertrophy, dilatation, and systolic and diastolic
dysfunction
atrial fibrillation
cardiorenal syndrome
References -
Nat Rev Dis Primers. 2017 Nov 23;3:17088
KDIGO. 2017 Jul PDF
Prim Care. 2008 Jun;35(2):329-44, vii full-text
neurological complications may include
depression affects approximately one-quarter of adults with CKD
manual acupressure and transcutaneous electrical acupoint stimulation
may reduce depressive symptoms in patients with chronic kidney disease
stage 3-5 receiving hemodialysis (level 2 [mid-level] evidence)
sertraline may not improve symptoms of depression in adults with
chronic kidney disease stage 3-5 and major depressive disorder (level 2
uremic encephalopathy
uremic polyneuropathy
uremic myopathy
central pontine myelinolysis from rapid correction of hyponatremia
References -
Handb Clin Neurol 2014;119:383
Kidney Int 2013 Jul;84(1):179
J Nephrol 2012 Mar-Apr;25(2):170
pruritus
chronic kidney disease-associated pruritus (CKD-aP) is itching that is directly
related to kidney disease, without another comorbid condition (such as a
comorbid liver or skin condition that includes itching)
treatments include
topical creams, ointments, or lotions
systemic medications such as gabapentin, antihistamines, or opioid-
receptor modulators
phototherapy
acupuncture
References -
Int J Nephrol Renovasc Dis 2017;10:11
Semin Nephrol 2015 Jul;35(4):383
calciphylaxis
form of calcific arteriolopathy leading to ischemia
characterized by calcification, microthrombosis, and fibrointimal hyperplasia
of small dermal and subcutaneous arteries and arterioles
clinical presentation includes cutaneous symptoms such as subcutaneous
nodules and infiltrated plaques initially, then purpuric and livedo-like lesions,
and at later stages development of progressive necrotic ulcers and severe pain
References -
Am J Kidney Dis 2015 Jul;66(1):133 full-text
Indian J Dermatol 2013 Mar;58(2):87 full-text
uremia
signs and symptoms of uremia can vary widely between patients and types of
renal disease
common clinical features of uremia include
neural and muscular features such as fatigue, decreased mental acuity,
anorexia and nausea, restless legs, defective taste and smell, peripheral
neuropathy, and sleep disturbances
endocrine and metabolic features such as amenorrhea and sexual
dysfunction, insulin resistance, reduced resting energy expenditure, and
increased protein/muscle catabolism
other features such as pruritus, decreased red cell survival, platelet
dysfunction, and oxidant stress
Reference - J Am Soc Nephrol 2014 Oct;25(10):2151 full-text
other potential complications include
malnutrition
anorexia, nausea, and vomiting
dyslipidemia
cancer
reproductive/sexual dysfunction
References -
Lancet 2017 Mar 25;389(10075):1238
KDIGO (2011) 2013 Nov PDF
Postgrad Med. 2002 Feb;111(2):115-22
treatment recommendations for adult patients with nondialysis-dependent chronic
kidney disease (CKD)
for treatment of anemia, consider
erythropoiesis-stimulating agents (ESAs) if hemoglobin concentration is < 10
g/dL
iron supplementation for those on ESA therapy and with evidence of iron
deficiency
see Anemia of chronic kidney disease for details
for treatment of mineral and bone disorders, consider
correction of vitamin D deficiency and insufficiency based on
recommendations for the general population
lowering elevated phosphate levels toward normal range and avoiding
hypercalcemia
treatment to lower abnormal parathyroid hormone (PTH) levels according to
CKD stage and severity of hyperparathyroidism; options include withholding
calcitriol or vitamin D analogs, lowering PTH with cinacalcet, calcitriol, and/or
vitamin D analogs, and parathyroidectomy
treatment of osteoporosis similar to that for the general population in patients
with CKD stages 1-3 and high risk of fracture
see Chronic kidney disease-mineral and bone disorder (CKD-MBD) for details
treatment of hypertension
encourage lifestyle modifications
treat adults with hypertension and CKD to a blood pressure goal of < 130/80
mm Hg
in adults with hypertension and CKD (stage 3 or higher or stage 1 or 2 with
albuminuria [≥ 300 mg/day or albumin-to-creatinine ratio ≥ 300 mg/g or
equivalent in first morning void]), consider treatment with an angiotensin
converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) to
slow kidney disease progression
see Hypertension treatment in patients with chronic kidney disease for details
treatment of acid-base and electrolyte abnormalities
in nondialysis-dependent patients with CKD, treat metabolic acidosis with
sodium bicarbonate
electrolyte abnormalities should be treated with caution in patients with stages
4-5 CKD
see Hyperkalemia, Hypokalemia, Hyponatremia, Hypernatremia and
Metabolic acidosis for details
to reduce cardiovascular risk in patients with dyslipidemia
offer a statin or statin/ezetimibe in adults aged ≥ 50 years with estimated
glomerular filtration rate (eGFR) < 60 ml/minute/1.73 m2
offer statin treatment in adults aged ≥ 50 years with CKD and eGFR ≥ 60
ml/minute/1.73 m2
References -
KDIGO (2011) 2013 Nov PDF
treatment options for pruritus include
topical creams, ointments, or lotions
systemic medications such as gabapentin, antihistamines, or opioid-receptor
modulators
phototherapy
acupuncture
Reference - Semin Nephrol 2015 Jul;35(4):383
treatment options for calciphylaxis include sodium thiosulfate, bisphosphonates,
and cinacalcet (Case Rep Nephrol Dial 2015 Jan-Apr;5(1):77 full-text)
see Complications of chronic kidney disease for details
Prognosis
mortality in patients with chronic kidney disease

risk prediction
12-variable index predicts 5-year mortality in patients with end-stage kidney
disease eligible for transplantation (level 1 [likely reliable] evidence)
Chronic Renal Impairment in Birmingham (CRIB) risk calculator may have
moderate predictive ability for 5-year mortality in patients with stage 3-5
in patients with diabetes, prediction of mortality using Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI) creatinine equation may be more
accurate than with Modification of Diet in Renal Disease (MDRD) study
equation (level 2 [mid-level] evidence)
in patients with acute decompensated heart failure, CKD-EPI creatinine
equation and MDRD study equation may have similar performance for
prediction of all-cause mortality (level 2 [mid-level] evidence)
CKD as risk factor for mortality
low estimated glomerular filtration rate (GFR) and high albumin to creatinine
ratio each associated with increased mortality regardless of age, sex, or
hypertension status
low estimated GFR and high albumin to creatinine ratio each associated
with increased mortality regardless of age
decreasing estimated GFR and increasing albumin to creatinine ratio
each associated with increasing all-cause mortality, cardiovascular
mortality, and end-stage renal disease regardless of sex
low estimated GFR and high albumin to creatinine ratio each associated
with increased all-cause mortality, cardiovascular mortality, and end-
stage renal disease regardless of hypertension status
CKD associated with increased postoperative mortality
CKD associated with increased mortality in patients with heart failure
CKD associated with increased maternal and fetal mortality and morbidity in
pregnant women
factors associated with increased mortality in patients with CKD
diabetic nephropathy, age ≥ 45 years, and body mass index < 20 kg/m2
atherosclerotic renovascular disease
increased serum phosphorus
lower plasma 1,25-dihydroxyvitamin D levels
hypocalcemia
higher fibroblast growth factor-23 (FGF-23)
disease progression in patients with chronic kidney disease
risk prediction for disease progression
risk model predicts progression to kidney failure in patients with CKD stages 3-
5 (level 1 [likely reliable] evidence)
Chronic Renal Impairment in Birmingham (CRIB) may have moderate
predictive ability for end-stage renal disease in patients with stage 3-5 chronic
kidney disease (level 2 [mid-level] evidence)
Veterans Affairs risk prediction tool may help predict low risk of progression to
end-stage renal disease within 1 year in elderly men (level 2 [mid-level]
evidence)
factors associated with increased risk for disease progression
decline in estimated GFR as little as 20%
high-dose nonsteroidal anti-inflammatory drug use
elevated blood pressure
male sex
older age
major depressive episode
black race
polycystic kidney disease and diabetic nephropathy
lead exposure
presence of certain apolipoprotein E genetic variants
higher phosphate-regulating hormone fibroblast growth factor 23 (FGF-23)
high levels of asymmetric dimethylarginine (ADMA), advanced glycation and
oxidation products, hypertension, and proteinuria may each be associated
with progression of CKD
see Dialysis for end-stage renal disease for prognosis in dialysis patients
see Prognosis of chronic kidney disease for details
Prevention and Screening

Prevention
prevention strategies for CKD include(4)

control of hypertension
control of diabetes mellitus
avoiding unnecessary use of potentially nephrotoxic drugs, especially nonsteroidal
anti-inflammatory drugs (NSAIDs)
bariatric surgery reported to be associated with improved risk classification for
chronic kidney disease in patients with obesity (level 3 [lacking direct] evidence)
based on nonclinical outcome and noncomparative data from prospective cohort
study
2,144 patients (median age 46 years, 79% women) who had bariatric surgery were
followed for up to 7 years
71% had Roux-en-Y gastric bypass
24% had laparoscopic adjustable banding
risk of chronic kidney disease (CKD) assessed by Kidney Disease Improving Global
Outcomes (KDIGO) criteria
at baseline, 83.4% were at low risk, 11.9% at moderate risk, 3.4% at high risk, and
1.4% at very high risk
1,807 patients who had data for CKD risk assessment at baseline and at ≥ 1 follow-up
visit were analyzed
changes in KDIGO risk categories at 7 years
in patients at low risk for CKD at baseline, 9% had worse risk (classified as
moderate)
in patients at moderate risk for CKD at baseline,
53% had improved risk (classified as low)
8% had worse risk (classified as high)
in patients at high risk for CKD at baseline,
56% had improved risk (classified as moderate)
10% had worse risk (classified as very high)
in patients at very high risk for CKD at baseline, 23% had improved risk
(classified as high)
Reference - J Am Soc Nephrol 2018 Apr;29(4):1289
increasing physical activity associated with reduced risk of rapid decline in kidney
function in older adults (level 3 [lacking direct] evidence)
based on prospective cohort study without clinical outcomes
4,011 participants ≥ 65 years old from Cardiovascular Health Study with ≥ 2 kidney
function measurements over 7 years were stratified by physical activity (kcal
expenditure), walking pace, and exercise intensity
rapid decline in kidney function defined as reduction in glomerular filtration rate
(GFR) ≥ 3 mL/minute/1.73 m2 per year
reduced incidence of rapid decline in kidney function associated with
increasing physical activity (p < 0.001)
increasing walking pace (p = 0.002)
increasing exercise intensity (p < 0.001)
Reference - Arch Intern Med 2009 Dec 14;169(22):2116 full-text, commentary can be
found in Arch Intern Med 2009 Dec 14;169(22):2124
healthy diet and moderate alcohol intake associated with reduced risk of
development and progression of chronic kidney disease in patients with type 2
diabetes (level 2 [mid-level] evidence)
6,214 patients with type 2 diabetes without macroalbuminuria had urinary albumin
and creatinine measurements at baseline and 5 years, serum creatinine
measurements at baseline and 5.5 years, and dietary assessment with the modified
Alternate Healthy Eating Index (mAHEI)
31.7% developed chronic kidney disease (new microalbuminuria or
macroalbuminuria or glomerular filtration rate decline of > 5% per year), and 8.3%
mortality at 5.5-year follow-up
compared with least healthy tertile of mAHEI score, the healthiest mAHEI tertile
associated with reduced risk of
chronic kidney disease (adjusted odds ratio [OR] 0.74, 95% CI 0.64-0.84)
mortality (adjusted OR 0.61, 95% CI 0.48-0.78)
compared with no alcohol intake, alcohol intake of 5 drinks per week associated
with reduced risk of
chronic kidney disease (adjusted OR 0.75, 95% CI 0.65-0.87)
mortality (adjusted OR 0.69, 95% CI 0.53-0.89)
sodium intake not associated with chronic kidney disease
Reference - JAMA Intern Med 2013 Oct 14;173(18):1682, editorial can be found in
JAMA Intern Med 2013 Oct 14;173(18):1692
Screening
regular testing of high-risk patients may show early signs of kidney damage and allow
early intervention(3)
high-risk patients include the elderly, those receiving potential nephrotoxic drugs, and
patients with(3)
diabetes
hypertension
structural renal tract disease
multisystem diseases with potential kidney involvement (such as systemic lupus
erythematosus)
family history of kidney failure
hereditary kidney disease
hematuria or proteinuria
United States Preventive Services Task Force (USPSTF) found insufficient evidence to
determine benefits and harms of routine screening for chronic kidney disease (CKD) in
asymptomatic adults (USPSTF Grade I) (Ann Intern Med 2012 Oct 16;157(8):567)
American College of Physicians recommends against screening for CKD in asymptomatic
adults without risk factors (ACP Grade Weak, Low quality evidence) (Ann Intern Med
2013 Dec 17;159(12):835)
American Heart Association (AHA) recommends screening for CKD in patients with
cardiovascular disease (Circulation 2006 Sep 5;114(10):1083 full-text)
quantitative point-of-care urine test may be helpful in identifying or ruling out
albuminuria compared with laboratory measurement in patients at risk for kidney
based on systematic review with uncertain independent validation of individual
studies
systematic review of 16 cross-sectional diagnostic cohort studies evaluating the
accuracy of machine-read point-of-care (POC) tests for detecting urinary albumin
creatinine ratio (uACR) in 3,356 patients in whom guidelines recommended routine
measurement of uACR for early detection of albuminuria (including patients with
diabetes, hypertension, or established kidney disease)
1 study included young patients aged 13-24 years with type 1 diabetes
reference standard was some form of laboratory uACR, including an
immunochemical albumin method
semiquantitative tests reported uACR as < 30, 30-300, or > 300 mg/g (< 3.4, 3.4-33.9, or
> 33.9 mg/mmol)
diagnostic performance of semiquantitative POC uACR for detection of albuminuria
in analysis of 10 studies
sensitivity 76%
specificity 93%
positive likelihood ratio 11
negative likelihood ratio 0.26
diagnostic performance of quantitative POC uACR for detection of albuminuria in
analysis of 5 studies
sensitivity 96%
specificity 98%
positive likelihood ratio 44.7
negative likelihood ratio 0.04
Reference - Ann Intern Med 2014 Apr 15;160(8):550
screening to identify chronic renal disease has higher yield in persons with
hypertension, diabetes, or age > 55 years old
based on 65,604 adults in Norway followed for 8 years
3,069 (4.7%) had CKD (estimated GFR < 60 mL/minute/1.73 m2)
need to screen 20.6 people to identify 1 case of CKD
93.2% persons with CKD would be identified by restricting screening to those with
hypertension, diabetes, or age > 55 years old (number needed to screen 8.7 to
identify 1 case)
only 38 (1.2%) of 3,069 people with CKD progressed to end-stage renal disease
BMJ 2006 Nov 18;333(7577):1047 full-text, correction can be found in BMJ 2007 Jan
20;334(7585), editorial can be found in BMJ 2006 Nov 18;333(7577):1030 full-text
SCreening for Occult REnal Disease (SCORED) scoring system may predict risk for
occult renal disease (level 1 [likely reliable] evidence)
based on derivation and validation cohorts
8,530 United States adults were included
601 (5.4%) had CKD defined as GFR < 60 mL/minute per 1.73 m2
SCORED score range 0-12 points for prediction of kidney disease
SCORED score derived from 5,666 persons
age
2 points if age 50-59 years
3 points if 60-69 years
4 points if ≥ 70 years
1 point for each of
female
diabetes
anemia
hypertension
history of cardiovascular disease
history of heart failure
peripheral vascular disease
proteinuria
SCORED performance in validation cohort of 2,864 persons
score ≥ 3 had 96% sensitivity, 58% specificity, 15% positive predictive value
(PPV), and 99% negative predictive value (NPV)
score ≥ 4 had 92% sensitivity, 68% specificity, 18% PPV, and 99% NPV
Reference - Arch Intern Med 2007 Feb 26;167(4):374 full-text, correction can be
found in Arch Intern Med 2007 May 14;167(9):965
SCORED system independently validated in 2 additional cohorts
score ≥ 4 had 88% sensitivity, 52% specificity, 14% PPV, and 98% NPV in cohort
of 20,993 patients ≥ 45 years old from 2 previously published studies
score ≥ 4 had 95% sensitivity, 65% specificity, 20% PPV, and 99% NPV in cohort
of 4,298 patients from National Health and Nutrition Examination Survey
(NHANES) 2003 to 2004
Reference - Arch Intern Med 2008 Feb 25;168(4):432
elevated albuminuria associated with increased risk for renal replacement therapy
and progressive decline in renal function
40,854 adults aged 28-75 years from general population had first morning void
urinary collection
0.1% patients began renal replacement therapy during 9-year follow-up
urine albumin concentration ≥ 20 mg/L associated with initiation of renal
replacement therapy during follow-up
Reference - J Am Soc Nephrol 2009 Apr;20(4):852 full-text, editorial can be found in J
Am Soc Nephrol 2009 Apr;20(4):686 full-text
no randomized trials found evaluating urinary dipstick screening in general

population or hospitalized patients
based on Cochrane review
Reference - Cochrane Database Syst Rev 2015 Jan 28;(1):CD010007
Quality Improvement
Physician Quality Reporting System Quality Measures
121. Adult Kidney Disease: Laboratory Testing (Lipid Profile)

Percentage of patients ≥ 18 years old with a diagnosis of chronic kidney disease
(CKD) (stage 3, 4, or 5, not receiving Renal Replacement Therapy [RRT]), who had a
fasting lipid profile performed at least once within a 12-month period
American College of Physicians does not support this measure
"The ACP guideline states that there is inconclusive evidence for periodic
monitoring (that is, lipid profile) in patients diagnosed with stage 1-3 CKD."
Reference - ACP Performance Measure Review 2013 Nov 23 PDF
122. Adult Kidney Disease: Blood Pressure Management

Percentage of patient visits for patients ≥ 18 years old with a diagnosis of chronic
kidney disease (CKD) (stage 3, 4, or 5, not receiving Renal Replacement Therapy
[RRT]) with a blood pressure < 140/90 mm Hg OR blood pressure ≥ 140/90 mm Hg
with a documented plan of care
American College of Physicians does not support this measure
"The ACP guideline states that there is no difference in outcomes between strict
blood pressure control and standard blood pressure control (128-133 mm Hg
vs. 134-141 mm Hg systolic, and 75-81 mm Hg vs. 81-87 mm Hg diastolic). This
measure lost NQF endorsement due to a lack of evidence. In addition, the
currently endorsed measure (NQF 0018) specifies the percentage of patients 18-
85 years of age who had a diagnosis of hypertension and whose blood pressure
was adequately controlled (< 140/90) during the measurement year. The
Performance Measurement Committee believes that NQF 0018 could be
sufficient for patients with stage 1-3 CKD."
Reference - ACP Performance Measure Review 2013 Nov 23 PDF
329. Adult Kidney Disease: Catheter Use at Initiation of Hemodialysis

Percentage of patients ≥ 18 years old with a diagnosis of end-stage renal disease
(ESRD) who initiate maintenance hemodialysis during the measurement period,
whose mode of vascular access is a catheter at the time maintenance hemodialysis
is initiated
330. Adult Kidney Disease. Catheter Use for ≥ 90 Days

(ESRD) receiving maintenance hemodialysis for ≥ 90 days whose mode of vascular
access is a catheter
403. Adult Kidney Disease: Referral to Hospice

(ESRD) who withdraw from hemodialysis or peritoneal dialysis who are referred to
hospice care
see Physician Quality Reporting System Quality Measures for additional information
Quality and Outcomes Framework Indicators

CKD5 (NM83). Contractor establishes and maintains a register of patients ≥ 18 years old
with CKD Stage G3a to G5 CKD
SMOK2 (NM38). Percentage of patients with any or any combination of the following
conditions: coronary heart disease, peripheral arterial disease, stroke or transient
ischemic attack, hypertension, diabetes, chronic obstructive pulmonary disease (COPD),
chronic kidney disease, asthma, schizophrenia, bipolar affective disorder, or other
psychoses who have a record of smoking status in the preceding 12 months
SMOK5 (NM39). Percentage of patients with any or any combination of the following
conditions: coronary heart disease, peripheral arterial disease, stroke or transient
ischemic attack, hypertension, diabetes, chronic obstructive pulmonary disease (COPD),
chronic kidney disease, asthma, schizophrenia, bipolar affective disorder, or other
psychoses who smoke who have a record of an offer of support and treatment within
preceding 12 months
see Quality and Outcomes Framework Indicators for additional information
Guidelines and Resources

Guidelines
International guidelines
Kidney Disease: Improving Global Outcomes (KDIGO) guideline on management of blood

pressure in chronic kidney disease can be found at KDIGO (2011) 2012 Dec PDF
Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on

evaluation and management of chronic kidney disease can be found at KDIGO
2012 PDF, KDOQI United States commentary can be found in Am J Kidney Dis 2014
May;63(5):713
lipid management in chronic kidney disease can be found at KDIGO 2013 Nov PDF,
synopsis can be found at Ann Intern Med 2014 Feb 4;160(3):182
anemia in chronic kidney disease can be found in Am J Kidney Dis 2006 May;47(5
Suppl 3):S11, 2007 update of hemoglobin target can be found in Am J Kidney Dis
2007 Sep;50(3):471
diagnosis, evaluation, prevention, and treatment of chronic kidney disease–mineral
and bone disorder (CKD-MBD) can be found at KDIGO 2017 Jul PDF, executive
summary can be found in Kidney Int 2017 Jul;92(1):26 full-text
prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney
disease can be found at KDIGO 2008 Apr PDF or in Kidney Int Suppl 2008 Apr;
(109):S1 full-text, KDOQI United States commentary can be found in Am J Kidney Dis
2008 Nov;52(5):811 PDF
care of kidney transplant recipients can be found in Am J Transplant 2009 Nov;9
Suppl 3:S1 full-text
KDIGO conference report on definition, classification, and prognosis of chronic kidney
disease can be found in Kidney Int 2011 Jul;80(1):17
synopsis of 10 key recommendations from KDIGO 2012 clinical practice guidelines
pertinent to definition, classification, monitoring, and management of CKD in adults can
be found in Ann Intern Med 2013 Jun 4;158(11):825
United States guidelines
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines
National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI)

clinical practice guideline on hemodialysis adequacy can be found in Am J Kidney Dis
2015 Nov;66(5):884 full-text
NKF KDOQI guidelines for chronic kidney disease (CKD) care guidelines on
anemia in CKD can be found in Am J Kidney Dis 2006 May;47(5 Suppl 3):S11,
correction can be found in Am J Kidney Dis 2006 Sep;48(3):518, 2007 update of
hemoglobin target can be found in Am J Kidney Dis 2007 Sep;50(3):471 full-text
bone metabolism and disease in CKD can be found in Am J Kidney Dis 2003 Oct;42(4
Suppl 3):S1
diabetes and CKD can be found in Am J Kidney Dis 2012 Nov;60(5):850
lipid management in CKD can be found at KDIGO (2011) 2013 Nov PDF
managing dyslipidemia in CKD can be found in Am J Kidney Dis 2003 Apr;41(4 Suppl
3):I-IV, S1, summary can be found in Nephrol News Issues 2003 Apr;17(5):81
nutrition in chronic kidney disease can be found in Am J Kidney Dis 2000 Jun;35(6
Suppl 2):S1
National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI)
clinical practice guidelines on dialysis care
2006 updates on hemodialysis adequacy, peritoneal dialysis adequacy, and vascular
access can be found at National Kidney Foundation 2006
KDOQI guidelines on hemodialysis adequacy, 2015 update, can be found in Am
J Kidney Dis 2015 Nov;66(5):884, previous version can be found in Am J Kidney
Dis 2006 Jul;48 Suppl 1:S2
KDOQI guidelines on peritoneal adequacy can be found in Am J Kidney Dis
2006 Jul;48 Suppl 1:S91
KDOQI guidelines on peritoneal dialysis adequacy can be found in Am J Kidney
Dis 2006 Jul;48 Suppl 1:S98
KDOQI guidelines on vascular access can be found in Am J Kidney Dis 2006
Jul;48 Suppl 1:S176
KDOQI guidelines on cardiovascular disease in dialysis patients can be found in Am
J Kidney Dis 2005 Apr;45(4 Suppl 3):S1, commentary can be found in Am J Kidney
Dis 2005 Aug;46(2):368
Other United States guidelines
Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) guidelines on

laparoscopic peritoneal dialysis access surgery can be found at SAGES 2014
American College of Physicians (ACP) clinical practice guideline on screening, monitoring,

and treatment of stage 1 to 3 chronic kidney disease can be found in Ann Intern Med
2013 Dec 17;159(12):835 full-text
University of Michigan Health System (UMHS) guideline on management of chronic

kidney disease can be found at UMHS 2014 Mar PDF
Department of Veteran Affairs/Department of Defense (VA/DoD) clinical practice
guideline on management of chronic kidney disease in primary care can be found at
VA/DoD 2014 PDF
Centers for Disease Control and Prevention (CDC) Expert Panel guideline on
comprehensive public health strategies for preventing development, progression, and
complications of CKD can be found in Am J Kidney Dis 2009 Mar;53(3):522
United States Preventative Services Task Force (USPSTF) guideline on screening for
chronic kidney disease can be found in Ann Intern Med 2012 Oct 16;157(8):567 full-text
Michigan Quality Improvement Consortium (MQIC) guideline on diagnosis and
management of adults with chronic kidney disease can be found at MQIC 2014 Nov PDF
Infectious Diseases Society of America (IDSA) clinical practice guideline on management

of chronic kidney disease in patients infected with HIV can be found in Clin Infect Dis
2014 Nov 1;59(9):e96
Association for Vascular Access (AVA) position statement on preservation of peripheral

veins in patients with chronic kidney disease can be found at AVA 2011 Mar
chronic kidney disease can be found at AND Evidence Analysis Library 2010 Jul

critical illness can be found at AND Evidence Analysis Library 2012 Sep PDF
American Society for Parenteral and Enteral Nutrition (ASPEN) clinical guideline on
nutrition support in adult acute and chronic renal failure can be found in JPEN J Parenter
Enteral Nutr 2010 Jul-Aug;34(4):366
American College of Radiology (ACR) appropriateness criteria on renal failure can be
found at ACR 2013 PDF
Acute Dialysis Quality Initiative (ADQI) Consensus Group statement on prevention of
cardio-renal syndromes can be found in Nephrol Dial Transplant 2010 Jun;25(6):1777 full-
text
American Heart Association (AHA) scientific statement on pharmacotherapy in chronic

kidney disease patients presenting with acute coronary syndrome can be found in
Circulation 2015 Mar 24;131(12):1123 full-text
United Kingdom guidelines
National Institute for Health and Care Excellence (NICE)

NICE guidance on early identification and management of CKD in adults in primary
and secondary care can be found at NICE 2014 Jul:CG182 PDF, summary can be
found in BMJ 2014 Jul 24;349:g4507
NICE guideline on hyperphosphatemia in CKD can be found at NICE 2013
Mar:CG157 PDF
NICE guideline on guideline on anaemia management in people with chronic kidney
disease can be found at NICE 2015 Jun:NG8 PDF
NICE guidance on cinacalcet for treatment of secondary hyperparathyroidism in
patients with end-stage renal disease (ESRD) on maintenance dialysis therapy can be
found at NICE 2007 Jan:TA117 PDF
Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on
diagnosis and management of CKD can be found at SIGN 2008 PDF
British Thoracic Society (BTS) guidelines on prevention and management of
Mycobacterium tuberculosis infection and disease in adult patients with CKD can be
found in Thorax 2010 Jun;65(6):557
Canadian guidelines
Hypertension Canada 2017 guideline update for pharmacists can be found in Can Pharm
J (Ott) 2018 Jan-Feb;151(1):33 full-text
Canadian Society of Nephrology (CSN) 2014 clinical practice guideline on timing initiation
of chronic dialysis can be found in CMAJ 2014 Feb 4;186(2):112 full-text
Registered Nurses' Association of Ontario (RNAO) clinical practice guideline on decision

support for adults living with chronic kidney disease can be found at RNAO 2009 Jul PDF
British Columbia Medical Association (BCMA) guideline on identification, evaluation, and
management of patients with chronic kidney disease can be found at BCMA 2014 Oct PDF
Canadian Society of Transplantation consensus guidelines on eligibility for kidney
transplantation can be found in CMAJ 2005 Nov 8;173(10):1181 full-text, supporting
details can be found in CMAJ 2005 Nov 8;173(10):S1 full-text
European guidelines
European Renal Best Practice (ERBP) clinical practice guideline on management of older
patients with chronic kidney disease stage 3b or higher (eGFR < 45 mL/min/1.73 m2) can
be found in Nephrol Dial Transplant 2016 Nov;31(suppl 2):ii1
European Renal Best Practice (ERBP) clinical practice guideline on management of

patients with diabetes and chronic kidney disease stage 3b or higher (estimated GFR < 45
mL/minute) can be found in Nephrol Dial Transplant 2015 May;30 Suppl 2:ii1
European Renal Best Practice (ERBP) clinical practice guideline on
Haute Autorite de Sante (HAS) quick reference guide on kidney transplantation

from identification to registration - referral criteria and indications can be found at
2015 Oct PDF
information to discuss with the patient can be found at 2015 Oct PDF
S3 Leitlinie Nierenerkrankungen bei Diabetes im Erwachsenenalter finden Sie unter

AWMF 2015 Sep PDF [Deutsch]
European Renal Best Practice (ERBP) position statements on

high-flux or low-flux dialysis can be found in Nephrol Dial Transplant 2010
Apr;25(4):1230 full-text
anemia management in patients with CKD can be found in Nephrol Dial Transplant
2009 Feb;24(2):348 full-text
Sistema Nazionale Linee Guida (SNLG) guideline on identification, prevention and
management of chronic kidney disease in adults can be found at SNLG 2015 PDF [Italian]
Italian Society of Nephrology (Societa Italiana di Nefrolgia) guidelines on assessment of
glomerular filtration and plasma creatinine can be found in G Ital Nefrol 2009 Jan-
Feb;26(1):4 [Italian]
Spanish Society of Nephrology (La Sociedad Española de Nefrologia [SEN])
SEN consensus statement on quality improvement for peritoneal dialysis can be
found in Nefrologia 2010;30(1):28 [Spanish]
SEN recommendations for controlling mineral and bone disorder in chronic kidney
disease patients can be found in Nefrologia 2011 Feb 15;31 Suppl 1:3
Spanish Society of Clinical Biochemistry and Molecular Pathology/Spanish Society of
Nephrology (Sociedad Española de Bioquímica Clínica y Patología Molecular/Sociedad
Espanola de Nefrología [SEQC/SEN]) consensus recommendations on assessing
proteinuria during diagnosis and follow-up of chronic kidney disease can be found in
Nefrologia 2011 May 18;31(3):331 [English, Spanish]
Scientific Council on Health guideline on amylase can be found at Conseil Scientifique
2008 Jul[French]
Haute Autorité de Santé conseils pour indications et non-indications de la dialyse

péritonéale chronique chez l'adulte se trouvent sur le site Haute Autorité de Santé 2007
Jun PDF [French], Nephrol Ther 2009 Jun;5 Suppl 4:S281 [French]
Asian guidelines
expert clinical practice guidebook on diagnosis and treatment of chronic kidney disease
2012 can be found in Nihon Jinzo Gakkai Shi 2012;54(8):1034 [Japanese]
Japanese Society for Dialysis Therapy guideline on peritoneal dialysis can be found in
Ther Apher Dial 2010 Dec;14(6):489
Japanese Society of Nephrology (JSN)
JSN clinical practice guidebook on treatment of CKD patients can be found in Clin
Exp Nephrol 2009 Jun;13(3):191
JSN evidence-based practice guideline on treatment of CKD can be found in Clin Exp
Nephrol 2009 Dec;13(6):537 or in Nippon Jinzo Gakkai Shi 2009;51(8):905 [Japanese]
Asian Forum for Chronic Kidney Disease Initiatives (AFCKDI) best practice
recommendations on early detection of chronic kidney disease can be found in
Nephrology (Carlton) 2011 Sep;16(7):633
Korean Academy of Medical Sciences guideline (preliminary report) on rating physical
impairment of kidney, bladder, urethra, male and female reproductive systems can be
found in J Korean Med Sci 2009 May;24 Suppl 2:S277 full-text
Central and South American guidelines
Sociedade Brasileira de Nefrologia (SBN) guidelines on

management of hyperphosphatemia in CKD can be found in J Bras Nefrol 2011 Apr-
Jun;33(2):191 [Portuguese]
prevention and treatment of secondary hyperparathyroidism in CKD can be found
in J Bras Nefrol 2011 Apr-Jun;33(2):197 [Portuguese]
dialysate calcium concentration and hypercalcemia in CKD can be found in J Bras
Nefrol 2011 Apr-Jun;33(2):205 [Portuguese]
adynamic bone disease can be found in J Bras Nefrol 2011 Apr-Jun;33(2):209
[Portuguese]
aluminum intoxication in chronic kidney disease can be found in J Bras Nefrol 2011
Apr-Jun;33(2):211 [Portuguese]
vascular calcification in CKD can be found in J Bras Nefrol 2011 Apr-Jun;33(2):216
[Portuguese]
parathyroidectomy in CKD can be found in J Bras Nefrol 2011 Apr-Jun;33(2):221
[Portuguese]
bone biopsy in chronic kidney disease can be found in J Bras Nefrol 2011 Apr-
bone and mineral disorders in CKD J Bras Nefrol 2012 Jun;34(2):199 full-text
[Portuguese]
bone and mineral disorders after kidney transplantation can be found in J Bras
Nefrol 2011 Apr-Jun;33(2):227 [Portuguese]
bone and mineral disorders in CKD children can be found in J Bras Nefrol 2011 Apr-
Australian and New Zealand guidelines
Queensland Health Chronic Conditions Manual: management of diagnosed conditions

can be found at Queensland 2015 PDF
Australasian Proteinuria Consensus Working Group position statement on chronic kidney
disease and measurement of albuminuria or proteinuria can be found in Med J Aust 2012
Aug 20;197(4):224
Australasian Creatinine Consensus Working Group new developments and revised
recommendations on chronic kidney disease and automatic reporting of estimated
glomerular filtration rate can be found in Med J Aust 2012 Aug 20;197(4):224
Kidney Health Australia - Caring for Australasians with Renal Impairment (KHA-CARI)
guidelines
on chronic kidney disease
on dialysis
acceptance onto dialysis
coronary artery, cerebrovascular and peripheral vascular disease can be
found in Nephrology (Carlton) 2010 Apr;15 Suppl 1:S19 PDF
diabetes can be found in Nephrology (Carlton) 2010 Apr;15 Suppl
1:S15 PDF
ethical considerations can be found in Nephrology (Carlton) 2010 Apr;15
Suppl 1:S12 PDF
level of renal function at which to initiate dialysis can be found at KHA-
CARI 2005 Oct PDF
mode of dialysis at initiation can be found at KHA-CARI 2005 Jul PDF
other criteria for starting dialysis can be found at KHA-CARI 2005 Jul PDF
peritoneal dialysis versus hemodialysis in adults can be found in
Nephrology (Carlton) 2010 Apr;15 Suppl 1:S24 PDF
predialysis education can be found at KHA-CARI 2004 Oct PDF
quality of life can be found in Nephrology (Carlton) 2010 Apr;15 Suppl
1:S32 PDF
timing of referral of chronic kidney disease patients to nephrology
services in adults can be found in Nephrology (Carlton) 2010 Apr;15 Suppl
1:S2 PDF
biochemical and hematological targets
calcium can be found at KHA-CARI 2006 Apr PDF
calcium x phosphate product can be found at KHA-CARI 2006 Apr PDF
magnesium can be found at KHA-CARI 2000 Mar PDF
parathyroid hormone can be found at KHA-CARI 2006 Apr PDF
hemoglobin can be found at KHA-CARI 2011 Nov PDF
iron can be found at KHA-CARI 2013 Jul PDF
guideline summary of biochemical and hematological targets:
hemoglobin concentrations in patients using erythropoietin-stimulating
agents can be found in Nephrology (Carlton) 2012 Jan;17(1):17 PDF
guideline summary of use of iron in chronic kidney disease patients can
be found in Nephrology (Carlton) 2013 Dec;18(12):747 PDF
dialysis adequacy
blood urea sampling methods can be found at KHA-CARI 2005 Jul PDF
dialysis membranes can be found at KHA-CARI 2013 Apr PDF
dose of hemodialysis can be found at KHA-CARI 2005 Jun PDF
duration and frequency of hemodialysis therapy can be found at KHA-
CARI 2005 Jul PDF
hemodialysis anticoagulation and adequacy can be found at KHA-CARI
2005 Jul PDF
water quality for hemodialysis can be found at KHA-CARI 2005 Jul PDF
peritonitis treatment and prophylaxis
influence of peritoneal dialysis (PD) systems and solutions on incidence of
peritonitis and catheter-related infections can be found at KHA-CARI 2014
Feb PDF
management of PD-associated peritonitis in adults and children can be
found at KHA-CARI 2014 Feb PDF
catheter removal, adjunct therapies and timing of reinsertion of PD
catheter after peritonitis can be found at KHA-CARI 2014 Feb PDF
type of PD catheter can be found at KHA-CARI 2014 Feb PDF
technique of insertion of peritoneal dialysis catheter can be found at
KHA-CARI 2014 Feb PDF
prophylactic antibiotics for insertion of peritoneal dialysis catheter can
be found at KHA-CARI 2014 Feb PDF
timing of commencement of peritoneal dialysis following catheter
insertion can be found at KHA-CARI 2014 Feb PDF
treatment of peritoneal dialysis-associated fungal peritonitis can be found
at KHA-CARI 2014 Feb PDF
PD catheter-related infection: exit site and tunnel can be found at KHA-
CARI 2014 Feb PDF
prophylaxis for exit-site/tunnel infections using mupirocin can be found
at KHA-CARI 2014 Feb PDF
guideline summary on peritonitis treatment and prophylaxis can be
found in Nephrology (Carlton) 2014 Feb;19(2):69 PDF
vascular access
insertion of catheters can be found at KHA-CARI 2012 Jun PDF
nursing care of central venous catheters can be found at KHA-CARI 2012
Jun PDF
pharmacological approaches to preventing vascular access failure can be
found at KHA-CARI 2008 Aug PDF
preoperative examination of the vessels - diagnostic evaluation prior to
permanent access selection can be found at KHA-CARI 2012 Jun PDF
preparation and placement of vascular access can be found at KHA-CARI
2012 Jun PDF
prevention of dialysis catheter infection can be found at KHA-CARI 2012
Jun PDF
selection of type of access can be found at KHA-CARI 2012 Jun PDF
treatment of the thrombosed AVF/AVG: surgical vs. radiological therapy
can be found at KHA-CARI 2012 Jun PDF
treatment of dialysis catheter infection can be found at KHA-CARI 2012
Jun PDF
treatment of vascular steal syndrome can be found at KHA-CARI 2012 Jun
PDF
vascular access surveillance can be found at KHA-CARI 2008 Jun PDF
guideline summary of vascular access - central venous catheters,
arteriovenous fistulae and arteriovenous grafts can be found in
Nephrology (Carlton) 2013 Nov;18(11):701 PDF, correction can be found in
Nephrology (Carlton) 2014 Jan;19(1):64
on transplantation
KHA-CARI adaptation of the KDIGO clinical practice guideline for the care of
kidney transplant recipients can be found at KHA-CARI 2012 Feb PDF or in
Nephrology (Carlton) 2012 Mar;17(3):204
KHA-CARI guideline on cytomegalovirus disease and kidney transplantation
can be found in Nephrology (Carlton) 2011 Nov;16(8):683 PDF
KHA-CARI guideline on recipient assessment for transplantation can be found
in Nephrology (Carlton) 2013 Jun;18(6):455 PDF
cardiovascular disease can be found at KHA-CARI 2013 Mar PDF
diabetes mellitus can be found at KHA-CARI 2013 Mar PDF
HIV, HBV and HCV infection can be found at KHA-CARI 2013 Mar PDF
malignancy can be found at KHA-CARI 2013 Mar PDF
obesity in renal transplantation can be found at KHA-CARI 2013 Mar PDF
pediatric recipients can be found at KHA-CARI 2013 Mar PDF
New South Wales (NSW) Ministry of Health policy on promoting early detection and
management of chronic kidney disease can be found at NSW 2010 Apr 15 PDF
Review articles
review of chronic kidney disease: detection and evaluation can be found in can be found
in Am Fam Physician 2017 Dec 15;96(12):776
review can be found in Ann Intern Med 2015 Jun 2;162(11):ITC1
review can be found in Lancet 2013 Jul 27;382(9889):353
review can be found in Lancet 2013 Jul 20;382(9888):260, commentary can be found in
Lancet 2013 Oct 12;382(9900):1244
review can be found in Lancet 2012 Jan 14;379(9811):165
reviews of measuring renal function
review of measuring renal function in clinical practice can be found in BMJ 2006 Oct
7;333(7571):733 full-text, correction can be found in BMJ 2006 Nov 18;333(7577),
commentary can be found in BMJ 2006 Oct 28;333(7574):918 full-text, BMJ 2006 Nov
18;333(7577):1072 full-text
review of understanding estimated glomerular filtration rate can be found in Curr
Opin Nephrol Hypertens 2007 May;16(3):242
review of assessing renal function in elderly patients can be found in Curr Opin
Nephrol Hypertens 2008 Nov;17(6):604
review of glomerular filtration rate and albuminuria for detection and staging of
acute and chronic kidney disease in adults can be found in JAMA 2015 Feb
24;313(8):837 full-text
review of tuberous sclerosis complex can be found in Pediatr Nephrol 2015
Oct;30(10):1771
review of acute kidney injury and chronic kidney disease can be found in N Engl J Med
2014 Jul 3;371(1):58
review of mortality risk in chronic kidney failure can be found in Lancet 2014 May
24;383(9931):1831
review of heart failure in patients with kidney disease can be found in Heart 2017
Dec;103(23):1848
review of rare inherited kidney diseases can be found in Lancet 2014 May
24;383(9931):1844 full-text
review of cardiovascular disease risk in patients with CKD can be found in Lancet 2013
Jul 27;382(9889):339, correction can be found in Lancet 2013 Jul 27;382(9889):310
review of metabolic acidosis
review of treatment of metabolic acidosis in patients with chronic kidney disease
can be found in Am J Kidney Dis 2014 Feb;63(2):311 full-text
review of consequences and therapy of metabolic acidosis in chronic kidney disease
can be found in Pediatr Nephrol 2011 Jan;26(1):19 full text
review of early recognition and prevention of CKD can be found in Lancet 2010 Apr
10;375(9722):1296, correction can be found in Lancet 2010 Jul 17;376(9736):162, editorial
can be found in Lancet 2010 Apr 10;375(9722):1227
review of staging of chronic kidney disease can be found in J Am Soc Nephrol 2008
May;19(5):844 full-text
review of detection and evaluation of CKD can be found in Am Fam Physician 2005 Nov
1;72(9):1723 full-text
review of early detection of CKD can be found in BMJ 2008 Oct 1;337:a1618
review of genetic kidney diseases can be found in Lancet 2010 Apr 10;375(9722):1287 full-
text, editorial can be found in Lancet 2010 Apr 10;375(9722):1227
review of recent developments in epigenetics of acute and chronic kidney diseases can be
found in Kidney Int 2015 May 20;: full-text
review of kidney regeneration can be found in Lancet 2010 Apr 10;375(9722):1310,
editorial can be found in Lancet 2010 Apr 10;375(9722):1227
review of prevention and treatment of common complications of CKD can be found in
Am Fam Physician 2004 Nov 15;70(10):1921 full-text
review of management of chronic kidney disease can be found in Am Fam Physician 2012
Oct 15;86(8):749 full-text
review of management of hypertensive renal disease can be found in Arch Intern Med
1999 Jan 11;159(1):23 full-text
review of 25-hydroxyvitmin D testing and supplementation in chronic kidney disease can
be found in Am J Kidney Dis 2014 Oct;64(4):499
review of chronic progressive proteinuric nephropathies can be found in N Engl J Med
1998 Nov 12;339(20):1448
review of end-stage renal disease symptom management and advance care planning can
be found in Am Fam Physician 2012 Apr 1;85(7):705 full-text, correction can be found in
Am Fam Physician 2012 May 15;85(10):950
review of management of chronic renal failure can be found in Mayo Clin Proc 1999
Mar;74(3):269, correction can be found in Mayo Clin Proc 1999 May;74(5):538
review of chronic kidney disease and dialysis access in women can be found in J Vasc
Surg 2013 Apr;57(4 Suppl):49S full-text
brief "What you should do" review can be found in BMJ 2007 Jun 16;334(7606):1273 full-
text
review of nondiabetic renal disease can be found in N Engl J Med 2002 Nov
7;347(19):1505, commentary can be found in N Engl J Med 2003 Feb 20;348(8):762
narrative review of epidemiology, diagnosis, and management of aristolochic acid
nephropathy can be found in Ann Intern Med 2013 Mar 19;158(6):469
Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review on
cardiac troponins used as diagnostic and prognostic tests in patients with kidney disease
can be found at AHRQ Comparative Effectiveness Review 2014 Aug:135 PDF
Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review on
biomarkers for assessing and managing iron deficiency anemia in late-stage chronic
kidney disease can be found at AHRQ Comparative Effectiveness Review 2012 Oct:83 PDF
(archived)
review of anemia in CKD can be found in Cleve Clin J Med 2006 Mar;73(3):289, editorial
can be found in Cleve Clin J Med 2006 Mar;73(3):298
review of lithium and CKD can be found in BMJ 2009 Jul 3;339:b2452
review of oral phosphate binders in patients with kidney failure can be found in N Engl J
Med 2010 Apr 8;362(14):1312, commentary can be found in N Engl J Med 2010 Sep
2;363(10):990
review of chronic renal disease in pregnancy can be found in Obstet Gynecol 2006
Dec;108(6):1531, correction can be found in Obstet Gynecol 2007 Mar;109(3):788
review of drug dosing adjustments in patients with CKD can be found in Am Fam
Physician 2007 May 15;75(10):1487 full-text, commentary can be found in Am Fam
Physician 2007 Nov 15;76(10):1454 full-text, Am Fam Physician 2007 Dec
15;76(12):1766 full-text
review of risk prediction models for patients with chronic kidney disease can be found in
Ann Intern Med 2013 Apr 16;158(8):596
editorial review of dialysis dose in acute kidney injury and chronic dialysis can be found
in Lancet 2010 Feb 27;375(9716):705
case presentation of stage IV CKD can be found in N Engl J Med 2010 Jan 7;362(1):56,
commentary can be found in N Engl J Med 2010 May 20;362(20):1942 full-text
case presentation of CKD induced by calcineurin inhibitor cyclosporine can be found in N
Engl J Med 2007 Apr 19;356(16):1657 full-text
case presentation can be found in JAMA 2004 Mar 10;291(10):1252, follow-up can be
found in JAMA 2005 Aug 17;294(7):841
successful pregnancy reported in case report of 2 patients with end-stage renal disease
can be found in J Med Case Reports 2008 Jan 20;2:10 full-text
MEDLINE search
to search MEDLINE for (Chronic kidney disease) with targeted search (Clinical Queries),
click therapy, diagnosis, or prognosis
Patient Decision Aids

interactive clinician and patient decision aid for treatment options for chronic kidney
disease can be found at Option Grid Collaborative
patient decision aid for dialysis for chronic kidney disease can be found at University of
Leeds PDF
Patient Information
handout from JAMA 2016 May 24
handout from National Kidney Foundation

handout from American Academy of Family Physicians or in Spanish
handout from Patient UK PDF
handout from KidsHealth
handout on chronic renal failure from Sociedad Española de Medicina de Familia y
Comunitaria PDF [Spanish]
handout on chronic kidney failure from Mayo Clinic
handout on nutrition and chronic kidney disease from National Kidney Foundation PDF
handout on nutrition for early chronic kidney disease in adults from National Kidney and
Urologic Diseases Information Clearinghouse PDF
handout on nutrition for advanced chronic kidney disease in adults from National
Kidney and Urologic Diseases Information Clearinghouse PDF
ICD-9/ICD-10 Codes
ICD-9 codes
585 chronic kidney disease

585.1 chronic kidney disease, stage I
585.2 chronic kidney disease, stage II (mild)
585.3 chronic kidney disease, stage III (moderate)
585.4 chronic kidney disease, stage IV (severe)
585.5 chronic kidney disease, stage V
585.6 end stage renal disease
585.9 chronic kidney disease, unspecified
403 hypertensive renal disease
403.0 malignant hypertensive kidney disease
403.00 hypertensive chronic kidney disease, malignant, with chronic kidney
disease Stage I-stage IV
403.01 hypertensive chronic kidney disease, malignant, with chronic kidney
disease stage V
403.1 benign hypertensive kidney disease
403.10 hypertensive chronic kidney disease, benign, with chronic kidney
disease stage I-stage IV
403.11 hypertensive chronic kidney disease, benign, with chronic kidney
disease stage V
403.9 unspecified hypertensive kidney disease
403.90 hypertensive chronic kidney disease, unspecified, with chronic kidney
disease stage 1-stage IV
403.91 hypertensive chronic kidney disease, unspecified, with chronic kidney
disease stage V
586 renal failure, unspecified [excluding hypertensive renal disease]
588.8 other specified disorders resulting from impaired renal function
588.81 secondary hyperparathyroidism (of renal origin)
588.89 other specified disorders resulting from impaired renal function
ICD-10 codes
N18 chronic kidney disease

N18.1 chronic kidney disease, stage 1
N18.6 end stage renal disease
N18.9 chronic renal failure, unspecified
I12 hypertensive chronic kidney disease
I12.0 hypertensive chronic kidney disease with stage 5 CKD or end stage renal
disease
I12.9 hypertensive renal disease with stage 1-stage 4 CKD, or unspecified CKD
ICD-10-CA modification in Canada: fourth character extensions were deleted to
allow for use of dual classification for I12
N25.8 other disorders resulting from impaired renal tubular function
N25.9 disorder resulting from impaired renal tubular function, unspecified
References
General references used
1. Meyer TW, Hostetter TH. Uremia. N Engl J Med. 2007 Sep 27;357(13):1316-25,
commentary can be found in N Engl J Med 2008 Jan 3;358(1):95
2. Obrador GT, Pereira BJ. Systemic complications of chronic kidney disease. Pinpointing
clinical manifestations and best management. Postgrad Med. 2002 Feb;111(2):115-22
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012
clinical practice guideline for the evaluation and management of chronic kidney disease.
KDIGO (2011) 2013 Jan PDF
4. Murphree DD, Thelen SM. Chronic kidney disease in primary care. J Am Board Fam
Med. 2010 Jul-Aug;23(4):542-50 full-text
Recommendation grading systems used
American College of Cardiology/American Heart Association (ACC/AHA)

classifications of recommendations
Class I - procedure or treatment should be performed or administered
Class IIa - reasonable to perform procedure or administer treatment, but
additional studies with focused objectives needed
Class IIb - procedure or treatment may be considered; additional studies with
broad objectives needed, additional registry data would be useful
Class III - procedure or treatment should not be performed or administered
because it is not helpful or may be harmful
Class III ratings may be subclassified as Class III No Benefit or Class III
Harm
levels of evidence
Level A - data derived from multiple randomized clinical trials or meta-
analyses
Level B - data derived from single randomized trial or nonrandomized studies
Level C - only expert opinion, case studies, or standard of care
Reference - Circulation 2006 Mar 21;113(11):e463 PDF (focused update can be found
in Circulation 2011 Nov 1;124(18):2020 full-text)
Eighth Joint National Committee (JNC 8) 2014 grades of recommendation

Strong recommendation - Grade A - high certainty based on evidence that net
benefit is substantial
Moderate recommendation - Grade B - moderate certainty based on evidence that
net benefit is moderate-to-substantial OR high certainty that net benefit is moderate
Weak recommendation - Grade C - at least moderate certainty based on evidence
that there is small net benefit
Recommendation against - Grade D - at least moderate certainty based on evidence
that no net benefit or that risks/harms outweigh benefits
Expert opinion - Grade E - "There is insufficient evidence or evidence is unclear or
conflicting, but this is what the committee recommends", net benefit unclear
No recommendation for or against - Grade N - "There is insufficient evidence or
evidence is unclear or conflicting", net benefit unclear
Reference - JNC8 2014 evidence-based guideline for the management of high blood
pressure in adults (JAMA 2014 Feb 5;311(5):507)
Hypertension Canada (formerly Canadian Hypertension Education Program [CHEP])

grades of recommendations
Grade A - recommendations based on randomized trials (or systematic reviews)
with high levels of internal validity and statistical precision for which study results
can be directly applied to patients because of similar clinical characteristics and
clinical evidence of study outcomes
Grade B - recommendations based on randomized trials, systematic reviews, or
prespecified subgroup analyses of randomized trials that have lower precision, or if
there is a need to extrapolate from studies because of differing populations or
reporting of validated intermediate/surrogate outcomes rather than clinically
important outcomes
Grade C - recommendations from trials with lower levels of internal validity and/or
precision, or that report unvalidated surrogate outcomes, or results from
nonrandomized observational studies
Grade D - recommendations based on expert opinion alone
detailed algorithms for assigning evidence grades to recommendations can be found
in Can J Cardiol 2006 May 15;22(7):559 full-text
Reference - Hypertension Canada recommendations on diagnosis, risk assessment,
prevention, and treatment of hypertension in adults (Can J Cardiol 2017
May;33(5):557)
European Society of Hypertension/European Society of Cardiology (ESH/ESC) grading

system
classifications of recommendations
Class I - evidence and/or general agreement that procedure or treatment is
beneficial, useful, effective
Class II - conflicting evidence and/or divergence of opinion about
usefulness/efficacy of given treatment of procedure
Class IIa - weight of evidence/opinion in favor of usefulness/efficacy
Class IIb - usefulness/efficacy less well established by evidence/opinion
Class III - evidence or general agreement that procedure or treatment is not
useful/effective, and in some cases may be harmful
levels of evidence
Level A - data derived from multiple randomized clinical trials or meta-
analyses
Level B - data derived from single randomized trial or large nonrandomized
studies
Level C - consensus opinions of experts, and/or small studies, retrospective
studies, or registries
Reference - ESH/ESC guideline on management of arterial hypertension (Eur Heart J
2013 Jul;34(28):2159 full-text)
American College of Radiology (ACR) rating scale

Rating 1, 2, and 3 - usually not appropriate
Rating 4, 5, and 6 - may be appropriate
Rating 7, 8, and 9 - usually appropriate
Reference - ACR appropriateness criteria on renal failure (ACR 2013 PDF)
Canadian Society of Transplantation (CST) uses Canadian Task Force on Preventive

Health Care (CTFPHC) grades of recommendation
Grade A - good evidence to support clinical preventive action
Grade B - fair evidence to support clinical preventive action
Grade C
existing evidence conflicts
other factors may influence decision making
Grade D - fair evidence to recommend against clinical preventive action
Grade E - good evidence to recommend against clinical preventive action
Reference - CST consensus guidelines on eligibility for kidney transplantation (CMAJ
2005 Nov 8;173(10):1181 full-text), supporting details can be found in CMAJ 2005
Nov 8;173(10):S1 full-text
United States Preventive Services Task Force (USPSTF) grades of recommendation (June
2007 to June 2012)
Grade A - USPSTF recommends the service with high certainty of substantial net
benefit
Grade B - USPSTF recommends the service with high certainty of moderate net
benefit or moderate certainty of moderate-to-substantial net benefit
Grade C - clinicians may provide the service to select patients depending on
individual circumstances; however, only small benefit is likely for most individuals
without signs or symptoms
Grade D - USPSTF recommends against providing the service with moderate-to-high
certainty of no net benefit or harms outweighing benefits
Grade I - insufficient evidence to assess balance of benefits and harms
Reference - USPSTF Grade Definitions
Kidney Disease: Improving Global Outcomes (KDIGO)

strength of recommendation
Level 1 ("we recommend") - most patients should receive recommended course
of action
Level 2 ("we suggest") - different choices appropriate for different patients,
based on patient's values and preferences
Not Graded - topic does not allow adequate application of evidence, not meant
to be interpreted as being stronger recommendations than Level 1 or 2
quality of evidence
Grade A - high-quality evidence, true effect lies close to that of estimate of
effect
Grade B - moderate-quality evidence, true effect likely to be close to estimate of
effect, but there is possibility it is substantially different
Grade C - low-quality evidence, true effect may be substantially different from
estimate of effect
Grade D - very low-quality evidence, estimate of effect very uncertain and
often far from truth
Reference -
KDIGO clinical practice guideline for evaluation and management of chronic
kidney disease (KDIGOl (2011) 2013 Jan PDF)
KDIGO clinical practice guideline for diagnosis, evaluation, prevention, and
treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD)
(KDIGO 2017 Jul PDF), executive summary can be found in Kidney Int 2017
Jul;92(1):26 full-text
National Kidney Foundation (NKF) strengths of recommendation
Grade A
strongly recommended that clinicians routinely follow guideline for eligible
patients
strong evidence that practice improves health outcomes
Grade B
recommended that clinicians routinely follow guideline for eligible patients
moderately strong evidence that practice improves health outcomes
Clinical Practice Recommendations (Grade CPR)
consider following guideline for eligible patients
based on weak evidence or opinions of Work Group and reviewers that
practice might improve health outcomes
Reference - NKF clinical practice guideline and recommendations on hemodialysis
adequacy, peritoneal dialysis adequacy and vascular access (NKF 2006, NKF 2006
Updates Clinical Practice Guidelines and Recommendations PDF)
American College of Physicians (ACP) guideline grading system

strength of recommendation
Strong - benefits clearly outweigh risks and burden, or risks and burden
clearly outweigh benefits
Weak - benefits closely balanced with risks and burden or uncertainty in
estimates of benefits, risks, and burdens
Insufficient - balance of benefits and risks cannot be determined
quality of evidence
High - randomized trials without important limitations, or overwhelming
evidence from observational studies
Moderate - randomized trials with important limitations (inconsistent results,
methodologic flaws, indirect, or imprecise), or exceptionally strong evidence
from observational studies
Low - observational studies or case series
Insufficient - evidence is conflicting, poor quality, or lacking
Reference - ACP methods for development of clinical practice guidelines and
guidance statements (Ann Intern Med 2010 Aug 3;153(3):194)
Synthesized Recommendation Grading System for DynaMed Plus
DynaMed systematically monitors clinical evidence to continuously provide a synthesis of

the most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-
Based Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided
with the recommendation grading system used in the original guideline(s), and allow
DynaMed users to quickly see where guidelines agree and where guidelines differ from
each other and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from
leading authorities, and clinical expertise to provide recommendations to support clinical
decision-making in the Overview & Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) to classify synthesized recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence,
clinicians (without conflicts of interest) consistently have a high degree of
confidence that the desirable consequences (health benefits, decreased costs and
burdens) outweigh the undesirable consequences (harms, costs, burdens).
Weak recommendations are used when, based on the available evidence,
clinicians believe that desirable and undesirable consequences are finely balanced,
or appreciable uncertainty exists about the magnitude of expected consequences
(benefits and harms). Weak recommendations are used when clinicians disagree in
judgments of relative benefit and harm, or have limited confidence in their
judgments. Weak recommendations are also used when the range of patient values
and preferences suggests that informed patients are likely to make different choices.
DynaMed Plus (DMP) synthesized recommendations (in the Overview &
Recommendations section) are determined with a systematic methodology:
Recommendations are initially drafted by clinical editors (including ≥ 1 with
methodological expertise and ≥ 1 with content domain expertise) aware of the best
current evidence for benefits and harms, and the recommendations from
guidelines.
Recommendations are phrased to match the strength of recommendation. Strong
recommendations use "should do" phrasing, or phrasing implying an expectation
to perform the recommended action for most patients. Weak recommendations
use "consider" or "suggested" phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak
recommendations when a qualified group has explicitly deliberated on making
such a recommendation. Group deliberation may occur during guideline
development. When group deliberation occurs through DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention,
Comparison, Outcome) framework for all outcomes of interest specific to the
recommendation to be developed.
Systematic searches will be conducted for any clinical questions where
systematic searches were not already completed through DynaMed content
development.
Evidence will be summarized for recommendation panel review including for
each outcome, the relative importance of the outcome, the estimated effects
comparing intervention and comparison, the sample size, and the overall
quality rating for the body of evidence.
Recommendation panel members will be selected to include at least 3
members that together have sufficient clinical expertise for the subject(s)
pertinent to the recommendation, methodological expertise for the evidence
being considered, and experience with guideline development.
All recommendation panel members must disclose any potential conflicts of
interest (professional, intellectual, and financial), and will not be included for
the specific panel if a significant conflict exists for the recommendation in
question.
Panel members will make Strong recommendations if and only if there is
consistent agreement in a high confidence in the likelihood that desirable
consequences outweigh undesirable consequences across the majority of
expected patient values and preferences. Panel members will make Weak
recommendations if there is limited confidence (or inconsistent assessment or
dissenting opinions) that desirable consequences outweigh undesirable
consequences across the majority of expected patient values and preferences.
No recommendation will be made if there is insufficient confidence to make a
recommendation.
All steps in this process (including evidence summaries which were shared
with the panel, and identification of panel members) will be transparent and
accessible in support of the recommendation.
Recommendations are verified by ≥ 1 editor with methodological expertise, not
involved in recommendation drafting or development, with explicit confirmation
that Strong recommendations are adequately supported.
Recommendations are published only after consensus is established with agreement
in phrasing and strength of recommendation by all editors.
If consensus cannot be reached then the recommendation can be published with a
notation of "dissenting commentary" and the dissenting commentary is included in
the topic details.
If recommendations are questioned during peer review or post publication by a
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to additional internal review.
DynaMed editorial process
DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
All editorial team members and reviewers have declared that they have no financial or
other competing interests related to this topic, unless otherwise indicated.
DynaMed provides Practice-Changing DynaMed Updates, with support from our partners,
McMaster University and F1000.
Special acknowledgements
Bruce Kaplan, MD (Professor of Medicine, Mayo Clinic Medical School; Professor, Arizona
State University College of Health Care Delivery; Arizona, United States)
Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United
Kingdom Cochrane Center, The Cochrane Collaboration; Awali, Bahrain)
Dr. Fedorowicz declares no relevant financial conflicts of interest.
William Aird, MD (Deputy Editor of Hematology, Endocrinology, and Nephrology;

Professor of Medicine, Harvard Medical School; Massachusetts, United States)
Dr. Aird declares no relevant financial conflicts of interest.
DynaMed Plus topics are written and edited through the collaborative efforts of the above
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Chronic kidney disease (CKD) in adults

Overview and Recommendations

Chronic kidney disease is characterized by abnormalities of kidney structure or function

Interventions to slow decline in kidney function:

prevalence of CKD stratiﬁed by stage, gender, and geographical region

see Risk factors for chronic kidney disease for details

Etiology and Pathogenesis

History and Physical

Chief concern (CC)

usually asymptomatic in early stages of kidney disease(3)

History of present illness (HPI)

onset is typically insidious and begins with nonspeciﬁc symptoms(1)

ask about nephrotoxic medications, including nonprescription medications and herbal

Past medical history (PMH)

hypertension (one of the earliest manifestations of kidney disease)(1)

Family history (FH)

family history of kidney disease

assess for pericarditis(1)

possible neurological signs may include(1)

acute renal failure (may be superimposed on chronic kidney disease)

laboratory evaluation of patients with CKD

Modiﬁcation of Diet in Renal Disease (MDRD)

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equations

CKD-EPI Equations for Estimating GFR in Women:

Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR,

see DynaMed calculator for Creatinine Clearance Estimate by Cockcroft-Gault Formula

Estimating GFR in elderly

Limitations of estimating GFR

Other blood tests

CystC and beta-2-microglobulin concentrations may have strong correlation with

markers of kidney damage include(3)

American College of Radiology recommendations for radiologic investigation of causes of

Biopsy and pathology

Other diagnostic testing

Kidney Disease Improving Global Outcomes (KDIGO) recommended markers to measure

renal iothalamate clearance, renal or plasma 51Cr-EDTA clearance, and plasma

whole-exome sequencing may identify diagnostic mutations in adults with CKD of

early referral to nephrologist associated with reduced mortality (level 2 [mid-level]

Fluid and electrolytes

Kidney Disease Improving Global Outcomes (KDIGO) recommendations(3)

Dietary electrolyte restriction

Fruit and vegetable intake

Nutrition in patients on dialysis

European Best Practice Guidelines nutritional recommendations for patients on

Academy of Nutrition and Dietetics (AND) evidence-based nutrition practice guideline on

exercise training associated with improvement in physical ﬁtness in adults with

predialysis educational intervention may improve clinical outcomes in patients

target blood pressure (BP) in patients with CKD

in patients on dialysis, blood pressure-lowering treatment associated with decreased

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers

addition of telmisartan to ACE inhibitors increases survival and reduces heart

addition of spironolactone to angiotensin-converting enzyme inhibitors and/or

Neprilysin/angiotensin receptor inhibitors

Statins in chronic kidney disease (CKD) patients not on dialysis

lipid-lowering therapy with statins reduces major cardiovascular events (level 1

Statins in dialysis patients

statins may not reduce all-cause mortality or cardiovascular mortality in patients

Statins in renal transplant recipients