Diabetic Kidney Disease

Diabetic kidney disease
The right clinical information, right where it's needed
Last updated: Jan 09, 2017

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Prevention 6
Primary prevention 6
Screening 6
Secondary prevention 7
Diagnosis 8
Case history 8
Step-by-step diagnostic approach 8
Risk factors 10
History & examination factors 11
Diagnostic tests 13
Differential diagnosis 14
Diagnostic criteria 16
Treatment 17
Step-by-step treatment approach 17

Treatment details overview 21
Treatment options 23
Emerging 45
Follow up 47
Recommendations 47
Complications 47
Prognosis 48
Guidelines 49
Diagnostic guidelines 49
Treatment guidelines 50
Online resources 53
References 54
Images 65
Disclaimer 67
Summary
◊ Symptoms, which may be absent until the disease is advanced, include fatigue, anorexia, and swelling of the
extremities. Symptoms of retinopathy (impaired vision) and neuropathy (decreased or abnormal sensation in
lower extremities) are common.
◊ Signs include hypertension, oedema, and findings of diabetic retinopathy and neuropathy. In clinical uraemia,
nausea and vomiting, dysgeusia (altered taste), and hiccoughs supervene.
◊ Proteinuria is the characteristic laboratory finding. Azotaemia may develop as the disease advances.
◊ Treatment includes intensive control of hyperglycaemia and hypertension with ACE inhibitors,
angiotensin-receptor blockers (ARBs), or other antihypertensives. Lipid reduction, low-protein diets, and smoking
cessation may be beneficial.
◊ Complications include hypoglycaemia due to intensive treatment of hyperglycaemia, hyperkalaemia as an

adverse effect of ACE inhibitors or ARBs, volume depletion due to diuresis, and inadequate protein/caloric intake
leading to malnutrition. Some patients may reach end-stage renal failure, requiring dialysis.
Diabetic kidney disease Basics
Definition
Diabetic kidney disease (DKD) is defined as macroalbuminuria (albumin to creatinine ratio [ACR] >34 mg/mmol [300
BASICS
mg/g]), or microalbuminuria (ACR 3.4-34.0 mg/mmol [30-300 mg/g]) associated with retinopathy (type 1 or type 2
diabetes) and/or >10 years' duration of type 1 diabetes mellitus.[1] The terms 'moderately increased albuminuria' and
'severely increased albuminuria' are now frequently used instead of microalbuminuria and macroalbuminuria. In most
patients with diabetes, chronic kidney disease (CKD) can be attributable to diabetes if these criteria are met. Other cause(s)
of CKD should be considered in the presence of any of the following circumstances: absence of diabetic retinopathy,
rapidly decreasing GFR, presence of active urinary sediment (e.g., cellular casts in urine), or signs or symptoms of other
systemic disease. The characteristic clinical presentation is progressive albuminuria, hypertension, and decline in GFR in
a long-standing (duration >10 years) diabetic patient. The diagnosis is most conclusively made by kidney biopsy, though
it is rarely necessary.
Epidemiology
The epidemiology of DKD has been best studied in patients with type 1 disease, since the time of clinical onset is usually
known. Approximately 20% to 30% will have microalbuminuria after a mean duration of diabetes mellitus of 15 years.[2]
However, approximately half of these patients will not progress to overt proteinuria.[3] Although in the past it was stated
that the risk of nephropathy was less in type 2 diabetes than in type 1 diabetes, data suggest that the renal risk is
equivalent.[4] Diabetes mellitus is the most common cause of chronic kidney disease (CKD) worldwide.
Aetiology
The aetiology of DKD is multifactorial, with the most important factors being extent and duration of hyperglycaemia,[5]
and hypertension.[6] Other factors that are thought to increase likelihood of DKD, or to increase its progression, are
glomerular hyperfiltration, smoking, obesity, physical inactivity, dyslipidaemia,[7] proteinuria, and high dietary content
of protein and fat. Genetic susceptibility appears to be a prerequisite to development of DKD.[8]
Pathophysiology
DKD is caused by both metabolic alterations (hyperglycaemia and possibly hyperlipidaemia) and haemodynamic alterations
(systemic and glomerular hypertension). Other factors that are the subject of intensive research include inflammation,[9]
endothelial dysfunction,[10] and oxidative stress.[11] Oxidative stress consumes nitric oxide, which prevents flow-mediated
dilation (FMD) of blood vessels (endothelial dysfunction), subjecting the endothelium to injury. This leads to production
of cytokines, acceleration of inflammation, worsening of blood vessel rigidity due to atherosclerosis, and further impairment
of FMD and susceptibility to oxidative stress. From a unified perspective, inflammation, endothelial dysfunction, and
oxidative stress are intertwined in a vicious cycle that leads to significant kidney damage and cardiovascular events. One
study demonstrated that endothelial dysfunction and inflammation were predictors of progression of diabetic kidney
disease in patients with type 2 diabetes and microalbuminuria.[12]
Diabetes mellitus is characterised by high glucose levels and increased glomerular pressure, both of which can cause
glomerular mesangium expansion via increased mesangial stretch. Platelet-derived growth factor (PDGF) and transforming
growth factor-beta (TGF-beta) mediate mesangial expansion and fibrosis via the stimulation of matrix protein (collagen
and fibronectin) synthesis and decreased matrix degradation. Glucose forms advanced glycation end products (AGEs) by
binding irreversibly to proteins. Over years, AGEs form crosslinks, stimulate the release of growth factors such as TGF-beta,
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 09, 2017.
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Diabetic kidney disease Basics
and cause fibrosis. Angiotensin II (ATII), elevated in DKD, constricts the efferent arteriole in the glomerulus, causing high
glomerular capillary pressures, and also stimulates fibrosis and glomerular inflammation. Mesangial expansion is
characteristic of early diabetic glomerulosclerosis and is followed by fibrosis in the late stages. [Fig-3] [Fig-4]
Kimmelstiel-Wilson nodules, [Fig-1] [Fig-2] areas of mesangial expansion on biopsy, are the hallmark of diabetic
BASICS
glomerulosclerosis and are seen in half of the cases of DKD. Increased glomerular basement membrane width, diffuse
mesangial sclerosis, hyalinosis, microaneurysm, and hyaline arteriosclerosis are present in addition to tubular and interstitial
changes.[13] Hypertension, via mesangial stretch, can aggravate progression of diabetic kidney disease.
Glomerular filtration rate (GFR) may be increased at the onset of diabetes mellitus (both in those destined to develop
nephropathy and in those who will not develop nephropathy), but once microalbuminuria is present the GFR is usually
normal. According to the natural history of the disease, macroalbuminuria occurs before a decline in GFR. However,
interventions, especially BP control with drugs that block the renin-angiotensin system, can alter the natural history, and
some patients have a decline in GFR in the absence of macroalbuminuria.
BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use
5
Diabetic kidney disease Prevention
Primary prevention
Intensive treatment of hyperglycaemia and hypertension prevents development of microalbuminuria, as well as progression
to macroalbuminuria, and may slow progression of chronic kidney disease.[5] [6] One systematic review found that ACE
inhibitors prevented new-onset DKD and death in normoalbuminuric people with diabetes; however, the review concluded
that more data were needed with regard to angiotensin receptor blockers (ARBs).[17]
Screening
Chronic kidney disease (CKD) screening is reported to be cost-effective in patients with diabetes and hypertension.[21]
Reason for screening for DKD:
• Detecting microalbuminuria is important because interventions such as renin-angiotensin system (RAS) inhibition
can prevent progression to macroalbuminuria, which is associated with significantly greater morbidity, mortality,
and progression to ESRD.[22] [23]
PREVENTION
• Advanced DKD is more resistant to treatment, is associated with greater cardiovascular morbidity and mortality,
and is more likely to progress to ESRD and dialysis. However, patients with DKD are likely to die of cardiovascular
causes before they progress to kidney failure.[22] [23]
Populations to screen for DKD:[1]
• Type 1 diabetics - 5 years after diagnosis.
• Type 2 diabetics - at the time of diagnosis.
Screening tests for DKD:
• Albumin to creatinine ratio (ACR) annually.[1] [24]
• Advanced DKD is often associated with diabetic retinopathy because of microvascular disease. In the US, screening
for diabetic retinopathy is recommended within 5 years of initial diagnosis of diabetes for adults with type 1 diabetes,
and at diagnosis for adults with type 2 diabetes, and then 2 years thereafter if no evidence of retinopathy. More
frequent follow-up may be required (e.g., annually) if findings are abnormal.[25] In the UK, screening for retinopathy
is offered at the time of diagnosis and annually to all type 1 diabetes patients over the age of 12.[26]
Screening for diabetes mellitus:[25]
• Risk factors for diabetes include:
• Age ≥45 years
• Overweight (body mass index [BMI] ≥25 kg/m2)
• Diabetes mellitus in a first-degree relative
• Sedentary lifestyle
• High-risk ethnic or racial group (e.g., African-American, Hispanic, Native American, Asian-American, and
Pacific Islander)
Diabetic kidney disease Prevention
• History of delivering a baby weighing >4.1 kg (9 lb) or of gestational diabetes mellitus
• Hypertension (blood pressure ≥140/90 mmHg)
• Dyslipidaemia (serum high-density lipoprotein cholesterol concentration ≤35 mg/dL [0.9 mmol/L] and/or
serum triglyceride concentration ≥250 mg/dL [2.8 mmol/L])
• A1C ≥5.7%, impaired glucose tolerance or impaired fasting glucose
• Polycystic ovary syndrome
• History of vascular disease.
The American Diabetes Association (ADA) recommends testing at 3-year intervals for diabetes or pre-diabetes in
all adults with BMI ≥25 kg/m2 and one or more additional risk factors for diabetes using either A1C, fasting plasma
glucose, or 2-hour oral glucose tolerance test. In individuals without risk factors, the ADA recommends that testing
begin at age 45 years.[27]
PREVENTION
The United States Preventive Services Task Force (USPSTF) recommends screening for abnormal glucose as part
of cardiovascular risk assessment in adults aged 40 to 70 years who are overweight or obese. The optimal interval
for screening is unknown. The USPSTF suggests screening every 3 years based on limited evidence.[28]
The Canadian Task Force on Preventive Health Care (CTFPHC) recommends using a validated risk calculator to
identify people at high risk for diabetes. They recommend screening individuals at increased risk with HbA1c, to
be repeated every 3 to 5 years for those at high risk, and yearly for those at very high risk.[29]
The UK National Institute for Health and Care Excellence (NICE) recommends risk assessment using a self-assessment
questionnaire or risk-assessment tool for diabetes for adults aged 40 and above, younger adults in high-risk ethnic
groups, those with a body mass index >30, or those with comorbidities including hypertension or cardiovascular
disease.[30]
Secondary prevention
ACE inhibitors and angiotensin receptor blockers (ARBs) reduce the incidence of microalbuminuria in diabetic patients
with hypertension. In addition, the use of ACE inhibitors or ARBs in patients with normal blood pressure (<130/80 mmHg)
who have microalbuminuria or macroalbuminuria stabilises albuminuria and may reduce progression of DKD, ESRD, and
death.[106] [134]
Aspirin (81 mg) is given in absence of contraindication.
Avoidance of NSAIDs, radiocontrast media, or other nephrotoxic drugs is warranted. For patients with elevated serum
creatinine still <177 micromol/L (<2 mg/dL), low-molecular-weight non-ionic contrast media are associated with decreased
risk for contrast nephropathy. Gadolinium-based MRI contrast agents should be avoided because of a risk of systemic
sclerosis in patients with DKD, especially when GFR is below 30 mL/min/1.73 m^2.
Lipid reducing agents (e.g., statins) to reduce LDL-cholesterol to <2.59 mmol/L (<100 mg/dL) are also indicated.
In a randomised trial, hydration with sodium bicarbonate was not superior to hydration with sodium chloride in preventing
contrast-induced nephropathy in patients with diabetic kidney disease undergoing coronary or endovascular angiography
or intervention.[135] In another randomised trial, rosuvastatin significantly reduced the risk of nephrotoxicity in patients
with DM and chronic kidney disease (CKD) undergoing arterial contrast medium injection.[136]
7
Diabetic kidney disease Diagnosis
Case history
Case history #1
A 25-year-old woman with a 12-year history of poorly controlled type 1 diabetes presents with anasarca (severe
generalised oedema) and impaired vision. She is found to have nephrotic syndrome and proliferative diabetic
retinopathy.
Case history #2
A 50-year-old man with a 15-year history of type 2 diabetes presents with oedema, fatigue, and impaired sensation
in the lower extremities. He is found to have proteinuria, azotaemia, anaemia, background diabetic retinopathy, and
peripheral neuropathy.
Other presentations
DKD can present with macroalbuminuria, and even nephrotic syndrome (massive proteinuria, hyperlipidaemia, oedema
and hypoalbuminaemia), in patients with type 2 diabetes without other microvascular complications (e.g., retinopathy).
Step-by-step diagnostic approach

History
Patients destined to develop DKD usually have poorly controlled diabetes and a family history of hypertension and/or
kidney disease. They may also have hypertension and in particular nocturnal hypertension (non-dippers). Patients
who do develop DKD may have no symptoms of kidney disease until the disease is quite far advanced. In advanced
stages, patients may develop constitutional symptoms such as fatigue and anorexia. As patients become clinically
uraemic, symptoms such as nausea and vomiting, dysgeusia (altered taste), and hiccoughs supervene.
Symptoms of numbness in the legs (suggestive of peripheral neuropathy), poor vision (suggestive of retinopathy or
DIAGNOSIS
cataracts), and pain in the legs (suggestive of neuropathy, or peripheral vascular disease) are typical of advanced
diabetes mellitus and should prompt further evaluation for DKD.
Physical examination
In the early stages of the disease, physical examination may be normal. Physical examination should assess for findings
of diabetic kidney disease, including hypertension and peripheral oedema, as well as for other microvascular
complications of diabetes mellitus, such as:
• Retinopathy: decreased vision, retinal findings including dot and blot haemorrhages, microaneurysms
(background retinopathy), and/or neovascularisation (proliferative retinopathy)
• Neuropathy: decreased sensation in lower extremities in 'stocking' pattern, foot ulcers, Charcot joints (peripheral
neuropathy), and/or orthostatic hypotension without increase in heart rate (autonomic neuropathy).
Physical examination should also assess for macrovascular complications, including hypertension, vascular bruits,
decreased pulses in extremities, and ischaemic ulcers. Other findings of long-standing and/or poorly controlled
diabetes may be evident, including:
• Skin changes, such as xerosis (abnormal dryness of the skin), hyperpigmentation, necrobiosis lipoidica, and
acanthosis nigricans
• Costovertebral tenderness or a positive kidney punch, which is a sign of pyelonephritis (a not uncommon
complication in diabetes)
• Muscular atrophy
• Pallor, which may signify anaemia.
In overtly uraemic patients, pericardial and/or pleuritic friction rubs, asterixis, and/or myoclonus may be evident.
There may be platelet dysfunction, which manifests as bleeding tendency. Metabolic acidosis may be accompanied
by Kussmaul's respirations.
Tests
Tests performed in the assessment of DKD include:
1. Urinalysis
• This may show proteinuria. Increased specific gravity may point to pre-renal causes of azotaemia.
• Urinary leukocytes, bacteria, and nitrites indicate urinary tract infection.
• An active urinary sediment with RBC casts should prompt evaluation for non-diabetic causes of glomerular
disease (glomerulonephritis). Other aetiologies of chronic kidney disease (CKD) need to be excluded if there is
active urine sediment (i.e., cellular casts), rapid progression of nephrosis and/or renal failure, absence of
retinopathy, short duration of diabetes mellitus, or manifestations of another systemic disease.[1]
• After the initial screen, urinalysis is not needed unless there is a specific indication (e.g., unexpected rapid decline
in renal function, symptoms of urinary tract infection).
DIAGNOSIS
2. Quantification of albuminuria
• Albuminuria may be quantified by the urinary albumin:creatinine ratio (ACR) in a spot sample, or quantified in
a timed (e.g., 24-hour) urine collection.
• If no urinary tract infection is present and the first ACR is increased, the test should be repeated with 2 subsequent
collections of first-void urine specimens during the next 3 to 6 months, to confirm diagnosis.[1]
• Detecting microalbuminuria is important because early intervention can prevent progression to

macroalbuminuria.
• ACR on a first-void spot urine specimen is the preferred test; a random spot urine specimen is an acceptable
alternative.[18]
3. Blood biochemistry
• Serum creatinine should be measured and the estimated glomerular filtration rate (GFR) calculated.[1] [National
Kidney Foundation: MDRD GFR Calculator]
9
4. Imaging
• Initial imaging should include ultrasound, which is useful to demonstrate kidney size and rule out differentials
such as hydronephrosis, pyelonephritis, and stones. Kidney size may initially be large if diabetes is uncontrolled,
but is usually normal once DKD supervenes. Doppler ultrasound may demonstrate renal artery stenosis.
• CT scan is useful to demonstrate hydronephrosis and kidney size and may also help to clarify a possible differential
diagnosis.
• Magnetic resonance angiography (MRA) is useful in diagnosing renal artery stenosis or vasculopathies.
5. Kidney biopsy:
• The most sensitive and specific test for diagnosing DKD is a kidney biopsy. Although rarely necessary, it may
be indicated under certain circumstances. Such circumstances include: people with type 1 diabetes who have
had diabetes mellitus for a short period of time; people with type 2 diabetes who do not have retinopathy; a
rapid decline in renal function associated with an active urine sediment; or evidence of another systemic disease.
Risk factors
Strong
sustained hyperglycaemia
• An elevated HbA1c increases the risk of developing DKD. Duration of diabetes is usually >10 years.[5]
hypertension (HTN)
• Uncontrolled HTN causes more rapid decline in glomerular filtration rate (GFR).
• Aggressive treatment of HTN reduces the rate of progression of chronic kidney disease, including the incidence
of microalbuminuria and the progression of microalbuminuria to macroalbuminuria.
DIAGNOSIS
FHx of HTN and/or kidney disease

• DKD is typically seen in patients with a FHx of HTN and/or kidney disease.
• The genetic predisposition is complex and is the subject of much current research.
• The importance of genetic factors is highlighted by the observation that only a minority of diabetic patients develop
DKD.
obesity
• Obesity can predict the development of type 2 diabetes as well as reduce GFR and increase proteinuria. Obese
patients have elevated leptins that stimulate the inflammatory process; although leptins should cause weight loss,
hypothalamic resistance in obese diabetic people creates a vicious cycle of leptin production, inflammation, and
weight gain.[14]
smoking
• Studies document a relation between smoking and loss of GFR. The mechanisms underlying the adverse renal
effects of smoking are still incompletely understood.
Weak
physical inactivity
• Physical inactivity is a known risk factor for the development of type 2 diabetes. Exercise may reduce proteinuria
and stabilise GFR decline in chronic kidney disease (CKD), but studies specifically in patients with DKD are needed.[15]
dyslipidaemia
• There are insufficient data on whether statins prevent decline in GFR or whether they decrease proteinuria.
high protein, fat and sodium intake

• Diets with high protein, high saturated fat, high cholesterol and high sodium are associated with progression of
DKD. There are weak data to support the claim that low-protein diets prevent decline in GFR and reduce progression
of proteinuria.[16]
History & examination factors

Key diagnostic factors
presence of risk factors (common)

• Key risk factors include sustained hyperglycaemia; hypertension (HTN), in particular nocturnal hypertension; FHx
of HTN/kidney disease; obesity; and smoking.
hypertension (HTN) (common)

• Characteristic of DKD.
signs of retinopathy (common)

• Chronic kidney disease (CKD) with microalbuminuria in diabetic people with retinopathy fulfils the criteria for
diagnosis of DKD.
• Retinal findings include dot and blot haemorrhages, microaneurysms (background retinopathy), and/or
neovascularisation (proliferative retinopathy).
DIAGNOSIS
oedema (common)
• May be present in advancing DKD, which can also present with nephrotic syndrome.
Other diagnostic factors

poor vision (common)
• Retinopathy is usually present in patients with DKD.
numbness of the lower extremities (common)

• Peripheral neuropathy is a sign of advanced diabetes mellitus and may be present in a patient with DKD. Its presence
should prompt further evaluation of kidney function to establish if DKD is also present.
• It presents with impaired sensation in the feet, and loss of vibration, pain, temperature, and position sense in the
lower extremities. Carpal tunnel syndrome may cause symptoms in the hands in patients with DKD. Charcot joints
may also be present.
pain of the lower extremities (common)
11
• Claudication in a patient with diabetes mellitus and CKD should prompt evaluation for prevention, screening, and
diagnosis of DKD.
• Reduced pulses may be detected on palpation.
• May also signify painful neuropathy.
constitutional symptoms (advanced disease) (common)

• Fatigue and anorexia may be present in advanced disease. As patients become clinically uraemic, symptoms such
as nausea and vomiting, dysgeusia (altered taste), and hiccoughs supervene.
foot changes (common)

• Foot ulcers and Charcot joints may be present in DKD.
orthostatic hypotension (uncommon)

• Can occur if autonomic neuropathy is present.
skin changes (uncommon)

• Xerosis (abnormal dryness of the skin) is due to atrophy of eccrine and sebaceous sweat glands. Hyperpigmentation
due to melanin deposition and sallow or yellow skin due to urochrome deposition is common in CKD. Necrobiosis
lipoidica and acanthosis nigricans may be found in DKD.
muscular atrophy (uncommon)

• Muscular atrophy may be present in DKD.
pallor (as GFR declines) (uncommon)

• Anaemia due to lack of erythropoietin or anaemia of chronic disease may cause pallor.
bleeding tendency (advanced disease) (uncommon)

• Platelet dysfunction manifests as easy bruising, bleeding gums, or epistaxis.
Kussmaul's respirations (advanced disease) (uncommon)

DIAGNOSIS
• Metabolic acidosis (due to either ketoacidosis or end-stage renal disease) may be accompanied by Kussmaul's
respirations, characterised by deep inspiratory efforts without tachypnoea.
Diagnostic tests
1st test to order
Test Result
urinalysis proteinuria
• Proteinuria indicates nephropathy is present.
• Increased specific gravity may point to pre-renal causes of azotaemia.
• Urinary leukocytes, bacteria and nitrites indicate urinary tract infection.
• An active urinary sediment with RBC casts should prompt evaluation for
glomerulonephritis. Other aetiologies of chronic kidney disease (CKD) need to
be excluded if there is active urine sediment (i.e., cellular casts), rapid
progression of nephrosis and/or renal failure, absence of retinopathy, short
duration of diabetes mellitus, or manifestations of another systemic disease.[1]
• After the initial screen, urinalysis is not needed unless there is a specific
indication (e.g., unexpected rapid decline in renal function, symptoms of urinary
tract infection).
urinary albumin to creatinine ratio (ACR) may be elevated
• Performed on spot urine collection.
• If no urinary tract infection is present and the first ACR is raised, the test should
be repeated with 2 subsequent collections of first-void urine specimens during
the next 3 to 6 months, to confirm diagnosis.[1]
blood biochemistry elevated creatinine
• Important baseline test.
serum creatinine with GFR estimation Glomerular filtration rate (GFR)
may be raised in CKD stage 1,
• GFR may be calculated using the patient's serum creatinine, age, race, and
normal in CKD stage 2, and
sex.[1] [National Kidney Foundation: MDRD GFR Calculator]
reduced in CKD stages 3 to 5
kidney ultrasound normal-to-large kidneys with

• Kidney size may initially be large if diabetes uncontrolled, but usually normal increased echogenicity; may
DIAGNOSIS
show hydronephrosis if
once DKD supervenes.
• Ultrasound is important to exclude other causes of renal impairment in diabetic vesiculopathy and/or
obstruction is superimposed
patients, such as obstruction, infection, cysts, or mass. Pyelonephritis may
show as swelling of the parenchyma.
Other tests to consider
Test Result
24-hour urine collection microalbuminuria: albumin 30
to 300 mg/24 hours;
• Allows quantification of albuminuria.
macroalbuminuria: albumin
>300 mg/24 hours
CT abdomen may show hydronephrosis;

• CT scan is rarely warranted but may be useful if ultrasound is of poor quality in wedge-shaped areas of low
obese patients or if follow-up imaging is required to clarify pathology seen on attenuation; loss of the ability
to distinguish the
ultrasound.
• Can exclude hydronephrosis, pyelonephritis, kidney stones, cysts, masses, renal corticomedullary border;
perinephric stranding; cysts;
cell carcinoma, and abnormal kidney ureter or bladder architecture.
masses; stones
13
Test Result
magnetic resonance angiography to rule out renal artery stenosis
• Magnetic resonance angiography (MRA) should be considered in patients who
develop renal failure shortly after an ACE inhibitor has been started, or in
patients with refractory HTN who have failed to respond to 3 of 4
antihypertensives. Gadolinium should not be given if the estimated GFR is <30
mL/min/1.73 m^2.
Doppler ultrasound may show renal artery stenosis
• Provides haemodynamic information about renal artery flow.
kidney biopsy mesangial expansion, fibrosis,
Kimmelstiel-Wilson nodules
• Considered in the following circumstances: in patients with type 1 diabetes
who have had diabetes mellitus for a short period of time; in patients with type
2 diabetes who do not have retinopathy; if there is a rapid decline in renal
function associated with an active urine sediment; or if there is evidence of
another systemic disease.
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Non-diabetic kidney disease • Since both diabetes mellitus and • Minimal proteinuria may indicate
chronic kidney disease (CKD) are non-diabetic kidney disease.
common disorders, patients with • Other specific diagnostic tests for
both conditions may or may not other systemic disorders
have DKD. associated with non-diabetic
• A diagnosis other than DKD kidney disease may be positive
should be considered if there is a (e.g., serum protein
rapid progression of renal failure, electrophoresis or serum free
evidence of another systemic light chains in myeloma, ANA in
DIAGNOSIS
disease, or short duration of SLE, ANCA in vasculitis,

diabetes (although onset is hypocomplementaemia in SLE,
insidious in type 2, and DKD may cryoglobulinaemia).
occasionally be the presenting
manifestation of type 2 diabetes
mellitus).

symptoms
Multiple myeloma • Multiple myeloma (MM) patients • The characteristic test results that
also may present with renal failure differ from DKD are: the presence
and proteinuria. of
• Symptoms of bone pain and paraproteinaemia/paraproteinuria;
anaemia are the most common hypercalcaemia; impaired
presenting features, affecting production of normal
80% of patients with MM. immunoglobulin; and lytic bone
lesions.[19]
• Urinalysis with sulfosalicylic acid
(SSA) was classically utilised to
evaluate for discrepancy between
albumin and total protein, as
standard urinalysis dipstick
detects albumin only. SSA causes
precipitation of all of the urinary
proteins, including paraproteins
(Bence Jones proteins).
• Serum protein electrophoresis
(PEP), urine protein
electrophoresis (UPEP):
paraprotein spike.
• Serum and urine free light chains:
increased concentrations of free
light chain in serum.
• Skull x-rays, CT, or MRI bone: lytic
lesions.
• Bone marrow biopsy: plasma cell
proliferation.
Renal tract obstruction • Can be caused by stones, cancer, • Passage of Foley catheter may
fibrosis, prostate result in flow of urine and relief of
hypertrophy/cancer, neurogenic obstruction.
bladder, or pelviureteric junction • Kidney ultrasound:
DIAGNOSIS
obstruction. hydronephrosis, stones.
• Obstruction to urine flow can • Prostate ultrasound: hypertrophy,
result in post-renal failure. cancer.
Symptoms include trouble • CT abdomen: hydronephrosis,
passing urine, anuria, oliguria, stones, mass, congenital
haematuria, pain (with kidney abnormalities, fibrosis.
stones), and urinary • PSA: elevated in BPH, prostate
leakage/incontinence. cancer.
• Physical examination findings • MRI: not routine but may show
include enlarged prostate on hydronephrosis, stones, mass,
rectal examination, costovertebral congenital abnormalities, fibrosis.
angle tenderness, suprapubic
tenderness, and bladder fullness.
15

symptoms
Glomerulonephritis • Glomerulonephritis, such as lupus • Urinalysis: haematuria,
nephritis and cryoglobulinaemia, proteinuria, RBC casts,
is in the differential for DKD. dysmorphic red cells.
• Patient presentation and physical • Albuminuria.
examination may be similar to • Positive serology (e.g., ANA, ANCA,
that of DKD. However, there may hepatitis serology).
be symptoms and signs of other • Complement: decreased in
systemic disease, such as rashes immune glomerulonephritis (e.g.,
or joint involvement. lupus).
• Kidney biopsy:
glomerulonephritis.
Renal artery stenosis • Renal artery stenosis presents • Ultrasound, CT scan, MRI:
either as HTN refractory to shrunken kidney, decreased flow
multiple maximised through the renal artery.
antihypertensives or as renal • Magnetic resonance angiography
failure shortly after the initiation (MRA): renal artery stenosis.
of an ACE inhibitor or • Renal angiogram: renal artery
angiotensin-receptor blockers stenosis.
(ARBs).
• Physical examination is significant
for an abdominal bruit.[20]
Diagnostic criteria
Staging of diabetic nephropathy[1]

DKD is classified according to presence of microalbuminuria (30-300 mg albumin/24 hours or albumin to creatinine ratio
[ACR] of 3.4-34.0 mg/mmol [30-300 mg/g]) or macroalbuminuria (>300 mg albumin/24 hours or ACR >34 mg/mmol
[300 mg/g]).
DIAGNOSIS
Diabetic kidney disease Treatment
Step-by-step treatment approach

General approach
In order to minimise the progression of DKD, treatment should be comprehensive and should involve simultaneous
evaluation and intervention of hyperglycaemia, hypertension, dyslipidaemia, nutrition, and behaviour. Patient behaviour
and self-management significantly improves diabetic outcomes and diabetic kidney disease outcomes.[31] [32]
Proper nutrition, with decreased intake of saturated fat, cholesterol, and salt, is beneficial. Treatment guidelines for
US practice have been published in 2012.[33] [34]
Treatment of hyperglycaemia
Treatments for hyperglycaemia include insulin and oral hypoglycaemic agents (e.g. sulfonylureas, meglitinides, and
dipeptidyl peptidase-4 [DPP-4] inhibitors). Regardless of which treatment is used, caution must be taken when
administering to patients with chronic kidney disease (CKD) as there is a risk for hypoglycaemia because of impaired
kidney clearance of medications such as insulin (two-thirds of insulin is degraded by the kidney) or sulfonylureas, and
because of impaired kidney gluconeogenesis.
Type 1 diabetes patients require treatment with insulin regardless of whether they are on dialysis or not. Type 2
diabetes patients with CKD who are not on dialysis may begin with an oral hypoglycaemic agent (e.g., metformin if
eGFR adequate; or else glipizide, repaglinide, or sitagliptin), and then insulin can be added or substituted as needed.
Metformin, generally the first choice oral hypoglycaemic agent for type 2 diabetes, is contraindicated when eGFR is
<30 mL/min/1.73 m^2 and should be used only with caution when 30-45 mL/min/1.73 m^2.[35] Glipizide is the
sulfonylurea agent of choice due to its metabolite having little or no hypoglycaemic activity.[34] Repaglinide is a
meglitinide and is considered within its drug class to be safest for CKD for similar reasons.[36] Sitagliptin, a DPP-4
inhibitor, can also be used, but the dose must be adjusted depending on the degree of renal dysfunction.[37] Other
DPP-4 inhibitors, such as saxagliptin and linagliptin, can also be used in patients with CKD, including ESRD, though
there is limited experience with their use. Saxagliptin requires a dose adjustment in renal impairment. Linagliptin has
the advantage that it is not renally cleared and thus a dose adjustment is not necessary. Type 2 diabetes patients who
are on dialysis (e.g., due to end-stage renal disease) are preferentially treated with insulin. However, low-dose oral
hypoglycaemic agents (e.g. glipizide or sitagliptin) can be used either instead of insulin or added to insulin. There is
no evidence to support the use of repaglinide in dialysis patients.
Although there is evidence showing that thiazolidinediones reduce hyperglycaemia, albuminuria, and proteinuria in
people with diabetes, the clinical significance of this finding is unclear.[38] Thiazolidinediones are associated with
fluid retention, and rosiglitazone has been withdrawn in Europe due to associated cardiovascular risk, though previous
restrictions applied to rosiglitazone have since been lifted in the US. Studies with sodium glucose co-transporter 2
(SGLT2) inhibitors suggest that they may be effective in mild to moderate CKD, though data are conflicting.[39] [40]
They are not effective in patients with eGFR <30 mL/min/1.73 m^2, including patients with ESRD who are on dialysis.
A number of studies have investigated the benefits of intensive glycaemic control for nephropathy, but this approach
remains under scrutiny. Intensive treatment may prevent DKD, including development of microalbuminuria, but there
is little evidence that it slows the progression of established CKD.[5] [41] In addition, it has not been shown to reduce
cardiovascular risk, which is the major cause of mortality in people with diabetes.
TREATMENT
In type 1 diabetes, the Diabetes Control and Complications (DCCT) Research Group trial demonstrated that intensive
treatment was associated with decreased incidence of microalbuminuria and reduced progression to macroalbuminuria
compared with conventional treatment.[42] The Stockholm study showed similar findings.[43]
17
In type 2 diabetes, the UK Prospective Diabetes Study (UKPDS) Group trial demonstrated a reduced incidence of
microalbuminuria in the intensively treated group compared with conventional treatment, but a parallel finding in
macroalbuminuria was not significant.[44] In another study, intensive management of patients with type 2 diabetes
detected by screening (including glucose control) was not associated with significant reductions in the frequency of
microvascular events at 5 years when compared with routine care.[45] The Kumamoto study[46] and the Veterans
Affairs Cooperative study[47] have both shown intensive treatment to be effective for primary prevention (decreased
incidence of microalbuminuria) and secondary prevention (reduced progression to macroalbuminuria).
The Epidemiology of Diabetes Interventions and Complications (EDIC)/DCCT follow-up study[5] and the UKPDS
study[44] also found that lowering HbA1c reduced decline in GFR in type 1 and type 2 diabetes, respectively. However,
it is not clear whether this is the case for long-standing type 2 diabetes, as shown in the Veterans Affairs Cooperative
study.[47]
The ADVANCE study treated hyperglycaemia with gliclazide and BP with perindopril/indapamide. The findings
demonstrated that intensive glucose control and BP lowering were independently beneficial and their combination
produced synergistic benefits in nephropathy, new-onset microalbuminuria, and new-onset macroalbuminuria.[48]
In fact, the combination of BP lowering and intensive glucose control reduced cardiovascular mortality and all-cause
mortality, and improved renal outcomes.[49] [50] Intensive glucose control was not associated with a significant
reduction in macrovascular events.[51] However, one analysis of ADVANCE found that the number of individuals
needed to treat with intensive glucose control to prevent one case of ESRD ranged from 410 individuals overall, to
41 individuals with overt albuminuria.[52]
The benefits of intensive glucose control have been re-demonstrated in a more recent review.[53] However, in the
Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, assignment of the treatment group to an HbA1c
goal of <42 mmol/mol (6%) led to increased mortality and cessation of the trial.[54] In contrast to findings of the
ADVANCE study, in one analysis of data from the ACCORD study, combined intensive BP and glycaemic control did
not produce an additive benefit on microvascular outcomes in type 2 diabetic patients.[55]
In one study in patients with type 2 diabetes, intensive glycaemic control had no significant effect on the progression
of renal disease. However, it was associated with some protection against increasing albuminuria in those with more
advanced microvascular disease, lower baseline DBP, or higher baseline BMI, and with worsening of eGFR in those
with high baseline ACR.[56]
UK guidelines recommend a target HbA1c in type 2 diabetes of 48 mmol/mol (6.5%) (although this may be set at a
slightly higher target depending on the individual).[57] Current American Diabetes Association guidelines recommend
keeping HbA1c at ≤53 mmol/mol (7%), except for patients with a history of severe hypoglycaemia, limited life
expectancy, advanced diabetic complications and comorbidity, or long-standing diabetes, where a less stringent goal
may be appropriate (e.g., <8%).[25] These guidelines have been adopted for patients with CKD by the National Kidney
Foundation, who also stress that less intensive control is warranted in individuals at risk for hypoglycaemia, substantial
comorbidities, or limited life expectancy.[33] A Cochrane review has concluded that intensive glucose control reduces
the risk of developing microvascular diabetes complications, but the evidence of benefit is mainly from studies in
younger patients at early stages of the disease. Benefits need to be weighed against risks including severe
hypoglycaemia in older patients and in those with diabetic complications. Treatment goals need to be individualised,
taking into account age, disease progression, and macrovascular risk, as well as the patient's lifestyle and disease
TREATMENT
management capabilities.[58]
Treatment of hypertension
Treatment of hypertension reduces progression of DKD.[6] Past recommendations were that BP should be maintained
at ≤130/80 mmHg.[59] Intensive blood pressure lowering provides protection against kidney failure, particularly
among those with proteinuria.[60] A BP goal of <140/90 mmHg is currently recommended by the Joint National
Committee 8 (JNC 8) for patients aged 18 to 59 years without major comorbidities (e.g., diabetes or CKD), and for
patients of all ages who have diabetes or CKD, or both.[61] The American Diabetes Association also recommend a BP
goal of <140/90 mmHg for patients with diabetes and hypertension.[25] This recommendation is based primarily on
the findings of the ACCORD BP trial, which found no significant cardiovascular benefit and more drug side effects at
a mean attained systolic pressure of 119.3 compared with 133.5 mmHg, with the exception of a reduction in
stroke.[62]Patients with DKD may, however, benefit from lower BP targets as recommended by Kidney Disease:
Improving Global Outcomes.[63] For adults with diabetes and CKD, the Kidney Disease: Improving Global Outcomes
(KDIGO) guidelines recommend a BP goal of ≤140/90 mmHg if urinary albumin excretion is less than 30 mg/24 hours,
or a BP goal of ≤130/80 mmHg if urinary albumin excretion is 30 mg/24 hours or more. The American Diabetes
Association (ADA) states that systolic blood pressure <130/80 mmHg may be appropriate for certain individuals with
diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional
atherosclerotic cardiovascular disease risk factors, if this can be achieved without undue treatment burden. A recent
analysis of the VA-NEPHRON D trial supports a BP goal of <140/80 mmHg.[64]
First-line treatment should include ACE inhibitors or angiotensin receptor blockers (ARBs). The ONTARGET study
demonstrated that ARBs and ACE inhibitors are equal in prevention of cardiovascular morbidity and mortality, MI, and
stroke.[65] [66] Moreover, renoprotective effects are also similar.[67] ACE inhibitors slow progression of DKD in type
1[68] and type 2[69] diabetic patients with microalbuminuria. One study could not demonstrate prevention of
nephropathy with renin-angiotensin system (RAS) blockade in normoalbuminuric patients, but did demonstrate
slowed progression of retinopathy.[70] Losartan, independent of its effect on BP, has been shown also to reduce
proteinuria in people with normotensive type 2 diabetes.[71] The ADVANCE trial demonstrated renoprotection with
perindopril/indapamide in normotensive individuals.[72] There is some research to suggest that drugs that block the
renin-angiotensin system (ACE inhibitors and ARBs) reduce the risk of ESRD and worsening creatinine but may not
have an effect on all-cause mortality.[73]
Dual therapy with ACE inhibitor and ARB has been extensively studied in patients with albuminuria, including DKD.[74]
Meta-analyses have found that dual blockade reduced proteinuria to a greater extent than monotherapy, and was
associated with a decrease in BP, but also a small decline in GFR and increase in serum potassium.[75] [76] However,
the Canadian Hypertension Education Program (CHEP) recommends against combining ACE inhibitors and ARBs in
people with uncomplicated hypertension, CKD without proteinuria, or coronary artery disease without co-existing
systolic heart failure.[77] The ONTARGET study also demonstrated that combined renin-angiotensin system inhibition
achieved no further benefits and was associated with more adverse events.[65] [66] In patients with vascular risk,
dual therapy reduced proteinuria but worsened renal outcomes (dialysis, doubling of creatinine, and death). The
patient population in ONTARGET was at low renal risk, and thus this study is possibly not applicable to patients with
overt proteinuria. However, two large clinical trials in diabetic patients with overt proteinuria (ALTITUDE,[78] NEPHRON-D
[79]) have been stopped due to adverse safety events. On the basis of this evidence, dual blockade should not be
employed in patients with overt DKD.[79]
Diuretics in conjunction with ACE inhibitors and ARBs provide the clinician with a greater ability to achieve
recommended BP levels in DKD patients with hypertension, most of whom will require 3 to 4 agents to reach BP
goals.[80] Diuretics are generally ineffective for BP management in dialysis patients due to markedly impaired renal
function. In selected patients with residual renal function, loop diuretics may still be efficacious in preventing fluid
TREATMENT
overload and hypertension as adjunctive therapy to ultrafiltration during dialysis. Moderation of dietary sodium
potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.[81]
Carvedilol has a beneficial effect on glycaemic control as well as insulin resistance and is a valuable agent as part of
antihypertensive regimens in patients with diabetes mellitus and CKD.[82]
19
Non-dihydropyridine calcium-channel blockers are also protective against proteinuria. Dihydropyridine calcium-channel
blockers such as amlodipine are not recommended as lone therapy because they worsen proteinuria and have not
been shown to improve outcomes.[83] However, they are acceptable if the patient is already on an ACE inhibitor or
an ARB.[84] One study found that trandolapril/verapamil was not superior to benazepril/amlodipine.[85] Another
study showed that benazepril/hydrochlorothiazide resulted in greater reduction in proteinuria than
benazepril/amlodipine.[86]
Finally, in a recent large meta-analysis examining efficacy and safety of antihypertensive agents in diabetic patients
with CKD, no blood pressure-lowering strategy prolonged survival. ACE inhibitors and ARBs, alone or in combination,
were the most effective strategies to prevent end-stage kidney disease. However, the authors confirmed that combined
ACE inhibitor and ARB treatment risks potential harms of hyperkalaemia and acute kidney injury.[87]
Treatment of dyslipidaemia
People with diabetes mellitus and CKD have a high risk of cardiovascular events. Owing to the high risk of cardiovascular
disease (CVD) in diabetic people, management of cardiovascular risk must be a strong consideration in people with
DKD in order to reduce mortality from CVD.[33] Guidelines from the American College of Cardiology/American Heart
Association (ACC/AHA),[88] ADA,[25] and KDIGO[89] recommend that lipid treatment (e.g., with statins) should be
guided by CVD risk. Diabetic patients with atherosclerotic cardiovascular disease should be treated with high-intensity
statin therapy. The addition of ezetimibe to moderate-intensity statin therapy should be considered for patients with
a recent acute coronary syndrome or for those patients who cannot tolerate high intensity statin therapy. One
systematic review and meta-analysis of fibrate therapy concluded that these agents also prevented cardiovascular
events and decreased proteinuria in mild to moderate CKD; however, their effects on long-term kidney outcomes
are unknown.[90] Fibrates are not generally recommended in CKD patients, especially those with eGFR <30
mL/min/1.73 m^2.
KDIGO considers non-dialysis CKD to be a CVD risk equivalent, and it recommends statin therapy (e.g., with atorvastatin
or rosuvastatin) for all non-dialysis CKD patients ages 50 years or older; no specific treatment target is given.[89]
Patients with diabetes and CKD may derive great cardiovascular benefit from statins,[7] and there is some evidence
that statins may have a beneficial effect on kidney function.[91]
In patients on dialysis, KDIGO recommends continuation of statin therapy if the patient is already receiving these
agents, but not to start statin therapy due to lack of evidence of benefit in ESRD. This is because the 4D study failed
to show any benefit of statins on cardiovascular outcomes in such patients.[92] Moreover, in the SHARP study, a
reduction of LDL-cholesterol with simvastatin plus ezetimibe reduced the incidence of major atherosclerotic events
in non-dialysis CKD, though there was no significant benefit in ESRD.[93]
Nutrition
According to the American Dietetic Association, medical nutrition therapy by a registered dietician is recommended
for patients with type 1 or type 2 diabetes.[94] An initial series of 3 to 4 encounters results in positive outcomes,
including reductions in HbA1c, lipids, and weight, a positive adjustment in medications, and a decrease in comorbidities.
In addition, patients should have a follow-up visit annually.[94] There are some data to support the claim that low-protein
diets prevent decline in GFR and reduce progression of proteinuria.[16] Dietary protein restriction of 0.8 g/kg of ideal
body weight per day is suggested.[16] High-protein diets should be avoided. However, other research has suggested
TREATMENT
that a low-protein diet does not improve renal function in type 1 or type 2 diabetic kidney disease.[95] In addition, a
systematic review was unable to show a benefit of protein restriction on renal failure.[96] Limited intake of saturated
fat, cholesterol, and sodium (2.3 g/day) is beneficial.[97] Salt restriction may prevent the onset of diabetic kidney
disease in diabetes.[98] Although a multivitamin is recommended, high doses of B vitamins have been found to result
in increased vascular events.[99]
Smoking cessation
Smoking cessation is strongly recommended, as studies document a relation between smoking and loss of GFR. The
mechanisms underlying the adverse renal effects of smoking are still incompletely understood. Beyond its effect on
progression of renal failure, smoking is also an important cardiovascular risk factor in CKD patients.[100]
Due to the increasing use of e-cigarettes, the American Diabetes Association guidelines make it clear that e-cigarettes
are not supported either as an alternative to smoking or to facilitate smoking cessation.[25]
Pancreas kidney transplantation

Diabetes is the most common cause of ESRD requiring renal replacement therapy (RRT). RRT is not only time consuming
and fraught with uncomfortable side effects such as cramps, fatigue, and central venous stenosis, but it is also
associated with significant morbidity and mortality. Pancreas kidney transplantation not only frees patients from the
need for RRT but also has a significant survival benefit. With modern surgical and immunosuppressive protocols,
5-year patient survival is 95%, kidney survival is 90%, and pancreas survival is greater than 80%.[101] In the US, in
2013, 760 simultaneous pancreas kidney (SPK) transplants, 127 pancreas transplants alone (PTA), and 107 pancreas
after kidney (PAK) transplants were performed.[102]
SPK recipients are generally younger (60 years or less) than kidney transplant recipients (70 years or less). They are
usually patients with type 1 diabetes who have hypoglycaemia unawareness or markedly uncontrolled diabetes; they
usually are on insulin therapy (typically <1 unit/kg/day) and their C-peptide is less than 2 nanograms/mL. Patients
with type 2 diabetes may be considered if they do not have significant insulin resistance (C-peptide >2 and BMI <30),
In addition, recipients must have a GFR <20 mL/min/1.73 m^2 or be dialysis dependent. They must go through strict
cardiovascular, psychosocial, and anatomical (CT angiogram) clearance.[101]
Treatment details overview

Consult your local pharmaceutical database for comprehensive drug information including contraindications, drug
interactions, and alternative dosing. ( see Disclaimer )
Ongoing ( summary )
Patient group Tx line Treatment
type 1 diabetes with nephropathy: not on 1st glycaemic control

dialysis
plus ACE inhibitor or angiotensin receptor blocker (ARB)
plus nutrition
plus smoking cessation
adjunct statin
with BP not controlled below plus added diuretic

130/80 to 140/90 by ACE
inhibitor/ARB
TREATMENT
with BP not controlled below plus added beta-blocker

130/80 to 140/90 by ACE
inhibitor/ARB + diuretic
with BP not controlled below plus added calcium-channel blocker

130/80 to 140/90 by ACE
21
Ongoing ( summary )
inhibitor/ARB + diuretic +
beta-blocker

dialysis
plus nutrition
adjunct statin

130/80 to 140/90 by ACE
inhibitor/ARB

130/80 to 140/90 by ACE
inhibitor/ARB + diuretic

130/80 to 140/90 by ACE
inhibitor/ARB + diuretic +
beta-blocker
on peritoneal dialysis or haemodialysis 1st glycaemic control
plus nutrition
adjunct statin

130/80 to 140/90 by ACE
inhibitor/ARB

130/80 to 140/90 by ACE
inhibitor/ARB + beta-blocker
2nd consideration for pancreas-kidney transplantation

TREATMENT
Treatment options
Ongoing
dialysis » In all type 1 diabetic patients, regardless of whether
they are on dialysis or not, treatment with insulin is
needed. Insulin is usually given subcutaneously.
» Diabetes patients with chronic kidney disease (CKD)

are at risk for hypoglycaemia because of impaired
clearance of insulin, and because of impaired kidney
gluconeogenesis.
» Current guidelines recommend keeping HbA1c at

≤7%, except for patients with a history of severe
hypoglycaemia, limited life expectancy, advanced
diabetic complications and comorbidity, or
long-standing diabetes, where a less stringent goal may
be appropriate (e.g., <8%).[25] [33] Treatment goals
need to be individualised, taking into account age,
disease progression, and macrovascular risk, as well as
the patient's lifestyle and disease management
capabilities.[58]
» Intensive treatment of hyperglycaemia may prevent

the development of microalbuminuria as well as
progression to macroalbuminuria, though there is little
evidence that it slows the progression of established
CKD.[5]
Primary options
» insulin lispro: injected subcutaneously three times

daily before meals
-and-
» insulin glargine: injected subcutaneously once
daily

» Treatment of hypertension reduces progression of
DKD.[6] BP should probably be maintained at ≤130/80
mmHg in patients with overt proteinuria.[59] [61] [63]
However, some guidelines recommend a less stringent
BP goal of <140/90 mmHg,[25] [61] which is based on
findings from the ACCORD BP trial.[62] One analysis of
the VA-NEPHRON D trial supports a BP goal of <140/80
mmHg.[64]
TREATMENT
» ACE inhibitors have been shown to slow progression

of DKD in type 1 diabetic patients with
microalbuminuria.[68] In type 2 diabetic patients with
microalbuminuria, ACE inhibitors and ARBs have been
shown to slow progression of DKD.[69] [104]
23
Ongoing
» ACE inhibitors and ARBs have been shown to be
equally protective against DKD progression in type 2
diabetes with microalbuminuria.[105] There are similar
findings in patients with macroalbuminuria for ACE
inhibitors in type 1 diabetes[106] and ARBs in type 2
diabetes.[107] However, there are few data on the
effectiveness of ACE inhibition in type 2 diabetic
patients with macroalbuminuria and on the
effectiveness of ARBs in type 1 diabetic patients with
macroalbuminuria.
» The combination of ACE inhibitors and ARBs can

further reduce proteinuria in people with type 1
diabetes[108] and type 2 diabetes.[109] However, the
combination is not commonly used in practice because
of the risk of hyperkalaemia. Moreover, several studies
involving diabetes patients with overt proteinuria have
been stopped early due to safety concerns with this
combination therapy.[78] [79]
Primary options
» captopril: 25-50 mg orally three times daily; dose

should be adjusted according to level of renal
impairment
OR
» enalapril: 2.5 to 20 mg orally once daily; dose
impairment
OR
» lisinopril: 2.5 to 40 mg orally once daily; dose
impairment
OR
» ramipril: 2.5 to 20 mg orally once daily; dose
impairment
OR
» trandolapril: 0.5 to 8 mg orally once daily; dose
impairment
OR
TREATMENT
» losartan: 25-100 mg orally once daily
OR
» valsartan: 80-320 mg orally once daily
Ongoing
OR
» candesartan: 4-32 mg orally once daily; dose
impairment
plus nutrition
» According to the American Dietetic Association,
medical nutrition therapy by a registered dietician is
recommended for people with type 1 or type 2
diabetes.[94] An initial series of 3 to 4 encounters
results in positive outcomes, including reductions in
HbA1c, lipids, and weight, a positive adjustment in
medications, and a decrease in comorbidities. In
addition, patients should have a follow-up visit
annually.[94]
» There are some data to support the claim that

low-protein diets prevent decline in GFR and reduce
progression of proteinuria.[16] Dietary protein
restriction of 0.8 g/kg of ideal body weight per day is
suggested.[16] High-protein diets should be avoided.
However, other research has suggested that a
low-protein diet does not improve renal function in
type 1 or type 2 diabetic kidney disease.[95] The 2016
American Diabetes Association guidelines do not
recommend protein restriction.[25] In addition, a
systematic review was unable to show a benefit of
protein restriction on renal failure.[96] Limited intake
of saturated fat, cholesterol, and sodium (2.3 g/day) is
beneficial.[97] Salt restriction may prevent the onset
of diabetic kidney disease in diabetes,[98] and
potentiates the renal and cardiovascular protective
effects of angiotensin receptor blockers (ARBs).[81]
Although a multivitamin is recommended, high doses
of B vitamins resulted in increased vascular events.[99]
Primary options
» low-protein diet: 0.8 g/kg/day maximum

May cause malnutrition; it should be ensured that
caloric intake is adequate.
-and-
» low-sodium diet: 2.3 g/day maximum
Reduces blood pressure and prevents oedema.
-and-
» low saturated fat diet
Prevents atherosclerosis.
TREATMENT

» Smoking cessation is strongly recommended, as
studies document a relation between smoking and loss
of GFR. The mechanisms underlying the adverse renal
25
Ongoing
Beyond its effect on progression of renal failure,
smoking is also an important cardiovascular risk factor
in chronic kidney disease patients.[100]
» E-cigarettes are not recommended either as an

alternative to smoking or to facilitate smoking
cessation.[25]
adjunct statin
» Patients with DKD are 5 to 10 times more likely to die
of cardiovascular causes than reach ESRD requiring
renal replacement therapy (dialysis and/or
transplantation).[110]
» Statins are likely to be beneficial because of their

anti-inflammatory properties and the correlation of
inflammation in chronic kidney disease (CKD) with
associated cardiovascular morbidity.
» A study involving non-dialysis patients with diabetic

CKD showed that atorvastatin has a beneficial effect
on both GFR and CVD.[91] However, a study involving
haemodialysis patients failed to show any benefit of
statins on cardiovascular outcomes.[92] In the SHARP
study, a reduction of LDL-cholesterol with simvastatin
plus ezetimibe reduced the incidence of major
atherosclerotic events in a wide range of patients with
advanced CKD.[93]
» There is current debate about whether there is a

recommended lower limit for LDL-cholesterol. Studies
have shown that the lower the LDL-cholesterol, the
greater the cardiovascular benefit. Previous guidelines
recommend that LDL should be maintained at least
<2.59 mmol/L (<100 mg/dL) and probably <1.81
mmol/L (<70 mg/dL).[111] However, many guidelines
now recommend that lipid treatment (e.g., with statins)
should be driven by cardiovascular risk rather than by
LDL levels.[25] [88] [89]For example, Kidney Disease:
Improving Global Outcomes (KDIGO) recommend statin
therapy (e.g., with atorvastatin or rosuvastatin) for all
non-dialysis CKD patients aged 50 years or older; no
specific treatment target is given.[89] In patients on
dialysis, KDIGO recommend continuation of statin
therapy if the patient is already receiving these agents,
but not to start statin therapy due to lack of evidence
of benefit in ESRD.
TREATMENT
Primary options
» atorvastatin: 20 mg orally once daily
OR
» rosuvastatin: 5-10 mg orally once daily
Ongoing
130/80 to 140/90 by ACE » Diuretics are considered second-line therapy for
inhibitor/ARB hypertension in DKD.
» In conjunction with ACE inhibitors and ARBs, they

provide a greater ability to achieve recommended BP
levels. Loop diuretics are generally needed when the
GFR falls to <30 mL/min/1.73 m^2.[103] Renal failure
is a complication of aggressive loop diuretic use.
» Beta-blockers or calcium-channel blockers may then

be added, if needed.
» Home BP monitoring may be beneficial in monitoring

response to treatment. Past recommendations were
that BP should be maintained at ≤130/80 mmHg.[59]
Intensive blood pressure lowering provides protection
against kidney failure, particularly among those with
proteinuria,[60] although in the absence of overt
proteinuria it is now thought that the BP goal may be
more liberal (i.e., 140/90 or below).[61]
Primary options
» hydrochlorothiazide: 12.5 to 50 mg orally once

daily
Not considered effective when CrCl is <30
mL/min/1.73 m^2.
OR
» chlortalidone: 12.5 to 50 mg orally once daily
mL/min/1.73 m^2.
Secondary options
» metolazone: 2.5 to 10 mg orally once daily or once

on alternate days; dose should be adjusted
according to level of renal impairment
OR
» furosemide: 20-160 mg orally twice daily; dose
impairment
Used in setting of oedema.
OR
TREATMENT
» spironolactone: 25-50 mg orally once daily; dose

impairment
Risk of hyperkalaemia when renal function is
impaired.
27
Ongoing
130/80 to 140/90 by ACE » Beta-blockers may be added if BP is not controlled
inhibitor/ARB + diuretic with a diuretic in combination with an ACE inhibitor or
ARB.
» Carvedilol is better than metoprolol at stabilising

glycaemic control and decreasing insulin resistance.
It is generally used with co-existing CHF.[82]

Primary options
» carvedilol: 3.125 to 50 mg orally twice daily
Secondary options
» propranolol: 40-240 mg orally twice daily
OR
» metoprolol: 25-200 mg orally (immediate-release)
twice daily
OR
» atenolol: 25-100 mg orally once daily; dose should
be adjusted according to level of renal impairment

130/80 to 140/90 by ACE » Non-dihydropyridine calcium-channel blockers are
inhibitor/ARB + diuretic + preferred, if heart rate allows. Dihydropyridine
beta-blocker calcium-channel blockers should not be used as sole
therapy as they may worsen proteinuria and renal
injury, but can be used in conjunction with ACE
inhibitors or ARBs.

TREATMENT

Primary options
Ongoing
» verapamil: 40-120 mg orally (immediate-release)
three times daily; 120-360 mg orally
(extended-release) once daily
OR
» diltiazem: 30-90 mg orally (immediate-release)
four times daily; 120-360 mg orally

dialysis » Type 2 diabetes patients with CKD who are not on
dialysis may begin with an oral hypoglycaemic agent
(e.g., metformin if estimated GFR [eGFR] adequate; or
else glipizide, repaglinide, or sitagliptin), and then
insulin can be added or substituted as needed.
Metformin, generally the first choice oral
hypoglycaemic agent for type 2 diabetes, is
contraindicated when when eGFR is <30 mL/min/1.73
m^2 and should be used only with caution when 30-45
mL/min/1.73 m^2.[35]
» Glipizide is the sulfonylurea agent of choice due to

its metabolite having little or no hypoglycaemic
activity.[112] Repaglinide is a meglitinide and is
considered within its drug class to be safest for CKD
for similar reasons.[36] Sitagliptin, a DPP-4 inhibitor,
can also be used, but this is based on limited
evidence.[37]
» Diabetes patients with CKD are at risk for

hypoglycaemia because of impaired clearance of
medications such as insulin and many oral
hypoglycaemic agents, and because of impaired kidney
gluconeogenesis.

capabilities.[58]
» The benefit of intensive glycaemic control for

TREATMENT
nephropathy remains under scrutiny. In one study,

compared with routine care, intensive management
of patients with type 2 diabetes detected by screening
(including glucose control) was not associated with
significant reductions in the frequency of microvascular
events at 5 years.[45] Intensive treatment of
29
Ongoing
hyperglycaemia may prevent the development of
microalbuminuria as well as progression to
macroalbuminuria, though there is little evidence that
it slows the progression of established CKD.[5] [41]
Primary options
» metformin: eGFR >45 mL/min/1.73 m^2: 500 mg

orally (regular-release) twice daily initially, increase
gradually according to response, maximum 2000
mg/day
Use is contraindicated in patients with eGFR <30
mL/min/1.73 m^2. Should not be started in
patients with eGFR 30-45 mL/min/1.73 m^2. In
patients who are started on metformin, if their eGFR
falls below 45 mL/min/1.73 m^2, assess
benefits/risks of continuing treatment and reduce
dose. Obtain eGFR at least annually.
OR
» glipizide: 2.5 to 5 mg orally (immediate-release)
once daily initially, increase by 2.5 to 5 mg/day
increments every 1-2 weeks according to response,
maximum 20 mg/day; 5 mg orally
(extended-release) once daily initially, increase
according to response, maximum 10 mg/day
Dose applies to patients with CKD (eGFR <50
mL/min/1.73 m^2) and those on dialysis.
OR
» repaglinide: 0.5 to 4 mg orally before each meal
up to three times daily
Dose should be started low and titrated carefully to
desired clinical response.
OR
» sitagliptin: 25-100 mg orally once daily; dose
impairment
OR
» metformin: eGFR >45 mL/min/1.73 m^2: 500 mg
orally (regular-release) twice daily initially, increase
gradually according to response, maximum 2000
mg/day
Use is contraindicated in patients with eGFR <30
TREATMENT
mL/min/1.73 m^2. Should not be started in

patients with eGFR 30-45 mL/min/1.73 m^2. In
patients who are started on metformin, if their eGFR
falls below 45 mL/min/1.73 m^2, assess
benefits/risks of continuing treatment and reduce
dose. Obtain eGFR at least annually.
-and-
Ongoing
daily before meals
-and-
daily
OR
» glipizide: 2.5 to 5 mg orally (immediate-release)
once daily initially, increase by 2.5 to 5 mg/day
increments every 1-2 weeks according to response,
maximum 20 mg/day; 5 mg orally
(extended-release) once daily initially, increase
-and-
daily before meals
-and-
daily
OR
» repaglinide: 0.5 to 4 mg orally before each meal
up to three times daily
Dose should be started low and titrated carefully to
desired clinical response.
-and-
daily before meals
-and-
daily
OR
» sitagliptin: 25-100 mg orally once daily; dose
impairment
-and-
daily before meals
-and-
daily
OR
TREATMENT
daily before meals

-and-
daily
31
Ongoing
mmHg.[64]


macroalbuminuria.

Primary options

impairment
OR
impairment
OR
TREATMENT

impairment
OR
Ongoing
impairment
OR
impairment
OR
OR
OR
impairment
plus nutrition
annually.[94]

TREATMENT

Primary options
33
Ongoing
-and-
-and-
» low saturated fat diet


cessation.[25]
adjunct statin


advanced CKD.[93]

TREATMENT

LDL levels.[25] [88] [89] For example, Kidney Disease:
Ongoing
of benefit in ESRD.
Primary options
OR

130/80 to 140/90 by ACE » Diuretics are considered second-line therapy for
inhibitor/ARB hypertension in DKD.
» In conjunction with ACE inhibitors and ARBs, they

provide a greater ability to achieve recommended BP
levels. Loop diuretics are generally needed when the
GFR falls to <30 mL/min/1.73 m^2.[103] Renal failure
is a complication of aggressive loop diuretic use.
» Beta-blockers or calcium-channel blockers may then

be added, if needed.

Primary options
» hydrochlorothiazide: 12.5 to 50 mg orally once

daily
mL/min/1.73 m^2.
OR
» chlortalidone: 12.5 to 50 mg orally once daily
TREATMENT

mL/min/1.73 m^2.
Secondary options
35
Ongoing
» metolazone: 2.5 to 10 mg orally once daily or once
on alternate days; dose should be adjusted
according to level of renal impairment
OR
» furosemide: 20-160 mg orally twice daily; dose
impairment
Used in setting of oedema.
OR
» spironolactone: 25-50 mg orally once daily; dose
impairment
Risk of hyperkalaemia when renal function is
impaired.

inhibitor/ARB + diuretic with a diuretic in combination with an ACE inhibitor or
ARB.


Primary options
Secondary options
OR
twice daily
TREATMENT
OR
Ongoing
inhibitor/ARB + diuretic + preferred, if heart rate allows. Dihydropyridine
beta-blocker calcium-channel blockers should not be used as sole
inhibitors or ARBs.

Primary options

OR
on peritoneal dialysis or haemodialysis 1st glycaemic control

» In all type 1 diabetic patients, regardless of whether
they are on dialysis or not, treatment with insulin is
needed. Patients with type 2 diabetes who are on
dialysis (e.g., due to ESRD) are preferentially treated
with insulin. Insulin is usually given subcutaneously.
» There is evidence to suggest that either low-dose

glipizide or sitagliptin can be used in dialysis patients
with type 2 diabetes. These oral hypoglycaemic agents
can be used either instead of insulin or added to insulin.
There is no evidence to support the use of repaglinide
in dialysis patients.
» Diabetes patients with chronic kidney disease (CKD)

are at risk for hypoglycaemia because of impaired
clearance of medications such as insulin and many oral
hypoglycaemic agents, and because of impaired kidney
TREATMENT
gluconeogenesis.

37
Ongoing
capabilities. [58]
» The benefit of intensive glycaemic control for

nephropathy remains under scrutiny. In one study,
compared with routine care, intensive management
of patients with type 2 diabetes detected by screening
(including glucose control) was not associated with
significant reductions in the frequency of microvascular
events at 5 years.[45] Intensive treatment of
hyperglycaemia may prevent the development of
microalbuminuria as well as progression to
macroalbuminuria, though there is little evidence that
it slows the progression of established CKD.[5] [41]
Primary options

daily before meals
-and-
daily
Secondary options
» glipizide: (type 2 diabetes) 2.5 to 5 mg orally

(immediate-release) once daily initially, increase by
2.5 to 5 mg/day increments every 1-2 weeks
according to response, maximum 20 mg/day; 5 mg
orally (extended-release) once daily initially, increase
OR
» sitagliptin: (type 2 diabetes) 25 mg orally once
daily; dose should be adjusted according to level of
renal impairment
OR
» glipizide: (type 2 diabetes) 2.5 to 5 mg orally
(immediate-release) once daily initially, increase by
2.5 to 5 mg/day increments every 1-2 weeks
TREATMENT
according to response, maximum 20 mg/day; 5 mg

orally (extended-release) once daily initially, increase
-and-
Ongoing
daily before meals
-and-
daily
OR
» sitagliptin: (type 2 diabetes) 25 mg orally once
daily; dose should be adjusted for renal impairment
-and-
daily before meals
-and-
daily

mmHg.[64]


macroalbuminuria.

TREATMENT

Primary options
39
Ongoing
impairment
OR
impairment
OR
impairment
OR
impairment
OR
impairment
OR
OR
OR
impairment
plus nutrition
annually.[94]
TREATMENT

Ongoing
Primary options

-and-
-and-
» low saturated fat diet:


cessation.[25]
adjunct statin

TREATMENT


41
Ongoing
advanced CKD.[93]

LDL levels.[25] [88] [89] For example, Kidney Disease:
of benefit in ESRD.
Primary options
OR

inhibitor/ARB with an ACE inhibitor or ARB.


TREATMENT
more liberal (i.e., 140/90 or below).[61] In dialysis

patients, BP goal should generally be <140/90
pre-dialysis with a post-dialysis value of <130/80. If
home BPs are measured, a mean BP of <135/85 is
reasonable.
Ongoing
Primary options
Secondary options
OR
twice daily
OR

inhibitor/ARB + beta-blocker preferred, if heart rate allows. Dihydropyridine
calcium-channel blockers should not be used as sole
inhibitors or ARBs.

more liberal (i.e., 140/90 or below).[61] In dialysis
patients, BP goal should generally be <140/90
pre-dialysis with a post-dialysis value of <130/80. If
home BPs are measured, a mean BP of <135/85 is
reasonable.
Primary options

OR
TREATMENT
2nd consideration for pancreas-kidney transplantation

» Diabetes is the most common cause of ESRD
requiring renal replacement therapy (RRT). RRT is not
43
Ongoing
only time consuming and fraught with uncomfortable
side effects such as cramps, fatigue, and central venous
stenosis, but it is also associated with significant
morbidity and mortality. Pancreas-kidney
transplantation not only frees patients from the need
for RRT, but it also has a significant survival benefit.
With modern surgical and immunosuppressive
protocols, 5-year patient survival is 95%, kidney survival
is 90%, and pancreas survival is greater than 80%.[101]
In the US, in 2013, 760 simultaneous pancreas-kidney
(SPK) transplants, 127 pancreas transplants alone (PTA),
and 107 pancreas after kidney (PAK) transplants were
performed.[102]
» SPK recipients are generally younger (60 years or

less) than kidney transplant recipients (70 years or less).
Patients with type 2 diabetes may be considered if they
do not have significant insulin resistance (C-peptide
>2 and BMI <30), In addition, recipients must have a
GFR <20 or be dialysis-dependent. They must go
through strict cardiovascular, psychosocial, and
anatomical (CT angiogram) clearance.[101]
» Other management strategies should be continued

as necessary.
TREATMENT
Emerging
Endothelin antagonists
Avosentan, an endothelin-A antagonist, in combination with ACE inhibitor/angiotensin receptor blocker (ARB), improves
proteinuria in patients with diabetic kidney disease and macroalbuminuria.[113] However, in larger doses, there have
been reports of a high incidence of serious, sometimes life-threatening adverse effects, including pulmonary oedema
and congestive heart failure.[114] Whether avosentan is safe in lower doses in diabetic kidney disease is not yet known.
More selective endothelin antagonists, such as atrasentan, are being studied.[115]
Aldosterone antagonists
Spironolactone, being an aldosterone antagonist, should theoretically be promising in the treatment of DKD. However,
data are lacking and there are concerns about hyperkalaemia in the presence of decreased renal function.[116] ACE
inhibitors or ARBs should be considered first-line agents; spironolactone may be used as a second- or third-line drug,
especially in the presence of heart failure, providing the serum potassium is normal and closely followed. In a study in
which some subjects had substantial renal dysfunction, serum potassium >6 mmol/L (>6mEq/L) was noted in 52% of
patients treated with combined high-dose ACE inhibitors plus low-dose spironolactone.[117] In a large study of
microalbuminuric patients with generally preserved renal function, eplerenone in combination with the ACE inhibitor
lisinopril decreased albuminuria by about 40%, but 8% of patients treated with the higher dose of eplerenone had to be
withdrawn from the study due to hyperkalaemia.[118] There are no long-term data demonstrating any beneficial effect
of combining an ACE inhibitor or ARB with aldosterone blockade in slowing the rate of loss of GFR.
Aliskiren
Recent research focused on the use of aliskiren in conjunction with an ACE inhibitor or ARB; however, in December 2011
the manufacturer recommended that physicians should no longer prescribe aliskiren-containing products with these
two classes of drugs based on the results, and subsequent early termination, of the ALTITUDE trial.[78] The trial was
testing the effect of aliskiren (in combination with ACE inhibitors or ARBs) in people with type 2 diabetes at high risk for
cardiovascular and renal events, and found an increased risk for non-fatal stroke, renal complications, hyperkalaemia,
and hypotension in patients taking the drug for 18-24 months. The US FDA now recommends that the combination of
aliskiren with ACE inhibitors or ARBs is contra-indicated in patients with diabetes because of the risk of renal impairment,
hypotension, and hyperkalaemia. It also recommends that this combination of drugs be avoided in patients with moderate
to severe renal impairment (i.e., GFR <60 mL/min/1.73 m^2). Further research is required into its use as monotherapy
as it has been shown to reduce urinary albumin to creatinine ratio (ACR) independently of its BP-lowering effect.[119]
[120] One study has shown no effects on hard renal outcomes (defined as a sustained doubling of serum creatinine,
ESRD, or renal death). Delayed progression to microalbuminuria and macroalbuminuria and improved regression to
microalbuminuria and normoalbuminuria have been demonstrated.[121]
Pentoxifylline
A number of small studies have suggested that pentoxifylline may decrease proteinuria and possibly slow decline of renal
function in DKD. A Cochrane review meta-analysis on pentoxifylline in DKD concluded that there was insufficient evidence
to support the use of pentoxifylline, but the authors of the review did stress the need for large-scale, rigorously designed,
multi-centre randomised trials to further assess its use in DKD.[122] The PREDIAN study reported that treatment with
pentoxifylline slowed the progression of diabetic kidney disease in type 2 diabetes patients with stage 3 to 4 chronic
kidney disease (CKD) who were receiving standard medical care, which included maximum RAS blockade.[123] Pentoxifylline
decreased proteinuria and urinary concentration of TNF-alpha, and slowed the decline in eGFR by 4.3 mL/min/1.73 m^2
when compared with standard medical care (P = 0.001). No serious adverse events were reported. Adverse events that
were more common in the treatment arm compared with placebo were mainly digestive symptoms (e.g., abdominal
discomfort, flatus, dyspepsia, nausea, and vomiting). The favourable safety profile of pentoxifylline is supported by its
TREATMENT
extensive clinical experience and use in treating peripheral vascular disease.
Paricalcitol
45
An active vitamin D analogue, paricalcitol has been reported to reduce albuminuria in patients with diabetes and could
be renoprotective.[124] However, further clinical trials using hard end points are needed before this therapy can be widely
recommended.[125]
Sevelamer
Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation
end products (AGEs) in food. Sevelamer carbonate, a phosphate-binding agent used in CKD and end-stage kidney disease
(ESKD) patients, sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced
abnormalities. In a single-centre, randomised, 2-month, open-label, intention-to-treat, crossover study which compared
sevelamer carbonate with calcium carbonate treatment in stage 2 to 4 diabetic CKD, sevelamer carbonate significantly
reduced HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress; it also markedly
increased anti-oxidant markers, independently of phosphorus in patients with diabetes and early kidney disease. Whether
or not these changes affect progression of early diabetic CKD requires further study.[126]
Genomics/proteomics/metabonomics
With the development of mass spectroscopy, liquid chromatography, and microarray protocols, evaluation of DNA, RNA,
or protein is increasingly being applied to all disease states. Genomics has, for example, been touted as a potential
replacement for kidney biopsies in the diagnosis of acute cellular rejection in kidney transplant patients. Similarly,
microRNAs in diabetic kidney disease will pave the way for development of future biomarkers and therapeutic options.[127]
TREATMENT
Diabetic kidney disease Follow up
Recommendations
Monitoring
FOLLOW UP
HbA1c should be checked twice per year. Blood pressure should be checked at each primary care visit. Lipids should
be checked every 3 to 6 months. Albumin to creatinine ratio (ACR) should be checked annually.
Patient instructions
Blood glucose and blood pressure are monitored at home. The patient should be encouraged to adhere to a low-protein,
low-saturated fat, low-sodium diet; stop smoking (including e-cigarettes); exercise regularly; and adhere to prescribed
medicines. Use of OTC drugs or complementary medicines should be avoided until they have been discussed with
physician.
Complications
Complications Timeframe Likelihood

chronic renal failure requiring dialysis long term high
DKD frequently progresses to dialysis, but patients with macroalbuminuria usually die due to cardiovascular causes
before reaching ESRD.[110]
hyperkalaemia long term high
The failing kidney fails to excrete potassium. Hyporeninaemic hypoaldosteronism due to diabetes may be present and
increases the risk of hyperkalaemia. In advanced chronic kidney disease (CKD), uncontrolled hyperkalaemia indicates
need for dialysis.
cardiovascular events long term high
DKD is complicated by a triad of inflammation, endothelial dysfunction, and oxidative stress and is associated with
marked cardiovascular morbidity and mortality. Cardiovascular events should be treated as in any other patient
population: with stenting and/or coronary artery bypass graft (CABG).
Angina pectoris and cardiovascular disease are common in DKD, and are reasons to aggressively treat coronary artery
disease with stent/CABG and to intensify treatment of DKD.[128]
Aspirin 81 mg/day is beneficial and has an acceptable risk:benefit ratio in CKD.[129] Aspirin has cardiovascular benefits
and is also anti-inflammatory. Bleeding has not been shown to be a concern.
blindness long term high
Advanced DKD is frequently associated with diabetic retinopathy because of microvascular disease.
peripheral vascular disease long term high
DKD is associated with progressive peripheral vascular disease because of microvascular and macrovascular disease.
Amputation may be necessary.
47
Diabetic kidney disease Follow up
Complications Timeframe Likelihood

refractory hypertension long term high
FOLLOW UP
With progressive loss of kidney function, hypertension becomes very difficult to control.
bone disease long term high
As in all patients with CKD, diabetic patients with CKD often develop secondary hyperparathyroidism due to
hyperphosphataemia and vitamin D deficiency. Treatment includes phosphorus (and protein) restriction, phosphate
binders (including calcium carbonate, calcium acetate, sevelamer, lanthanum carbonate), and vitamin D replacement,
generally with ergocalciferol in early stages of CKD and calcitriol or an active analogue (such as paricalcitol) in later
stages.
Compared with non-diabetic people, patients with diabetes mellitus are more likely to have adynamic bone disease.[130]
anaemia long term high
As CKD progresses, there is a progressive increase in the prevalence and severity of anaemia. Iron indices should be
obtained and iron deficiency treated.
Erythropoietic stimulating agents (ESAs) (e.g., epoetin alfa, darbepoetin) are indicated to reduce the need for blood
transfusions.
Although there is some variability in results among studies, the CHOIR and CREATE trials indicate better outcomes in
CKD patients with Hb values between 110 and 120 g/L, or between 11 and 12 g/dL (i.e., Hct between 33% and 36%)
compared with values above this range.[131] [132] Thus, normalisation of Hb values is not recommended. However,
in another study, improvement in quality of life has been noted with near-normal Hb in diabetic patients with CKD, so
the issue is not completely settled.[133]
Treatment includes iron compounds (ferrous sulfate, iron dextran, ferric gluconate, iron sucrose) and ESAs. ESAs should
be avoided in a Hb >130 g/L (13 g/dL) due to increased risk of cardiovascular events.
hypoglycaemia variable high
Intensive treatment of hyperglycaemia may result in hypoglycaemia because of impaired gluconeogenesis and because
insulin and other oral hypoglycaemics are poorly cleared by the kidney. Reduction in antidiabetic treatment is warranted.
Prognosis
DKD, compared with other types of chronic kidney diseases (CKD), is associated with continued worsening of proteinuria,
earlier appearance of complications, and worse performance on dialysis. However, morbidity and mortality can be avoided
or delayed with intensive treatment of hyperglycaemia, hypertension, and dyslipidaemia and with careful attention to
diet and avoidance of nephrotoxic agents. Diabetes mellitus itself is responsible for significant morbidity and mortality,
including blindness, myocardial infarctions, cerebrovascular accidents, amputations, and death.
Diabetic kidney disease Guidelines
Diagnostic guidelines
Europe
Management of diabetes: a national clinical guideline

Published by: Scottish Intercollegiate Guidelines Network Last published: 2010
Systematic review on urine albumin testing for early detection of diabetic complications
Published by: Health Technology Assessment NHS R&D HTA Programme Last published: 2005
North America
Standards of medical care in diabetes - 2017
GUIDELINES
Published by: American Diabetes Association Last published: 2017
Summary: Updated annually by the American Diabetes Association.
Abnormal blood glucose and type 2 diabetes mellitus: screening

Published by: US Preventive Services Task Force Last published: 2015
Summary: Recommends screening for abnormal glucose as part of cardiovascular risk assessment in adults aged 40
to 70 years who are overweight or obese. The optimal interval for screening is unknown.
KDOQI clinical practice guideline for diabetes and CKD: update 2012
Published by: National Kidney Foundation Last published: 2012
Summary: Provides updates of some guidelines from the 2007 KDOQI clinical practice guidelines and clinical practice
recommendations for diabetes and chronic kidney disease that address haemoglobin A1c (HbA1c) targets, treatments
to lower low-density lipoprotein cholesterol (LDL-C) levels, and use of angiotensin converting enzyme inhibitor (ACE-I)
and angiotensin receptor blocker (ARB) treatment in diabetic patients with and without albuminuria.
49
North America
KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and
chronic kidney disease
Summary: In patients with type 1 diabetes of 5 years' duration, screening is done with albumin to creatinine ratio
(ACR). In patients with type 2 diabetes, screening for microalbuminuria is started from the onset of diagnosis. In diabetic
patients with microalbuminuria and retinopathy, the diagnosis of DKD is highly likely. In patients with type 1 diabetes
of 10 years' duration and microalbuminuria, the diagnosis of DKD is highly likely. In patients with diabetes mellitus and
macroalbuminuria, the diagnosis of DKD is highly likely. The differential diagnosis of DKD must be explored in type 1
diabetic patients who have had diabetes mellitus for a short period of time, in type 2 diabetic patients who do not have
retinopathy, in patients who have a rapid decline in renal function, and in patients in whom decline in GFR is not
accompanied by albuminuria. DKD is classified according to presence of microalbuminuria (30 to 300 mg albumin/24
hours or ACR of 3.4 to 34.0 mg/mmol [30-300 mg/g]) and macroalbuminuria (>300 mg albumin/24 hours or ACR >34
mg/mmol [300 mg/g]). The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines
suggest the use of chronic kidney disease (CKD) staging to determine the likelihood that CKD in diabetic patients is
due to DKD. Using the CKD staging likelihood of DKD can be determined as follows: - Normoalbuminuria in CKD stages
GUIDELINES
3 to 5 (GFR <60 mL/min/1.73 m^2) is unlikely to be DKD. - Microalbuminuria in CKD stages 1 to 3 (GFR >30 mL/min/1.73
m^2) is possible DKD. - Microalbuminuria in CKD stages 4 to 5 (GFR <30 mL/min/1.73 m^2) is unlikely to be DKD. -
Macroalbuminuria at all stages of CKD is highly likely to be DKD.
Treatment guidelines
Europe
Chronic kidney disease: early identification and management of chronic kidney disease in
adults in primary and secondary care
Published by: National Institute for Health and Care Excellence Last published: 2015
Management of diabetes: a national clinical guideline

Type 2 diabetes in adults: management

Published by: National Institute for Health and Care Excellence Last published: 2015
Diagnosis and management of chronic kidney disease: a national guideline

Summary: All patients with DM should have their renal function monitored regularly. Albumin/creatinine ratio is
recommended for detecting and monitoring diabetic kidney disease, and may also be used to exclude diabetic kidney
disease in patients with diabetes. Patients with type 2 DM with CKD and microalbuminuria should be treated with an
ACE inhibitor or ARB, irrespective of their BP. Statins and low-dose antiplatelet therapy should both be considered in
all patients who have stage 1 to 3 CKD and a predicted 10-year cardiovascular risk of 20% or greater. Restricting dietary
protein (< 0.8 g/kg/day) is not recommended in patients with stage 1 to 3 CKD. A high protein intake (>1 g/kg/day)
is not recommended in stage 4 CKD. Reducing sodium intake to <2.4 g/day is recommended for patients with CKD
and hypertension.
Europe
Diabetes commissioning toolkit

Published by: National Diabetes Support Team; Diabetes UK; Primary Care DiabetesLast published: 2006
Society; Department of Health; Association of British Clinical Diabetologists; Yorkshire
and Humber Public Health Observatory
North America
Standards of medical care in diabetes - 2017

Published by: American Diabetes Association Last published: 2017
Summary: Updated annually by the American Diabetes Association.
2015 Canadian Hypertension Education Program recommendations
GUIDELINES
Published by: Canadian Hypertension Education Program Last published: 2015
Summary: Annually updated standardised recommendations and practice guidelines for healthcare professionals in
clinical and community settings to detect, treat, and control hypertension.
2014 evidence-based guideline for the management of high blood pressure in adults: report
from the panel members appointed to the Eighth Joint National Committee
Published by: Eighth Joint National Committee (JNC 8) Last published: 2014
Summary: Evidence-based recommendations regarding the management of high blood pressure. The guideline
provides analysis of treatment thresholds, treatment goals, and strategies to achieve those goals.
KDOQI clinical practice guideline for diabetes and CKD: update 2012
Summary: Provides updates of some guidelines from the 2007 KDOQI clinical practice guidelines and clinical practice
recommendations for diabetes and chronic kidney disease that address haemoglobin A1c (HbA1c) targets, treatments
to lower low-density lipoprotein cholesterol (LDL-C) levels, and use of angiotensin converting enzyme inhibitor (ACE-I)
and angiotensin receptor blocker (ARB) treatment in diabetic patients with and without albuminuria.
KDIGO clinical practice guideline for the management of blood pressure in chronic kidney
disease
Published by: Kidney Disease: Improving Global Outcomes Last published: 2012
Summary: Provides evidence-based guidance on blood pressure management and treatment for chronic kidney
disease (CKD) nondialysis patients with diabetes mellitus.
51
North America
Diabetes mellitus type 1 and 2 evidence-based nutrition practice guideline

Published by: Academy of Nutrition and Dietetics (American Dietetic Association)Last published: 2015
Summary: The registered dietician plays an integral role on the inter-disciplinary healthcare team by making the
optimal nutrition prescription, and by developing the nutrition intervention plan for patients undergoing diabetes
therapy. Based on the treatment plan and comorbid conditions, other nutrition practice guidelines, such as adult
weight management, hypertension, disorders of lipid metabolism, critical illness, and nutrition care in bariatric surgery
may be needed in order to provide optimal treatment.
KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and
chronic kidney disease
Summary: Treatment is multi-factorial. Intensive treatment of hyperglycaemia is essential. Goal HbA1c is <53 mmol/mol
(7%). Intensive treatment of hypertension is also important. ACE inhibitors and ARBs are first-line antihypertensives,
GUIDELINES
followed by diuretics, beta-blockers and non-dihydropyridine calcium-channel blockers. Aggressive treatment of

dyslipidaemia is important. LDL goal is <2.59 mmol/L (<100 mg/dL), but <1.81 mmol/L (<70 mg/dL) is likely to be
better. Dietary restriction of protein to 0.8 g/kg is beneficial. Diet low in saturated fats, cholesterol, and sodium (2 to
3 g/day) is recommended. Aspirin has a beneficial risk:benefit profile and should be utilised. Nephrotoxic agents such
as NSAIDs and radiocontrast media should be avoided.
Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure
Published by: National Heart, Lung, and Blood Institute Last published: 2004
Summary: Intensive treatment of hypertension is also important. ACE inhibitors and ARBs are first-line antihypertensives,
followed by diuretics, beta blockers and non-dihydropyridine calcium-channel blockers.
Implications of recent clinical trials for the National Cholesterol Education Program Adult
Treatment Panel III guidelines
Published by: National Heart, Lung, and Blood Institute Last published: 2004
Summary: Aggressive treatment of dyslipidaemia is important. LDL goal is <2.59 mmol/L (<100 mg/dL), but <1.81
mmol/L (<70 mg/dL) is likely to be better.
Diabetic kidney disease Online resources
Online resources
1. National Kidney Foundation: MDRD GFR Calculator (external link)
ONLINE RESOURCES
53
Diabetic kidney disease References
Key articles
REFERENCES
• Lv J, Perkovic V, Foote CV, et al. Antihypertensive agents for preventing diabetic kidney disease.Cochrane Database
Syst Rev. 2012;(12):CD004136. Full text Abstract
• American Diabetes Association. Standards of medical care in diabetes - 2017. Diabetes Care. 2017;40(suppl
1):S1-S135. Full text
• National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis.
2012;60:850-886. Full text Abstract
• Coca SG, Ismail-Beigi F, Haq N, et al. Role of intensive glucose control in development of renal end points in type 2
diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern
Med. 2012;172:761-769. Full text Abstract
• Shichiri M, Kishikawa H, Ohkubo Y, et al. Long-term results of the Kumamoto Study on optimal diabetes control in
type 2 diabetic patients. Diabetes Care. 2000;23(Suppl 2):B21-B29. Abstract
• Zoungas S, de Galan BE, Ninomiya T, et al; ADVANCE Collaborative Group. Combined effects of routine blood pressure
lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2
diabetes: New results from the ADVANCE trial. Diabetes Care. 2009;32:2068-2074. Full text Abstract
• Ismail-Beigi F, Craven TE, O'Connor PJ, et al. Combined intensive blood pressure and glycemic control does not
produce an additive benefit on microvascular outcomes in type 2 diabetic patients. Kidney Int. 2012;81:586-594.
Abstract
• Fullerton B, Jeitler K, Seitz M, et al. Intensive glucose control versus conventional glucose control for type 1 diabetes
mellitus. Cochrane Database Syst Rev. 2014;(2):CD009122. Full text Abstract
• Maione A, Navaneethan SD, Graziano G, et al. Angiotensin-converting enzyme inhibitors, angiotensin receptor
blockers and combined therapy in patients with micro- and macroalbuminuria and other cardiovascular risk factors:
a systematic review of randomized controlled trials. Nephrol Dial Transplant. 2011;26:2827-2847. Full text
• Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for treatment of diabetic nephropathy. N
Engl J Med. 2013;369:1892-1903. Full text Abstract
• Suckling RJ, He FJ, Macgregor GA. Altered dietary salt intake for preventing and treating diabetic kidney disease.
Cochrane Database Syst Rev. 2010;(12):CD006763. Full text Abstract
• National Kidney Foundation. KDOQI clinical practice guidelines on hypertension and antihypertensive agents in
chronic kidney disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1-S290. Full text Abstract
• Grundy SM, Cleeman JI, Mertz CN, et al; National Heart, Lung, and Blood Institute; American College of Cardiology
Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education
Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. Full text Abstract
• Lee SW, Kim WJ, Kim YH, et al. Preventive strategies of renal insufficiency in patients with diabetes undergoing
intervention or arteriography (the PREVENT Trial). Am J Cardiol. 2011;107:1447-1452. Abstract
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133. Ritz E, Laville M, Bilous RW, et al. Target level for hemoglobin correction in patients with diabetes and CKD: primary
results of the Anemia Correction in Diabetes (ACORD) study. Am J Kidney Dis. 2007;49:194-207. Abstract
REFERENCES
134. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients
with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. Full text Abstract
135. Lee SW, Kim WJ, Kim YH, et al. Preventive strategies of renal insufficiency in patients with diabetes undergoing
intervention or arteriography (the PREVENT Trial). Am J Cardiol. 2011;107:1447-1452. Abstract
136. Han Y, Zhu G, Han L, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury
in patients with diabetes and chronic kidney disease. J Am Coll Cardiol. 2014;63:62-70. Full text Abstract
Diabetic kidney disease Images
Images
Figure 1: Diabetic kidney disease: at 5 o'clock - early Kimmelstiel-Wilson nodule, a rounded increase in mesangial matrix
that probably originated in relation to a microaneurysm
From the collection of Dr Raoul Fresco
IMAGES
Figure 2: Diabetic kidney disease: at 12 o'clock - early Kimmelstiel-Wilson nodule, a rounded form of mesangial expansion
Figure 3: Diabetic kidney disease: mesangial expansion due to increased mesangial matrix and decreased degradation
of glycosylated collagen
65
IMAGES
Diabetic kidney disease Images
Figure 4: Diabetic kidney disease: mesangial expansion is usually recognised when it has exceeded 1.5 times the normal
mesangial matrix
Diabetic kidney disease Disclaimer
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Group Ltd ("BMJ Group") tries to ensure that the information provided is accurate and up-to-date, but we do not warrant
that it is nor do our licensors who supply certain content linked to or otherwise accessible from our content. The BMJ
Group does not advocate or endorse the use of any drug or therapy contained within nor does it diagnose patients.
Medical professionals should use their own professional judgement in using this information and caring for their patients
and the information herein should not be considered a substitute for that.
This information is not intended to cover all possible diagnosis methods, treatments, follow up, drugs and any
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67
Contributors:
// Authors:
David J. Leehey, MD, FACP

Professor of Medicine
Division of Nephrology, Loyola University Medical Center, Maywood, IL, Associate Chief of Staff for Clinical Affairs and Education,
Veterans Affairs Hospital, Hines, IL
DISCLOSURES: DJL declares that he has no competing interests.
Irfan Moinuddin, MD
Assistant Professor of Medicine
Southern Illinois University School of Medicine, Springfield, IL
DISCLOSURES: IM declares that he has no competing interests.
// Peer Reviewers:
Rajiv Agarwal, MD
Professor of Medicine
Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN
DISCLOSURES: RA declares that he has no competing interests.
Merlin C. Thomas, PhD

Associate Professor
Baker IDI Heart and Diabetes Institute, Melbourne, Australia
DISCLOSURES: MCT has received honoraria for speaking and educational sessions conducted by Sanofi-Aventis, Servier,
Boehringer-Ingleheim, Abbott, Amgen, and Jansen-Cilag.
Damian Fogarty, BSc, MD, FRCP

Consultant/Senior Lecturer in Renal Medicine
Belfast City Hospital and Queen's University Belfast, Belfast City Hospital, Belfast, Northern Ireland, UK
DISCLOSURES: DF has no share options, research support, or employment with pharmaceutical companies. He has received
one-time speaking fees to cover his time preparing educational talks in the broad areas of diabetic nephropathy and chronic
kidney disease, promoting early recognition and evidence-based or best practice management.

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Diabetic kidney disease

The right clinical information, right where it's needed

Last updated: Jan 09, 2017

Step-by-step treatment approach 17

◊ Complications include hypoglycaemia due to intensive treatment of hyperglycaemia, hyperkalaemia as an

Reason for screening for DKD:

Populations to screen for DKD:[1]

• Type 1 diabetics - 5 years after diagnosis.

• Type 2 diabetics - at the time of diagnosis.

Screening tests for DKD:

• Albumin to creatinine ratio (ACR) annually.[1] [24]

Screening for diabetes mellitus:[25]

• Risk factors for diabetes include:

• Age ≥45 years

• Overweight (body mass index [BMI] ≥25 kg/m2)

• Diabetes mellitus in a first-degree relative

• History of delivering a baby weighing >4.1 kg (9 lb) or of gestational diabetes mellitus

• Hypertension (blood pressure ≥140/90 mmHg)

• A1C ≥5.7%, impaired glucose tolerance or impaired fasting glucose

• Polycystic ovary syndrome

• History of vascular disease.

Aspirin (81 mg) is given in absence of contraindication.

Step-by-step diagnostic approach

• Pallor, which may signify anaemia.

• Urinary leukocytes, bacteria, and nitrites indicate urinary tract infection.

• Detecting microalbuminuria is important because early intervention can prevent progression to

FHx of HTN and/or kidney disease

high protein, fat and sodium intake

History & examination factors

presence of risk factors (common)

hypertension (HTN) (common)

signs of retinopathy (common)

Other diagnostic factors

numbness of the lower extremities (common)

pain of the lower extremities (common)

constitutional symptoms (advanced disease) (common)

foot changes (common)

orthostatic hypotension (uncommon)

skin changes (uncommon)

muscular atrophy (uncommon)

pallor (as GFR declines) (uncommon)

bleeding tendency (advanced disease) (uncommon)

Kussmaul's respirations (advanced disease) (uncommon)

kidney ultrasound normal-to-large kidneys with

Other tests to consider

CT abdomen may show hydronephrosis;

Condition Differentiating signs / Differentiating tests

disease, or short duration of SLE, ANCA in vasculitis,

Condition Differentiating signs / Differentiating tests

Condition Differentiating signs / Differentiating tests

Staging of diabetic nephropathy[1]

Step-by-step treatment approach

Pancreas kidney transplantation

Treatment details overview

type 1 diabetes with nephropathy: not on 1st glycaemic control

plus ACE inhibitor or angiotensin receptor blocker (ARB)

plus smoking cessation

with BP not controlled below plus added diuretic

with BP not controlled below plus added beta-blocker

with BP not controlled below plus added calcium-channel blocker