83

Clinical Evaluation and Management

of Chronic Kidney Disease
David C. Wheeler

Although many patients with chronic kidney disease (CKD) progress with an increased prevalence of CKD, which is termed case-­finding.
to end-­stage kidney disease (ESKD) and require kidney replacement Subgroups of interest include those with diabetes, hypertension, pre-
therapy (KRT), the majority die of nonrenal causes, particularly pre- vious acute kidney injury (AKI), CV disease (CVD), structural kid-
mature cardiovascular (CV) events.1 Early diagnosis of CKD is there- ney tract disease, kidney calculi, prostatic hypertrophy, multisystem
fore important because it provides opportunities to delay progression diseases with potential kidney involvement (e.g., systemic lupus ery-
of CKD (see Chapter 82) and prevent CV complications (see Chapters thematosus), a family history of category G5 CKD, and hereditary
84 and 85). kidney disease, and after opportunistic detection of hematuria or
proteinuria.5
DEFINITIONS Evaluation of Chronic Kidney Disease
CKD is defined as abnormalities of kidney structure or function, pres- Establishing Chronicity
ent for at least 3 months, with implications for health (Table 83.1). When eGFR of less than 60 mL/min/1.73 m2 is detected, careful atten-
The relevant Kidney Disease: Improving Global Outcomes (KDIGO) tion should be paid to previous blood and urine test results and the
guideline recommends classification of CKD based on cause, cat- clinical history to determine whether this is a result of AKI (i.e., an
egory of glomerular filtration rate (GFR), and albuminuria (see Fig. abrupt decrease in kidney function or CKD that has been present but
82.2).2 Because of the impracticalities of using radioisotopes and 24-­ asymptomatic for some time).
hour urine collections, the KDIGO classification system recommends A detailed medical history covering issues, including other medical
that kidney function be assessed by estimating GFR (eGFR) from the conditions, family history of kidney disease, prescribed medication,
serum creatinine concentration using an appropriate equation, except and recreational drug use, may suggest an underlying cause. There
in circumstances in which eGFR estimations are known to be less may be hints of a history of kidney problems (e.g., hypertension, pro-
accurate, such as when there is significant muscle wasting. Initially, the teinuria, microhematuria) or symptoms suggestive of prostatic disease.
Modification of Diet in Renal Disease (MDRD) equation was used, but The findings of a physical examination are not always helpful, although
this has predominantly been replaced by the Chronic Kidney Disease skin pigmentation, scratch marks, left ventricular hypertrophy, and
Epidemiology Collaboration (CKD-­EPI) equation, which more accu- hypertensive fundal changes favor a chronic presentation (Fig. 83.1).
rately categorizes the risk for mortality and progression to ESKD (see Details of the social and personal circumstances are also crucial, par-
Chapter 3).3 Recently, this formula has been updated in order to elim- ticularly for patients with progressive kidney disease in whom KRT is
inate race from the equation (https://www.kidney.org/professionals/ likely to be required.
kdoqi/gfr_calculator/formula), and although the formula is less precise Blood tests for other conditions can be helpful because they may
than the earlier CKD-EPI equation, it is sufficiently accurate for clin- indicate evidence of an acute illness that could be the cause of kidney
ical practice. Although staging systems for CKD based on eGFR have failure, such as systemic vasculitis or multiple myeloma. A normochro-
limitations, they have proved useful in many clinical settings and are mic normocytic anemia is usual in CKD but also may be a feature of
now deeply embedded in KDIGO and other guidelines developed for acute systemic illnesses and therefore is not discriminatory. Low serum
CKD management and in research. calcium and raised phosphate levels also have little discriminatory value,
The evidence base for the management of CKD is evolving. but normal levels of parathyroid hormone (PTH) are more in keeping
Although every effort has been made to ensure this chapter reflects with AKI. Patients with grossly abnormal biochemical values (e.g., blood
current recommendations, the reader is advised to check for any new urea > 300 mg/dL [>50 mmol/L] and/or serum creatinine > 13.5 mg/dL
clinical trials and relevant guideline updates. [>1200 μmol/L]) who appear relatively well and are still passing normal
volumes of urine are much more likely to have CKD than AKI.
CLINICAL PRESENTATION Assessment of Glomerular Filtration Rate
CKD is commonly detected by routine blood testing and is usually For patients in whom the distinction between AKI and CKD is unclear,
asymptomatic until late stage G4 or stage G5. Symptoms of CKD are repeat testing of kidney function should be performed within 2 weeks
nonspecific and need to be asked about directly (Box 83.1). There of the initial finding of eGFR less than 60 mL/min/1.73 m2. However,
is some evidence that early diagnosis with appropriate management if previous results confirm that this is a chronic finding, or if repeated
may slow the rate of decline of kidney function and reduce CV risk.4 blood test results over a 3-­month period are consistent, CKD is con-
Screening of the general population for CKD is not recommended, firmed. Other tests (such as cystatin C or an isotope-­clearance mea-
but in the UK, the National Institute for Health and Care Excellence surement of GFR) can be used to confirm CKD in circumstances in
(NICE) proposes offering testing to people with conditions associated which eGFR based on serum creatinine is known to be less accurate.

959
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960 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

TABLE 83.1 Criteria for Definition of

Chronic Kidney Disease (CKD)
CKD is defined as abnormalities of kidney structure or function, present for
more than 3 months, with implications for health. These may include the
following:
Markers of kidney Albuminuria (AER ≥ 30 mg/24 h; uACR ≥ 30 mg/g [≥
damage 3 mg/mmol])
Urine sediment abnormalities
Electrolyte and other abnormalities caused by tubular
disorders
Abnormalities detected through histology
Structural abnormalities detected through imaging
History of kidney transplantation
Decreased GFR GFR < 60 mL/min/1.73 m2
AER, Albumin excretion rate; GFR, glomerular filtration rate; uACR, uri-
nary albumin-­to-­creatinine ratio.
From Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work
Group. KDIGO 2012 clinical practice guideline for the evaluation and Fig. 83.1 Uremic Pigmentation. Diffuse brown pigmentation as seen
management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150. here suggests chronic kidney disease rather than acute kidney injury.

BOX 83.1 Symptoms and Signs of Severe The degree of albuminuria is graded by the A1 to A3 category system,
Chronic Kidney Disease replacing previous terms such as microalbuminuria (see Fig. 82.1).
However, it is important to be aware that some patients will excrete
• 
Difficulty sleeping proteins other than albumin, and a urine protein-­to-­creatinine ratio
• 
Nocturia (uPCR) may be more useful for certain conditions.8 Serial uPCR mea-
• 
Headache surements may be particularly useful in glomerular disease because
• 
Restless leg syndrome of the higher variability of uACR and the greater cost of determining
• 
Metallic taste in the mouth albumin in urine. Where appropriate, urine tests for Bence Jones pro-
• 
Shortness of breath on exertion or at rest, paroxysmal nocturnal dyspnea tein (immunoglobulin light chains) may be required because this is not
• 
Fatigue, often profound detected by standard proteinuria or albuminuria testing.
• 
Muscle cramps and twitches
• 
Seizures Kidney Imaging
• 
Lack or loss of appetite for food, abdominal pain, nausea, vomiting, and Imaging of the kidneys with ultrasound is useful for a number of reasons.
weight loss Small kidneys with reduced cortical thickness, showing increased echo-
• 
Itch, particularly on the trunk and worse at night genicity, scarring, or multiple cysts, suggest a chronic process. Structural
• 
Altered respiration including Kussmaul breathing and Cheyne-­Stokes respi- abnormalities such as those observed in autosomal dominant polycys-
ration tic kidney disease (ADPKD), hydronephrosis caused by obstruction, or
• 
Icteric sclera or “red eye” because of calcium deposition coarse kidney scarring may be detected. NICE guidelines propose that
• 
Muscle weakness kidney ultrasound scanning is important only in certain circumstances
• 
Oral lesions including gingival bleeding or petechiae, xerostomia, periodon- and suggest counseling patients if ADPKD is suspected before imaging.5
titis, and candidiasis In some situations, imaging with computed tomography (CT), magnetic
• 
Pericardial and/or pleural rub resonance (MR), or angiography may be useful, taking into account the
• 
Pulmonary and peripheral edema risks of administering contrast media (see Chapter 6).
• 
Skin changes including xerosis (abnormal dryness), scratch marks, pallor,
sallow coloration or hyperpigmentation Further Investigations
• 
Uremic flap (asterixis) Establishing the cause of CKD is important whenever possible, and
• 
Uremic fetor: Ammonia or urine-­like odor to the breath further specific testing, as indicated by the history and results of initial
• 
Uremic frost: Crystallized urea deposits that can be found on the skin investigations, may be required. There may be an underlying treatable
condition that requires appropriate management, or there may be a
genetic cause such as ADPKD, for which counseling should be offered.
Assessment of Proteinuria or Albuminuria Furthermore, some kidney diseases may recur after transplantation
Dipstick testing of the urine and urine culture may reveal microhema- (see Chapter 113) and an accurate diagnosis may therefore influence
turia, which can be a useful pointer toward an underlying diagnosis.6 later management. Despite thorough investigation, however, the cause
Workup of hematuria is discussed in Chapters 4 and 63. Whether or of CKD is often unclear, with an unhelpful medical history, minimal
not proteinuria is detected by dipstick, there should be a further mea- abnormalities on urinalysis, and small kidneys on ultrasound. In such
surement of urinary albumin excretion. Albuminuria is an important patients, investigation should not be pursued relentlessly because the
diagnostic and prognostic marker, and its presence indicates a higher implications for treatment are often minimal. Attempting to obtain
risk for both progression of kidney disease and CV complications.7 biopsy material from small kidneys is associated with risk, and even if
KDIGO guidelines recommend that the preferred method of assessing a biopsy is performed, histologic assessment may simply show nonspe-
proteinuria is by measurement of the urinary albumin-­to-­creatinine cific chronic scarring rather than diagnostic features that explain the
ratio (uACR) using an early morning urine sample where practical.2 cause of kidney damage.

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 CHAPTER 83 Clinical Evaluation and Management of Chronic Kidney Disease 961

given to detection of reversible causes (e.g., kidney tract obstruction)

PREDICTING PROGNOSIS
and a specialist referral may be required.
With the cause of CKD established if possible, the GFR and the level of
albuminuria measured, and other comorbidities categorized, it is pos- When to Refer to the Nephrologist
sible to estimate the risk for CKD progression and likely future need Chronic management of patients with early nonprogressive CKD is
for KRT. KDIGO recommends consideration of the GFR and the albu- becoming the responsibility of primary care physicians in many well-­
minuria categories together according to a heatmap of risk (see Fig. developed health care systems, with follow-­up in secondary care lim-
82.2),2 and there are online tools to assist with risk prediction using ited to those likely to progress to ESKD and require KRT. However,
this approach (e.g., kidneyfailurerisk.com). Other factors associated early assessment by nephrologists is useful for all patients newly diag-
with CKD progression may help inform prognosis. These include the nosed with CKD in whom a treatable underlying cause is suspected,
cause of CKD, age, sex, ethnicity, dyslipidemia, smoking, obesity, his- even in those with advanced disease at presentation, to rule out treat-
tory of CVD, ongoing exposure to nephrotoxic agents, and degree of able causes. Timely referral of those with progressive CKD allows
control of hypertension and hyperglycemia. However, often the best preparation for dialysis, kidney transplantation, or initiation of a pal-
guide to future change in kidney function is the previous pattern of liative approach if more appropriate. Substantially similar criteria for
decline, highlighting the importance of considering results of previous referral have been developed by NICE and KDIGO (Table 83.2). Such
blood and urine testing during the initial assessment. criteria are not absolute but should provide a guide to the primary care
physician as to which patients are likely to benefit from specialist care.
Monitoring and Defining Progression For example, many patients with stable category G4 CKD are success-
Once CKD has been identified, arrangements should be made to ensure fully managed in the community, often after initial assessment by or
regular monitoring of kidney function and proteinuria. In patients at with virtual advice from secondary care colleagues.
low risk for rapid eGFR decline, this can be done annually in either Unfortunately, a substantial proportion of patients with advanced
a primary or secondary care setting. However, assessment should be CKD are referred late, often at the time when they need KRT. Late
undertaken more regularly if the trajectory of the disease is not clear referral is often avoidable, although in some cases, patients may have
and in patients at higher risk for progression. had a truly silent illness or an acute presentation of a disease with rapid
Determining a true change in kidney function over time may be decline in kidney function.9 Over recent years, the introduction of
difficult because small fluctuations in eGFR are common and not nec- routine reporting of eGFR in some health care systems has facilitated
essarily indicative of progression. These fluctuations may be caused by better communication between primary and secondary care providers
reversible factors, such as intravascular depletion or high meat intake, and has led to a substantial fall in late referrals.10
so repeat testing may be required. Both NICE and KDIGO guidelines Late presentation is disadvantageous to the patient because it limits
define accelerated progression as a sustained decrease in GFR of 25% the time to select the mode of dialysis or to be listed for “preemptive”
or more and a change in GFR category within 12 months.2,5 In addi- kidney transplantation. There may be increased psychological stress,
tion, the NICE guidance refers to accelerated progression as a sus- making it difficult for the patient to come to terms with the illness.
tained decrease in GFR of 15 mL/min/1.73 m2 or greater per year.5 In Furthermore, because an arteriovenous fistula (AVF) takes several
patients with accelerated CKD progression, consideration should be weeks to mature, patients presenting late start hemodialysis (HD) with

TABLE 83.2 Suggested Criteria for Referral of Patients With CKD to a Nephrologist
NICE 2021 KDIGO 2012
Advanced CKD Category G4 and G5 CKD Category G4 and G5 CKD
A 5-­year risk of needing kidney replacement therapy of >5%
(measured using the 4-­variable Kidney Failure Risk Equation)
Proteinuria High proteinuria: uACR ≥ 70 mg/mmol unless known to be Consistent proteinuria: uACR ≥ 300 mg/g (≥ 30 mg/mmol)
caused by diabetes and appropriately treated
Hematuria Proteinuria (uACR ≥ 30 mg/mmol) together with hematuria Urinary RBC casts, RBCs > 20/hpf sustained; not readily
explained
Progression of CKD Rapidly declining eGFR: Progression of CKD:
Sustained decrease in GFR of ≥25% and a change in GFR Sustained decrease in GFR of ≥25% and a change in GFR
category within 12 mo category within 12 mo
Sustained decrease in GFR of ≥15 mL/min/1.73 m2 within 12 mo Sustained decrease in GFR of ≥5 mL/min/1.73 m2 within 12 mo
NEW: 5-­year risk of needing kidney replacement therapy of >5%
(measured using the 4-­variable Kidney Failure Risk Equation)
Uncontrolled hypertension Hypertension that remains poorly controlled despite the use of at CKD and hypertension refractory to treatment with four or
least four antihypertensive drugs at therapeutic doses more antihypertensive agents
Hereditary kidney disease Known or suspected rare or genetic causes of CKD Hereditary kidney disease
Other conditions Suspected renal artery stenosis Recurrent or extensive nephrolithiasis
Persistent abnormalities of serum potassium
CKD, Chronic kidney disease; eGFR, estimated glomerular filtration rate; hpf, high power field; KDIGO, Kidney Disease: Improving Global Outcomes;
NICE, National Institute for Health and Care Excellence; RBC, red blood cell; uACR, urinary albumin-­to-­creatinine ratio.
Data from Kidney Disease: Improving Global Outcomes [KDIGO] CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and
management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150; and National Institute for Health and Care Excellence. Chronic kidney
disease assessment and management. 2021. NICE guideline [NG203].

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962 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

central venous catheters. Catheters are prone to infectious complica-

tions and inevitably damage central veins, leading to thromboses and Sodium Glucose Cotransporter 2 Inhibitors and
stenoses, which may manifest at a later stage when venous return from Mineralocorticoid Receptor Antagonists
one or the other arm is increased by the subsequent construction of SGLT2 inhibitors enhance urinary excretion of sodium and glucose
an AVF (see Chapter 96).11 Late presentation of CKD also precludes by blocking their uptake in the proximal tubule. Although originally
effective treatment of complications such as hypertension and anemia, developed as drugs to improve glycemic control in patients with
which may contribute to CVD and ultimately limit life span.12 Most type 2 diabetes (see Chapter 33), these agents have both kidney and
importantly, late referral is associated with greater subsequent costs of cardioprotective effects that extend to patients with CKD who do
medical care and a worse prognosis.13 not have diabetes.21 A new nonsteroidal mineralocorticoid receptor
antagonist (Finerenone) has also recently been demonstrated to have
PREVENTION OF CHRONIC KIDNEY DISEASE cardiorenal benefits in patients with CKD and type 2 diabetes.22 It
seems likely that these newer agents will be used more extensively in
PROGRESSION the future in the management of CKD in addition to ACE inhibitors
Management of CKD should be aimed at slowing the rate of decline and ARBs.
of kidney function and minimizing the effects of other complications.
Except for specific management of the underlying kidney disease Dietary Advice
where possible, the most effective intervention is control of blood pres- Detailed dietary advice and education, along with ongoing support
sure (BP) and introduction of nephroprotective medications including from an appropriately trained professional, are important in the man-
(in patients with albuminuria) angiotensin-­converting enzyme (ACE) agement of patients with CKD. Obesity is associated with a more rapid
inhibitors or angiotensin receptor blockers (ARBs; see Chapter 82) and decline of kidney function, so in early CKD, weight loss may be appro-
sodium glucose cotransporter 2 (SGLT2) inhibitors. Control of glyce- priate. However, in advanced CKD, malnutrition is common (see
mia in patients with diabetes and CKD is covered in Chapter 33. Chapter 90). The causes are multifactorial but include anorexia, acido-
sis, insulin resistance, inflammation, oxidative stress, and urinary pro-
Hypertension and Renin Angiotensin Aldosterone tein loss. Biochemical indicators may demonstrate a decrease in serum
System Blockade albumin, transferrin, and cholesterol. Weight should be monitored in
Hypertension is very common in patients with CKD, the level of BP patients who progress to CKD categories G4 and G5. Serum creatinine
being associated with the rate of loss of kidney function,14 and BP con- concentrations, which, in part, reflect muscle mass, may stop rising
trol slows the rate of decline (see Chapter 82). BP targets have changed despite a progressive loss of kidney function because of compromised
to reflect the available evidence. Although observational studies link nutritional status.
low BP to higher mortality,15 interventional trials such as SPRINT In light of this, recommendations to restrict protein intake are
have demonstrated the advantages of more intensive BP control in controversial. Although reduced protein intake may slow progression
CKD patients.16 Guidelines by both NICE and KDIGO emphasize the of decline of kidney function, many patients develop protein-­calorie
importance of considering coexistent CVD, other comorbidities, and malnutrition on a low-­protein diet.23 KDIGO has recommended that
side effects when choosing medications and BP targets, particularly protein intake should be lowered to 0.8 g/kg/day in adults with CKD
for elderly patients.5,17 Lifestyle modifications should be encouraged, and GFR less than 30 mL/min/1.73 m2, whereas high protein intake
including maintenance of a healthy weight, reductions in salt and alco- (>1.3 g/kg/day) should be avoided in adults with CKD at risk for pro-
hol intake, and regular exercise (see Chapter 36). gression. When this recommendation is followed, detailed dietary
Although current recommendations are based on office BP record- assessment and supervision are needed to ensure that malnutrition is
ings, these should be standardized if possible (i.e., obtained according to prevented (see Chapter 90).
a recommended preparation protocol).18 Home and ambulatory mon- One of the earliest effects of CKD is to limit the ability of the
itoring readings, where available, should be used to complement stan- kidney to compensate for large changes in sodium and water intake
dardized office recordings. It has been shown that up to 30% of CKD (see Chapter 8). Salt and water retention are major factors contrib-
patients who were thought to have hypertension have normal BPs at uting to hypertension in CKD patients and, in more advanced stages,
home, whereas 40% of patients who were thought to be normotensive (or to morbidity and mortality through systemic or pulmonary edema.
to have adequately treated hypertension) were hypertensive at home.19 Therefore, sodium intake should ideally be restricted to less than 90
Although ambulatory monitoring is not universally recommended, there mmol/day (5 g/day of sodium chloride), except in salt-­wasting condi-
should be a low threshold for undertaking 24-­hour monitoring or asking tions. Advice about optimal fluid intake at each stage of CKD is needed
patients to undertake self-­measurements at home if they prefer. to prevent volume overload. Salt substitutes containing potassium
Target BP levels and antihypertensive therapy in CKD patients are should be avoided because of the risk for hyperkalemia. In stages G4
discussed in Chapter 82. ACE inhibitors or ARBs are recommended as and G5 CKD, education and advice about restriction of potassium and
first-­line agents for patients with evidence of proteinuria, both to slow phosphate may be required.
progression of CKD and to reduce CV risk.20 However, multidrug reg-
imens are usually required to obtain good control. Patients with CKD MANAGEMENT OF COMPLICATIONS OF CHRONIC
are vulnerable to drug side effects, particularly during intercurrent
KIDNEY DISEASE
illness, when they may develop hyperkalemia and AKI. The KDIGO
guidelines recommend the temporary discontinuation of certain drugs A detailed discussion of the complications of CKD is provided in
that may exacerbate AKI or are prone to increased adverse events at Chapters 84 to 92. With the exception of hypertension, there are usu-
low GFR (including ACE inhibitors, ARBs, aldosterone inhibitors, ally few clinical manifestations associated with CKD stages G1 and G2
direct renin inhibitors, diuretics, nonsteroidal anti-­ inflammatory (GFR > 60 mL/min/1.73 m2). Other complications (discussed in the
drugs, metformin, lithium, and digoxin) in patients with a GFR of less following sections) tend to develop progressively as GFR declines to
than 60 mL/min/1.73 m2 (CKD categories G3a–G5) who have serious less than 60 and in particular less than 30 mL/min/1.73 m2 (i.e., during
intercurrent illness. CKD stages G4 and G5).

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 CHAPTER 83 Clinical Evaluation and Management of Chronic Kidney Disease 963

Anemia and their choice is discussed in Chapter 88. Prescription of vitamin

Anemia is common in CKD stages G3a to G5 and is caused by a relative D supplements or analogs, in the absence of documented deficiency,
deficiency of erythropoietin, although reduced availability of iron and to suppress elevated PTH concentrations in patients with CKD not
chronic inflammation are frequent contributory factors (see Chapter on dialysis is not recommended.29 Calcimimetics are a group of drugs
86). Anemia may have multiple adverse effects, including worsening that mimic the action of calcium on parathyroid glands by activation
cardiac dysfunction by increasing cardiac output and exacerbating of the calcium-sensing receptor and thus reduce the release of PTH.
left ventricular hypertrophy, thereby accelerating the decline of kid- At present, cinacalcet (an oral calcimimetic) and etelcalcetide (which
ney function. Anemia may also reduce cognition and concentration. is given intravenously) are generally used in patients receiving dial-
However, clear evidence that reversal of anemia using erythropoiesis-­ ysis, particularly those that are unfit for surgical parathyroidectomy.
stimulating agents (ESAs) is associated with improved clinical out- Whether these drugs have additional health benefits is not clear (see
comes is lacking, and randomized trials have suggested that in some Chapter 88).
circumstances these agents may cause harm.24 A new approach to the
treatment of renal anemia is the use of oral small-­molecule stabilizers Metabolic Acidosis
of hypoxia inducible factor. These agents, which are currently being The metabolic acidosis associated with CKD is caused by failure of
evaluated in phase 3 studies, could offer a simpler and cheaper ther- hydrogen ion excretion and may be compounded by the accumulation
apy compared with ESAs, with potential benefits beyond increases in of organic acids and bicarbonate loss, particularly in interstitial kid-
hemoglobin (Hb) level.25 ney diseases. Clinical symptoms resulting from acidosis are rare until
The relevant KDIGO guideline recommends that all patients iden- patients reach CKD stage G5, when dyspnea may occur as a result of
tified as having CKD categories G3a and below should have their Hb respiratory compensation. Other causes of dyspnea in advanced CKD,
levels monitored annually, increasing to twice a year for stages G4 such as anemia and pulmonary edema, should always be considered.
and G5.26 Anemia in adults is diagnosed when the Hb concentra- Acidosis aggravates hyperkalemia, inhibits protein anabolism, and
tion is less than 13.0 g/dL in males and less than 12.0 g/dL in females. accelerates calcium loss from bone where the hydrogen ions are buff-
NICE recommends that management of anemia should be considered ered.31 Correction of metabolic acidosis may slow progression of kid-
in patients with CKD when the Hb level is up to 11 g/dL.5 In anemic ney disease,32 although larger trials are required to confirm this.
patients, investigations for other causes should be conducted, includ- KDIGO recommends that in patients with CKD and serum bicar-
ing measurement of iron stores, serum vitamin B12, and folate levels. bonate concentrations less than 22 mmol/L (NICE recommends a
ESAs should not be started until treatment of iron deficiency or other threshold of <20 mmol/L), oral bicarbonate supplementation should
underlying causes have been addressed and then only after consider- be given to maintain serum bicarbonate within the normal range,
ing the balance of benefits (from the reduced requirement for blood unless contraindicated. However, the associated sodium loading may
transfusions and abrogation of anemia-­related symptoms) against the aggravate hypertension and fluid retention, and severe metabolic aci-
potential harms, which may include an increased risk for stroke and dosis associated with symptoms in a patient with CKD stage G5 may
malignancy. be an indication to start dialysis.2 Novel pipeline drugs include an oral
If anemia does not respond to correction of underlying causes, such polymer designed to remove acid from the body with high capacity and
as iron deficiency, KDIGO recommends that ESAs be commenced specificity. This raises the possibility of treatment of acidosis without
when Hb concentrations are less than 10.0 g/dL, if indicated.26 Hb tar- the problems associated with increased sodium intake.
get ranges are discussed in Chapter 86.
Cardiovascular Risk
Bone and Mineral Metabolism Patients with CKD have an increased prevalence of CVD and are far
Hyperphosphatemia, together with a deficiency of 1,25-­dihydroxyvitamin more likely to die of a CVD-­related cause than to progress to ESKD
D3, can contribute to secondary hyperparathyroidism and ultimately to (see Chapter 85). Therefore, appropriate management of existing CVD
the development of renal bone disease. These biochemical and endo- and minimization of future CV risk is vital for all patients with CKD.
crine changes, in association with the closely related histologic abnor- Agents used to slow progression of CKD, including ACE/ARBs, SGLT2
malities of bone and soft tissue calcification, are collectively termed the inhibitors, and mineralocorticoid receptor antagonists (MRAs), may
CKD–mineral and bone disorder (see Chapter 88).27 Bone disease may themselves have cardiovascular benefits in the context of CKD.
already be manifested in CKD category G3b and may be well established Unfortunately, many trials of interventions for CVD have excluded
in ESKD, even though patients may remain asymptomatic. In addition patients with CKD,33 and there is doubt about the relevance of exist-
to the need to prevent bone complications, active management of CKD– ing standards of care of CVD to patients with CKD.34 Nonetheless, the
mineral and bone disorder may help prevent some of the CV complica- level of care for coronary heart disease offered to patients with CKD
tions of CKD.28 should not be prejudiced by their CKD. NICE suggests that antiplatelet
KDIGO recommends measuring serum levels of calcium, phos- drugs should be offered to patients with CKD for the secondary pre-
phate, PTH, and alkaline phosphatase activity in adults with GFR less vention of CVD, and some experts would extend this recommenda-
than 45 mL/min/1.73 m2 (GFR stages G3b–G5). Determining the opti- tion to primary prevention for those at risk for atherosclerotic events.
mal level of PTH in CKD has been controversial. For patients with levels However, there is an increased risk for minor bleeding, and a recent
of intact PTH above the upper normal limit of the assay, efforts should systematic review of antiplatelet agents for patients with CKD found
be made to correct hyperphosphatemia, hypocalcemia, and vitamin D that although the incidence of myocardial infarction is reduced, major
deficiency if present. KDIGO guidelines recommend that serum phos- bleeding is increased.35 Thus, the risks may outweigh benefits among
phate concentrations be maintained in the normal range according to individuals with low risk for CV events, including those with early
local laboratory reference values,29 whereas the UK Kidney Association stages of CKD who do not have clinically evident occlusive arterial
support a level between 0.9 and 1.5 mmol/L for patients with category disease.
G4 and G5 CKD.30 Early advice on dietary phosphate management For reduction of cardiovascular risk, KDIGO guidelines rec-
by a specialist dietician or other professional is important in help- ommend that statin treatment be routinely offered to patients with
ing patients achieve this. Phosphate-­binding drugs may be required, CKD who are aged older than 50 years and to younger patients with

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964 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

additional risk factors, irrespective of baseline lipid values.36 NICE rec- TABLE 83.3 Important Causes of Common
ommends that all people with CKD should be offered atorvastatin 20
Gastrointestinal Symptoms in Patients With
mg for the primary or secondary prevention of CVD.37
CKD
Risk for Infections Clinical Feature Causes
Infection is the second most common cause of death after CVD in
Anorexia Uremic toxicity
patients with ESKD. This is, in part, because of defects in both cellular
Inadequate dialysis clearances
and humoral immunity, which make CKD a state of chronic immuno-
Delayed gastric emptying
suppression (see Chapter 87).38 T-­cell responses to de novo antigens are
Nausea and vomiting Uremic toxicity
deficient, partly because of impaired antigen presentation by monocytes.
Delayed gastric emptying/gastroparesis
Neutrophil activation is defective, and although serum immunoglobu-
Gastritis, duodenitis
lin levels are usually normal, antibody responses to immunization may
Peptic ulcer disease
be poor. Patients with CKD have an increased susceptibility to bacterial
Drugs
infection (particularly staphylococcal), increased risk for reactivation
Constipation Drugs, including opioid analgesia
of tuberculosis (typically with a negative tuberculin skin test response),
GI pseudo-­obstruction
and failure to eliminate hepatitis B and C viruses after infection.
Diverticular disease
In view of these increased risks, the KDIGO guidelines recommend
Diarrhea Diabetic enteropathy
that all adults with CKD be offered annual vaccination with influenza
Diverticular disease
vaccine unless contraindicated and that all adults with eGFR less than
Clostridium difficile infection
30 mL/min/1.73 m2 (GFR categories G4–G5) and those at high risk for
Dialysis-­related amyloidosis (very rare)
pneumococcal infection (e.g., patients with nephrotic syndrome, with
GI hemorrhage Gastritis, duodenitis
diabetes, or who are receiving immunosuppression) receive vaccination
Esophagitis
with polyvalent pneumococcal vaccine unless contraindicated.2 Patients
Peptic ulcer disease
who have received pneumococcal vaccination are offered revaccina-
Angiodysplasia
tion within 5 years. In addition, those at high risk for progression of
Intestinal ischemia
CKD with eGFR less than 30 mL/min/1.73 m2 (GFR categories G4–G5)
Vasculitis
should be immunized against hepatitis B and the response confirmed
Dialysis-­related amyloidosis (very rare)
by appropriate serologic testing. This should happen as early as possible
Acute abdominal pain Gastritis, duodenitis
to maximize the chances of seroconversion.39 Response to COVID-­19
Complications of peptic ulcer disease
vaccination is also attenuated in CKD.40
Acute pancreatitis
Gastrointestinal Problems in Chronic Kidney Disease Intestinal ischemia
Diverticulitis
Gastrointestinal (GI) symptoms and disease are common in patients
GI pseudo-­obstruction
with CKD (Table 83.3). Anorexia, nausea, and vomiting related to
Colonic perforation from fecal impaction
advanced CKD may contribute to malnutrition and wasting, which,
Complications of peritoneal dialysis (peritonitis,
in turn, herald an adverse prognosis (see Chapter 90). In addition,
dialysis catheter malposition, dialysate
uremia-­ associated reduced taste sensation or abnormal taste can
infusion or drain pain)
impair dietary intake. Gastroesophageal reflux is also common in
Complications of autosomal dominant
patients with CKD and related to GI tract dysmotility or delayed gas-
polycystic kidney disease
tric emptying, in particular in diabetes or amyloidosis or patients on
Retroperitoneal hemorrhage
peritoneal dialysis, given their increased intra-­abdominal pressure.
Extensive peptic ulcer disease, gastritis, and duodenitis occur more CKD, Chronic kidney disease; GI, gastrointestinal.
commonly in CKD than in the general population, with the highest
incidence in dialysis patients.41 Peptic ulcers are often multilocular and ischemia. Predisposing factors include hypotension, cardiac failure,
postbulbar, but pain is less frequent. Helicobacter pylori infection is not hypoxia, increased plasma viscosity, and constipation. Abdominal
increased in CKD. There is a risk for excess calcium and magnesium examination can be misleadingly benign at presentation, but often
absorption with some antacids in CKD, and aluminum-­or bismuth-­ peripheral neutrophil leukocytosis and progressive lactic acidosis are
containing preparations should be avoided, given their potential for present. GI hemorrhage resulting from peptic ulcers, gastritis, duo-
accumulation in CKD. denitis, angiodysplasia (Fig. 83.2), or nonulcer, nonvariceal bleeding
In the large bowel, the incidence of diverticular disease is increased because of uremic hemostatic defects is also common in CKD and is
in patients with ADPKD (see Chapter 46). Constipation is common associated with high mortality. Idiopathic ascites with a high protein
in CKD and results from dietary restrictions, restricted fluid intake, content may occur in HD patients, sometimes related to inadequate
electrolyte abnormalities (including hypercalcemia), and commonly dialysis dose. The diagnosis is by exclusion of other causes. Management
prescribed drugs, such as calcium-­ based phosphate binders, seve- includes optimization of volume and small-­solute clearance. The con-
lamer, oral iron, opioid analgesics, and calcium resonium. In extreme dition may resolve after transplantation or a modality switch to PD.
cases, constipation may result in intestinal pseudo-­obstruction, which
may also be acutely precipitated by surgery and retroperitoneal hem- CARE OF THE PATIENT WITH PROGRESSIVE
orrhage. Patients with CKD are at risk for more frequent or severe CHRONIC KIDNEY DISEASE
Clostridium difficile infection, slower treatment response, and more
frequent relapse and have a higher risk for death.42 To optimize the care of patients with progressive CKD, management
Intestinal ischemia is an important cause of an acute abdomen in is provided in a multidisciplinary setting where a range of profession-
older CKD patients. Some cases result from nonocclusive mesenteric als are able to provide education and information about diet, different

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 CHAPTER 83 Clinical Evaluation and Management of Chronic Kidney Disease 965

Fig. 83.2 Examples of gastric angiodysplasia (arrows) in a dialysis patient. (Courtesy Drs. R. Winograd and
C. Trautwein, Aachen, Germany.)

KRT modalities, transplant options, vascular access surgery, and social KRT modality (see Chapter 95). If HD is the preferred option, an AVF
care. Psychological comorbidity is common among patients with CKD. should be constructed, remembering that it may take 8 to 12 weeks
Health care professionals working with patients with CKD should take for veins to become adequately arterialized before needling can be
account of the psychological aspects of coping with the condition attempted (see Chapter 96). Similar plans need to be made for pre-
and offer access to support groups, counseling, or a specialist nurse. emptive insertion of a peritoneal dialysis catheter to allow time for
The aim is to create an environment in which patients can become healing and training before any acute need for commencement of dial-
informed and proactive in their care. ysis (see Chapter 101).
Early kidney transplantation may be associated with improved
Chronic Kidney Disease and Risk of Acute Kidney Injury long-­term outcome,45 so patients should be assessed for their suit-
All patients with CKD are at increased risk for AKI, and AKI is asso- ability and, when feasible, activated on the waiting list before dialysis
ciated with the development and progression of CKD.43,44 Imaging is commenced. This maximizes the chances of the potential recipi-
studies that require iodinated radiocontrast media carry a risk for ent remaining in reasonable health. The availability of a living donor
AKI, and the benefit of a diagnostic scan needs to be balanced against should be explored to increase the chances of preemptive transplanta-
the risks (Chapter 6). If the investigation is needed, the lowest dose tion before the patient begins dialysis. The KDIGO guidelines recom-
of radiocontrast should be used, the patient should be adequately mend that living donor preemptive kidney transplantation in adults
hydrated, and potentially nephrotoxic agents should be withdrawn be considered when GFR is less than 20 mL/min/1.73 m2 and there is
before and after the procedure; however, the fear of radiocontrast-­ evidence of progressive and irreversible CKD over the preceding 6 to
induced AKI should not prevent or impair a necessary diagnostic 12 months.2
workup. The potential risk for nephrogenic systemic fibrosis from Planned early initiation of dialysis is not associated with improve-
gadolinium-­based contrast media and measures to reduce it are also ment in outcomes compared with commencement when indicated
discussed in Chapter 6. by signs and symptoms of uremia.46 KDIGO suggests that dialysis be
Many commonly used medications increase the risk for AKI, and initiated when one or more of the following are present: symptoms
the level of GFR should be considered when any drug is prescribed. or signs attributable to kidney failure (serositis, acid-­base or electro-
As discussed earlier, the need for temporary cessation of some med- lyte abnormalities, pruritus); inability to control volume status or BP;
ications should be considered during periods of severe intercurrent a progressive deterioration in nutritional status refractory to dietary
illness. Other causes of reduction in kidney perfusion can lead to AKI, intervention; or cognitive impairment.2 These problems often but not
including volume depletion from excessive diuretics, insufficient fluid invariably occur when the GFR is less than 15 mL/min/1.73 m2 (see
intake in hot weather, diarrhea or vomiting, heart failure, myocardial Chapter 95).
infarction, and tachyarrhythmias. Severe hypercalcemia, resulting
from either coadministration of high doses of vitamin D and calcium-­ Conservative Management
containing phosphate binders or from underlying disease, can also The potential burden of commencing KRT in terms of high short-­term
cause AKI. mortality rates, recurrent hospitalizations, time spent traveling, and
Clinicians should always consider whether acceleration of loss of limited improvement in quality of life for some elderly patients and
kidney function is a result of relapse of the underlying disease or of a those with multiple comorbid disease is increasingly recognized. This
superimposed problem such as acute interstitial nephritis (see Chapter has led to the practice of offering patients with incipient kidney failure
64), obstructive uropathy (see Chapter 61), or renal vein thrombosis. the option of choosing not to start dialysis but to maintain ongoing fol-
low-­up and symptomatic support through conservative management.
Timing the Initiation of Kidney Replacement Therapy Although dialysis may offer longer survival, those choosing conserva-
Despite all attempts to optimize the management of CKD, many tive management may have as many hospital-­free days as those who
patients will progress to needing KRT. Patients with eGFR less than 20 choose HD.47 The symptoms of advanced uremia can be distressing,
mL/min/1.73 m2 and/or who are likely to progress to ESKD within 12 and it is important to ensure that patients who choose this pathway
months should receive education and counseling, with the support of have access to members of the multidisciplinary team with expertise in
a multidisciplinary team, to aid their selection of the most appropriate palliative care to facilitate a death free of suffering.

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966 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

  S E L F -­A S S E S S M E N T Q U E S T I O N S
1. Which of the following is the most common cause of death for peo- C. Race
ple with CKD and eGFR < 60 mL/min/1.73 m2? D. Sex
A. Failure of dialysis access E. Creatinine
B. Sepsis 4. Which of the following symptoms is suggestive of CKD, regardless
C. Withdrawal from dialysis of cause?
D. Cardiovascular disease A. Pain in the renal angle
E. Cerebrovascular disease B. Nocturia
2. The equation recommended by KDIGO for estimating GFR is: C. Urinary frequency
A. The Modification of Diet in Renal Disease (MDRD) equation D. Tremor
B. The Cockcroft-­Gault formula E. Anuria
C. The CKD-­EPI formula 5. In a well patient, which of the following biochemical or hematologic
D. The Mayo Clinic Quadratic formula abnormalities is suggestive of CKD rather than acute kidney injury?
E. The Schwartz formula A. Calcium 3.5 mmol/L
3. Which of the following variables is not needed to calculate eGFR B. Potassium 7.5 mmol/L
from the CKD-­EPI formula? C. Hemoglobin 10.7 g/dL
A. Age D. Creatinine 13.5 mg/dL
B. Weight E. Sodium 132 mmol/L
  

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966.e1
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