81

Cardiovascular Disease in
Chronic Kidney Disease
Peter Stenvinkel, Charles A. Herzog

Diminished estimated glomerular filtration rate (eGFR) and albuminuria cardiac deaths in the U.S. Renal Data System (USRDS) database are
are powerful graded, independent predictors of cardiovascular (CV) attributable to arrhythmias.
morbidity and mortality1 and all-cause mortality (Fig. 81.1). Even subtle Of incident dialysis patients, 75% have LVH and 75% to 85% have
kidney dysfunction, as suggested by albuminuria, increases CV risk hypertension. Hypertension, anemia, vascular noncompliance, and
because it may reflect microvasculature health, including endothelial volume overload contribute to LVH. Based on echocardiography, 85%
function. Patients with end-stage renal disease (ESRD) face an extraor- to 90% of patients have a left ventricular (LV) ejection fraction (EF)
dinary risk for premature death, largely because of CV complications. of 50% or higher, despite frequent congestive heart failure (CHF), that
However, patients with eGFR below 60 ml/min/1.73 m2 are much more is, heart failure with preserved EF (HFpEF), not heart failure with reduced
likely to die than to develop ESRD, reflecting the burden of cardiovas- EF (HFrEF), characterizes most CHF episodes. Therefore, many volume
cular disease (CVD) in this population. The most effective strategy for overload episodes in dialysis patients may be attributable to diastolic
reducing CV morbidity and mortality would be to target patients with dysfunction or circulatory congestion. Fig. 81.3 provides a snapshot of
mildly reduced eGFR for prevention and treatment. CVD event rates in prevalent dialysis patients.
Patients with chronic kidney disease (CKD) were often excluded
from randomized controlled trials (RCTs) targeting CVD, possibly Cardiovascular Disease Is Present Before the Start of
reducing acceptance of evidence-based therapies (validated in nonrenal Renal Replacement Therapy
patients) and fostering “therapeutic nihilism” in clinicians who treat In elderly CKD patients at stage 2 or 3, traditional risk factors seem to
CKD patients. Thus novel treatment strategies are urgently needed to be the major contributors to CV mortality. Atherosclerosis Risk in Com-
reduce the unacceptable high CV event rate. munities (ARIC) data suggest that both traditional and novel risk factors
Like conventional atheromatous occlusive vascular disease, CKD is are relevant at CKD stage 4, and novel risk factors are far more prevalent
characterized by generalized vasculopathy, with other characteristics, in dialysis patients than in the general population (Fig. 81.4).3 The
including left ventricular hypertrophy (LVH), vascular calcification, Framingham predictive instrument does not accurately predict coronary
and vascular noncompliance. Numerous CVD risk factors are specific events in CKD. Mild to moderate CKD is associated with increased risk
to CKD and operate in addition to conventional risk factors found in for venous thromboembolism, supporting the concept of hypercoagu-
the general population. lability in CKD. Fig. 81.5 shows the burden of CVD in elderly patients
with CKD. Because the incidence of CV events is much higher in the
EPIDEMIOLOGY first weeks after hemodialysis (HD) initiation, concerns have been raised
that the dialysis procedure per se may trigger CV events.4
Prevalence of Cardiovascular Complications in Chronic
Kidney Disease Racial and International Differences in Cardiovascular
Interpretation of epidemiologic studies of CVD is problematic because Disease Prevalence
of the difficulty in defining cause of death. Unexpected sudden death In the United States, survival is better for African American than for
most likely results from arrhythmia, but a subarachnoid hemorrhage, White dialysis patients. However, overall CV mortality among dialysis
massive embolic stroke, or aortic dissection might be indistinguishable patients from the United States is significantly greater than is observed
from a primary arrhythmic event without an autopsy. Defining “coronary in Japan and Europe, even after adjustment for standard risk factors
heart disease” (CHD) is also problematic: in the general population, and dialysis dose. Higher mortality rates in U.S. dialysis patients may
sudden cardiac death is a primary complication of CHD, but this is be related to higher prevalence of sicker or diabetic patients, differences
unlikely to be true for dialysis patients. A history of angina cannot in dialysis practice patterns, cultural habits, differences in diet, or genetic
reliably classify a patient as having CHD because angina (resulting from variations.
supply-demand mismatch) can occur in patients with LVH and angio-
graphically pristine coronary arteries. This probably relates to the Reverse Epidemiology
increased myocardial fibrosis, diminished relative capillary density, and Reverse epidemiology (preferably called confounded epidemiology) refers
increased thickening of the intramyocardial vessel walls in uremia. At to the paradoxical observation that the association among hypercho-
lower levels of eGFR (especially in dialysis patients), the burden of lesterolemia, hypertension, obesity, and poor outcomes, including CV
nonatherosclerotic (vs. atherosclerotic) CVD is relatively increased (Fig. death, in the general population does not exist and may be reversed in
81.2).2 Although occlusive CHD is common in CKD, acute myocardial CKD. Patients with wasting and inflammation appear to mostly account
infarction (AMI) accounts for only 14% of cardiac deaths; 66% of for poor survival and confounded epidemiology.

942
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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 943

Age-Standardized Rates of Death from Any

Cause, Cardiovascular Events, and
Hospitalizations

A 15 14.14
from any cause (per 100 person-yr)

14
Age-standardized rate of death

13
12 11.36
11
10
9
8 Nonatherosclerotic CVD
7 LVH
6 Arrhythmias
4.76
5 Sudden cardiac death Risk
4 Arterial calcification
3 Valve calcification
2 1.08 hemorrhagic stroke
1 0.76
Others
0
≥60 59-45 44-30 29-15 <15
Atherosclerotic CVD event
Estimated GFR (ml/min/1.73 m2) CAD
No. of events 25,803 11,569 7802 4408 1842
ischemic stroke
PAD
CKD stages
Time
B
Age-standardized rate of cardiovascular

40 36.60 No CKD Stage G3 Stage G5D

35
events (per 100 person-yr)

30
Risk for fatality after CVD event
25 21.80
20 Risk

15
11.29
10
5 3.65
2.11
0 Fig. 81.2 Change in cardiovascular risk during chronic kidney
≥60 59-45 44-30 29-15 <15 disease (CKD) progression. Cardiovascular disease (CVD) event (upper
triangle), contributions of atherosclerotic CVD (tan), nonatherosclerotic
Estimated GFR (ml/min/1.73 m2)
CVD (orange), and risk for fatality after CVD event (blue). PAD, Peripheral
No. of events 73,108 34,690 18,580 8809 3824 artery disease. (From reference 2.)

C 144.61 ETIOLOGY AND RISK FACTORS

Age-standardized rate of hospitalization

150
140
130 Traditional Risk Factors
120
110 Age, Gender, and Smoking
(per 100 person-yr)

100 86.75 The U.S. National Health and Nutrition Examination Surveys (NHANES)
90
80 show the prevalence of CV factors and CVD prevalence in relation to
70 age and CKD stage. In the United States, the average age at renal replace-
60 ment therapy (RRT) initiation is 63 years, when CVD is common. An
50 45.26
40 individual-level meta-analysis including more than 2 million participants
30 showed that low eGFR and high albuminuria were independently asso-
13.54 17.22
20 ciated with mortality and ESRD regardless of age. Female gender is
10
0 associated with a 4% independent increased risk for mortality in incident
≥60 59-45 44-30 29-15 <15 dialysis patients and smoking with a 52% increased risk for death in
Estimated GFR (ml/min/1.73 m2) dialysis patients.

No. of events 366,757 106,543 49,177 20,581 11,593 Diabetes Mellitus

Fig. 81.1 Age-standardized rates of death from any cause (A), Diabetes accounted for 44% of incident U.S. ESRD patients in 20105
cardiovascular events (B), and hospitalization (C) according to and is the most common cause of ESRD in many countries. Diabetic
estimated glomerular filtration rate (GFR) among 1,120,295
patients starting RRT have numerous CV risk factors, including dys-
ambulatory adults. A cardiovascular event was defined as hospitaliza-
lipidemia, hypertension, persistent inflammation, increased oxidative
tion for coronary heart disease, heart failure, ischemic stroke, or peripheral
arterial disease. Error bars represent 95% confidence intervals. The rate stress, and protein-energy wasting. Diabetes at dialysis initiation is a
of events is listed above each bar. (From reference 1.)

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944 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Event Rates of Cardiovascular Diagnoses and Procedures by Modality

300

Hemodialysis
Rate per 1000 patient-yr

Peritoneal dialysis
200 Transplant

100

0
CHF CVA/TIA PAD Cardiac AMI Revasc: Revasc: ICD/
arrest PCI surg CRT-D
Fig. 81.3 Event rates of cardiovascular diagnoses and procedures by modality. Point prevalent
end-stage renal disease (ESRD) patients on January 1, 2005, age 20 and older, with Medicare as primary
payer and survival for 90 days after ESRD diagnosis. AMI, Acute myocardial infarction; CHF, congestive heart
failure; CRT-D, cardiac resynchronization therapy defibrillator; CVA, cerebrovascular accident; ICD, implantable
cardioverter-defibrillator; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; TIA, tran-
sient ischemic attack. (From U.S. Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic
Kidney Disease & End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases; 2009.)

TABLE 81.1 Lipid Abnormalities in Renal Disease

Lipid Abnormalities in Renal Disease. Common Patterns of Hyperlipidemia in Different Stages of Renal
Disease, Compared With the Healthy Population.
CHOLESTEROL LEVELS
Stage of Renal Disease Total High-Density Lipoproteins Low-Density Lipoproteins Triglycerides
Nephrotic syndrome ↑↑↑ ↓ ↑↑ ↑
Chronic kidney disease No change ↓ No change* ↑↑
Hemodialysis No change ↓ No change* ↑↑
Peritoneal dialysis ↑ ↓ ↑ ↑
Transplantation ↑↑ No change ↑ ↑
*Composition altered.

potent independent risk factor for all-cause and CVD-related deaths, mean arterial and diastolic pressure may decrease. The relationship
including after coronary revascularization or AMI. Nevertheless the between BP and mortality is U shaped; isolated systolic hypertension
rate of incident AMI is even higher for patients with CKD stages and increased pulse pressure probably indicate high long-term risk in
3b to 4 without diabetes than for patients with diabetes and CKD dialysis patients, whereas low mean and diastolic BPs (DBPs) predict
stages 1 or 2. early mortality. CKD patients are frequently “nondippers” and experi-
ence sleep apnea and sympathetic nervous system activation.
Hypertension
Hypertension is common but variably treated in CKD patients. Of Dyslipidemia
NHANES subjects with CKD stages 3 to 4, 80% had a blood pressure The relationship between hypercholesterolemia, CVD, and mortality
(BP) of 130 or greater/80 or greater mm Hg, and only 20% were aware in CKD is weak because some CV abnormalities, such as cardiomyopathy
of it and had BP adequately controlled. In CKD stages 1 and 2, 63% and arteriosclerosis, may be less dependent on dyslipidemia than on
were hypertensive and only 11% were adequately controlled. Recent other factors. Low rather than high serum cholesterol level is associated
NHANES data suggest modest improvement in hypertensive people with poor survival in HD patients, likely related to confounding by
with CKD stages 3 or 4.6 Hypertension predicts mortality in CKD patients protein-energy wasting and inflammation. After adjustment for C-reactive
before or at dialysis initiation. Isolated systolic hypertension with protein (CRP) levels, high cholesterol level predicts risk in noninflamed
increased pulse pressure is by far the most prevalent BP anomaly in ESRD patients.
dialysis patients, resulting from arterial medial sclerosis with secondary Progressive CKD leads to changes in blood lipids typically associated
stiffening. Stiff vessels cause increased pulse wave velocity, resulting in with vascular disease, including decreased apolipoprotein A (apoA)-con-
increased systolic BP (SBP) peak pressure by a prematurely reflected taining lipoproteins and increased apoB-containing lipoproteins (Table
pulse wave, progressive LV dysfunction, and finally CHF. At this stage, 81.1). Serum triglycerides are elevated in most ESRD patients, whereas

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CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 945
946 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

total serum cholesterol is variable, depending on nutritional status and

presence of inflammation. High-density lipoprotein (HDL) cholesterol Sources of Elevated Oxidative Stress
is typically reduced, and low-density lipoprotein (LDL), intermediate-
density lipoprotein, and very low-density lipoprotein cholesterol, as
well as lipoprotein(a) levels, tend to be increased. Because of altered Malnutrition
molecular composition, the antiinflammatory activity of HDL is reduced
in the uremic milieu. Compared with long-term HD patients, peritoneal Bacterial products Chronic kidney
dialysis (PD) patients more often have both hypercholesterolemia and in dialysate disease
hypertriglyceridemia. Both groups are characterized by low HDL and
elevated oxidized LDL cholesterol levels; elevated lipoprotein(a) levels
are associated with increased CVD mortality. Elevated
oxidative
Insulin Resistance and Atherosclerosis stress

In the general population, impaired insulin-stimulated glucose disposal

in muscle is often part of a metabolic syndrome that includes dyslip- Interactions between Loss of antioxidants
idemia, hypertension, endothelial dysfunction, and sympathetic over- blood and membrane during dialysis
activity. Many of these abnormalities are present in CKD. Although
insulin resistance was found to be an independent predictor of CV Fig. 81.6 Sources of elevated oxidative stress.
mortality in dialysis patients, its magnitude of contribution in CKD
mortality is uncertain. primary causes are not always evident. The senescence-associated secre-
tory phenotype caused by increased numbers of senescent vascular cells
Nontraditional and Uremia-Specific Risk Factors also may be a significant contributor to uremic inflammation. Whether
Even mild CKD is an independent risk factor for CVD, and similar in the acute-phase response reflects only established atherosclerotic disease
magnitude to diabetes and hypertension. The uremic milieu may affect or is involved in the initiation and progression of atherosclerosis is
both quality and quantity of the atherosclerotic plaques. Coronary unclear. Some inflammatory biomarkers, such as IL-6, PTX3, and tumor
lesions in uremic patients, compared with nonrenal controls, are char- necrosis factor, may have proatherogenic properties, such as promoting
acterized by increased media thickness, infiltration and activation of vascular calcification, oxidative stress, and endothelial dysfunction (Fig.
macrophages and marked media calcification. The mechanism(s) by 81.7). Evidence suggests associations between inflammation and devel-
which a uremic milieu may promote vascular senescence and accelerate opment of albuminuria. Persistent inflammation may change the risk
premature vascular aging7 are not well established, but prevalence and factor profile for traditional risk factors, such as cholesterol and obesity.9
magnitude of several nontraditional risk factors, such as oxidative stress, The link between septicemia and subsequent increased risk for death
inflammation, and advanced glycation end-products (AGEs), increase and CV events, including AMI, further supports inflammation as a
as renal function deteriorates. Other uremic retention solutes, such as trigger for CV events.
asymmetric dimethylarginine (ADMA), guanidine, indoxyl sulfate, and
p-cresol, which accumulate in CKD, may have proatherogenic proper- Gut Dysbiosis
ties.8 Finally, failing kidneys produce fewer substances that may inhibit The uremic milieu affects the intestinal microbiota and the integrity
CVD and atherogenesis—for example, renalase, a soluble monoamine of the intestinal wall, possibly contributing to inflammation and increased
oxidase that regulates cardiac function and BP. production of uremic toxins such as proatherogenic indoxyl sulfate,
phenylacetic acid, and p-cresol sulfate. The uremic milieu and volume
Oxidative Stress retention may damage the intestinal wall, promoting increased leakiness
Oxidative stress may be implicated in the pathogenesis of atherosclerosis, of endotoxins and translocation of intestinal bacteria. The microbial
the increased risk for atherosclerotic CV events, protein-energy wasting, metabolite trimethylamine N-oxide contributes to the development of
and anemia. Increased production of reactive oxygen species in the atherosclerotic heart disease and is related to adverse CV outcomes in
vascular wall characterizes atherosclerosis. Moderate CKD, and in par- the general population10 and in CKD patients.
ticular uremia, is a prooxidant state resulting from reduced antioxidant
systems (vitamin C and selenium deficiency, reduced intracellular vitamin Endothelial Dysfunction
E levels, reduced glutathione system activity), and increased prooxidant Endothelial dysfunction (as evaluated by impaired endothelium-
activity associated with advanced age, diabetes, chronic inflammation, dependent vasodilation) is common in CKD. Reasons include inflam-
retained uremic solutes, and dialysis membranes and solutions. mation, ADMA retention, oxidative stress, elevated fibroblastic growth
Four oxidative stress pathways can be hypothesized in CKD: carbonyl factor-23 (FGF-23), dyslipidemia, hyperglycemia, and hypertension.
stress, nitrosative stress, chlorinated stress, and classic oxidative stress Serum ADMA concentrations are associated with endothelial function
(Fig. 81.6). in uremic resistance vasculature. Surrogate markers of endothelial dys-
function, such as ADMA, PTX3, and adhesion molecules, independently
Inflammation predict death.3 Detached circulating endothelial cells are potential markers
Most dialysis patients are in a state of chronic inflammation. Inflam- of endothelial damage and have prognostic value in HD patients.3 Nor-
matory biomarkers, such as CRP, interleukin 6 (IL-6), pentraxin 3 mally, in response to an ischemic insult and cytokine stimulation,
(PTX3), fibrinogen, and white blood cell count, are independent pre- endothelial progenitor cells are mobilized from the bone marrow to
dictors of mortality in CKD patients. Hypoalbuminemia, strongly repair endothelial injury, and this seems to be impaired in CKD.
associated with systemic inflammation, is another strong outcome
predictor in CKD. Whereas both dialysis-related factors and non–dialysis- Anemia
related factors (infection, comorbidity, genetic factors, hypogonadism, Anemia is a major cause of LVH and LV dilation in CKD. Although
diet, renal function loss) may contribute to chronic inflammation, its partial correction of anemia with erythropoiesis-stimulating agents

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 947

Effect of Altered Cytokine Production in Uremia on Various Target Organs

Unfriendly uremic milieu

Monocyte/macrophage

↑ Proinflammatory cytokines
↓ Antiinflammatory cytokines

↑ Bone remodeling

↑ Insulin resistance

↑ Muscle catabolism

↑ Acute-phase reactants
↓ Fetuin-A
↑ Endothelial dysfunction
↑ Monocyte adhesion
↑ ↑ Smooth muscle cell proliferation
↑ Adipocytokine Appetite
↑ LDL oxidation
production ↑ REE
↑ Vascular calcification
Fig. 81.7 Potential mechanisms by which elevated circulating levels of proinflammatory and
antiinflammatory cytokines may promote accelerated atherosclerosis, other uremic complica-
tions, and wasting. LDL, Low-density lipoprotein; REE, resting energy expenditure. (From reference 8.)

(ESAs) results in LVH regression, current information suggests no CV artery, calcification can occur at young ages. Calciphylaxis (calcific uremic
outcome benefit of normalized hemoglobin (see Chapter 82). arteriolopathy) is discussed in Chapter 88.
Vascular calcification is not derived only from passive calcium and
Secondary Hyperparathyroidism and Mineral Metabolism phosphate precipitation. Rather, it involves differentiation of vascular
Disturbances of calcium and phosphate metabolism might accelerate smooth muscle cells toward osteoblasts induced by phosphate, calcium,
calcifying atherosclerosis and arteriosclerosis (see also Chapter 85). and other factors, such as calcitriol and proinflammatory cytokines.
Recent evidence suggests that chronically elevated FGF-23 levels con- Uremic bone disease and protein-energy wasting may be additional risk
tribute directly to high rates of LVH, atrial fibrillation (AF), and mortality. factors for vascular calcification.11 One way by which chronic inflam-
In registry data, a strong independent mortality risk is predicted by mation promotes vascular calcification may involve downregulation of
hyperphosphatemia, an intermediate risk by elevated serum calcium fetuin-A, the most potent circulating inhibitor of extraosseous calcifica-
levels, and a weak risk by high or low serum intact parathyroid hormone tion and a component of calciprotein particles. Apart from fetuin-A,
(PTH) levels. The overall mortality risk prediction attributable to mineral other inhibitors, such as magnesium, probably counteract unwanted
metabolism disorders is estimated to be about 17% in HD patients. calcification. Leptin, matrix GLA protein, FGF-23, pyrophosphates,
bone morphogenic proteins (e.g., BMP-2 and BMP-7), and osteopro-
Cardiovascular Calcification tegerin may be related to accelerated vascular calcification in ESRD.
CV calcification may affect the arterial media, atherosclerotic plaques, Deficiency of vitamin K and/or treatment with vitamin K antagonists
myocardium, and heart valves. Medial calcification causes arterial stiff- (warfarin) may accelerate the vascular calcification process in the
ness and, consequently, increased pulse pressure. The pathophysiologic uremic milieu.
role of plaque calcification is less clear because soft plaques are assumed
to rupture and cause AMI; atherosclerotic calcification is a potent risk Advanced Glycation End-Products
marker for CV events, but its utility as a risk marker for clinical man- AGEs accumulate in CKD patients as a result of nonenzymatic gly-
agement of CKD patients remains controversial. Valvular calcification cation, oxidative stress, intestinal food components, and diminished
mostly affects the aortic and mitral (annulus) valves in dialysis patients clearance of AGE precursors. Stable AGE residues of long-lived proteins
and contributes to progressive stenosis and associated morbidity and are biomarkers of cumulative metabolic, inflammatory, and oxidative
mortality. In dialysis patients, extensive vascular, especially coronary stress; carbonyl stress is speculated to contribute to tissue aging and

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948 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

long-term CKD complications. Whether AGE inhibition may affect CV occurred only in patients with ST-segment elevation myocardial infarc-
disease in CKD is unknown. tion (STEMI), specifically related to in-hospital mortality. Rates of
non-STEMI (NSTEMI) mortality or postdischarge mortality have not
Dialysis Modality improved.12 In-hospital deaths increase with decreasing GFR.13 This
Reports from dialysis registries are inconsistent regarding whether poor outcome has been attributed to underrecognition resulting from
HD or PD is associated with better outcomes. Valid mortality compari- atypical presentations, underuse of appropriate diagnostic investiga-
sons between HD and PD modalities are not available because this tions, and undertreatment (therapeutic nihilism).14 A U.S. registry of
would require stratification of patients according to underlying ESRD dialysis patients hospitalized for AMI found the following14:
cause, age, and level of baseline comorbidity. Cardiac arrhythmias,
such as AF, seem to occur more often on the day of HD compared incorrectly with respect to acute coronary syndrome (ACS).
with PD.
chest pain.
CLINICAL MANIFESTATIONS AND
elevation.
NATURAL HISTORY
Fig. 81.8 shows survival of patients with CV diagnoses and procedures, nondialysis patients, were eligible for acute coronary reperfusion.
by RRT modality.
patients actually received reperfusion.
Chest Pain, Coronary Heart Disease, and Acute
Myocardial Infarction patients. In-hospital cardiac arrest occurred twice as frequently in
AMI in dialysis patients is associated with poor long-term survival. The dialysis as in nondialysis patients (11% vs. 5%).
unadjusted 2-year mortality rate is not changing: 71% in 1977 to 1984 Similar findings occur across the CKD spectrum; the likelihood of
and 72% in 2008,12 despite dramatic improvements in AMI outcomes increased mortality and lower prevalence of both STEMI and chest
in the general population (Fig. 81.9). Significant improvement has pain are correlated with severity of non–dialysis-dependent CKD in

Survival of Patients with Cardiovascular Diagnoses and Procedures by Modality

CHF CVA/TIA PAD Cardiac arrest

1.0

0.8

0.6

0.4 Hemodialysis
Peritoneal dialysis
Probability of survival

0.2
Transplant

0.0
AMI Coronary revascularization: Coronary revascularization: ICD/CRT-D
1.0 PCI Surgical

0.8

0.6

0.4

0.2

0.0
0 3 6 9 12 0 3 6 9 12 0 3 6 9 12 0 3 6 9 12
Months
Fig. 81.8 Survival of patients with cardiovascular diagnoses and procedures, by modality. January
1, 2005, point prevalent end-stage renal disease patients, age 20 and older, with a first cardiovascular diag-
nosis or procedure in 2005-2007. AMI, Acute myocardial infarction; CHF, congestive heart failure; CRT-D,
cardiac resynchronization therapy defibrillator; CVA, cerebrovascular accident; ICD, implantable cardioverter-
defibrillator; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; TIA, transient ischemic
attack. (Modified from U.S. Renal Data System. USRDS 2009 Annual Data Report: Atlas of Chronic Kidney
Disease & End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases; 2009.)

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 949

Among AF patients with stage 3 CKD, adjusted-dose warfarin was asso-

Estimated Mortality of Dialysis Patients
ciated with a 76% reduction in the relative risk for ischemic stroke or
After Acute Myocardial Infarction (MI) systemic embolism.23 In AMI patients with AF, warfarin treatment was
associated with a lower 1-year risk for the composite outcome of death,
100 Overall mortality
AMI, and ischemic stroke without a higher risk for bleeding, irrespec-
tive of CKD severity. In contrast, the usefulness of warfarin for primary
prevention of stroke in dialysis patients with AF is controversial; some
80 observational studies suggest harm, and current Kidney Disease: Improv-
ing Global Outcomes (KDIGO) recommendations do not include routine
Mortality from warfarin therapy for primary prevention of stroke in AF patients with
60 cardiac causes
Mortality (%)

CKD stage 5D (however, warfarin for secondary prevention of stroke

is recommended).17,24
40 The therapeutic approach to primary prevention of stroke in ESRD
remains controversial. There are few data on the safety and efficacy of
novel oral anticoagulants (NOACs), and warfarin use is made challeng-
20 ing by the difficulty of maintaining dialysis patients in optimal antico-
agulation range and the potential for accelerated vascular calcification
with vitamin K antagonists. The case favoring NOACs rather than
0
0 2 4 6 8 10 warfarin in moderate CKD is less controversial, based on post hoc
analysis of RCTs (Fig. 81.10). No data support the sole use of aspirin
Years
for prevention of stroke in CKD patients with AF.
No. at risk 34,189 6753 2284 834 304 105
Fig. 81.9 Estimated mortality of dialysis patients after acute myo- Left Ventricular Remodeling and Hypertrophy
cardial infarction. (Reprinted with permission from Herzog CA, Ma LVH occurs early in progressive CKD, probably because of high hyper-
JZ, Collins AJ. Poor long-term survival after acute myocardial infarction tension prevalence, including frequent nocturnal hypertension. Pressure
among patients on long-term dialysis. N Engl J Med 1998;339:799-805.) overload, caused by hypertension and arterial stiffness, results in con-
centric hypertrophy. Volume overload manifests as eccentric hypertrophy.
patients with AMI.13,15 Patients with eGFR below 45 ml/min/1.73 m2 LV dilation strongly predicts poor outcome. It may be an end result of
are three times as likely to present with AMI as the initial manifestation severe LVH, diffuse ischemic damage, or recurrent volume overload; a
of CHD, rather than stable angina. high-output arteriovenous fistula may contribute. Diastolic dysfunction
is strongly associated with LVH and with increased risk for intradialytic
Peripheral Arterial Disease hypotension because relatively small reductions in left atrial filling sig-
Risk for peripheral arterial disease (PAD) is highest for dialysis patients nificantly affect cardiac output in these stiff, hypertrophied preload-
with diabetes or preexisting atherosclerosis. In HD patients, PAD is also sensitive hearts, together with the Bezold-Jarisch reflex activation through
associated with time on dialysis, hypoalbuminemia, low PTH levels, stimulation of LV posterior wall stretch receptors in underfilled, hyper-
and low predialysis DBP. Vascular medial calcification of large peripheral contractile, hypertrophied ventricles.
arteries may not indicate occlusive disease, and peripheral gangrene is The term uremic cardiomyopathy is misleading; cardiomyopathy of
often caused by diabetic or other small-vessel disease or rarely by calcific advanced CKD more accurately describes the structural heart disease
uremic arteriolopathy (see Chapter 88). PAD is associated with increased that occurs before ESRD onset. There is no change in LV mass index
mortality; outcomes after revascularization are worse than for the general in patients with eGFR below 20 ml/min/1.73 m2 (not on dialysis) seri-
population, in part reflecting advanced vasculopathy. Although one ally imaged with echocardiograms and subsequently imaged after dialysis
fourth of CKD patients and half of HD patients have PAD,5,16 knowledge initiation (i.e., after incident ESRD).25 Dialysis initiation was associated
gaps regarding their treatment are large.17 with a small drop in LVEF in some but not all studies. In patients with
stage 4 CKD (and no clinical heart failure), 75% had LVH and only
Cerebrovascular Disease and Atrial Fibrillation about 10% had normal LV geometry.26
Cognitive impairment is severe in more than a third of dialysis patients, Conventional HD delivery can produce repetitive myocardial injury,
and only 15% have normal cognition. Cognitive impairment prevalence leading to global and segmental reduction in LV systolic function; the
increases approximately 10% per 10 ml/min/1.73 m2 of eGFR less than occurrence of HD-induced myocardial stunning is associated with
60 ml/min/1.73 m2. Microalbuminuria and stage 3 CKD increased stroke increased 1-year mortality. Even pediatric HD patients can experience
risk 1.5-fold to 2-fold in a multivariate model and stroke risk increases HD-induced myocardial stunning, indicating that large-vessel obstruc-
to 6-fold in incident dialysis patients; 11% of stroke hospitalizations tive CHD is not a prerequisite for this pathologic finding. Biofeedback
in dialysis patients were attributed to hemorrhagic stroke. Silent cerebral dialysis or reduced dialysate temperature both help reduce intradialytic
microbleeds occur in 20% of CKD patients, predict CVD,18 and may hypotension and severity of HD-induced myocardial stunning.
explain the fourfold to sevenfold increase in stroke incidence that imme-
diately follows dialysis initiation.19 Stroke accounts for 3% of ESRD Extracellular Volume Overload
deaths in the USRDS registry5 (see Chapter 86 for more details). Extracellular volume overload resulting from loss of sodium excretory
AF is the most common dysrhythmia in CKD patients, and its inci- capacity is the major cause of hypertension in dialysis patients. Whether
dence is increasing in older patients initiating dialysis in the United prevention of recurrent hypervolemia reduces CV morbidity and mor-
States.20 Incident AF is an independent risk factor for development of tality remains unproved. If adjustments are made for comorbidity and
ESRD in CKD.21 Prevalence among dialysis patients is 15% to 20%, advanced age, a strong, incremental risk for all-cause and CV mortality
and this increased to 27% (58% of these episodes were paroxysmal is associated with interdialytic weight gains. Recurrent hypervolemia
AF22) and 40% in small series employing implantable loop recorders. may result in LVH and LV dilation, peripheral or pulmonary edema,

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950 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Intervention Hazard ratio (95% Cl)

Dabigatran 150 mg (n = 1,232)

systemic embolism
Dabigatran 110 mg (n = 1,196)

Stroke or
Rivaroxaban 15 mg (n = 1,474)

Apixaban 5 mg* (n = 1,508)

Edoxaban 30 mg (n = 1,302)

Dabigatran 150 mg (n = 1,232)

Major bleeding
Dabigatran 110 mg (n = 1,196)

Rivaroxaban 15 mg (n = 1,474)

Apixaban 5 mg* (n = 1,508)

Edoxaban 30 mg (n = 1,302)

0.2 0.5 1.0 2.0

Favors NOAC Favors warfarin
Fig. 81.10 Efficacy and safety of novel oral anticoagulants (NOACs) versus warfarin in the sub-
group of patients with moderate chronic kidney disease from randomized, clinical trials in atrial
fibrillation. (From Qamar A, Bhatt DL. Stroke prevention in atrial fibrillation in patients with chronic kidney
disease. Circulation 2016;133(15):1512-1515.)

raised jugular vein pulse, or a third heart sound, or it may be largely receiving tissue versus mechanical valves and fewer valve-related com-
asymptomatic. Tolerance of large ultrafiltration volumes may indi- plications with tissue valves. The overall mortality is high, with in-
cate that the dry weight target (see Chapter 96) has not been reached. hospital mortality about 20% (four times higher than in non-CKD
Reaching an optimal dry weight, however, does not necessarily lead patients) and 2-year survival of 40%. Transcatheter aortic valve replace-
to immediate BP correction; a lag phase of some weeks can precede ment may be appropriate in dialysis patients with symptomatic aortic
improvement. stenosis who are not good candidates for surgery. In kidney transplant
recipients, in-hospital mortality was 11% for tissue and 15% for mechani-
Pericarditis cal valve patients, and 2-year mortality rates were 62% and 60%, respec-
Dialysis-associated pericarditis may be related to intercurrent illnesses tively. In the entire cohort of kidney transplant patients, the rate of
(including viral infections), fistula recirculation leading to underdialysis, endocarditis after valve surgery was 5% per year.28
or underlying diseases such as systemic lupus. Fever with pericardial
pain or a rub on heart auscultation, unexplained cardiomegaly on chest Infective Endocarditis
films, or hemodynamic instability should prompt echocardiography. Estimated incidence of infective endocarditis in U.S. dialysis patients
An effusion causing overt hemodynamic compromise (i.e., pericardial is 267 cases per 100,000 patient-years. Vascular access, including tem-
tamponade) or large pericardial effusions judged unlikely to resolve with porary and semipermanent catheters, is an important source of infection;
conservative measures require echocardiographically guided or com- heightened risk for bacteremia related to HD therapy is likely an impor-
puted tomography (CT)-guided pericardiocentesis or surgical drainage. tant aspect of endocarditis risk. Dialysis patients with bacterial endo-
Intensive dialysis is indicated for true uremic pericarditis; the optimal carditis have poor in-hospital and long-term survival. One-year survival
treatment of dialysis-associated pericarditis is much less clear in patients for U.S. dialysis patients with endocarditis who subsequently received
without hemodynamic compromise. Citrate-based anticoagulation is valve replacement surgery was about 50%.29 A risk model for operative
preferred given the risk for hemorrhage-induced pericardial tamponade. mortality may be helpful in managing these high-risk patients.

Autonomic Dysfunction Sudden Cardiac Arrest

There is decreased baroreflex sensitivity in CKD, which has been linked In the USRDS database, two thirds of all cardiac deaths and one quarter
to increased risk for sudden death. Increased sympathetic nerve activity, of all-cause mortality in dialysis patients are attributable to arrhythmias.5
including secondary to sleep apnea, is a common alteration in CKD The reported rate of cardiac arrest in HD centers is 3.8 to 7.1 events
patients and associated with adverse outcome. per 100,000 dialysis sessions. Strong predictors of sudden cardiac death
are history of CHD, PAD, diabetes, elevated inflammatory biomarkers,
Valvular Disease and reduced LVEF. Even a modest reduction in LVEF to 40% to 50%
The rate of progression of calcific aortic stenosis is approximately three is prognostically important in both HD30 and PD patients. Myocardial
times faster in dialysis patients than in the general population. Annual fatty acid imaging might identify patients at risk for sudden death.
echocardiography is recommended for asymptomatic dialysis patients Factors probably contributing to the special vulnerability of ESRD
with an aortic valve area of 1.0 cm2 or less27 who are suitable candidates patients to sudden cardiac arrest include LVH; rapid electrolyte shifts
for valve replacement. A meta-analysis of dialysis patients undergoing and hyperkalemia in HD; autonomic dysfunction and sympathetic
valve replacement surgery found no difference in survival for patients overactivity, including sleep apnea; and abnormalities in myocardial

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 951

ultrastructure and function, including endothelial dysfunction, interstitial mortality. As in the general population, CKD patients with LVEF below
fibrosis, decreased perfusion reserve, and diminished ischemia toler- 40% should be evaluated for CHD (exceptions are pediatric or young
ance.31 Low-potassium dialysate (<2 mmol/l) doubles the risk for cardiac adult patients with nondiabetic CKD and other patients known to be
arrest.32 The rate of cardiac arrest is 50% higher for HD than for PD at low risk for CHD).
patients 3 months after dialysis initiation but is higher for PD patients A new classification scheme for CHF staging specifically targeted
at 3 years. The highest rate of sudden cardiac death occurs in the first for dialysis patients has been proposed by the Acute Dialysis Quality
2 months after HD initiation.33 In cardiac arrests occurring in HD Initiative (ADQI) XI Workgroup.35 The three key elements are as follows:
centers, the predominant rhythm is ventricular fibrillation (66%), fol- 1. Standardized echocardiographic evidence of structural and/or func-
lowed by pulseless electrical activity (23%), and asystole (10%). tional cardiac abnormalities.
In women with CHD, eGFR below 40 ml/min/1.73 m2 was associ- 2. Dyspnea occurring in the absence of primary lung disease, including
ated with a 2.3-fold increased risk for sudden cardiac death. Despite a isolated pulmonary hypertension (i.e., not secondary to elevated
graded, incremental risk for arrhythmic death and impaired renal func- pulmonary capillary wedge pressure).
tion, the overall magnitude of risk in stage 3 CKD patients is small 3. Improvement of congestive symptoms after RRT/ultrafiltration.
compared with that in dialysis patients. The justification for the KDOQI 2005 Guidelines (recommending
Onsite defibrillation capability in HD centers (preferably with auto- echocardiograms in incident dialysis patients) and the validity of the
matic external defibrillators) was recommended in a U.S. practice first element of the proposed ADQI XI heart failure staging scheme
guideline in 2005.27 The role that implantable cardioverter-defibrillators (standardized echocardiographic evidence of structural and/or functional
(ICDs) may play in reducing mortality in CKD patients is controversial, heart disease) are both supported by the finding that right ventricular
particularly regarding primary prevention. CKD may attenuate the dysfunction was associated with a 66% increased risk for death.36
survival advantage of ICDs, but older age and medical comorbidity
should not routinely exclude patients from receiving ICDs. In dialysis Stress Tests and Screening Renal
patients who survived cardiac arrest, ICD implantation was associated Transplant Candidates
with a 14% to 42% reduction in long-term mortality.34 The role of ESRD patients are poorly suited for conventional exercise stress elec-
ICDs in dialysis patients is uncertain: the Wearable Cardioverter Defi- trocardiography because of limited exercise tolerance and frequent
brillator in Hemodialysis Patients (WED-HED) trial (clinicaltrials.gov, resting electrocardiographic abnormalities. Accuracies of pharmacologic
NCT02481206) was a prospective RCT, testing wearable defibrillators stress echocardiographic and nuclear scintigraphic techniques are remark-
for prevention of sudden cardiac death in incident HD patients who ably variable across the world; they are operator dependent, and the
do not qualify for ICDs under current guidelines. Unfortunately, the approach of individual sites to cardiac screening should rely on insti-
trial was terminated in 2017 due to low enrollment. tutional expertise. Moreover, prediction of the likelihood of future events
may differ considerably from prediction of coronary anatomy. In severe
CKD, dobutamine stress echocardiography is an independent predictor
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS of long-term mortality. Sensitivities and specificities for detection of
Key issues in the diagnosis of CVD are underrecognition of symptoms, CHD in renal transplant candidates have been reported to range from
underuse of appropriate diagnostic investigations, and interpretation 44% to 90%. A meta-analysis concluded that presence of inducible
of those investigations. myocardial ischemia by any stress-imaging test is independently predic-
tive of increased AMI risk and cardiac death, whereas a fixed or resting
Blood Pressure Measurements defect or abnormality is predictive of cardiac death but not AMI. A
Outcome prediction by ambulatory BP monitoring is not necessarily subsequent meta-analysis by the Cochrane Collaboration (Fig. 81.11)
better than by office BP measurements. However, ambulatory monitor- concluded that dobutamine stress echocardiography is probably more
ing is useful to identify high-risk nondippers and inverted dippers, accurate than myocardial stress nuclear scintigraphy for noninvasive
allowing consequent treatment adjustments. detection of CHD in renal transplant candidates.37
The major problem with “screening” is use of test results for clinical
Electrocardiography and Echocardiography management. The evidence for prophylactic revascularization of asymp-
The National Kidney Foundation’s Kidney Disease Outcomes Quality tomatic renal transplant candidates (or any other patient group) is
Initiative (KDOQI) clinical practice guidelines for CVD in dialysis weak.38 The International Study of Comparative Health Effectiveness
patients recommend an electrocardiogram at dialysis initiation and with Medical and Invasive Approaches–Chronic Kidney Disease Trial
then annually.27 Diabetic HD patients presenting without sinus rhythm (ISCHEMIA-CKD; clinicaltrials.gov, NCT01985360) is a prospective
(11% of the cohort) were 89% more likely to die and 164% more likely RCT testing the comparative efficacy of a conservative versus invasive
to sustain a stroke. CKD patients (eGFR <60 ml/min/1.73 m2) with strategy for treatment of stable CHD in patients with eGFR less than
increased QRS duration had 15% greater risk for incident CHF, 13% 30 ml/min/1.73 m2, including dialysis patients. The best observational
greater risk of incident CHD, and 17% greater risk for mortality per data supporting the usefulness of preemptive coronary revascularization
10-ms increase; prolongation of the QT interval was independently showed 3-year cardiac event–free survival of 90% for wait-listed revas-
associated with adverse outcome. cularized patients.39 Optimal medical therapy (which should constitute
KDOQI guidelines recommend echocardiography in all dialysis the treatment strategy for all patients) may potentially attenuate the
patients after they achieve “dry weight” targets, preferably 1 to 3 months putative benefit of prophylactic coronary revascularization. One algo-
after dialysis initiation on an interdialytic day for HD patients and at rithm for screening and management of CHD in renal transplant can-
3-year intervals thereafter.27 The rationale for this guideline is that didates is presented in Fig. 81.12.
diminished LV systolic function, an important independent risk factor
for CVD and mortality,27 is not accurately diagnosed by history, physical Coronary Angiography
examination, or chest radiography. Detection of unsuspected cardio- Coronary angiography should be considered in stable ESRD patients with
myopathy is also important, given that carvedilol therapy in such patients evidence for inducible myocardial ischemia, unstable patients with ACS
improved LV systolic function, decreased hospitalization, and reduced (performed urgently for STEMI), and patients with LVEF below 40%. In

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952 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

1.0

0.8

Posttest probability
0.6

0.4
MPS (positive)
DSE (positive)
0.2 MPS (negative)
DSE (negative)
0.0
0.0 0.2 0.4 0.6 0.8 1.0

Post-test probability

Test Pretest probability of (%) Posttest probability (%) Posttest probability (%)
coronary artery disease after positive result after negative result*

Low risk (10-29) 42-72 3-10

Dobutamine Stress
Echocardiography (DSE) Intermediate risk (30-59) 73-90 10-27
High risk (60-90) 91-98 28-70

Low risk (10-29) 24-54 5-15

Myocardial Perfusion
Scintigraphy (MPS) Intermediate risk (30-59) 55-81 16-38
High risk (60-90) 81-96 39-79

Fig. 81.11 Accuracy of dobutamine stress echocardiography versus myocardial perfusion scin-
tigraphy for diagnosing coronary artery disease coronary artery disease in renal transplant
candidates. (From reference 67.)

CKD and dialysis patients with residual renal function, fear of contrast Imaging of Vascular Calcification
nephropathy may restrain use of coronary angiography (see Chapter Vascular calcification can be visualized by conventional x-ray techniques
70 for preventive measures); one retrospective study of 76 nondialysis and by multislice spiral CT or electron-beam CT. Valvular and large-
patients with mean eGFR of 12.5 ml/min/1.73 m2 found no significant artery calcification can be visualized by ultrasound techniques, and (if
postangiographic deterioration in renal function. However, patients present) predicts worse outcome in dialysis patients, although the value
sustaining acute kidney injury (AKI) after coronary angiography are at of coronary artery calcification in dialysis patients as a surrogate for
heightened risk for long-term mortality, ESRD, and hospitalization.40 CHD severity has been questioned.
However, fear of AKI should not deter clinically mandated coronary
angiography. Echocardiography should be performed before any non- Biomarkers
emergent coronary angiography in CKD patients to diagnose clinically Plasma brain natriuretic peptides (BNP and NT-proBNP), cardiac tro-
unsuspected valvular disease or cardiomyopathy, to gauge preprocedure ponins (cTnT, cTnI), and high-sensitivity (hs) CRP are prognostic risk
volume status, and to assess LV function (to avoid excessive exposure to markers in the evaluation of heart disease in ESRD.42 BNP reflects cardiac
radiocontrast media through unwarranted ventriculography). filling pressures (not limited to the left heart), troponins reflect myocardial
Noninvasive coronary CT angiography (CCTA) may be problematic cell death (but not necessarily ischemia), and hsCRP reflects inflamma-
in dialysis patients because of medial calcification interfering with tion. Elevation of cTnT occurs even in pediatric CKD patients and is
angiographic interpretation. Nevertheless, noninvasive CCTA has diag- associated with cardiac dysfunction. Elevated levels of serum troponin
nostic sensitivity to detect obstructive CHD nearly comparable to invasive in ESRD patients should not be uncritically attributed to myocardial
coronary angiography and markedly superior to noninvasive nuclear ischemia caused by obstructive coronary artery disease. Elevated levels
single-photon emission computed tomography imaging.41 Generaliz- of cTnT are associated with the presence and severity of HD-induced
ability of these findings must be interpreted in the context of individual myocardial stunning.43 The cardiac biomarker–based diagnosis of ACS
institutional expertise. Noninvasive gadolinium-based magnetic reso- requires a time-appropriate rise and fall of the biomarker. The most
nance angiographic imaging in patients with severe CKD remains cost-effective combination of biomarkers for risk stratification in dialysis
problematic because of lingering concerns about nephrogenic fibrosing patients might be high-sensitivity cardiac troponin and a natriuretic
dermopathy; the usefulness of imaging without contrast media is peptide, but this is speculative. A recent study underscored the robust-
uncertain. ness of IL-6 as a classifier of clinically overt CVD and predictor of

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 953

Algorithm for Management of Coronary Artery Disease in Renal Transplant Candidates

Low-risk Evaluation before High-risk

patients transplant patients

Two-dimensional
echocardiography

Atypical chest pain, Symptomatic CAD

asymptomatic diabetes,
previous MI, multiple
risk factors
Fractional flow
reserve
Dobutamine Positive Coronary Ambiguous/flow-limiting
echocardiography angiography lesions? or
Dobutamine
Negative echocardiography
Transplant Post PCI

<75% stenosis ≥75% stenosis

Low-risk High-risk
patients patients Intervention Negative Positive
No intervention CABG or PCI

No intervention Consider further

intervention
Transplant
No transplant
(severe diffuse disease)
Dobutamine
echocardiography

Fig. 81.12 Algorithm for management of coronary heart disease in renal transplant candidates.
CABG, Coronary artery bypass graft surgery; CAD, coronary artery disease; MI, myocardial infarction; PCI,
percutaneous coronary intervention. (Modified from Herzog CA. Acute MI in dialysis patients: How can we
improve the outlook? J o Critical Illness 1999;14(11):613-621.)

all-cause mortality in CKD stage 5.44 In CKD, NT-proBNP and BNP are TREATMENT AND PREVENTION OF
equivalent predictors of decompensated heart failure, but NT-proBNP CARDIOVASCULAR DISEASE
is a better predictor of survival. Fig. 81.13 graphically displays the rela-
tionship of cTnT and cTnI levels in asymptomatic dialysis patients and Risk Factor Reduction
long-term survival. On the basis of these data, the U.S. Food and Drug Lifestyle Factors and Smoking
Administration approved the measurement of cTnT in dialysis patients Because physical inactivity is associated with albuminuria and CV mor-
for risk stratification (mortality prediction).27 tality, CKD patients should be advised to stay as physically active as
High-sensitivity cardiac troponin (hs-cTn) assays, which offer the possible and to avoid smoking.
advantage of high precision, serve dual, complementary (but distinct)
roles: the diagnosis of AMI, which now includes cardiac biomarkers and Weight and Diet
risk stratification based on detection of hs-cTn in an asymptomatic, Lifestyle changes, including balanced diets with regard to saturated fat
nonischemic setting (e.g., perhaps a marker for apoptosis). Hs-cTn–based and carbohydrates (in diabetic patients), probably reduce CV morbidity
risk stratification should employ reference change values over time, and should be encouraged. However, in all CKD stages, protein-energy
rather than simple thresholds, particularly when data are inconclusive wasting must be avoided; especially in dialysis patients, increased body
regarding acceptable normal values in special populations, such as dialysis mass index has been associated with improved outcomes, possibly
patients, known to have chronically elevated cardiac troponin levels.45 reflecting confounded epidemiology; thus the obesity paradox only
FGF-23 has also proven to be a strong outcome predictor in CKD exists in HD patients with inflammation.9
patients, but further studies are needed to demonstrate its role as an
additional clinical biomarker. Hypertension and Coronary Heart Disease
An improved CV prediction risk score was recently developed for BP targets for CKD patients, in particular those with diabetes or pro-
use in HD patients (http://aro-score.askimed.com/).46 teinuria greater than 1 g/day, are discussed in Chapter 79. A goal of

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954 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Diabetes Mellitus
Kaplan-Meier Survival Curves Optimal glycemic control (see Chapter 32), reaching BP target levels,
by Baseline Troponin Cutoffs and lipid monitoring (with subsequent dyslipidemia treatment) are
crucial in managing diabetic CKD patients. CHD and other CVD should
be treated aggressively in this high-risk group. Because the harm associ-
100
ated with severe hypoglycemia might counterbalance the potential benefit
Cumulative survival (%)

90 of intensive glucose-lowering treatment, treating to a hemoglobin A1c

80 (HbA1c) level below 7.0% (53 mmol/mol) is not recommended in CKD
70 stages 3 to 5.47
60 Dyslipidemia
50 cTnT <0.01 µg/L
Because CKD, like diabetes and hypertension, is considered a CV risk
cTnT ≥0.01 to <0.04 µg/L
40 cTnT ≥0.04 to <0.10 µg/L equivalent, CKD patients should be treated to achieve the guideline
cTnT ≥0.10 µg/L
30 goal for secondary prevention for LDL cholesterol (<100 mg/dl
0 0.5 1.0 1.5 2.0 2.5 3.0 [2.6 mmol/l]). This goal is not supported by clinical trials targeting
Time since blood draw (years) dialysis patients. Post hoc subgroup analyses in the Heart Protection
Number of
Patients at Risk: Baseline 1 yr 2 yrs 2.5 yrs
Study, Cholesterol and Recurring Events (CARE) study, and Treating
cTnT <0.01 µg/L 132 106 25 12 to New Targets (TNT) study, together with a meta-analysis, provide
cTnT ≥0.01 to <0.04 µg/L 214 166 41 15
cTnT ≥0.04 to <0.10 µg/L 239 180 63 18 inferential support for the role of statins in improving outcomes in
cTnT ≥0.10 µg/L 148 93 20 8 CKD stages 1 and 2. The Study of Heart and Renal Protection (SHARP)
showed that reducing LDL cholesterol with simvastatin 20 mg/day plus
ezetimibe 10 mg/day safely reduced the incidence of major atheroscle-
100
rotic events in patients with advanced CKD.48 Thus statin treatment is
Cumulative survival (%)

90 recommended in CKD patients older than 20 years, with LDL cholesterol

80 level goals below 130 mg/dl (3.4 mmol/l) or below 100 mg/dl (2.6 mmol/l)
70 cTnl <0.01 µg/L for secondary prevention; however, the negative results from the 4D
study and A Study to Evaluate the Use of Rosuvastatin in Subjects on
60
Regular Hemodialysis: An Assessment of Survival and Cardiovascular
50 Events (AURORA) do not support this guideline in dialysis patients.
cTnl ≥0.10 µg/L
40 The possibility that statins have a procalcifying effect in the uremic
30 milieu deserves further attention.49
0 0.5 1.0 1.5 2.0 2.5 3.0
Time since blood draw (years) Volume
Number of
Patients at Risk: Baseline 1 yr 2 yrs 2.5 yrs In predialysis CKD, sodium restriction and diuretics are important to
cTnl <0.01 µg/L 688 514 120 51 counteract fluid retention. In ESRD, longer and more frequent HD
cTnl ≥0.10 µg/L 45 31 6 2
sessions may permit more effective volume control. In the HD center
Fig. 81.13 Kaplan-Meier survival curves by baseline troponin in Tassin, France, more than 90% of patients were normotensive with
cutoffs. cTnI, Cardiac troponin I; cTnT, cardiac troponin T. (From refer- 8 hours of dialysis three times per week, with dietary salt restriction
ence 42.)
and no antihypertensive drugs. In the Frequent Hemodialysis Network
(FHN) trial, frequent (six times per week) HD (vs. conventional three
therapy is volume control (see Chapter 79) and prevention of sodium times per week) led to better hypertension control, a drop in LV mass
overload, particularly through dietary sodium restriction. Longer or index over 12 months,50,51 and less myocardial stunning.50,51 Episodes
more frequent HD sessions may be beneficial in controlling hyperten- of dialysis-related hypotension should prompt reevaluation of dry weight,
sion. Because of their parallel cardioprotective effects, angiotensin- antihypertensive treatment, and exclusion of pericardial effusions, val-
converting enzyme (ACE) inhibitors, angiotensin receptor blockers vular disease, cardiomyopathy, and silent myocardial ischemia (see
(ARBs), and vasodilating β-blockers (e.g., carvedilol) are the first-line Chapter 98).
drugs to treat CKD- and ESRD-related hypertension. Calcium channel
blockers and most other antihypertensive drugs, including centrally Anemia
acting sympathetic inhibitors, are useful in combination with first-line Partial correction of severe anemia with ESAs results in regression of
agents. Pure vasodilators (e.g., minoxidil) should be avoided because LVH. Treatment of severe anemia is also associated with fewer ischemic
they may increase volume overload or occasionally cause pericardial symptoms in CHD patients. However, evidence for reduction of CV
effusion. Novel approaches to drug-resistant hypertension, such as renal mortality by ESAs is based on observational data only. To date, RCTs
sympathetic denervation, have become controversial in view of recent in HD and CKD patients have shown no benefit of normalized anemia
trials. Because sleep-disordered breathing occurs in about 50% of CKD on mortality as a primary end-point (see Chapter 82). Thus anemia
stage 4 and 5 patients and is associated with hypertension, sleep apnea correction in patients with advanced CKD to a hemoglobin level of 10
should be considered in therapy-resistant hypertension. to 12 g/dl appears logical.
CHD and CHD-related events should be treated with the same medi-
cations and active interventions indicated in the general population in Inflammation
the absence of convincing CKD-specific data to the contrary. Medical Data from statin trials in dialysis patients (4D, AURORA) showed lower
treatment includes use of antiplatelet agents, ACE inhibitors, ARBs, CRP levels in the statin arms but no association with fewer CV events.
β-blockers, nitroglycerin, and statins. There is no rationale for a less A careful search for infectious processes, such as periodontal disease,
aggressive therapeutic approach in CKD than in the nonrenal population. is recommended in dialysis patients with inflammation. Restriction of

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 955

catheter use is also important; short daily dialysis with better fluid Revascularization During Instability in Coronary Artery Disease (FRISC
status was associated with decreasing CRP levels compared with con- II) trial indicated a superior outcome with an early invasive strategy in
ventional HD. Volume status should be carefully monitored to avoid ACS compared with conservative management. However, the optimal
inflammation. Altered intestinal microbial flora as a potential risk factor coronary revascularization method in CKD remains controversial. A post
for systemic uremic inflammation merits further study. It was recently hoc analysis of CKD patients enrolled in the Arterial Revascularization
demonstrated that medium cut-off dialysis membranes reduce uremic Therapies Study (ARTS) found similar outcomes for coronary artery
inflammation52; thus larger trials with longer treatment periods are bypass grafting (CABG) or multivessel percutaneous coronary interven-
encouraged. tion (PCI) with non–drug-eluting stents (DESs) for death, myocardial
infarction, or stroke. In elderly non–dialysis-dependent CKD patients,
Oxidative Stress the incidence of ESRD is lower after PCI (5.4% at 3 years vs. 6.8% for
Two placebo-controlled interventional studies showed that vitamin E CABG), but long-term risk for death (28% 3-year mortality with CABG,
and N-acetylcysteine decreased the number of CV events in HD patients. 33% with PCI) or the combined event of death or ESRD is lower after
Unfortunately, both studies were small and of limited duration, so CABG. The relative survival advantage of CABG (vs. PCI) occurs only
adequately powered randomized trials are warranted. A recent meta- more than 6 months after revascularization.63 Dialysis patient survival
analysis showed that use of ultrapure dialysate results in decreased after CABG is better than after PCI with non-DESs64 and DESs,65 but
markers of inflammation and oxidative stress in HD patients.53 However, 2-year mortality remains high at 44% (vs. 52% for PCI).64 Based on
administration of mixed tocopherols and α-lipoic acid did not influence three large observational studies,64-67 we recommend the following strat-
biomarkers of inflammation and oxidative stress or the erythropoietic egy for dialysis patients who do not require acute reperfusion therapy
response in a recent randomized trial in HD patients.54 Because CKD for STEMI, which would typically be treated with emergent PCI first:
4 patients allocated to the antioxidant synthetic triterpenoid bardoxolone 1. Patients with multivessel CHD (including the left anterior descend-
experienced excessive CVD and especially CHF,55 the beneficial effects ing coronary artery [LAD]) who are anatomically suitable candidates
of antioxidant treatment strategies in this patient group remains to for internal mammary artery grafts should undergo CABG surgery;
be proven. concomitant ACS additionally favors CABG surgery.
2. The CABG survival advantage occurs more than 6 months after
Chronic Kidney Disease–Mineral Bone Disorder revascularization. Patients with limited life expectancy or who are
Recent meta-analyses and the updated KDIGO CKD-MBD guidelines concerned about perioperative morbidity (higher with CABG) might
(www.kdigo.org) conclude that calcium-free phosphate binders such choose PCI (better outcomes at less than 6 months).
as sevelamer reduce CV events, calcifications, and mortality compared 3. If the left internal mammary graft (to the LAD) is not part of the
with calcium-containing binders (see Chapter 85). Thus, these agents surgical strategy, CABG likely provides no advantage.
should be preferred for CKD patients with significant life expectancy, In the general population, advantages of DESs (compared with non-
particularly patients on the transplant waiting list, independent of the DESs) include lower incidence of in-stent restenosis and improved
presence or absence of calcifications. survival.67 In dialysis patients, reliance on clinical surrogates (e.g., chest
Because vitamin D treatment is associated with improved survival pain) leads to underestimation of the true restenosis incidence. The
in dialysis patients, vitamin D insufficiency should be considered. most complete angiographic follow-up of DESs noted a 22% to 31%
However, results from the Dialysis Outcomes and Practice Patterns incidence of restenosis with DESs and 24% to 43% with non-DESs.
Study (DOPPS) call into question the survival advantage for HD patients Clinically silent restenosis is a rationale for surveillance stress imaging
taking vitamin D. In the Paricalcitol Capsules Benefits Renal Failure (see Fig. 81.12).
Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease
Stage 3/4 (PRIMO) study, 48 weeks of paricalcitol therapy did not alter
LV mass index or improve measures of diastolic dysfunction.56
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9. Stenvinkel P, Gillespie IA, Tunks J, et al. Inflammation Modifies the 29. Leither MD, Shroff GR, Ding S, et al. Long-term survival of dialysis
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Hemodialysis Patients. J Am Soc Nephrol. 2016;27:1479–1486. surgery in the United States. Circulation. 2013;128:344–351.
10. Tang WH, Hazen SL. The contributory role of gut microbiota in 30. Yamada S, Ishii H, Takahashi H, et al. Prognostic value of reduced left
cardiovascular disease. J Clin Invest. 2014;124:4204–4211. ventricular ejection fraction at start of hemodialysis therapy on
11. Chen Z, Qureshi AR, Ripsweden J, et al. Vertebral bone density cardiovascular and all-cause mortality in end-stage renal disease patients.
associates with coronary artery calcification and is an independent Clin J Am Soc Nephrol. 2010;5:1793–1798.
predictor of poor outcome in end-stage renal disease patients. Bone. 31. Foley RN, Gilbertson DT, Murray T, Collins AJ. Long interdialytic interval
2016;92:50–57. and mortality among patients receiving hemodialysis. N Engl J Med.
12. Shroff GR, Li S, Herzog CA. Trends in Mortality Following Acute 2011;365:1099–1107.
Myocardial Infarction Among Dialysis Patients in the United States Over 32. Pun PH, Lehrich RW, Honeycutt EF, et al. Modifiable risk factors
15 Years. J Am Heart Assoc. 2015;4:e002460. associated with sudden cardiac arrest within hemodialysis clinics. Kidney
13. Szummer K, Lundman P, Jacobson SH, et al. Relation between renal Int. 2011;79:218–227.
function, presentation, use of therapies and in-hospital complications in 33. Peer Kidney Care Initiative. Peer Report: Dialysis Care and Outcomes in
acute coronary syndrome: data from the SWEDEHEART register. J Intern The United States. Minneapolis, MN: Chronic Disease Research Group;
Med. 2010;268:40–49. 2014:Page9.
14. Herzog CA, Littrell K, Arko C, et al. Clinical characteristics of dialysis 34. Charytan DM, Patrick AR, Liu J, et al. Trends in the use and outcomes of
patients with acute myocardial infarction in the United States: a implantable cardioverter-defibrillators in patients undergoing dialysis in
collaborative project of the United States Renal Data System and the the United States. Am J Kidney Dis. 2011;58:409–417.
National Registry of Myocardial Infarction. Circulation. 2007;116: 35. Chawla LS, Herzog CA, Costanzo MR, et al. Proposal for a functional
1465–1472. classification system of heart failure in patients with end-stage renal
15. Shroff GR, Frederick PD, Herzog CA. Renal failure and acute myocardial disease: proceedings of the acute dialysis quality initiative (ADQI) XI
infarction: clinical characteristics in patients with advanced chronic workgroup. J Am Coll Cardiol. 2014;63:1246–1252.
kidney disease, on dialysis, and without chronic kidney disease. A 36. Hickson LJ, Negrotto SM, Onuigbo M, et al. Echocardiography Criteria
collaborative project of the United States Renal Data System/National for Structural Heart Disease in Patients With End-Stage Renal Disease
Institutes of Health and the National Registry of Myocardial Infarction. Initiating Hemodialysis. J Am Coll Cardiol. 2016;67:1173–1182.
Am Heart J. 2012;163:399–406. 37. Wang LW, Fahim MA, Hayen A, et al. Cardiac testing for coronary artery
16. Garimella PS, Hart PD, O’Hare A, et al. Peripheral artery disease and disease in potential kidney transplant recipients. Cochrane Database Syst
CKD: a focus on peripheral artery disease as a critical component of Rev. 2011;(12):CD008691.
CKD care. Am J Kidney Dis. 2012;60:641–654. 38. Lentine KL, Costa SP, Weir MR, et al. Cardiac disease evaluation and
17. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in management among kidney and liver transplantation candidates: a
chronic kidney disease. A clinical update from Kidney Disease: Improving scientific statement from the American Heart Association and the
Global Outcomes KDIGO). Kidney Int. 2011;80:572–586. American College of Cardiology Foundation. J Am Coll Cardiol. 2012;
18. Shima H, Mori T, Ooi M, et al. Silent Cerebral Microbleeds and 60:434–480.
Longitudinal Risk of Renal and Cardiovascular Events in Patients with 39. Kumar N, Baker CS, Chan K, et al. Cardiac survival after pre-emptive
CKD. Clin J Am Soc Nephrol. 2016;11:1557–1565. coronary angiography in transplant patients and those awaiting
19. Murray AM, Seliger S, Lakshminarayan K, et al. Incidence of Stroke transplantation. Clin J Am Soc Nephrol. 2011;6:1912–1919.
Before and After Dialysis Initiation in Older Patients. J Am Soc Nephrol. 40. James MT, Ghali WA, Knudtson ML, et al. Associations between acute
2013;24:1166–1173. kidney injury and cardiovascular and renal outcomes after coronary
20. Goldstein BA, Arce CM, Hlatky MA, et al. Trends in the incidence of angiography. Circulation. 2011;123:409–416.
atrial fibrillation in older patients initiating dialysis in the United States. 41. Winther S, Svensson M, Jorgensen HS, et al. Diagnostic Performance of
Circulation. 2012;126:2293–2301. Coronary CT Angiography and Myocardial Perfusion Imaging in Kidney
21. Bansal N, Fan D, Hsu CY, et al. Incident Atrial Fibrillation and Risk of Transplantation Candidates. JACC Cardiovasc Imaging. 2015;8:553–562.
End-Stage Renal Disease in Adults with Chronic Kidney Disease. 42. Apple FS, Murakami MM, Pearce LA, Herzog CA. Predictive value of
Circulation. 2013;127:569–574. cardiac troponin I and T for subsequent death in end-stage renal disease.
22. Konigsbrugge O, Posch F, Antlanger M, et al. Prevalence of Atrial Circulation. 2002;106:2941–2945.
Fibrillation and Antithrombotic Therapy in Hemodialysis Patients: 43. Breidthardt T, Burton JO, Odudu A, et al. Troponin T for the detection of
Cross-Sectional Results of the Vienna InVestigation of AtriaL Fibrillation dialysis-induced myocardial stunning in hemodialysis patients. Clin J Am
and Thromboembolism in Patients on HemoDIalysis (VIVALDI). PLoS Soc Nephrol. 2012;7:1285–1292.
ONE. 2017;12(1):e0169400. 44. Sun J, Axelsson J, Machowska A, et al. Biomarkers of Cardiovascular
23. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial Disease and Mortality Risk in Patients with Advanced CKD. Clin J Am
fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Soc Nephrol. 2016;11:1163–1172.
Nephrol. 2011;6:2599–2604. 45. Sandoval Y, Herzog CA, Love SA, et al. Prognostic Value of Serial Changes
24. Hart RG, Eikelboom JW, Ingram AJ, Herzog CA. Anticoagulants in atrial in High-Sensitivity Cardiac Troponin I and T over 3 Months Using
fibrillation patients with chronic kidney disease. Nat Rev Nephrol. 2012;8: Reference Change Values in Hemodialysis Patients. Clin Chem. 2016;62:
569–578. 631–638.
25. Whalley GA, Marwick TH, Doughty RN, et al. Effect of Early Initiation 46. Anker SD, Gillespie IA, Eckardt KU, et al. Development and validation of
of Dialysis on Cardiac Structure and Function: Results From the Echo cardiovascular risk scores for haemodialysis patients. Int J Cardiol.
Substudy of the IDEAL Trial. Am J Kidney Dis. 2013;61:262–270. 2016;216:68–77.
26. Park M, Hsu CY, Li Y, et al. Associations between kidney function and 47. ACCORD Study Group: Gerstein HC, Miller ME, Genuth S, et al.
subclinical cardiac abnormalities in CKD. J Am Soc Nephrol. 2012;23: Long-term effects of intensive glucose lowering on cardiovascular
1725–1734. outcomes. N Engl J Med. 2011;364:818–828.
27. KDOQI Workgroup. K/DOQI clinical practice guidelines for 48. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL
cardiovascular disease in dialysis patients. Am J Kidney Dis. 2005;45 cholesterol with simvastatin plus ezetimibe in patients with chronic
(4 suppl 3):S1–S153. kidney disease (Study of Heart and Renal Protection): a randomised
28. Sharma A, Gilbertson DT, Herzog CA. Survival of kidney transplantation placebo-controlled trial. Lancet. 2011;377:2181–2192.
patients in the United States after cardiac valve replacement. Circulation. 49. Chen Z, Qureshi AR, Parini P, et al. Does statins promote vascular
2010;121:2733–2739. calcification in chronic kidney disease? Eur J Clin Invest. 2016;47:137–148.

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 957

50. FHN Trial Group, Chertow GM, Levin NW, et al. In-center hemodialysis 60. Moe SM, Chertow GM, Parfrey PS, et al. Cinacalcet, Fibroblast Growth
six times per week versus three times per week. N Engl J Med. 2010;363: Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation
2287–2300. of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE)
51. Jefferies HJ, Virk B, Schiller B, et al. Frequent hemodialysis schedules are Trial. Circulation. 2015;132:27–39.
associated with reduced levels of dialysis-induced cardiac injury 61. Best PJM, Lennon R, Ting HH, et al. The impact of renal insufficiency on
(myocardial stunning). Clin J Am Soc Nephrol. 2011;6:1326–1332. clinical outcomes in patients undergoing percutaneous coronary
52. Zickler D, Schindler R, Willy K, et al. Medium Cut-Off (MCO) interventions. J Am Coll Cardiol. 2002;39:1113–1119.
Membranes Reduce Inflammation in Chronic Dialysis Patients-A 62. Cooper WA, O’Brien SM, Thourani VH, et al. Impact of renal
Randomized Controlled Clinical Trial. PLoS ONE. 2017;12(1):e0169024. dysfunction on outcomes of coronary artery bypass surgery: results from
53. Susantitaphong P, Riella C, Jaber BL. Effect of ultrapure dialysate on the Society of Thoracic Surgeons National Adult Cardiac Database.
markers of inflammation, oxidative stress, nutrition and anemia Circulation. 2006;113:1063–1070.
parameters: a meta-analysis. Nephrol Dial Transplant. 2013;28: 63. Charytan DM, Li S, Liu J, Herzog CA. Risks of death and end-stage renal
438–446. disease after surgical compared with percutaneous coronary
54. Himmelfarb J, Ikizler TA, Ellis C, et al. Provision of antioxidant therapy revascularization in elderly patients with chronic kidney disease.
in hemodialysis (PATH): a randomized clinical trial. J Am Soc Nephrol. Circulation. 2012;126(11 suppl 1):S164–S169.
2014;25:623–633. 64. Shroff GR, Solid CA, Herzog CA. Long-term survival and repeat coronary
55. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 revascularization in dialysis patients after surgical and percutaneous
diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369: coronary revascularization with drug-eluting and bare metal stents in the
2492–2503. United States. Circulation. 2013;127:1861–1869.
56. Thadhani R, Appelbaum E, Pritchett Y, et al. Vitamin D therapy and 65. Chang TI, Shilane D, Kazi DS, et al. Multivessel coronary artery bypass
cardiac structure and function in patients with chronic kidney disease: grafting versus percutaneous coronary intervention in ESRD. J Am Soc
the PRIMO randomized controlled trial. JAMA. 2012;307:674–684. Nephrol. 2012;23:2042–2049.
57. EVOLVE Trial Investigators, Chertow GM, Block GA, et al. Effect of 66. Shroff GR, Solid CA, Herzog CA. Impact of acute coronary syndromes
cinacalcet on cardiovascular disease in patients undergoing dialysis. on survival of dialysis patients following surgical or percutaneous
N Engl J Med. 2012;367:2482–2494. coronary revascularization in the United States. Eur Heart J Acute
58. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a Cardiovasc Care. 2016;5:205–213.
randomized study to evaluate the effects of cinacalcet plus low-dose 67. Shroff GR, Herzog CA. Coronary Revascularization in Patients with
vitamin D on vascular calcification in patients on hemodialysis. Nephrol CKD Stage 5D: Pragmatic Considerations. J Am Soc Nephrol. 2016;27:
Dial Transplant. 2011;26:1327–1339. 3521–3529.
59. Scialla JJ, Lau WL, Reilly MP, et al. Fibroblast growth factor 23 is not
associated with and does not induce arterial calcification. Kidney Int.
2013;83:1159–1168.

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 CHAPTER 81 Cardiovascular Disease in Chronic Kidney Disease 957.e1

SELF-ASSESSMENT
QUESTIONS
1. Which of the following is not an established risk factor for cardio-
vascular disease in patients with advanced chronic kidney disease?
A. Inflammation
B. Smoking
C. Dyslipidemia
D. Hyperhomocysteinemia
E. Diabetes
2. What is not true about cardiovascular complications in end-stage
renal disease patients?
A. Left ventricular hypertrophy is present in about 75% of the
patients.
B. In dialysis patients the incidence of atrial fibrillation is about
15% per year.
C. Low levels of cholesterol predict death.
D. In dialysis patients, extensive vascular, especially coronary artery,
calcification can occur even at young ages.
E. The calcific aortic stenosis progression rate is only slightly higher
in dialysis patients compared to the general population.
3. What is the most common cause of death in dialysis patients?
A. Congestive heart failure
B. Infection
C. Arrhythmic death
D. Stroke
E. Valvular heart disease
4. Which drug has been shown to reduce mortality in dialysis patients
with dilated cardiomyopathy and systolic heart failure?
A. Atorvastatin
B. Digoxin
C. Carvedilol
D. Metoprolol
E. Atenolol

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 82
Anemia in Chronic Kidney Disease
Iain C. Macdougall, Kai-Uwe Eckardt

Anemia is an almost universal complication of chronic kidney disease tive β subunit. The production of HIF-1α and HIF-2α is largely inde-
(CKD). It contributes considerably to reduced quality of life of patients pendent of oxygen, but their degradation is related to cellular oxygen
with CKD and has been associated with a number of adverse clinical concentrations. Hydroxylation of specific prolyl and asparagyl residues
outcomes. Before the availability of recombinant human erythropoietin of HIF-α, for which molecular oxygen is required as a substrate, deter-
(rHuEPO, or epoetin), patients on dialysis frequently required blood mines proteasomal destruction of HIF and inhibits its transcriptional
transfusions, exposing them to the risks of iron overload, transmission activity. Apart from EPO, several hundred HIF target genes have been
of viral hepatitis, and human leukocyte antigen (HLA) sensitization, identified. HIF-2, rather than HIF-1, is the transcription factor primarily
which reduced the chances of successful transplantation. The advent responsible for the regulation of EPO production.5,6
of rHuEPO in the late 1980s changed this situation completely. The The role of renal EPO production in the pathogenesis of renal anemia
ability to correct anemia has had consequences beyond simply an is supported by the particularly severe anemia in anephric individuals.
improvement in general fatigue and reduced physical capacity, to impact However, the mechanisms impairing renal EPO production in diseased
on a broad spectrum of physiologic functions. Thus there is a strong kidneys remain poorly understood. The production capacity for EPO
rationale for managing anemia in CKD patients, and yet the optimal remains significant, even in end-stage renal disease. Thus patients with
treatment strategies are still incompletely defined. Apart from therapy anemia and CKD can respond with a significant increase in EPO pro-
with erythropoiesis-stimulating agents (ESAs), iron replacement is duction to an additional hypoxic stimulus.1 The main problem therefore
essential for anemia management. It is important to note that CKD appears to be a failure of EPO production to increase in response to
patients on dialysis require target thresholds of iron parameters different chronically reduced hemoglobin (Hb) concentrations. In line with this
from those for normal individuals to ensure optimal rates of red blood view, endogenous EPO production can be induced in CKD patients by
cell (RBC) production. The costs of anemia management are consider- pharmacologic inhibition of HIF degradation (see later discussion).
able, and it has become apparent that full anemia correction may cause EPO is a glycoprotein hormone consisting of a 165–amino acid
harm; therefore a rational and careful consideration of the risks and protein backbone and four complex, heavily sialylated carbohydrate
benefits is mandatory. chains.1 The latter are essential for the biologic activity of EPO in vivo
because partially or completely deglycosylated EPO is rapidly cleared
from the circulation. This is why rHuEPO has to be manufactured in
PATHOGENESIS mammalian cells; bacteria lack the capacity to glycosylate recombinant
Renal anemia is typically an isolated normochromic, normocytic anemia proteins.
with no leukopenia or thrombocytopenia. Both RBC life span and the EPO stimulates RBC production by binding to homodimeric EPO
rate of RBC production are reduced, but the latter is more important. receptors, which are primarily located on early erythroid progenitor
The normal bone marrow has considerable capacity to increase the rate cells, the burst-forming units erythroid (BFU-e) and the colony-forming
of erythropoiesis, and compensation normally could be easily made units erythroid (CFU-e). Binding of EPO to its receptors salvages these
for the reduction in erythrocyte life observed in association with CKD. progenitor cells and the subsequent earliest erythroblast generation
However, this EPO-induced compensatory increase in erythrocyte pro- from apoptosis, thereby permitting cell division and maturation into
duction is impaired in CKD. Serum EPO levels remain within the normal RBCs.7 Inhibition of RBC production by yet unknown uremic inhibi-
range and fail to show the inverse exponential relationship with blood tors of erythropoiesis may contribute to the pathogenesis of renal
oxygen content characteristic of other types of anemia. EPO is normally anemia, and dialysis per se can improve renal anemia and the efficacy
produced by interstitial fibroblasts in the renal cortex, in close proximity of ESAs. Moreover, the interindividual dose requirements for ESAs
to tubular epithelial cells and peritubular capillaries.1,2 In addition, vary significantly among CKD patients, and the average weekly dose is
hepatocytes and perisinusoidal, or Ito, cells in the liver can produce much higher than estimated production rates of endogenous EPO in
EPO (Fig. 82.1). Hepatic EPO production dominates during fetal and healthy individuals. An alternative view to the accumulation of inhibi-
early postnatal life but does not compensate for the loss of renal pro- tors of erythropoiesis in CKD is that in many patients there is overlap
duction in adult organisms. Subtle changes in blood oxygen content between renal anemia and the anemia of chronic disease, which is
induced by anemia, reduced environmental oxygen concentrations, and characterized by inhibition of EPO production and EPO efficacy, as
high altitude stimulate the secretion of EPO through a widespread well as by reduced iron availability, mediated through inflammatory
system of oxygen-dependent gene expression.2-4 Central to this process cytokines.8 The hepatic release of hepcidin, the key regulator of iron
is a family of hypoxia-inducible transcription factors (HIFs). The two metabolism, is upregulated in states of inflammation; it simultaneously
most important members of this family, HIF-1 and HIF-2, are composed blocks iron absorption from the gut and promotes iron sequestration in
of an oxygen-regulated α subunit (HIF-1α or HIF-2α) and a constitu- macrophages.9

958
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 CHAPTER 82 Anemia in Chronic Kidney Disease 959

Feedback Control of Erythropoiesis Relationship Between

Hemoglobin and eGFR

Hemoglobin Arterial oxygen A Males

concentration saturation 17

Hemoglobin (g/dl)
15

13

11
Blood oxygen
content 9 95th percentile
Median
7 5th percentile
Tissue perfusion

0 30 60 90 120 150

Erythropoiesis Tissue Estimated GFR (ml/min per 1.73 m2)

oxygenation

B
17 Females

Hemoglobin (g/dl)
15
Hypoxia-inducible
factors (HIF-1, HIF-2)
13

11

9 95th percentile
Median
EPO/other HIF target genes 7 5th percentile
→ increases in oxygen
supply or hypoxia tolerance
0 30 60 90 120 150
Fig. 82.1 Feedback control of erythropoiesis. EPO, Erythropoietin.
Estimated GFR (ml/min per 1.73 m2)

Fig. 82.2 Relationship between hemoglobin (Hb) concentration

and estimated glomerular filtration rate (GFR). Data are from a
EPIDEMIOLOGY AND NATURAL HISTORY cross-sectional survey of individuals randomly selected from the general
U.S. population (Third National Health and Nutrition Examination Survey
In general, there is a progressive increase in the incidence and severity [NHANES III]). Results and 95% confidence interval are shown for males
of anemia with declining renal function. The reported prevalence of (A) and females (B) at each estimated GFR interval. (From reference 11.)
anemia by CKD stage varies significantly and depends to a large extent
on the definition of anemia and whether study participants are selected
from the general population, are at high risk for CKD, are diabetic, or
are already under the care of a nephrologist. Data from the National variability in practice patterns (Table 82.1).13 Moreover, Hb values vary
Health and Nutrition Examination Survey (NHANES) showed that the considerably among patients in the same treatment setting as well as
distribution of Hb levels starts to fall at an estimated glomerular filtra- within patients over time, mainly reflecting persistent and time-dependent
tion rate (eGFR) of less than 75 ml/min/1.73 m2 in men and 45 ml/ changes in responsiveness (see later discussion).
min/1.73 m2 in women (Fig. 82.2).10 The prevalence of Hb values below
13 g/dl increases below an eGFR of 60 ml/min/1.73 m2 in men and
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS
45 ml/min/1.73 m2 in women in the general population. Among patients
under regular care for CKD, the prevalence of anemia was found to be The diagnosis of anemia and the assessment of its severity are best
much greater, with mean Hb values of 12.8 (CKD stages 1 and 2), 12.4 made by measuring the Hb concentration rather than the hematocrit
(CKD stage 3), 12.0 (CKD stage 4), and 10.9 (CKD stage 5).11 Although (Hct). Hb is a stable analyte that is measured directly in a standardized
anemia develops largely independently of the cause of kidney disease, fashion, whereas the Hct is relatively unstable, indirectly derived by
there are two important exceptions. Diabetic patients develop anemia automatic analyzers, and lacking standardization. Within-run and
more frequently, at earlier stages of CKD, and more severely at a given between-run coefficients of variation in automated analyzer measure-
level of renal impairment.12,13 Conversely, in patients with polycystic ments of Hb are half and one third those for Hct, respectively.12
kidney disease, Hb is on average higher than in other patients with There is considerable variability in the Hb threshold used to define
similar degrees of renal failure, and polycythemia may occasionally anemia. According to the most recent definition in the Kidney Disease:
develop. Improving Global Outcomes (KDIGO) guidelines, anemia should be
With the advent of rHuEPO and its derivatives, Hb values in patients diagnosed at Hb concentrations of less than 13.0 g/dl in men and less
with CKD have changed. In particular, in patients on dialysis, average than 12.0 g/dl in women.14 These values represent the World Health
Hb values have steadily increased for many years and then declined Organization definition of anemia. In children, age-dependent differ-
again in view of new evidence suggesting lower target levels.12 The ences in the normal values have to be taken into account. Normal Hb
average Hb value still varies considerably among countries, reflecting values are increased in high-altitude residents. It is important to note

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960 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

TABLE 82.1 Hemoglobin Levels in Patients on Dialysis

AMONG PATIENTS ON DIALYSIS FOR LONGER AMONG PATIENTS NEW TO ESRD, AT
THAN 180 DAYS START OF DIALYSIS
Hb <11 g/dl Hb <11 g/dl
Country n Mean Hb (g/dl) (% of patients) n Mean Hb (g/dl) (% of patients)
Sweden 456 12.0 23 168 10.7 55
United States 1690 11.7 27 458 10.4 65
Spain 513 11.7 31 170 10.6 61
Belgium 442 11.6 29 213 10.3 66
Canada 479 11.6 29 150 10.1 70
Australia and New Zealand 423 11.5 36 108 10.1 70
Germany 459 11.4 35 142 10.5 61
Italy 447 11.3 38 167 10.2 68
United Kingdom 436 11.2 40 93 10.2 67
France 341 11.1 45 86 10.1 65
Japan 1210 10.1 77 131 8.3 95
Mean hemoglobin (Hb) levels and percentage of patients with Hb levels below 11 g/dl who have been on dialysis therapy for more than 180
days and at the time of starting dialysis, by country.
Data are from the Dialysis Outcomes and Practice Patterns Study, Phase II (DOPPS 2), and are derived from 308 randomly selected,
representative dialysis facilities. Note that there are marked differences among countries, but at least one fourth and up to three fourths of
dialysis patients, and, in most countries, more than two thirds of patients starting chronic dialysis have Hb values below the recommended
lower target of 11 g/dl.
ESRD, End-stage renal disease.
Modified from reference 13.

that thresholds for the diagnosis of anemia and evaluation of the causes additional causes. Because there is significant variability in the degree
should not be interpreted as being thresholds for treatment of anemia.14 of anemia in relation to the impairment in renal function, no simple
In addition to the Hb value, the evaluation of anemia in CKD patients diagnostic criteria can be applied. Causes of anemia other than EPO
should include a complete blood count with RBC indices (mean cor- deficiency should be considered when (1) the severity of anemia is
puscular Hb concentration [MCHC], mean corpuscular volume [MCV]), disproportionate to the impairment of renal function, (2) there is evi-
white blood cell count (including differential), and platelet count. dence of iron deficiency, or (3) there is evidence of leukopenia or
Although renal anemia is typically normochromic and normocytic, thrombocytopenia. Concomitant conditions such as sickle cell disease
deficiency of vitamin B12 or folate may lead to macrocytosis, whereas may exacerbate the anemia, as can drug therapy. For example, inhibitors
iron deficiency or inherited disorders of Hb formation (such as thalas- of the renin-angiotensin system may reduce Hb levels by (1) direct
semia) may produce microcytosis. Macrocytosis with leukopenia or effects of angiotensin II (Ang II) on erythroid progenitor cells,15 (2)
thrombocytopenia suggests a generalized disorder of hematopoiesis accumulation of N-acetyl-seryl-lysyl-proline (Ac-SDKP), an endogenous
caused by toxins, nutritional deficit, or myelodysplasia. Hypochromia inhibitor of erythropoiesis in patients treated with angiotensin-converting
probably reflects iron-deficient erythropoiesis. An absolute reticulocyte enzyme (ACE) inhibitors,16 and (3) reduction of endogenous EPO
count, which normally ranges between 40,000 and 50,000 cells/μl of production, possibly because of the hemodynamic effects of Ang II
blood, is a useful marker of erythropoietic activity. inhibition. Myelosuppressive effects of immunosuppressants may further
Iron status tests should be performed to assess the level of iron in contribute to anemia.17 The measurement of serum EPO concentrations
tissue stores or the adequacy of iron supply for erythropoiesis. Although is usually not helpful in the diagnosis of renal anemia because there is
serum ferritin is the only available marker of storage iron, several tests relative rather than absolute deficiency, with a wide range of EPO con-
reflect the adequacy of iron for erythropoiesis, including transferrin centrations for a given Hb concentration that extends far beyond the
saturation (TSAT), the percentage of hypochromic red blood cells normal range of EPO levels in healthy, nonanemic individuals. Abnor-
(PHRC), the reticulocyte hemoglobin content (CHr), the MCV, and malities of other laboratory parameters should be looked for, such as
the MCHC. Storage time of the blood sample may elevate PHRC, and a very low MCV or MCHC, a high MCV, or an abnormal leukocyte or
MCV and MCHC are below the normal range only after long-standing platelet count, and further tests should be performed as indicated to
iron deficiency; in clinical practice, TSAT remains the most frequently explore these potential contributory causes (see earlier). However, when
used parameter. there are no such pointers to other confounding causes of anemia, and
It is important to identify anemia in CKD patients because it may iron deficiency has been excluded, a trial with rHuEPO or its derivatives
signify nutritional deficits, systemic illness, or other conditions that is warranted, even when the eGFR is only moderately reduced.
warrant attention. Moreover, even at modest degrees, anemia reflects
an independent risk factor for hospitalizations, cardiovascular disease
(CVD), and mortality.12 The diagnosis of renal anemia, that is, anemia
CLINICAL MANIFESTATIONS
caused by CKD, requires careful judgment of the degree of anemia in In the early clinical trials of rHuEPO performed in the late 1980s, the
relation to the degree of renal impairment and exclusion of other or mean baseline Hb concentration was about 6 to 7 g/dl, and this

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 CHAPTER 82 Anemia in Chronic Kidney Disease 961

progressively increased to about 11 or 12 g/dl after treatment. Patients studies have indicated increased risks associated with attempts to com-
subjectively felt much better, with reduced fatigue, increased energy pletely correct anemia. In particular, no survival benefit is evident at a
levels, and enhanced physical capacity, and there were also objective higher level of anemia correction,20-23 and attempts to normalize Hb
improvements in cardiorespiratory function.18 Thus it is now clear that concentrations have shown various risks, including increased rates of
many of the symptoms previously attributed to the “uremic syndrome” thromboembolic events, strokes, and possibly death. Thus there is a
may have been caused by severe anemia associated with CKD (Boxes possible tradeoff among improved quality of life, reduced transfusion
82.1 and 82.2). Although the avoidance of blood transfusions and requirements, and risk for harm (see discussion later), and a target Hb
improvement in quality of life are obvious early changes, there are also level of above 13 g/dl should be avoided.12,14
possible effects on the cardiovascular system (see Box 82.1). The physi-
ologic consequences of long-standing anemia are an increase in cardiac TREATMENT
output and a reduction in peripheral vascular resistance. Anemia is
associated with the development of left ventricular hypertrophy in CKD Erythropoiesis-Stimulating Agents
patients and is thought to exacerbate left ventricular dilation. Sustained Epoetin Therapy
correction of severe anemia in CKD patients tends to reverse most of Manufacture of rHuEPO is achieved by gene transfer into a suitable
these CV abnormalities, with the notable exception of left ventricular mammalian cell line such as Chinese hamster ovary (CHO) cells. The
dilation (although anemia correction may prevent further dilation in early clinical trials of rHuEPO were conducted with both EPO alfa and
some patients19). Other effects of anemia correction reported in clinical EPO beta, both produced in CHO cells. Like the endogenous hormone,
trials include improvements in quality of life, cognitive function, sleep rHuEPO consists of a 165–amino acid backbone with one O-linked
patterns, nutrition, sexual function, menstrual regularity, immune and three N-linked glycosylation chains. Invariably, however, there are
responsiveness, and platelet function. The majority of these trials, some differences in the glycosylation pattern among different prepara-
however, were not placebo-controlled, so the spectrum and extent of tions of rHuEPO and the endogenous hormone. “Biosimilar” EPO
possible benefits remain uncertain. preparations have been licensed in Europe after demonstration of their
Over the years, there has been considerable debate about the optimal efficacy and safety in an abbreviated trial program.24 Many other “copy”
target range of Hb in CKD patients. A presumed improvement in quality EPOs are available in several parts of the world, which are not neces-
of life and expectations of positive effects on CV function and renal sarily produced to the same regulatory standards.
disease progression with increasing Hb concentrations led to sugges- Before 1998, EPO alfa in Europe was formulated with human serum
tions of a level above 10 to 11 g/dl in all CKD patients,12,13 but several albumin, but this was replaced with polysorbate 80. EPO beta is for-
mulated with polysorbate 20, along with urea, calcium chloride, and
five amino acids as excipients. The importance of the formulation of
BOX 82.1 Cardiovascular Effects Resulting the EPO products was highlighted in 2002 with an upsurge in cases of
from Anemia Correction antibody-mediated pure red cell aplasia (PRCA) in association with
the subcutaneous use of EPO alfa after its change of formulation. Patients
Reduction in high cardiac output affected by this complication develop neutralizing antibodies against
Reduced stroke volume both rHuEPO and the endogenous hormone, which result in severe
Reduced heart rate anemia and transfusion dependence.25 The cause of this serious com-
Increase in peripheral vascular resistance plication in which there is a break in B cell tolerance remains obscure,
Reduction in anginal episodes although it seems likely that factors such as a breach of the cold storage
Reduction in myocardial ischemia chain are relevant, and the subcutaneous application route is a prereq-
Regression of left ventricular hypertrophy uisite; circumstantial evidence also suggests that rubber stoppers of
Stabilization of left ventricular dilation prefilled syringes used in one of the albumin-free EPO alfa formulations
Increase in whole blood viscosity may have released organic compounds that acted as immunologic adju-
vants.26 Although this unfortunate combination of adverse factors was
specific for one compound, the development of neutralizing anti-EPO
BOX 82.2 Other Effects of Anemia antibodies was subsequently also observed during a clinical trial with
Correction an epoetin alfa biosimilar27 and a low rate of PRCA also occurs with
EPO beta and darbepoetin alfa.
Beneficial
The EPOs are administered either intravenously or subcutaneously.
Reduced blood transfusions
The bioavailability after intraperitoneal administration (in peritoneal
Increased quality of life
dialysis [PD] patients) is too low. The earliest clinical trials of EPO
Increased exercise capacity
used intravenous injections two or three times per week. This was
Improved cognitive function
partly because of the short half-life of EPO (6 to 8 hours after intra-
Improved sleep patterns
venous administration)28 and partly because of the convenience for
Improved immune function
the patient on dialysis. With use of this regimen, 90% of patients show
Improved muscle function
a significant increase in Hb concentration. Good iron management is
Improved depression
pivotal for the success of EPO therapy (see later discussion). Although
Improved nutrition
the bioavailability of subcutaneous EPO is 20% to 30%, the prolonged
Improved platelet function
half-life after subcutaneous administration compared with intravenous
Adverse administration allows less frequent injections. Furthermore, the dose
Hypertension required to achieve the same Hb response is about 30% lower with
Vascular access thrombosis subcutaneous than with intravenous administration.28 There appears
Increased risk for stroke to be little difference in efficacy among the thigh, arm, or abdomen
as injection sites.

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962 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Darbepoetin Alfa Hypoxia-Inducible Transcription Factor Stabilizers

Darbepoetin alfa is a second-generation ESA that is a supersialylated The HIF stabilizers are competitive inhibitors of HIF prolyl hydroxy-
analogue of EPO, possessing two extra N-linked glycosylation chains. lases 2,24,34 and asparagyl hydroxylase enzymes involved in the metabolism
This property confers a lower clearance rate in vivo, and the elimination of HIF and its transcriptional activity. The HIF stabilizers, also referred
half-life of this compound in humans after a single intravenous admin- to as prolyl-hydroxylase domain protein inhibitors (PHD-inhibitors) cause
istration is 25.3 hours versus 8.5 hours for epoetin alfa. Thus this agent an increase in endogenous EPO production from both liver and the
can generally be given less frequently than the standard epoetins, with diseased, nonfunctioning kidneys.34,35 Such compounds are orally active,
administration intervals of once weekly and once every 2 weeks with and several of these drugs (e.g., roxadustat, daprodustat, vadadustat,
similar dose requirements.29 In contrast to the epoetins, dosage require- and molidustat) are currently being tested in phase II and III clinical
ments for darbepoetin alfa in CKD patients are the same for intravenous trials.34 The results of phase II trials published so far have shown efficacy
and subcutaneous administration. The conversion factor for switching in terms of increasing or maintaining the Hb level in both dialysis-
patients from epoetin alfa or beta to darbepoetin alfa is usually quoted dependent and non–dialysis dependent CKD patients and revealed no
as 200 : 1, but there may be considerable variability in this, depending evidence of acute adverse effects.36-38 Levels of endogenous EPO induced
on the patient population, the dose, and the route of administration. by prolyl-hydroxylase inhibitors are lower than those observed under
intravenous treatment with ESAs, potentially avoiding dose-dependent
Methoxy Polyethylene Glycol–Epoetin Beta (C.E.R.A.) toxicity of ESAs. On the other hand, prolyl-hydroxylase inhibitors are
Alternative bioengineering techniques to prolong the half-life of EPO likely to have a range of consequences additional to increasing levels
further resulted in the development of C.E.R.A., a pegylated derivative of EPO through activation of other HIF-target genes or interference
of epoetin beta with an elimination half-life of around 130 hours when with other cellular pathways.2,34 Such pleiotropic effects could be ben-
administered either intravenously or subcutaneously. Phase III studies eficial, for example, by improving iron availability or reducing lipid
suggested that many patients are able to be maintained with once- levels.35 However, given the widespread biological role of HIF, including
monthly administration of C.E.R.A., and a superiority study suggested its effects on neoangiogenesis and vascular function, the long-term
greater efficacy with this frequency of administration compared with benefit-to-risk relationship is difficult to predict and can be assessed
once-monthly dosing of darbepoetin alfa when administered intrave- only through rigorous long-term observation.
nously to hemodialysis (HD) patients.30
Initiation of and Maintenance Therapy With
Adverse Effects of the Erythropoiesis-Stimulating Agents Erythropoiesis-Stimulating Agents
Adverse effects of ESA therapy include a moderate increase in blood Before ESA therapy is considered in CKD patients, it is essential to
pressure and an increased rate of thromboembolic events, including exclude and to correct causes of anemia other than EPO deficiency,
vascular access thrombosis. Whereas these effects probably depend to such as iron and vitamin deficiencies (Fig. 82.3). If the serum ferritin
a large degree on the increase in Hb concentration, there are some concentration is below 100 ng/ml, the first therapeutic approach in
concerns that ESA therapy may enhance thrombogenicity and tumor anemic patients should be iron supplementation. Iron is best given by
growth in patients with malignant disease, as well as exacerbate vascular intravenous administration, although oral iron can be considered in
events in CKD independently of Hb concentrations. Thus attempts patients not yet on dialysis.39 Some patients may respond to intravenous
should be made to use the lowest doses of ESA possible to avoid the iron alone (see later discussion). If the ferritin level is above 100 μg/l
presumed pleiotropic effects of this class of drugs. Similarly, because (in the absence of systemic inflammation) or there is a suboptimal
no “safe” upper dose level has been determined, it is advisable to avoid response to iron, ESA therapy is an option. However, the Hb level at
repeated dose escalations.14 In the Trial to Reduce Cardiovascular Events which ESAs should be initiated remains controversial, mainly because
with Aranesp Therapy (TREAT), patients with a history of malignancy the topic has not been rigorously studied. In TREAT, the largest ESA
were found to have an increased rate of cancer-related deaths when trial performed so far, darbepoetin therapy (with a target Hb level of
treated with darbepoetin.23 Although no study has investigated anemia 13 g/dl) was compared with placebo, with a rescue protocol when a
management in patients with CKD and active cancer, ESAs should be patient’s Hb dropped below 9 g/dl.23 In the darbepoetin arm, the number
used only with great caution in such patients, in particular when cure of patients transfused was lower and there was a small increase in
from cancer is the anticipated outcome.14 Similarly, in patients with a quality of life, but the stroke rate was twice as high, so that the benefit-
history of stroke or recent venous thromboembolic event, careful con- to-risk relationship was clearly negative. Whereas these data argue
sideration should be given to the benefit-to-risk ratio of using ESA strongly against the initiation of ESA therapy in patients with mild
therapy (see later discussion). anemia, there is only one, much smaller randomized controlled trial
(RCT) (in HD patients) that tested two different target ranges of
Peginesatide 9.5 to 11.0 g/dl and 11.5 to 13.0 g/dl against placebo in patients with
Peginesatide (previously called Hematide) is an EPO-mimetic peptide, severe anemia.40 Patients in both EPO treatment arms experienced
the amino acid sequence of which is completely unrelated to native or improved quality of life and exercise capacity, but there was no differ-
recombinant EPO,24 although it shares the same functional and biologic ence between the arms. Based on these findings, the KDIGO guidelines
properties as EPO. It has been shown to be an effective treatment for recommend use of ESAs to prevent the Hb level from falling below 9 g/
anti-EPO antibody–mediated pure RBC aplasia because of a lack of dl.14 However, individualization is possible, acknowledging the fact that
cross-reactivity with anti-EPO antibodies.31 Peginesatide was also shown some patients have improved symptoms at higher Hb levels and are
to be equivalent to epoetin and darbepoetin in raising Hb concentra- prepared to take increased risks. A commonly used target Hb range is
tions in dialysis and nondialysis patients, respectively, but in nondialysis between 10 and 12 g/dl.
patients, a higher rate of CV events was observed.32,33 Approximately a The usual intravenous or subcutaneous starting dose of epoetin is
year after its introduction, peginesatide had to be withdrawn from the about 25 to 50 IU/kg (e.g., 2000 IU two or three times weekly), of
market because of severe hypersensitivity reactions, including fatal darbepoetin alfa is 20 to 30 mcg once weekly, and of C.E.R.A. is 30 to
anaphylactic events. Currently no EPO-mimetic peptide is available as 60 mcg once every 2 weeks. Within 3 to 4 days after treatment initia-
rescue therapy for anti-EPO antibody–induced PRCA. tion, an increase in the reticulocyte count is seen, and within 1 to 2

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 CHAPTER 82 Anemia in Chronic Kidney Disease 963

TABLE 82.2 Causes of a Poor Response to

Management of Anemia in CKD Erythropoiesis-Stimulating Agent Therapy
MAJOR
(FREQUENT) MINOR (LESS COMMON)
Anemia of CKD

Iron deficiency Poor compliance, poor adherence to ESA therapy

Infection, inflammation Blood loss
Underdialysis Hyperparathyroidism
Aluminum toxicity (now rare)
Exclude causes other than EPO deficiency
(e.g., iron, B12, folate deficiency)
Vitamin B12 or folate deficiency
Hemolysis
Primary bone marrow disorders (e.g.,
myelodysplastic syndrome)
Hemoglobinopathies (e.g., sickle cell disease)
If ferritin < 100 µg/l, consider trial ACE inhibitors, angiotensin receptor blockers
of IV iron alone, 200-500 mg Carnitine deficiency
Anti-EPO antibodies causing PRCA
ACE, Angiotensin-converting enzyme; EPO, erythropoietin; PRCA,
pure red cell aplasia.
If ferritin !100 µg/l or no response
to IV iron, start EPO, 4000-6000 IU/wk
or darbepoetin alfa 20-30 !g/wk

(see later discussion), infection or inflammation, and underdialysis.12,14

If the patient is self-administering (e.g., for PD patients), poor adher-
Adjust ESA dose by 25%-50% monthly ence to or compliance with therapy must be excluded. If there is any
until Hb in target range of 10-12 g/dl doubt about the possibility of iron deficiency, a trial of intravenous
iron may be useful. Vitamin B12, folate, and thyroxine deficiency may
be excluded easily by the appropriate laboratory tests, as may be severe
hyperparathyroidism. Aluminum toxicity is no longer a significant cause
of ESA resistance. Depending on the ethnic origin of the patient, a
Maintain iron status according to levels
in Table 82-3 giving IV iron as required
hemoglobinopathy should be excluded by performing Hb electropho-
resis. Some patients taking ACE inhibitors or angiotensin receptor
Fig. 82.3 Management of anemia in patients with chronic kidney blockers may require higher doses of ESA therapy, although it is rarely
disease (CKD). EPO, Erythropoietin; ESA, erythropoiesis-stimulating necessary to stop these drugs. The possibility of a primary bone marrow
agent; Hb, hemoglobin; IV, intravenous. disorder, such as myelodysplastic syndrome, should be investigated by
a bone marrow examination (aspirate and trephine) if all other causes
have been excluded. A bone marrow test also may be necessary in the
diagnosis of antibody-mediated PRCA, although measurement of the
weeks, there is a significant rise in the Hb concentration, usually of the reticulocyte count and anti-EPO antibodies may provide an earlier
order of 0.25 to 0.5 g/dl/wk. Thus, over the course of 1 month, a sig- clue.25 If a patient receiving ESA therapy has a high reticulocyte count,
nificant increase of 1 to 2 g/dl in Hb concentration is usually achieved. the bone marrow is generating more than adequate quantities of new
If a patient fails to respond satisfactorily to ESAs, the dose is increased RBCs and bleeding or hemolysis should be investigated by means of
in stepwise upward titrations of 25% to 50%, and if there is still an endoscopy or hemolysis screen (Coombs test, serum bilirubin, lactate
inadequate response, causes of resistance to ESA therapy should be dehydrogenase, and haptoglobin levels).
investigated (see later discussion). There is no defined upper dose limit of ESA, and doses of 60,000 IU
Given the risks observed in trials aiming at Hb normalization, it is of EPO per week have not uncommonly been used in the United States,
recommended that the Hb level should not be intentionally increased but there is recent concern that high doses of ESA may increase side
to 13 g/dl or higher and should generally not be maintained above effects independently of Hb concentrations, as described earlier. In
11.5 g/dl. patients with acute illness requiring hospitalization, Hb frequently falls
despite continued ESA therapy, indicating increased blood loss and
Hyporesponsiveness to Erythropoiesis-Stimulating Agents temporary hyporesponsiveness. The optimal management of anemia
According to the most recent guidelines, hyporesponsiveness to ESA under these conditions remains unclear. Whereas cost considerations
therapy is identified when the Hb concentration does not increase from may speak for withholding of ESA therapy until responsiveness is rees-
baseline after the first month of ESA treatment on appropriate weight- tablished, it has been proposed that doses should be increased in an
based dosages or if after treatment with stable doses, patients require attempt to overcome hyporesponsiveness. Anecdotally, very high doses
two increases in ESA doses up to 50% beyond the dose at which their can be effective even in critically ill patients in intensive care units, but
condition had previously been stable.14 Patients who are hyporesponsive an RCT42 failed to demonstrate a reduction in transfusion requirements
have a worse prognosis than those who do respond.41 The causes of and observed an increase in deep vein thrombosis. From a practical
resistance to ESA therapy are listed in Table 82.2, and it is important point of view, and pending evidence to the contrary, it seems sensible
to correct them when possible. The major causes include iron deficiency to continue the same dose of ESA.

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964 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

who are not on iron and ESA therapy and in whom an increase in Hb
Iron Management concentration is desired and in patients on ESA therapy in whom an
Iron is an essential ingredient for heme synthesis, and adequate amounts increase in Hb concentration or a decrease in ESA dose is required
of this mineral are required for the manufacture of new RBCs. Thus, when TSAT is 30% or lower and ferritin level is 500 ng/ml or lower14
under enhanced erythropoietic stimulation, greater amounts of iron (see Table 82.3). Levels of ferritin above this threshold usually do not
are used, and many CKD patients (particularly those on HD) have confer any clinical advantage and may exacerbate iron toxicity. The
inadequate amounts of available iron to satisfy the increased demands optimal TSAT is above 20% to 30% to ensure a readily available supply
of the bone marrow.43 Even before the introduction of ESA therapy, of iron to the bone marrow. No upper limits of ferritin or TSAT were
many CKD patients were in negative iron balance as a result of poor specified in the KDIGO anemia guidelines, largely because there is no
dietary intake, poor appetite, and increased iron losses from occult and robust evidence to determine a threshold beyond which harm or loss
overt blood losses (see Chapter 86). Losses in HD patients are up to 5 of efficacy supervenes. However, until more informative data become
or 6 mg/day, compared with 1 mg in healthy individuals, and this may available, the treating nephrologist would be well advised to exercise
easily exceed the absorption capacity of the gastrointestinal tract, par- caution in administering intravenous iron to patients with ferritin levels
ticularly when there is any underlying inflammation. Iron absorption above 800 ng/ml or TSAT above 30%. Several studies support maintain-
capacity in patients with CKD is considerably lower than in nonuremic ing the percentage of hypochromic RBCs at less than 6% and the CHr
individuals, particularly in the presence of systemic inflammation, and at greater than 29 pg/cell. Other measures of iron status, such as serum
this is mediated by hepcidin upregulation.9 For this reason also, tradi- transferrin receptor levels and erythrocyte zinc protoporphyrin levels,
tional oral iron therapy (e.g., with ferrous sulfate) is ineffective in many are mainly research tools.
CKD patients, and parenteral iron administration is required, particularly Oral iron is generally poorly absorbed in uremic individuals, and
in those receiving HD.43 However, recently, a newer preparation of oral there is a high incidence of gastrointestinal side effects. Intramuscular
iron (ferric citrate) that shows greater absorption of iron from the gut administration of iron is not recommended in CKD, given the enhanced
has become available in the United States and Japan, and the role that bleeding tendency, the pain of the injection, and the potential for brown-
ferric citrate may play in iron management in CKD awaits further ish discoloration of the skin. Thus intravenous administration of iron
elucidation. has become the standard of care for many CKD patients, particularly
An inadequate supply of iron to the bone marrow may be caused those receiving HD.43 Several intravenous iron preparations are available
by an absolute or a functional iron deficiency.43 Absolute iron deficiency worldwide, including iron dextran, iron sucrose, iron gluconate, and
occurs when there are low whole-body iron stores, as indicated by a the newer iron preparations ferric carboxymaltose, ferumoxytol, and
serum ferritin level less than 30 ng/ml. Functional iron deficiency occurs iron isomaltoside 1000. The last three iron preparations allow higher
when there is ample or even increased storage iron but the iron stores doses of intravenous iron to be administered more rapidly, without the
fail to release iron rapidly enough to satisfy the demands of the bone need for a test dose. All of the iron preparations contain elemental iron
marrow. Several markers of iron status are available, but none of them surrounded by a carbohydrate shell, which allows them to be injected
is ideal (Table 82.3). Serum ferritin is a marker of storage iron but is intravenously. The lability of iron release from these preparations varies,
spuriously raised in inflammatory conditions and liver disease. TSAT with iron dextran being the most stable and iron gluconate being the
is a function of the circulating serum iron in relation to the total iron- least stable. Iron is released from these compounds to plasma transferrin
binding capacity and is often regarded as a better measure of available and other iron-binding proteins and is then taken up by the reticulo-
iron; however, levels can be highly fluctuant because of significant diurnal endothelial system.
variation in the measurement of serum iron.43 The percentage of hypo- In HD patients, it is easy and practical to give low doses of intra-
chromic RBCs and the CHr are RBC and reticulocyte parameters, venous iron (e.g., 10 to 20 mg) at every dialysis session or, alternatively,
respectively, that are indirect measures of how much iron is being 100 mg weekly. In PD and nondialysis CKD patients, however, such
incorporated into the newly developing or mature RBC. No one measure low-dose regimens are impractical and larger doses may be administered.
of iron status is usually adequate to exclude iron deficiency, and the The more stable the iron preparation, the larger the dose administration
recommended levels for these measures are based on limited scientific rate that can be used. For example, 1 g of iron dextran may be given
evidence. Functional iron deficiency is usually diagnosed when there by intravenous infusion, whereas the maximum recommended dose of
is a normal or increased ferritin level and a reduced TSAT (<20%) or iron gluconate is 125 mg. The usual dose of ferumoxytol is 510 mg,
increased hypochromic RBCs (>10%). The KDIGO guidelines on renal whereas up to 1 g of ferric carboxymaltose or iron isomaltoside 1000
anemia management suggest a trial of iron in CKD patients with anemia may be given as a single administration. All intravenous iron prepara-
tions carry a risk for immediate hypersensitivity reactions, which may
be characterized by hypotension, dizziness, and nausea. These reactions
are usually short-lived and caused by too large a dose given in too short
TABLE 82.3 Recommended Iron Status a time. Iron dextran also carries the risk for acute anaphylactic reactions
Levels in CKD because of preformed dextran antibodies, although this was largely a
Test Recommended Range problem with the high molecular weight intravenous iron dextran
preparations, which have now been withdrawn from the market. Other,
Serum ferritin 100-500 μg/l (CKD)
longer term concerns about intravenous administration of iron include
200-500 μg/l (HD)
the potential for increased susceptibility to infections and oxidative
Transferrin saturation 20%-40% stress. Much of the scientific evidence for this has been generated from
Hypochromic red cells <10% in vitro experiments, the clinical significance of which is unclear.43
Reticulocyte hemoglobin content (CHr) >29 pg/cell Despite these concerns, the lack of efficacy of traditional oral iron
Serum transferrin receptor Not established preparations in HD patients has resulted in the widespread use of intra-
venous iron to correct the negative iron balance in this patient popula-
Erythrocyte zinc protoporphyrin Not established
tion. In general, the greater the use of intravenous iron, the lower is
CKD, Chronic kidney disease; HD, hemodialysis. the dose requirement of ESA therapy; however, the optimum balance

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 CHAPTER 82 Anemia in Chronic Kidney Disease 965

between intravenous iron and ESA therapy remains unknown. This 17. Winkelmayer WC, Kewalramani R, Rutstein M, et al.
gap in knowledge may be partly addressed by the ongoing PIVOTAL Pharmacoepidemiology of anemia in kidney transplant recipients.
RCT, which is comparing a more liberal use of intravenous iron versus J Am Soc Nephrol. 2004;15:347–352.
a restrictive policy in 2141 HD patients recruited across 50 sites in the 18. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term
cardiorespiratory effects of amelioration of renal anaemia by
United Kingdom.44
erythropoietin. Lancet. 1990;335:489–493.
In nondialysis patients, both oral and intravenous iron may be used 19. Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of
and there are advantages and disadvantages for each route of admin- full and partial anemia correction in incident hemodialysis patients
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in a faster and greater rise in Hb, with no safety concerns.39 The REVOKE compared with low hematocrit values in patients with cardiac disease
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adherence to treatment, gastrointestinal side effects, and reduced efficacy; epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:
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2012;2:279–335. hydroxylases increases erythropoietin production in ESRD. J Am Soc
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erythropoiesis causes anemia in angiotensin-converting enzyme–deficient 36. Provenzano R, Besarab A, Wright S, et al. Roxadustat (FG-4592) Versus
mice. J Clin Invest. 2000;106:391–398. Epoetin Alfa for Anemia in Patients Receiving Maintenance
16. Le Meur Y, Lorgeot V, Comte L, et al. Plasma levels and metabolism of Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label,
AcSDKP in patients with chronic renal failure: Relationship with Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.
erythropoietin requirements. Am J Kidney Dis. 2001;38:10–17. Am J Kidney Dis. 2016;67:912–924.

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37. Holdstock L, Meadowcroft AM, Maier R, et al. Four-Week Studies of Oral 41. Solomon SD, Uno H, Lewis EF, et al. Erythropoietic response and
Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:
Treatment of Anemia. J Am Soc Nephrol. 2015;27:1234–1244. 1146–1155.
38. Pergola BE, Spinowitz BS, Hartman CS, et al. Vadadustat, a novel oral 42. Corwin HL, Gettinger A, Fabian TC, et al, EPO Critical Care Trials
HIF stabilizer, provides effective anemia treatment in nondialysis- Group. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J
dependent chronic kidney disease. Kidney Int. 2016;90:1115–1122. Med. 2007;357:965–976.
39. Macdougall IC, Bock AH, Carrera F, et al. FIND-CKD: a randomized trial 43. Macdougall IC, et al. Iron management in chronic kidney disease:
of intravenous ferric carboxymaltose versus oral iron in patients with conclusions from a “Kidney Disease: Improving Global Outcomes”
chronic kidney disease and iron deficiency anaemia. Nephrol Dial (KDIGO) Controversies Conference. Kidney Int. 2016;89:28–39.
Transplant. 2014;29:2075–2084. 44. https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002267-25/GB.
40. Canadian Erythropoietin Study Group. Association between recombinant Accessed November 26, 2016.
human erythropoietin and quality of life and exercise capacity of patients 45. Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and
receiving haemodialysis. BMJ. 1990;300:573–578. oral iron in chronic kidney disease. Kidney Int. 2015;88:905–914.

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 CHAPTER 82 Anemia in Chronic Kidney Disease 966.e1

SELF-ASSESSMENT
QUESTIONS
1. Which of the following statements is false regarding the character-
istics of renal anemia?
A. The red blood cells (RBCs) produced are usually normochromic
and normocytic.
B. There is usually no associated leukopenia or thrombocytopenia.
C. The reticulocyte count is usually around 40,000 to 50,000/μl of
blood.
D. Serum erythropoietin levels are usually within the normal range.
E. The RBC life span is usually normal.
2. Which of the following statements is false?
A. Dose requirements of epoetin are generally 20% to 30% less
when the agent is administered subcutaneously compared with
intravenously.
B. Erythropoiesis-stimulating agent (ESA) therapy should be used
with caution in patients with previous or current malignancy.
C. Patients who are hyporesponsive to ESA therapy have a worse
prognosis than those who do respond.
D. The defined upper dose limit of epoetin is 60,000 IU/wk because
it is known that cardiovascular toxicity occurs above this dose
level.
E. Angiotensin-converting enzyme (ACE) inhibitors may confer
resistance to ESA therapy in some patients.
3. Which of the following statements is false regarding the TREAT
study?
A. Patients receiving darbepoetin alfa were randomized to either a
target hemoglobin (Hb) of 13 or a target Hb of 9 g/dl.
B. Patients randomized to a target Hb of 13 g/dl had a small increase
in quality of life compared with the control arm.
C. There was a significant reduction in the use of RBC transfusions
in patients randomized to a target Hb of 13 g/dl.
D. There was a doubling of the rate of stroke in patients random-
ized to a target Hb of 13 g/dl.
E. There was a significant increase in cancer-related mortality in
the subset of patients with a history of malignancy who were
randomized to a target Hb of 13 g/dl.
4. Which of the following statements is true regarding intravenous
iron supplementation?
A. All intravenous iron preparations require a test dose before their
first administration, as per their product label.
B. All the newer intravenous iron preparations (ferumoxytol, ferric
carboxymaltose, and iron isomaltoside 1000) have the advantage
that up to 1 g may be administered as a single dose.
C. Intravenous iron preparations vary in their lability and speed
of iron release from the carbohydrate shell, with iron gluco-
nate being the most stable and iron dextran the least stable
compound.
D. Intravenous iron may improve the anemia of chronic kidney
disease in up to 30% of patients not receiving ESA therapy who
have a low ferritin level.
E. Hypersensitivity reactions are more common with low molecular
weight iron dextrans than with high molecular weight iron dextran
compounds.

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 83
Other Blood and Immune Disorders in
Chronic Kidney Disease
Matthias Girndt, Gunnar H. Heine

IMMUNE DYSFUNCTION often have excess pulmonary fluid, which may impair alveolar bacterial
clearance and contribute to the risk for pneumonia. Repeated breaks
Patients with chronic kidney disease (CKD) have a high morbidity and in the skin barrier by cannulation provide opportunity for bacterial
mortality as a result of infection. This is in part directly caused by invasion. Finally, dialysis patients frequently receive intravenous iron
alterations in the immune system, although multiple other factors are preparations, and iron overload is a risk factor for bacterial infection
involved. as a result of inhibition of monocyte and macrophage function.

Bacterial Infections Viral Infections

Infections are a major cause of hospitalization in patients with CKD; Viral hepatitis has been a scourge of dialysis ever since renal replace-
infection-related hospitalization rates are at least three to four times ment therapy (RRT) became a routine treatment. Only rigorous stan-
(nondialysis CKD) or eight times (dialysis) higher than in individuals dard hygienic precautions and active vaccination against hepatitis B
with normal renal function.1 The number of days spent in hospital for virus (HBV) made large-scale HD safe. However, impaired immune
infections has slightly decreased over the last decade. Nevertheless, they defense was only one among other causes for the high prevalence of
are still higher than those for cardiovascular disease (4 vs. 2.2 days per viral hepatitis in this patient group. The viruses can be easily transmitted
patient year1). Infection is also an important cause of mortality, account- nosocomially in HD patients without proper precautions. Neverthe-
ing for 8% of deaths in dialysis patients. Pulmonary infections and less, the early outbreaks of HBV infection showed an abnormal clini-
infections of the genitourinary system in particular increase with decreas- cal course related to the immune defect in CKD.5 The acute infection
ing renal function. For example, patients with CKD stage 4 have a could sometimes only be detected by measurement of transaminases.
15-fold higher risk for severe pulmonary infections compared with The clinical syndrome of icterus, subfebrile temperatures, and malaise,
those with an estimated glomerular filtration rate (eGFR >60 ml/ which is typical for patients with normal renal function, was missing.
min/1.73 m2). Furthermore, mortality from pneumonia is markedly The majority of affected dialysis patients developed chronic persis-
enhanced by concurrent CKD.2 tent infection, which occurs in only 10% of patients with intact renal
In hemodialysis (HD) patients, bloodstream infections are another function.
major cause of infection-related hospitalization, particularly in patients The clinical manifestations of HCV infection are not significantly
with central venous catheters as dialysis access.3 Catheter-based HD is influenced by the immune deficiency of renal failure. The infection
among the major risk factors for the development of bacterial endocar- usually runs a rather subclinical course and becomes chronic even in
ditis. More than 50% of cases of bacteremia are caused by Staphylococcus the absence of CKD.
aureus. Nevertheless, there is also a relevant rate of gram-negative bac-
teremias in dialysis patients, indicating that contamination or infection Vaccinations in Chronic Kidney Disease
of the dialysis access is not the only cause for bloodstream infection. Immune deficiency leads to a high rate of nonresponse to hepatitis B
The high incidence of bacterial infection in CKD patients may be vaccination. Dialysis patients should always receive double-dose vac-
one clinical consequence of immune dysfunction; another is atypical cination and extended vaccination protocols (Fig. 83.1), but even with
clinical presentations of infections such as the lack of fever in 20% to the most recent vaccines some 20% of patients do not develop protec-
40% of bacteremic patients. When bacteremia is suspected, blood cultures tive antibody levels.6 This impaired response led to the development of
should be obtained frequently. Another aspect of immune dysfunction specifically adjuvanted vaccines or intracutaneous application protocols7
is the high rate of false-negative tuberculin (Mantoux) skin tests with with improved efficiency in former nonresponders.
anergic skin reactions in the presence of positive interferon-γ release Other vaccinations are also affected by the immune defect in CKD.
assays (IGRA tests), indicating impaired T-lymphocyte function.4 The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines8
However, other factors besides immune dysfunction also predispose recommend annual influenza vaccinations. Studies comparing vacci-
to infection in persons with CKD. Thirty-nine percent of patients with nation efficiency in patients with CKD and healthy individuals have
end-stage renal disease reported by the U.S. Renal Data System are methodologic limitations; therefore the extent to which immune dys-
above 65 years of age,1 and in other countries this fraction exceeds 50%. function compromises these vaccination results is not clear. Most likely,
Besides their age, many CKD patients have underlying renal or extrarenal the efficacy is lower in dialysis patients. A recent systematic review on
autoimmune disease that requires therapeutic immunosuppression and the protective effects with regard to hard end-points such as mortality
other comorbidities that facilitate infection such as diabetes or heart or hospitalization pointed out that the universal recommendation to
failure. Dialysis patients and patients with the cardiorenal syndrome vaccinate—albeit very plausible—has a weak evidence base.9

967
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968 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Hepatitis B Vaccination Scheme for

Patients with Chronic Kidney Disease

Serologic testing At least 1

No vaccination
(HBsAg, anti-HBs, anti-HBc) marker positive

All negative

3-4x double dose vaccination*

intramuscularly

Serologic testing
(anti-HBs)
4 weeks after inj.

Anti-HBs > 100 IE/L Anti-HBs 10 - 100 IE/L Anti-HBs < 10 IE/L

Serologic testing 3-4x double dose vaccination*

(anti-HBs) intramuscularly
annually or 8 x 5µg intradermally

Serologic testing
Anti-HBs ≥
Anti-HBs < 100 IE/L (anti-HBs)
10 IE/L
4 weeks after inj.

Anti-HBs < 10 IE/L

Single booster dose No further vaccination attempts

40 µg i.m. HBsAg monitoring annually
Fig. 83.1 Hepatitis B vaccination scheme for patients with chronic kidney disease (CKD). *The
schedule varies with different vaccine preparations.

In contrast to antiviral vaccinations, those against bacteria appear

to be less influenced by CKD. Vaccination against pneumococcal infec- TABLE 83.1 Vaccination
tions is universally recommended8 for adults with eGFR less than 30 ml/ Recommendations for Adult Patients With
min/1.73 m2. Evidence of efficacy in terms of antibody titers comes Chronic Kidney Disease
from very old studies or series with small patient numbers. Likely, Vaccination
maximum antibody titers are lower and protection lasts shorter in CKD Against Recommendation
patients,10 but data on hospitalization or mortality can be derived only
from observational studies.11 Because multiple vaccine preparations are Hepatitis B All patients susceptible to HBV infection,
available, the congruence of local epidemiology and the vaccine cover- virus (HBV) double dose (see Fig. 83.1)
age should be considered (Fig. 83.2). Newer conjugate vaccines have a Influenza Annually according to WHO recommendation,
rather narrow spectrum of serotype coverage while being highly effective standard dose
in inducing seroprotection; thus there is an argument to vaccinate CKD Streptococcus All patients, conjugate vaccine, can be
patients sequentially with conjugate vaccine first, followed in 6 to 12 pneumoniae boostered by polysaccharide vaccine at
months by the broad polysaccharide vaccine. Revaccination with the 6 mo, revaccination after 6 y
polysaccharide vaccine is recommended after 6 years. Tetanus All patients according to recommendations for
Further recommendations for vaccination in CKD are given in general population, standard dose
Table 83.1. Diphtheria All patients according to recommendations for
general population, standard dose
INFLAMMATION Hepatitis A Not routinely indicated, can be given for travel
Chronic inflammation is typical for patients with CKD 4 or 5 or on Modified from reference 49.
RRT, and C-reactive protein (CRP) and plasma cytokines increase steadily WHO, World Health Organization.

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 969

Streptococcus Pneumoniae Serotypes in Clinical Isolates from

Europe and United States in Relation to Vaccine Serotype Coverage

Europe USA
1500 400

300

Number of cases
Number of cases

1000

200

500
100

0
19A
19F

12F

22F

5
9V
14
1
18C
23F
4
6B
19F
7F
6A
3
19A
12F
9N
15B

22F
15B
7F
14

11A
4

Str. pneumonia serotype Str. pneumonia serotype

Konj-10 Konj-13 PS-23

Fig. 83.2 Streptococcus pneumoniae serotypes in clinical isolates (as of 2010) from Europe (Euro-
pean Center of Disease Control) and United States (Centers for Disease Control and Prevention)
in relation to vaccine serotype coverage. Conj-10: 10-valent conjugate vaccine; Conj-13: 13-valent con-
jugate vaccine; PS-23: 23-valent polysaccharide vaccine. Low isolate numbers for the serotypes covered by
Conj-10 in the United States are result of successful vaccination programs.

with every stage of CKD. The majority of HD and peritoneal dialysis (IL-10) influence the quantity of its production in response to inflam-
patients periodically or permanently have CRP values above the normal matory stimuli and thus the way a patient can contain and limit
limit in the absence of clinical infection.12 inflammation.16

Causes of Inflammation Consequences of Inflammation

Although early research in this field focused on dialysis membrane Inflammation is closely associated with the occurrence of CV complica-
bioincompatibility, contamination of dialysis fluids, or vascular access tions (reviewed in Chapter 81) and immune dysfunction. When using
as causes of inflammation, chronic inflammation also occurs in patients the response to HBV vaccination as a surrogate for clinical immune
with CKD stages 3 and 4. One important reason may be the renal function, there is a close correlation between inflammation and decreased
clearance of circulating proinflammatory cytokines.13 Impaired kidney immunity. This is confirmed by the finding that the IL-10 gene poly-
function leads to prolonged cytokine serum half-life, thus enhanc- morphism, which influences the extent of inflammation, also predicts
ing and prolonging inflammatory episodes that usually would have vaccination responses in dialysis patients.16
abated quickly.
At least 30% of patients with advanced CKD have diabetes mellitus, IMMUNE CELL ABNORMALITIES
a comorbidity that promotes inflammation both by itself and through
diabetic complications such as ulcers. In addition, many patients with Monocytes
CKD have poor dental health and periodontitis is associated with sys- Monocytes are bone marrow–derived cells with specific functions in
temic inflammation.14 immune surveillance and antigen presentation. During their differentia-
Whether inflammation is also related to classic uremic toxicity remains tion, they briefly circulate in the blood, produce cytokines, and then
a matter of debate. Typical toxins with increased plasma levels are indoxyl migrate into tissues to become macrophages.17 Injury and infection
sulfate, paracresyl sulfate, and trimethylamine N-oxide (TMAO). Across lead to rapid enhancement of circulating monocyte numbers, which
stages of CKD, plasma levels of TMAO show a positive correlation with then migrate to the site of tissue injury and initiate the local immune
inflammatory markers, and both decrease after renal transplantation.15 response. Monocyte-derived macrophages are constituents of athero-
Several studies show that serum levels of indoxyl sulfate or paracresyl sclerotic plaques, and imaging studies have revealed that monocytes
sulfate increase with renal dysfunction in parallel with inflammatory patrol along the vascular endothelium, where they detect endothelial
markers; however, a causal relationship remains to be proven. defects.18
The extent of inflammation is at least in part controlled by the Monocyte subpopulations are defined by the expression of the lipo-
genetic predisposition of the individual. This may be clinically relevant polysaccharide (LPS) receptor CD14 and the immunoglobulin Fcγ
in patients with CKD because inherited single-nucleotide polymor- receptor CD16.19 The classic monocytes only express CD14 and account
phisms in the gene of the antiinflammatory cytokine interleukin-10 for some 80% of all circulating monocytes in healthy individuals;

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970 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

intermediate monocytes express both CD14 and CD16 (~5% to 7%), signals. Only T cells with specificity of their T cell receptor toward the
and nonclassic monocytes express high levels of CD16 while showing particular antigen are activated and proliferate.
limited staining for CD14 (~10% to 12%). Genetic analysis revealed Major APCs are dendritic cells and their precursors are monocytes.
that CD14++CD16+ intermediate monocytes particularly express markers Early studies showed that proliferative T cell responses are impaired in
related to antigen presentation, inflammation, and angiogenesis.20 dialysis patients and this impairment is directly correlated with nonre-
In CKD, the intermediate and nonclassic monocyte subtypes are sponses to HBV vaccination. Both replacement of the patient’s APCs
significantly expanded. This finding is related to the CV risk21; patients in in vitro assays with cells from healthy donors and overexpression
with the highest rate of CD14++CD16+ monocytes in blood had the of costimulatory molecules on the APCs normalize proliferation of T
lowest CV event-free survival. cells, indicating that the major defect leading to reduced T cell activa-
Mouse models confirm differences between monocyte subpopula- tion is in the APC.29 However, these rather crude assays did not con-
tions in their ability to invade atherosclerotic plaques.22 In CKD the sider T cell subpopulations. Helper T cells express the surface marker
expansion of proinflammatory monocyte subsets and their epidemiologic CD4 and interact with various other cell types. The CD4+ helper T
association with CV events make a causal role of these cells for athero- cell is particularly needed for activation of B cells for antigen-specific
sclerotic disease likely. Furthermore, monocytes also express components seroresponses to viral antigens as in HBV vaccination. The CD8+ cyto-
of the angiotensin system. The angiotensin-converting enzyme (ACE) toxic T cells are important for antiviral defense because they are able
that turns angiotensin I (Ang I) into vasoactive angiotensin II (Ang II) to lyse infected host cells. In CKD the relation of CD4+/CD8+ T cells
is expressed in atherosclerotic plaques and colocalizes with monocyte- is reduced.
derived macrophages.23 ACE is also expressed on circulating monocytes, CD4+ helper cells can be further distinguished into cells that mainly
particularly on those with the CD14++CD16+ phenotype.24 Dialysis support cellular immune reactions (T helper cells Type 1, Th1) and
patients with high expression of ACE on intermediate monocytes have others that are more important for immunoglobulin production by
a dramatically enhanced CV mortality risk.24 members of the B cell lineage (Th2). These cell types differ in the pattern
Expression of ACE on monocytes is strongly upregulated by the of cytokines they produce, with interferon-γ being the major cytokine
uremic milieu.25 A consequence of this might be that monocytes trans- of Th1 and IL-4 the main cytokine of Th2 cells. CKD leads to a marked
migrate into the subendothelial space of arteries and provide high levels deviation of T cell differentiation toward the Th1 phenotype.30 Most
of ACE in the atherosclerotic plaque. The local production of Ang II likely the major cause is elevated production of IL-12 by monocytes
through ACE is thought to contribute to further leukocyte attraction, and APCs in the context of their inflammatory activation.30
inflammatory activation, and plaque growth. In addition, expression Another T-lymphocyte subpopulation is regulatory T cells (Tregs)
of ACE on monocytes alters their functional capacities. In vitro assays that are important for the downregulation of immune responses once
show that a higher expression of ACE leads to stronger endothelial the aim of an antiinfectious response is reached. They prevent ongoing
adhesion and transmigration of the monocytes. This effect appears to inflammation and the development of autoimmunity. The typical Treg
be mediated via locally produced Ang II, because adhesion and trans- cells originate in the thymus and have a distinct pattern of surface
migration could be inhibited by losartan.25 molecule expression. In patients with CKD the number of circulating
Monocytes also express ACE-2, a peptidase that degrades Ang II to Treg cells is unaltered, but their capacity to downregulate CD4+ helper
Ang1-7, a vasodilatory peptide. Whereas CKD leads to the overexpres- T cell activity is impaired.31
sion of ACE, the ACE-2 enzyme is downregulated compared with healthy
individuals.26 Experimental overexpression of ACE-2 in a rodent model B Lymphocytes
of atherosclerosis limited the progression of disease. These findings Impaired vaccination efficacy in CKD suggests impaired function of
suggest that the uremic milieu alters monocyte function in a strongly immunoglobulin producing B-lymphocytes and plasma cells; thus a
proatherogenic way. major dysfunction of this cell type might be expected. However, CKD
Monocytes are closely related to circulating blood dendritic cells. patients have normal circulating immunoglobulin levels. Their B cell
Dendritic cells are mainly found in organs and tissues, where they have lymphopenia is modest and probably not very clinically relevant. It is
strong capabilities in antigen presentation and activation of immune caused by a higher rate of apoptosis of these cells compared with healthy
reactions. Their immature precursors circulate in blood in low numbers. individuals.32 Lymphopenia appears to result from reduced numbers
There are different subtypes of circulating dendritic cells, but investiga- of the majority of B cell subpopulations (naïve B cells, memory B cells,
tors have used different marker sets for their detection. This limits etc.).33 Taken together, the alterations of B-lymphocytes in CKD appear
comparison among different studies, so that understanding of dendritic to be less pronounced than alterations of other immune cell types.
cell quantification and pathophysiology remains limited. There is a Impaired vaccination responses are caused by altered interaction of
relation between elevated numbers of CD14++CD16+ monocytes in the APCs, helper T lymphocytes, and the cytokine network in CKD rather
blood and the propensity of these cells to differentiate into dendritic than by abnormalities of B lymphocytes.
cells in cell culture.27 Other studies28 found significantly lower numbers
of dendritic cells in advanced CKD compared with healthy controls. Granulocytes
The finding may be related to CV disease, because studies in patients Polymorphonuclear granulocytes (neutrophils) are components of the
with coronary heart disease and normal renal function also reported antigen-independent innate immune system. Their main activity is to
reduced circulating numbers of dendritic cells. kill and phagocytose invading pathogens via numerous enzymes that
produce bactericidal substances. Among them are defensins, proteolytic
T Lymphocytes enzymes, and enzymes that produce highly active oxygen species such
Impaired vaccination responses against viral antigens such as HBV or as hypochlorous acid. In CKD patients these nonspecific defense systems
influenza, as well as reduced skin reaction in the Mantoux test, result are highly activated and the cells spontaneously release more reactive
from impaired T cell activation. T cells are an important component oxygen species.34 Inflammation, activation of different cell types, anti-
of the antigen-specific adaptive immune defense. Their activation depends infectious defense, and vascular disease are closely interwoven. Thus
on antigen-presenting cells (APCs) that present foreign antigens with the elevation of oxygen species H2O2 and malondialdehyde has predictive
major histocompatibility complex and provide important costimulatory value for CV events and mortality in CKD.35

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 971

Another important function of granulocytes is phagocytosis, which to fibrin. Subsequent cross-linking of insoluble fibrin results in a stable
is also mildly compromised in CKD.36 hemostatic plug.
It is difficult to establish whether these alterations can be improved
by dialysis. HD inevitably involves marked contact between blood and Hemorrhagic Diathesis and Uremic Platelet Dysfunction
foreign surfaces. When cellulose-based membranes were still in use, Patients with CKD have a high risk for bleeding. This hemorrhagic
the activation of the complement system by these membranes led to diathesis frequently has cutaneous (easy bruising, ecchymoses, or pro-
marked depletion of circulating granulocytes within the first 20 minutes longed hemorrhage from needle puncture or postoperative sites) and
of a dialysis session.37 Newer synthetic membranes lead to minimal mucosal (epistaxis; gastrointestinal or gingival bleeding) manifestations.
complement activation, and the leukocyte drop is much less pronounced. More dramatic—albeit infrequent—manifestations are hemorrhagic
These findings on immune cells relate to CKD. It is important to con- pericarditis/hemopericardium, hemorrhagic pleural effusion/hemothorax,
sider that some primary diseases, in particular diabetes mellitus, further and intracranial and retroperitoneal bleeding.38
influence immune cell function. This hemorrhagic diathesis is not reflected in a prolongation of the
prothrombin time or the partial thromboplastin time. Similarly, even
PLATELET DYSFUNCTION AND PLATELET though platelet counts may be moderately decreased because of platelet
consumption outperforming platelet production, severe thrombocyto-
INHIBITORS IN CHRONIC KIDNEY DISEASE penia is rarely seen in uremia; the occurrence of very low platelet counts
Normal hemostasis begins with platelet adhesion to vascular endothe- therefore requires a thorough search for alternative causes.39 Instead,
lium and requires a relatively vasoconstricted vessel wall, integrity of platelet dysfunction is generally considered as the central contributor
platelet glycoproteins (GPs), and a normal quantity of large molecular to the high bleeding risk, and a high number of pathophysiologic altera-
weight, multimeric von Willebrand factor (vWF) (Figs. 83.3 and 83.4). tions have been suggested to contribute, comprising alterations in platelet
Main platelet GPs are GPIb, the platelet receptor for vWF, involved in function and structure, and extrinsic factors (see Table 83.1). Unfor-
platelet adhesion, and GPIIb/IIIa, the platelet receptor for fibrinogen, tunately, many studies on platelet functions in CKD date back to early
involved in platelet aggregation. days of clinical nephrology, when clinical care and dialysis treatment
Under static conditions, GPIb and vWF have no affinity for each were less sophisticated, and when less advanced laboratory methods
other. However, these molecules develop a specific affinity for each were available for evaluation of hemostasis. For the various pathophysi-
other at high shear stress, resulting in arterial platelet adhesion. Aggre- ologic alterations listed in Box 83.1, controversial data have been
gated fibrinogen-platelet mesh acts as a trap for binding and activation published.
of other plasma clotting factors. The exposure of the preceding clotting In the search for uremic toxins inducing platelet dysfunction, a
factors to tissue factors, present on damaged endothelial cells, catalyzes direct pathologic role of urea can be ruled out because no correlation
the conversion of prothrombin to thrombin, which converts fibrinogen exists between blood urea levels and bleeding time40 and individuals

Platelet Adhesion and Aggregation

Red blood cell von Willebrand

factor

GpIIb/IIIa Fibrinogen
Platelet

GpIb

Fibrin
mesh
Platelet
Coagulation
cascade IIa

Endothelial Collagen-laden Platelet Activated Inset expanded Tissue

cell subendothelium adhesion GpIIb/IIIa in Figure 83-4 factor
Fig. 83.3 Platelet adhesion and aggregation. Platelets are pushed peripherally toward the vascular wall
by red blood cells traversing centrally through the bloodstream. Damage to the vessel wall results in a dis-
ruption of the nonthrombogenic endothelial cell lining and exposure of subendothelial structures. Whereas
collagen supports initial platelet adhesion (and subsequent aggregation), von Willebrand factor (vWF) deposi-
tion on the subendothelium serves as the main anchor for platelet adhesion through platelet GPIb receptor.
Postadhesion conformational change in platelet GPIIb/IIIa receptor (fibrinogen or vWF receptor) results in
interlinking platelet aggregation.

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972 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Clotting Cascade
Fibrinogen Cross-linking
II
IX X
VII VIIIa†
Fibrin
Va†
(Thrombin)
* IIa*
Tissue
factor VIIa VIIa IXa Xa

Endothelial cell

Fig. 83.4 Clotting cascade. Expansion of the inset in Fig. 83.3 shows the clotting cascade that takes place
at the damaged vessel wall. Exposure of subendothelial tissue factor, present on pericytes and fibroblasts,
allows eventual activation of prothrombin (factor II) to thrombin. Thrombin converts fibrinogen to fibrin,
activates fibrin cross-linking, stimulates further platelet aggregation, and activates anticoagulant protein C.
Naturally occurring anticoagulants antithrombin III, protein C, and protein S help maintain control and coun-
terbalance on coagulation. *Site of anticoagulant effect for antithrombin III. †Site of anticoagulant effect for
protein C–protein S complex. (Courtesy James A. Sloand, MD, FACP, FASN, Baxter Healthcare Corporation,
Deerfield, Ill.)

platelets from the axial flow toward the vessel walls. This allows platelets
BOX 83.1 Proposed Contributors to
to adhere to injured endothelial cells and initiate the formation of a
Platelet Dysfunction in Uremia platelet plug. In anemia, platelets are more dispersed, which impairs
Intrinsic Factors That Contribute to Platelet Dysfunction their adherence to the endothelium. Moreover, in CKD, red blood cells
Dysfunction of glycoprotein IIb/IIIa may affect coagulation by releasing adenosine diphosphate (ADP), by
Abnormal expression of platelet glycoprotein inactivating PGI2, and by scavenging nitric oxide (NO), which are all
Altered release of adenosine diphosphate (ADP) and serotonin from platelet central regulators of platelet function.39
α-granules
Faulty arachidonic acid and depressed prostaglandin metabolism, decreased Treatment of Uremic Platelet Dysfunction
platelet thromboxane A2 generation Despite the previously discussed pathophysiologic considerations, few
Abnormal platelet cytoskeletal assembly with reduced incorporation of actin data establish the extent to which initiation of RRT reduces the risk
and diminished association of actin binding proteins (α-actin and tropomyosin) for bleeding in CKD.
with the cytoskeleton In the early decades of HD, the interaction of blood with cellulose-
based dialyzer membranes resulted in complement activation and tran-
Extrinsic Factors That Contribute to Platelet Dysfunction sient thrombocytopenia during the dialysis procedure. When using more
The action of uremic toxins biocompatible dialyzer membranes, such complement-induced platelet
Anemia reduction no longer has clinical relevance. Nonetheless, HD treatment
Increased nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) may still affect bleeding disorders; while potentially removing uremic
production toxins, which affect platelet function, it requires systemic anticoagula-
Functional von Willebrand factor abnormalities tion and exposes patients to the potential risk for heparin-induced
Decreased platelet production thrombocytopenia (HIT). Moreover, HD may disrupt the platelet
Abnormal interactions between the platelet and the endothelium of the cytoskeleton, induce repeated platelet stress, decrease the percentage
vessel wall of RNA-rich platelets, and reduce the percentage of available reticu-
lated platelets.42 As RNA-rich and reticulated platelets are more able
Modified from Berns JS, Coutre S. Platelet dysfunction in uremia.
UpToDate, http://www.annemergmed.com/article/S0196-0644(15)
to be activated, the accumulation of less RNA-rich and less reticulated
00034-7/pdf; reference 38. platelets indicates the presence of less reactive platelets. Although treat-
ment of anemia may improve some parameters of platelet dysfunc-
tion,42 it has not been demonstrated to ameliorate bleeding or risk for
bleeding.
with high serum urea levels but otherwise normal renal function have In summary, dialysis and anemia treatment will not completely
no bleeding tendency.41 normalize platelet function. Therefore drug treatment should be
Among the different extrinsic factors that contribute to platelet considered for those patients who have active bleeding or are scheduled
dysfunction, the contribution of anemia has gained particular interest. to undergo an invasive diagnostic or therapeutic procedure with bleed-
Physiologically, erythrocytes occupy the center of a vessel, displacing ing risk.

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 973

of l-arginine, which is a precursor of NO. Thus estrogens may lower

Desmopressin elevated NO production in CKD patients and subsequently reduce NO-
Desmopressin (1-deamino-8-d-arginine-vasopressin, DDAVP) is a syn- induced guanylyl cyclase stimulation and cyclic guanosine monophos-
thetic derivative of the antidiuretic hormone with little vasopressor activ- phate (cGMP) synthesis, which will finally increase thromboxane A
ity. It acts by stimulating the release of large factor VIII:von Willebrand and ADP availability. Estrogens may additionally lower hemorrhagic
factor multimers from endothelial cells into the plasma and potentially diathesis by affecting production of coagulation factors and their
by increasing the membrane glycoprotein expression of platelets. inhibitors.
At a dose of 0.3 mcg/kg (if given intravenously [in 50 ml of saline Estrogens may be given intravenously, orally, or cutaneously. Com-
over 15 to 30 minutes] or subcutaneously]) or 3 mcg/kg (if given intra- pared with other approaches, estrogen treatment may affect bleeding
nasally), desmopressin improves the bleeding time over the subsequent tendency for a prolonged time. However, its long-term safety has again
4 to 8 hours. Typical side effects include water retention, hyponatremia, not been assessed in prospective studies.
moderate thrombocytopenia, facial flushing, mild transient headache,
nausea, abdominal cramps, and mild tachycardia; thrombotic events IMPLICATIONS FOR ANTIPLATELET
are rarely observed.38
Although its efficacy on laboratory measures of platelet function is
AGENT THERAPY
undisputed, its clinical efficacy for preventing or treating bleeding remains Uremic platelet dysfunction and the increased bleeding risk also implies
unproven. Additionally, depletion of endothelial stores of the factor that treatment with antiplatelet agents—particularly aspirin, clopidogrel,
VIII:von Willebrand factor multimers after a second DDAVP injection prasugrel, and ticagrelor—may induce more bleeding events among
may result in tachyphylaxis, which precludes its chronic use. CKD patients than in the general population. At the same time, CKD
patients are at high CV risk and use of aspirin or other antiplatelet
Cryoprecipitate agents may reduce their risk for myocardial infarctions and stroke.
In many uremic patients, cryoprecipitate may improve the bleeding A recent KDIGO guideline8 recommends that “adults with CKD at
time within 1 hour after infusion. This effect is supposed to be medi- risk for atherosclerotic events be offered treatment with antiplatelet
ated by the provision of factor VIII:von Willebrand factor multimers, agents unless there is an increased bleeding risk that needs to be bal-
fibrinogen, and by other factors that enhance platelet aggregation. anced against the possible CV benefits.” However, it remains unclear
However, this effect is short-lasting (4 to 24 hours). Moreover, cryo- how to identify the patients who may benefit from antiplatelet agents,
precipitate may have infectious, hemorrhagic and anaphylactic com- and risk scores from the general population work poorly among CKD
plications, and not all patients respond to cryoprecipitate.38,39,42 Thus patients.
use of cryoprecipitate should be limited to patients with life-threatening Antiplatelet agents should not routinely be prescribed to all CKD
bleeding who are resistant to treatment with desmopressin and blood patients because the increased risk for major bleeding appears to out-
transfusions. weigh the CV benefits, at least in CKD patients with low risk for ath-
erosclerotic events.44 Their use among CKD patients with overt
Tranexamic Acid atherosclerotic vascular disease is strongly recommended (see Chapter
As an antifibrinolytic agent, tranexamic acid (TXA) is licensed for treat- 81). However, dual-antiplatelet therapy should be limited to the very
ment of heavy bleeding, as well as before dental interventions in patients early period after acute myocardial infarction or after coronary stenting
with coagulopathies. Its use in CKD has been reported in several (mostly among CKD patients, whose bleeding risk with dual-antiplatelet therapy
small) cohort studies, which often focused on surrogate markers of is much higher than in patients with intact renal function.
hemorrhagic diathesis. Therefore TXA may be considered for life-
threatening bleeding events in CKD patients. However, it should be
reserved for those in whom other treatments have failed to control
CIRCULATING COAGULATION FACTORS
bleeding, because renal excretion is the main route of TXA clearance. Despite their elevated bleeding risk, patients with advanced CKD also
TXA has an unpredictable pharmacokinetic profile in advanced CKD may show features of a hypercoagulable state. Although general mea-
patients, who are at particular risk for neurologic side effects of TXA sures of the coagulation system—prothrombin time and partial throm-
(i.e., seizures).43 boplastin time—are within normal ranges, venous thromboembolism
(VTE) occurs more frequently in patients with low GFR and/or high
albuminuria than among individuals with intact kidney function. A
RECOMBINANT ACTIVATED FACTOR VII variety of factors may contribute, which include elevated levels of factor
Recombinant activated factor VII (rFVIIa) was developed for treatment VIII and vWF, and a variety of comorbidities, including immobiliza-
of hemorrhage in individuals with hemophilia with antibodies inacti- tion, congestive heart failure, and obesity. Iatrogenic factors may addi-
vating factor VIII or IV. Because of the central role of activated factor tionally play a part in CKD-associated hypercoagulation, such as drug
VII in coagulation, rFVIIa has been used off label in a variety of other treatment (erythropoietin, corticosteroids), intravascular interventions,
severe bleeding disorders, including some case reports that claimed and devices.
successful use of rFVIIa for treatment of bleeding in CKD patients.39
This very limited evidence, together with a substantial risk for throm-
boembolic events, mandates very prudent use of rFVIIa, which should
THERAPEUTIC INTERVENTION
be considered only in very severe bleeding when other interventions Components of the coagulation system are targets of many drugs for
have failed. prevention or treatment of thrombotic disease, including unfraction-
ated and low molecular weight heparin (LMWH), vitamin K antag-
onists (VKA) and of non–vitamin K antagonist oral anticoagulants
ESTROGENS (NOAC).
Estrogens may improve bleeding time in CKD patients in a dose- First, unfractionated and LMWH are routinely used during HD for
dependent manner. Their mode of action involves a reduced production preventing clotting in the extracorporeal circulation. Thus nearly all

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974 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

HD patients are exposed to potential side effects of heparin, which likelihood but focused on patients in whom HIT is suspected clinically
comprise an increased bleeding risk and some less frequent adverse (as suggested by the 4T score; Table 83.2). This is of particular impor-
events, of which the development of HIT is the most serious complica- tance for HD patients, in whom an incorrect diagnosis may result in
tion. HIT is a clinical syndrome induced by antibodies that bind to the withdrawal of heparin treatment during HD and in the initiation
heparin and platelet factor IV complexes on the platelet surface and of less established (and more expensive) anticoagulation strategies. In
thereby cause platelet activation. Clinically, HIT often manifests with the absence of CKD-specific pathways, the diagnosis of HIT should
arterial or venous thrombosis; less frequent complications are venous follow recommendations from the general population. Here, the likeli-
limb gangrene, adrenal hemorrhagic necrosis, necrotizing skin lesions hood of HIT should first be estimated with clinical prediction tools
at heparin injections sites, and acute systemic reactions within a few and use of antigen assays for confirmation of HIT antibodies should
minutes after exposure to unfractionated heparin or LMWH injections. focus on patients with high and intermediate clinical likelihood (Fig.
Of note, many patients have heparin-dependent antibodies without 83.5). Importantly, these antigen assays for detection of HIT antibodies
clinically apparent HIT. Therefore, to avoid over-diagnosing HIT, immu- have a high sensitivity but poor specificity. Wherever available, functional
nologic tests should not be ordered in patients with a low clinical assays (serotonin release assays or heparin-induced platelet activation)

TABLE 83.2 4 Ts Score to Determine the Likelihood of Heparin-Induced

Thrombocytopenia (HIT)
Score = 2 Score = 1 Score = 0
Thrombocytopenia: >50% platelet fall and nadir >50% platelet fall but surgery within <30% platelet fall
Compare the highest of ≥20 k per uL and no preceding 3 days or Any platelet fall with nadir <10
platelet count within the surgery within preceding 3 Any combination of platelet fall and
sequence of declining days nadir that does not fit criteria for
platelet counts with the score 2 or score 0 (e.g., 30%-50%
lowest count to determine platelet fall or nadir 10-19)
the percent of platelet fall
(select only one option)
T iming (of platelet count Platelet fall day 5-10 after Consistent with platelet fall days 5-10 Platelet fall day 4 or earlier without exposure
fall or thrombosis*) start of heparin but not clear (e.g., missing counts) to heparin in past 100 days
Day 0 = First day of most Platelet fall within 1 day of Platelet fall within 1 day of start of
recent heparin exposure start of heparin and heparin AND exposure to heparin in
(select only one option) exposure to heparin past 31-100 days
within past 5-30 days Platelet fall after day 10
T hrombosis (or other Confirmed new thrombosis Recurrent venous thrombosis in a Thrombosis suspected
clinical sequelae) (select (venous or arterial) patient receiving therapeutic
only one option) Skin necrosis at injection site anticoagulants
Anaphylactoid reaction to Suspected thrombosis (awaiting
intravenous heparin bolus confirmation with imaging)
Adrenal hemorrhage Erythematous skin lesions at heparin
injection sites
oT her cause for No alternative explanation Possible other cause is evident: Probable other cause present:
Thromboycytopenia† for platelet fall is evident Sepsis without proven microbial source Within 72 h of surgery
(select only one option) Thrombocytopenia associated with Confirmed bacteremia/fungemia
initiation of ventilator Chemotherapy or radiation within past 20 days
Other DIC as a result of non-HIT cause
Post-transfusion purpura (PTP)
Platelet count <20 and given a drug implicated
in causing D-ITP‡(see list)
Non-necrotizing skin lesions at LMWH
injection site (presumes DTH)
Other

See Figure 83.5 for interpretation of score results.

*Timing of clinical sequelae, such as thrombocytopenia, thrombosis, or skin lesions.
†
Two points if necrotizing heparin-induced skin lesions even if thrombocytopenia not present.
‡
Drugs implicated in drug-induced immune thrombocytopenia (D-ITP):
Relatively common: Glycoprotein IIb/IIIa antagonists (abciximab, eptifibatide, tirofiban), quinine, quinidine, sulfa antibiotics, carbamazepine,
vancomycin.
Less common: Actinomycin, amitriptyline, amoxicillin/piperacillin/nafcillin, cephalosporins (cefazolin, ceftazidime, ceftriaxone), celecoxib,
ciprofloxacin, esomeprazole, fexofenadine, fentanyl, fusidic acid, furosemide, gold salts, levofloxacin, metronidazole, naproxen, oxaliplatin,
phenytoin, propranolol, propoxyphene, ranitidine, rifampin, suramin, trimethoprim. NOTE: This is a partial list.
This table follows the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed, American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines (Chest. 2012;141[2 Suppl]:e495S-e530S).

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 975

Evaluation of Suspected Heparin Induced Thrombocytopenia (HIT)

4 Ts score ≥ 4 High / 4 Ts score ≤ 3

intermediate clinical probability Low clinical probability

Depends on physicians preference

Discontinue heparin immediately Discontinue heparin immediately

Continue
and start nonheparin and consider nonheparin
heparin
anticoagulant anticoagulant

HIT antigen assay HIT antigen assay

Positive Negative Positive Negative

Optical density Optical density

Moderate Moderate
High titre High titre
/ low titre / low titre

HIT con- HIT

FA* FA* HIT excluded
firmed excluded
Fig. 83.5 Diagnostic work-up of suspected heparin-induced thrombocytopenia (HIT). Because of
the high number of patients with antibodies against heparin without clinical HIT, a diagnostic algorithm is
needed to have a high a priori likelihood of HIT before ordering antibody tests. There is no algorithm specific
to patients with CKD, and the diagnosis should be made as in patients with normal renal function. *Confirm
with functional assay (FA), if available. “4T” refers to a risk score based on four clinical parameters (throm-
bocytopenia, timing of platelet count fall or thrombosis, thrombosis [or other clinical sequelae], and other
cause for thrombocytopenia; see Table 83.2 for a detailed description).

should be used to confirm positive findings from antigen assays in the anticoagulation with LMWH. When considering indefinite anticoagula-
majority of patients with suspected HIT. tion in patients with advanced CKD, their elevated bleeding risk must
Once a patient has a high or intermediate clinical probability be considered.
of HIT, all heparin treatment must be stopped and alternative antico- For patients with advanced CKD, the use of anticoagulants in atrial
agulation initiated. The most relevant treatment options are listed in fibrillation is controversial (see also Chapter 81). In the general popula-
Table 83.3. Of note, no VKA should be initiated at this stage because tion, patients who have one or more risk factors for cerebral stroke or
these agents may reduce activation of anticoagulatory protein C and systemic embolization (defined as a CHA2DS2-VASc score of ≥1 in men
thus further perpetuate the prothrombotic state. and ≥2 in women) should receive oral anticoagulation. Similarly, use
Additionally, anticoagulants are approved for prevention of throm- of warfarin (if adjusted to target INR 2.0-3.0) has been shown to reduce
boembolic stroke in patients with atrial fibrillation, for prevention and stroke risk substantially in patients with CKD 3a/3b.45 In these patients,
treatment of VTE (particularly deep-vein thrombosis and pulmonary NOACs are at least as efficient as VKA for prevention of thromboembolic
embolism), and for prevention of clotting in patients with mechanical events, but may cause fewer intracerebral bleeding events. For patients
heart valves. In the latter case, the need for life-long anticoagulation with GFR <30 ml/min/1.73 m2, few data demonstrate the efficacy (i.e.,
with VKA is indisputable. Similarly, in patients with proximal deep-vein prevention of thromboembolic events) and safety (i.e., major bleeding
thrombosis and symptomatic pulmonary embolism, anticoagulation is events) of either VKA or NOAC because most prospective clinical trials
indicated for a minimum of 3 months. Recommendations on extended excluded patients with advanced CKD. Moreover, VKA accelerates vas-
anticoagulation are mainly derived from the general population, in cular calcification46 and possibly also CKD progression, in particular
whom indefinite anticoagulation with either VKA or NOAC (Table 83.4) if overdosed.47 In dialysis patients with atrial fibrillation, retrospective
may be considered in patients with unprovoked proximal deep-vein cohort studies yielded conflicting findings on whether oral anticoagula-
thrombosis and symptomatic pulmonary embolism, whereas antico- tion lowers stroke incidence.48
agulation should be stopped after 3 months in patients with provoked For the time being, patients with atrial fibrillation and at least mod-
VTE with one or more transient risk factors. In patients with active erate risk for thromboembolism (defined by CHA2DS2-VASc score ≥2
cancer and VTE, data from the general population suggest indefinite for women, and ≥1 for men) should be offered NOACs if they have

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976 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

TABLE 83.3 Characteristics of Anticoagulants Used to Treat Patients With Heparin-Induced

Thrombocytopenia
Characteristic Argatroban Danaparoid Bivalirudin Fondaparinux
Target Thrombin Factor Xa (predominantly) Thrombin Factor Xa
Elimination Hepatobiliary Renal Enzymatic (80%)/renal (20%) Renal
Approved for patients with HIT* Treatment/PCI Treatment PCI/cardiac surgery No
Method of administration IV IV, SC IV SC
Monitoring aPTT Anti-Xa level aPTT Anti-Xa level
ACT ACT or ECT (high doses)
Effect on INR +++ 0 ++ 0
Immunologic features None 5% cross-reactivity with Potentially cross-reactive May cause HIT‡
HIT Ab† with antilepirudin Ab
Antidote available No No No No
Dialyzable 20 % Yes 25 % 20 %

*In some countries (check with local health regulatory authorities).

†
Clinical significance is uncertain and routine testing for cross-reactivity is not recommended.
‡
Case reports only.
Ab, Antibodies; ACT, activated clotting time; aPTT, activated partial thromboplastin time; ECT, ecarin clotting time; FDA = U.S. Food and Drug
Administration; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio; IV, intravenous; PCI, percutaneous coronary
intervention; SC, subcutaneous.
This table follows the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed, American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines (Chest. 2012;141[2 Suppl]:e495S-e530S).

TABLE 83.4 Absorption and Metabolism of Novel Oral Anticoagulants

Dabigatran Apixaban Edoxaban Rivaroxaban
Bioavailability 3%-7% 50% 62% 66% without food
Almost 100% with food
Prodrug Yes No No No
Clearance nonrenal/renal, 20%/80% 73%/27% 50%/50% 65%/35%
percent of absorbed dose*
Liver metabolism: CYP3A4 No Yes (elimination, moderate Minimal (<4% of Yes (hepatic
involved contribution ∼25%) elimination) elimination ∼18%)
Absorption with food No effect No effect 6%-22% more; minimal +39% more
effect on exposure
Intake with food recommended? No No No Mandatory
Absorption with H2B/PPI −12% to 30% (not No effect No effect No effect
clinically relevant)
Dose if Asian ethnicity +25% No effect No effect No effect
GI tolerability Dyspepsia No problem No problem No problem
5%-10%
Elimination half-life 12 to 17 h 12 h 10-14 h 5-9 h (young)
11-13 h (elderly)
*For clarity, data are presented as single values, which are the mid-point of ranges as determined in different studies.
H2B, H2 blocker; GI, gastrointestinal; PPI, proton pump inhibitor.
This table follows The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in
patients with atrial fibrillation (Eur Heart J 2018 in press).

mild to moderate CKD (CKD 1 to 3b), unless they have prohibitive (apixaban) has been licensed for use among dialysis patients in the
high risk for bleeding. For CKD 4 and 5 patients with atrial fibrillation, United States, but not yet in Europe. Compared with other NOACs,
lack of evidence precludes strong recommendations whether to use apixaban is characterized by the least accumulation in CKD, but still
NOACs, VKA, or no anticoagulation. requires (like all NOACs) dose adjustment for renal function. Notably,
Both LMWH and NOACs require dose adjustment in patients with pharmacokinetic studies (and subsequent recommendations on NOAC
CKD because they undergo renal excretion. As of 2017, only one NOAC dosages) used GFR estimated with the Cockcroft-Gault equation. In

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 977

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 CHAPTER 83 Other Blood and Immune Disorders in Chronic Kidney Disease 978.e1

SELF-ASSESSMENT
QUESTIONS
1. The following diagnostic finding is reliable (sensitive and specific
enough to be useful) in patients with chronic kidney disease (CKD)
even in the presence of their typical immune dysfunction:
A. Fever as a sign of bacteremia
B. Radiologic infiltration on chest x-ray film for pneumonia
C. Mendel-Mantoux skin reaction for tuberculosis
D. Blood culture for bacteremia
E. C-reactive protein for infection
2. Viral hepatitis is a typical complication of hemodialysis treatment.
Which statement describes viral hepatitis in advanced CKD
correctly?
A. Hepatitis B virus (HBV) infection leads to chronic infection in
the majority of affected CKD patients.
B. Acute HBV infection in CKD patients is typically severe, char-
acterized by jaundice and fever.
C. HBV infection can be easily prevented in CKD patients by vac-
cination as recommended to the general population.
D. The clinical course of hepatitis C infection is largely different in
CKD patients and those with normal renal function.
E. Standard hygienic precautions have largely failed to reduce HBV
transmission in dialysis centers. Only vaccination succeeded in
preventing nosocomial transmission.
3. The hemorrhagic diathesis in CKD patients is typically mirrored
by which of the following?
A. A prolongation of the prothrombin time
B. A prolongation of the partial thromboplastin time
C. Severely thrombocytopenia
D. Hyperchromic anemia
E. None of these
4. The spectrum of interventions that may allow reducing hemorrhages
in advanced CKD does not include which of the following?
A. Desmopressin
B. Conjugated estrogens
C. Tranexamic acid (TXA)
D. Cryoprecipitates
E. Clopidogrel

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 84
Bone and Mineral Disorders in Chronic
Kidney Disease
Kevin J. Martin, Jürgen Floege, Markus Ketteler

DEFINITION PATHOGENESIS
Disturbances of mineral metabolism are common if not ubiquitous in Several biochemical and hormonal abnormalities associated with CKD
chronic kidney disease (CKD) and lead to serious and debilitating com- contribute to renal osteodystrophy and can be affected by efforts at
plications unless these abnormalities are addressed and treated. The prevention and therapy. The major factors may vary as CKD progresses
spectrum of disorders includes abnormal concentrations of serum (Fig. 84.3). Similarly, the predominance of one particular pathogenetic
calcium, phosphate, and magnesium and disorders of parathyroid mechanism over another may contribute to the heterogeneity of bone
hormone (PTH), fibroblast growth factor-23 (FGF-23), and vitamin D disorders. We therefore discuss separately the two major entities—high-
metabolism. These abnormalities as well as other factors related to the and low-turnover osteodystrophy.
uremic state affect the skeleton and result in the complex disorders of
bone known as renal osteodystrophy; it is now recommended that this OSTEITIS FIBROSA: HYPERPARATHYROIDISM—
term be used exclusively to define the bone disease associated with
CKD. The clinical, biochemical, and imaging abnormalities heretofore
HIGH-TURNOVER RENAL BONE DISEASE
identified as correlates of renal osteodystrophy should be defined more Elevated levels of PTH in blood, hyperplasia of the parathyroid glands,
broadly as a clinical entity or syndrome called chronic kidney disease– and elevations in FGF-23 are seen once eGFR declines below approxi-
mineral and bone disorder (CKD-MBD).1 The spectrum of skeletal mately about 50 ml/min/1.73 m2. Whereas the level of free (i.e., non–
abnormalities seen in renal osteodystrophy includes the following protein bound) calcium in blood is normally the principal determinant
(Fig. 84.1): of PTH secretion, several metabolic disturbances associated with CKD
- also alter the regulation of the secretion of PTH.
ized by increased osteoclast and osteoblast activity, peritrabecular
fibrosis, and increased bone turnover. Abnormalities of Calcium Metabolism
There are three main body pools of calcium: the bony skeleton (mineral
formed osteoid most often caused by aluminum deposition; bone component), the intracellular pool (mostly protein bound), and the
turnover is decreased. extracellular pool (see Chapter 10). The calcium in the extracellular
- pool is in continuous exchange with that of bone and cells and is
mally low bone turnover. altered by diet and excretion. Calcium metabolism depends on the
close interaction of two hormonal systems: PTH and vitamin D. Per-
mixed renal turbations of both systems occur during the course of CKD, with
osteodystrophy. adverse consequences on the skeleton. Total serum calcium tends to
- decrease during the course of CKD as a result of phosphate retention
dosis, β2 β2M amyloidosis]). and decreased production of 1,25-dihydroxyvitamin D (calcitriol) from
the kidney, decreased intestinal calcium absorption, and skeletal resis-
tance to the calcemic action of PTH, but the levels of free calcium
EPIDEMIOLOGY remain within the normal range in most patients3 as a result of com-
The prevalence of the various types of renal osteodystrophy in patients pensatory hyperparathyroidism. Because calcium is a major regulator
with end-stage renal disease (ESRD) is illustrated in Fig. 84.2.2 In patients of PTH secretion, persistent hypocalcemia is a powerful stimulus for
development of hyperparathyroidism and also contributes to parathy-
equal frequency. In contrast, in patients on peritoneal dialysis (PD), roid growth.

a small fraction of cases in either group but is more common in certain Abnormalities of Phosphate Metabolism
- With progressive CKD, phosphate is retained, at least, transiently, by
ated with CKD start while the estimated glomerular filtration rate (eGFR) the failing kidney. However, hyperphosphatemia usually does not
is still relatively preserved (~50 ml/min/1.73 m2). become evident before CKD stage 4. Until then, compensatory

979
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980 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Skeletal Abnormalities in Percentage of Patients Exhibiting

Renal Osteodystrophy Elevated Circulating Levels of Calcium,
Phosphate, iPTH, 25OH-Vitamin D3,
Adynamic bone Normal Mild Osteitis fibrosa
Calcitriol, and FGF-23 in Advancing CKD
Osteomalacia

100
Mixed Calcium <8.4 mg/dl (2.1 mmol/l)
80 Phosphate >4.6 mg/dl (1.5 mmol/l)

Patients (%)
Hyperparathyroidism 60 iPTH >65 pg/ml
High
turnover
40
Calcium, calcitriol
Low 20
turnover Aluminum
0
>80 79-70 69-60 59-50 49-40 39-30 29-20 <20
Fig. 84.1 The spectrum of renal osteodystrophy. The range of
eGFR (ml/min)
skeletal abnormalities in renal bone disease encompasses syndromes
with both high and low bone turnover.
100
25(OH)D3 <15 ng/ml
80 1,25(OH)2D3 <22 pg/ml

Patients (%)
Prevalence of Renal Osteodystrophy in
60
Patients with End-Stage Renal Disease
40
50
20
40 HPT 0
>80 79-70 69-60 59-50 49-40 39-30 29-20 <20
% Patients/yr

30 MUO eGFR (ml/min)

20 LTOM 100
FGF-23 > 100 RU/ml
ABD iPTH >65 pg/ml
10 80
Phosphate >4.6 mg/dl
Patients (%)

0 60 (1.5 mmol/l)
1995 1996 1997 1998 1999 2000 2001
40
Years
20
Fig. 84.2 Prevalence of renal osteodystrophy in patients with
end-stage renal disease. ABD, Adynamic bone disease; HPT, high- 0
turnover renal osteodystrophy; LTOM, low-turnover osteomalacia; MUO, >70 69-60 59-50 49-40 39-30 29-20 <20
mixed uremic osteodystrophy. (From reference 32.) eGFR (ml/min/1.73 m2)
Fig. 84.3 Percentage of patients exhibiting elevated circulating
levels of calcium, phosphate, intact parathyroid hormone (iPTH),
hyperparathyroidism and increases in circulating FGF-23 result in 25OH-vitamin D3, calcitriol, and fibroblastic growth factor-23
increased phosphaturia, maintaining serum phosphate levels in the (FGF-23) in advancing chronic kidney disease (CKD). Particularly
normal range.4 in early CKD stages there is wide variability at the individual level, and
- some patients, for example, may exhibit increased FGF-23 and normal
parathyroidism is by a decrease in serum free calcium, which in turn iPTH, whereas others may have elevated iPTH levels with normal FGF-23
stimulates the secretion of PTH (Fig. 84.4). Thus a new steady state is or elevations of both. (Data from references 54 and 55.)
achieved in which serum phosphate is restored to normal at the expense
of a sustained high level of PTH. This cycle is repeated as renal function serum calcium or serum calcitriol.5,6 Phosphate may have an effect on
declines until sustained and severe hyperparathyroidism is present. parathyroid growth independent of serum calcium.7,8 Regardless of the
Second, phosphate retention leads to decreased production of calcitriol mechanism by which phosphate retention causes hyperparathyroidism,
by the kidney, either directly or by increasing the levels of FGF-23 experimental studies suggest that restriction of dietary phosphate in
(which decreases the activity of 1α-hydroxylase). The decrease in cal- proportion to the decrease in GFR can prevent development of hyper-
citriol allows increases in PTH gene transcription by direct action and parathyroidism. Current evidence suggests that FGF-23 also acts directly
also decreases intestinal calcium absorption, leading to hypocalcemia, on the parathyroid gland and has inhibitory effects on PTH secretion
which in turn stimulates PTH secretion. Third, hyperphosphatemia is and parathyroid growth.9,10 This suggests that the main effects of FGF-23
associated with resistance to the actions of calcitriol in the parathyroid on the pathogenesis of hyperparathyroidism are indirect as a result of
glands, which also favors development of hyperparathyroidism and the potent effect of FGF-23 to decrease calcitriol production. These
induces resistance to the actions of PTH in bone. Finally, phosphate various actions may explain, at least in part, the association between
per se appears to affect PTH secretion independently of changes in higher levels of FGF-23 and adverse clinical outcomes.11

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 981

Phosphate Retention and Secondary Hyperparathyroidism

Hyperphosphatemia

Skeletal Calcitriol resistance ↑ Parathyroid

↓ Calcitriol
PTH resistance in parathyroids cell growth

Decreased intestinal
calcium absorption

Hypocalcemia

↑ PTH secretion

Fig. 84.4 Role of phosphate retention in the pathogenesis of secondary hyperparathyroidism.

Hyperphosphatemia stimulates parathyroid hormone (PTH) secretion indirectly by inducing hypocalcemia,
skeletal resistance to PTH, low levels of calcitriol, and calcitriol resistance. Hyperphosphatemia also has
direct effects on the parathyroid gland to increase PTH secretion and parathyroid cell growth. eGFR, Estimated
glomerular filtration rate.

Mechanisms Contributing to Decreased Calcitriol and Secondary

Levels of Calcitriol in CKD Hyperparathyroidism

Kidney disease Low levels of calcitriol

Direct effects Indirect effects

↓ GFR ↑ Pi ↓ 25 (OH)D3

Decreased repression Decreased intestinal

of parathyroid hormone calcium absorption
↑ FGF-23 (PTH) gene transcription Skeletal resistance to
Decreased parathyroid the calcemic action of PTH
vitamin D receptors
Decreased repression of
↓ 1.25 (OH)2 D3 ↑ C-PTH fragments parathyroid cell proliferation
Decreased expression
Fig. 84.5 Mechanisms contributing to decreased levels of cal- of calcium receptor?
citriol in chronic kidney disease (CKD). C-PTH, Carboxyl-terminal Increased set-point for
calcium-regulated PTH
parathyroid hormone; FGF-23, fibroblast growth factor-23; GFR, glomerular secretion
filtration rate; Pi, inorganic phosphate.

Abnormal
parathyroid function Hypocalcemia

Abnormalities of Vitamin D Metabolism

Hyperparathyroidism
The conversion of 25-hydroxyvitamin D to its active metabolite
1,25-dihydroxyvitamin D occurs mainly in the kidney by the enzyme Fig. 84.6 Role of low levels of calcitriol in the pathogenesis of
1α-hydroxylase. Extrarenal production of calcitriol also occurs and secondary hyperparathyroidism.
contributes to the circulating levels of calcitriol. Renal calcitriol produc-
tion progressively declines in parallel with eGFR as a result of several
mechanisms (Fig. 84.5).
Calcitriol production is compromised in CKD by a reduction in mechanisms as described earlier (Fig. 84.6). Low levels of calcitriol
25-hydroxyvitamin D levels12 and the decrease in GFR, which further directly release the gene for PTH from suppression by the vitamin D
limits the delivery of 25-hydroxyvitamin D to the site of the 1α-hydroxylase receptor and allow increased PTH secretion. In many tissues, vitamin
in the proximal tubule. Phosphate retention either directly or by induc- D regulates its own receptor by positive feedback; in CKD the vitamin
ing an increase in FGF-23 also decreases the activity of 1α-hydroxylase.
Finally, circulating PTH fragments may directly decrease calcitriol pro- of calcitriol has been shown to increase the vitamin D receptor content
duction. The resultant decreased levels of calcitriol contribute to the in the parathyroid glands coincident with the suppression of PTH secre-
pathogenesis of hyperparathyroidism by several direct and indirect tion. Studies in vitro have shown that calcitriol is a negative growth

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982 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

BOX 84.1 Parathyroid Abnormalities in Clinical Manifestations of High-Turnover

Chronic Kidney Disease Renal Osteodystrophy
Parathyroid gland hyperplasia: diffuse, nodular Clinical manifestations of hyperparathyroidism are usually nonspecific
Decreased expression of vitamin D receptors and often preceded by biochemical or imaging abnormalities. Nonspe-
Decreased expression of calcium receptors cific aches and pains are common, occur in the lower back, hips, and
Increased set-point of calcium-regulated parathyroid hormone secretion
can occur and may be suggestive of acute arthritis. Pain around joints
may be caused by acute periarthritis, which is associated with periar-
ticular deposition of calcium phosphate crystals, especially in patients
regulator of parathyroid cells, and therefore calcitriol deficiency in with marked hyperphosphatemia. The symptoms may be confused
clinically with gout or pseudogout and often respond to nonsteroidal
direct consequences of low levels of calcitriol contributing to the patho- -
genesis of secondary hyperparathyroidism include an increase in the ness is also common in patients with ESRD. Many factors are probably
parathyroid set-point for calcium-regulated PTH secretion and possibly involved in its pathogenesis, including hyperparathyroidism and abnor-
a decrease in the expression of calcium receptors. malities of vitamin D. β2 β2M) (see later
Low levels of calcitriol also may promote the development of hyper- discussion) should be considered in the differential diagnosis in very-
parathyroidism indirectly. First, decreased calcitriol production as renal long-term dialysis patients.
function decreases can lead to progressive reductions in intestinal Bone abnormalities may occur in patients with severe hyperpara-
absorption of calcium, leading to hypocalcemia and stimulation of thyroidism, particularly in children, and are manifested on x-ray films
PTH release. Second, low levels of calcitriol have been implicated in by subperiosteal erosions, resorption of terminal digits. In adults, defor-
skeletal resistance to the calcemic actions of PTH, which may contribute mities arise as a result of fractures, sometimes induced by brown tumors
to the development of hyperparathyroidism. (see later discussion); the axial skeleton is most commonly affected.
This can lead to kyphoscoliosis or chest wall deformities. Slipped epiphysis
Abnormalities of Parathyroid may occur in children, and frank rachitic features are occasionally evident.
Gland Function Growth retardation is also common in children, and although some
CKD is associated with intrinsic abnormalities in parathyroid gland improvement has been shown with calcitriol, this has not been the
function, in addition to those caused by hypocalcemia, low levels of universal finding.
calcitriol, and skeletal resistance to the actions of PTH (Box 84.1). Extraskeletal calcifications are frequently encountered in patients
Parathyroid hyperplasia is an early finding in CKD. In experimental with advanced CKD and are aggravated by persistent elevation of the
models, hyperplasia begins within a few days after the induction of calcium-phosphate product. Most commonly, vascular calcifications
CKD and can be prevented by dietary phosphate restriction or by the are seen, but calcifications may occur in other sites, such as the lung,
use of calcimimetic agents.8,13 Resected parathyroid glands from patients myocardium, and periarticular areas (Fig. 84.7).
with severe hyperparathyroidism have nodular areas throughout the In the skin, hyperparathyroidism can manifest as pruritus (see Chapter
gland, which represent monoclonal expansions of parathyroid cells. 87). Rarely, it can also underlie the development of calciphylaxis, or
Within these nodules, there is decreased expression of vitamin D recep- calcific uremic arteriolopathy (see Chapter 87, Figs. 87.6 and 87.7).
tors as well as of calcium receptors. The decreased expression of calcium
receptors renders efforts to therapeutically affect these enlarged hyper- Diagnosis and Differential Diagnosis
plastic glands difficult. In addition to the clinical manifestations of renal osteodystrophy, a
The parathyroid calcium receptor is centrally involved in the regula- variety of biochemical and radiographic techniques are helpful to estab-
tion of PTH secretion by calcium.14 Its expression and synthesis are lish the specific diagnosis and serve as a guide for the initiation and
decreased in the parathyroid glands from hyperparathyroid patients,
leading to altered calcium-regulated PTH secretion. Increased concen- clinical practice, it remains the gold standard for the diagnosis of renal
trations of calcium are required in vitro to suppress PTH release from osteodystrophy.
the parathyroid cells of uremic patients compared with those of normal
controls. Thus the set-point for the concentration of calcium required Serum Biochemistry
to decrease PTH release by 50% appears to be increased. The levels of free calcium and phosphate in serum are usually normal
in patients with mild to moderate CKD. Normally in stage 4 CKD the
Abnormal Skeletal Response to Parathyroid Hormone levels of serum calcium tend to fall and hyperphosphatemia manifests.
In patients with CKD, there is an impaired response of serum calcium Hypercalcemia may result from the administration of large doses of
to the administration of PTH and a delay in the recovery from induced calcium-containing antacids or vitamin D metabolites or from severe
hypocalcemia in the presence of larger increments in PTH levels. Thus hyperparathyroid bone disease. It is important to identify the cause of
in CKD the skeleton is relatively resistant to the calcemic actions of hypercalcemia in patients with CKD (see Chapter 10) because the man-
PTH. The resultant decrease in serum calcium levels stimulates PTH
secretion and contributes to the pathogenesis of secondary hyperpara- serum calcium and phosphate, when used alone, are not useful in pre-
thyroidism. Factors involved in the skeletal resistance to PTH in CKD dicting the specific type of bone disease.
include decreased levels of calcitriol, downregulation of the PTH recep-
tor, and phosphate retention. In addition, circulating fragments of PTH, Parathyroid Hormone
truncated at the N-terminus, which still react in the older, second- Measurements of PTH are important for diagnostic purposes and thera-
generation two-site PTH assays, have been suggested to oppose the peutic guidance in the management of renal osteodystrophy. With renal
calcemic actions of PTH, possibly acting at a presumed receptor for impairment, there is accumulation of circulating PTH fragments, which
the C-terminal region of PTH.15,16 complicates the interpretation of PTH assays, including the two-site

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 983

A B C
Fig. 84.7 Extraskeletal calcification in chronic renal failure. (A) Arterial calcification (arrows). (B) Pul-
monary calcification. (C) Periarticular calcification (arrows).

immunometric assays, which were thought to measure “intact” PTH

(iPTH). Refinements in PTH assays have demonstrated that these iPTH 25-hydroxyvitamin D3.
assays also measure some large fragments of PTH, which are truncated
at the N-terminus. More specific assays for so-called “biointact” PTH Markers of Bone Formation and
(PTH 1-84) have been developed that exclude these fragments from Bone Resorption
measurement, but their clinical usefulness continues to be defined.17-19 Levels of circulating alkaline phosphatase offer an approximate index
The presence of oxidized PTH, which is biologically inactive, in patients of osteoblast activity in patients with CKD. High levels are commonly
with ESRD may further complicate PTH measurements.20 Standardiza- present in hyperparathyroid bone disease. The discriminatory power
tion needs to be improved among different PTH assays from various of alkaline phosphatase measurements is enhanced by measurement
laboratories and various manufacturers of assay reagents. With existing
iPTH assays (upper limit of the reference range, ~60 pg/ml), only values conjunction with PTH values. Serial measurements of alkaline phos-
at the extremes are useful in the noninvasive diagnosis of renal osteo- phatase may be useful in assessing the progression of bone disease.
dystrophy. In dialysis patients, iPTH levels above approximately 600 pg/
ml are characteristic of patients with osteitis fibrosa. The threshold superior to alkaline phosphatase. Tartrate-resistant acid phosphatase
values for earlier stages of CKD are not well defined. It is well accepted, and collagen degradation products are both markers of osteoclastic
however, that there is an element of skeletal resistance to PTH in patients activity but are considered investigational at present.
with CKD; therefore supranormal levels of PTH appear to be required
to maintain normal bone turnover. Serial measurements of PTH are Radiology of the Skeleton
useful in the initial evaluation of patients with renal osteodystrophy Routine x-ray examination of the skeleton is relatively insensitive for
and are essential during the management of these disorders to assess the diagnosis of renal osteodystrophy, and x-ray films can appear virtu-
response to therapy and to avoid overtreatment and undertreatment ally normal in patients with severe histologic evidence of renal osteo-
because either can have detrimental effects on bone histology. There dystrophy. However, subperiosteal erosions are often present in severe
are marked differences among commercial PTH assay results so that secondary hyperparathyroidism, detected in the hands (Fig. 84.8),
precise recommendations of desired ranges cannot reliably be provided clavicles, and pelvis. Skull x-ray films may show focal radiolucencies
and results obtained in different laboratories cannot be easily and a ground-glass appearance, known as pepper pot
compared.21 of the vertebrae is responsible for the “rugger-jersey” appearance of the
spine (Fig. 84.9). Very rarely, brown tumors, focal collections of giant
Vitamin D Metabolites cells and typical of severe hyperparathyroidism, are seen as well-
The levels of calcitriol in patients with CKD are not helpful in differ- demarcated radiolucent zones in long bones, clavicles, and digits (Fig.
entiating the histologic lesions of renal osteodystrophy. Measurements 84.10). They may be confused with osteolytic metastases. Looser zones
of calcitriol are not used routinely for diagnostic purposes unless extra- or pseudofractures are characteristic of osteomalacia. Routine skeletal
renal production of this metabolite is suspected, as in granulomatous x-ray films are not indicated unless there are symptoms.
disorders (see Chapter 10).
Vitamin D deficiency in CKD rarely results in osteomalacia in the Measurements of Bone Density
United States and Europe but may contribute to hyperparathyroidism.
In patients with CKD and marked proteinuria, there is loss of vitamin -
D–binding protein in the urine, which may result in decreased levels lying osteodystrophy or distinguish this from osteoporosis, it does
of 25-hydroxyvitamin D. Vitamin D deficiency may be encountered in allow prediction of fracture risk in patients with CKD. Vascular and
patients with limited sun exposure, in those with intestinal malabsorp- soft tissue calcifications may contribute to errors in bone density
tion or malnutrition, and in susceptible racial groups, particularly South measurements.

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984 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Fig. 84.8 Subperiosteal erosions in hyperparathyroidism. Severe

subperiosteal erosions as a manifestation of hyperparathyroidism (arrows).
The extensive scalloped appearance of the middle phalanx on the left
(arrowheads) represents a small brown tumor. Fig. 84.10 Brown tumor (arrow) in a hemodialysis patient with
severe hyperparathyroidism. The tumor can easily be confused with
a lytic bone metastasis.

from high bone turnover, there is considerable overlap, and therefore

biopsy might be required for definitive diagnosis when biochemistry
is not conclusive (e.g., PTH in recommended range but bone alkaline
phosphatase elevated, hypercalcemia with PTH only modestly elevated,
or bone pain).

increased bone turnover, increased number and activity of osteoblasts

and osteoclasts, and variable amounts of peritrabecular fibrosis (Fig.

-
terized by increased osteoid seam width, increase in the trabecular surface
covered with osteoid, and decreased bone mineralization as assessed
by tetracycline labeling (see Fig. 84.11B). The presence of aluminum
can be detected on the mineralization front by specific staining (see

staining exceeding 15% of the trabecular surface and a bone formation

rate of less than 220 mm2/day. Features of osteitis fibrosa may occur
Fig. 84.9 “Rugger-jersey spine” in hyperparathyroidism. Vertebral together with features of osteomalacia; the combination is termed mixed
bodies show the increased density of the ground plates and central
renal osteodystrophy.
radiolucency, which gives the striped appearance of a rugger jersey.
Treatment of High-Turnover Bone Disease
Prevention is the primary goal in management of renal osteodystrophy.
Therapy for hyperparathyroidism ideally should be initiated in CKD
Bone Biopsy stage 3 so parathyroid gland hyperplasia can be prevented. Because
Biopsy of bone and the microscopic analysis of undercalcified sections renal osteodystrophy is usually asymptomatic early in the course of
after double tetracycline labeling provide a definitive and quantitative CKD, attention often is not paid to secondary hyperparathyroidism.
diagnosis of renal osteodystrophy.22 To standardize reports on bone By the time CKD is advanced, patients may have already developed
significant skeletal abnormalities or nodular parathyroid hyperplasia,
Chronic Kidney Disease–Epidemiology Collaboration (CKD-MBD) and more aggressive therapy is required to prevent the long-term con-
work group proposed the TMV classification, an assessment of turnover sequences of renal osteodystrophy. The successful approach to the pre-
(T), mineralization (M), and bone volume (V).1 Bone mineralization vention and management of this disorder involves the integration of a
is assessed by the administration of two different tetracyclines spaced variety of measures directed toward the suppression of PTH secretion
apart (e.g., tetracycline 500 mg three times daily for 2 days, followed and prevention of parathyroid hyperplasia.
by a 10-day interval, then demeclocycline 300 mg three times daily for
3 days) and biopsy 4 days later; the quantitation of bone mineralization Prevention of Hypocalcemia
rate is achieved by measuring the distance between the two fluorescent Hypocalcemia, if present, should be corrected because it is a potent
tetracycline bands. stimulus for PTH secretion. In patients with hypoalbuminemia, ionized

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 985

A B C D
Fig. 84.11 Bone histology in renal osteodystrophy. (A) Osteitis fibrosa: Characteristic manifestations
of severe hyperparathyroidism with increased osteoclast and osteoblast activity and peritrabecular fibrosis
(stained blue; arrow). (B) Adynamic bone disease: There is no cellular activity along the bone surface and no
osteoid visible. (C) (arrowhead) Mixed renal osteodystrophy: There is evidence of active osteoclasts on one
bone surface (arrowhead) and evidence of thickened osteoid (stained red; asterisk) indicating a mineralization
defect on the other. (D) Osteomalacia: Marked excess of unmineralized osteoid (stained red) surrounding
the mineralized bone (stained blue).

calcium should be measured. The initial approach to therapy for hypo- Dietary Phosphate Restriction
calcemia in patients with mild to moderate CKD is the administration In experimental animals with mild CKD, dietary phosphate restriction
of calcium supplements such as calcium carbonate, taken between can prevent excessive PTH synthesis and secretion, as well as parathyroid
cell proliferation, independently of changes in serum calcium and cal-
should be undertaken by measurement of 25-hydroxyvitamin D, and
this should be corrected if it is below 30 ng/ml. The determination of intake might be considered in patients with CKD stage 2 or 3. The
1,25-dihydroxyvitamin D levels is not helpful in this respect, given its input of a dietician is essential. Protein restriction and avoidance of
- dairy products (especially processed foods containing high amounts of
added phosphate) are the mainstays of the regimen. Phosphate-protein
vitamin D sterols should be considered if hyperparathyroidism or restriction increases the serum levels of calcitriol in patients with mild
hypocalcemia persists. In patients with ESRD, active vitamin D sterols to moderate CKD. However, restriction of phosphate by severe dietary
are often required. In dialysis patients, the goal is to achieve levels of protein restriction below 0.8 g/kg/day may lead to protein-calorie
iPTH that are approximately two to nine times above the upper limit malnutrition.
of the assay used.23 -
tored. In CKD stages 3 to 5, progressive rises in iPTH above the normal Phosphate Binders
range should be abrogated by correction of hypocalcemia, vitamin D Whereas dietary phosphate restriction is usually sufficient in early CKD,
deficiency, and hyperphosphatemia. The latter should be corrected before the control of phosphate becomes more difficult as renal function dete-
the correction of hypocalcemia. riorates. It then becomes necessary to also use agents that bind ingested
phosphate in the intestinal lumen to limit its absorption. Compounds
Control of Phosphate used for this purpose include calcium-containing antacids, magnesium
Control of phosphate is the cornerstone of effective management of salts, aluminum hydroxide, and non–calcium-containing, non–
secondary hyperparathyroidism. In mild to moderate CKD, a normal aluminum-containing phosphate binders (Fig. 84.12). Most phosphate
serum phosphate concentration does not necessarily indicate normal binders, especially in advanced CKD, have to be given in large numbers
parathyroid status, and except for the late stages of CKD, normophos- (often accounting for 50% of the daily pill burden) and consequently
phatemia may be maintained at the expense of elevated serum PTH patient adherence with the medication is a major problem.
and FGF-23. Therefore efforts to control phosphate, including dietary
phosphate restriction and the use of phosphate binders, should not be in patients with CKD, their long-term use can no longer be recom-
delayed until frank hyperphosphatemia develops. mended because of the risk for aluminum toxicity. Ingestion of

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986 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Phosphorus Balance and Hemodialysis

Removed by HD
Dietary phosphorus 3 × 800 mg
Phosphorus
intake Absorption 2400 mg/wk
requiring
removal
1000 mg/day 60%
or
4200 mg/wk Phosphorus balance
7000 mg/wk
+1800 mg/wk

To achieve neutral phosphate balance,

binders must remove
1800 / 7 = 257 mg/day

Approximate potential phosphate-binding capacities of

commonly used agents:
Calcium carbonate: 1 g binds 40 mg
Calcium acetate: 1 g binds 45 mg
Sevelamer: 1 g binds 36 mg
Lanthanum carbonate: 1 g binds 93 mg
Aluminum hydroxide (liquid): 1 g binds 60-75 mg

Fig. 84.12 Phosphate balance and phosphate binders used in hemodialysis patients.

aluminum-containing antacids together with foods containing citric lanthanum appears to accumulate in bone, liver, and gastric mucosa.
acid (e.g., fruit juices and foods with sodium, calcium, or potassium Newly approved iron-containing phosphate binders include ferric citrate
citrate) may significantly increase aluminum absorption and therefore and sucroferric oxyhydroxide. Ferric citrate allows significant oral iron
should be avoided. uptake and therapy necessitates monitoring of iron stores, whereas iron
Calcium carbonate or calcium acetate taken with meals effectively uptake from sucroferric oxyhydroxide is low.24
binds phosphates and limits their absorption. They are effective phos-
phate binders in 60% to 70% of patients on HD. The doses required Use of Vitamin D Metabolites
to prevent hyperphosphatemia may vary according to patient compli- Calcitriol and other 1α-hydroxylated vitamin D sterols, such as
ance with dietary phosphate restriction as well as the CKD stage. 1α-hydroxyvitamin D3 (alfacalcidol), 1α-hydroxyvitamin D2 (doxer-
Hypercalcemia and calcium loading are the major potentially serious calciferol), and 19-nor-1α,25-dihydroxyvitamin D2 (paricalcitol), are
side effects. Current recommendations are to limit the ingestion of effective in the control of secondary hyperparathyroidism. Calcitriol
elementary calcium to 1500 mg/day. Consideration of overall calcium lowers PTH levels and improves bone histologic status. In patients with
balance may be important with the use of calcium-containing phos- very high levels of PTH and markedly enlarged glands with severe
phate binders. nodular hyperplasia, the effectiveness of vitamin D metabolites may be
Magnesium salts are effective phosphate binders for patients who limited because the levels of vitamin D receptor are low in such tissue.
become hypercalcemic with calcium-containing phosphate binders, but
they should be administered with caution in CKD patients not on hyperparathyroidism with vitamin D metabolites early in CKD when
dialysis because hypermagnesemia may have serious adverse effects. In the parathyroid glands are more sensitive to such therapy and thereby
patients on dialysis, magnesium carbonate (elemental magnesium 200
to 500 mg/day) has been used successfully, with prevention of hyper- D metabolite therapy in treatment of secondary hyperparathyroidism
magnesemia through a reduction in dialysate magnesium concentration. in patients with mild to moderate CKD has been shown, but the concern
The use of magnesium carbonate also allows reduction of the dose of with initiation of vitamin D therapy at this stage of CKD is acceleration
calcium carbonate required by about half, but its use is frequently com- of the progression of renal disease should hypercalcemia occur. Because
plicated by diarrhea. of the effect of calcitriol to increase intestinal phosphate absorption,
Nonabsorbable, calcium-free polymers, such as sevelamer hydro- hyperphosphatemia and elevations in calcium-phosphate product may
chloride in a dose range of 2.4 to 4.8 g/day, provide effective phosphate predispose patients to the development of metastatic calcification;
however, it appears that doses of 1α-hydroxyvitamin D3 or calcitriol
containing phosphate binders in terms of limiting the calcium load, up to 0.5 mcg/day are not commonly associated with hypercalcemia,
although they are significantly more expensive. Studies have suggested
that the use of sevelamer is associated with decreased progression of with the use of vitamin D metabolites before dialysis is that oversup-
vascular calcification.24 Sevelamer hydrochloride has largely been replaced pression of hyperparathyroidism may increase the risk for adynamic
by sevelamer carbonate, which has similar properties. Sevelamer may
be combined with both calcium- and magnesium-containing phosphate and should not be instituted without documentation of hyperparathy-
binders if necessary. Lanthanum carbonate also is an effective phosphate roidism, correction of 25-hydroxyvitamin D deficiency, and prior control
binder. No significant toxicity has been observed, although some of serum phosphate.

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 987

In patients with ESRD, indications for therapy with vitamin D

BOX 84.2 Indications for
metabolites are better defined; however, hypercalcemia and aggravation
of hyperphosphatemia are frequent complications of therapy. Vitamin
Parathyroidectomy
D metabolites are increasingly used as oral or intravenous pulses given Severe hyperparathyroidism
intermittently (e.g., three times weekly) rather than as continuous oral With persistent hyperphosphatemia
Unresponsive to calcitriol and calcium
parent compound and yet retain the ability to suppress PTH release in With hypercalcemia
vivo have been developed. Such analogues of vitamin D studied in With intolerance or unresponsiveness to calcimimetics
patients with ESRD are 22-oxacalcitriol, 1α-hydroxyvitamin D2, and In renal transplantation candidate
19-nor-1α,25-dihydroxyvitamin D2 (paricalcitol). Direct comparisons With evidence of metastatic calcification
between these compounds are not available. It is likely that a wider Calciphylaxis with evidence of hyperparathyroidism
therapeutic window may be offered by these analogues. Several but not Severe pruritus, only if additional evidence of hyperparathyroidism
all studies have suggested there may be a survival advantage associated
with active vitamin D administration in patients with CKD as well as
with ESRD.25,26 For hypercalcemia to occur because of hyperparathyroidism in CKD,

Role of Calcimimetics elevated. Surgical parathyroidectomy might be considered in patients

with very severe hyperparathyroidism who may receive a renal transplant
ESRD is the use of a calcimimetic agent, such as cinacalcet, which in the near future, particularly if they are female and have significant
targets the calcium-sensing receptor and increases its sensitivity to osteopenia. Parathyroidectomy in these patients can help avoid post-
calcium. In dialysis patients, cinacalcet results in a significant fall in transplantation hypercalcemia and hypophosphatemia (caused by PTH-
PTH levels and can facilitate the control of hyperparathyroidism. The induced phosphaturia), as well as osteopenia. By avoiding hypercalcemia,
addition of cinacalcet to standard therapy in patients with iPTH serum this may lead to improved graft function and possibly to less intragraft
levels exceeding 300 pg/ml while receiving standard therapy allowed calcification. Parathyroidectomy might be considered in patients with
significantly more dialysis patients to achieve guideline targets for calcium, severe hyperparathyroidism who have evidence of metastatic calcifica-
phosphate, and iPTH.27 Cinacalcet is especially useful in patients with tion. The development of calciphylaxis is an urgent indication for para-
marginal or frank hypercalcemia or with hyperphosphatemia and can thyroidectomy if PTH levels are elevated (see Chapter 87). Before
be used in conjunction with other therapies. Central side effects include parathyroidectomy, consideration should be given to the possibility of
hypocalcemia and nausea and vomiting; the latter can be somewhat coexisting aluminum accumulation, with deferoxamine testing and bone
improved by administering cinacalcet at night. Cinacalcet may attenuate biopsy performed if necessary, because this might predispose to osteo-
progression of cardiovascular (CV) calcification.28 malacia after parathyroidectomy.
controlled trial (RCT)—Evaluation of Cinacalcet HCl Therapy to Lower The most commonly used surgical procedures are subtotal removal
of the parathyroid glands and total removal of the parathyroid glands
therapy on CV events and survival in HD patients with secondary with reimplantation of parathyroid tissue in the forearm. Recurrence
hyperparathyroidism was nondefinitive because of, at least in part, of hyperparathyroidism occurs in about 10% of patients. Total para-
significant migration from the control arm to commercial cinacalcet thyroidectomy alone is less commonly performed; although this is an
and an age difference between the two arms, whereby the cinacalcet appropriate procedure for patients remaining on dialysis, hypopara-
patients were older on average and thus at higher CV risk.29 In that thyroidism after renal transplantation may lead to marked hypercalciuria
trial, however, cinacalcet significantly reduced rates of parathyroidec- with nephrocalcinosis and progressive renal failure. This may become
tomies and of calciphylaxis.29 In CKD patients not on dialysis, the use less of an issue now that recombinant PTH has become available. Total
of calcimimetics is accompanied by significant phosphate retention parathyroidectomy with forearm implantation (our preference) or sub-
and is currently not recommended. The potent, parental peptide-based total parathyroidectomy in the neck, marking remaining tissue with
calcimimetic etelcalcetide was recently licensed in dialysis patients. clips, may be performed. Unregulated tumor-like growth of parathyroid
- tissue implants has been described and may be related to the monoclonal
ence, gastrointestinal adverse events were similar to those with nature of the nodular hyperplasia of severe hyperparathyroidism.
cinacalcet.30 Recurrence of hyperparathyroidism may respond to further medical
therapy, but more surgery to remove the forearm implant or further
Role of Parathyroidectomy neck exploration to search for additional glands is often necessary and
may be guided by parathyroid imaging.
of hyperparathyroidism in many patients, there are occasions when
these steps fail or are contraindicated and surgery should be considered Synthesis of Therapeutic Strategies
(Box 84.2). Parathyroidectomy is indicated for patients with severe The general recommendations for the prevention and therapy of renal
hyperparathyroidism that cannot be controlled medically. Severe hyper- osteodystrophy are summarized in Fig. 84.13, in which therapeutic
phosphatemia in these patients precludes the use of vitamin D metabolites maneuvers are stratified according to the degree of CKD.
because of the risk for metastatic calcification. Some control of iPTH Therapy should be initiated if possible in stage 2 or 3 CKD (GFR,
levels may be obtained with calcimimetics, but even these compounds 30 to 90 ml/min), and dietary phosphate intake may be restricted once
may fail in severe hyperparathyroidism because of downregulated patients enter CKD stage 3. Levels of iPTH should be measured; if
calcium-sensing receptors in the parathyroid glands. Some patients elevated above the normal range, the levels of 25-hydroxyvitamin D
with severe hyperparathyroidism may become hypercalcemic. It is should be measured and corrected if less than 30 ng/ml. If hyperpara-
important to be certain that hypercalcemia represents severe hyper-
parathyroidism and is not caused by adynamic bone or other disease. progresses within stage 3, dietary phosphate restriction should be con-
In some cases, a bone biopsy may be required for a definite diagnosis. tinued or intensified, and the doses of phosphate binders should be

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988 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Treatment of Renal Osteodystrophy at Various Stages

of Renal Impairment

Monitor Ca/P/iPTH levels

Evaluate vitamin D status

and treat as necessary

Treat acidosis

Consider:
- Dietary Pi restriction
- P binders

CKD 3
Consider:
Active vitamin D sterols
Limiting Ca intake

CKD 4
Consider:
Parathyroidectomy
Calcimimetic*
Dialysis regimen*
Dialysate calcium*

CKD 5

Fig. 84.13 Treatment of renal osteodystrophy at various stages of renal impairment. *Consider
in CDK5D (i.e., dialysis dependent) only. Ca, Calcium; CKD, chronic kidney disease; iPTH, intact parathyroid
hormone; P, phosphate; Pi, inorganic phosphate. (Modified from reference 56.)

adjusted based on serial measurements of iPTH, with careful attention combination with the other strategies if iPTH levels do not fall into
the target range. Parathyroidectomy should be considered in selected
should be treated with oral sodium bicarbonate because persistent aci- circumstances. Bone biopsy may be indicated in selected patients, par-
dosis has deleterious effects on the skeleton. The additional sodium
load may require further salt restriction or increases in diuretics. require chelation therapy with deferoxamine in selected circumstances,
- especially if it is symptomatic, but in most patients the prevention of
thyroidism (iPTH more than two to three times above the upper normal further aluminum exposure is sufficient to allow a gradual reduction
range of the assay) persists despite these measures, consideration should in the serum levels of aluminum. During therapy with potent vitamin
be given to the addition of calcitriol (0.25 to 0.5 mcg/day), vitamin D D metabolites, attention should be given to the dialysate calcium con-
analogues, or vitamin D prohormones to the regimen. This therapy centrations because high concentrations may aggravate hypercalcemia.
should be monitored carefully to avoid hypercalcemia and acceleration However, the increasingly frequent use of lower dialysate calcium levels,
of progression of CKD. such as 1.25 mmol/l, requires careful monitoring of the patient to ensure
In CKD stages 4 and 5, the preceding therapies may need to be compliance with calcium-containing phosphate binders and vitamin
intensified and larger amounts of phosphate binders may be required D metabolites to avoid progressive negative calcium balance. Dialysate
to avoid hyperphosphatemia. The use of aluminum-containing phos- calcium should remain within the range of 1.25 to 1.75 mmol/l and,
phate binders is particularly undesirable at this stage in view of the when possible, should be individually prescribed.
increased risk for aluminum accumulation with worsening renal func-
tion. In patients on dialysis, calcitriol therapy can be intensified, with
attention to the serum levels of calcium and phosphate and monitoring
LOW-TURNOVER RENAL BONE DISEASE
of iPTH levels. In CKD stage 5, iPTH levels should be maintained -
approximately two to nine times above the upper limit of the assay
used to maintain normal bone turnover.23 Calcitriol may be administered develops as an adaptive response to counteract the increasing skeletal
orally either daily or intermittently (pulse therapy) or administered
intravenously to patients on HD. During therapy with calcitriol, it is
imperative to ensure serum phosphate remains controlled and eleva- important in CKD-MBD because of the high percentage of affected
tions of serum calcium do not occur to prevent metastatic calcification. individuals (>40% in CKD stage 5) and because of its association with
Vitamin D analogues, which are less calcemic and phosphatemic than CV calcification and mortality.31,32 Furthermore, fracture incidence is
calcitriol and yet retain the ability to suppress the levels of PTH, may estimated to be twice as high in individuals with low than in those with
be useful. Cinacalcet provides additional effective control of hyperpara-
thyroidism in patients with ESRD and may be used alone or in biopsy registries of dialysis patients, which may relate to the increasing

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 989

Pathogenesis of Adynamic Bone Disease

Better phosphate control Diabetes

Diabetes ↑ Age
↑ Age Uremic toxins
↑ Aluminum Relative Decreased bone Altered growth
hypoparathyroidism formation rate factors and cytokines
Vitamin D therapy
Malnutrition
VDR polymorphism
↑ Aluminum
CAPD ↑ Serum Ca
Vitamin D therapy
↓ PTH-1 receptor
↑ Calcium intake
Fig. 84.14 Pathogenesis of adynamic bone disease. Ca, Calcium; CAPD, continuous ambulatory peri-
toneal dialysis; PTH, parathyroid hormone; VDR, vitamin D receptor. (Modified reference 57.)

prevalence of its key risk factors—advanced age and diabetes mellitus. In CKD stages 3 and 4, there are uncertainties about the diagnosis
PD also represents a risk factor, possibly because of an often continuous
exposure to high dialysate calcium as opposed to the cyclic exposure are required to maintain adequate bone turnover in these stages. It
associated with HD. seems reasonable to correct vitamin D deficiency, hyperphosphatemia,
and hypocalcemia when PTH levels start to rise, but beyond that, no
Pathogenesis of Adynamic Bone Disease firm recommendations can be given.
Given that the bone develops a relative resistance of the PTH-1 receptor
to its ligand PTH as CKD progresses, PTH levels above the normal Bone Biopsy
range are required to maintain adequate bone turnover. Unfortunately,
there are no definite ranges of elevated PTH levels that can reliably the TMV classification (see earlier discussion),1
differentiate an adaptive response (normal bone turnover) from a mal- by low turnover, normal (or high secondary) mineralization, and low
adaptive response (increased bone turnover) because PTH resistance bone (osteoid) volume. The individual indication to perform bone
- biopsy should be considered in symptomatic patients based on incon-
sistencies of biochemical parameters associated with unexplained frac-
cause suppression or cessation of both osteoblast and osteoclast activities, tures, bone pain, progressive extraosseous calcifications, or hypercalcemia.
resulting in a reduced bone formation rate and low bone mass. Iatro-
genic oversuppression of PTH in CKD mainly results from high-dose samples and concomitant serum samples to identify biomarker patterns
active vitamin D metabolite treatment, from calcium loading (high
doses of calcium-containing phosphate binders, high dialysate calcium
concentration), or after parathyroidectomy. The effects of calcimimetic
treatment on bone turnover have been prospectively evaluated in HD from non-high bone formation rate.36 However, there is considerable
patients, and patients in this cohort had significant high-turnover oste-
opathy at baseline (average iPTH >1200 pg/ml). Therapy with cinacalcet
decreased elevated bone formation rate and improved bone histologic significant aluminum exposure, aluminum bone deposition should be
status.33 excluded by measurement of serum aluminum and specific staining of
target range of two to nine times the upper reference range of the assay. a bone biopsy specimen.
Finally, diabetes, uremic toxins, malnutrition, and potentially, C-terminal
PTH fragments may be additional factors favoring a state of low bone Radiology and Measurements of Bone Density
turnover (Fig. 84.14).

Diagnosis and Differential Diagnosis depending on the primary or secondary mineralization state, but it
Serum Biochemistry never reflects the actual turnover and is therefore not a helpful diagnostic
Low iPTH levels (<100 to 150 pg/ml) are almost always indicative of
low bone turnover in CKD stage 5D. However, histologically proven radiographs may raise the suspicion of a low bone turnover state if
accompanying biochemical parameters are compatible with this diagnosis.
300 pg/ml and, in exceptions, of up to 600 pg/ml.34,35 Therefore PTH
calcification in dialysis patients.31
activities of alkaline phosphatase or bone alkaline phosphatase are usually
normal or low; downward trends may indicate the development of Treatment of Adynamic Bone Disease
-
dent on the choices of cotreatment (phosphate binders, vitamin D PTH overexpression and restore adequate PTH levels, without triggering
metabolites) and nutritional status. Particularly in instances of calcium the progressive development of secondary hyperparathyroidism. Such
and phosphate loading, hypercalcemia and hyperphosphatemia may a stepwise treatment approach may include avoidance of calcimimetics,
be pronounced because adynamic bone is unable to buffer calcium and reduction or withdrawal of active vitamin D metabolites, reduction or
phosphate loads by osseous deposition (Fig. 84.15). withdrawal of calcium-containing phosphate binders, and reduction

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990 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

of the dialysate calcium concentration (usually to 1.25 mmol/l). Indeed,

a recent RCT found a histologic improvement of low bone turnover be monitored more frequently than usual.
when the dialysate calcium concentrations were decreased from 1.5 or Studies comparing calcium-containing with non–calcium-containing
1.75 mmol/l to 1.25 mmol/l.37 phosphate binders in dialysis patients35,38 found that the administration
of calcium-containing phosphate binders was associated with a higher

associated with a fall in serum PTH because of the higher calcium load.
In an observational study, high-dose calcium-containing phosphate
binder intake was associated with both low bone turnover and increased
Extraskeletal Calcification in aortic calcification.39
Adynamic Bone Disease
studied. They include optimized diabetes control, a change from PD
Normal bone turnover to HD to facilitate a more flexible dialysate calcium prescription, the
administration of recombinant PTH (e.g., for patients after total para-
Deposition Mobilization
thyroidectomy), and calcilytics (agents that antagonize the calcium
receptor and thus increase endogenous PTH).40
Ca2+
Bone
PO4
OSTEOPOROSIS IN CHRONIC KIDNEY DISEASE
Whereas abnormal bone is common and fracture risk is increased in
Low bone turnover CKD patients, the relative contribution of classic osteoporosis (as defined
(adynamic bone)
complex is not well defined. Data from studies of antiosteoporosis agents
are mostly available for patients in CKD stages 1 to 3, and subjects with
features of CKD-MBD were largely excluded. Nevertheless, postmeno-
Ca2+
pausal women and elderly men are highly prevalent in late-stage CKD
Bone
populations, and it is thus likely that classic osteoporosis also contributes
PO4 to their bone disease.

Pathogenesis of Osteoporosis in Chronic

Kidney Disease
Fig. 84.15 Bone turnover in adynamic bone disease. Reduced
bone turnover leads to increased extraskeletal calcification.Ca2+, Calcium and is characterized by thin and disconnected trabeculae and loss of
ion; PO4, phosphate. the plate-like bone structure. Many patients with CKD have abnormal

The Value of Bone Density Measurements

in the Assessment of CKD-Related Bone Disease
Adynamic Secondary Hyper-
Clinical Situation: Normal bone Osteoporosis Osteomalacia Bone Disease parathyroidism

Normal or
Low bone Normal Low bone increased
Normal mass bone mass bone mass
bone mass mass
Bone Decreased
Composition: Normal Normal secondary
primary primary Abnormal High mineralization
mineralization mineralization primary secondary
mineralization mineralization Increased
osteoid volume

Measured BMD: 1.250 g/cm2 0.625 g/cm2 0.625 g/cm2 0.625 g/cm2 0.625 g/cm2

Densitometry
Normal BMD “Osteoporosis”
Report:
Fig. 84.16 The value of bone density measurements in the assessment of chronic kidney disease
(CKD)–related bone disease. Pink boxes indicate mineralized bone; red boxes indicate osteoid. BMD,
Bone mineral density. (Courtesy Prof. M. H. Lafage-Proust, St. Etienne, France.)

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 991

mineralization and increased osteoid, which is quite atypical for osteo- hypocalcemia when treated with denosumab; coadministration of vitamin
porosis. Typical pathogenetic factors of osteoporosis, including hypoes- D analogues may be required to blunt this effect. However, given the
trogenemia, immobilization, and corticosteroid use, are frequent in growing evidence that antiresorptive therapies may be effective at least
CKD patients, although some postmenopausal women with late-stage in patients with CKD stages 3 and 4, and the lack of definite evidence
CKD may have relatively normal estrogen levels. However, the sum of
CKD-MBD–related biochemical disturbances probably represents the to perform a bone biopsy before treatment initiation, if a clinical response
decisive factors as to which bone phenotype predominates. Secondary is otherwise suspected.

25-hydroxyvitamin D, as well as 1,25-dihydroxyvitamin D deficiencies,

may dominate and “overrule” the bone phenotype of osteoporosis even
β2-MICROGLOBULIN–DERIVED AMYLOID
if classic risk factors are present. β2 β2M) amyloidosis, also termed dialysis-
associated amyloidosis, exclusively affects patients with stage 5 CKD. It
Diagnosis and Differential Diagnosis is a systemic amyloidosis. Clinical manifestations are largely confined
In patients with advanced CKD, bone turnover biomarkers and mea- to the musculoskeletal system. In recent years the disease has become
β2M amyloidosis in CKD stage 5 should not be
84.16) in the differential diagnosis of classic osteoporosis versus other confused with a rare hereditary systemic amyloidosis derived from the
β2-microglobulin, which manifests in the absence
β-CrossLaps (C-terminal cross-linked, CTX; marker of bone collagen of CKD.
degradation), procollagen type I N-terminal propeptide (PINP; marker
of bone collagen synthesis), and tartrate-resistant alkaline phosphatase Pathogenesis
β2M amyloid are derived from the circulating precursor
in CKD patients, and low bone mineral density can be found in protein β2-microglobulin, the nonvariable light chain of the human

(see Fig. 84.16). However, there is recent evidence that bone mineral involve three events:
1. Pronounced renal retention of β2-microglobulin (11.8 kDa), leading
patients to an extent similar to that in the general population, so this to plasma levels that can be elevated up to 60-fold in dialysis patients48;
method may become useful in monitoring therapeutic drug effects or however, even massive overproduction of β2-microglobulin in mice
was not sufficient to induce amyloid deposits and thus further steps
from CKD-MBD–associated bone phenotypes. Peripheral quantitative must be important.49
tomography (pQCT) of the radius may be a superior methodology for 2. Modifications of the β2-microglobulin molecule that render it more
assessment of CKD patients in the future but awaits validation in suf- amyloidogenic, such as limited proteolysis or the formation of dif-
ficiently large patient cohorts.41 The only reliable methodology to diagnose ferent sugar-protein cross-links.50
osteoporosis and discriminate it from other bone manifestations in 3. Local factors that contribute to and determine the spatial localiza-
CKD patients is bone biopsy. In a large bone biopsy study, including tion of the amyloidosis.
1429 samples from dialysis patients, osteoporosis was diagnosed in 52%
42
These proportions Epidemiology
may be quite different in patients in earlier CKD stages, but there are Histologic studies from the 1990s observed amyloid deposits in 100%
no systematic data available on such cohorts. of dialysis patients treated for more than 13 years.51 Most amyloid
β2M
Treatment of Osteoporosis in Chronic amyloid deposition are age at onset of renal replacement therapy (RRT)
Kidney Disease and the duration of (nontransplant) RRT.48-50 β2M amyloid–related
Post hoc analyses of large prospective treatment studies using antios- symptoms presently are largely confined to patients who have been
teoporotic medications indicate that it is safe and efficacious to treat dialyzed for more than 15 years.
postmenopausal women in stages CKD 1 to 3 if they have a high risk
Clinical Manifestations and Diagnosis
43-46
CKD-MBD. In such populations, bisphosphonates, denosumab, β2M amyloidosis mainly manifests at osteoarticular sites, particularly
raloxifene, and teriparatide appear to be feasible therapeutic options. synovial membranes; visceral manifestations are rare.48-50 Carpal tunnel
The former three drugs antagonize high bone turnover with an anti- syndrome occurs and symptoms typically worsen at night and during
resorptive mode of action; teriparatide exerts bone anabolic effects
(PTH analogue). With bisphosphonates, there may be concerns of an of peripheral joints, resulting from amyloid deposition in periarticular
extended oversuppression of osteoclasts, but only in patients with bone and the synovial capsule (Fig. 84.17), is characterized by recurrent
or persistent arthralgias, stiffness of large and medium-sized joints, and
from the Following Rehabilitation, Economics and Everyday-Dialysis swelling of capsules and adjacent tendons. Recurrent joint effusions
and synovitis, often in the shoulders and knees, may occur. The clinical
reduced fracture risk with denosumab treatment versus placebo, inde- presentation may vary from frank, acute arthritis to slow, progressive
pendent of the stage of CKD.47 In contrast, for patients in CKD stages destruction of the affected joints. Destructive spondyloarthropathy (Fig.
3 to 5 with features of CKD-MBD, no data are available on the safety β2M amyloidosis can manifest as asymptomatic
and efficacy of any of these antiosteoporotic medications. In CKD deposits, radiculopathy, stiffness, “mechanical ache,” and, finally, medul-
lary compression with resulting paraplegia or cauda equina syndrome.
osteoclast paralysis. In CKD patients with secondary hyperparathyroid- -
ism, these antiresorptive agents may upregulate PTH secretion. Patients ing in bent fingers that cannot completely extend or straighten) resulting
with advanced CKD (stages 4 and 5) may develop particularly severe from amyloid deposits along the flexor tendons of the hands (Fig. 84.19).

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992 SECTION XVI Chronic Kidney Disease and the Uremic Syndrome

Patients undergoing dialysis also can have subcutaneous tumorous see also Fig. 84.17). Such bone defects are prone to pathologic fractures.
β2M amyloid; however, diffuse infiltration of the subcu- β2M amyloid–induced cystic bone radiolucen-
taneous fat or skin has not been observed. cies have been published.52 They include (1) diameter of lesions more
Case reports of clinically relevant organ manifestations are usually than 5 mm in wrists and more than 10 mm in shoulders and hips, (2)
in patients treated with HD for more than 15 years and have described normal joint space adjacent to the bone defect, (3) exclusion of small
heart failure, odynophagia (painful swallowing), intestinal perforation subchondral cysts in the immediate weight-bearing area of the joint
of both small and large bowel, gastrointestinal bleeding and pseudoob- and of defects of the “synovial inclusion” type, (4) increase of defect
struction, gastric dilation, paralytic ileus, persistent diarrhea, macroglossia diameter of more than 30% per year, and (5) presence of defects in at
or functional tongue disturbances (abnormal taste, mobility, articula- least two joints. Scintigraphy, using either radiolabeled serum amyloid
tion), ureteral stenosis, and renal calculi. P component or β2-microglobulin,53 offers more specific detection of
amyloid deposits but is not widely available. The definitive diagnosis
Diagnosis β2M amyloidosis relies on histologic findings. Fat aspiration and
Serum levels of β2M do not distinguish between patients with amy- β2M amyloidosis, but diagnostic mate-
β 2M rial can be obtained from synovial membranes, synovial fluid, or bone
amyloidosis as thickening of the joint capsules of the hip and knee, lesions.48
biceps tendons, and rotator cuffs, as well as the presence of echogenic
structures between muscle groups and joint effusions.48-50 Treatment and Prevention
examination, affected joints may present with single or multiple jux- β2
taarticular, “cystic” (i.e., amyloid-filled) bone radiolucencies (Fig. 84.20; and physical and surgical measures, such as carpal tunnel

Fig. 84.17 Aβ2M amyloid deposition in the femoral head. Post-

mortem specimen from a long-term hemodialysis patient. Two large Fig. 84.19 Hand involvement in Aβ2M amyloidosis. Hand of a
lesions (arrowheads), partly filled with grayish amyloid and partly cystic, long-term hemodialysis patient showing maximal extension. Note the
are noted in the femoral head. Also note the marked thickening of the prominence of shrunken flexor tendons (arrows). This is also known as
synovial capsule from amyloid deposition (arrow). the guitar string sign.

A B
Fig. 84.18 Aβ2M amyloidosis–associated spondyloarthropathy. (A) Destruction of an intervertebral
disk (arrow) in the neck vertebrae of a long-term hemodialysis patient. (B) Magnetic resonance image of the
same patient as in A. Note destruction of the intervertebral space and protrusion of material into the spinal
canal (arrow).

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 CHAPTER 84 Bone and Mineral Disorders in Chronic Kidney Disease 993

A B

C D
Fig. 84.20 Peripheral bone cystic radiolucencies in Aβ2M amyloidosis. Radiographic findings in a
long-term hemodialysis patient. (A) Multiple cystic lesions (arrows) are present in the hand bones. (B) Large
cysts (arrows) in the neck of the femur and adjacent pelvic bones. (C and D) Anterior and lateral views of
the head of the tibia with two very large, cystic lesions (arrows) resulting in posterior bulging of the tibial
plateau.

decompression, endoscopic coracoacromial ligament release, and bone REFERENCES

stabilization in areas of cystic destruction, are all used.48
1. Moe S, Drueke T, Cunningham J, et al. Definition, evaluation, and
dialysis modalities allow significant removal of β2M, there is at present
classification of renal osteodystrophy: a position statement from Kidney
no convincing evidence that this is of therapeutic value in established
Kidney Int. 2006;69:
β2M amyloidosis. Renal transplantation is the preferred treatment 1945–1953.
because it leads to rapid symptomatic improvement and halts further 2. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in
progress of the disease, but whether this can actually lead to regression end-stage renal failure–an evolving disorder. Kidney Int. 1993;43:
β2M amyloid deposits is a subject of controversy. 436–442.
- 3. Martinez I, Saracho R, Montenegro J, Llach F. The importance of dietary
β2M amyloidosis.48 The risk for carpal tunnel syndrome is calcium and phosphorous in the secondary hyperparathyroidism of
reduced by 40% to 50% in patients treated with high-flux hemo(dia) patients with early renal failure. Am J Kidney Dis. 1997;29:496–502.
filtration and minimal in patients receiving online hemodiafiltration.
mitigates hyperphosphatemia but accentuates calcitriol deficiency in
chronic kidney disease. J Am Soc Nephrol. 2005;16:2205–2215.
occurred in patients dialyzed with ultrapure dialysate. In another study,
an 80% reduction of amyloid signs in a chronic HD population appeared on PTH secretion from whole rat parathyroid glands in vitro. J Bone
to relate to dialysate factors such as microbiologic purity and the use Miner Res. 1996;11:970–976.
of bicarbonate buffer. Finally, in uncontrolled studies a β2M adsorption 6. Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents
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