61

Chronic Kidney Disease

Joanna Q. Hudson, Lori D. Wazny, and Paul Komenda

KEY CONCEPTS
Chronic kidney disease (CKD) is classified based on the cause of kidney
disease, assessment of glomerular filtration rate, and extent of albuminuria
over at least a 3-month period.
The most common causes of CKD 5D (requiring dialysis or kidney
transplantation), often called end-stage renal disease (ESRD), are diabetes
mellitus and hypertension.
Anemia of CKD is multifactorial with loss of erythropoietin synthesis by
the kidney, iron deficiency, and chronic inflammation all implicated.
CKD-mineral and bone disorder (CKD-MBD) includes abnormalities in
parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23),
phosphorus, calcium, vitamin D, and bone turnover, and contributes to soft-
tissue and extravascular calcifications.
Guidelines from the Kidney Disease: Improving Global Outcomes
(KDIGO) provide information to assist healthcare providers in clinical
decision making and the design of appropriate therapy to manage CKD
progression and the associated complications.
Patient education and shared decision making play a critical role in the
appropriate management of patients with CKD and its associated
complications. A high functioning multidisciplinary team structure for
patients at high risk of progression to ESRD is preferred to effectively
design and implement the recommended nonpharmacologic and
pharmacologic interventions.
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin
receptor blockers (ARBs) are primary pharmacologic treatments to delay
progression of CKD because of their effects on renal hemodynamics to
 reduce intraglomerular pressure and proteinuria.
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are emerging as
potential agents to prevent progression to later stages of CKD and ESRD
and these effects seem to be independent of glucose lowering.
Management of anemia includes administration of erythropoiesis-
stimulating agents (ESAs) (eg, epoetin alfa, epoetin alfa-epbx, darbepoetin
alfa, methoxy polyethylene glycol-epoetin beta) and regular iron
supplementation to maintain hemoglobin concentration and prevent the
need for blood transfusions. There is a higher risk of cardiovascular events
when hemoglobin is targeted to a value of greater than 11 g/dL (110 g/L;
6.83 mmol/L).
Management of CKD-MBD includes dietary phosphorus restriction,
phosphate-binding agents, activated vitamin D supplementation, and
calcimimetic therapy to achieve KDIGO targets.
Although statins are not recommended for primary prevention of
hyperlipidemia in patients receiving dialysis, they are indicated for primary
prevention in those with nondialysis dependent CKD.

Preclass Engaged Learning Activity

Visit the National Institute of Diabetes and Digestive and Kidney Diseases
Website. This Website is useful to enhance student understanding of chronic
kidney disease, its causes, diagnosis, prevention, and treatment. Review the
information under ‘Kidney Disease’. Watch the video titled “How do you
check for kidney disease?”. The video provides a brief description of tests to
monitor for kidney disease.

INTRODUCTION
Chronic kidney disease (CKD) is defined as abnormalities in kidney
structure or function, present for 3 months or longer. Lower glomerular filtration
rate (GFR) and a higher urinary albumin-to-creatinine ratio (uACR) are both
independently associated with adverse events.1 For decades, kidney disease was
primarily considered to be present only when the patient’s estimated or measured
creatinine clearance (CLcr) was reduced to less than 50 mL/min (0.83 mL/s). In
2012, a new classification system was proposed that incorporated GFR and
uACR. Documentation of the presence of structural changes in those with what
previously would have been classified with normal kidney function (ie, CLcr or
GFR >90 mL/min [1.50 mL/s]) became the most sensitive indicator of CKD and
was designated as stage 1 CKD based on recommendations from the Kidney
Disease: Improving Global Outcomes (KDIGO) guideline for evaluation and
management of CKD.1 The KDIGO classification system is referred to as CGA
staging (Cause, GFR, Albuminuria). Figure 61-1 shows the KDIGO GFR and
albuminuria categories along with the prognosis based on these factors. A patient
is classified with end-stage renal disease (ESRD) when the GFR is below 15
mL/min/1.73 m2 (0.14 mL/s/m2) and either chronic dialysis (Chapter 62) or
kidney transplantation (Chapter 105) is needed to sustain life. Throughout this
chapter CKD stages based on KDIGO classification will be used (eg, CKD 3a or
CKD 5). The term CKD 5D indicates a patient with ESRD requiring dialysis as
either hemodialysis (CKD 5HD) or peritoneal dialysis (CKD 5PD).
FIGURE 61-1 KDIGO GFR and albuminuria categories and prognosis of CKD
by category.14 To meet criteria for CKD there must be a significant reduction in
GFR (categories 3a-5) or there must also be evidence of kidney damage
(categories 1 and 2) for 3 months or greater. Prognosis Scale – Green: low risk
(if no other markers of kidney disease, no CKD); Yellow: moderately increased
risk; Orange: high risk; Red: very high risk. (CKD, chronic kidney disease;
GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global
Outcomes.) (Reprinted with permission from Reference 14.)
 The prognosis of CKD is dependent on the following factors: (a) cause of
kidney disease; (b) GFR at time of diagnosis; (c) degree of albuminuria
measured by uACR; and (d) presence of other comorbid conditions. Patients
with any of the following should be referred to a nephrologist for evaluation and
collaborative management: persistent and significant albuminuria (uACR >1000
mg/g or 110 mg/mmol), progression of CKD (eg, a marked but nonacute decline
in GFR), presence of a nonsurgical cause of hematuria, hypertension refractory
to treatment (eg, ≥4 antihypertensive agents), persistent abnormalities of serum
potassium, recurrent or extensive nephrolithiasis, GFR less than 30 mL/min/1.73
m2 (0.29 mL/s/m2), or hereditary kidney disease such as polycystic kidney
disease even in the presence of normal GFR and uACR.1

Patient Care Process for Chronic Kidney Disease

(CKD)
Collect
• Patient characteristics (eg, age, sex, CKD stage [see Fig. 61-1] and cause
of CKD, medication allergies)
• Past medical history
• Social history (eg, smoking), family/friend supports
• Current medications including OTC (eg, NSAID use), herbals, dietary
supplements
• Objective data:
Blood pressure, heart rate, weight
Labs as outlined in ‘Clinical Presentation’.

Assess
• Serum creatinine, glomerular filtration rate (GFR), or creatinine clearance
• Presence of albuminuria (see Fig 61-1 and Table 61-5)
• Serum potassium concentration—assess frequently in patients with CKD
and heart failure requiring adjustment of diuretics and/or ACE inhibitors
• Hemoglobin concentration (see Table 61-6 for ESA initiation)
• Iron indices (transferrin saturation and ferritin)—for patients on an ESA,
assess transferrin saturation (TSAT) and ferritin at least every 3 months
and assess when clinically indicated (eg, following blood loss)
• Concentrations of calcium, albumin (to calculate corrected calcium),
phosphorus, and parathyroid hormone (PTH) (see Table 61-9)
• Blood pressure (see targets in Fig. 61-6)—consider use of home blood
pressure monitor
• Insurance coverage of medications, current out-of-pocket cost of
medications
• Medication adherence
• Potential drug interactions
• Need for renal dose adjustments
• Other recommendations as outlined in Table 61-3 (eg, vaccines, lifestyle
modifications)

Plan
• Drug therapy recommendations, including dose, route, frequency, and
duration
 • Monitoring parameters, including frequency and timing of follow-up
• Patient education, including purpose of new or changed treatment, lifestyle
modifications, medication administration (eg, timing of phosphate binders
with meals), injection technique
• Self-monitoring for resolution of symptoms and blood pressure targets,
medication to hold on sick days if vomiting or diarrhea occur (eg,
ACEI/ARB)
• Referrals to other providers when appropriate (eg, dietitian, occupational
therapist, social worker, endocrinologist, CKD nurse)

Implement*
• Provide patient education on all elements of the treatment plan
• Use motivational interviewing strategies to maximize adherence
• Schedule follow-up labs and appointment, adherence assessment

Follow-up: Monitor and Evaluate

• Resolution of CKD symptoms
• Presence of adverse effects (eg, dizziness, constipation, pruritus,
hypoglycemia)
• Patient adherence to treatment plan using multiple sources of information
*Collaborate with patient, caregivers, and other healthcare professionals.

Often complications of CKD are unrecognized or are inappropriately

managed, and for many patients this contributes to significant morbidity,
premature mortality, or a poorer prognosis if and when they require dialysis.
Frequent complications of advanced CKD include hypervolemia, hypertension,
hyperkalemia, metabolic acidosis, anemia, CKD-related mineral and bone
disorder (CKD-MBD), and a disproportionate risk of cardiovascular disease
(CVD). This chapter primarily covers the pathophysiology and treatment of
progressive CKD, anemia, CKD-MBD, and select cardiovascular (CV)
complications. Table 61-1 lists other complications of advanced CKD not
covered in detail. The reader is referred to Chapters 66, 68, and 69 for a more
detailed discussion of management and monitoring strategies for CKD patients
with hypervolemia, hyperkalemia, and metabolic acidosis, respectively.
TABLE 61-1 Other Complications of Chronic Kidney Diseasea

EPIDEMIOLOGY
CKD is recognized as a significant global public health problem.2 People with
CKD experience high morbidity and mortality rates with a resulting economic
burden to healthcare systems due to frequent hospitalizations and the high cost
of chronic dialysis and kidney transplantation. From 1990 to 2013 the age-
adjusted death rates attributable to CKD increased by 37% in 188 countries
surveyed and CKD is now the 19th leading cause of life years lost.3 Worldwide,
an estimated 8% to 16% of the general population has CKD and 1.9 million
patients are undergoing renal replacement therapy (hemodialysis, peritoneal
dialysis, or kidney transplantation).4,5 As a result, many countries have
implemented public health initiatives to reduce the proportion of the population
with CKD, increase CKD patient awareness through targeted screening
programs, reduce the rate of new cases of ESRD, and reduce mortality in
persons with CKD.6
In the United States, it is estimated that 15% of the adult population has
CKD. In 2016, over 726,000 individuals had ESRD, with 124,000 new cases
alone.7 In the United States and other first-world countries, the leading cause of
new ESRD cases is diabetes mellitus followed by hypertension (Fig. 61-2).7,8 It
is estimated that diabetes accounts for 50% of cases of ESRD in the developed
world.9 Despite the fact that the incidence rate of ESRD from all major causes
has leveled off since 2009, it is projected that the aging population and other
changes in the demographics will result in an increased incidence and
subsequent increase in prevalence of ESRD by 2030.10 The prevalence of CKD
increases with age, with the highest prevalence in individuals over 60 years
mainly attributed to a decrease in estimated GFR (eGFR, less than 60
mL/min/1.73 m2).7 While there is some debate as to whether the eGFR decline
in older individuals as a consequence of the normal physiological aging process
should be considered a disease necessitating the label of CKD, the fact remains
that patients with reduced eGFR and albuminuria suffer from worse health
outcomes regardless of age.1

FIGURE 61-2 Trends in adjusteda end-stage renal disease (ESRD) incidence

rate by primary diagnosis in the US population (1996-2014).8 aAdjusted for age,
sex, and race.

Racial health disparities in CKD also exist and contribute to differing CKD
rates. In the United States, the incident rate of ESRD is 2.9 times greater for
blacks compared to whites, with hypertension significantly higher among blacks
than all other racial groups.7 Incidence and prevalence of albuminuria are also
greater in black than in white individuals. Variants in the APOL1 gene may
contribute to this increased risk of nondiabetic kidney disease and albuminuria in
individuals of African descent.11 The incident rate is approximately 31% higher
in Hispanics than in non-Hispanics.7,12 Greater prevalence of obesity,
uncontrolled hypertension, and diabetes among non-white individuals are the
most common reasons suggested for racial differences in CKD. In terms of
socioeconomic factors, the likelihood of ESRD is higher in individuals with low
income and less education.11 A survey in England found that high albuminuria
was associated with low socioeconomic status even after adjustment for
ethnicity, lifestyle, and clinical variables such as obesity, diabetes, hypertension,
and smoking.13 The specific social and environmental factors are important to
consider when evaluating risk of progressive CKD in individual patients.

ETIOLOGY
Susceptibility and Initiation Risk Factors
Clinical and sociodemographic risk factors for susceptibility to and initiation of
CKD are listed in Table 61-2 and are useful for identifying individuals at high
risk of developing CKD.14

TABLE 61-2 Risk Factors for Susceptibility to and Initiation of Chronic

Kidney Disease
Predicting Risk of Progression
KDIGO recommends that all patients with CKD be staged according to eGFR
and uACR and that their prognosis be considered to help guide further testing
and treatment decisions (Fig. 61-1). Estimating equations such as the kidney
failure risk equation (KFRE), which incorporates urine data, sex, age, and GFR,
have also been used, and these equations provide an accurate 2- and 5-year risk
of progression to kidney failure for individuals with stage 3 to 5 CKD.15 The
KFRE has been widely validated in multiple international cohorts and pediatric
populations and provides the best current evidence-based approach to assess risk
of progression and should be used in combination with expert clinical
judgment.16 Risk equations may also be beneficial to help align resources with
risk in assigning priority for referral to nephrologists.

Progression Risk Factors

Progression risk factors are those associated with further decline in kidney
function. Persistence of the underlying initiation factors (eg, diabetes mellitus,
hypertension, glomerulonephritis) appears to be the most important predictor of
progressive CKD.

Diabetes Mellitus
Achieving a hemoglobin A1C (HbA1c) target of approximately 7% (0.07; 53
mmol/mol Hb) has been shown to prevent the surrogate endpoints of
microalbuminuria and macroalbuminuria associated with diabetic chronic kidney
disease (DCKD).17 The evidence to support this recommendation comes from
the type 1 diabetes DCCT trial, the long-term follow-up of these participants in
the EDIC trial, and subsequent analyses.18 The evidence for individuals with
type 2 diabetes comes from the United Kingdom Prospective Diabetes Study
(UKPDS) and the Veterans Affairs Cooperative Study on Glycemic Control and
Complications in Type 2 Diabetes Trial.9,17 While the highest survival rates in
individuals with DCKD were associated with HbA1c levels in the range of 7%
to 8% (0.07-0.08; 53-64 mmol/mol Hb), the recommendation by the American
Diabetes Association and consensus panels is to generally target these levels
while being cautious of the limitations of using this marker in patients with CKD
and the risk of hypoglycemia.9,19

Hypertension
Hypertension is both a cause and result of progressive kidney disease and
accounts for just over 31% of cases of ESRD in the United States.7 KDIGO
guidelines for the management of blood pressure in CKD recommend the goal is
to control blood pressure at all categories of CKD regardless of the underlying
cause since early treatment of hypertension and achievement of target blood
pressure have been demonstrated to slow the rate of progression of CKD.20

Proteinuria
Proteinuria is a strong independent predictor of accelerated progression of CKD
and also a risk factor for CV mortality and morbidity.1 Albuminuria remains the
primary modifiable risk factor associated with CKD progression in most
patients.

Smoking
Smoking is associated with kidney damage in the general population as well as
in patients with diabetes and hypertension.21 Acute reductions in GFR and an
increase in urinary albumin excretion, heart rate, and blood pressure, likely
secondary to nicotine exposure, have been reported.22 Smoking is also
associated with an increase in CV events in people with CKD.1

Obesity
Population data from Kaiser Permanente revealed an increased risk of CKD 5 in
overweight and obese subjects.23 The risk of CKD 5 was directly related to the
magnitude of obesity and remained even after adjustment for diabetes and
hypertension. A body mass index (BMI) greater than or equal to 25 kg/m2 at age
20 has been associated with a threefold increase in risk of CKD compared with a
BMI lower than 25 kg/m2.24 This association has also been shown in
metabolically healthy, young, and middle-aged individuals without CKD or
proteinuria.25 Intentional weight loss in individuals with CKD was associated
with decreases in proteinuria, systolic blood pressure, and stabilization in GFR
during a mean follow-up of 7.4 months.26 These data suggest that weight
reduction be included as part of the treatment of CKD.

PATHOPHYSIOLOGY
Chronic Kidney Disease
Progression of CKD to more advanced stages (stages 4-5) occurs over decades in
the majority of people, with the precise mechanism of kidney damage dependent
on the etiology of the disease and strongly associated with age, sex, and urine
ACR. As evidenced by the variety of initiation and progression factors, kidney
damage can result from an array of heterogeneous causes. Diabetic CKD is
characterized by glomerular mesangial expansion, while with hypertensive
nephrosclerosis, the kidney’s arterioles have arteriolar hyalinosis (thickening of
the arterial walls). Polycystic kidney disease is characterized by the development
and expansion of renal cysts. While the initial structural damage depends on the
primary disease affecting the kidney, the key elements of the pathway to ESRD
are (a) loss of nephron mass, (b) glomerular capillary hypertension, and (c)
proteinuria (Fig. 61-3).
FIGURE 61-3 Proposed mechanisms of progression of kidney disease.

Exposure to any of the initiation risk factors can result in loss of nephron
mass. In response to the decrease in nephron function, the remaining nephrons
compensate through the process of autoregulation. With nephron loss and the
resulting reduction in perfusion pressure and GFR, renin release from the
juxtaglomerular apparatus increases and converts angiotensinogen to angiotensin
I, which is then converted to angiotensin II (ATII). ATII is a potent
vasoconstrictor of both afferent and efferent arterioles, but it preferentially
affects the efferent arterioles, leading to increased pressure within the glomerular
capillaries and consequent increased filtration fraction. Initially, this
compensatory action may be adaptive and beneficial; however, over time it can
lead to the development of intraglomerular hypertension and hypertrophy and a
further decline in the number of functioning nephrons. High intraglomerular
capillary pressure impairs the size-selective function of the glomerular
permeability barrier, resulting in increased urinary excretion of albumin and
proteinuria. The development of intraglomerular hypertension usually parallels
the development of systemic hypertension. ATII, as well as aldosterone, may
also mediate CKD progression through nonhemodynamic effects by increasing
growth factors (eg, transforming growth factor beta [TGF-β]) and causing
cellular proliferation and hypertrophy of the glomerular endothelial cells,
epithelial cells, and fibroblasts ultimately resulting in further inflammation and
fibrosis.27
Proteinuria alone may promote progressive loss of nephrons as a result of
direct cellular damage. Filtered proteins such as albumin, transferrin,
complement factors, immunoglobulins, cytokines, and ATII are toxic to kidney
tubular cells. Studies have demonstrated that the presence of these proteins in the
renal tubule leads to increased production of inflammatory and vasoactive
cytokines such as endothelin and monocyte chemoattractant protein-1 (MCP-
1).28 Proteinuria is also associated with the activation of complement
components on the apical membrane of proximal tubules. Intratubular
complement activation may be the key mechanism of damage in the progressive
proteinuric nephropathies.28 Furthermore, these events ultimately lead to
scarring of the interstitium, progressive loss of structural nephron units, and a
reduction in GFR.

Anemia of Chronic Kidney Disease

The primary cause of anemia of CKD is a decrease in production of
erythropoietin, the glycoprotein hormone necessary for erythropoiesis (red blood
cell production), by interstitial fibroblasts in the renal cortex of the kidney where
approximately 90% of production occurs. In individuals with normal kidney
function, plasma concentrations of erythropoietin increase exponentially in
response to hypoxia; however, this response is lost as kidney disease progresses
to CKD 3 and higher.29
Iron deficiency anemia is common in individuals with advanced kidney
disease (ie, CKD 4 and 5) due to decreased gastrointestinal (GI) absorption of
iron, inflammation, frequent blood testing, blood loss from hemodialysis (HD),
and increased iron demands from erythropoiesis stimulating agent (ESA)
therapy. It is the leading cause of resistance to ESAs and the reason frequent iron
supplementation is necessary.29,30 Hepcidin, a hormone produced by the liver,
directly inhibits the protein ferroportin that transports iron out of storage cells.
When iron stores are high, hepcidin production is increased and results in a
decrease in intestinal iron absorption, impairment of iron recycling from
macrophages, and decreased mobilization of stored iron from hepatocytes.
Hepcidin production is also induced by inflammation or infection. As a result,
the increase in hepcidin in inflammatory conditions may lead to a sequestering
of iron and ineffective red blood cell production. Conversely, hepcidin
production is decreased when iron stores are low. The fact that hepcidin plays
such a role in iron regulation has prompted the development of agents to target
hepcidin and potentially alter iron transport.31 At this time there are no
commercially available agents.
Additional factors contributing to the development of anemia of CKD are the
decreased red cell life span (from the normal of 120 days to approximately 60
days in individuals with CKD 5D), the effects of accumulation of uremic toxins
and inflammatory cytokines, and vitamin B12 and folate deficiencies.

Chronic Kidney Disease–Related Mineral and Bone

Disorder
Disorders of mineral and bone metabolism are common in the CKD
population and include abnormalities in PTH, calcium, phosphorus, vitamin D,
fibroblast growth factor-23 (FGF-23), bone turnover, as well as soft-tissue
calcifications. Historically these abnormalities have been described as
characteristics of secondary hyperparathyroidism (sHPT) and renal
osteodystrophy (ROD). The term CKD-MBD encompasses these abnormalities
in mineral and bone metabolism as well as associated calcifications.
The pathophysiology of CKD-MBD is complex (Fig. 61-4). Calcium and
phosphorus homeostasis is mediated through the effects of PTH, 1,25-
dihydroxyvitamin D3 (calcitriol), and FGF-23 on bone, the GI tract, kidney, and
the parathyroid gland. As kidney function declines, there is a decrease in
phosphate elimination, which results in hyperphosphatemia and a decrease in
serum calcium concentration. Hypocalcemia is the primary stimulus for
secretion of PTH by the parathyroid glands. Hyperphosphatemia also increases
PTH synthesis and release through its direct effects on the parathyroid gland and
production of prepro-PTH messenger RNA.32 In an attempt to normalize ionized
calcium, PTH increases calcium reabsorption by the distal tubules and decreases
phosphate reabsorption in the proximal tubules of the kidney (at least until the
GFR falls to approximately 30 mL/min/1.73 m2 [0.29 mL/s/m2]) and also
increases calcium mobilization from bone. FGF-23 production in bone also
increases in response to high phosphate levels and increased PTH and promotes
phosphate excretion by the kidney. The result is a relative normalization of
calcium and phosphorus, at least in the early stages of CKD; however, this
occurs at the expense of an elevated PTH and FGF-23 (“the trade-off
hypothesis”). The increase in PTH is most notable when GFR is less than 60
mL/min/1.73 m2 (0.58 mL/s/m2) (CKD 3a and higher) and worsens as kidney
function further declines.32 With advanced kidney disease, the kidney fails to
respond to PTH or to FGF-23 and abnormalities in calcium and phosphorus
worsen. Over time, the negative effects of sustained hyperparathyroidism on
bone are realized as calcium resorption from bone persists.
FIGURE 61-4 Pathophysiology of CKD-MBD. (Ca, calcium; FGF-23,
fibroblast growth factor-23; PTH, parathyroid hormone.) FGF-23 also increases
in response to 1,25-dihydroxyvitamin D3. These adaptations are lost as kidney
disease progresses.

1,25-dihydroxyvitamin D3 or calcitriol promotes increased intestinal

absorption of calcium and phosphorus, which helps normalize ionized calcium.
Calcitriol also works directly on the parathyroid gland to suppress PTH
production. The enzyme 1-α-hydroxylase is responsible for the final
hydroxylation and conversion of the vitamin D precursor, 25-hydroxyvitamin D
or 25(OH)D, to calcitriol in the kidney (Fig. 61-5). As kidney disease
progresses, the concentrations of calcitriol decline due to loss of 1-α-hydroxylase
activity. The resultant vitamin D deficiency leads to reduced intestinal calcium
and phosphorus absorption and worsening hyperparathyroidism. Increases in
FGF-23 also promote calcitriol deficiency.32 Calcitriol deficiency is more
prevalent in individuals with CKD 4-5. Deficiency in 25(OH)D (levels of <30
ng/mL [75 nmol/L]) is also common in individuals with CKD due to decreased
dermal synthesis of vitamin D, decreased exposure to sunlight, and reduced
dietary intake of vitamin D.

FIGURE 61-5 Vitamin D metabolism. Production of active vitamin D requires

conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) by sunlight,
followed by the first hydroxylation step in the liver to form 25-hydroxyvitamin
D3 or 25(OH)D3, and the final conversion step in the kidney to form 1,25-
dihydroxyvitamin D3 or calcitriol. Within the kidney vitamin D may also be
converted to an inactive form 24,25(OH)D3. *If NVD is administered the
resulting compound will be either a D2 compound (as with ergocalciferol) or a
D3 compound (as with cholecalciferol). Paricalcitol and doxercalciferol are
vitamin D analogs. (DBP, vitamin D–binding protein; NVD, nutritional vitamin
D; VDRs, vitamin D receptors.)
 The abnormalities of CKD-MBD lead to alterations in structural integrity of
bone and other associated consequences. The continuous high rate of production
of PTH by the parathyroid glands promotes parathyroid hyperplasia. Nodular
tissue demonstrates more rapid growth potential and appears to be associated
with fewer vitamin D and calcium-sensing receptors, resulting in resistance to
exogenous calcitriol therapy. Bone abnormalities are almost universal in dialysis
patients and observed in the majority of those with CKD 3-5.33 The bone
abnormalities include osteitis fibrosa cystica (high bone turnover disease),
osteomalacia (low bone turnover disease), and adynamic bone disease. Osteitis
fibrosa cystica is most common and is characterized by areas of peritrabecular
fibrosis. Bone marrow fibrosis and decreased erythropoiesis are also
consequences of severe osteitis fibrosa cystica. Osteomalacia was historically
noted in HD patients with aluminum toxicity, a finding less common today due
to the decreased use of aluminum-containing phosphate binders and changes in
the processing of dialysate solutions to decrease aluminum content. Adynamic
lesions are characterized by low amounts of fibrosis or osteoid tissue and low
bone formation rates. Multiple risk factors for the development of this bone
disease include high concentrations of dialysate calcium along with high doses
of calcium-containing phosphate binders, aggressive management with vitamin
D therapy, diabetes, and aluminum toxicity.32
The morbidity and mortality of CKD patients is increased in individuals with
both severe hypo- and hyperparathyroidism.34 Elevations of serum phosphorus,
even within the upper limits of the normal range, have been associated with
increased risk of CV events and/or mortality (all-cause or CV mortality) in
patients with CKD 3-5.35 FGF-23 has also been associated with increased
mortality and cardiovascular events in individuals with CKD. The incidence of
calciphylaxis, or rapid calcification of subcutaneous tissue, in patients with
advanced kidney disease has increased over the past decade and has been
associated with CKD-MBD, an elevated calcium times phosphorus product, and
warfarin use.34,36 Warfarin inhibits the matrix Gla protein, which is a vitamin K–
dependent protein that prevents calcium deposition in arteries, and may therefore
promote vascular calcification in individuals at risk.37 Intake of calcium from
calcium-based binders may also contribute to coronary artery calcification.
These data underscore the need to consider all the consequences of elevated
PTH, calcium, and phosphorus, not just their effects on bone.

CLINICAL PRESENTATION OF CHRONIC

KIDNEY DISEASE
CKD is often asymptomatic, which is a reason many patients are not diagnosed
with the disease until they reach CKD stage 4 or 5 and are at or near the point of
requiring renal replacement therapy. This problem has prompted automated
reporting by clinical laboratories of the eGFR as determined by the estimating
equations (Modification of Diet in Renal Disease [MDRD] equation or Chronic
Kidney Disease Epidemiology Collaboration equations [CKD-EPI equation]) for
the purpose of identifying individuals with CKD earlier (see Chapter e59).
Comprehensive screening for CKD includes analysis of eGFR and uACR and
risk stratification for progression (Fig. 61-1) or estimating equations such as the
kidney failure risk equation. Clinicians must understand how to interpret the
eGFR and values for urine albumin excretion to appropriately stage individuals
with CKD. Chapter e59 provides a detailed discussion of the methods available
for detection of urinary albumin and protein.

Diagnostic Considerations for Anemia of Chronic

Kidney Disease
Signs and symptoms of anemia of CKD include fatigue, shortness of breath, cold
intolerance, chest pain, tingling in the extremities, tachycardia, headaches, and
general malaise. Since individuals with anemia of CKD may be asymptomatic,
laboratory evaluation is commonly the initial approach to diagnosing anemia of
CKD. According to KDIGO guidelines, Hb concentrations should be measured
annually in CKD 3, biannually in CKD 4-5, and at least every 3 months in CKD
5D patients.30 The diagnosis of anemia is made and further workup of anemia is
required when the Hb is less than 13 g/dL (130 g/L; 8.07 mmol/L) for adult
males and less than 12 g/dL (120 g/L; 7.45 mmol/L) for adult females. As iron
deficiency is the primary cause of resistance to treatment of anemia with ESAs,
assessment of the iron status is necessary. The TSat provides information on iron
immediately available for use in the bone marrow for red blood cell production
and the serum ferritin is in indirect measure of storage iron. The TSat is
calculated as follows: (serum iron/total iron-binding capacity [TIBC]) × 100).
Transferrin is the carrier protein for iron and may be affected by nutritional
status. Serum ferritin as an indirect measure of storage iron is an acute-phase
reactant, meaning it may be elevated under certain inflammatory conditions and
give a false indication of storage iron. Patients may be diagnosed with absolute
iron deficiency when whole-body iron stores are low (low TSat and ferritin), or
with functional iron deficiency when the TSat is low, but the serum ferritin is at
or above goal. In this situation, iron is not released rapidly enough to satisfy the
demands for erythropoiesis and further evaluation is warranted. If the TSat and
serum ferritin values are below the desired thresholds, iron supplementation is
necessary.

CLINICAL PRESENTATION
Stage 5 Chronic Kidney Disease (eGFR <15
mL/min/1.73 m2)
Symptoms
• Fatigue, weakness, shortness of breath, confusion, nausea and vomiting,
bleeding, loss of appetite, itching, cold intolerance, and peripheral
neuropathies are common.

Signs
• Edema, weight gain (from accumulation of fluid), changes in urine output
(volume and consistency), “foaming” of urine (indicative of proteinuria).

Laboratory Tests
• Decreased: eGFR, bicarbonate (metabolic acidosis), Hb/hematocrit (Hct)
(anemia), transferrin saturation (TSat) and/or ferritin (iron deficiency;
note: ferritin may be increased due to inflammatory conditions), vitamin
D levels, albumin (malnutrition), glucose (may result from decreased
degradation of insulin with impaired kidney function or poor oral intake),
and calcium (in early stages of CKD).
• Increased: Serum creatinine, blood urea nitrogen, potassium, phosphorus,
PTH, FGF-23, uACR, PCR, blood pressure (hypertension is a common
cause and result of CKD), glucose (uncontrolled diabetes is a cause of
CKD), low-density lipoprotein (LDL) and triglycerides, and calcium
(more likely in CKD 5 and CKD 5D).
• Other: May be hemoccult-positive if GI bleeding occurs secondary to
uremia.

Other Diagnostic Tests

 • Urine sediment abnormalities (hematuria, red blood cell and white blood
cell casts, renal tubular epithelial cells)
• Pathologic abnormalities indicating glomerular, vascular, tubulointerstitial
disease, or cystic and congenital diseases
• Structural abnormalities such as polycystic kidneys, renal masses, renal
artery stenosis, cortical scarring due to infarcts and pyelonephritis, or
small kidneys (common in more severe CKD) detected by imaging
studies (eg, ultrasound, computed tomography, magnetic resonance
imaging, angiography)

Additional workup should be done to evaluate other causes of anemia such as

blood loss, deficiencies in vitamin B12 or folate, or other disease states that
contribute to anemia, including human immunodeficiency virus infection and
malignancies (see Chapter 118). Red blood cell indices (mean corpuscular
volume, mean corpuscular Hb concentration), white blood cell count, differential
and platelet count, and absolute reticulocyte count should also be assessed. A
stool guaiac test should be performed to rule out GI bleeding. Measurement of
serum erythropoietin concentrations is not generally useful since levels may fall
into what is considered a “normal” range, but are insufficient relative to the
degree of decline in Hb.

Diagnostic Considerations for Chronic Kidney

Disease–Related Mineral and Bone Disorder
Symptoms of CKD-MBD are often not evident until significant skeletal damage
has developed; consequently, prevention is the key to minimize the risk of long-
term complications. When signs and symptoms such as bone pain and skeletal
fractures are evident, the disease is not easily amenable to treatment. Thus, the
identification of biochemical or imaging abnormalities which typically precede
clinical manifestations is an essential component of patient evaluation. The
biochemical abnormalities of CKD-MBD that are commonly present in patients
with CKD include alterations in serum phosphorus, calcium, PTH, 25(OH)D,
1,25(OH)2D3 or calcitriol, and FGF-23. Because deficiency in the vitamin D
precursor, 25(OH)D is common and has been associated with negative outcomes
in the CKD population, measurement of 25(OH)D levels in patients with CKD
3-5D is suggested.34 It should be noted, however, that the assay methods for
25(OH)D are not standardized, which creates a challenge regarding the clinical
implications of abnormal values and limits its value as an indicator of
therapeutic response.38 Current monitoring recommendations and goals of
therapy are covered in the section “Treatment of CKD.”
In addition to evaluating biochemical indices that define CKD-MBD,
evaluation of bone architecture may be desirable. The gold standard test for
diagnosing bone manifestations of CKD-MBD is a bone biopsy for histologic
analysis; however, this is a very invasive test that is not easily performed.
KDIGO guidelines recommend bone biopsy only in patients in whom the
etiology of clinical symptoms and biochemical abnormalities is not clear and the
results may lead to changes in therapy.34 This includes patients experiencing
unexplained fractures, persistent hypercalcemia, osteomalacia, an atypical
response to standard therapies for elevated PTH, or progressive decreases in
bone mineral density despite therapy. Bone biopsy findings are described on the
basis of turnover rate, mineralization, and volume. Bone mineral density testing
is recommended in patients with CKD 3-5D with evidence of CKD-MBD and/or
risk factors for osteoporosis.34 CKD-MBD is also highly associated with
vascular and soft-tissue calcifications, known risk factors for mortality;
therefore, diagnostic testing for calcifications should be considered in the
evaluation for CKD-MBD.

TREATMENT OF CKD
Desired Outcome of CKD Treatment
The overall goal of therapy in CKD patients is to delay or prevent progression of
the disease while minimizing the development or severity of associated
complications. Planning for renal replacement therapy (transplantation, HD or
PD) should begin for patients deemed high risk for progression to ESRD (eg, at
stage 4 CKD). Planning should include patient education about home and
facility-based dialysis modalities and options for transplantation. With CKD 5D,
the primary goal is to sustain and improve the patient’s quality of life and
prevent adverse outcomes by aggressively managing complications of CKD.

General Approach to Treatment of CKD

Individuals with CKD should be evaluated frequently to assess the risk of
progression of CKD, to identify the presence and causes of secondary
complications and comorbid conditions, and to receive treatment for these
complications prior to development of Stage 5 CKD. Many nonpharmacologic
and pharmacologic recommendations can be broadly applied as part of the
general approach to care for all CKD patients Table 61-3.

TABLE 61-3 Recommendations for Individuals with Chronic Kidney

Disease
 Management of CKD should be based on KDIGO consensus guidelines,
which are based on evidence and expert recommendations. There are guidelines
provided by the Kidney Disease Outcome Quality Initiative Guideline (KDOQI)
on CKD and many of the associated complications; however, this chapter
emphasizes KDIGO guidelines, which are international guidelines and, in most
cases, based on more recent data or opinion. These recommendations should not
replace clinical judgment, but rather provide a basis on which treatment
decisions can be made in the context of both evidence and opinion. In addition to
evaluation and management of CKD, the secondary complications of CKD that
are addressed in the currently available KDIGO clinical practice guidelines
include blood pressure, CKD-MBD, anemia, lipid management, and hepatitis C.
A diabetes guideline is currently under development. Table 61-4 provides a
guide to the grading and strength of recommendations used in these guidelines.

TABLE 61-4 KDIGO Guidelines: Grading and Strength of

Recommendations
 Appropriate management of CKD ideally involves a multidisciplinary
approach to address the nonpharmacologic and pharmacologic interventions,
dietary education, and social/financial concerns. Multidisciplinary CKD team
models that have included members such as a nephrologist, nurse, dietitian,
pharmacist, and social worker have demonstrated significantly lower risks of
starting dialysis and all-cause mortality.39 Estimates in the pediatric population
indicate that the additional salary costs of the multidisciplinary team
(pharmacist, nurse, social worker, dietician, data manager) could be recovered in
1 year if dialysis was delayed by 1 year in 2% of patients.40 The typical team in
outpatient dialysis facilities includes physicians (nephrologists), nurses,
dietitians, and social workers as mandated by the US government. Although not
mandated to be part of the care team, nephrology-trained pharmacists are active
members of the care team in some CKD and especially dialysis settings in the
United States and their inclusion has resulted in a reduction of MRPs.41 In
Canada, pharmacists’ involvement is more standardized and pharmacists have a
more clearly delineated role in the care of the CKD population.42
Drug-dosing guidelines based on the degree of kidney function should be
followed, and a complete medication history of prescription and nonprescription
medications, as well as herbals and nutritional supplements, should be obtained
and routinely updated. Appropriate measures should also be taken for patients
with CKD to decrease the risk of nephrotoxicity from radiocontrast agents,
antibiotics such as aminoglycosides, as well as from nonsteroidal anti-
inflammatory drugs and ACEIs (Chapter 63).

Nonpharmacologic Therapy for CKD

Nonpharmacologic therapies for CKD include diet and lifestyle interventions
targeted at reducing the risk for CKD progression and are outlined in Table 61-3.
With regard to nonpharmacologic strategies to control blood pressure, a low
sodium diet in people with CKD has been shown to decrease systolic blood
pressure by 6 to 11 mm Hg and diastolic blood pressure by 2 to 5 mm Hg, and is
associated with lower antihypertensive dose requirements.43

Pharmacologic Therapy for CKD

Pharmacologic therapies used to slow down CKD progression include drugs
with demonstrated benefits to reduce proteinuria and to manage the causal
factors for CKD; primarily hypertension and diabetes. The next sections focus
on pharmacologic therapy targeting these factors. Glomerular disease is the third
leading cause of CKD and almost all of the many variants are associated with
significant proteinuria. A thorough review of the epidemiology, pathophysiology,
and treatment strategies for glomerular diseases is provided in Chapter 64.

Proteinuria
ACEIs and ARBs
Evidence from clinical trials has confirmed the beneficial effects of ACEIs
and ARBs on kidney function for DCKD. A meta-analysis has shown that the
effects of ACEIs or ARBs on key CKD outcomes such as doubling of serum
creatinine and prevention of progression of albuminuria are equivalent, and,
thus, they can be used interchangeably.44 An ACEI or an ARB should be used as
first-line therapy if the urine albumin excretion is in category A2 or greater
(uACR >30 mg/g; 3.4 mg/mmol) (see Fig. 61-6 and Table 61-5). The
antiproteinuric effect of ACEIs and ARBs is a class effect and not specific to any
one agent.20 For patients with hypertension, the primary goal is to achieve the
target blood pressure while a secondary goal is to control proteinuria. Specific
dosing recommendations for ACEIs and ARBs for the treatment of proteinuria
have not been established; consequently, the lowest recommended dose should
be initiated. The dose is usually increased until albuminuria is reduced by 30%
to 50% or side effects such as a greater than 30% decrease in eGFR or elevation
in serum potassium occur (see Fig. 61-6). If patients exhibit a cough with an
ACEI, a switch to an ARB is appropriate. A thorough discussion of dose, dose
titration, monitoring, and adverse effects of ACEIs and ARBs is presented in
Chapter 30.
FIGURE 61-6 Treatment of hypertension in chronic kidney disease.20 (ACEI,
angiotensin-converting enzyme inhibitor; ACR, albumin-to-creatinine ratio;
AKI, acute kidney injury; ARB, angiotensin receptor blocker; BP, blood
pressure; CCB, calcium channel blocker; eGFR, estimated glomerular filtration
rate.)

TABLE 61-5 Recommended Monitoring Intervals for Outcome Measure in

Patients with Chronic Kidney Disease (Evidence Rating: Not
Graded)

The lack of response of some patients to ACEI or ARB therapy may be due to
aldosterone escape from renin–angiotensin–aldosterone system (RAAS)
blockade. Combination therapy with an ACEI plus an ARB or direct renin
inhibitor (aliskiren) produces a more complete blockade of the RAAS and results
in a greater reduction in macroalbuminuria.45 However, several trials have failed
to show that dual blockade of the RAAS either slowed progression of CKD or
decreased CV events.46–49 Combination therapy in these trials was also
associated with increased risks of hyperkalemia and acute kidney injury. Thus,
the combination of an ACEI plus an ARB or aliskiren for the treatment of
proteinuria is no longer recommended.
Sodium Glucose Transport-2 Inhibitors
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors show considerable
promise in slowing progression of DCKD with benefits that seem to be
independent of the glucose lowering effect.50 By reducing glucose and sodium
reabsorption in the proximal tubule of the kidney, these agents decrease
glomerular hyperfiltration and reduce glomerular hypertension. Post-hoc
analysis of the empagliflozin cardiovascular trial (EMPA-REG) showed
beneficial kidney effects including reduced albuminuria, slowed eGFR decline,
and a 50% reduced risk for progressing to ESRD; these benefits were consistent
across patients with eGFR ≥30 mL/min/1.73 m2.51 The CREDENCE trial
assessed whether canagliflozin 100 mg daily added to renin–angiotensin–
aldosterone blockade and baseline diabetic treatments slowed progression of
DCKD in participants with Type 2 diabetes mellitus, albuminuria of >300 to
5000 mg/g (34 to 570 mg/mmol), and eGFR of 30 to <90 mL/min/1.73 m2.52
The number needed to treat was 22 out of 1,000 patients treated over 2.5 years to
prevent the composite outcome of ESRD, doubling of serum creatinine or renal
or cardiovascular death. In addition, canagliflozin was shown to prevent 22
hospitalizations for heart failure and 25 events of the composite endpoint of
cardiovascular death, myocardial infarction or stroke for every 1,000 subjects
treated. The US Food and Drug Administration approved canagliflozin for
treatment of DCKD to reduce the risk of renal events, cardiovascular mortality,
and hospitalization for heart failure. The Dapa-CKD trial is examining the
effects of dapagliflozin on renal outcomes and cardiovascular mortality.53 A
more detailed discussion of SGLT-2 inhibitors may be found in Chapter 91.

Other Agents
The concept of aldosterone escape has led to the search for other drug
combinations to further suppress the RAAS in an effort to improve kidney
outcomes. A Cochrane systematic review examined the addition of an
aldosterone antagonist (spironolactone) to an ACEI or ARB (or both) in patients
with CKD 1-4.54 Aldosterone antagonists significantly reduced proteinuria and
blood pressure, but doubled the risk of hyperkalemia and significantly increased
the risk of gynecomastia. However, it is unknown whether adding spironolactone
to ACEI or ARB (or both) will reduce the risk of major CV events or ESRD.
Another meta-analysis of spironolactone in DCKD reported similar results.55
Dihydropyridine calcium channel blockers (CCBs) do not appear to have any
beneficial effects beyond those attributable to reducing blood pressure.
Nondihydropyridine agents (diltiazem and verapamil), however, have yielded
beneficial effects on proteinuria, although not as profoundly as ACEIs.56 The
postulated mechanisms for this decrease in kidney injury include suppression of
glomerular hypertrophy, inhibition of platelet aggregation, and a decrease in salt
accumulation. These agents have been used to reduce proteinuria in combination
with an ACEI or ARB despite the fact that there are limited data to support this
strategy. In general, nondihydropyridine CCBs should be considered second- or
third-line antiproteinuric drugs when an ACEI or ARB is contraindicated or not
tolerated (Fig. 61-6).57

Hypertension
Figure 61-6 provides an algorithm for recommended blood pressure goals based
on the degree of albuminuria present and the choice of antihypertensive agent.
The Systolic Blood Pressure Intervention Trial (SPRINT) assessed whether a
lower systolic blood pressure goal of less than 120 mm Hg versus a target of less
than 140 mm Hg was desirable.58 Patients aged 50 years or older with a systolic
blood pressure of 130 to 180 mm Hg and an increased risk of CV events were
included. CKD 3a to 4 patients (eGFR of 20-59 mL/min/1.73 m2) were enrolled
into this trial as they were considered to be at high CV risk (see Chapter 30 for a
discussion of non-CKD results). It is important to note that patients with a
history of diabetes, category A3 proteinuria defined as greater than or equal to 1
g/24 hours of protein or albuminuria greater than or equal to 600 mg/24 hours,
polycystic kidney disease, or a history of stroke were excluded. In the 2,646
participants with CKD, the composite renal outcome of a decrease in eGFR of
50% or more or the need for chronic dialysis or kidney transplantation was not
significant over the 3.3 years duration of this trial. There were also potential
harms to all participants (with and without CKD) in the intensive systolic blood
pressure group that included significantly increased risks of syncope,
hypotension, electrolyte abnormalities, AKI and CKD progression.58 A target
SBP of <120 mm Hg may be appropriate in patients with a Framingham risk
score of >15% who do not have comorbidities such as diabetes, stroke, or
advanced CKD. It may also be appropriate in patients who achieve SBP in the
120s without requiring a high number of antihypertensives and who are not
experiencing adverse effects of therapy. Lastly, patients prescribed ACEI/ARBs
or diuretics who are targeting an SBP <120 mm Hg need to be reliable and able
to follow instructions to hold these medications when they are unable to
maintain adequate fluid intake (eg, vomiting/diarrhea) due to the risk of AKI.
Diabetes
Patients with diabetes should be screened annually for CKD starting at the time
of diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes
by ordering a serum creatinine, eGFR, and a uACR.17
The management of diabetes in patients with CKD includes reduction of
proteinuria and achievement of desired blood pressure and HbA1c (Chapter 91).
The HbA1c target in this patient population should be 7% (0.07; 53 mmol/mol
Hb); however, clinicians may consider a target greater than 7% (0.07; 53
mmol/mol Hb) if there is a risk of hypoglycemia or limited life expectancy
(Evidence rating: 1A).9,17 It should be noted that HbA1C measurements are
based on an assumed red blood cell life span of 120 days. In CKD, the red blood
cell life span is decreased, so HbA1c values may be falsely low.9 Hence, in
patients with CKD, the HbA1c should be interpreted along with the patient’s
home blood glucose readings when assessing diabetic control. It is also
important to note that patients with CKD 3 and 4 are at higher risk of developing
hypoglycemia because of the reduction in metabolism of insulin by the kidney as
GFR declines. As a result, these patients may require reduced doses of oral or
injectable hypoglycemic agents. Metformin is still considered a first-line agent
in individuals with type 2 diabetes and CKD. As previously discussed, SGLT-2
inhibitors are emerging as a potential new treatment of DCKD. These agents
may be used in patients with an eGFR above 25 to 30 mL/min/1.73 m2 (see
Chapter 91 for more details). Metformin can be initiated and/or continued in
individuals with an eGFR greater than or equal to 45 mL/min/1.73 m2. It is not
recommended to initiate metformin in patients with an eGFR between 30 and 44
mL/min/1.73 m2, and the decision whether to continue therapy in patients who
reach this level of kidney function should be made only after weighing the risks
and benefits.19 Metformin is contraindicated in individuals with an eGFR less
than 30 mL/min/1.73 m2 and should be temporarily discontinued before
administering iodinated contrast agents for imaging studies. Dose adjustments or
avoidance of other renally eliminated hypoglycemic agents may also be
necessary; the dosing, monitoring, and goals of therapies to treat diabetes
mellitus are provided in Chapter 91 and an evidence-based approach to drug
therapy individualization is presented in Chapter 65.

Evaluation of Therapeutic Outcomes

Frequency of laboratory and urine testing based on CKD category and degree of
albuminuria as defined by KDIGO is shown in Table 61-5. The monitoring
necessary for patients with hypertension and diabetes is the same in the CKD
population as it is in the non-CKD population, and readers should refer to the
appropriate chapters in this textbook for further information.

TREATMENT OF SECONDARY
COMPLICATIONS
Anemia of CKD
Treatment of anemia often requires a combination of iron supplementation and
ESA therapy to promote and maintain erythropoiesis and to achieve the
individual patient goals.

Desired Outcome
The desired outcomes of anemia management are to increase oxygen-carrying
capacity, decrease signs and symptoms of anemia, and decrease the need for
blood transfusions. Hb is the preferred monitoring parameter for red blood cell
production because, unlike Hct, its concentration is not affected by blood storage
conditions and instrumentation used for analysis. Initiation of iron or ESA
therapy is guided by the patient’s Hb, TSat, and ferritin (Table 61-6).30 The risk
of mortality and CV events is higher in CKD patients treated to higher Hb target
values with an ESA. There are discrepancies, however, in the FDA-approved
labeling for ESAs and KDIGO anemia guidelines in terms of when to initiate
therapy and the target Hb.30,59

TABLE 61-6 KDIGO Recommendations for Initiation of Erythropoiesis

Stimulating Agents and Iron in Anemia of Chronic Kidney
Disease
 Despite associations of development of left ventricular hypertrophy (LVH)
with worsening anemia, there are no prospective studies demonstrating that early
and aggressive treatment improves CV endpoints or reduces LVH in CKD
patients. Improvements in quality of life are not universally observed with
increases in Hb and such perceived improvements must be weighed against
reported risks associated with using ESAs to achieve near-normal Hb levels in
the CKD population.60

Target Hemoglobin and Use of Erythropoiesis-

Stimulating Agents
The target range for Hb in the CKD population has been a topic of much debate.
Although the benefits of achieving a normal or near-normal Hb seemed rational
when ESAs became available in the late 1980s, the Normal Hematocrit Cardiac
Trial (NHCT),61,62 the Correction of Hb and Outcomes in Renal Insufficiency
(CHOIR),63 and the Cardiovascular Risk Reduction by Early Anemia Treatment
with Epoetin Beta (CREATE)64 trials later proved otherwise, and the suggested
target Hb at the time of those trials of 11 to 12 g/dL (110-120 g/L; 6.83-7.45
mmol/L) was subsequently lowered. Several FDA advisories have been released
and changes made to the precautions, black box warning, and dosing sections of
ESA product labeling promoting more conservative use of ESAs.65 The current
labeling for all ESAs warns that dosing ESAs to target Hb levels greater than 11
g/dL (110 g/L; 6.83 mmol/L) for CKD patients increases the risk for death,
serious CV reactions, and stroke. Practitioners are advised to consider ESAs in
patients with CKD only when the Hb is below 10 g/dL (100 g/L; 6.21 mmol/L)
and to individualize therapy to use the lowest ESA dose necessary to decrease
the need for red blood cell transfusions. The goal is not to normalize Hb in
patients with CKD treated with an ESA.
Of concern is the fact that CHOIR demonstrated that targeting Hb levels
above 11 g/dL (110 g/L; 6.83 mmol/L) with ESA therapy in individuals with
CKD not requiring dialysis resulted in increased risk of mortality and CV events
compared with patients maintained in a lower Hb range (trial was terminated
early).63 CREATE demonstrated no benefit of targeting a higher Hb target (13-
15 g/dL [130-150 g/L; 8.07-9.31 mmol/L]) to reduce CV events in the
nondialysis CKD patients.64 An increased risk of all-cause mortality with ESA
treatment was also reported in a meta-analysis of nine randomized controlled
trials that included over 5,100 CKD patients treated to Hb targets in the range of
12 to 16 g/dL (120-160 g/L; 7.45-9.93 mmol/L).66 There was also a higher risk
of dialysis access thrombosis and uncontrolled blood pressure in the higher Hb
groups. Results from the Trial to Reduce Cardiovascular Events with Aranesp
Therapy (TREAT) also failed to support a higher Hb.67 In addition, there was
also an almost twofold increase in the risk of stroke (5% in the treatment group
vs 2.6% in the placebo group), a finding that was not associated with baseline
characteristics of the patients or other potential risk factors. Those patients with
a history of cancer in the higher Hb group also had a higher risk of death.
The overall negative CV outcomes observed with higher Hb targets in the
randomized trials have prompted much discussion about the potential causes,
including not only ESA dose and Hb target, but also the rate of rise in Hb and the
variability in Hb over time (eg, degree of fluctuation in Hb). High-dose ESA use
has been associated with greater risk of death.68 Individuals in the CHOIR study
who were able to achieve the target Hb did not have worse outcomes. Further
analysis of the NHCT data also showed a reduction in mortality by 60% for
those individuals who responded to epoetin therapy compared with
nonresponders.62 Such findings have led to discussion of whether
hyporesponsiveness to ESAs due to other conditions such as inflammation may