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CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

Educational Review Manual


in Nephrology
Second Edition • 2008

Editor-in-Chief
Ajay K. Singh, MB, FRCP(UK)
Associate Professor of Medicine, Harvard Medical School
Director, Postgraduate Medical Education
Department of Medicine and Renal Division,
Brigham and Women’s Hospital
Chapter 6:
Chronic Kidney Disease
Ajay K. Singh, MB, FRCP
Daniel W. Coyne, MD

Contents

1. Introduction

2. Staging and Classification of CKD

3. Epidemiology of CKD

4. CKD Economics

5. Importance of Early Recognition of CKD and


Timely Referral to Nephrological Care

6. Cardiovascular Risk Stratification in Patients


With Kidney Disease

7. Screening for CKD

8. Measurement of Kidney Function

9. Clinical Aspects of CKD

10. Key Complications of CKD

11. Management of Kidney Disease Progression

12. References

CHAPTER 6: CHRONIC KIDNEY DISEASE 197


1. Introduction 2. Staging and
Classification of CKD

Chronic kidney disease (CKD) is defined by the CKD is staged by using glomerular filtration rate
National Kidney Foundation as either: 1.) a (GFR) categories. The NKF-K-DOQI has classified
glomerular filtration rate (GFR) of <60 mL/min CKD into 5 stages (Table 1).1 The strengths of the
with or without kidney damage for 3 or more NKF K-DOQI classification are its simplicity and
months; or 2.) the presence of kidney damage for 3 its use of estimated GFR (eGFR) to classify CKD
or more months demonstrated by pathologic abnor- into different stages. Furthermore, the widespread
malities, markers of kidney damage (eg, blood or adoption of the classification has resulted in, per-
urine composition), or imaging tests.1 In the United haps for the first time, a uniform system understood
States, it is estimated that CKD affects 7%-10% of and applied worldwide. Indeed, the classification
the adult population, or 15 to 20 million individuals, serves as a useful starting point in evaluating a
although specific subgroups such as African-Ameri- patient with depressed GFR. It also provides the
cans and Hispanics are at especially high risk. impetus to either refer a patient to a nephrologist for
further work-up, or to identify a patient at higher
There is growing consensus on the importance of risk of developing cardiovascular complications.
using a prediction equation to estimate kidney func-
tion rather than relying on serum creatinine. Recent The major limitations of the NKF CKD classifica-
observational data has also emphasized the connec- tion are as follows. It stages the severity of kidney
tion between kidney disease and cardiovascular dis- disease on the basis of GFR without incorporating
ease (CVD), indicating the primary importance of other important parameters such as albuminuria.
CVD as a source of mortality among CKD patients. Two patients with similar GFR but with wide differ-
Also, the importance of CKD as a risk factor in ences in the degree of proteinuria at baseline are
patients with CVD has emerged. It has become evi- likely to have very different prognosis. The patient
dent that the level of kidney function as assessed by with high degree proteinuria is more likely to have a
either serum creatinine or estimated glomerular fil- worse prognosis. The NKF classification also
tration rate is a key factor in predicting survival after leaves unaddressed the significance of reduced GFR
an acute myocardial infarction (MI). From a thera- below 60 mL/min/1.73m2 in certain subgroups,
peutic standpoint, considerable progress has been such as the elderly, the undernourished, and mem-
made in demonstrating the critical role of the renal- bers of specific ethnic groups. For example, elderly
angiotensin system in mechanistically influencing individuals with reduced GFR may never develop
the progression of kidney disease. Angiotensin
blockade slows the progression of every stage of
CKD, whether CKD is caused by diabetes or not
(although the role of angiotensin blockade in retard-
ing the progression of specific disorders has not
Table 1

been established). Angiotensin converting enzyme


inhibitors and angiotensin receptor blockers have
NKF Classification of CKD

become an essential part of the armamentarium of


the practicing nephrologists. K-DOQI guidelines
from the National Kidney Foundation (NKF) and
Stage 1: Kidney damage with normal or supranormal

similar documents from the Renal Physician’s


GFR, GFR ≥90

Association (RPA) have sought to organize nephrol-


ogy practice by establishing consensus around the
Stage 2: Kidney damage with mild reduction in GFR,

evaluation and treatment of CKD. The purpose of


GFR 60-89

this chapter is to review the definition and epidemi-


ology of CKD, gain an understanding of the differ-
Stage 3: Moderate reduction in GFR, GFR 30-59

ent methods of measuring kidney function, and


evaluate and manage the major complications of
Stage 4: Severe reduction in GFR, GFR 15-29

CKD—in particular anemia, cardiovascular dis-


ease, and renal osteodystrophy.
Stage 5: Kidney failure, GFR <15 or on dialysis

198 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


3. Epidemiology of CKD

end-stage renal disease. Patients with congestive Using extrapolations from the NHANES study, it is
cardiac failure may have a low GFR because of estimated that approximately 19 million individuals
hemodynamic reasons but do not have any struc- in the United States have CKD.2,3 These estimations
tural evidence of kidney disease, and kidney func- provide a ballpark prevalence number because the
tion may normalize once the heart failure is treated. NHANES data relies on a single creatinine mea-
However, it is important to note that the use of NKF surement. As well, the NHANES White Sands labo-
CKD criteria may not apply to some racial groups ratory did not calibrate creatinine measurement with
since their GFR may be naturally lower than West- the Cleveland Clinic laboratory where the MDRD
ern levels as a consequence of smaller stature, lower predictive equation was generated.4 Thus, these
muscle mass, and vegetarianism. NHANES-based CKD prevalence estimates are
likely to be somewhat higher than the true figure.

Most individuals with CKD are people with earlier


stages of CKD. The prevalence estimates of CKD
stages in 1999-2004 are approximately 1.8% (stage
1); 3.2% (stage 2); 7.7% (stage 3) and 0.35% (stage
4). This number has increased approximately
10%-13% from 1998-1994 to 1999-2004. 2 ,3 Of
those with stage 5 CKD, the number of individuals
with kidney failure treated by dialysis and trans-
plantation exceeded 440,000 with 0.03% of the US
population beginning renal replacement therapy in
2004, an adjusted incidence rate of 339 per million,5
and while the prevalence is likely to demonstrate
continued growth, recent data reported from the
USRDS suggests that the incidence rate of ESRD
(new cases of kidney failure) appears to have stabi-
lized after 20 years of annual increase of 5%-10%
per year. (In the latest numbers from USRDS, the
ESRD incidence rate was 338 per million with an
annual increase of just 1%.)6

CKD as a Global Problem

CKD is an emerging global problem largely because


of the diversity of the risk factors involved in CKD
causality (Table 2),7 and because the world is in the
midst of a diabetes epidemic.8 Superimposed on the
diabetes epidemic is the problem of poverty. Data
recently published suggests that poverty and impov-
erishment are key risk factors for CKD.8 It is esti-
mated that the majority of the world’s population
lives in low-income countries, such as China, India,
Indonesia, and Pakistan, where incident rates of dia-
betes are also the highest.9 Furthermore, the stakes
are much higher in the developing world because
poverty frequently precludes the possibility of renal
replacement therapy if ESRD does ensue.

CHAPTER 6: CHRONIC KIDNEY DISEASE 199


4. CKD Economics

Data on the prevalence of CKD in the developing The cost of medical care for patients with CKD is
world is quite limited.10-12 CKD in the developing high, and is reviewed in detail elsewhere.17 The
world suggests a prevalence of approximately average cost of care for a CKD patient is approxi-
5%-10% (Pakistan data is based on the Cockcroft- mately $1,300 per month compared to approxi-
Gault estimation of creatinine clearance and the mately $500 per month for a non-CKD patient.
estimate for CKD prevalence is 29%).12 This would This number is dwarfed by the cost of care for an
suggest that there are many millions of people ESRD patient—approximately $5000 each
among these that have CKD. However, it is impor- month. CKD patients consume a disproportion-
tant to be cautious in reaching this conclusion since ate share of health care resources.18 In 2002, the
the published studies, so far at least, have method- total cost of the ESRD program in the United
ologic limitations. These include the reliance on a States was $25.2 billion in 2002, an 11.5%
single creatinine as the measure of kidney function; increase from the previous year. Despite the cost
the lack of creatinine standardization against any of treatment of ESRD and improvements in the
international laboratory standard; and the absence quality of dialysis therapy, mortality and morbid-
of studies validating an estimating equation in a ity remains significant. In 2002, 71,006 ESRD
non-American population.13 patients died. Incidence and prevalence counts
for ESRD are expected to increase by 44% and
In the United States, there are notable racial differ- 85%, respectively, from 2000 to 2015 and inci-
ences in the epidemiology of CKD. This is reviewed dence and prevalence rates per million popula-
in detail elsewhere.14-16 African Americans, Pacific tion by 32% and 70%, respectively. Survival
Islanders, Latinos, and Native Indians have a higher probabilities for dialysis patients at 1, 2, 5 and 10
prevalence of CKD than Caucasians. African- years are approximately 80%, 67%, 40%, and
Americans are at especially high risk—a 3- to 4- 18%, respectively. Moreover, 50% of dialysis
fold higher risk than Caucasians. In particular, patients have three or more comorbid conditions,
African-Americans appear to have a higher preva- the mean number of hospital days per year is
lence of hypertensive kidney disease than Cau- approximately 14 per patient, and self-reported
casians (Table 3). quality of life is far lower in dialysis patients than
in the general population.

200 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


Table 2

Risk Factors for Chronic Kidney Disease

Susceptibility Initiation Progression End-Stage


Factors Factors Factors Factors

Older age Diabetes Proteinuria Low dialysis dose


Family history Hypertension Hypertension Vascular access
Low kidney mass Autoimmune disease Poor glycemic control Anemia
Low birth weight Systemic infections Smoking Low serum albumin
Low income Urinary tract infections Late referral
Minimal education Lower urinary tract
Obstruction
Drug toxicity

Levey, et al. Ann Intern Med. 2003;139:137

Table 3

Prevalence of CKD in the United States by CKD Stage

Stage Description GFR* Population (thousands) Prevalence

1 Kidney damage with ≥90 5,900 3.3%


normal or supranormal
GFR

2 Kidney damage with 60-89 5,300 3.0%


mild decrease in GFR

3 Moderate decrease 30-59 7,600 4.3%


in GFR

4 Severe decrease in GFR 15-29 400 0.2%

5 Kidney failure <15 300 0.2%

* GFR expressed in mL/min/1.73 m2

CHAPTER 6: CHRONIC KIDNEY DISEASE 201


5. Importance of Early
Recognition of CKD and Timely
Referral to Nephrological Care

Looming large over concerns about the current man- data suggests that decreased morbidity and mortality
agement of CKD are the issues of CKD under-recog- and lower costs are associated with early referral.
nition and late referral to nephrology.19 Under-recog- Indeed, patients referred late in the course of their
nition partly reflects the continued use of serum crea- kidney disease are more likely to have anemia and
tinine as a screening test for kidney disease. Since hypoalbuminemia, less likely to have been started
there is a nonlinear relationship between serum crea- on erythropoietin, and are less likely to have perma-
tinine and GFR20,21 and because women have lower nent AV access.
muscle mass than men, the problem of under-recog-
nition is particularly acute among women.3 Only
approximately 4% of women with moderate CKD
(GFR 15 to 59 mL/min/1.73m2) are aware that they
have CKD.

Specific components of CKD care are associated


with substantial quality gaps.22 Under-utilization of
angiotensin blockers has been noted; high blood
pressure is poorly controlled generally; and under-
treatment is common in those with CKD, despite evi-
dence that blood pressure can be safely and effec-
tively lowered in CKD by combinations of antihy-
pertensives. Patients with diabetes are inconsistently
screened for early nephropathy. Patients with hyper-
tension or diabetes often do not have serum creatinine
checked in primary care. This despite evidence from
the Steno study23 that demonstrated that in the setting
of a specialized clinic, intensified multiple risk factor
intervention results in better outcomes in diabetics
compared to usual care.24

Several authors have argued that CKD patients


should be referred to nephrologists early in the
course of their disease because this is associated
with improved outcomes.24 The National Kidney
Foundation recommends that referral to a nephrolo-
gist should be made at least by the time the GFR has
reached 25 mL/min/1.73m2. However, there is a
lack of consensus among nephrologists regarding
the kidney function criteria for referral because of a
fear that nephrologists may not be able to accommo-
date an excess of patients into their practice. Late
referral appears to result in higher rates of major
complications, longer and more frequent stays in
hospital, worse values for homeostatic indicators at
the start of dialysis, suboptimal vascular access, and
worse survival than patients referred early. Studies
suggest that CKD patients referred early have better
vocational outcomes, a delay in the onset of ESRD,
better values for homeostatic indicators, less use of
temporary devices for vascular access, and lower
consumption of hospital resources. Observational

202 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


6. Cardiovascular Risk
Stratification in Patients
With Kidney Disease

CVD is common in patients with all stages of kid- older age, diabetes mellitus, systolic hypertension,
ney disease (Table 4).25 Approximately 25% of and LVH are highly prevalent in CKD patients and
patients with mild to moderate CKD (stages 2 and 3) their relationship to CVD is the same regardless of
have evidence of left ventricular hypertrophy and CKD status. On the other hand, there appears to be
this increases to 40%-70% of patients by the time of what has been termed a reverse epidemiology for
end stage renal disease (stage 5 CKD). Patients with other factors, such as hypertension and LDL choles-
CKD also have a higher prevalence of congestive terol among dialysis patients. The increased risk at
heart failure (CHF). CHF represents a significant lower levels of blood pressure and cholesterol may
risk factor for mortality, especially when anemia is reflect confounding from cardiomyopathy and mal-
also present. A number of factors contribute to the nutrition, respectively, although this has not been
increased prevalence of CVD in patients with kid- proved.
ney disease.26 These can be divided into traditional
and nontraditional. The definition of traditional risk The role of nontraditional risk factors in influencing
factors are those factors that have been used to esti- CVD risk in CKD is more controversial. Observa-
mate the risk of developing symptomatic ischemic tional studies strongly suggest that factors such as
heart disease in the Framingham study (Table 5). proteinuria, hemoglobin level, inflammation, and
Traditional Framingham CVD risk factors, such as calcium-phosphorous abnormalities are important.
However, definitive evidence remains currently
lacking. Some of these nontraditional risk factors
are specific to kidney disease and worsen with pro-
gressive impairment of kidney function.27 It is likely
Table 4

that the increase in cardiovascular risk in patients


with CKD is a multifactorial composite of both tra-
Guidelines for Referral to Nephrology

ditional CV risk factors and nontraditional renal


specific risk factors. Many of these traditional and
nontraditional risk factors are modifiable and there-
Serum Creatinine (SCr)

fore need to be studied in order to assess whether


treatment of these factors improves outcome.
Males: SCr ≥2.0 mg/dL
Females: SCr ≥1.5 mg/dL

GFR

GFR≤60 mL/min/1.73m2
In patients who are fast progressors (defined as a
GFR decline ≥4 mL/min/1.73 m2 per year)

Proteinuria

Dipstick proteinuria >3+


Spot urine protein (mg/dL) to
creatinine (mg/dL) ratio >1.0
24-hour urine collection >1.0 gm/24 hrs/1.73 m2

Complications of CKD that are Refractory to


Management and Require Subspecialist Input

Anemia
Hypertension
Acidosis
Renal osteodystrophy

CHAPTER 6: CHRONIC KIDNEY DISEASE 203


7. Screening for CKD

The justification for screening for CKD continues lines for CKD recommend that all individuals
to be debated.28 Because of the relatively low preva- should be assessed as part of routine health examina-
lence of CKD, screening of the general population tions to determine whether they are at increased risk
is unlikely to be cost effective. On the other hand, for developing CKD. Individuals at high risk for kid-
since kidney disease becomes symptomatic in the ney disease, particularly those with diabetes, hyper-
late stages of CKD, and since therapeutic strategies tension, or a family history for these conditions
such as angiotensin blockade and tighter blood and/or for kidney disease, should undergo formal
pressure control have been proven to be effective at testing. Such testing can be performed easily with a
earlier stages, detection of CKD early could poten- urinalysis, a first morning or a random “spot” urine
tially prevent ESRD in a significant proportion of sample for albumin or protein and creatinine assess-
patients. ment, and a serum creatinine level. The American
Diabetes Association (ADA) recommends that for
African Americans and Native Americans have a all type 2 diabetics at the time of diagnosis and all
higher risk of CKD than others (953 and 652 cases type 1 diabetics 5 years after initial diagnosis, an
per million in African Americans and Native Amer- evaluation for microalbuminuria should be per-
icans, respectively, compared to 237 per million formed.30 If the dipstick is positive for either red or
among Caucasians). Also, patients with diabetes white blood cells, a microscopic analysis should be
mellitus and hypertension and those with urine dip- performed of the urinary sediment.
stick positive for protein have a higher risk of devel-
oping CKD. Indeed, in a recent position paper
De Jong and Brenner recommend routine urine
albumin screening as a cost effective way of detect-
ing progressive CKD.29 The NKF-K/DOQI guide-

Table 5

Traditional Framingham CVD Risk Factors are Highly Prevalent in CKD Patients

Traditional Risk Factors Hypothesized Nontraditional Risk Factors

Age Albuminuria
Male sex Abnormal calcium/phosphate metabolism
Diabetes Anemia
Hypertension Inflammation
Higher LDL cholesterol Oxidative stress
Lower HDL cholesterol
Smoking
Extracellular fluid volume overload
Physical inactivity
Menopause
Family history of CVD
LVH

204 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


8. Measurement of
Kidney Function

Given these limitations with serum creatinine as a


measure of actual GFR, the NKF K-DOQI and the
Use of Serum Creatinine

Measurement of serum creatinine is currently the National Kidney Disease Education Program
most widely utilized measure for the assessment of (NKDEP) have recommended the use of actual
kidney function. However, the use of serum creati- GFR or, when this is unavailable, a prediction equa-
nine has several limitations31 (Table 6). Because cre- tion for estimating GFR.35 Since in most situations
atinine production is dependent on muscle mass, it direct measurement of GFR is not feasible, a pre-
needs to be interpreted cautiously among individu- diction equation to estimate GFR is the most practi-
als with low muscle mass, among females, and in cal and accurate method to assess kidney function.35
elderly patients. In patients with low muscle mass, The MDRD and Cockcroft-Gault equations are
the serum creatinine underestimates the degree of now the most popular prediction equations to assess
kidney function impairment, whereas among indi- GFR in adults.
viduals with large muscle mass (such as body-
builders) the serum creatinine overestimates actual Recently, an isotope dilution mass spectroscopy
GFR. Another source of inaccuracy is the effect of traceable (IDMS) MDRD equation (also known as
noncreatinine chromogens when the alkaline picrate the MDRD 3 equation) has been developed.34 In
assay (Jaffe reaction) for creatinine is utilized.32 essence this is a modified MDRD equation used
These factors include acetoacetate, cephalosporins, when creatinine values are generated from a labora-
and high concentrations of furosemide. Modern tory that has calibrated its creatinine measurement
versions of the Jaffe assay have reduced these to a set of creatinine standards. Until recently, one of
effects by adjusting temperature, assay con- the major limitations of using an estimated GFR
stituents, and various calibration settings. How- equation, such as the MDRD equation, was that
ever, in order to truly reduce the effect of non-crea- there was significant variability in the measurement
tine chromogens, alternative methods are neces- of serum creatinine that results in reduced accuracy
sary. These include an enzymatic creatinine assay, of the MDRD equation in the normal to slightly ele-
HPLC, or isotope dilution mass spectroscopy vated creatinine range (up to 1.5 mg/dL). This is
(IDMS). Furthermore, calibration of the serum cre- because assays in most laboratories are not cali-
atinine is important to reduce intra- and interlabora- brated to the alkaline picrate method used by the
tory variability.33,34 Cleveland Clinic laboratory during the conduct of
the MDRD study. Mass spectroscopy is the most
ideal method to obtain a “true” creatinine value and,
therefore, creatinine standardization using an IDMS
traceable panel for creatinine is now being recom-
Table 6

Limitations of Serum Creatinine as a mended. The MDRD 3 equation is as follows:

175x [SCr]-1.154 x [Age]-0.203 x [0.742 if patient


Measure of Kidney Function

is female] x [1.21 if patient is black]


1. Influence of muscle mass
2. Effect of creatinine secretion Prediction Equations for GFR (Table 7)

Cockroft-Gault (CG) Equation: This prediction


a.) Patients with CKD – greater proportion of

equation is commonly used in clinical practice. Its


creatinine is secreted than filtered

major limitations are: 1.) It has limited generaliz-


b.) Medications blocking proximal secretion

ability. This is because it was originally formulated


a. cimetidine

to calculate the creatinine clearance in patients with-


b. trimethoprim

out kidney disease (Canadian males). It has not been


c. probenecid

widely validated in different populations and under


different clinical situations. 2.) CG tends to overes-
timate GFR, especially among patients with chronic
kidney disease. This is because it utilizes serum cre-

CHAPTER 6: CHRONIC KIDNEY DISEASE 205


atinine to estimate creatinine clearance. The limita- predialysis patients and renal transplant recipients.
tions of measuring creatinine clearance apply to the Validation for other subgroups, such as Asians, chil-
CG equation. Among patients with moderate to dren, and the elderly still needs to be performed. In
severe kidney disease, creatinine secretion as a pro- 2000, a simplified MDRD equation (MDRD 2) was
portion of total creatinine excretion increases, made available. It is based on serum creatinine as
resulting in an overestimation of the creatinine the only laboratory value—in the absence of urea or
clearance. 3.) Like the MDRD equation, the CG albumin.37 The MDRD formula yields an eGFR nor-
equation is inaccurate among individuals with nor- malized to 1.73m2 body surface area. Adjusting for
mal or near-normal kidney function. 4.) The CG body surface area is necessary when comparing a
equation uses weight, which frequently results in patient’s eGFR with normal values or when deter-
inaccuracies at extremes of weight and/or when mining the stage of CKD. However, an uncorrected
there is a measurement error in the assessment of eGFR may be preferred for clinical use in some situ-
weight. Despite these limitations, CG remains pop- ations, such as drug dosing (Table 9).
ular, especially among pharmacists who utilize it for
drug-dosing adjustments in patients with reduced
kidney function (Table 8).
Clearance by Radiologic Contrast Agents
and Radioactive Isotopes

MDRD: “The Modification of Diet in Renal Dis- GFR can be calculated by the measurement of uri-
ease Study” GFR prediction equation was devel- nary or plasma clearances of isotopes or via images
oped in 1999.36 The equation is based on 1,628 non- produced from a gamma camera.38 There are 4 dif-
diabetic subjects, age 18-70, with renal insuffi- ferent agents that are used in clinical practice: [125
ciency. The formula utilizes urea, creatinine and I] iothalamate,51 Cr-ethylenediaminetetraacetic acid,
albumin as well as demographics of age, gender, 99m Tc-diethylenetriaminepentaacetic acid, and
and race (black or white). If race is unavailable and iohexol. These agents have been shown to correlate
white race is assumed, the GFR will be underesti- well with inulin clearance. They also have high pre-
mated by 18% if the patient is black. This equation cision in the setting of moderate to severe renal dys-
has been validated in American black and white function. Inulin clearance is the gold standard for
racial groups. It has also been validated in diabetics, measurement of actual GFR, since it is freely fil-
tered and neither secreted nor reabsorbed by the kid-
ney. However, it is not widely used in clinical prac-
tice largely for logistical reasons.38
Table 7

GFR Equations

Table 8
Cockcroft-Gault (CG): CrCl × BSA/1.73 m2
Advantages of the MDRD Over CG Equation
For men: CrCl = [(140-Age(yr)) xWeight (kg)]/
SCr x72
Direct comparison of the MDRD and the Cock-
For women: CrCl = ([(140 -Age) xWeight (kg)]/SCr x croft–Gault equation demonstrate the MDRD equation
72) x 0.85 to be superior for estimating GFR, particularly in the
range GFR < 60 mL/min/1.73m2
MDRD 1: GFR = 170 x [SCr]-0.999 x[Age]-0.176 x[0.762
if patient is female] x[1.18 if patient is black] x [BUN]- More widespread validation of MDRD than CG
0.170 x[Alb]0.318 (eg, in various populations).

MDRD(abbreviated): GFR = 186 x[SCr]-1.154 x [Age]-0.203 No requirement for additional information for MDRD
x[0.742 if patient is female] x [1.212 if patient is black] (eg, measurements of weight) beyond that already
collected by pathology laboratories.

206 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


estimates GFR because creatinine is both filtered by
the glomerulus and to a lesser degree, secreted by
Table 9

the proximal tubule. On the other hand, urea under-


estimates GFR since it is both filtered and reab-
Situations in which the MDRD Equation

sorbed. The mean value of the creatinine and urea


Should be Used Cautiously

clearance more closely approximates the actual


GFR in the setting of GFR measurements less than
15 ml/min/1.73 m2.
Populations in which the MDRD equation is not vali-
dated or in which validation studies have not been
performed
Cystatin C

Cystatin C is a nonglycosylated basic protease


Individuals with near normal or normal kidney function

inhibitor produced by nucleated cells at a constant


rate, is freely filtered by glomeruli, and is com-
Severe malnutrition or obesity

pletely metabolized after tubular reabsorption.39


Unlike creatinine, serum cystatin C level is not
Extremes of body size and age

dependent on muscle mass, and is not differentially


expressed based on gender. GFR is estimated from
Exceptional dietary intake (eg, vegetarian diet or

the plasma cystatin C concentration, which has been


creatine supplements)

found to correlate well with iothalamate GFR mea-


surements in Pima Indians with DM and normal or
Disease of skeletal muscle, paraplegia

supranormal GFR. Cystatin has greater sensitivity


than Cr for small changes in GFR. Recent studies
Rapidly changing kidney function

suggest that cystatin C may be a better indicator of


predicting risk for cardiovascular disease than either
serum creatinine or a GFR prediction equation.40,41
Creatinine Clearance Measurement by
24-Hour Urine Collection

Difficulties with 24-hour urine creatinine measure-


ments include variations in urine collection (ie,
incorrect collections) and variations in the tubular
secretion of creatinine. Studies have shown that in
trained patients there can be up to a 14% variation in
urine Cr quantity secondary to incorrect collection,
and in untrained patients this can be as high as
70%.31,33 With regard to variations in tubular secre-
tion, in patients with moderate to severe renal dys-
function, greater than 50% of the urinary Cr can
result from tubular secretion, thus leading to overes-
timation of the creatinine clearance by this method.
In order to compensate for overestimation of GFR
from tubular secretion of Cr in the 24-hour urine
collection, the collection can be performed after oral
administration of cimetidine, an organic cation that
is a known competitive inhibitor of creatinine secre-
tion. In order to compensate for the overestimation
of GFR by the 24-hour urine creatinine method, the
use of the mean of urea and creatinine clearance
measurements calculated from 24-hour urine collec-
tions has been suggested. Creatinine clearance over-

CHAPTER 6: CHRONIC KIDNEY DISEASE 207


9. Clinical Aspects of CKD

As a clinical syndrome, CKD is characterized by symptomatic and may be severely disabled. In the
progressive decline in kidney function such that the early stages of CKD (stage 1 and 2), using the NKF
kidney’s ability to adequately excrete waste prod- K-DOQI CKD stages, patients may present simply
ucts and to contribute to the constancy of the body’s with an elevated serum creatinine and blood urea
homeostatic functions is severely impaired. Mild nitrogen (BUN) level but no symptoms. These indi-
CKD is asymptomatic; moderate CKD is frequently viduals are usually unaware that they have any
characterized by hypertension, anemia, and abnor- abnormalities in their kidney function, and usually
malities in mineral metabolism; whereas advanced fail to register on the “radar screen” of their
CKD is characterized by uremia. CKD may become internists. However, even at this early stage, insidi-
relentlessly progressive as the damage to function- ous effects on target organs may become manifest.
ing nephrons leads to a maladaptive response For example, patients may have mild to moderate
among the remaining nephrons. The progressive hypertension, mild anemia, left ventricular hyper-
decline in kidney function in individuals with CKD trophy, and subtle changes in bone structure due to
is variable and depends on both the cause of the renal osteodystrophy. As kidney function gradually
underlying insult and on patient-specific factors.42 declines further—with glomerular filtration rates
There is consensus that renal disease progression reaching less than 30 mL/min—early features of
rates are heterogeneous both between different eti- uremia become evident. These include worsening or
ologies and within the same etiology. Thus, patients more difficult to control hypertension, extracellular
with polycystic kidney disease (PKD) may progress volume expansion (manifest as edema and dysp-
more slowly than patients with diabetic nephropa- nea), hyperkalemia and acidosis, anemia, and cog-
thy; however, among patients with diabetic nitive, psychological and physical abnormalities.
nephropathy there are patients who progress fast Uremia reflects the accumulation of metabolic tox-
and others who progress hardly at all. Evidence ins, some characterized and others unknown, that
points to the importance of several factors in modu- influence the functioning of a variety of organ sys-
lating kidney progression.42 These include protein- tems. In this late stage, the need for renal replace-
uria, the presence of systemic hypertension, age, ment therapy is imminent and dialysis and/or trans-
gender, genetic factors, and smoking. plantation become inevitable in order to sustain life.

End stage renal disease is the term used to denote The indications for initiating renal replacement
CKD requiring renal replacement therapy (dialysis therapy include severe refractory abnormalities in
or transplantation). The incidence of ESRD in the biochemistry (severe hyperkalemia and acidosis),
United States is approximately 268 cases per mil- severe pulmonary edema, bleeding, metabolic
lion population per year. However, ESRD is over- encephalopathy, and the presence of pericarditis.
represented among African-Americans (829 per Subtler but no less important indications include
million population per year, as compared with 199 malnutrition and severe disability (marked tiredness
per million population per year among white Amer- and lethargy) (Table 10).
icans). The major causes of ESRD in the United
States are diabetes mellitus (44%), hypertension Life expectancy in patients with ESRD for a 49-
(30%), glomerular disease (15%), polycystic kidney year-old is, on average, approximately 7 years,
disease, and obstructive uropathy. Elsewhere in the lower than colon cancer and prostate cancer and
world, where the incidence of diabetes mellitus has one-quarter that of the general population. This
not reached epidemic proportions—for example in reduction in life expectancy is largely attributable to
Europe and parts of the developing world—chronic cardiovascular complications. Nearly 50% of all
glomerulonephritis (20%) and chronic reflux deaths in patients with ESRD are due to cardiovas-
nephropathy (25%) are the commonest causes cular causes.43 The risk is 17 times that of the gen-
of ESRD. eral population. Remarkably, this gap is largest in
young patients with end-stage renal disease. The
CKD is usually asymptomatic when there is mild risk factors for cardiovascular disease in individuals
impairment in kidney function, whereas when GFR with chronic renal failure include, but are not lim-
is markedly reduced the patient is usually clearly ited to, the magnitude of the calcium/phosphorous

208 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


10. Key Complications of CKD

The most important complications of CKD are


hypertension, disturbances in mineral metabolism,
Table 10

anemia, acidosis and dyslipidemias. Hypertension


is discussed in detail elsewhere in this book and will
Indications for Initiation of Renal Replace-

not be reviewed further in this chapter.


ment Therapy

Refractory hyperkalemia Secondary Hyperparathyroidism and


Metabolic Bone Disease

Secondary hyperparathyroidism (SHPT) is a multi-


Acute pericarditis

factorial syndrome that begins early in CKD but


ultimately is present in most patients with CKD.44
Fluid overload or pulmonary edema refractory to

Notably, bone disease in CKD and ESRD patients


diuretics

represents a spectrum from low and high turnover


disease and osteomalacia and osteoporosis. A
Encephalopathy

detailed discussion is beyond the scope of this chap-


ter and can be reviewed elsewhere.45 The central
abnormality is an excess secretion of parathyroid
Severe peripheral neuropathy

hormone (PTH) by the parathyroid glands.46 This


results from progressively worsening kidney func-
Hypertension refractory to antihypertensive

tion that causes phosphorus retention and diminish-


medications

ing production of 1, 25 (OH2), D3 (calcitriol), the


Severe uremic bleeding; clinically significant

active form of vitamin D. Starting early in CKD,


reduced kidney function results in reduced activity
bleeding; diathesis attributable to uremia

of a hormone, 1α-hydroxylase, synthesized by renal


tubular cells and responsible for activation of vita-
Intractable nausea and vomiting

min D. Reduced 1α-hydroxylase activity results in


decreased levels of calcitriol (1, 25-dihydroxyvita-
product with its attendant risk of coronary calcifica- min D). Circulating calcitriol levels begin to fall
tion, the presence of dyslipidemia, hypertension, when the glomerular filtration rate is less than 40
hyperhomocystemia, and the presence of LVH. The mL/min. By the time patients have progressed to
clinical manifestations of cardiovascular disease in end-stage renal disease the calcitriol level is
ESRD patients include left ventricular hypertrophy, markedly reduced. The removal of the normal sup-
left ventricular dilatation, diastolic dysfunction, pressive effect of calcitriol on the parathyroid
macro and microvascular disease, and abnormalities glands results in PTH secretion.
in autonomic function—increased sympathetic dis-
charge and increased circulating catecholamine lev- As a consequence of calcitriol deficiency there is
els. Vascular disease may involve calcification of reduced absorption of calcium in the gut and
coronary vessels and valve disease. Indeed, calcifi- reduced mobilization of calcium. In addition, excess
cation of the mitral valve annulus and the aortic extracellular phosphorus binds to calcium and fur-
valve cusps is common among ESRD patients. ther drives down the ionized plasma calcium con-
centration. Both factors result in a relative decrease
in serum calcium. In compensation, parathyroid
hormone (PTH) secretion is stimulated, maintaining
serum calcium and phosphorus in the normal range
in most CKD stage 3 and 4 patients (Table 11). PTH
secretion is influenced by this balance of extracellu-
lar calcium and phosphorus. As kidney disease pro-
gresses there is a decrease in the number of vitamin
D (VDR) and calcium sensing (CaR) receptors on
the parathyroid gland. Reduction in VDR and CaR

CHAPTER 6: CHRONIC KIDNEY DISEASE 209


density causes resistance of the parathyroid glands ments and the target range for intact PTH is based on
to both calcitriol and calcium. In parallel, excess the stage of CKD.
extracellular phosphorus induces hyperplasia of the
parathyroid glands independent of calcium and cal- Sustained exposure of bone to elevated PTH results
citriol. The initial hyperplasia of the parathyroid in osteitis fibrosa, a disease of high bone turnover
gland is followed in later stages by nodularity, with and accelerated bone resorption. Bone biopsy stud-
evidence at a cellular level of monoclonal cellular ies in CKD stage 3 and 4 patients indicate that
expansion. The lack of calcitriol is thought to cause osteitis fibrosa is present in approximately 70% of
down-regulation of vitamin D receptors, which then patients, and another 10%-15% develop osteitis
promotes parathyroid chief cell hyperplasia and fibrosa with osteomalacia or mixed bone lesions.
nodule formation. The resistance of parathyroid These pathologic changes may result in a reduction
cells to calcitriol appears to serve as second stimu- in bone mineral density on DEXA scanning, which
lus for PTH secretion in patients with advanced may be misinterpreted as osteoporosis, a condition
CKD. Reduction of calcitriol receptor density in of low bone turnover. Effective treatments, which
parathyroid glands is currently considered the lower PTH, include dietary phosphorus restriction,
mechanism responsible for the resistance to fairly use of calcium-based phosphorus binders, treatment
robust doses of vitamin D in chronic renal failure. of vitamin D deficiency and use of calcitriol or other
As renal failure progresses, this disturbance may active vitamin D analogs.48
form a vicious cycle of further reducing calcitriol
receptor density leading to progressive resistance to
calcitriol.
Control of Hyperphosphatemia

Dietary phosphorus restriction is an important ele-


As GFR declines with advancing CKD, renal phos- ment in the management of osteitis fibrosa. In stage
phate excretion is reduced and serum levels of phos- 3 CKD, a reduction in dietary phosphorus to
phate rise.47 Circulating levels of phosphate are also 800-1000 mg/day results in a decline in PTH, an
influenced by a variety of other factors: dietary increase in endogenous calcitriol production, and
phosphorus intake, intestinal absorption, and typically no appreciable change in serum phospho-
exchange with bone reservoirs. The major hor- rus. In stage 4 CKD, dietary phosphorus restriction
mones that regulate phosphate homeostasis through lowers PTH and serum phosphorus, but does not
these mechanisms are 1, 25 (OH)2D3 and parathy- usually result in an increase in calcitriol production.
roid hormone. An emerging role for a novel class of In patients with CKD stages 3 and 4, daily phospho-
proteins termed phosphatonins has also emerged. rous intake should be restricted to 800-1000 mg/day
Phosphatonins are a group of proteins discovered in in the setting of a phosphorous level greater than 4.6
the characterization of a group of pathologic condi- m/dL or when PTH exceeds the target range. Target
tions characterized by phosphate wasting. FGF-23 serum phosphorus is 2.7 to 4.6 mg/dL in stage 3 and
is the most extensively studied. Increased FGF-23 4 CKD. Phosphorus binders taken with meals
may contribute to maintaining normal phosphate decrease absorbed phosphorus and have effects sim-
levels early in CKD through its phosphaturic effect, ilar to dietary phosphorus restriction. The dose of
which may explain the lack of laboratory phosphate binders required in CKD stages 3 and 4 is much less
derangement seen early in SHPTH. than that required in dialysis patients. Calcium based
binders may be used as initial therapy (such as cal-
cium carbonate or calcium acetate), but the dose of
elemental calcium should not exceed 1500 mg/day.
Management of Osteitis Fibrosa

The management of osteitis fibrosa is reviewed in Use of calcium further suppresses PTH by increas-
the NKF KDOQI guideline document.44 It is impor- ing serum calcium, but this may result in a chroni-
tant to emphasize that the measurement of calcium, cally positive calcium balance and contribute to vas-
phosphorus, and intact plasma parathyroid hormone cular calcification. Noncalcium based binders—
is important in all patients with a GFR less than 60 such as sevelamer HCl 800 mg TID or lanthanum
ml/min/1.73 m2. The frequency of these measure- carbonate 250 mg TID—offer effective phosphorus

210 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


Table 11

Frequency of Measurement and Target Range for Intact PTH Based on CKD Stage

CKD GFR Range Measurement Measurement Target intact


Stage mL/min1.73m2 of PTH of Ca and Phos PTH (pg/mL)

3 30-59 Every 12 months Every 12 months 35-70

4 15-29 Every 3 months Every 3 months 70-110

5 <15 or dialysis Every 3 months Every month 150-300

control without the dangers of calcium loading, but daily or 0.5 mcg thrice weekly and significantly
are substantially more expensive than calcium enhances intestinal absorption of calcium and phos-
based binders. Additionally, sevelamer can induce phorus. Hypercalcemia is common when doses
acidosis due to HCl release upon binding of phos- exceed 0.5 mcg per day.
phorus.
Vitamin D analogs were developed to reduce the
stimulation of intestinal calcium and phosphorus
absorption.48 Paricalcitol (Zemplar®) appears to have
Vitamin D and/or Vitamin D

the least effect on intestinal mineral absorption, and


Analogue Therapy

A deficiency of both 25(OH)D and 1,25(OH)2D3 in randomized trials had an incidence of hypercal-
are common abnormalities in CKD patients. Both cemia and hyperphosphatemia similar to placebo.
may contribute to the development and progression Paricalcitol is usually started at 1 mcg daily or 2 mcg
of SHPT and/or associated osteomalacia and osteo- thrice weekly. Doxercalciferol (Hectorol®) is a pro-
porosis. Vitamin D stores are assessed by determi- hormone (1(OH)D2), and is metabolized constitu-
nation of serum 25(OH)D level, the stable liver tively by the liver to 1, 25(OH)2D2, an active form
metabolite of vitamin D. A normal level is >30 of vitamin D. Other metabolites of doxercalciferol
ng/ml, and lower levels should be supplemented. may also be formed and may account for the appar-
Most 25(OH)D circulates bound to D binding pro- ently lower incidence of hypercalcemia and hyper-
tein (DBP) and serum DBP may be greatly phosphatemia seen with this analog. Doxercalcif-
decreased in nephrotic syndrome due to heavy pro- erol is usually started at 1 mcg daily. (See Table 12
teinuria, making interpretation of the laboratory for recommended doses of ergocalciferol.)
results questionable. Nevertheless, restoration of
25(OH) D levels to normal is appropriate, although After three or more weeks on any form of the above
there is limited data that this lowers PTH. active vitamin D products, serum PTH should be
remeasured and the dose of the active D product
Treatment with vitamin D or one of its analogues is increased by 50%-100% if necessary to achieve
a key element in CKD management (Table 12). PTH suppression into the CKD stage specific target.
Active vitamin D analogs suppress PTH in a dose Adequate suppression of PTH should be balanced
dependent manner.48,49 One of these agents should be with maintenance of normal serum calcium (8.4 to
used whenever PTH is above the target range 10.2 mg/dL) and phosphorus (2.7 to 4.6 mg/dL).
despite vitamin D repletion and phosphorus control. Serum calcium and phosphorus should be measured
Doses are usually administered orally daily or thrice at least quarterly, and more frequently if calcitriol is
weekly, resulting in similar PTH suppression. Cal- used at a dose of 0.5 mcg per day or more.
citriol (Rocaltrol®) is typically begun at 0.25 mcg

CHAPTER 6: CHRONIC KIDNEY DISEASE 211


Table 12

Recommended Treatment of Vitamin D Deficiency in CKD

25(OH)D level (ng/mL) Recommended Dose of Vitamin D2


(Ergocalciferol, 50,000 IU Capsules)

<5 1 capsule weekly x 12 weeks, then monthly x 3 months

5-14 1 capsule weekly x 4 weeks, then monthly x 5 months

15-29 1 capsule monthly x 6 months

method of determining whether cellular indices are


normocytic and normochromic is to multiply the
Anemia

Anemia is a common complication in CKD patients, RBC and Hb by 3. The RBC multiplied by 3 should
affecting approximately 40% of patients in stage 4 equal the Hb, and the Hb multiplied by 3 should
and 5 CKD (anemia defined herein as a Hb of <11 equal the Hct. Deviation from the calculated values
g/dL) (Table 13). Estimates suggest that almost suggests microcytosis, macrocytosis, or hypochro-
1,000,000 patients in the United States with CKD mia versus the presence of spherocytes (MCHC,
are anemic.52 Diabetes seems to be an additional risk >36). In patients suspected of CKD anemia, mea-
factor for anemia in CKD and more than 20% of dia- surement of an erythropoietin level (EPO) is not
betics with an eGFR of 30-59 mL/min/1.73 m2 are necessary. This is because a low normal or even a
anemic. The etiology of anemia in CKD is multifac- normal EPO level may suggest EPO deficiency. On
torial. While erythropoietin deficiency is the most the other hand, excluding the possibility of iron defi-
common cause (Tables 14, 15), iron deficiency, ciency is important. The diagnosis of iron deficiency
nutritional deficiencies (in vitamin B6 and B12), is made by demonstrating that the patient has a
occult blood loss and hyperparathyroidism are also transferrin saturation (TSAT) level of <20% and/or a
important causes. serum ferritin level of <100 ng/mL. While the gold
standard for iron deficiency is the absence of stain-
able iron in a bone marrow specimen, under most
circumstances a bone marrow evaluation is imprac-
Clinical Features and Diagnosis of CKD

tical. The presence of microcytosis and hypochro-


Anemia

Mild anemia (Hb levels >11 g/dL) is usually asymp- mia is helpful but not diagnostic. Every patient with
tomatic in CKD patients. By the time the Hb level is iron deficiency anemia should have a stool examina-
<10 g/dL, patients complain of tiredness and tion for occult blood. A positive result necessitates a
fatigue. Some patients may complain of a reduction careful search of the gastrointestinal tract to identify
in exercise capacity, well being, tiredness, and cold the site of bleeding. Unfortunately, a negative result
intolerance. Impairment in neurocognitive ability does not exclude gastrointestinal blood loss because
may be evident using formal tests but may be too bleeding can be intermittent and require several
subtle to detect by routine clinical evaluation. In examinations for detection. Also, less than 20-30
several observational studies, anemia increases the mL of blood in the stool per day may go undetected
risk of cardiovascular complications including left due to the insensitivity of the test.
ventricular hypertrophy, left ventricular dilatation,
and myocardial ischemia.53,54 From a diagnostic
standpoint, CKD anemia is characterized by normo-
cytic, normochromic hematologic indices. A rapid

212 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


100 units/kg or 10,000 units SC weekly. Darbepo-
etin is usually initiated at 0.45 mcg/kg weekly or 60
Table 13

Key Recommendations in the mcg SC every other week.

Hgb should be checked every two weeks initially,


2006 KDOQI Anemia Update51

and the dose of drug adjusted by ~25% to achieve


The initial evaluation of anemia should include a CBC, and maintain Hgb 11-12 g/dL. Once the target Hgb
absolute reticulocyte count, serum ferritin and serum
transferrin saturation (TSAT).
Table 14
The hemoglobin range should be at least 11.0 g/dL;
however, there is insufficient evidence to recommend Key Facts on Erythropoetin55
maintaining Hb concentrations. ≥13.0 g/dL can be
used for all other CKD patients (CPR 2.1.2).
EPO is produced by peritubular cells in the kidneys of
The iron parameter goals for hemodialysis patients the adult and in hepatocytes in the fetus. Small
should be a serum ferritin concentration ≥200 ng/mL, amounts of extrarenal EPO are produced by the liver
and a transferrin saturation ≥20% or a reticulocyte in adult human subjects.
hemoglobin content ≥29 pg/cell (CPR 3.2.3.1).
EPO acts primarily to rescue erythroid cells from
The goals for non-dialysis-dependent CKD and peri- apoptosis (programmed cell death) to increase their
toneal dialysis patients should be a serum ferritin con- survival.
centration ≥100 ng/mL and a transferrin saturation
≥ 20% (CPR 3.2.3.2). EPO binds to an erythroid progenitor cell surface
receptor to regulate bone marrow erythroid cell prolif-
The preferred route of administration for iron is IV in eration, differentiation, and survival.
patients with hemodialysis dependent CKD (CPG
3.2.5.1). EPO receptors are also on mesangial cells in the kid-
ney, brain, testes, myocardium.
Routine administration of IV iron if the ferritin concen-
tration exceeds 500 ng/mL. EPO binds to an erythroid progenitor cell surface
receptor to regulate bone marrow erythroid cell prolif-
eration, differentiation, and survival.

Treatment of CKD Anemia Benefits of treating anemia with EPO include:

In the United States, there are 2 erythropoiesis-stim-


improved exercise tolerance and less fatigue, lower

ulating agents that are available: epoetin alfa and


transfusion rate, and potentially, regression of LVH.

darbepoetin.51,55 Epoetin beta is also available in


Europe and other countries. A large number of
generic or biosimilar molecules to epoetin have also is achieved, the epoetin or darbepoetin dose can be
emerged into the marketplace, particularly in the approximately doubled and dosing frequency also
developing countries. doubled.58

Treatment with epoetin or darbepoetin should be


initiated in most patients when hemoglobin is less
Hemoglobin Target in CKD Patients

than 10 mg/dL, and preferably when Hgb is 10 to 11 The 2002 NKF Anemia Update had recommended a
g/dL.51 For convenience reasons, less frequent dos- hemoglobin range of 11 to 12 g/dL.50 However, more
ing regimens are used in CKD than in dialysis recently, the NKF Anemia Update has recom-
patients.56-58 The initial dose of epoetin is usually mended that the target hemoglobin range should be

CHAPTER 6: CHRONIC KIDNEY DISEASE 213


generally 11 to 12 g/dL.51 The lower Hb level is
based on evidence, whereas the upper Hb level is
Table 15

considered an opinion-based recommendation.51


Treating CKD anemia with erythropoietin has been
Practical Guide to Using

shown to enhance quality of life; however, evidence


Erythropoetin for CKD Anemia60

supporting a benefit of anemia correction in improv-


ing cardiovascular morbidity and mortality has
largely rested on data derived from observational
1. Start when Hb <11.0 g/dL

studies. The recent publication of the CHOIR and


2. Use epotein alfa or darbepoetin

CREATE studies have demonstrated increased risk


3. For epoetin alfa:

with targeting a higher hemoglobin level.56,57


a. Starting dose 10,000 units subcutaneously

CHOIR56 was an open-label, randomized trial that


each week, or 20,000 units every other week

studied 1432 patients with CKD: 715 patients ran-


b. Single vials come in 2,000, 3,000, 4,000,

domized to receive epoetin alfa targeted to achieve a


10,000, and 40,000 unit doses; multi-dosing

hemoglobin of 13.5 g/dL, and 717 were randomized


vials comes in 10,000 and 20,000 unit doses

to receive epoetin alfa targeted to achieve a


c. Maintenance dosing uses an extended dose

hemoglobin of 11.3 g/dL.3 The median study dura-


strategy—every other, every third, or every

tion was 16 months. The primary end point was a


fourth week.

composite of death, myocardial infarction, conges-


4. For darbepoetin:

tive heart failure (CHF), hospitalization (excluding


a. Initial dose: 0.45 mcg/kg QW

hospitalization during which renal replacement


b. Can use 25, 40, 60, 100, 150, 200, 300, 500

therapy occurred), and stroke. Two hundred twenty-


mcg/mL single-dose vials or prefilled syringes

two composite events occurred: 125 events among


c. Maintenance: multiply for longer intervals up to

the high hemoglobin group and 97 events among the


4 weeks.

low hemoglobin group (P=0.03), hazard ratio of


1.34; with 95% confidence interval of 1.03 and 1.74.
The higher rate of composite events was explained statistically significantly higher rate of the first car-
largely by a higher rate of death (48% higher risk, diovascular event (58 events in the high
P=0.07) or CHF hospitalization (41%, P=0.07). hemoglobin group versus 47 events in the low
Although neither death nor CHF hospitalization hemoglobin group; hazard ratio of 0.78, 95% confi-
were statistically significantly higher in the higher dence interval, 0.53 to 1.14; P=0.20). However, left
versus lower hemoglobin group, the study was not ventricular mass index remained stable in both
powered for this purpose. Among other secondary groups but dialysis was required in more patients in
endpoints, quality of life showed improvement in the higher versus lower hemoglobin group (127 vs.
both groups but was not significantly better in the 111, P=0.03). On the other hand, unlike CHOIR, in
higher versus lower hemoglobin groups. Notably, CREATE a quality of life benefit, at least in year 1
more subjects in the high hemoglobin group experi- of the study, was observed for the higher versus
enced at least one serious adverse event compared to lower hemoglobin group. Therefore, both studies
the low hemoglobin group. The Cardiovascular showed either risk or no benefit with regards to car-
Risk Reduction by Early Anemia Treatment with diovascular outcomes aiming to completely correct
Epoetin beta (CREATE)57 study enrolled approxi- the hemoglobin in CKD patients not receiving dial-
mately 600 patients. Subjects were randomized to ysis. The CHOIR study was larger and showed a
an early anemia correction or a late anemia correc- statistically significant difference for the primary
tion group.4 The early anemia correction group endpoint, whereas the CREATE study was under-
received epoetin beta therapy immediately for a tar- powered for the primary event and showed a trend
get hemoglobin 13-15 g/dL. The late anemia correc- for increased risk but did not reveal statistically sig-
tion group did not receive treatment until their nificant differences for the primary endpoint. On
hemoglobin was <10.5 g/dL; their target the other hand, in both CHOIR and CREATE, qual-
hemoglobin was 10.5-11.5 g/dL. The study showed ity of life improved in patients treated with epoetin.
that “complete correction” was not associated with a While in CHOIR there was no incremental

214 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


improvement in QOL in the higher versus lower
hemoglobin group, in CREATE patients random-
Iron Deficiency in CKD Patients

ized to the higher hemoglobin level did experience While several mechanisms may account for iron
improved quality of life. Indeed, several large ran- deficiency among dialysis patients (loss through the
domized controlled studies in both ESRD and pre- dialysis procedure, acute and chronic inflammation,
ESRD patients have either failed to demonstrate a and reduced oral absorption and reduced dietary
benefit of anemia correction, or have shown a trend intake), among predialysis CKD patients the most
towards worse outcomes such as cardiovascular dis- important reason appears to be reduced GI absorp-
ease or death. A recent meta-analysis concurs – tion (Table 16). The likeliest reason for this is a
increased risk with targeting a hemoglobin concen- block, through the action of hepcidin, in iron
tration of >12 g/dL in pre-dialysis and dialysis absorption through the intestinal iron transporter
patients. 58 In light of the evidence from interven- ferroportin.61 Hepcidin, a liver synthesized protein,
tional studies, as alluded to above, a recent boxed regulates ferroportin mediated iron absorption.
advisory from the Food and Drug Administration
(FDA) has recommended a Hgb target of High hepcidin levels result in reduced iron absorp-
10 to 12 g/dL. tion.62 Since hepcidin is excreted by the kidneys, it is
postulated that renal dysfunction results in progres-
Initiation of erythropoietic agents frequently con- sively higher levels of hepcidin and thus attenuated
sumes the patient’s iron stores, and the inflamma- iron absorption. CKD patients’ reduced dietary
tion present in CKD inhibits adequate intestinal iron intake, especially of foods high in iron, such as
absorption, resulting in iron deficiency. High levels meats and leafy vegetables, may further exacerbate
of C-reactive protein, a marker of inflammation, iron deficiency. It is estimated that approximately
have been associated with low iron absorption in 40% of patients with CKD have iron deficiency.63
patients on HD. As kidney disease progresses, iron deficiency

Table 16

Indicators and Causes of Iron Deficiency

Form Indicator Cause

Absolute iron deficiency TSAT <20% and serum Increased blood loss
serum ferritin <100 ng/mL Decreased iron
absorption

Functional iron deficiency TSAT may be <20% and Intense stimulation of


ferritin may be 100-700 ng/mL RBC production by EPO
therapy outstrips iron
supply. May develop
even when storage iron
appears normal

RE blockade Dramatic increase in serum Acute or chronic inflam-


ferritin along with drop in TSAT mation often seen in HD
patient. Blocks release of
iron stores from RES

CHAPTER 6: CHRONIC KIDNEY DISEASE 215


worsens because of a postulated increase in hep- be discerned by examining the patient’s response to
cidin levels due to reduced hepcidin excretion by a trial dose of IV iron. A rise in Hgb and Hct levels
the kidneys. Another possibility is that progres- and/or a reduction in EPO dose requirement will
sively increased levels of inflammation result in an signify functional iron deficiency. In contrast, in
increased expression of hepcidin and thus a block in the presence of inflammation-mediated RE block-
GI absorption of iron. ade, iron supplementation may not be effective
until the underlying inflammation has subsided.
The probability of RE blockade exists in situations
where either serum ferritin levels have risen, EPO
Assessment of Iron Deficiency

TSAT (calculated by the formula serum iron/total dose requirements have remained high despite IV
iron binding capacity x 100) and serum ferritin are iron, or no erythropoietic response has occurred (ie,
the primary measures used to assess patients’ iron Hgb level does not increase).
stores. Although neither has optimal sensitivity nor
specificity, they are inexpensive and widely avail- There are limitations to both the serum ferritin and
able. Tissue ferritin is a large protein molecule con- TSAT markers in accurately diagnosing iron defi-
tained within the reticuloendothelial system (RES), ciency.51,64-66 Serum ferritin is an acute-phase reac-
with iron at its core. Serum ferritin is ferritin that has tant, and levels are elevated in cases of inflamma-
leaked from tissues, and it is an indicator of tissue tion and infection, which are common in HD
iron stores. Most normal patients have serum fer- patients. Because iron is an acute-phase reactant,
ritin levels below 30 ng/mL; however, levels are TSAT levels also may be affected by inflammation
much higher in uremic patients. Transferrin is the or infection. In addition, because transferrin is pro-
body’s iron transport molecule, delivering iron duced primarily in the liver, hepatic disease can
from the RES to the bone marrow for erythro- reduce transferrin production. As a result, if trans-
poiesis. The TSAT represents the body’s circulating ferrin levels are low, the TSAT level may appear to
iron. According to the K/DOQI guidelines, a TSAT be normal in the presence of iron deficiency. TSAT
level <20% and a serum ferritin level <100 ng/mL levels also are affected by nutritional status. TSAT
represents iron deficiency, and a serum ferritin and serum ferritin levels may have greater diagnos-
level >500 ng/mL represents iron overload. How- tic utility for iron deficiency and iron overload when
ever, the 500 ng/mL level set by K/DOQI is opinion they are very low or very high, respectively.
based, not evidence based. Functional iron defi-
ciency and reticuloendothelial (RE) blockade may

Table 17

Pharmakinetic Profiles of IV Irons

Iron Dextran Iron Sucrose Ferric Gluconate

Molecular weight, INFeD 165,000 34,000-60,000 289,000-440,000


Daltons Dexferrum 265,000

Half-life 40-60 h ~6 h ~1 h

Direct transfer to RES Yes Yes Yes

Direct transfer No Yes No


to transferrin

216 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


<200 mg/dL, consideration should be given to iron
repletion. Alternative markers of iron deficiency
Treatment of Iron Deficiency

The treatment of iron deficiency in CKD anemia is include an increased number of hypochromic red
reviewed extensively elsewhere.51,64-66 There is a lim- blood cells (percentage >10%), or a low reticulocute
ited role for oral iron in the treatment of iron defi- hemoglobin content (CHr <31 pg). Intravenous iron
ciency in patients with advanced CKD. Intravenous preparations include iron dextran (1000 mg IV as a
iron is recommended in these circumstances. Very single dose, with an initial test dose of 25 mg); ferric
little oral iron is absorbed and side effects of oral gluconate (initial dose 125 mg IV); or iron sucrose
iron may be quite considerable. A healthy individual (initial dose 100 to 200 mg IV). Iron dextrans have a
only absorbs about 1% of the total iron ingested in low but serious risk of anaphylactic reactions. Oral
an oral dose, while in CKD patients, impaired gas- iron therapy can be attempted in CKD. To maximize
trointestinal absorption can lead to even lower absorption, at least 200 mg of elemental iron should
absorption of iron. Side effects of oral iron include be consumed daily in divided doses taken between
constipation and gastrointestinal upset. meals. Oral iron salts may be bound by calcium-
based phosphorus binders and thus should be taken
Despite a clear rationale for intravenous iron ther- separately. Thyroid hormone supplements may also
apy, there continues to exist an underutilization of be bound by ferrous sulfate and therefore should be
these preparations. This is most likely because of taken separately.
expense, inconvenience of administration, and lim-
ited access to infusion facilities. There are 3 avail-
able forms of IV iron (ferric gluconate, iron sucrose,
Acidosis

and iron dextran); and there are 2 types of iron dex- Chronic metabolic acidosis begins to develop when
tran: INFeD® and Dexferrum®. Studies of mainte- eGFR falls below 40-50 mL/min, and most stage 4
nance IV iron therapy have demonstrated a consis- CKD patients have serum bicarbonate levels
tent improvement in erythropoiesis as measured by <22 meq/L.67,68 Unless patients have concomitant
decreased EPO requirements to maintain or renal tubular acidosis, the ensuing metabolic acido-
improve Hct levels. This improvement has been sis tends to be mild and easily treated. Even mild
seen with all 3 available forms of IV iron. The sig- metabolic acidosis results in increased resorption of
nificant decrease in EPO requirements in HD bone, weakening of bone structure, and can increase
patients may translate into substantial savings, the risk of fractures. Additionally, acidosis enhances
given the high cost of EPO therapy. protein catabolism and can contribute to malnutri-
tion in CKD. Treatment is usually started when
The IV irons differ based on their pharmacokinetic serum bicarbonate is persistently < 22 meg/L. One
profiles, which may have a potentially significant or two sodium bicarbonate tablets (650 mg, ~8 meq
impact on their safety profiles and bioavailability each) are usually administered TID to maintain
(Table 17). Among the IV irons, ferric gluconate has serum bicarbonate >22 meq/L. Use of citrate salts
the shortest elimination half-life (1 hour), approach- may increase the absorption of dietary aluminum in
ing the maximum rate of physiologic clearance by patients with CKD, and therefore should be
the RES. Ferric gluconate also has the largest avoided.
molecular size, reducing the risk of dialyzability.
All of the IV irons are delivered directly to the RES,
where they are stored as ferritin and turned over to
Dyslipidemia

transferrin. However, iron sucrose appears to have a Hypercholesterolemia is considered a major risk
dual method of turnover, with a portion of the iron factor and cause of atherosclerotic disease in the
complex being delivered directly to transferrin— general population; however, there is a lack of asso-
thereby raising the risk of transferrin oversaturation. ciation between this traditional risk factor and
atherosclerotic cardiovascular disease among dialy-
Iron stores should also be assessed periodically with sis patients, and limited data in patients with CKD.
evaluation of transferrin saturation and ferritin. If Multiple complex lipid abnormalities, known col-
transferrin saturation is <20% or ferritin is lectively as uremic dyslipidemia, are commonly

CHAPTER 6: CHRONIC KIDNEY DISEASE 217


observed in dialysis and CKD patients due to the statins on CVD outcomes in CKD patients. One
reduced lipolysis of apolipoprotein B-containing study—the 4D study conducted in hemodialysis
triglyceride (TG)-rich very-low-density lipoprotein patients—used atorvastatin and failed to show a
(VLDL) particles.69 This defect is associated with beneficial effect.71 However, several post hoc analy-
near normal total cholesterol, elevated VLDL and ses of statin trials do suggest that CKD patients
intermediate density lipoproteins (IDL), low high- should benefit from statin therapy.72 Until more data
density lipoprotein (HDL), and a shift of LDL parti- from randomized controlled studies becomes avail-
cle size toward a small dense LDL. The concentra- able, it is reasonable to treat CKD patients like those
tions of LDL particles, small dense LDL, large without kidney disease and reduce lipid levels
HDL, IDL, and large VLDL are better indicators of according to NCEP/ATP guidelines.70
cardiovascular risk than the elements of the tradi-
tional lipid profile. However, the traditional lipid Assessment of a complete fasting lipid panel (total
profiles do not directly determine the concentration cholesterol, LDL-C, HDL-C, and triglycerides) is
or the size of these known atherogenic apolipopro- recommended annually in all CKD patients. Initial
tein B-containing lipid subclasses (VLDL-C, IDL- therapy should target LDL-C to less than 100 mg/dL
C, and LDL-C). To address this problem, the NCEP —usually with statin therapy. No HMG-CoA
(National Cholesterol Education Program) recom- inhibitor is contraindicated in CKD, but rosuvas-
mends assessment of non-HDL cholesterol as a rea- tatin should be started at a lower dose. Ezitimibe
sonable surrogate parameter to estimate total inhibits intestinal transport of dietary cholesterol,
apolipoprotein B, and treatment when non-HDL is and is a useful adjunct to statin therapy. Secondary
>130 mg/dL.70 Virtually all patients with CKD have lipid therapy should target non-HDL cholesterol to
a 10-year risk of cardiovascular events >20%. less than 130 mg/dL if fasting triglycerides are
Therefore the target LDL-C should be less than 100 greater than 200 mg/dL. In these latter patients, use
mg/dL, and non-HDL-C less than 130 mg/dL. of niacin or gemfibrizol may be efficacious. Physi-
cians should be vigilant for the development of
There is limited data on the beneficial effects of myalgias or myopathy.

Table 18

Management of Kidney Disease

Type of Kidney Disease Target Blood Preferred Agents for Other Agents to
Pressure CKD With or Without Reduce CVD Risk
(mmHg) Hypertension and Reach Blood
Pressure Target

Diabetic kidney disease <130/80 ACE Inhibitor or ARB Diuretics preferred,


then BB or CCB

Non-diabetic kidney disease with spot <130/80 ACE Inhibitor Diuretics preferred,
Up/Uc ratio ≥ 200 mg/g then BB or CCB

Non-diabetic kidney disease with spot <130/80 No preference Diuretics preferred,


Up/Uc ratio < 200 mg/g then ACI inhibitor, ARB,
BB, CCB

Disease in the kidney transplant <130/80 No preference CCB, Diuretic, BB, ACE
recipient inhibitor, ARB

218 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


11. Management of Kidney
Disease Progression

contraindicated in patients who are pregnant, and in


patients with a history of angioedema.)
KDOQI Action Plan by Stage of CKD

The NKF KDOQI group has released an action plan


for management of patients with CKD as deter- 2. Control of blood pressure. The MDRD study
mined by stage of CKD.1 In addition, a more demonstrated that patients targeted to MAP of 92
detailed discussion regarding the slowing of kidney and 107 mmHg had rates of decline of GFR of
progression can be reviewed elsewhere.73 In stage 1 -3.56 and -4.10 mL/min/year, respectively, and
CKD, these guidelines suggest the diagnosis and that there was greater effect with increasing levels
treatment of CKD, treatment of comorbid condi- of albuminuria.79 This study, taken in conjunction
tions, prevention of progression of renal disease, with several other studies that have been pub-
and CVD risk reduction. In stage 2, the issue of pri- lished, subsequently suggest a key role for blood
mary concern is that of estimating and managing pressure reduction in retarding the progression of
renal disease progression. The focus of stage 3 dis- kidney disease. Indeed, a recent study suggests
ease is that of evaluating and treating complica- that this beneficial effect of controlling blood
tions; while stage 4 CKD, the immediate pre-dialy- pressure on kidney disease extends for a pro-
sis stage, consists of preparation for renal replace- longed period of time.80 The 2003 NKF-KDOQI
ment therapy. The management of stage 5 CKD is clinical practice guidelines for antihypertensive
that of initiation and maintenance of renal replace- therapy recommend:81
ment therapy. Thus, in addition to the task of diag-
nosing and treating the specific etiology of renal • Blood pressure measurement at each health care
disease, the broad themes that govern early versus encounter.
late renal disease management are those of preven-
tion of progression in the early stages of CKD, man- • Target blood pressure of less than 130/80 for all
agement of complications beginning in the early patients with kidney disease, including those with
stages and continuing throughout the follow-up of diabetic kidney disease and non-diabetic kidney
patients, and preparation for renal replacement in disease, regardless of degree of proteinuria, and
the later predialysis phase. in renal allograft recipients.

There are three important elements to the manage- • Use of an ACE-I/ARB in patients with diabetic
ment of progression in CKD patients (Table 18): kidney disease, and use of ACE-I in non-diabetic
kidney disease with proteinuria (spot Up/Ucr
1. The use of angiotensin blockers to protect the ratio of ≥200 mg/g), to retard progression of kid-
kidney. Both landmark studies in animals by ney disease, irrespective of the presence of hyper-
Brenner and colleagues,74 as well as studies in tension.
humans, supports an independent role for
angiotensin blockade in renoprotection.75-77 ACE With regard to adjunctive anti-hypertensive
inhibitors (ACEi) or angiotensin receptor block- agents, the guidelines suggest diuretics followed
ers (ARB) can be used. It is important to titrate by either beta-blockers or calcium channel block-
the dose of ACEi or ARB to maximal levels using ers in diabetic kidney disease as well as in non-
reduction of proteinuria as the yardstick for effi- diabetic proteinuric kidney disease (spot Up/Ucr
cacy. Emerging evidence (from the COOPER- ratio of ≥200 mg/g). Diuretics are the preferred
ATE study)78 suggests a beneficial effect of using agent in patients with kidney disease in the
both ACEi and ARB in a synergistic strategy to absence of significant proteinuria, as defined by
reduce proteinuria and enhance renoprotection. In spot Up/Ucr ratio of <200 mg/g, followed by
addition, sodium restriction and diuretics in con- ACE-I, ARB, beta-blocker, or calcium channel
junction with ACE-I/ARB therapy increase their blocker. Finally, in recipients of renal allografts,
antiproteinuric effects and should be used in an the NKF-DOQI guidelines recommend calcium
adjunctive fashion. (ACE inhibitors or ARB are channel blockade, diuretic therapy, and beta
blockade, ACE-I or ARB.

CHAPTER 6: CHRONIC KIDNEY DISEASE 219


12. References

3. Adjunctive strategies in retarding progression 1. National Kidney Foundation: K/DOQI clinical


include: practice guidelines for chronic kidney disease:
a.) Strict glycemic control. The DCCT and Evaluation, classification and stratification.
UKPDS studies for type 1 and type 2 diabetics, Am J Kidney Dis. 2002;39(Suppl. 1):S1.
respectively, have unequivocally demonstrated
the benefits of tight glycemic control with a goal 2. Coresh J, Selvin E, Stevens LA, Manzi J,
HbA1C of <7.0. Kusek JW, Eggers P, Van Lente F, Levey AS.
b.) Protein restriction. The K/DOQI Guidelines Prevalence of chronic kidney disease in the
for Nutrition in Chronic Renal Failure recom- United States. JAMA. 2007 Nov
mend restriction of protein intake to 0.8 7;298(17):2038-47.
gm/kg/day in all patients with CKD, with further
restriction to 0.6 gm/kg/day in those with CrCl 3. Coresh J, Byrd-Holt D, Astor BC, Briggs JP,
less than 25 ml/min. The guidelines also recom- Eggers PW, Lacher DA, Hostetter TH.
mend a caloric intake of 30-35 kcal/kg/day. Chronic kidney disease awareness, preva-
c.) Smoking cessation. Smoking has been impli- lence, and trends among U.S. adults, 1999 to
cated as a risk factor in the progression of kidney 2000. J Am Soc Nephrol. 2005 Jan;16(1):180-
disease, particularly diabetic kidney disease. The 8. Epub 2004 Nov 24.
postulated mechanisms of injury include a height-
ened risk of atherosclerosis, vascular occlusion, 4. Coresh J, Eknoyan G, Levey AS. Estimating
and reduction in renal blood flow. Smoking ces- the prevalence of low glomerular filtration
sation is recommended in all patients. rate requires attention to the creatinine assay
d.) Management of obesity. Obesity may result in calibration. J Am Soc Nephrol. 2002
an acquired resistance to the beneficial effects of Nov;13(11):2811-2
inhibition of the RAS axis. Further, weight loss
may facilitate the actions of ACE-inhibi- 5. Foley RN, Collins AJ. End-stage renal disease
tion/angiotensin receptor blockade. In addition, in the United States: an update from the United
obesity may induce certain renal diseases, such as States Renal Data System. J Am Soc Nephrol.
FSGS, postulated to be due to a mechanism of 2007 Oct;18(10):2644-8. Epub 2007 Jul 26.
hyperfiltration. Weight loss is recommended in
CKD patients with a goal body mass index (BMI) 6. Gilbertson DT, Liu J, Xue JL, Louis TA, Solid
of <25. CA, Ebben JP, Collins AJ. Projecting the num-
ber of patients with end-stage renal disease in
the United States to the year 2015. J Am Soc
Nephrol. 2005 Dec;16(12):3736-41. Epub
2005 Nov 2. Erratum in: J Am Soc Nephrol.
2006 Feb;17(2):591.

7. McClellan WM. Epidemiology and risk fac-


tors for chronic kidney disease. Med Clin
North Am. 2005 May;89(3):419-45.

8. King H, Aubert RE, Herman WH. Global bur-


den of diabetes, 1995-2025: prevalence,
numerical estimates, and projections.
Diabetes Care. 1998 Sep;21(9):1414-31.

9. Agodoa L, Norris K, Pugsley D. The dispro-


portionate burden of kidney disease in those
who can least afford it. Kidney Int Suppl. 2005
Aug;(97):S1-3

220 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


10. Barsoum RS. Chronic kidney disease in the 19. John R, Webb M Young, A, Stevens, PE.
developing world. N Engl J Med. 2006 Mar Unreferred chronic kidney disease: a longitu-
9;354(10):997-9. dinal study. Am J Kidney Dis. 2004;43:825.

11. Atkins RC. The changing patterns of chronic 20. Schmidt R, Domico J, Sorkin M, Hobbs G.
kidney disease: the need to develop strategies Early referral and its impact on emergent first
for prevention relevant to different regions dialyses, health care costs, and outcome.
and countries. Kidney Int. (Suppl.) 2005 Am J Kidney Dis. 1998;32:278.
Sep;(98):S83-5.
21. Arora P, Obrador G, Ruthazer R, et al. Preva-
12. Jafar TH, Schmid CH, Levey AS. Serum crea- lence, predictors and consequences of late
tinine as marker of kidney function in South nephrology referral at a tertiary care center.
Asians: a study of reduced GFR in adults in J Am Soc Nephrol. 1999;10:1281.
Pakistan. J Am Soc Nephrol. 2005;16:1413.
22. Winkelmayer WC, Owen WF Jr, Levin R,
13. Lamb EJ, Tomson CR, Roderick PJ. Clinical Ahorn J. A propensity analysis of late versus
Sciences Reviews Committee of the Associa- early nephrologist referral and mortality on
tion for Clinical Biochemistry. Estimating dialysis. J Am Soc Nephrol. 2003;14:486.
kidney function in adults using formulae.
Ann Clin Biochem. 2005 Sep;42(Pt 5):321-45. 23. Gaede P, Vedel P, Larsen N, Jensen GV, Parv-
ing HH, Pedersen O. Multifactorial interven-
14. Grassmann A, Gioberge S, Moeller S, Brown tion and cardiovascular disease in patients
G. End-stage renal disease: global demograph- with type 2 diabetes. N Engl J Med. 2003 Jan
ics in 2005 and observed trends. Artif Organs. 30;348(5):383-93.
2006 Dec;30(12):895-7.
24. St. Peter WL, Schoolwerth AC, McGowan T,
15. Hallan SI, Coresh J, Astor BC, Asberg A, McClellan WM. Chronic kidney disease:
Powe NR, Romundstad S, Hallan HA, Lyder- issues and establishing programs and clinics
sen S, Holmen J. International comparison of for improved patient outcomes. Am J Kidney
the relationship of chronic kidney disease Dis. 2003 May;41(5):903-24.
prevalence and ESRD risk. J Am Soc Nephrol.
2006 Aug;17(8):2275-84. Epub 2006 Jun 21. 25. Sarnak MJ, Levey AS, Schoolwerth AC,
Coresh J. Kidney disease as a risk factor for
16. Peralta CA, Shlipak MG, Fan D, Ordoñez J, development of cardiovascular disease: a
Lash JP, Chertow GM, Go AS. Risks for end- statement from the American Heart Associa-
stage renal disease, cardiovascular events, and tion Councils on Kidney in Cardiovascular
death in Hispanic versus non-Hispanic white Disease, High Blood Pressure Research, Clini-
adults with chronic kidney disease. J Am Soc cal Cardiology, and Epidemiology and Pre-
Nephrol. 2006 Oct;17(10):2892-9. Epub 2006 vention. Circulation. 2003;108.
Sep 7.
26. Shlipak MG, Fried LF, Cushman M, et al. Car-
17. Garella S. The costs of dialysis in the US. diovascular mortality risk in chronic kidney
Nephrol Dial Transplant, 1997;12 (Suppl.) disease: comparison of traditional and novel
1:10. risk factors. JAMA. 2005;293:1737.

18. St. Peter WL, Khan SS, Ebben JP, Pereira BJ,
Collins AJ. Chronic kidney disease: the distri-
bution of health care dollars. Kidney Int. 2004
Jul;66(1):313-21.

CHAPTER 6: CHRONIC KIDNEY DISEASE 221


27. Menon V, Gul A, Sarnak MJ. Cardiovascular 36. Levey AS, Bosch JP, Lewis JB, Greene T,
risk factors in chronic kidney disease. Rogers N, Roth D. A more accurate method to
Kidney Int. 2005 Oct;68(4):1413-8. estimate glomerular filtration rate from serum
creatinine: a new prediction equation. Modifi-
28. McClellan WM, Ramirez SP, Jurkovitz C. cation of Diet in Renal Disease Study Group.
Screening for chronic kidney disease: unre- Ann Intern Med. 1999 Mar 16;130(6):461-70.
solved issues. J Am Soc Nephrol. 2003
Jul;14(7 Suppl. 2):S81-7. 37. Levey AS, Greene T, Kusek JW, Beck GJ, and
MDRD study group: A simplified equation to
29. de Jong PE, Brenner BM. From secondary to predict glomerular filtration rate from serum
primary prevention of progressive renal dis- creatinine (abstract). J Am Soc Nephrol.
ease: the case for screening for albuminuria. 2000;11:155A.
Kidney Int. 2004 Dec;66(6):2109-18.
38. Perrone RD, Steinman TI, Beck GJ, Skibinski
30. Gross JL, de Azevedo MJ, Silveiro SP, Canani CI, Royal HD, Lawlor M, Hunsicker LG. Util-
LH, Caramori ML, Zelmanovitz T. Diabetic ity of radioisotopic filtration markers in
nephropathy: diagnosis, prevention, and treat- chronic renal insufficiency: simultaneous
ment. Diabetes Care. 2005 Jan;28(1):164-76. comparison of 125I-iothalamate, 169Yb-
DTPA, 99mTc-DTPA, and inulin. The Modifi-
31. Perrone RD, Madias NE, Levey AS. Serum cation of Diet in Renal Disease Study.
creatinine as an index of renal function: new Am J Kidney Dis. 1990 Sep;16(3):224-35.
insights into old concepts. Clin Chem. 1992
Oct;38(10):1933-53. 39. Hojs R, Bevc S, Ekart R, Gorenjak M,
Puklavec L. Serum cystatin C as an endoge-
32. Coresh J, Astor BC, McQuillan G, et al. Cali- nous marker of renal function in patients with
bration and random variation of the serum cre- mild to moderate impairment of kidney func-
atinine assay as critical elements of using tion. Nephrol Dial Transplant. 2006
equations to estimate glomerular filtration Jul;21(7):1855-62. Epub 2006 Mar 8.
rate. Am J Kidney Dis. 2002;39:920.
40. Shlipak MG, Sarnak MJ, Katz R, et al. Cys-
33. Stevens LA, Levey AS. Measurement of kid- tatin C and the risk of death and cardiovascular
ney function. Med Clin North Am. 2005 events among elderly persons. N Engl J Med.
May;89(3):457-73. 2005;352:2049.

34. Myers GL, Miller WG, Coresh J, Fleming J, 41. Sarnak MJ, Katz R, Stehman-Breen CO, et al.
Greenberg N, Greene T, Hostetter T, Levey Cystatin C concentration as a risk factor for
AS, Panteghini M, Welch M, Eckfeldt JH; heart failure in older adults. Ann Intern Med.
National Kidney Disease Education Program 2005;142:497.
Laboratory Working Group. Recommenda-
tions for improving serum creatinine measure- 42. Brenner BM. Retarding the progression of
ment: a report from the Laboratory Working renal disease. Kidney Int. 2003 Jul;64(1):
Group of the National Kidney Disease Educa- 370-8.
tion Program. Clin Chem. 2006 Jan;52(1):
5-18. Epub 2005 Dec 6. 43. Foley RN, Parfrey PS, Sarnak MJ. Epidemiol-
ogy of cardiovascular disease in chronic renal
35. Coresh J, Stevens LA. Kidney function disease. J Am Soc Nephrol. 1998 Dec;9
estimating equations: where do we stand? (12 Suppl.):S16-23.
Curr Opin Nephrol Hypertens. 2006
May;15(3):276-84.

222 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


44. K/DOQI clinical practice guidelines for bone 54. Ross SD, Fahrbach K, Frame D, Scheye R,
metabolism and disease in chronic kidney Connelly JE, Glaspy J. The effect of anemia
disease. Am J Kidney Dis. 2003;42:S1-201. treatment on selected health-related quality-
of-life domains: a systematic review.
45. Spasovski GB, Bervoets AR, Behets GJ, et al. Clin Ther. 2003 Jun;25(6):1786-805.
Spectrum of renal bone disease in end-stage
renal failure patients not yet on dialysis. 55. Fisher JW. Erythropoietin: physiology and
Nephrol Dial Transplant. 2003;18(6): pharmacology update. Exp Biol Med
1159-66. (Maywood). 2003 Jan;228(1):1-14. Review.

46. Goodman WG. The consequences of uncon- 56. Spiegel DM. Anemia management in chronic
trolled secondary hyperparathyroidism and its kidney disease: what have we learned after 17
treatment in chronic kidney disease. years? Semin Dial. 2006 Jul-Aug;19(4):
Sem Dial. 17:209-216 2004. 269-72.

47. Qunibi WY. Consequences of hyperphos- 57. Paoletti E, Cannella G. Update on erythropoi-
phatemia in patients with end-stage renal etin treatment: should hemoglobin be normal-
disease (ESRD). Kidney Int. (Suppl.) ized in patients with chronic kidney disease?
2004(90):S8-S12. J Am Soc Nephrol. 2006 Apr;17(4 Suppl.
2):S74-7.
48. Slatopolsky E, Finch J, Brown A. New vita-
min D analogs. Kidney Int Suppl. 2003 58. Phrommintikul A, Haas SJ, Elsik M, Krum H.
Jun;(85)583-7. Mortality and target haemoglobin concentra-
tions in anaemic patients with chronic kidney
49. Slatopolsky E, Brown A, Dusso A. Calcium, disease treated with erythropoietin: a meta-
phosphorus and vitamin D disorders in uremia. analysis. Lancet. 2007 Feb 3;369(9559):
Contrib Nephrol. 2005;149:261-71. 381-8.

50. National Kidney Foundation. Am J 59. http://www.fda.gov/cder/drug/infopage/RHE/


Kidney Dis. 2002;39(Suppl 1):S1-S266. default.htm Accessed March 2, 2008.

51. KDOQI Clinical Practice Guideline and Clini- 60. Pendse S, Singh AK. Complications of
cal Practice Recommendations for Anemia in chronic kidney disease: anemia, mineral
Chronic Kidney Disease, 2007 Update of metabolism, and cardiovascular disease. Med
Hemoglobin Target. American Journal of Kid- Clin North Am. 2005 May;89(3):549-61.
ney Diseases. September 2007 supplement.
61. Ganz T. Hepcidin—a peptide hormone at
52. Astor BC, Muntner P, Levin A, Eustace JA, the interface of innate immunity and iron
Coresh J. Association of kidney function with metabolism. Curr Top Microbiol Immunol.
anemia: the Third National Health and Nutri- 2006;306:183-98.
tion Examination Survey (1988-1994).
Arch Intern Med. 2002 Jun 24;162(12): 62. Nemeth E, Ganz T. Regulation of iron
1401-8. metabolism by hepcidin. Annu Rev Nutr.
2006;26:323-42.
53. Jones M, Ibels L, Schenkel B, Zagari M.
Impact of epoetin alfa on clinical end points in
patients with chronic renal failure: a meta-
analysis. Kidney Int. 2004 Mar;65(3):757-67.

CHAPTER 6: CHRONIC KIDNEY DISEASE 223


63. Gotloib L, Silverberg D, Fudin R, Shostak A. 72. Steinmetz OM, Panzer U, Stahl RA, Wenzel
Iron deficiency is a common cause of anemia UO. Statin therapy in patients with chronic
in chronic kidney disease and can often be cor- kidney disease: to use or not to use. Eur J Clin
rected with intravenous iron. J Nephrol. 2006 Invest. 2006 Aug;36(8):519-27.
Mar-Apr;19(2):161-7.
73. Zandi-Nejad K, Brenner BM. Strategies to
64. Nissenson AR, Charytan C. Controversies in retard the progression of chronic kidney
iron management. Kidney Int Suppl. 2003 disease. Med Clin North Am. 2005
Nov;(87):S64-71. May;89(3):489-509.

65. Agarwal R, Warnock D. Issues related to iron 74. Anderson S, Rennke HG, Garcia DL, Brenner
replacement in chronic kidney disease. BM. Short and long term effects of antihyper-
Semin Nephrol. 2002 Nov;22(6):479-87. tensive therapy in the diabetic rat. Kidney Int.
1989;36:526.
66. Hudson JQ, Comstock TJ. Considerations for
optimal iron use for anemia due to chronic kid- 75. Rosenberg ME, Smith LJ, Correa-Rotter R,
ney disease. Clin Ther. 2001 Oct;23(10): Hostetter TH. The paradox of the renin-
1637-71. angiotensin system in chronic renal disease.
Kidney Int. 1994;45:403.
67. Uribarri, J. Acidosis in chronic renal insuffi-
ciency [In Process Citation]. Semin Dial. 76. Weir, MR. Progressive renal and cardiovascu-
2000;13:232. lar disease: Optimal treatment strategies.
Kidney Int. 2002;62:1482.
68. Warnock, DG. Uremic acidosis. Kidney Int.
1988; 34:278. 77. Remuzzi G, Ruggenenti P, Perico N. Chronic
renal diseases: Renoprotective benefits of
69. K/DOQI clinical practice guidelines for man- renin-angiotensin system inhibition. Ann
agement of dyslipidemias in patients with kid- Intern Med. 2002;136:604.
ney disease. Am J Kidney Dis. 2003;41:I-IV,
S1-91. 78. Nakao N, Yoshimura A, Morita H, et al. Com-
bination treatment of angiotensin-II receptor
70. Expert Panel on Detection Evaluation and blocker and angiotensin-converting-enzyme
Treatment of High Blood Cholesterol in inhibitor in non-diabetic renal disease (COOP-
Adults. Executive Summary of the Third ERATE): A randomized controlled trial.
Report of the National Cholesterol Education Lancet. 2003;361:117.
Program (NCEP) Expert Panel on Detection,
Evaluation, and Treatment of High Blood 79. Klahr S, Levey AS, Beck GJ, Caggiula AW,
Cholesterol in Adults (Adult Treatment Panel Hunsicker L, Kusek JW, Striker G. The effects
III). JAMA. 2001;285:2486-2497. of dietary protein restriction and blood-pres-
sure control on the progression of chronic
71. Wanner C, Krane V, Marz W, Olschewski M, renal disease. Modification of Diet in Renal
Mann JF, Ruf G, Ritz E. German Diabetes and Disease Study Group. N Engl J Med. 1994
Dialysis Study Investigators. Atorvastatin in Mar 31;330(13):877-84.
patients with type 2 diabetes mellitus undergo-
ing hemodialysis. N Engl J Med. 2005 Jul: 80. Sarnak MJ, Greene T, Wang X, et al. The
21;353(3):238-48. Erratum in: N Engl J Med. effect of a lower target blood pressure on the
2005 Oct 13;353(15):1640. progression of kidney disease: Long-term fol-
low-up of the Modification of Diet in Renal
Disease Study. Ann Intern Med. 2005;
142:342.

224 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY


81. K/DOQI Clinical Practice Guidelines on
Hypertension and antihypertensive agents in
chronic kidney disease. Am J Kidney Dis.
2004;43:5(Suppl. 1):S1.

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