castle connolly graduate board review series

Educational Review Manual in NephrologySecond Edition • 2008

Editor-in-Chief

Ajay K. Singh, MB, FRCP(UK) Associate Professor of Medicine, Harvard Medical School Director, Postgraduate Medical EducationDepartment of Medicine and Renal Division, Brigham and Women’s Hospital

CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

CHAPTER 6: CHRONIC KIDNEY DISEASE 197

Contents

1. Introduction

2. Staging and Classification of CKD

3. Epidemiology of CKD

4. CKD Economics

5. Importance of Early Recognition of CKD andTimely Referral to Nephrological Care

6. Cardiovascular Risk Stratification in PatientsWith 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

Chapter6:ChronicKidneyDisease

AjayK. Singh,MB, FRCPDanielW.Coyne,MD

2. Staging andClassification of CKD

CKD is staged by using glomerular filtration rate(GFR) categories. The NKF-K-DOQI has classifiedCKD into 5 stages (Table 1).1 The strengths of theNKF K-DOQI classification are its simplicity andits use of estimated GFR (eGFR) to classify CKDinto different stages. Furthermore, the widespreadadoption of the classification has resulted in, per-haps for the first time, a uniform system understoodand applied worldwide. Indeed, the classificationserves as a useful starting point in evaluating apatient with depressed GFR. It also provides theimpetus to either refer a patient to a nephrologist forfurther work-up, or to identify a patient at higherrisk of developing cardiovascular complications.

The major limitations of the NKF CKD classifica-tion are as follows. It stages the severity of kidneydisease on the basis of GFR without incorporatingother important parameters such as albuminuria.Two patients with similar GFR but with wide differ-ences in the degree of proteinuria at baseline arelikely to have very different prognosis. The patientwith high degree proteinuria is more likely to have aworse prognosis. The NKF classification alsoleaves unaddressed the significance of reduced GFRbelow 60 mL/min/1.73m2 in certain subgroups,such as the elderly, the undernourished, and mem-bers of specific ethnic groups. For example, elderlyindividuals with reduced GFR may never develop

1. Introduction

Chronic kidney disease (CKD) is defined by theNational Kidney Foundation as either: 1.) aglomerular filtration rate (GFR) of <60 mL/minwith or without kidney damage for 3 or moremonths; or 2.) the presence of kidney damage for 3or more months demonstrated by pathologic abnor-malities, markers of kidney damage (eg, blood orurine composition), or imaging tests.1 In the UnitedStates, it is estimated that CKD affects 7%-10% ofthe adult population, or 15 to 20 million individuals,although specific subgroups such as African-Ameri-cans and Hispanics are at especially high risk.

There is growing consensus on the importance ofusing a prediction equation to estimate kidney func-tion rather than relying on serum creatinine. Recentobservational data has also emphasized the connec-tion between kidney disease and cardiovascular dis-ease (CVD), indicating the primary importance ofCVD as a source of mortality among CKD patients.Also, the importance of CKD as a risk factor inpatients with CVD has emerged. It has become evi-dent that the level of kidney function as assessed byeither serum creatinine or estimated glomerular fil-tration rate is a key factor in predicting survival afteran acute myocardial infarction (MI). From a thera-peutic standpoint, considerable progress has beenmade in demonstrating the critical role of the renal-angiotensin system in mechanistically influencingthe progression of kidney disease. Angiotensinblockade slows the progression of every stage ofCKD, whether CKD is caused by diabetes or not(although the role of angiotensin blockade in retard-ing the progression of specific disorders has notbeen established). Angiotensin converting enzymeinhibitors and angiotensin receptor blockers havebecome an essential part of the armamentarium ofthe practicing nephrologists. K-DOQI guidelinesfrom the National Kidney Foundation (NKF) andsimilar documents from the Renal Physician’sAssociation (RPA) have sought to organize nephrol-ogy practice by establishing consensus around theevaluation and treatment of CKD. The purpose ofthis chapter is to review the definition and epidemi-ology of CKD, gain an understanding of the differ-ent methods of measuring kidney function, andevaluate and manage the major complications ofCKD—in particular anemia, cardiovascular dis-ease, and renal osteodystrophy.

198 EDUCATIONAL REVIEW MANUAL IN NEPHROLOGY

Table 1

NKF Classification of CKD

Stage 1: Kidney damagewith normal or supranormalGFR,GFR ≥90

Stage 2: Kidney damagewithmild reduction inGFR,GFR60-89

Stage 3:Moderate reduction inGFR,GFR30-59

Stage 4: Severe reduction inGFR,GFR15-29

Stage 5: Kidney failure, GFR<15 or on dialysis


end-stage renal disease. Patients with congestivecardiac failure may have a low GFR because ofhemodynamic reasons but do not have any struc-tural evidence of kidney disease, and kidney func-tion may normalize once the heart failure is treated.However, it is important to note that the use of NKFCKD criteria may not apply to some racial groupssince their GFR may be naturally lower than West-ern levels as a consequence of smaller stature, lowermuscle mass, and vegetarianism.

3. Epidemiology of CKD

Using extrapolations from the NHANES study, it isestimated that approximately 19 million individualsin the United States have CKD.2,3 These estimationsprovide a ballpark prevalence number because theNHANES data relies on a single creatinine mea-surement. As well, the NHANES White Sands labo-ratory did not calibrate creatinine measurement withthe Cleveland Clinic laboratory where the MDRDpredictive equation was generated.4 Thus, theseNHANES-based CKD prevalence estimates arelikely to be somewhat higher than the true figure.

Most individuals with CKD are people with earlierstages of CKD. The prevalence estimates of CKDstages in 1999-2004 are approximately 1.8% (stage1); 3.2% (stage 2); 7.7% (stage 3) and 0.35% (stage4). This number has increased approximately10%-13% from 1998-1994 to 1999-2004. 2 ,3 Ofthose with stage 5 CKD, the number of individualswith kidney failure treated by dialysis and trans-plantation exceeded 440,000 with 0.03% of the USpopulation beginning renal replacement therapy in2004, an adjusted incidence rate of 339 per million,5

and while the prevalence is likely to demonstratecontinued growth, recent data reported from theUSRDS 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, theESRD incidence rate was 338 per million with anannual increase of just 1%.)6

CKD as a Global Problem

CKD is an emerging global problem largely becauseof the diversity of the risk factors involved in CKDcausality (Table 2),7 and because the world is in themidst of a diabetes epidemic.8 Superimposed on thediabetes epidemic is the problem of poverty. Datarecently 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 populationlives in low-income countries, such as China, India,Indonesia, and Pakistan, where incident rates of dia-betes are also the highest.9 Furthermore, the stakesare much higher in the developing world becausepoverty frequently precludes the possibility of renalreplacement therapy if ESRD does ensue.


Data on the prevalence of CKD in the developingworld is quite limited.10-12 CKD in the developingworld suggests a prevalence of approximately5%-10% (Pakistan data is based on the Cockcroft-Gault estimation of creatinine clearance and theestimate for CKD prevalence is 29%).12 This wouldsuggest that there are many millions of peopleamong these that have CKD. However, it is impor-tant to be cautious in reaching this conclusion sincethe published studies, so far at least, have method-ologic limitations. These include the reliance on asingle creatinine as the measure of kidney function;the lack of creatinine standardization against anyinternational laboratory standard; and the absenceof studies validating an estimating equation in anon-American population.13

In the United States, there are notable racial differ-ences in the epidemiology of CKD. This is reviewedin detail elsewhere.14-16 African Americans, PacificIslanders, Latinos, and Native Indians have a higherprevalence of CKD than Caucasians. African-Americans are at especially high risk—a 3- to 4-fold higher risk than Caucasians. In particular,African-Americans appear to have a higher preva-lence of hypertensive kidney disease than Cau-casians (Table 3).

4. CKD Economics

The cost of medical care for patients with CKD ishigh, and is reviewed in detail elsewhere.17 Theaverage cost of care for a CKD patient is approxi-mately $1,300 per month compared to approxi-mately $500 per month for a non-CKD patient.This number is dwarfed by the cost of care for anESRD patient—approximately $5000 eachmonth. CKD patients consume a disproportion-ate share of health care resources.18 In 2002, thetotal cost of the ESRD program in the UnitedStates was $25.2 billion in 2002, an 11.5%increase from the previous year. Despite the costof treatment of ESRD and improvements in thequality of dialysis therapy, mortality and morbid-ity remains significant. In 2002, 71,006 ESRDpatients died. Incidence and prevalence countsfor ESRD are expected to increase by 44% and85%, respectively, from 2000 to 2015 and inci-dence and prevalence rates per million popula-tion by 32% and 70%, respectively. Survivalprobabilities for dialysis patients at 1, 2, 5 and 10years are approximately 80%, 67%, 40%, and18%, respectively. Moreover, 50% of dialysispatients have three or more comorbid conditions,the mean number of hospital days per year isapproximately 14 per patient, and self-reportedquality of life is far lower in dialysis patients thanin the general population.


Table 2

Risk Factors for Chronic Kidney Disease

Susceptibility Initiation Progression End-StageFactors Factors Factors Factors

Older age Diabetes Proteinuria Lowdialysis doseFamily history Hypertension Hypertension Vascular accessLow kidneymass Autoimmunedisease Poor glycemic control AnemiaLowbirth weight Systemic infections Smoking Low serumalbuminLow income Urinary tract infections Late referralMinimal education Lower urinary tract

ObstructionDrug 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 damagewith ≥90 5,900 3.3%normal or supranormalGFR

2 Kidney damagewith 60-89 5,300 3.0%mild decrease inGFR

3 Moderate decrease 30-59 7,600 4.3%inGFR

4 Severe decrease inGFR 15-29 400 0.2%

5 Kidney failure <15 300 0.2%

* GFR expressed in mL/min/1.73 m2


5. Importance of EarlyRecognition of CKD and TimelyReferral to Nephrological Care

Looming large over concerns about the current man-agement of CKD are the issues of CKD under-recog-nition and late referral to nephrology.19 Under-recog-nition partly reflects the continued use of serum crea-tinine as a screening test for kidney disease. Sincethere is a nonlinear relationship between serum crea-tinine and GFR20,21 and because women have lowermuscle mass than men, the problem of under-recog-nition is particularly acute among women.3 Onlyapproximately 4% of women with moderate CKD(GFR 15 to 59 mL/min/1.73m2) are aware that theyhave CKD.

Specific components of CKD care are associatedwith substantial quality gaps.22 Under-utilization ofangiotensin blockers has been noted; high bloodpressure 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 inconsistentlyscreened for early nephropathy. Patients with hyper-tension or diabetes often do not have serum creatininechecked in primary care. This despite evidence fromthe Steno study23 that demonstrated that in the settingof a specialized clinic, intensified multiple risk factorintervention results in better outcomes in diabeticscompared to usual care.24

Several authors have argued that CKD patientsshould be referred to nephrologists early in thecourse of their disease because this is associatedwith improved outcomes.24 The National KidneyFoundation recommends that referral to a nephrolo-gist should be made at least by the time the GFR hasreached 25 mL/min/1.73m2. However, there is alack of consensus among nephrologists regardingthe kidney function criteria for referral because of afear that nephrologists may not be able to accommo-date an excess of patients into their practice. Latereferral appears to result in higher rates of majorcomplications, longer and more frequent stays inhospital, worse values for homeostatic indicators atthe start of dialysis, suboptimal vascular access, andworse survival than patients referred early. Studiessuggest that CKD patients referred early have bettervocational outcomes, a delay in the onset of ESRD,better values for homeostatic indicators, less use oftemporary devices for vascular access, and lowerconsumption of hospital resources. Observational

data suggests that decreased morbidity and mortalityand lower costs are associated with early referral.Indeed, patients referred late in the course of theirkidney disease are more likely to have anemia andhypoalbuminemia, less likely to have been startedon erythropoietin, and are less likely to have perma-nent AV access.


older age, diabetes mellitus, systolic hypertension,and LVH are highly prevalent in CKD patients andtheir relationship to CVD is the same regardless ofCKD status. On the other hand, there appears to bewhat has been termed a reverse epidemiology forother factors, such as hypertension and LDL choles-terol among dialysis patients. The increased risk atlower levels of blood pressure and cholesterol mayreflect confounding from cardiomyopathy and mal-nutrition, respectively, although this has not beenproved.

The role of nontraditional risk factors in influencingCVD risk in CKD is more controversial. Observa-tional studies strongly suggest that factors such asproteinuria, hemoglobin level, inflammation, andcalcium-phosphorous abnormalities are important.However, definitive evidence remains currentlylacking. Some of these nontraditional risk factorsare specific to kidney disease and worsen with pro-gressive impairment of kidney function.27 It is likelythat the increase in cardiovascular risk in patientswith CKD is a multifactorial composite of both tra-ditional CV risk factors and nontraditional renalspecific risk factors. Many of these traditional andnontraditional risk factors are modifiable and there-fore need to be studied in order to assess whethertreatment of these factors improves outcome.

6. Cardiovascular RiskStratification in PatientsWith Kidney Disease

CVD is common in patients with all stages of kid-ney disease (Table 4).25 Approximately 25% ofpatients with mild to moderate CKD (stages 2 and 3)have evidence of left ventricular hypertrophy andthis increases to 40%-70% of patients by the time ofend stage renal disease (stage 5 CKD). Patients withCKD also have a higher prevalence of congestiveheart failure (CHF). CHF represents a significantrisk factor for mortality, especially when anemia isalso present. A number of factors contribute to theincreased prevalence of CVD in patients with kid-ney disease.26 These can be divided into traditionaland nontraditional. The definition of traditional riskfactors are those factors that have been used to esti-mate the risk of developing symptomatic ischemicheart disease in the Framingham study (Table 5).Traditional Framingham CVD risk factors, such as

Table 4

Guidelines for Referral to Nephrology

Serum Creatinine (SCr)

Males: SCr ≥2.0mg/dLFemales: SCr ≥1.5mg/dL

GFR

GFR≤60mL/min/1.73m2

In patients who are fast progressors (defined as aGFRdecline ≥4mL/min/1.73m2 per year)

Proteinuria

Dipstick proteinuria >3+Spot urine protein (mg/dL) tocreatinine (mg/dL) ratio >1.024-hour urine collection >1.0 gm/24 hrs/1.73m2

Complications of CKD that are Refractory toManagement and Require Subspecialist Input

AnemiaHypertensionAcidosisRenal osteodystrophy

7. Screening for CKD

The justification for screening for CKD continuesto be debated.28 Because of the relatively low preva-lence of CKD, screening of the general populationis unlikely to be cost effective. On the other hand,since kidney disease becomes symptomatic in thelate stages of CKD, and since therapeutic strategiessuch as angiotensin blockade and tighter bloodpressure control have been proven to be effective atearlier stages, detection of CKD early could poten-tially prevent ESRD in a significant proportion ofpatients.

African Americans and Native Americans have ahigher risk of CKD than others (953 and 652 casesper million in African Americans and Native Amer-icans, respectively, compared to 237 per millionamong Caucasians). Also, patients with diabetesmellitus and hypertension and those with urine dip-stick positive for protein have a higher risk of devel-oping CKD. Indeed, in a recent position paperDe Jong and Brenner recommend routine urinealbumin screening as a cost effective way of detect-ing progressive CKD.29 The NKF-K/DOQI guide-


lines for CKD recommend that all individualsshould be assessed as part of routine health examina-tions to determine whether they are at increased riskfor developing CKD. Individuals at high risk for kid-ney disease, particularly those with diabetes, hyper-tension, or a family history for these conditionsand/or for kidney disease, should undergo formaltesting. Such testing can be performed easily with aurinalysis, a first morning or a random “spot” urinesample for albumin or protein and creatinine assess-ment, and a serum creatinine level. The AmericanDiabetes Association (ADA) recommends that forall type 2 diabetics at the time of diagnosis and alltype 1 diabetics 5 years after initial diagnosis, anevaluation for microalbuminuria should be per-formed.30 If the dipstick is positive for either red orwhite blood cells, a microscopic analysis should beperformed of the urinary sediment.

Table 5

Traditional Framingham CVD Risk Factors are Highly Prevalent in CKD Patients

Traditional Risk Factors Hypothesized Nontraditional Risk Factors

Age AlbuminuriaMale sex Abnormal calcium/phosphatemetabolismDiabetes AnemiaHypertension InflammationHigher LDL cholesterol Oxidative stressLowerHDL cholesterolSmokingExtracellular fluid volume overloadPhysical inactivityMenopauseFamily history of CVDLVH


8. Measurement ofKidney Function

Use of Serum Creatinine

Measurement of serum creatinine is currently themost widely utilized measure for the assessment ofkidney function. However, the use of serum creati-nine has several limitations31 (Table 6). Because cre-atinine production is dependent on muscle mass, itneeds to be interpreted cautiously among individu-als with low muscle mass, among females, and inelderly patients. In patients with low muscle mass,the serum creatinine underestimates the degree ofkidney function impairment, whereas among indi-viduals with large muscle mass (such as body-builders) the serum creatinine overestimates actualGFR. Another source of inaccuracy is the effect ofnoncreatinine chromogens when the alkaline picrateassay (Jaffe reaction) for creatinine is utilized.32

These factors include acetoacetate, cephalosporins,and high concentrations of furosemide. Modernversions of the Jaffe assay have reduced theseeffects by adjusting temperature, assay con-stituents, and various calibration settings. How-ever, in order to truly reduce the effect of non-crea-tine chromogens, alternative methods are neces-sary. These include an enzymatic creatinine assay,HPLC, or isotope dilution mass spectroscopy(IDMS). Furthermore, calibration of the serum cre-atinine is important to reduce intra- and interlabora-tory variability.33,34

Given these limitations with serum creatinine as ameasure of actual GFR, the NKF K-DOQI and theNational Kidney Disease Education Program(NKDEP) have recommended the use of actualGFR or, when this is unavailable, a prediction equa-tion for estimating GFR.35 Since in most situationsdirect measurement of GFR is not feasible, a pre-diction equation to estimate GFR is the most practi-cal and accurate method to assess kidney function.35

The MDRD and Cockcroft-Gault equations arenow the most popular prediction equations to assessGFR in adults.

Recently, an isotope dilution mass spectroscopytraceable (IDMS) MDRD equation (also known asthe MDRD 3 equation) has been developed.34 Inessence this is a modified MDRD equation usedwhen creatinine values are generated from a labora-tory that has calibrated its creatinine measurementto a set of creatinine standards. Until recently, one ofthe major limitations of using an estimated GFRequation, such as the MDRD equation, was thatthere was significant variability in the measurementof serum creatinine that results in reduced accuracyof the MDRD equation in the normal to slightly ele-vated creatinine range (up to 1.5 mg/dL). This isbecause assays in most laboratories are not cali-brated to the alkaline picrate method used by theCleveland Clinic laboratory during the conduct ofthe MDRD study. Mass spectroscopy is the mostideal method to obtain a “true” creatinine value and,therefore, creatinine standardization using an IDMStraceable panel for creatinine is now being recom-mended. The MDRD 3 equation is as follows:

175x [SCr]-1.154 x [Age]-0.203 x [0.742 if patientis female] x [1.21 if patient is black]

Prediction Equations for GFR (Table 7)

Cockroft-Gault (CG) Equation: This predictionequation is commonly used in clinical practice. Itsmajor limitations are: 1.) It has limited generaliz-ability. This is because it was originally formulatedto calculate the creatinine clearance in patients with-out kidney disease (Canadian males). It has not beenwidely validated in different populations and underdifferent clinical situations. 2.) CG tends to overes-timate GFR, especially among patients with chronickidney disease. This is because it utilizes serum cre-

Table 6

Limitations of Serum Creatinine as aMeasure of Kidney Function

1. Influence ofmusclemass2. Effect of creatinine secretion

a.) Patients with CKD–greater proportion ofcreatinine is secreted than filtered

b.)Medications blocking proximal secretiona. cimetidineb. trimethoprimc. probenecid


predialysis patients and renal transplant recipients.Validation for other subgroups, such as Asians, chil-dren, and the elderly still needs to be performed. In2000, a simplified MDRD equation (MDRD 2) wasmade available. It is based on serum creatinine asthe only laboratory value—in the absence of urea oralbumin.37 The MDRD formula yields an eGFR nor-malized to 1.73m2 body surface area. Adjusting forbody surface area is necessary when comparing apatient’s eGFR with normal values or when deter-mining the stage of CKD. However, an uncorrectedeGFR may be preferred for clinical use in some situ-ations, such as drug dosing (Table 9).

Clearance by Radiologic Contrast Agentsand Radioactive Isotopes

GFR can be calculated by the measurement of uri-nary or plasma clearances of isotopes or via imagesproduced from a gamma camera.38 There are 4 dif-ferent agents that are used in clinical practice: [125I] iothalamate,51 Cr-ethylenediaminetetraacetic acid,99m Tc-diethylenetriaminepentaacetic acid, andiohexol. These agents have been shown to correlatewell with inulin clearance. They also have high pre-cision in the setting of moderate to severe renal dys-function. Inulin clearance is the gold standard formeasurement 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

atinine to estimate creatinine clearance. The limita-tions of measuring creatinine clearance apply to theCG equation. Among patients with moderate tosevere kidney disease, creatinine secretion as a pro-portion of total creatinine excretion increases,resulting in an overestimation of the creatinineclearance. 3.) Like the MDRD equation, the CGequation is inaccurate among individuals with nor-mal or near-normal kidney function. 4.) The CGequation uses weight, which frequently results ininaccuracies at extremes of weight and/or whenthere is a measurement error in the assessment ofweight. Despite these limitations, CG remains pop-ular, especially among pharmacists who utilize it fordrug-dosing adjustments in patients with reducedkidney function (Table 8).

MDRD: “The Modification of Diet in Renal Dis-ease Study” GFR prediction equation was devel-oped in 1999.36 The equation is based on 1,628 non-diabetic subjects, age 18-70, with renal insuffi-ciency. The formula utilizes urea, creatinine andalbumin as well as demographics of age, gender,and race (black or white). If race is unavailable andwhite race is assumed, the GFR will be underesti-mated by 18% if the patient is black. This equationhas been validated in American black and whiteracial groups. It has also been validated in diabetics,

Table 7

GFR Equations

Cockcroft-Gault (CG):CrCl ×BSA/1.73m2

For men:CrCl = [(140-Age(yr)) xWeight (kg)]/SCr x72

For women:CrCl = ([(140 -Age) xWeight (kg)]/SCr x72) x 0.85

MDRD 1:GFR=170 x [SCr]-0.999 x[Age]-0.176 x[0.762if patient is female] x[1.18 if patient is black] x [BUN]-0.170 x[Alb]0.318

MDRD(abbreviated):GFR=186 x[SCr]-1.154 x [Age]-0.203

x[0.742 if patient is female] x [1.212 if patient is black]

Table 8

Advantages of the MDRD Over CG Equation

Direct comparison of theMDRDand theCock-croft–Gault equation demonstrate theMDRDequationto be superior for estimatingGFR, particularly in therangeGFR<60mL/min/1.73m2

Morewidespread validation ofMDRD thanCG(eg, in various populations).

No requirement for additional information forMDRD(eg,measurements of weight) beyond that alreadycollected by pathology laboratories.


estimates GFR because creatinine is both filtered bythe glomerulus and to a lesser degree, secreted bythe proximal tubule. On the other hand, urea under-estimates GFR since it is both filtered and reab-sorbed. The mean value of the creatinine and ureaclearance more closely approximates the actualGFR in the setting of GFR measurements less than15 ml/min/1.73 m2.

Cystatin C

Cystatin C is a nonglycosylated basic proteaseinhibitor produced by nucleated cells at a constantrate, is freely filtered by glomeruli, and is com-pletely metabolized after tubular reabsorption.39

Unlike creatinine, serum cystatin C level is notdependent on muscle mass, and is not differentiallyexpressed based on gender. GFR is estimated fromthe plasma cystatin C concentration, which has beenfound to correlate well with iothalamate GFR mea-surements in Pima Indians with DM and normal orsupranormal GFR. Cystatin has greater sensitivitythan Cr for small changes in GFR. Recent studiessuggest that cystatin C may be a better indicator ofpredicting risk for cardiovascular disease than eitherserum creatinine or a GFR prediction equation.40,41Creatinine 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 tubularsecretion of creatinine. Studies have shown that intrained patients there can be up to a 14% variation inurine Cr quantity secondary to incorrect collection,and in untrained patients this can be as high as70%.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 canresult from tubular secretion, thus leading to overes-timation of the creatinine clearance by this method.In order to compensate for overestimation of GFRfrom tubular secretion of Cr in the 24-hour urinecollection, the collection can be performed after oraladministration of cimetidine, an organic cation thatis a known competitive inhibitor of creatinine secre-tion. In order to compensate for the overestimationof GFR by the 24-hour urine creatinine method, theuse of the mean of urea and creatinine clearancemeasurements calculated from 24-hour urine collec-tions has been suggested. Creatinine clearance over-

Table 9

Situations in which the MDRD EquationShould be Used Cautiously

Populations inwhich theMDRDequation is not vali-dated or in which validation studies have not beenperformed

Individuals with near normal or normal kidney function

Severemalnutrition or obesity

Extremes of body size and age

Exceptional dietary intake (eg, vegetarian diet orcreatine supplements)

Disease of skeletalmuscle, paraplegia

Rapidly changing kidney function

symptomatic and may be severely disabled. In theearly stages of CKD (stage 1 and 2), using the NKFK-DOQI CKD stages, patients may present simplywith an elevated serum creatinine and blood ureanitrogen (BUN) level but no symptoms. These indi-viduals are usually unaware that they have anyabnormalities in their kidney function, and usuallyfail to register on the “radar screen” of theirinternists. However, even at this early stage, insidi-ous effects on target organs may become manifest.For example, patients may have mild to moderatehypertension, mild anemia, left ventricular hyper-trophy, and subtle changes in bone structure due torenal osteodystrophy. As kidney function graduallydeclines further—with glomerular filtration ratesreaching less than 30 mL/min—early features ofuremia become evident. These include worsening ormore difficult to control hypertension, extracellularvolume expansion (manifest as edema and dysp-nea), hyperkalemia and acidosis, anemia, and cog-nitive, psychological and physical abnormalities.Uremia reflects the accumulation of metabolic tox-ins, some characterized and others unknown, thatinfluence the functioning of a variety of organ sys-tems. In this late stage, the need for renal replace-ment therapy is imminent and dialysis and/or trans-plantation become inevitable in order to sustain life.

The indications for initiating renal replacementtherapy include severe refractory abnormalities inbiochemistry (severe hyperkalemia and acidosis),severe pulmonary edema, bleeding, metabolicencephalopathy, and the presence of pericarditis.Subtler but no less important indications includemalnutrition and severe disability (marked tirednessand lethargy) (Table 10).

Life expectancy in patients with ESRD for a 49-year-old is, on average, approximately 7 years,lower than colon cancer and prostate cancer andone-quarter that of the general population. Thisreduction in life expectancy is largely attributable tocardiovascular complications. Nearly 50% of alldeaths in patients with ESRD are due to cardiovas-cular causes.43 The risk is 17 times that of the gen-eral population. Remarkably, this gap is largest inyoung patients with end-stage renal disease. Therisk factors for cardiovascular disease in individualswith chronic renal failure include, but are not lim-ited to, the magnitude of the calcium/phosphorous

208 EDUCATIONAL REVIEWMANUAL IN NEPHROLOGY

9. Clinical Aspects of CKD

As a clinical syndrome, CKD is characterized byprogressive decline in kidney function such that thekidney’s ability to adequately excrete waste prod-ucts and to contribute to the constancy of the body’shomeostatic functions is severely impaired. MildCKD is asymptomatic; moderate CKD is frequentlycharacterized by hypertension, anemia, and abnor-malities in mineral metabolism; whereas advancedCKD is characterized by uremia. CKD may becomerelentlessly progressive as the damage to function-ing nephrons leads to a maladaptive responseamong the remaining nephrons. The progressivedecline in kidney function in individuals with CKDis variable and depends on both the cause of theunderlying insult and on patient-specific factors.42

There is consensus that renal disease progressionrates are heterogeneous both between different eti-ologies and within the same etiology. Thus, patientswith polycystic kidney disease (PKD) may progressmore slowly than patients with diabetic nephropa-thy; however, among patients with diabeticnephropathy there are patients who progress fastand others who progress hardly at all. Evidencepoints to the importance of several factors in modu-lating kidney progression.42 These include protein-uria, the presence of systemic hypertension, age,gender, genetic factors, and smoking.

End stage renal disease is the term used to denoteCKD requiring renal replacement therapy (dialysisor transplantation). The incidence of ESRD in theUnited States is approximately 268 cases per mil-lion population per year. However, ESRD is over-represented among African-Americans (829 permillion population per year, as compared with 199per million population per year among white Amer-icans). The major causes of ESRD in the UnitedStates are diabetes mellitus (44%), hypertension(30%), glomerular disease (15%), polycystic kidneydisease, and obstructive uropathy. Elsewhere in theworld, where the incidence of diabetes mellitus hasnot reached epidemic proportions—for example inEurope and parts of the developing world—chronicglomerulonephritis (20%) and chronic refluxnephropathy (25%) are the commonest causesof ESRD.

CKD is usually asymptomatic when there is mildimpairment in kidney function, whereas when GFRis markedly reduced the patient is usually clearly


product with its attendant risk of coronary calcifica-tion, the presence of dyslipidemia, hypertension,hyperhomocystemia, and the presence of LVH. Theclinical manifestations of cardiovascular disease inESRD patients include left ventricular hypertrophy,left ventricular dilatation, diastolic dysfunction,macro and microvascular disease, and abnormalitiesin autonomic function—increased sympathetic dis-charge and increased circulating catecholamine lev-els. Vascular disease may involve calcification ofcoronary vessels and valve disease. Indeed, calcifi-cation of the mitral valve annulus and the aorticvalve cusps is common among ESRD patients.

10. Key Complications of CKD

The most important complications of CKD arehypertension, disturbances in mineral metabolism,anemia, acidosis and dyslipidemias. Hypertensionis discussed in detail elsewhere in this book and willnot be reviewed further in this chapter.

Secondary Hyperparathyroidism andMetabolic Bone Disease

Secondary hyperparathyroidism (SHPT) is a multi-factorial syndrome that begins early in CKD butultimately is present in most patients with CKD.44

Notably, bone disease in CKD and ESRD patientsrepresents a spectrum from low and high turnoverdisease and osteomalacia and osteoporosis. Adetailed discussion is beyond the scope of this chap-ter and can be reviewed elsewhere.45 The centralabnormality is an excess secretion of parathyroidhormone (PTH) by the parathyroid glands.46 Thisresults from progressively worsening kidney func-tion that causes phosphorus retention and diminish-ing production of 1, 25 (OH2), D3 (calcitriol), theactive form of vitamin D. Starting early in CKD,reduced kidney function results in reduced activityof a hormone, 1α-hydroxylase, synthesized by renaltubular cells and responsible for activation of vita-min D. Reduced 1α-hydroxylase activity results indecreased levels of calcitriol (1, 25-dihydroxyvita-min D). Circulating calcitriol levels begin to fallwhen the glomerular filtration rate is less than 40mL/min. By the time patients have progressed toend-stage renal disease the calcitriol level ismarkedly reduced. The removal of the normal sup-pressive effect of calcitriol on the parathyroidglands results in PTH secretion.

As a consequence of calcitriol deficiency there isreduced absorption of calcium in the gut andreduced mobilization of calcium. In addition, excessextracellular phosphorus binds to calcium and fur-ther drives down the ionized plasma calcium con-centration. Both factors result in a relative decreasein serum calcium. In compensation, parathyroidhormone (PTH) secretion is stimulated, maintainingserum calcium and phosphorus in the normal rangein most CKD stage 3 and 4 patients (Table 11). PTHsecretion is influenced by this balance of extracellu-lar calcium and phosphorus. As kidney disease pro-gresses there is a decrease in the number of vitaminD (VDR) and calcium sensing (CaR) receptors onthe parathyroid gland. Reduction in VDR and CaR

Table 10

Indications for Initiation of Renal Replace-ment Therapy

Refractory hyperkalemia

Acute pericarditis

Fluid overload or pulmonary edema refractory todiuretics

Encephalopathy

Severe peripheral neuropathy

Hypertension refractory to antihypertensivemedications

Severe uremic bleeding; clinically significantbleeding; diathesis attributable to uremia

Intractable nausea and vomiting


density causes resistance of the parathyroid glandsto both calcitriol and calcium. In parallel, excessextracellular phosphorus induces hyperplasia of theparathyroid glands independent of calcium and cal-citriol. The initial hyperplasia of the parathyroidgland is followed in later stages by nodularity, withevidence at a cellular level of monoclonal cellularexpansion. The lack of calcitriol is thought to causedown-regulation of vitamin D receptors, which thenpromotes parathyroid chief cell hyperplasia andnodule formation. The resistance of parathyroidcells to calcitriol appears to serve as second stimu-lus for PTH secretion in patients with advancedCKD. Reduction of calcitriol receptor density inparathyroid glands is currently considered themechanism responsible for the resistance to fairlyrobust doses of vitamin D in chronic renal failure.As renal failure progresses, this disturbance mayform a vicious cycle of further reducing calcitriolreceptor density leading to progressive resistance tocalcitriol.

As GFR declines with advancing CKD, renal phos-phate excretion is reduced and serum levels of phos-phate rise.47 Circulating levels of phosphate are alsoinfluenced by a variety of other factors: dietaryphosphorus intake, intestinal absorption, andexchange with bone reservoirs. The major hor-mones that regulate phosphate homeostasis throughthese mechanisms are 1, 25 (OH)2D3 and parathy-roid hormone. An emerging role for a novel class ofproteins termed phosphatonins has also emerged.Phosphatonins are a group of proteins discovered inthe characterization of a group of pathologic condi-tions characterized by phosphate wasting. FGF-23is the most extensively studied. Increased FGF-23may contribute to maintaining normal phosphatelevels early in CKD through its phosphaturic effect,which may explain the lack of laboratory phosphatederangement seen early in SHPTH.

Management of Osteitis Fibrosa

The management of osteitis fibrosa is reviewed inthe NKF KDOQI guideline document.44 It is impor-tant to emphasize that the measurement of calcium,phosphorus, and intact plasma parathyroid hormoneis important in all patients with a GFR less than 60ml/min/1.73 m2. The frequency of these measure-

ments and the target range for intact PTH is based onthe stage of CKD.

Sustained exposure of bone to elevated PTH resultsin osteitis fibrosa, a disease of high bone turnoverand accelerated bone resorption. Bone biopsy stud-ies in CKD stage 3 and 4 patients indicate thatosteitis fibrosa is present in approximately 70% ofpatients, and another 10%-15% develop osteitisfibrosa with osteomalacia or mixed bone lesions.These pathologic changes may result in a reductionin bone mineral density on DEXA scanning, whichmay be misinterpreted as osteoporosis, a conditionof low bone turnover. Effective treatments, whichlower PTH, include dietary phosphorus restriction,use of calcium-based phosphorus binders, treatmentof vitamin D deficiency and use of calcitriol or otheractive vitamin D analogs.48

Control of Hyperphosphatemia

Dietary phosphorus restriction is an important ele-ment in the management of osteitis fibrosa. In stage3 CKD, a reduction in dietary phosphorus to800-1000 mg/day results in a decline in PTH, anincrease in endogenous calcitriol production, andtypically no appreciable change in serum phospho-rus. In stage 4 CKD, dietary phosphorus restrictionlowers PTH and serum phosphorus, but does notusually result in an increase in calcitriol production.In patients with CKD stages 3 and 4, daily phospho-rous intake should be restricted to 800-1000 mg/dayin the setting of a phosphorous level greater than 4.6m/dL or when PTH exceeds the target range. Targetserum phosphorus is 2.7 to 4.6 mg/dL in stage 3 and4 CKD. Phosphorus binders taken with mealsdecrease absorbed phosphorus and have effects sim-ilar to dietary phosphorus restriction. The dose ofbinders required in CKD stages 3 and 4 is much lessthan that required in dialysis patients. Calcium basedbinders may be used as initial therapy (such as cal-cium carbonate or calcium acetate), but the dose ofelemental calcium should not exceed 1500 mg/day.Use of calcium further suppresses PTH by increas-ing serum calcium, but this may result in a chroni-cally positive calcium balance and contribute to vas-cular calcification. Noncalcium based binders—such as sevelamer HCl 800 mg TID or lanthanumcarbonate 250 mg TID—offer effective phosphorus


control without the dangers of calcium loading, butare substantially more expensive than calciumbased binders. Additionally, sevelamer can induceacidosis due to HCl release upon binding of phos-phorus.

Vitamin D and/or Vitamin DAnalogue Therapy

A deficiency of both 25(OH)D and 1,25(OH)2D3are common abnormalities in CKD patients. Bothmay contribute to the development and progressionof SHPT and/or associated osteomalacia and osteo-porosis. Vitamin D stores are assessed by determi-nation of serum 25(OH)D level, the stable livermetabolite of vitamin D. A normal level is >30ng/ml, and lower levels should be supplemented.Most 25(OH)D circulates bound to D binding pro-tein (DBP) and serum DBP may be greatlydecreased in nephrotic syndrome due to heavy pro-teinuria, making interpretation of the laboratoryresults questionable. Nevertheless, restoration of25(OH) D levels to normal is appropriate, althoughthere is limited data that this lowers PTH.

Treatment with vitamin D or one of its analogues isa key element in CKD management (Table 12).Active vitamin D analogs suppress PTH in a dosedependent manner.48,49 One of these agents should beused whenever PTH is above the target rangedespite vitamin D repletion and phosphorus control.Doses are usually administered orally daily or thriceweekly, resulting in similar PTH suppression. Cal-citriol (Rocaltrol®) is typically begun at 0.25 mcg

daily or 0.5 mcg thrice weekly and significantlyenhances intestinal absorption of calcium and phos-phorus. Hypercalcemia is common when dosesexceed 0.5 mcg per day.

Vitamin D analogs were developed to reduce thestimulation of intestinal calcium and phosphorusabsorption.48 Paricalcitol (Zemplar®) appears to havethe least effect on intestinal mineral absorption, andin randomized trials had an incidence of hypercal-cemia and hyperphosphatemia similar to placebo.Paricalcitol is usually started at 1 mcg daily or 2 mcgthrice weekly. Doxercalciferol (Hectorol®) is a pro-hormone (1(OH)D2), and is metabolized constitu-tively by the liver to 1, 25(OH)2D2, an active formof vitamin D. Other metabolites of doxercalciferolmay also be formed and may account for the appar-ently lower incidence of hypercalcemia and hyper-phosphatemia seen with this analog. Doxercalcif-erol is usually started at 1 mcg daily. (See Table 12for recommended doses of ergocalciferol.)

After three or more weeks on any form of the aboveactive vitamin D products, serum PTH should beremeasured and the dose of the active D productincreased by 50%-100% if necessary to achievePTH suppression into the CKD stage specific target.Adequate suppression of PTH should be balancedwith maintenance of normal serum calcium (8.4 to10.2 mg/dL) and phosphorus (2.7 to 4.6 mg/dL).Serum calcium and phosphorus should be measuredat least quarterly, and more frequently if calcitriol isused at a dose of 0.5 mcg per day or more.

Table 11

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

CKD GFR Range Measurement Measurement Target intactStage mL/min1.73m2 of PTH of Ca and Phos PTH (pg/mL)

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

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

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


Anemia

Anemia is a common complication in CKD patients,affecting approximately 40% of patients in stage 4and 5 CKD (anemia defined herein as a Hb of <11g/dL) (Table 13). Estimates suggest that almost1,000,000 patients in the United States with CKDare anemic.52 Diabetes seems to be an additional riskfactor for anemia in CKD and more than 20% of dia-betics with an eGFR of 30-59 mL/min/1.73 m2 areanemic. The etiology of anemia in CKD is multifac-torial. While erythropoietin deficiency is the mostcommon cause (Tables 14, 15), iron deficiency,nutritional deficiencies (in vitamin B6 and B12),occult blood loss and hyperparathyroidism are alsoimportant causes.

Clinical Features and Diagnosis of CKDAnemia

Mild anemia (Hb levels >11 g/dL) is usually asymp-tomatic in CKD patients. By the time the Hb level is<10 g/dL, patients complain of tiredness andfatigue. Some patients may complain of a reductionin exercise capacity, well being, tiredness, and coldintolerance. Impairment in neurocognitive abilitymay be evident using formal tests but may be toosubtle to detect by routine clinical evaluation. Inseveral observational studies, anemia increases therisk of cardiovascular complications including leftventricular hypertrophy, left ventricular dilatation,and myocardial ischemia.53,54 From a diagnosticstandpoint, CKD anemia is characterized by normo-cytic, normochromic hematologic indices. A rapid

method of determining whether cellular indices arenormocytic and normochromic is to multiply theRBC and Hb by 3. The RBC multiplied by 3 shouldequal the Hb, and the Hb multiplied by 3 shouldequal the Hct. Deviation from the calculated valuessuggests microcytosis, macrocytosis, or hypochro-mia versus the presence of spherocytes (MCHC,>36). In patients suspected of CKD anemia, mea-surement of an erythropoietin level (EPO) is notnecessary. This is because a low normal or even anormal EPO level may suggest EPO deficiency. Onthe other hand, excluding the possibility of iron defi-ciency is important. The diagnosis of iron deficiencyis made by demonstrating that the patient has atransferrin saturation (TSAT) level of <20% and/or aserum ferritin level of <100 ng/mL. While the goldstandard for iron deficiency is the absence of stain-able iron in a bone marrow specimen, under mostcircumstances a bone marrow evaluation is imprac-tical. The presence of microcytosis and hypochro-mia is helpful but not diagnostic. Every patient withiron deficiency anemia should have a stool examina-tion for occult blood. A positive result necessitates acareful search of the gastrointestinal tract to identifythe site of bleeding. Unfortunately, a negative resultdoes not exclude gastrointestinal blood loss becausebleeding can be intermittent and require severalexaminations for detection. Also, less than 20-30mL of blood in the stool per day may go undetecteddue to the insensitivity of the test.

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 capsuleweekly x 12weeks, thenmonthly x 3months

5-14 1 capsuleweekly x 4weeks, thenmonthly x 5months

15-29 1 capsulemonthly x 6months


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

Hgb should be checked every two weeks initially,and the dose of drug adjusted by ~25% to achieveand maintain Hgb 11-12 g/dL. Once the target Hgb

Treatment of CKD Anemia

In the United States, there are 2 erythropoiesis-stim-ulating agents that are available: epoetin alfa anddarbepoetin.51,55 Epoetin beta is also available inEurope and other countries. A large number ofgeneric or biosimilar molecules to epoetin have alsoemerged into the marketplace, particularly in thedeveloping countries.

Treatment with epoetin or darbepoetin should beinitiated in most patients when hemoglobin is lessthan 10 mg/dL, and preferably when Hgb is 10 to 11g/dL.51 For convenience reasons, less frequent dos-ing regimens are used in CKD than in dialysispatients.56-58 The initial dose of epoetin is usually

Table 13

Key Recommendations in the2006 KDOQI Anemia Update51

The initial evaluation of anemia should include aCBC,absolute reticulocyte count, serum ferritin and serumtransferrin saturation (TSAT).

The hemoglobin range should be at least 11.0 g/dL;however, there is insufficient evidence to recommendmaintainingHbconcentrations. ≥13.0 g/dL can beused for all other CKDpatients (CPR2.1.2).

The iron parameter goals for hemodialysis patientsshould be a serum ferritin concentration ≥200 ng/mL,and a transferrin saturation ≥20%or a reticulocytehemoglobin content ≥29pg/cell (CPR3.2.3.1).

The goals for non-dialysis-dependent CKDandperi-toneal dialysis patients should be a serum ferritin con-centration ≥100 ng/mL and a transferrin saturation≥ 20% (CPR3.2.3.2).

The preferred route of administration for iron is IV inpatients with hemodialysis dependent CKD (CPG3.2.5.1).

Routine administration of IV iron if the ferritin concen-tration exceeds 500 ng/mL.

Table 14

Key Facts on Erythropoetin55

EPO is producedby peritubular cells in the kidneys ofthe adult and in hepatocytes in the fetus. Smallamounts of extrarenal EPOare producedby the liverin adult human subjects.

EPOacts primarily to rescue erythroid cells fromapoptosis (programmedcell death) to increase theirsurvival.

EPObinds to an erythroid progenitor cell surfacereceptor to regulate bonemarrow erythroid cell prolif-eration, differentiation, and survival.

EPO receptors are also onmesangial cells in the kid-ney, brain, testes,myocardium.

EPObinds to an erythroid progenitor cell surfacereceptor to regulate bonemarrow erythroid cell prolif-eration, differentiation, and survival.

Benefits of treating anemiawith EPO include:improved exercise tolerance and less fatigue, lowertransfusion rate, andpotentially, regression of LVH.

is achieved, the epoetin or darbepoetin dose can beapproximately doubled and dosing frequency alsodoubled.58

Hemoglobin Target in CKD Patients

The 2002 NKF Anemia Update had recommended ahemoglobin range of 11 to 12 g/dL.50 However, morerecently, the NKF Anemia Update has recom-mended that the target hemoglobin range should be


statistically significantly higher rate of the first car-diovascular event (58 events in the highhemoglobin group versus 47 events in the lowhemoglobin group; hazard ratio of 0.78, 95% confi-dence interval, 0.53 to 1.14; P=0.20). However, leftventricular mass index remained stable in bothgroups but dialysis was required in more patients inthe higher versus lower hemoglobin group (127 vs.111, P=0.03). On the other hand, unlike CHOIR, inCREATE a quality of life benefit, at least in year 1of the study, was observed for the higher versuslower hemoglobin group. Therefore, both studiesshowed either risk or no benefit with regards to car-diovascular outcomes aiming to completely correctthe hemoglobin in CKD patients not receiving dial-ysis. The CHOIR study was larger and showed astatistically significant difference for the primaryendpoint, whereas the CREATE study was under-powered for the primary event and showed a trendfor increased risk but did not reveal statistically sig-nificant differences for the primary endpoint. Onthe other hand, in both CHOIR and CREATE, qual-ity of life improved in patients treated with epoetin.While in CHOIR there was no incremental

generally 11 to 12 g/dL.51 The lower Hb level isbased on evidence, whereas the upper Hb level isconsidered an opinion-based recommendation.51

Treating CKD anemia with erythropoietin has beenshown to enhance quality of life; however, evidencesupporting a benefit of anemia correction in improv-ing cardiovascular morbidity and mortality haslargely rested on data derived from observationalstudies. The recent publication of the CHOIR andCREATE studies have demonstrated increased riskwith targeting a higher hemoglobin level.56,57

CHOIR56 was an open-label, randomized trial thatstudied 1432 patients with CKD: 715 patients ran-domized to receive epoetin alfa targeted to achieve ahemoglobin of 13.5 g/dL, and 717 were randomizedto receive epoetin alfa targeted to achieve ahemoglobin of 11.3 g/dL.3 The median study dura-tion was 16 months. The primary end point was acomposite of death, myocardial infarction, conges-tive heart failure (CHF), hospitalization (excludinghospitalization during which renal replacementtherapy occurred), and stroke. Two hundred twenty-two composite events occurred: 125 events amongthe high hemoglobin group and 97 events among thelow hemoglobin group (P=0.03), hazard ratio of1.34; with 95% confidence interval of 1.03 and 1.74.The higher rate of composite events was explainedlargely by a higher rate of death (48% higher risk,P=0.07) or CHF hospitalization (41%, P=0.07).Although neither death nor CHF hospitalizationwere statistically significantly higher in the higherversus lower hemoglobin group, the study was notpowered for this purpose. Among other secondaryendpoints, quality of life showed improvement inboth groups but was not significantly better in thehigher versus lower hemoglobin groups. Notably,more subjects in the high hemoglobin group experi-enced at least one serious adverse event compared tothe low hemoglobin group. The CardiovascularRisk Reduction by Early Anemia Treatment withEpoetin beta (CREATE)57 study enrolled approxi-mately 600 patients. Subjects were randomized toan early anemia correction or a late anemia correc-tion group.4 The early anemia correction groupreceived epoetin beta therapy immediately for a tar-get hemoglobin 13-15 g/dL. The late anemia correc-tion group did not receive treatment until theirhemoglobin was <10.5 g/dL; their targethemoglobin was 10.5-11.5 g/dL. The study showedthat “complete correction” was not associated with a

Table 15

Practical Guide to UsingErythropoetin for CKD Anemia60

1. Start whenHb<11.0 g/dL2. Use epotein alfa or darbepoetin3. For epoetin alfa:

a. Starting dose 10,000 units subcutaneouslyeachweek, or 20,000 units every other week

b. Single vials come in 2,000, 3,000, 4,000,10,000, and 40,000 unit doses;multi-dosingvials comes in 10,000 and 20,000 unit doses

c.Maintenance dosing uses an extendeddosestrategy—every other, every third, or everyfourthweek.

4. For darbepoetin:a. Initial dose: 0.45mcg/kgQWb.Can use 25, 40, 60, 100, 150, 200, 300, 500mcg/mL single-dose vials or prefilled syringes

c.Maintenance:multiply for longer intervals up to4weeks.


Iron Deficiency in CKD Patients

While several mechanisms may account for irondeficiency among dialysis patients (loss through thedialysis procedure, acute and chronic inflammation,and reduced oral absorption and reduced dietaryintake), among predialysis CKD patients the mostimportant reason appears to be reduced GI absorp-tion (Table 16). The likeliest reason for this is ablock, through the action of hepcidin, in ironabsorption through the intestinal iron transporterferroportin.61 Hepcidin, a liver synthesized protein,regulates ferroportin mediated iron absorption.

High hepcidin levels result in reduced iron absorp-tion.62 Since hepcidin is excreted by the kidneys, it ispostulated that renal dysfunction results in progres-sively higher levels of hepcidin and thus attenuatediron absorption. CKD patients’ reduced dietaryintake, especially of foods high in iron, such asmeats and leafy vegetables, may further exacerbateiron deficiency. It is estimated that approximately40% of patients with CKD have iron deficiency.63

As kidney disease progresses, iron deficiency

improvement in QOL in the higher versus lowerhemoglobin group, in CREATE patients random-ized to the higher hemoglobin level did experienceimproved quality of life. Indeed, several large ran-domized controlled studies in both ESRD and pre-ESRD patients have either failed to demonstrate abenefit of anemia correction, or have shown a trendtowards worse outcomes such as cardiovascular dis-ease or death. A recent meta-analysis concurs –increased risk with targeting a hemoglobin concen-tration of >12 g/dL in pre-dialysis and dialysispatients. 58 In light of the evidence from interven-tional studies, as alluded to above, a recent boxedadvisory from the Food and Drug Administration(FDA) has recommended a Hgb target of10 to 12 g/dL.

Initiation of erythropoietic agents frequently con-sumes the patient’s iron stores, and the inflamma-tion present in CKD inhibits adequate intestinal ironabsorption, resulting in iron deficiency. High levelsof C-reactive protein, a marker of inflammation,have been associated with low iron absorption inpatients on HD.

Table 16

Indicators and Causes of Iron Deficiency

Form Indicator Cause

Absolute iron deficiency TSAT<20%and serum Increasedblood lossserum ferritin <100 ng/mL Decreased iron

absorption

Functional iron deficiency TSATmaybe<20%and Intense stimulation offerritinmay be 100-700 ng/mL RBCproduction by EPO

therapy outstrips ironsupply.May developevenwhen storage ironappears normal

REblockade Dramatic increase in serum Acute or chronic inflam-ferritin alongwith drop in TSAT mation often seen inHD

patient. Blocks release ofiron stores fromRES

worsens because of a postulated increase in hep-cidin levels due to reduced hepcidin excretion bythe kidneys. Another possibility is that progres-sively increased levels of inflammation result in anincreased expression of hepcidin and thus a block inGI absorption of iron.

Assessment of Iron Deficiency

TSAT (calculated by the formula serum iron/totaliron binding capacity x 100) and serum ferritin arethe primary measures used to assess patients’ ironstores. Although neither has optimal sensitivity norspecificity, they are inexpensive and widely avail-able. Tissue ferritin is a large protein molecule con-tained within the reticuloendothelial system (RES),with iron at its core. Serum ferritin is ferritin that hasleaked from tissues, and it is an indicator of tissueiron stores. Most normal patients have serum fer-ritin levels below 30 ng/mL; however, levels aremuch higher in uremic patients. Transferrin is thebody’s iron transport molecule, delivering ironfrom the RES to the bone marrow for erythro-poiesis. The TSAT represents the body’s circulatingiron. According to the K/DOQI guidelines, a TSATlevel <20% and a serum ferritin level <100 ng/mLrepresents iron deficiency, and a serum ferritinlevel >500 ng/mL represents iron overload. How-ever, the 500 ng/mL level set by K/DOQI is opinionbased, not evidence based. Functional iron defi-ciency and reticuloendothelial (RE) blockade may

be discerned by examining the patient’s response toa trial dose of IV iron. A rise in Hgb and Hct levelsand/or a reduction in EPO dose requirement willsignify functional iron deficiency. In contrast, inthe presence of inflammation-mediated RE block-ade, iron supplementation may not be effectiveuntil the underlying inflammation has subsided.The probability of RE blockade exists in situationswhere either serum ferritin levels have risen, EPOdose requirements have remained high despite IViron, or no erythropoietic response has occurred (ie,Hgb level does not increase).

There are limitations to both the serum ferritin andTSAT markers in accurately diagnosing iron defi-ciency.51,64-66 Serum ferritin is an acute-phase reac-tant, and levels are elevated in cases of inflamma-tion and infection, which are common in HDpatients. Because iron is an acute-phase reactant,TSAT levels also may be affected by inflammationor infection. In addition, because transferrin is pro-duced primarily in the liver, hepatic disease canreduce transferrin production. As a result, if trans-ferrin levels are low, the TSAT level may appear tobe normal in the presence of iron deficiency. TSATlevels also are affected by nutritional status. TSATand serum ferritin levels may have greater diagnos-tic utility for iron deficiency and iron overload whenthey are very low or very high, respectively.


Table 17

Pharmakinetic Profiles of IV Irons

Iron Dextran Iron Sucrose Ferric Gluconate

Molecular weight, INFeD165,000 34,000-60,000 289,000-440,000Daltons Dexferrum265,000

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

Direct transfer to RES Yes Yes Yes

Direct transfer No Yes Noto transferrin


Treatment of Iron Deficiency

The treatment of iron deficiency in CKD anemia isreviewed extensively elsewhere.51,64-66 There is a lim-ited role for oral iron in the treatment of iron defi-ciency in patients with advanced CKD. Intravenousiron is recommended in these circumstances. Verylittle oral iron is absorbed and side effects of oraliron may be quite considerable. A healthy individualonly absorbs about 1% of the total iron ingested inan oral dose, while in CKD patients, impaired gas-trointestinal absorption can lead to even lowerabsorption of iron. Side effects of oral iron includeconstipation and gastrointestinal upset.

Despite a clear rationale for intravenous iron ther-apy, there continues to exist an underutilization ofthese preparations. This is most likely because ofexpense, inconvenience of administration, and lim-ited access to infusion facilities. There are 3 avail-able forms of IV iron (ferric gluconate, iron sucrose,and iron dextran); and there are 2 types of iron dex-tran: INFeD® and Dexferrum®. Studies of mainte-nance IV iron therapy have demonstrated a consis-tent improvement in erythropoiesis as measured bydecreased EPO requirements to maintain orimprove Hct levels. This improvement has beenseen with all 3 available forms of IV iron. The sig-nificant decrease in EPO requirements in HDpatients may translate into substantial savings,given the high cost of EPO therapy.

The IV irons differ based on their pharmacokineticprofiles, which may have a potentially significantimpact on their safety profiles and bioavailability(Table 17). Among the IV irons, ferric gluconate hasthe shortest elimination half-life (1 hour), approach-ing the maximum rate of physiologic clearance bythe RES. Ferric gluconate also has the largestmolecular 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 totransferrin. However, iron sucrose appears to have adual method of turnover, with a portion of the ironcomplex being delivered directly to transferrin—thereby raising the risk of transferrin oversaturation.

Iron stores should also be assessed periodically withevaluation of transferrin saturation and ferritin. Iftransferrin saturation is <20% or ferritin is

<200 mg/dL, consideration should be given to ironrepletion. Alternative markers of iron deficiencyinclude an increased number of hypochromic redblood cells (percentage >10%), or a low reticulocutehemoglobin content (CHr <31 pg). Intravenous ironpreparations include iron dextran (1000 mg IV as asingle dose, with an initial test dose of 25 mg); ferricgluconate (initial dose 125 mg IV); or iron sucrose(initial dose 100 to 200 mg IV). Iron dextrans have alow but serious risk of anaphylactic reactions. Oraliron therapy can be attempted in CKD. To maximizeabsorption, at least 200 mg of elemental iron shouldbe consumed daily in divided doses taken betweenmeals. Oral iron salts may be bound by calcium-based phosphorus binders and thus should be takenseparately. Thyroid hormone supplements may alsobe bound by ferrous sulfate and therefore should betaken separately.

Acidosis

Chronic metabolic acidosis begins to develop wheneGFR falls below 40-50 mL/min, and most stage 4CKD patients have serum bicarbonate levels<22 meq/L.67,68 Unless patients have concomitantrenal tubular acidosis, the ensuing metabolic acido-sis tends to be mild and easily treated. Even mildmetabolic acidosis results in increased resorption ofbone, weakening of bone structure, and can increasethe risk of fractures. Additionally, acidosis enhancesprotein catabolism and can contribute to malnutri-tion in CKD. Treatment is usually started whenserum bicarbonate is persistently < 22 meg/L. Oneor two sodium bicarbonate tablets (650 mg, ~8 meqeach) are usually administered TID to maintainserum bicarbonate >22 meq/L. Use of citrate saltsmay increase the absorption of dietary aluminum inpatients with CKD, and therefore should beavoided.

Dyslipidemia

Hypercholesterolemia is considered a major riskfactor and cause of atherosclerotic disease in thegeneral population; however, there is a lack of asso-ciation between this traditional risk factor andatherosclerotic cardiovascular disease among dialy-sis patients, and limited data in patients with CKD.Multiple complex lipid abnormalities, known col-lectively as uremic dyslipidemia, are commonly


observed in dialysis and CKD patients due to thereduced lipolysis of apolipoprotein B-containingtriglyceride (TG)-rich very-low-density lipoprotein(VLDL) particles.69 This defect is associated withnear normal total cholesterol, elevated VLDL andintermediate density lipoproteins (IDL), low high-density lipoprotein (HDL), and a shift of LDL parti-cle size toward a small dense LDL. The concentra-tions of LDL particles, small dense LDL, largeHDL, IDL, and large VLDL are better indicators ofcardiovascular risk than the elements of the tradi-tional lipid profile. However, the traditional lipidprofiles do not directly determine the concentrationor the size of these known atherogenic apolipopro-tein B-containing lipid subclasses (VLDL-C, IDL-C, and LDL-C). To address this problem, the NCEP(National Cholesterol Education Program) recom-mends assessment of non-HDL cholesterol as a rea-sonable surrogate parameter to estimate totalapolipoprotein B, and treatment when non-HDL is>130 mg/dL.70 Virtually all patients with CKD havea 10-year risk of cardiovascular events >20%.Therefore the target LDL-C should be less than 100mg/dL, and non-HDL-C less than 130 mg/dL.

There is limited data on the beneficial effects of

statins on CVD outcomes in CKD patients. Onestudy—the 4D study conducted in hemodialysispatients—used atorvastatin and failed to show abeneficial effect.71 However, several post hoc analy-ses of statin trials do suggest that CKD patientsshould benefit from statin therapy.72 Until more datafrom randomized controlled studies becomes avail-able, it is reasonable to treat CKD patients like thosewithout kidney disease and reduce lipid levelsaccording to NCEP/ATP guidelines.70

Assessment of a complete fasting lipid panel (totalcholesterol, LDL-C, HDL-C, and triglycerides) isrecommended annually in all CKD patients. Initialtherapy should target LDL-C to less than 100 mg/dL—usually with statin therapy. No HMG-CoAinhibitor is contraindicated in CKD, but rosuvas-tatin should be started at a lower dose. Ezitimibeinhibits intestinal transport of dietary cholesterol,and is a useful adjunct to statin therapy. Secondarylipid therapy should target non-HDL cholesterol toless than 130 mg/dL if fasting triglycerides aregreater than 200 mg/dL. In these latter patients, useof niacin or gemfibrizol may be efficacious. Physi-cians should be vigilant for the development ofmyalgias or myopathy.

Table 18

Management of Kidney Disease

Type of Kidney Disease

Diabetic kidney disease

Non-diabetic kidney diseasewith spotUp/Uc ratio ≥ 200mg/g

Non-diabetic kidney diseasewith spotUp/Uc ratio < 200mg/g

Disease in the kidney transplantrecipient

Target BloodPressure(mmHg)

<130/80

<130/80

<130/80

<130/80

Preferred Agents forCKD With or WithoutHypertension

ACE Inhibitor or ARB

ACE Inhibitor

No preference

Nopreference

Other Agents toReduce CVD Riskand Reach BloodPressure Target

Diuretics preferred,thenBBorCCB

Diuretics preferred,thenBBorCCB

Diuretics preferred,thenACI inhibitor, ARB,BB,CCB

CCB,Diuretic, BB, ACEinhibitor, ARB


11. Management of KidneyDisease Progression

KDOQI Action Plan by Stage of CKD

The NKF KDOQI group has released an action planfor management of patients with CKD as deter-mined by stage of CKD.1 In addition, a moredetailed discussion regarding the slowing of kidneyprogression can be reviewed elsewhere.73 In stage 1CKD, these guidelines suggest the diagnosis andtreatment of CKD, treatment of comorbid condi-tions, prevention of progression of renal disease,and CVD risk reduction. In stage 2, the issue of pri-mary concern is that of estimating and managingrenal disease progression. The focus of stage 3 dis-ease is that of evaluating and treating complica-tions; while stage 4 CKD, the immediate pre-dialy-sis stage, consists of preparation for renal replace-ment therapy. The management of stage 5 CKD isthat of initiation and maintenance of renal replace-ment therapy. Thus, in addition to the task of diag-nosing and treating the specific etiology of renaldisease, the broad themes that govern early versuslate renal disease management are those of preven-tion of progression in the early stages of CKD, man-agement of complications beginning in the earlystages and continuing throughout the follow-up ofpatients, and preparation for renal replacement inthe later predialysis phase.

There are three important elements to the manage-ment of progression in CKD patients (Table 18):

1. The use of angiotensin blockers to protect thekidney. Both landmark studies in animals byBrenner and colleagues,74 as well as studies inhumans, supports an independent role forangiotensin blockade in renoprotection.75-77 ACEinhibitors (ACEi) or angiotensin receptor block-ers (ARB) can be used. It is important to titratethe dose of ACEi or ARB to maximal levels usingreduction of proteinuria as the yardstick for effi-cacy. Emerging evidence (from the COOPER-ATE study)78 suggests a beneficial effect of usingboth ACEi and ARB in a synergistic strategy toreduce proteinuria and enhance renoprotection. Inaddition, sodium restriction and diuretics in con-junction with ACE-I/ARB therapy increase theirantiproteinuric effects and should be used in anadjunctive fashion. (ACE inhibitors or ARB are

contraindicated in patients who are pregnant, and inpatients with a history of angioedema.)

2. Control of blood pressure. The MDRD studydemonstrated that patients targeted to MAP of 92and 107 mmHg had rates of decline of GFR of-3.56 and -4.10 mL/min/year, respectively, andthat there was greater effect with increasing levelsof albuminuria.79 This study, taken in conjunctionwith several other studies that have been pub-lished, subsequently suggest a key role for bloodpressure reduction in retarding the progression ofkidney disease. Indeed, a recent study suggeststhat this beneficial effect of controlling bloodpressure on kidney disease extends for a pro-longed period of time.80 The 2003 NKF-KDOQIclinical practice guidelines for antihypertensivetherapy recommend:81

• Blood pressure measurement at each health careencounter.

• Target blood pressure of less than 130/80 for allpatients with kidney disease, including those withdiabetic kidney disease and non-diabetic kidneydisease, regardless of degree of proteinuria, andin renal allograft recipients.

• Use of an ACE-I/ARB in patients with diabetickidney disease, and use of ACE-I in non-diabetickidney disease with proteinuria (spot Up/Ucrratio of ≥200 mg/g), to retard progression of kid-ney disease, irrespective of the presence of hyper-tension.

With regard to adjunctive anti-hypertensiveagents, the guidelines suggest diuretics followedby either beta-blockers or calcium channel block-ers in diabetic kidney disease as well as in non-diabetic proteinuric kidney disease (spot Up/Ucrratio of ≥200 mg/g). Diuretics are the preferredagent in patients with kidney disease in theabsence of significant proteinuria, as defined byspot Up/Ucr ratio of <200 mg/g, followed byACE-I, ARB, beta-blocker, or calcium channelblocker. Finally, in recipients of renal allografts,the NKF-DOQI guidelines recommend calciumchannel blockade, diuretic therapy, and betablockade, ACE-I or ARB.

3. Adjunctive strategies in retarding progressioninclude:a.) Strict glycemic control. The DCCT andUKPDS studies for type 1 and type 2 diabetics,respectively, have unequivocally demonstratedthe benefits of tight glycemic control with a goalHbA1C of <7.0.b.) Protein restriction. The K/DOQI Guidelinesfor Nutrition in Chronic Renal Failure recom-mend restriction of protein intake to 0.8gm/kg/day in all patients with CKD, with furtherrestriction to 0.6 gm/kg/day in those with CrClless than 25 ml/min. The guidelines also recom-mend a caloric intake of 30-35 kcal/kg/day.c.) Smoking cessation. Smoking has been impli-cated as a risk factor in the progression of kidneydisease, particularly diabetic kidney disease. Thepostulated mechanisms of injury include a height-ened risk of atherosclerosis, vascular occlusion,and reduction in renal blood flow. Smoking ces-sation is recommended in all patients.d.) Management of obesity. Obesity may result inan acquired resistance to the beneficial effects ofinhibition of the RAS axis. Further, weight lossmay facilitate the actions of ACE-inhibi-tion/angiotensin receptor blockade. In addition,obesity may induce certain renal diseases, such asFSGS, postulated to be due to a mechanism ofhyperfiltration. Weight loss is recommended inCKD patients with a goal body mass index (BMI)of <25.

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