Castle Connolly Graduate Board Review Series | Renal Function | Chronic Kidney Disease


Educational Review Manual in Nephrology
Second Edition • 2008

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


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. 11. 12. Key Complications of CKD Management of Kidney Disease Progression References



1. Introduction
Chronic kidney disease (CKD) is defined by the National Kidney Foundation as either: 1.) a glomerular filtration rate (GFR) of <60 mL/min with or without kidney damage for 3 or more months; or 2.) the presence of kidney damage for 3 or more months demonstrated by pathologic abnormalities, markers of kidney damage (eg, blood or urine composition), or imaging tests.1 In the United States, it is estimated that CKD affects 7%-10% of the adult population, or 15 to 20 million individuals, although specific subgroups such as African-Americans and Hispanics are at especially high risk.

2. Staging and Classification of CKD
CKD is staged by using glomerular filtration rate (GFR) categories. The NKF-K-DOQI has classified CKD into 5 stages (Table 1).1 The strengths of the NKF K-DOQI classification are its simplicity and its use of estimated GFR (eGFR) to classify CKD into different stages. Furthermore, the widespread adoption of the classification has resulted in, perhaps for the first time, a uniform system understood and applied worldwide. Indeed, the classification serves as a useful starting point in evaluating a patient with depressed GFR. It also provides the impetus to either refer a patient to a nephrologist for further work-up, or to identify a patient at higher risk of developing cardiovascular complications.

There is growing consensus on the importance of using a prediction equation to estimate kidney function rather than relying on serum creatinine. Recent observational data has also emphasized the connection between kidney disease and cardiovascular disease (CVD), indicating the primary importance of CVD as a source of mortality among CKD patients. Also, the importance of CKD as a risk factor in patients with CVD has emerged. It has become evident that the level of kidney function as assessed by either serum creatinine or estimated glomerular filtration rate is a key factor in predicting survival after an acute myocardial infarction (MI). From a therapeutic standpoint, considerable progress has been made in demonstrating the critical role of the renalangiotensin system in mechanistically influencing 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 retarding the progression of specific disorders has not been established). Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have become an essential part of the armamentarium of the practicing nephrologists. K-DOQI guidelines from the National Kidney Foundation (NKF) and similar documents from the Renal Physician’s Association (RPA) have sought to organize nephrology practice by establishing consensus around the evaluation and treatment of CKD. The purpose of this chapter is to review the definition and epidemiology of CKD, gain an understanding of the different methods of measuring kidney function, and evaluate and manage the major complications of CKD—in particular anemia, cardiovascular disease, and renal osteodystrophy.

The major limitations of the NKF CKD classification are as follows. It stages the severity of kidney disease on the basis of GFR without incorporating other important parameters such as albuminuria. Two patients with similar GFR but with wide differences in the degree of proteinuria at baseline are likely to have very different prognosis. The patient with high degree proteinuria is more likely to have a worse prognosis. The NKF classification also leaves unaddressed the significance of reduced GFR below 60 mL/min/1.73m2 in certain subgroups, such as the elderly, the undernourished, and members of specific ethnic groups. For example, elderly individuals with reduced GFR may never develop

Table 1 NKF Classification of CKD

Stage 1: Kidney damage with normal or supranormal GFR, GFR ≥90 Stage 2: Kidney damage with mild reduction in GFR, GFR 60-89 Stage 3: Moderate reduction in GFR, GFR 30-59 Stage 4: Severe reduction in GFR, GFR 15-29 Stage 5: Kidney failure, GFR <15 or on dialysis



3. Epidemiology of CKD
end-stage renal disease. Patients with congestive cardiac failure may have a low GFR because of hemodynamic reasons but do not have any structural evidence of kidney disease, and kidney function may normalize once the heart failure is treated. However, it is important to note that the use of NKF CKD criteria may not apply to some racial groups since their GFR may be naturally lower than Western levels as a consequence of smaller stature, lower muscle mass, and vegetarianism. Using extrapolations from the NHANES study, it is estimated that approximately 19 million individuals in the United States have CKD.2,3 These estimations provide a ballpark prevalence number because the NHANES data relies on a single creatinine measurement. As well, the NHANES White Sands laboratory did not calibrate creatinine measurement with the Cleveland Clinic laboratory where the MDRD predictive equation was generated.4 Thus, these 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 transplantation 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 stabilized 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 impoverishment are key risk factors for CKD.8 It is estimated that the majority of the world’s population lives in low-income countries, such as China, India, Indonesia, and Pakistan, where incident rates of diabetes 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.



4. CKD Economics
Data on the prevalence of CKD in the developing world is quite limited.10-12 CKD in the developing world suggests a prevalence of approximately 5%-10% (Pakistan data is based on the CockcroftGault estimation of creatinine clearance and the estimate for CKD prevalence is 29%).12 This would suggest that there are many millions of people among these that have CKD. However, it is important to be cautious in reaching this conclusion since the published studies, so far at least, have methodologic limitations. These include the reliance on a single creatinine as the measure of kidney function; the lack of creatinine standardization against any international laboratory standard; and the absence of studies validating an estimating equation in a non-American population.13 The cost of medical care for patients with CKD is high, and is reviewed in detail elsewhere.17 The average cost of care for a CKD patient is approximately $1,300 per month compared to approximately $500 per month for a non-CKD patient. This number is dwarfed by the cost of care for an ESRD patient—approximately $5000 each month. CKD patients consume a disproportionate share of health care resources.18 In 2002, the total cost of the ESRD program in the United States was $25.2 billion in 2002, an 11.5% increase from the previous year. Despite the cost of treatment of ESRD and improvements in the quality of dialysis therapy, mortality and morbidity remains significant. In 2002, 71,006 ESRD patients died. Incidence and prevalence counts for ESRD are expected to increase by 44% and 85%, respectively, from 2000 to 2015 and incidence and prevalence rates per million population by 32% and 70%, respectively. Survival probabilities for dialysis patients at 1, 2, 5 and 10 years are approximately 80%, 67%, 40%, and 18%, respectively. Moreover, 50% of dialysis patients have three or more comorbid conditions, the mean number of hospital days per year is approximately 14 per patient, and self-reported quality of life is far lower in dialysis patients than in the general population.

In the United States, there are notable racial differences in the epidemiology of CKD. This is reviewed in detail elsewhere.14-16 African Americans, Pacific Islanders, Latinos, and Native Indians have a higher prevalence of CKD than Caucasians. AfricanAmericans are at especially high risk—a 3- to 4fold higher risk than Caucasians. In particular, African-Americans appear to have a higher prevalence of hypertensive kidney disease than Caucasians (Table 3).



Table 2 Risk Factors for Chronic Kidney Disease
Susceptibility Factors Initiation Factors Progression Factors End-Stage Factors

Older age Family history Low kidney mass Low birth weight Low income Minimal education

Diabetes Hypertension Autoimmune disease Systemic infections Urinary tract infections Lower urinary tract Obstruction Drug toxicity

Proteinuria Hypertension Poor glycemic control Smoking

Low dialysis dose Vascular access Anemia Low serum albumin Late referral

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

Table 3 Prevalence of CKD in the United States by CKD Stage




Population (thousands)



Kidney damage with normal or supranormal GFR Kidney damage with mild decrease in GFR Moderate decrease in GFR Severe decrease in GFR Kidney failure












4 5

15-29 <15

400 300

0.2% 0.2%

* GFR expressed in mL/min/1.73 m2



Looming large over concerns about the current management of CKD are the issues of CKD under-recognition and late referral to nephrology.19 Under-recognition partly reflects the continued use of serum creatinine as a screening test for kidney disease. Since there is a nonlinear relationship between serum creatinine and GFR20,21 and because women have lower muscle mass than men, the problem of under-recognition 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 undertreatment is common in those with CKD, despite evidence that blood pressure can be safely and effectively lowered in CKD by combinations of antihypertensives. Patients with diabetes are inconsistently screened for early nephropathy. Patients with hypertension 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 nephrologist 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 accommodate 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

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

data suggests that decreased morbidity and mortality and lower costs are associated with early referral. Indeed, patients referred late in the course of their kidney disease are more likely to have anemia and hypoalbuminemia, less likely to have been started on erythropoietin, and are less likely to have permanent AV access.

6. Cardiovascular Risk Stratification in Patients With Kidney Disease

CVD is common in patients with all stages of kidney disease (Table 4).25 Approximately 25% of patients with mild to moderate CKD (stages 2 and 3) have evidence of left ventricular hypertrophy and this increases to 40%-70% of patients by the time of end stage renal disease (stage 5 CKD). Patients with CKD also have a higher prevalence of congestive heart failure (CHF). CHF represents a significant risk factor for mortality, especially when anemia is also present. A number of factors contribute to the increased prevalence of CVD in patients with kidney disease.26 These can be divided into traditional and nontraditional. The definition of traditional risk factors are those factors that have been used to estimate the risk of developing symptomatic ischemic heart 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: Females:

SCr ≥2.0 mg/dL SCr ≥1.5 mg/dL

The role of nontraditional risk factors in influencing CVD risk in CKD is more controversial. Observational studies strongly suggest that factors such as proteinuria, hemoglobin level, inflammation, and 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 progressive impairment of kidney function.27 It is likely that the increase in cardiovascular risk in patients with CKD is a multifactorial composite of both traditional CV risk factors and nontraditional renal specific risk factors. Many of these traditional and nontraditional risk factors are modifiable and therefore need to be studied in order to assess whether treatment of these factors improves outcome.

older age, diabetes mellitus, systolic hypertension, and LVH are highly prevalent in CKD patients and their relationship to CVD is the same regardless of CKD status. On the other hand, there appears to be what has been termed a reverse epidemiology for other factors, such as hypertension and LDL cholesterol among dialysis patients. The increased risk at lower levels of blood pressure and cholesterol may reflect confounding from cardiomyopathy and malnutrition, respectively, although this has not been proved.

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)

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



7. Screening for CKD
The justification for screening for CKD continues to be debated.28 Because of the relatively low prevalence of CKD, screening of the general population is unlikely to be cost effective. On the other hand, since kidney disease becomes symptomatic in the late stages of CKD, and since therapeutic strategies such as angiotensin blockade and tighter blood pressure control have been proven to be effective at earlier stages, detection of CKD early could potentially prevent ESRD in a significant proportion of patients. lines for CKD recommend that all individuals should be assessed as part of routine health examinations to determine whether they are at increased risk for developing CKD. Individuals at high risk for kidney disease, particularly those with diabetes, hypertension, or a family history for these conditions and/or for kidney disease, should undergo formal testing. Such testing can be performed easily with a urinalysis, a first morning or a random “spot” urine sample for albumin or protein and creatinine assessment, and a serum creatinine level. The American Diabetes Association (ADA) recommends that for all type 2 diabetics at the time of diagnosis and all type 1 diabetics 5 years after initial diagnosis, an evaluation for microalbuminuria should be performed.30 If the dipstick is positive for either red or white blood cells, a microscopic analysis should be performed of the urinary sediment.

African Americans and Native Americans have a higher risk of CKD than others (953 and 652 cases per million in African Americans and Native Americans, respectively, compared to 237 per million among Caucasians). Also, patients with diabetes mellitus and hypertension and those with urine dipstick positive for protein have a higher risk of developing CKD. Indeed, in a recent position paper De Jong and Brenner recommend routine urine albumin screening as a cost effective way of detecting 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 Male sex Diabetes Hypertension Higher LDL cholesterol Lower HDL cholesterol Smoking Extracellular fluid volume overload Physical inactivity Menopause Family history of CVD LVH

Albuminuria Abnormal calcium/phosphate metabolism Anemia Inflammation Oxidative stress



8. Measurement of Kidney Function
Given these limitations with serum creatinine as a measure of actual GFR, the NKF K-DOQI and the National Kidney Disease Education Program (NKDEP) have recommended the use of actual GFR or, when this is unavailable, a prediction equation for estimating GFR.35 Since in most situations direct measurement of GFR is not feasible, a prediction equation to estimate GFR is the most practical and accurate method to assess kidney function.35 The MDRD and Cockcroft-Gault equations are now the most popular prediction equations to assess GFR in adults. Recently, an isotope dilution mass spectroscopy traceable (IDMS) MDRD equation (also known as the MDRD 3 equation) has been developed.34 In essence this is a modified MDRD equation used when creatinine values are generated from a laboratory that has calibrated its creatinine measurement to a set of creatinine standards. Until recently, one of the major limitations of using an estimated GFR equation, such as the MDRD equation, was that there was significant variability in the measurement of serum creatinine that results in reduced accuracy of the MDRD equation in the normal to slightly elevated creatinine range (up to 1.5 mg/dL). This is because assays in most laboratories are not calibrated to the alkaline picrate method used by the 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 recommended. The MDRD 3 equation is as follows: 175x [SCr]-1.154 x [Age]-0.203 x [0.742 if patient is female] x [1.21 if patient is black]
Prediction Equations for GFR (Table 7)

Use of Serum Creatinine

Measurement of serum creatinine is currently the most widely utilized measure for the assessment of kidney function. However, the use of serum creatinine has several limitations31 (Table 6). Because creatinine production is dependent on muscle mass, it needs to be interpreted cautiously among individuals with low muscle mass, among females, and in elderly patients. In patients with low muscle mass, the serum creatinine underestimates the degree of kidney function impairment, whereas among individuals with large muscle mass (such as bodybuilders) the serum creatinine overestimates actual GFR. Another source of inaccuracy is the effect of noncreatinine chromogens when the alkaline picrate assay (Jaffe reaction) for creatinine is utilized.32 These factors include acetoacetate, cephalosporins, and high concentrations of furosemide. Modern versions of the Jaffe assay have reduced these effects by adjusting temperature, assay constituents, and various calibration settings. However, in order to truly reduce the effect of non-creatine chromogens, alternative methods are necessary. These include an enzymatic creatinine assay, HPLC, or isotope dilution mass spectroscopy (IDMS). Furthermore, calibration of the serum creatinine is important to reduce intra- and interlaboratory variability.33,34
Table 6 Limitations of Serum Creatinine as a Measure of Kidney Function

1. Influence of muscle mass 2. Effect of creatinine secretion a.) Patients with CKD – greater proportion of creatinine is secreted than filtered b.) Medications blocking proximal secretion a. cimetidine b. trimethoprim c. probenecid

Cockroft-Gault (CG) Equation: This prediction equation is commonly used in clinical practice. Its major limitations are: 1.) It has limited generalizability. This is because it was originally formulated to calculate the creatinine clearance in patients without kidney disease (Canadian males). It has not been widely validated in different populations and under different clinical situations. 2.) CG tends to overestimate GFR, especially among patients with chronic kidney disease. This is because it utilizes serum creCHAPTER 6: CHRONIC KIDNEY DISEASE


atinine to estimate creatinine clearance. The limitations of measuring creatinine clearance apply to the CG equation. Among patients with moderate to severe kidney disease, creatinine secretion as a proportion of total creatinine excretion increases, resulting in an overestimation of the creatinine clearance. 3.) Like the MDRD equation, the CG equation is inaccurate among individuals with normal or near-normal kidney function. 4.) The CG equation uses weight, which frequently results in inaccuracies at extremes of weight and/or when there is a measurement error in the assessment of weight. Despite these limitations, CG remains popular, especially among pharmacists who utilize it for drug-dosing adjustments in patients with reduced kidney function (Table 8). MDRD: “The Modification of Diet in Renal Disease Study” GFR prediction equation was developed in 1999.36 The equation is based on 1,628 nondiabetic subjects, age 18-70, with renal insufficiency. The formula utilizes urea, creatinine and albumin as well as demographics of age, gender, and race (black or white). If race is unavailable and white race is assumed, the GFR will be underestimated by 18% if the patient is black. This equation has been validated in American black and white racial groups. It has also been validated in diabetics,
Table 7 GFR Equations

predialysis patients and renal transplant recipients. Validation for other subgroups, such as Asians, children, and the elderly still needs to be performed. In 2000, a simplified MDRD equation (MDRD 2) was made available. It is based on serum creatinine as the only laboratory value—in the absence of urea or albumin.37 The MDRD formula yields an eGFR normalized to 1.73m2 body surface area. Adjusting for body surface area is necessary when comparing a patient’s eGFR with normal values or when determining the stage of CKD. However, an uncorrected eGFR may be preferred for clinical use in some situations, such as drug dosing (Table 9).
Clearance by Radiologic Contrast Agents and Radioactive Isotopes

GFR can be calculated by the measurement of urinary or plasma clearances of isotopes or via images produced from a gamma camera.38 There are 4 different agents that are used in clinical practice: [125 I] iothalamate,51 Cr-ethylenediaminetetraacetic acid, 99m Tc-diethylenetriaminepentaacetic acid, and iohexol. These agents have been shown to correlate well with inulin clearance. They also have high precision in the setting of moderate to severe renal dysfunction. Inulin clearance is the gold standard for measurement of actual GFR, since it is freely filtered and neither secreted nor reabsorbed by the kidney. However, it is not widely used in clinical practice largely for logistical reasons.38
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
For women: CrCl = ([(140 -Age) xWeight (kg)]/SCr x

72) x 0.85
MDRD 1: GFR = 170 x [SCr]-0.999 x[Age]-0.176 x[0.762

Direct comparison of the MDRD and the Cockcroft–Gault equation demonstrate the MDRD equation to be superior for estimating GFR, particularly in the range GFR < 60 mL/min/1.73m2 More widespread validation of MDRD than CG (eg, in various populations). No requirement for additional information for MDRD (eg, measurements of weight) beyond that already collected by pathology laboratories.

if 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 9 Situations in which the MDRD Equation Should be Used Cautiously

Populations in which the MDRD equation is not validated or in which validation studies have not been performed Individuals with near normal or normal kidney function Severe malnutrition or obesity Extremes of body size and age Exceptional dietary intake (eg, vegetarian diet or creatine supplements) Disease of skeletal muscle, paraplegia Rapidly changing kidney function

estimates GFR because creatinine is both filtered by the glomerulus and to a lesser degree, secreted by the proximal tubule. On the other hand, urea underestimates GFR since it is both filtered and reabsorbed. The mean value of the creatinine and urea clearance more closely approximates the actual GFR in the setting of GFR measurements less than 15 ml/min/1.73 m2.
Cystatin C

Creatinine Clearance Measurement by 24-Hour Urine Collection

Difficulties with 24-hour urine creatinine measurements 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 secretion, in patients with moderate to severe renal dysfunction, greater than 50% of the urinary Cr can result from tubular secretion, thus leading to overestimation 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 secretion. 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 collections has been suggested. Creatinine clearance over-

Cystatin C is a nonglycosylated basic protease inhibitor produced by nucleated cells at a constant rate, is freely filtered by glomeruli, and is completely metabolized after tubular reabsorption.39 Unlike creatinine, serum cystatin C level is not dependent on muscle mass, and is not differentially expressed based on gender. GFR is estimated from the plasma cystatin C concentration, which has been found to correlate well with iothalamate GFR measurements in Pima Indians with DM and normal or supranormal GFR. Cystatin has greater sensitivity than Cr for small changes in GFR. Recent studies 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



9. Clinical Aspects of CKD
As a clinical syndrome, CKD is characterized by progressive decline in kidney function such that the kidney’s ability to adequately excrete waste products and to contribute to the constancy of the body’s homeostatic functions is severely impaired. Mild CKD is asymptomatic; moderate CKD is frequently characterized by hypertension, anemia, and abnormalities in mineral metabolism; whereas advanced CKD is characterized by uremia. CKD may become relentlessly progressive as the damage to functioning nephrons leads to a maladaptive response among the remaining nephrons. The progressive decline in kidney function in individuals with CKD is variable and depends on both the cause of the underlying insult and on patient-specific factors.42 There is consensus that renal disease progression rates are heterogeneous both between different etiologies and within the same etiology. Thus, patients with polycystic kidney disease (PKD) may progress more slowly than patients with diabetic nephropathy; however, among patients with diabetic nephropathy there are patients who progress fast and others who progress hardly at all. Evidence points to the importance of several factors in modulating kidney progression.42 These include proteinuria, the presence of systemic hypertension, age, gender, genetic factors, and smoking. symptomatic and may be severely disabled. In the early stages of CKD (stage 1 and 2), using the NKF K-DOQI CKD stages, patients may present simply with an elevated serum creatinine and blood urea nitrogen (BUN) level but no symptoms. These individuals are usually unaware that they have any abnormalities in their kidney function, and usually fail to register on the “radar screen” of their internists. However, even at this early stage, insidious effects on target organs may become manifest. For example, patients may have mild to moderate hypertension, mild anemia, left ventricular hypertrophy, and subtle changes in bone structure due to renal osteodystrophy. As kidney function gradually declines further—with glomerular filtration rates reaching less than 30 mL/min—early features of uremia become evident. These include worsening or more difficult to control hypertension, extracellular volume expansion (manifest as edema and dyspnea), hyperkalemia and acidosis, anemia, and cognitive, psychological and physical abnormalities. Uremia reflects the accumulation of metabolic toxins, some characterized and others unknown, that influence the functioning of a variety of organ systems. In this late stage, the need for renal replacement therapy is imminent and dialysis and/or transplantation become inevitable in order to sustain life. The indications for initiating renal replacement therapy include severe refractory abnormalities in biochemistry (severe hyperkalemia and acidosis), severe pulmonary edema, bleeding, metabolic encephalopathy, and the presence of pericarditis. Subtler but no less important indications include malnutrition and severe disability (marked tiredness and lethargy) (Table 10).

End stage renal disease is the term used to denote CKD requiring renal replacement therapy (dialysis or transplantation). The incidence of ESRD in the United States is approximately 268 cases per million population per year. However, ESRD is overrepresented among African-Americans (829 per million population per year, as compared with 199 per million population per year among white Americans). The major causes of ESRD in the United States are diabetes mellitus (44%), hypertension (30%), glomerular disease (15%), polycystic kidney disease, and obstructive uropathy. Elsewhere in the world, where the incidence of diabetes mellitus has not reached epidemic proportions—for example in Europe and parts of the developing world—chronic glomerulonephritis (20%) and chronic reflux nephropathy (25%) are the commonest causes of ESRD. CKD is usually asymptomatic when there is mild impairment in kidney function, whereas when GFR is markedly reduced the patient is usually clearly

Life expectancy in patients with ESRD for a 49year-old is, on average, approximately 7 years, lower than colon cancer and prostate cancer and one-quarter that of the general population. This reduction in life expectancy is largely attributable to cardiovascular complications. Nearly 50% of all deaths in patients with ESRD are due to cardiovascular causes.43 The risk is 17 times that of the general population. Remarkably, this gap is largest in young patients with end-stage renal disease. The risk factors for cardiovascular disease in individuals with chronic renal failure include, but are not limited to, the magnitude of the calcium/phosphorous

10. Key Complications of CKD
The most important complications of CKD are hypertension, disturbances in mineral metabolism, anemia, acidosis and dyslipidemias. Hypertension is discussed in detail elsewhere in this book and will not be reviewed further in this chapter. Secondary hyperparathyroidism (SHPT) is a multifactorial syndrome that begins early in CKD but ultimately is present in most patients with CKD.44 Notably, bone disease in CKD and ESRD patients represents a spectrum from low and high turnover disease and osteomalacia and osteoporosis. A detailed discussion is beyond the scope of this chapter and can be reviewed elsewhere.45 The central abnormality is an excess secretion of parathyroid hormone (PTH) by the parathyroid glands.46 This results from progressively worsening kidney function that causes phosphorus retention and diminishing production of 1, 25 (OH2), D3 (calcitriol), the active form of vitamin D. Starting early in CKD, reduced kidney function results in reduced activity of a hormone, 1α-hydroxylase, synthesized by renal tubular cells and responsible for activation of vitamin D. Reduced 1α-hydroxylase activity results in decreased levels of calcitriol (1, 25-dihydroxyvitamin D). Circulating calcitriol levels begin to fall when the glomerular filtration rate is less than 40 mL/min. By the time patients have progressed to end-stage renal disease the calcitriol level is markedly reduced. The removal of the normal suppressive effect of calcitriol on the parathyroid glands results in PTH secretion.
Secondary Hyperparathyroidism and Metabolic Bone Disease

Table 10 Indications for Initiation of Renal Replacement Therapy

Refractory hyperkalemia Acute pericarditis Fluid overload or pulmonary edema refractory to diuretics Encephalopathy Severe peripheral neuropathy Hypertension refractory to antihypertensive medications Severe uremic bleeding; clinically significant bleeding; diathesis attributable to uremia Intractable nausea and vomiting

product with its attendant risk of coronary calcification, the presence of dyslipidemia, hypertension, hyperhomocystemia, and the presence of LVH. The clinical manifestations of cardiovascular disease in ESRD patients include left ventricular hypertrophy, left ventricular dilatation, diastolic dysfunction, macro and microvascular disease, and abnormalities in autonomic function—increased sympathetic discharge and increased circulating catecholamine levels. Vascular disease may involve calcification of coronary vessels and valve disease. Indeed, calcification of the mitral valve annulus and the aortic valve cusps is common among ESRD patients.

As a consequence of calcitriol deficiency there is reduced absorption of calcium in the gut and reduced mobilization of calcium. In addition, excess extracellular phosphorus binds to calcium and further drives down the ionized plasma calcium concentration. 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 extracellular calcium and phosphorus. As kidney disease progresses 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


As GFR declines with advancing CKD, renal phosphate excretion is reduced and serum levels of phosphate rise.47 Circulating levels of phosphate are also influenced by a variety of other factors: dietary phosphorus intake, intestinal absorption, and exchange with bone reservoirs. The major hormones that regulate phosphate homeostasis through these mechanisms are 1, 25 (OH)2D3 and parathyroid hormone. An emerging role for a novel class of proteins termed phosphatonins has also emerged. Phosphatonins are a group of proteins discovered in the characterization of a group of pathologic conditions characterized by phosphate wasting. FGF-23 is the most extensively studied. Increased FGF-23 may contribute to maintaining normal phosphate levels early in CKD through its phosphaturic effect, which may explain the lack of laboratory phosphate derangement seen early in SHPTH. The management of osteitis fibrosa is reviewed in the NKF KDOQI guideline document.44 It is important to emphasize that the measurement of calcium, phosphorus, and intact plasma parathyroid hormone is important in all patients with a GFR less than 60 ml/min/1.73 m2. The frequency of these measureManagement of Osteitis Fibrosa

density causes resistance of the parathyroid glands to both calcitriol and calcium. In parallel, excess extracellular phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol. The initial hyperplasia of the parathyroid gland is followed in later stages by nodularity, with evidence at a cellular level of monoclonal cellular expansion. The lack of calcitriol is thought to cause down-regulation of vitamin D receptors, which then promotes parathyroid chief cell hyperplasia and nodule formation. The resistance of parathyroid cells to calcitriol appears to serve as second stimulus for PTH secretion in patients with advanced CKD. Reduction of calcitriol receptor density in parathyroid glands is currently considered the mechanism responsible for the resistance to fairly robust doses of vitamin D in chronic renal failure. As renal failure progresses, this disturbance may form a vicious cycle of further reducing calcitriol receptor density leading to progressive resistance to calcitriol.

ments and the target range for intact PTH is based on the stage of CKD. Sustained exposure of bone to elevated PTH results in osteitis fibrosa, a disease of high bone turnover and accelerated bone resorption. Bone biopsy studies in CKD stage 3 and 4 patients indicate that osteitis fibrosa is present in approximately 70% of patients, and another 10%-15% develop osteitis fibrosa with osteomalacia or mixed bone lesions. These pathologic changes may result in a reduction in bone mineral density on DEXA scanning, which may be misinterpreted as osteoporosis, a condition of low bone turnover. Effective treatments, which lower PTH, include dietary phosphorus restriction, use of calcium-based phosphorus binders, treatment of vitamin D deficiency and use of calcitriol or other active vitamin D analogs.48
Control of Hyperphosphatemia

Dietary phosphorus restriction is an important element in the management of osteitis fibrosa. In stage 3 CKD, a reduction in dietary phosphorus to 800-1000 mg/day results in a decline in PTH, an increase in endogenous calcitriol production, and typically no appreciable change in serum phosphorus. In stage 4 CKD, dietary phosphorus restriction lowers PTH and serum phosphorus, but does not usually result in an increase in calcitriol production. In patients with CKD stages 3 and 4, daily phosphorous intake should be restricted to 800-1000 mg/day in the setting of a phosphorous level greater than 4.6 m/dL or when PTH exceeds the target range. Target serum phosphorus is 2.7 to 4.6 mg/dL in stage 3 and 4 CKD. Phosphorus binders taken with meals decrease absorbed phosphorus and have effects similar to dietary phosphorus restriction. The dose of binders required in CKD stages 3 and 4 is much less than that required in dialysis patients. Calcium based binders may be used as initial therapy (such as calcium carbonate or calcium acetate), but the dose of elemental calcium should not exceed 1500 mg/day. Use of calcium further suppresses PTH by increasing serum calcium, but this may result in a chronically positive calcium balance and contribute to vascular calcification. Noncalcium based binders— such as sevelamer HCl 800 mg TID or lanthanum carbonate 250 mg TID—offer effective phosphorus



Table 11 Frequency of Measurement and Target Range for Intact PTH Based on CKD Stage

CKD Stage

GFR Range mL/min1.73m2

Measurement of PTH

Measurement of Ca and Phos

Target intact PTH (pg/mL)

3 4 5

30-59 15-29 <15 or dialysis

Every 12 months Every 3 months Every 3 months

Every 12 months Every 3 months Every month

35-70 70-110 150-300

control without the dangers of calcium loading, but are substantially more expensive than calcium based binders. Additionally, sevelamer can induce acidosis due to HCl release upon binding of phosphorus.
Vitamin D and/or Vitamin D Analogue Therapy

Treatment with vitamin D or one of its analogues is a key element in CKD management (Table 12). Active vitamin D analogs suppress PTH in a dose dependent manner.48,49 One of these agents should be used whenever PTH is above the target range despite vitamin D repletion and phosphorus control. Doses are usually administered orally daily or thrice weekly, resulting in similar PTH suppression. Calcitriol (Rocaltrol®) is typically begun at 0.25 mcg

A deficiency of both 25(OH)D and 1,25(OH)2D3 are common abnormalities in CKD patients. Both may contribute to the development and progression of SHPT and/or associated osteomalacia and osteoporosis. Vitamin D stores are assessed by determination of serum 25(OH)D level, the stable liver metabolite of vitamin D. A normal level is >30 ng/ml, and lower levels should be supplemented. Most 25(OH)D circulates bound to D binding protein (DBP) and serum DBP may be greatly decreased in nephrotic syndrome due to heavy proteinuria, making interpretation of the laboratory results questionable. Nevertheless, restoration of 25(OH) D levels to normal is appropriate, although there is limited data that this lowers PTH.

Vitamin D analogs were developed to reduce the stimulation of intestinal calcium and phosphorus absorption.48 Paricalcitol (Zemplar®) appears to have the least effect on intestinal mineral absorption, and in randomized trials had an incidence of hypercalcemia and hyperphosphatemia similar to placebo. Paricalcitol is usually started at 1 mcg daily or 2 mcg thrice weekly. Doxercalciferol (Hectorol®) is a prohormone (1(OH)D2), and is metabolized constitutively by the liver to 1, 25(OH)2D2, an active form of vitamin D. Other metabolites of doxercalciferol may also be formed and may account for the apparently lower incidence of hypercalcemia and hyperphosphatemia seen with this analog. Doxercalciferol is usually started at 1 mcg daily. (See Table 12 for recommended doses of ergocalciferol.) After three or more weeks on any form of the above active vitamin D products, serum PTH should be remeasured and the dose of the active D product increased by 50%-100% if necessary to achieve PTH suppression into the CKD stage specific target. Adequate suppression of PTH should be balanced with maintenance of normal serum calcium (8.4 to 10.2 mg/dL) and phosphorus (2.7 to 4.6 mg/dL). Serum calcium and phosphorus should be measured at least quarterly, and more frequently if calcitriol is used at a dose of 0.5 mcg per day or more.

daily or 0.5 mcg thrice weekly and significantly enhances intestinal absorption of calcium and phosphorus. Hypercalcemia is common when doses exceed 0.5 mcg per day.



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 5-14 15-29

1 capsule weekly x 12 weeks, then monthly x 3 months 1 capsule weekly x 4 weeks, then monthly x 5 months 1 capsule monthly x 6 months

Anemia is a common complication in CKD patients, affecting approximately 40% of patients in stage 4 and 5 CKD (anemia defined herein as a Hb of <11 g/dL) (Table 13). Estimates suggest that almost 1,000,000 patients in the United States with CKD are anemic.52 Diabetes seems to be an additional risk factor for anemia in CKD and more than 20% of diabetics with an eGFR of 30-59 mL/min/1.73 m2 are anemic. The etiology of anemia in CKD is multifactorial. While erythropoietin deficiency is the most common cause (Tables 14, 15), iron deficiency, nutritional deficiencies (in vitamin B6 and B12), occult blood loss and hyperparathyroidism are also important causes.
Clinical Features and Diagnosis of CKD Anemia


Mild anemia (Hb levels >11 g/dL) is usually asymptomatic in CKD patients. By the time the Hb level is <10 g/dL, patients complain of tiredness and fatigue. Some patients may complain of a reduction in exercise capacity, well being, tiredness, and cold intolerance. Impairment in neurocognitive ability may be evident using formal tests but may be too subtle to detect by routine clinical evaluation. In several observational studies, anemia increases the risk of cardiovascular complications including left ventricular hypertrophy, left ventricular dilatation, and myocardial ischemia.53,54 From a diagnostic standpoint, CKD anemia is characterized by normocytic, normochromic hematologic indices. A rapid

method of determining whether cellular indices are normocytic and normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation from the calculated values suggests microcytosis, macrocytosis, or hypochromia versus the presence of spherocytes (MCHC, >36). In patients suspected of CKD anemia, measurement of an erythropoietin level (EPO) is not necessary. This is because a low normal or even a normal EPO level may suggest EPO deficiency. On the other hand, excluding the possibility of iron deficiency is important. The diagnosis of iron deficiency is made by demonstrating that the patient has a transferrin saturation (TSAT) level of <20% and/or a serum ferritin level of <100 ng/mL. While the gold standard for iron deficiency is the absence of stainable iron in a bone marrow specimen, under most circumstances a bone marrow evaluation is impractical. The presence of microcytosis and hypochromia is helpful but not diagnostic. Every patient with iron deficiency anemia should have a stool examination for occult blood. A positive result necessitates a careful search of the gastrointestinal tract to identify the site of bleeding. Unfortunately, a negative result does not exclude gastrointestinal blood loss because bleeding can be intermittent and require several examinations for detection. Also, less than 20-30 mL of blood in the stool per day may go undetected due to the insensitivity of the test.

Table 13 Key Recommendations in the 2006 KDOQI Anemia Update51

100 units/kg or 10,000 units SC weekly. Darbepoetin is usually initiated at 0.45 mcg/kg weekly or 60 mcg SC every other week. Hgb should be checked every two weeks initially, and the dose of drug adjusted by ~25% to achieve and maintain Hgb 11-12 g/dL. Once the target Hgb
Table 14

The initial evaluation of anemia should include a CBC, absolute reticulocyte count, serum ferritin and serum transferrin saturation (TSAT). The hemoglobin range should be at least 11.0 g/dL; however, there is insufficient evidence to recommend maintaining Hb concentrations. ≥13.0 g/dL can be used for all other CKD patients (CPR 2.1.2). The iron parameter goals for hemodialysis patients should be a serum ferritin concentration ≥200 ng/mL, and a transferrin saturation ≥20% or a reticulocyte hemoglobin content ≥29 pg/cell (CPR The goals for non-dialysis-dependent CKD and peritoneal dialysis patients should be a serum ferritin concentration ≥100 ng/mL and a transferrin saturation ≥ 20% (CPR The preferred route of administration for iron is IV in patients with hemodialysis dependent CKD (CPG Routine administration of IV iron if the ferritin concentration exceeds 500 ng/mL.

Key Facts on Erythropoetin55

EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extrarenal EPO are produced by the liver in adult human subjects. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO binds to an erythroid progenitor cell surface receptor to regulate bone marrow erythroid cell proliferation, differentiation, and survival. EPO receptors are also on mesangial cells in the kidney, brain, testes, myocardium. EPO binds to an erythroid progenitor cell surface receptor to regulate bone marrow erythroid cell proliferation, differentiation, and survival. Benefits of treating anemia with EPO include: improved exercise tolerance and less fatigue, lower transfusion rate, and potentially, regression of LVH.

In the United States, there are 2 erythropoiesis-stimulating agents that are available: epoetin alfa and 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 emerged into the marketplace, particularly in the developing countries. Treatment with epoetin or darbepoetin should be initiated in most patients when hemoglobin is less than 10 mg/dL, and preferably when Hgb is 10 to 11 g/dL.51 For convenience reasons, less frequent dosing regimens are used in CKD than in dialysis patients.56-58 The initial dose of epoetin is usually

Treatment of CKD Anemia

is achieved, the epoetin or darbepoetin dose can be approximately doubled and dosing frequency also doubled.58 The 2002 NKF Anemia Update had recommended a hemoglobin range of 11 to 12 g/dL.50 However, more recently, the NKF Anemia Update has recommended that the target hemoglobin range should be

Hemoglobin Target in CKD Patients


generally 11 to 12 g/dL.51 The lower Hb level is based on evidence, whereas the upper Hb level is considered an opinion-based recommendation.51 Treating CKD anemia with erythropoietin has been shown to enhance quality of life; however, evidence supporting a benefit of anemia correction in improving cardiovascular morbidity and mortality has largely rested on data derived from observational studies. The recent publication of the CHOIR and CREATE studies have demonstrated increased risk with targeting a higher hemoglobin level.56,57 CHOIR56 was an open-label, randomized trial that studied 1432 patients with CKD: 715 patients randomized to receive epoetin alfa targeted to achieve a hemoglobin of 13.5 g/dL, and 717 were randomized to receive epoetin alfa targeted to achieve a hemoglobin of 11.3 g/dL.3 The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, congestive heart failure (CHF), hospitalization (excluding hospitalization during which renal replacement therapy occurred), and stroke. Two hundred twentytwo composite events occurred: 125 events among the high hemoglobin group and 97 events among the 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 largely by a higher rate of death (48% higher risk, P=0.07) or CHF hospitalization (41%, P=0.07). Although neither death nor CHF hospitalization were statistically significantly higher in the higher versus lower hemoglobin group, the study was not powered for this purpose. Among other secondary endpoints, quality of life showed improvement in both groups but was not significantly better in the higher versus lower hemoglobin groups. Notably, more subjects in the high hemoglobin group experienced at least one serious adverse event compared to the low hemoglobin group. The Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin beta (CREATE)57 study enrolled approximately 600 patients. Subjects were randomized to an early anemia correction or a late anemia correction group.4 The early anemia correction group received epoetin beta therapy immediately for a target hemoglobin 13-15 g/dL. The late anemia correction group did not receive treatment until their hemoglobin was <10.5 g/dL; their target hemoglobin was 10.5-11.5 g/dL. The study showed that “complete correction” was not associated with a

Table 15 Practical Guide to Using Erythropoetin for CKD Anemia60

1. Start when Hb <11.0 g/dL 2. Use epotein alfa or darbepoetin 3. For epoetin alfa: a. Starting dose 10,000 units subcutaneously each week, 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-dosing vials comes in 10,000 and 20,000 unit doses c. Maintenance dosing uses an extended dose strategy—every other, every third, or every fourth week. 4. For darbepoetin: a. Initial dose: 0.45 mcg/kg QW b. Can use 25, 40, 60, 100, 150, 200, 300, 500 mcg/mL single-dose vials or prefilled syringes c. Maintenance: multiply for longer intervals up to 4 weeks.

statistically significantly higher rate of the first cardiovascular event (58 events in the high hemoglobin group versus 47 events in the low hemoglobin group; hazard ratio of 0.78, 95% confidence interval, 0.53 to 1.14; P=0.20). However, left ventricular mass index remained stable in both groups but dialysis was required in more patients in the higher versus lower hemoglobin group (127 vs. 111, P=0.03). On the other hand, unlike CHOIR, in CREATE a quality of life benefit, at least in year 1 of the study, was observed for the higher versus lower hemoglobin group. Therefore, both studies showed either risk or no benefit with regards to cardiovascular outcomes aiming to completely correct the hemoglobin in CKD patients not receiving dialysis. The CHOIR study was larger and showed a statistically significant difference for the primary endpoint, whereas the CREATE study was underpowered for the primary event and showed a trend for increased risk but did not reveal statistically significant differences for the primary endpoint. On the other hand, in both CHOIR and CREATE, quality of life improved in patients treated with epoetin. While in CHOIR there was no incremental

improvement in QOL in the higher versus lower hemoglobin group, in CREATE patients randomized to the higher hemoglobin level did experience improved quality of life. Indeed, several large randomized controlled studies in both ESRD and preESRD patients have either failed to demonstrate a benefit of anemia correction, or have shown a trend towards worse outcomes such as cardiovascular disease or death. A recent meta-analysis concurs – increased risk with targeting a hemoglobin concentration of >12 g/dL in pre-dialysis and dialysis patients. 58 In light of the evidence from interventional studies, as alluded to above, a recent boxed advisory from the Food and Drug Administration (FDA) has recommended a Hgb target of 10 to 12 g/dL. Initiation of erythropoietic agents frequently consumes the patient’s iron stores, and the inflammation present in CKD inhibits adequate intestinal iron absorption, resulting in iron deficiency. High levels of C-reactive protein, a marker of inflammation, have been associated with low iron absorption in patients on HD.

Iron Deficiency in CKD Patients

While several mechanisms may account for iron deficiency among dialysis patients (loss through the dialysis procedure, acute and chronic inflammation, and reduced oral absorption and reduced dietary intake), among predialysis CKD patients the most important reason appears to be reduced GI absorption (Table 16). The likeliest reason for this is a block, through the action of hepcidin, in iron absorption through the intestinal iron transporter ferroportin.61 Hepcidin, a liver synthesized protein, regulates ferroportin mediated iron absorption.

High hepcidin levels result in reduced iron absorption.62 Since hepcidin is excreted by the kidneys, it is postulated that renal dysfunction results in progressively higher levels of hepcidin and thus attenuated iron absorption. CKD patients’ reduced dietary intake, especially of foods high in iron, such as meats and leafy vegetables, may further exacerbate iron deficiency. It is estimated that approximately 40% of patients with CKD have iron deficiency.63 As kidney disease progresses, iron deficiency

Table 16 Indicators and Causes of Iron Deficiency




Absolute iron deficiency

TSAT <20% and serum serum ferritin <100 ng/mL

Increased blood loss Decreased iron absorption Intense stimulation of RBC production by EPO therapy outstrips iron supply. May develop even when storage iron appears normal Acute or chronic inflammation often seen in HD patient. Blocks release of iron stores from RES

Functional iron deficiency

TSAT may be <20% and ferritin may be 100-700 ng/mL

RE blockade

Dramatic increase in serum ferritin along with drop in TSAT



worsens because of a postulated increase in hepcidin levels due to reduced hepcidin excretion by the kidneys. Another possibility is that progressively increased levels of inflammation result in an increased expression of hepcidin and thus a block in GI absorption of iron.
Assessment of Iron Deficiency

TSAT (calculated by the formula serum iron/total iron binding capacity x 100) and serum ferritin are the primary measures used to assess patients’ iron stores. Although neither has optimal sensitivity nor specificity, they are inexpensive and widely available. Tissue ferritin is a large protein molecule contained within the reticuloendothelial system (RES), with iron at its core. Serum ferritin is ferritin that has leaked from tissues, and it is an indicator of tissue iron stores. Most normal patients have serum ferritin levels below 30 ng/mL; however, levels are much higher in uremic patients. Transferrin is the body’s iron transport molecule, delivering iron from the RES to the bone marrow for erythropoiesis. The TSAT represents the body’s circulating iron. According to the K/DOQI guidelines, a TSAT level <20% and a serum ferritin level <100 ng/mL represents iron deficiency, and a serum ferritin level >500 ng/mL represents iron overload. However, the 500 ng/mL level set by K/DOQI is opinion based, not evidence based. Functional iron deficiency and reticuloendothelial (RE) blockade may
Table 17 Pharmakinetic Profiles of IV Irons

be discerned by examining the patient’s response to a trial dose of IV iron. A rise in Hgb and Hct levels and/or a reduction in EPO dose requirement will signify functional iron deficiency. In contrast, in the presence of inflammation-mediated RE blockade, 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 dose requirements have remained high despite IV iron, or no erythropoietic response has occurred (ie, Hgb level does not increase).

There are limitations to both the serum ferritin and TSAT markers in accurately diagnosing iron deficiency.51,64-66 Serum ferritin is an acute-phase reactant, and levels are elevated in cases of inflammation and infection, which are common in HD patients. Because iron is an acute-phase reactant, TSAT levels also may be affected by inflammation or infection. In addition, because transferrin is produced primarily in the liver, hepatic disease can reduce transferrin production. As a result, if transferrin levels are low, the TSAT level may appear to be normal in the presence of iron deficiency. TSAT levels also are affected by nutritional status. TSAT and serum ferritin levels may have greater diagnostic utility for iron deficiency and iron overload when they are very low or very high, respectively.

Iron Dextran

Iron Sucrose

Ferric Gluconate

Molecular weight, Daltons Half-life Direct transfer to RES Direct transfer to transferrin

INFeD 165,000 Dexferrum 265,000 40-60 h Yes No



~6 h Yes Yes

~1 h Yes No



Despite a clear rationale for intravenous iron therapy, there continues to exist an underutilization of these preparations. This is most likely because of expense, inconvenience of administration, and limited access to infusion facilities. There are 3 available forms of IV iron (ferric gluconate, iron sucrose, and iron dextran); and there are 2 types of iron dextran: INFeD® and Dexferrum®. Studies of maintenance IV iron therapy have demonstrated a consistent improvement in erythropoiesis as measured by decreased EPO requirements to maintain or improve Hct levels. This improvement has been seen with all 3 available forms of IV iron. The significant decrease in EPO requirements in HD patients may translate into substantial savings, given the high cost of EPO therapy.

The treatment of iron deficiency in CKD anemia is reviewed extensively elsewhere.51,64-66 There is a limited role for oral iron in the treatment of iron deficiency in patients with advanced CKD. Intravenous iron is recommended in these circumstances. Very little oral iron is absorbed and side effects of oral iron may be quite considerable. A healthy individual only absorbs about 1% of the total iron ingested in an oral dose, while in CKD patients, impaired gastrointestinal absorption can lead to even lower absorption of iron. Side effects of oral iron include constipation and gastrointestinal upset.

Treatment of Iron Deficiency

<200 mg/dL, consideration should be given to iron repletion. Alternative markers of iron deficiency include an increased number of hypochromic red blood cells (percentage >10%), or a low reticulocute hemoglobin content (CHr <31 pg). Intravenous iron preparations include iron dextran (1000 mg IV as a single dose, with an initial test dose of 25 mg); ferric gluconate (initial dose 125 mg IV); or iron sucrose (initial dose 100 to 200 mg IV). Iron dextrans have a low but serious risk of anaphylactic reactions. Oral iron therapy can be attempted in CKD. To maximize absorption, at least 200 mg of elemental iron should be consumed daily in divided doses taken between meals. Oral iron salts may be bound by calciumbased phosphorus binders and thus should be taken separately. Thyroid hormone supplements may also be bound by ferrous sulfate and therefore should be taken separately.

The IV irons differ based on their pharmacokinetic profiles, which may have a potentially significant impact on their safety profiles and bioavailability (Table 17). Among the IV irons, ferric gluconate has the shortest elimination half-life (1 hour), approaching the maximum rate of physiologic clearance by the RES. Ferric gluconate also has the largest 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 transferrin. However, iron sucrose appears to have a dual method of turnover, with a portion of the iron complex being delivered directly to transferrin— thereby raising the risk of transferrin oversaturation. Iron stores should also be assessed periodically with evaluation of transferrin saturation and ferritin. If transferrin saturation is <20% or ferritin is

Chronic metabolic acidosis begins to develop when eGFR falls below 40-50 mL/min, and most stage 4 CKD patients have serum bicarbonate levels <22 meq/L.67,68 Unless patients have concomitant renal tubular acidosis, the ensuing metabolic acidosis tends to be mild and easily treated. Even mild metabolic acidosis results in increased resorption of bone, weakening of bone structure, and can increase the risk of fractures. Additionally, acidosis enhances protein catabolism and can contribute to malnutrition in CKD. Treatment is usually started when serum bicarbonate is persistently < 22 meg/L. One or two sodium bicarbonate tablets (650 mg, ~8 meq each) are usually administered TID to maintain serum bicarbonate >22 meq/L. Use of citrate salts may increase the absorption of dietary aluminum in patients with CKD, and therefore should be avoided.

Hypercholesterolemia is considered a major risk factor and cause of atherosclerotic disease in the general population; however, there is a lack of association between this traditional risk factor and atherosclerotic cardiovascular disease among dialysis patients, and limited data in patients with CKD. Multiple complex lipid abnormalities, known collectively as uremic dyslipidemia, are commonly


observed in dialysis and CKD patients due to the reduced lipolysis of apolipoprotein B-containing triglyceride (TG)-rich very-low-density lipoprotein (VLDL) particles.69 This defect is associated with near normal total cholesterol, elevated VLDL and intermediate density lipoproteins (IDL), low highdensity lipoprotein (HDL), and a shift of LDL particle size toward a small dense LDL. The concentrations of LDL particles, small dense LDL, large HDL, IDL, and large VLDL are better indicators of cardiovascular risk than the elements of the traditional lipid profile. However, the traditional lipid profiles do not directly determine the concentration or the size of these known atherogenic apolipoprotein B-containing lipid subclasses (VLDL-C, IDLC, and LDL-C). To address this problem, the NCEP (National Cholesterol Education Program) recommends assessment of non-HDL cholesterol as a reasonable surrogate parameter to estimate total apolipoprotein B, and treatment when non-HDL is >130 mg/dL.70 Virtually all patients with CKD have a 10-year risk of cardiovascular events >20%. Therefore the target LDL-C should be less than 100 mg/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. One study—the 4D study conducted in hemodialysis patients—used atorvastatin and failed to show a beneficial effect.71 However, several post hoc analyses of statin trials do suggest that CKD patients should benefit from statin therapy.72 Until more data from randomized controlled studies becomes available, it is reasonable to treat CKD patients like those without kidney disease and reduce lipid levels according to NCEP/ATP guidelines.70

Assessment of a complete fasting lipid panel (total cholesterol, LDL-C, HDL-C, and triglycerides) is recommended annually in all CKD patients. Initial therapy should target LDL-C to less than 100 mg/dL —usually with statin therapy. No HMG-CoA inhibitor is contraindicated in CKD, but rosuvastatin should be started at a lower dose. Ezitimibe inhibits intestinal transport of dietary cholesterol, and is a useful adjunct to statin therapy. Secondary lipid therapy should target non-HDL cholesterol to less than 130 mg/dL if fasting triglycerides are greater than 200 mg/dL. In these latter patients, use of niacin or gemfibrizol may be efficacious. Physicians should be vigilant for the development of myalgias or myopathy.

Table 18 Management of Kidney Disease
Type of Kidney Disease Target Blood Pressure (mmHg) Preferred Agents for CKD With or Without Hypertension Other Agents to Reduce CVD Risk and Reach Blood Pressure Target

Diabetic kidney disease


ACE Inhibitor or ARB

Diuretics preferred, then BB or CCB Diuretics preferred, then BB or CCB Diuretics preferred, then ACI inhibitor, ARB, BB, CCB

Non-diabetic kidney disease with spot <130/80 Up/Uc ratio ≥ 200 mg/g Non-diabetic kidney disease with spot <130/80 Up/Uc ratio < 200 mg/g

ACE Inhibitor

No preference

Disease in the kidney transplant recipient


No preference

CCB, Diuretic, BB, ACE inhibitor, ARB



11. Management of Kidney Disease Progression
contraindicated in patients who are pregnant, and in patients with a history of angioedema.)

The NKF KDOQI group has released an action plan for management of patients with CKD as determined by stage of CKD.1 In addition, a more detailed discussion regarding the slowing of kidney progression can be reviewed elsewhere.73 In stage 1 CKD, these guidelines suggest the diagnosis and treatment of CKD, treatment of comorbid conditions, prevention of progression of renal disease, and CVD risk reduction. In stage 2, the issue of primary concern is that of estimating and managing renal disease progression. The focus of stage 3 disease is that of evaluating and treating complications; while stage 4 CKD, the immediate pre-dialysis stage, consists of preparation for renal replacement therapy. The management of stage 5 CKD is that of initiation and maintenance of renal replacement therapy. Thus, in addition to the task of diagnosing and treating the specific etiology of renal disease, the broad themes that govern early versus late renal disease management are those of prevention of progression in the early stages of CKD, management of complications beginning in the early stages and continuing throughout the follow-up of patients, and preparation for renal replacement in the later predialysis phase. There are three important elements to the management of progression in CKD patients (Table 18):

KDOQI Action Plan by Stage of CKD

2. Control of blood pressure. The MDRD study demonstrated that patients targeted to MAP of 92 and 107 mmHg had rates of decline of GFR of -3.56 and -4.10 mL/min/year, respectively, and that there was greater effect with increasing levels of albuminuria.79 This study, taken in conjunction with several other studies that have been published, subsequently suggest a key role for blood pressure reduction in retarding the progression of kidney disease. Indeed, a recent study suggests that this beneficial effect of controlling blood pressure on kidney disease extends for a prolonged period of time.80 The 2003 NKF-KDOQI clinical practice guidelines for antihypertensive therapy recommend:81 • Blood pressure measurement at each health care encounter.

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

1. The use of angiotensin blockers to protect the kidney. Both landmark studies in animals by Brenner and colleagues,74 as well as studies in humans, supports an independent role for angiotensin blockade in renoprotection.75-77 ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB) can be used. It is important to titrate the dose of ACEi or ARB to maximal levels using reduction of proteinuria as the yardstick for efficacy. Emerging evidence (from the COOPERATE study)78 suggests a beneficial effect of using both ACEi and ARB in a synergistic strategy to reduce proteinuria and enhance renoprotection. In addition, sodium restriction and diuretics in conjunction with ACE-I/ARB therapy increase their antiproteinuric effects and should be used in an adjunctive fashion. (ACE inhibitors or ARB are

• Use of an ACE-I/ARB in patients with diabetic kidney disease, and use of ACE-I in non-diabetic kidney disease with proteinuria (spot Up/Ucr ratio of ≥200 mg/g), to retard progression of kidney disease, irrespective of the presence of hypertension. With regard to adjunctive anti-hypertensive agents, the guidelines suggest diuretics followed by either beta-blockers or calcium channel blockers in diabetic kidney disease as well as in nondiabetic proteinuric kidney disease (spot Up/Ucr ratio of ≥200 mg/g). Diuretics are the preferred agent in patients with kidney disease in the absence of significant proteinuria, as defined by spot Up/Ucr ratio of <200 mg/g, followed by ACE-I, ARB, beta-blocker, or calcium channel blocker. Finally, in recipients of renal allografts, the NKF-DOQI guidelines recommend calcium channel blockade, diuretic therapy, and beta blockade, ACE-I or ARB.



12. References
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