RENAL ANEMIA MANAGEMENT PERIOD

Transcription

1 R A M P RENAL ANEMIA MANAGEMENT PERIOD A Call for the Early Recognition and Appropriate Management of Anemia in Chronic Renal Insufficiency

2 Acknowledgement The RAMP concept presented in this monograph represents a collaboration of the following contributors: Anatole Besarab, MD W. Kline Bolton, MD David N. Churchill, MD Steven Fishbane, MD Robert N. Foley, MD Annamaria Kausz, MD Alan S. Kliger, MD Adeera Levin, MD Jill S. Lindberg, MD Allen R. Nissenson, MD Brian J.G. Pereira, MD, MBA Richard A. Sherman, MD John C. Stivelman, MD Paul M. Zabetakis, MD Amgen gratefully acknowledges their efforts Amgen Inc. All rights reserved.

3 Table of Contents Introduction 2 Profile of the CRI Population 4 Complications and Comorbidities of CRI 6 The Anemia of CRI: Definition, Etiology, Prevalence 10 Adverse Sequelae of the Anemia of CRI 12 CRI, Anemia, and Cardiac Disease 16 1 Benefits of Anemia Management with rhuepo in CRI 18 The RAMP: Heightened Vigilance for Anemia Treatment 22 Summary 24 Bibliography 25

4 Introduction Chronic renal insufficiency (CRI) is an insidious disease that can arise as a consequence of diabetes mellitus, hypertensive nephrosclerosis, chronic glomerulonephritis, polycystic kidney disease, and a host of other disorders. Regardless of the etiology, CRI generally progresses over time to end-stage renal disease (ESRD), when either dialysis or renal transplantation is required to sustain life. The wide-reaching physiological consequences 2 ANEMIA CONTRIBUTES TO MANY MANIFESTATIONS OF CHRONIC KIDNEY DISEASE Risk of Comorbid Conditions R A M P Renal Anemia Management Period Time Anemia (can develop at any time after onset of CRI) Renal Function CRI Renal replacement therapy (RRT) RAMP NHANES III data suggest up to 6,200,000 people in the United States may have CRI with estimated SCr values 1.5 mg/dl. 11 CRI-related anemia begins early during kidney disease; however, it is underrecognized and undertreated. 3,23 NIH Consensus Conference Statement on Morbidity and Mortality: Refer to a nephrologist when SCr levels reach >1.5 mg/dl in women and >2.0 mg/dl in men. 1 ESRD KEY: rhuepo= recombinant human erythropoietin; QOL=quality of life; GFR=glomerular filteration rate; Hb=hemoglobin; Hct=hematocrit; SCr=serum creatinine; NIH=National Institutes of Health; LVH=left ventricular hypertrophy; NHANES III=Third National Health and Nutrition Examination Survey. Cognitive Function/QOL Partial correction of anemia with rhuepo treatment in dialysis patients improves both cognitive function and brain electrophysiology, which ultimately enhances learning and memory. 18 Treatment of anemia with rhuepo in CRI patients shows significant improvement in Hb/Hct levels that results in improvements in health-related QOL. 57 Correction of anemia with rhuepo is associated with significant improvement in patients energy level. 32 rhuepo treatment increases Hb/Hct in uremic CRI patients, resulting in an improved exercise capacity without affecting GFR. 31 Cardiovascular Function Anemia is an important predictor of LVH in CRI patients. 41 Each 1-g/dL decrease in mean Hb increases the risk of LVH by 6%. 41 LVH is present in nearly 40% of patients attending CRI clinics. 41 LVH is present in 74% of patients at initiation of dialysis. 67 Cardiovascular disease accounts for ~40% of deaths in dialysis patients. 35 Each 1-g/dL decrease in mean Hb is independently associated with a 14% increased risk of mortality in dialysis patients. 42 Sexual Function An increase in Hb levels following anemia treatment with rhuepo has been associated with improvements in sexual function in dialysis patients. 63 Figure 1 Anemia that develops in patients over the course of disease progression is responsible, partially or wholly, for manifestations that in the past have been attributed to uremia. 5 As patients progress to ESRD, anemia has been shown to 6 9, 69,70 be associated with the development of cardiac sequelae, increased hospitalization, and increased mortality.

5 of CRI typically give rise to a host of sequelae, and patients who reach ESRD often have anemia, left ventricular hypertrophy (LVH), congestive heart failure (CHF), metabolic bone disease, and malnutrition. Clinical trials have demonstrated that many of these conditions develop early in the course of CRI, greatly increasing the risk of morbidity and mortality over the course of 1 4, 68 disease progression. Anemia is one of the most common manifestations of progressive CRI, and can develop at any time after its onset, often well before ESRD develops. Clinical evidence has demonstrated that the anemia that develops over the course of disease progression is partially or wholly responsible for many of the debilitating manifestations that have historically been attributed to uremia (Figure 1). 5 Symptoms such as lethargy, weakness, chest pain, and shortness of breath hamper quality of life (QOL) and affect patients ability to work, perform household chores, and participate in even the simplest activities of daily life. As patients progress to ESRD, anemia has been shown to be associated with the development of cardiac sequelae (such as LVH), increased 6-9, 69,70 hospitalization, and increased mortality. Despite the negative short- and long-term ramifications associated with anemia, it is a silent disorder that is often underrecognized and undertreated in patients with CRI. Health Care Financing Administration data indicate that 51% of patients have hematocrit (Hct) levels of less than 28% at the onset of dialysis, and that there is no evidence of anemia management in 80% of these patients. 3 This educational monograph reviews scientific data identifying the need for a Renal Anemia Management Period (RAMP) the critical time following the onset of CRI when anemia develops and requires diagnosis and treatment. On the basis of the preponderance of data illustrating the deleterious effects of anemia in CRI and ESRD populations, it follows that appropriate management of this treatable complication should be initiated as early as possible in the progression of CRI well before ESRD develops. 3 Major Points CRI is prevalent in the general population. CRI is associated with a host of sequelae that advance as kidney disease progresses, contributing to significant morbidity and mortality. Anemia often develops early in CRI and is associated with many debilitating sequelae. The anemia of CRI is manageable. Hence, the anemia of CRI should be identified early and managed appropriately.

6 Profile of the CRI Population 4 Defining and Identifying CRI Serum creatinine (SCr) is a widely used indirect measure of kidney function that is employed by many clinicians to confirm the diagnosis of CRI. On the basis of definitions developed by the National Institutes of Health (NIH), CRI is diagnosed when SCr levels exceed 1.5 mg/dl in men, 1.2 mg/dl in women, or age-specific normal values in children. Although these SCr levels signal significant kidney impairment, the systemic manifestations of CRI are typically minimal, and most patients are asymptomatic. 10 Despite widespread use, SCr does not accurately measure or represent true kidney function and is an insensitive marker of early CRI. 2,10 12 Factors such as changes in dietary creatine absorption, fluctuations in muscle mass, and secretion of creatinine by renal tubules and extrarenal sources can lead to low or stable SCr concentrations, even in the presence of severe renal damage. Indeed, studies have shown that SCr levels can be within the normal range in the presence of a glomerular filtration rate (GFR) as low as 20 ml/min/1.73 m As a result, loss of kidney function, especially in the early stages of renal deterioration, may be missed when SCr alone is used to assess function or when isolated measurements are used. The need to follow trends in clinical and laboratory parameters over time is fundamental. Because deterioration in kidney function occurs progressively, regular clinical and laboratory follow-up can proactively detect subtle changes indicative of worsening kidney 1, 3,10,11,13 function. Several other laboratory tests may provide a more comprehensive and accurate assessment of kidney function. The GFR a direct measure of kidney function provides the best overall index of kidney function. 12 GFR correlates directly with the severity of renal impairment, is less likely to be affected by external variables, and declines before the onset of uremia. Patients with CRI typically have a GFR between 30 and 75 ml/min/1.73m 2. 10,13 Because GFR is difficult to measure in clinical practice, most clinicians use an estimated value calculated from the SCr concentration and other factors. 12 Screenings for microalbuminuria and proteinuria can also PREVALENCE OF CRI IN THE UNITED STATES 8,000,000 No. of People 6,000,000 4,000, ,200,000 2,500, , Serum Creatinine (mg/dl) Figure 2 Depending on the serum creatinine cutoff point, as many as 6,200,000 Americans may have CRI, according to the NIH s Third National Health and Nutrition Examination Survey. 11

7 be useful indicators that can signal the need for a more in-depth evaluation. 2 Demographics of CRI The best evaluation of the scope of the CRI population was provided by the NIH s Third National Health and Nutrition Examination Survey (NHANES III). This 7-year retrospective analysis examined the occurrence of renal impairment among a representative sample of the US population (N = 18,723); these data were used to project the probable prevalence of CRI in the United States. Results were categorized on the basis of serum creatinine levels and revealed an estimated population of 6,200,000 patients with a serum creatinine of 1.5 mg/dl or higher (Figure 2). 11 Causes of CRI A wide range of diseases can give rise to progressive loss of kidney function. In the population as a whole, diabetes and high blood pressure are the most common causes of kidney damage. However, a host of other disorders, including glomerulonephritis, vasculitis, interstitial nephritis, and genetic and congenital disorders, are also significant contributors. 10 The increasing incidence of hypertension and diabetes as causes of ESRD contributes significantly to the growing population of patients requiring attention. Many of these high-risk patients are not being identified and managed early, when timely interventions could delay or arrest progression. A multicenter retrospective analysis of 587 randomly selected Medicare patients diagnosed with diabetes or hypertension revealed inconsistent methods of screening for kidney disease. Although serum creatinine was reviewed in most patients, microalbuminuria was assessed in only 2% of patients with diabetes and 1% of those with hypertension. Similarly, a urinalysis was conducted in 68% of patients with diabetes and 59% of those with hypertension. Further, even when laboratory markers indicating renal insufficiency were present, more than 60% of patients failed to receive therapies that could have delayed the progression of renal damage. 2 Estimates of the enormity of the CRI patient population and reports on the inconsistent application of kidney disease screening methods and therapies illustrate that the great majority of patients with CRI are not being identified and managed, pointing to the need for early, comprehensive, nephrologist-directed interventions. This conclusion is supported by the fact that only a minority of patients 20% to 25% are referred to a nephrologist before dialysis is initiated. These results persist, despite the availability of therapeutic approaches that may modify the course of disease (examples include control of hypertension and use of angiotensin-converting enzyme inhibitors and lipid-lowering agents). These and other proven measures can potentially prevent the development of some of the more serious long-term sequelae associated with kidney disease. 1 5 Major Points SCr alone may not be an adequate indicator of kidney function. Loss of kidney function in the early stages of chronic kidney disease is often missed when isolated or insufficient assessments are used. The prevalence of CRI is high. The incidence of contributing risk factors, such as diabetes and hypertension, is increasing. The goal of early and comprehensive intervention is to improve patient outcomes and reduce the burden to society and the healthcare system.

8 Complications and Comorbidities of CRI As patients with CRI pass through the spectrum of deteriorating renal function, the kidneys become unable to fulfill normal metabolic and endocrine demands, resulting in a wide range of systemic manifestations. The disorders associated with CRI can develop early in the course of the disease and progressively worsen as kidney function declines. Numerous clinical studies have proven that many of these disorders, when left uncontrolled, can lead to an increase in mortality. Common comorbidities of CRI include: (1) diabetes, (2) hypertension, (3) dyslipidemia, and (4) cardiovascular disease*. CRI leads to these common complications: (1) hypoalbuminemia, (2) renal osteodystrophy, (3) anemia*, (4) decreased exercise capacity, (5) cognitive dysfunction, and (6) sexual dysfunction. Diabetes Diabetes is the most common cause of ESRD, and its management is of considerable importance when caring for patients with CRI. Patients with diabetes should be screened regularly for microalbuminuria and if renal disease is detected, interventions should be employed to delay disease progression. Tight glycemic and blood pressure control, along with treatment of proteinuria, should also be considered SERUM ALBUMIN LEVELS AT INITIATION OF DIALYSIS % % of Patients % 22% 23% 10% 5 0 < Serum Albumin Level (g/dl) Figure 3 Data based on 110,843 patients who began dialysis in the United States between 1995 and *The evolution and consequences of anemia and cardiovascular disorders are addressed in subsequent sections of this monograph.

9 Hypertension A large body of evidence has shown that uncontrolled hypertension during CRI increases future cardiovascular mortality once patients reach ESRD. Hypertension is one of the key factors responsible for the evolution of LVH, diastolic dysfunction, coronary artery disease, and cerebrovascular disease. Data suggest that failure to control blood pressure early in the course of CRI results in changes that are irreversible or only slowly reversible at the onset of ESRD. 1 Dyslipidemia Abnormalities in lipid metabolism appear to occur early in the course of CRI lipoprotein lipase activity falls at a GFR of 50 ml/min/1.73m 2. Common lipid abnormalities include hypercholesterolemia, elevated ratio of low- to high-density lipoproteins, and elevated lipoprotein(a) levels. Hyperlipidemia is a primary contributor to atherosclerosis as patients progress to ESRD. 14 Hypoalbuminemia The pathogenesis of hypoalbuminemia in patients with CRI is multifactorial: contributing factors include urinary albumin loss, altered serum oncotic pressure, and decreased dietary protein. Hypoalbuminemia causes or may contribute to several complications characteristic of chronic kidney disease, such as altered blood volume and composition, edema formation, increased platelet aggregability, enhanced potential for drug toxicity, compromised renal function, and hyperlipidemia. 14 In one study of 153 incident patients, it was found that 62% had hypoalbuminemia at the start of dialysis. 15 Another analysis examining the prevalence of and factors associated with hypoalbuminemia at initiation of dialysis found that serum albumin was 3.5 g/dl in 67% of patients (Figure 3). 4 Renal Osteodystrophy It is known that the factors mediating renal osteodystrophy are present early in the course of CRI. Bone disease is caused by a number of interrelated disorders, including hypocalcemia, phosphorus retention, impaired calcemic response to parathyroid hormone (PTH), altered degradation of PTH by the kidney, disordered regulation of PTH release, altered vitamin D metabolism, and acid-base disorders of uremia. The resulting renal osteodystrophy syndrome can lead to severe bone erosion. The NIH has recommended that renal osteodystrophy be managed throughout CRI to prevent the development of potentially irreversible secondary hyperparathyroidism. 1,16 Cognitive Dysfunction Patients with chronic kidney disease typically develop a neurobehavioral syndrome characterized by confusion, inability to concentrate, decreased mental alertness, and impaired memory that worsens as renal function declines. Patients with the most severe form can develop hallucinations, tremors, myoclonus, and seizures. In dialysis patients, it has been proven that uremic toxins and anemia play major roles. 17,18 Quality of Life QOL and psychosocial relations can be impaired in the early stages of CRI. In a study by Klang and colleagues, 19 patients (N = 38) were questioned to determine self-perception of their illness. Results indicated that patients with early-stage CRI had a negative perception of their illness that was associated with decreased well-being and functional activity and an increase in anxiety that contributed to an overall decrease in QOL (Figure 4). Mortality Comorbid complications that develop during CRI can contribute to an increase in short- and long-term mortality over the course of disease progression. Cardiac disorders, anemia, hypoalbuminemia, and dyslipidemia are manageable conditions that have been shown to be associated with increased mortality. Studies have also shown that timely nephrologist-directed care can improve patient outcomes. In one study that tracked patient mortality, for example, it was found that patients who died 7

10 within the first year of dialysis were under a nephrologist s care for a median of 36 days before the onset of renal replacement therapy. By comparison, in patients who survived more than 1 year, nephrologists had directed care for a median of 30 months. 20 In a similar study, patients with ESRD who had been referred early in the course of CRI had substantially better survival than those who were referred later in their illness. 21 These data have led the NIH to recommend that patients with CRI, including children, be referred to a nephrologist early in the course of their disease to improve patient outcomes. 1 8 SICKNESS IMPACT PROFILE (SIP) IN CRI PATIENTS COMPARED WITH CONTROLS VS NORMALS Predialytic uremic patients Reference group Mean SIP Overall SIP Physical Psychosocial Sleep and rest Home management Recreation and pastime Eating Work Figure 4 The overall SIP and its subcategories in predialytic uremic patients and a healthy reference group (graph shows means). 19

11 9 Major Points From onset of kidney disease to the time renal replacement therapy begins, patients may develop significant complications and comorbidities. Common comorbidities of CRI include: (1) diabetes, (2) hypertension, (3) dyslipidemia, and (4) cardiovascular disease. Common complications of CRI include: (1) hypoalbuminemia, (2) renal osteodystrophy, (3) anemia, (4) decreased exercise capacity, (5) cognitive dysfunction, and (6) sexual dysfunction. Poor outcomes have been associated with delayed or suboptimal care in CRI. Referral to a nephrologist early in the course of kidney disease may help reduce the morbidity that begins before dialysis is initiated.

12 The Anemia of CRI: Definition, Etiology, Prevalence Anemia is a characteristic but often asymptomatic manifestation of CRI. In normal individuals, hypoxia signals the kidneys to secrete the natural hormone erythropoietin, thereby stimulating the hematopoietic cascade responsible for the production of red blood cells. In patients with progressive CRI, the diseased kidneys are typically unable to secrete enough erythropoietin, and a normocytic, normochromic anemia results. Other factors may also contribute to the severity of anemia in CRI: (1) a shortened life span for red blood cells, (2) iron or other nutritional deficiencies, (3) uremic inhibitors, and (4) etiologies such as infection and inflammation that can inhibit normal red blood cell development. These factors should be actively assessed and treated whenever possible. 22 PERCENTAGE OF ANEMIC CRI PATIENTS (HCT <28%) TREATED WITH rhuepo % Treated with rhuepo 80 % Not treated with rhuepo Figure 5 Of 67,057 patients with Hct <28% who required dialysis between April 1995 and June 1997, 80% did not receive rhuepo therapy during CRI. 3

13 No clear definition of anemia in patients with CRI has been established. In other fields of medicine, anemia is identified when hemoglobin (Hb) levels are below the physiological normal ranges of 13 to 16 g/dl in men and 12 to 14 g/dl in women. 23 In dialysis patients, a comprehensive review of the benefits associated with higher Hb levels by the National Kidney Foundation s Kidney Disease Outcomes Quality Initiative (K/DOQI) Anemia Work Group resulted in a recommended target Hb range of 11 to 12 g/dl. 6 Studies are under way to establish a clear target Hb range for patients with CRI. analysis of factors associated with suboptimal care before initiation of dialysis in the United States (N=131,484). In this study, 68% of patients had Hct levels <30% immediately before starting dialysis; 51% had Hct values <28%. Overall, only 23% of patients were receiving recombinant human erythropoietin (rhuepo) therapy before they began dialysis; rhuepo had not been prescribed for 80% of patients whose Hct levels were <28% (Figure 5). 3 Anemia is an important predictor of morbidity and mortality and is prevalent early during the course of CRI well before the need for renal replacement therapy. 23,24,36,75 The overriding prevalence of anemia in patients with CRI was demonstrated in a retrospective 11 Major Points Anemia develops early in the course of chronic kidney disease. Anemia of CRI is often underrecognized and undertreated. Most patients do not receive comprehensive anemia management before starting renal replacement therapy.

14 Adverse Sequelae of the Anemia of CRI The anemia of CRI can have debilitating effects that compromise QOL and are associated with significant morbidity and mortality. Manifestations of anemia are apparent throughout the body and have historically been attributed to progressive kidney disease and uremia. Evidence, however, demonstrates that anemia is partially or wholly responsible for these symptoms. 5 Systemic Effects of Anemia Commonly cited manifestations of anemia, including lethargy, weakness, increased angina, and shortness of breath, are outlined in Figure 6. MANIFESTATIONS OF ANEMIA 12 Lethargy Cardiac enlargement Malaise/depression Angina Impaired cognition Impaired immune system Anorexia Intolerance to cold Endocrine/ metabolic abnormalities Cardiorespiratory disturbances Gastrointestinal disturbances Weakness Shortness of breath Exertional chest pain Impaired concentration Impaired libido/ impotence Insomnia Headache Pallor Neuromuscular disturbances Cutaneous disturbances Tendency toward bleeding Reduced exercise tolerance Musculoskeletal symptoms Pruritus Figure 6 Anemia contributes to many manifestations of chronic kidney disease.

15 Anemia and Hospitalization Several studies have shown an association between anemia and the risk of future hospitalization. In a retrospective study of 362 patients with CRI conducted by Holland and Lam, 25 the presence of anemia independently predicted hospitalization; that is, patients with anemia were hospital-free for a median of 13.3 months, compared with a median of 21.5 months (P= ) for those with higher Hb levels. Similar results have been observed as patients progress from CRI to ESRD. In a large, retrospective, observational study of 71,717 hemodialysis patients, an association was demonstrated between Hct levels and the future risk of hospitalization. Compared with the baseline group (Hct 30% to <33%), the risk of hospitalization for patients with a Hct below 30% increased 14% to 30% before adjustment for disease severity (P= ) and 7% to 18% after adjustment (P= ). Patients in the 33% to <36% cohort had the lowest risk of hospitalization. Compared with the baseline group, the risk was 0.93 with adjustment for disease severity and 0.88 without it (P= ). 8 These results are supported by a 6-month retrospective analysis by Collins et al of 66,761 Medicare hemodialysis patients. Compared with the group with Hct of 33% to <36%, hospitalization risks were 30% to 76% higher in the group with Hct <30% (P<0.0001). Hct 33% was associated with the lowest risk of hospitalization. Anemia and Mortality A growing body of evidence indicates that anemia is independently associated with an increase in mortality in patients who progress from CRI to ESRD. Harnett and colleagues 26 studied 433 dialysis patients in three centers for a mean of 41 months and found that anemia predicted mortality independent of age, diabetes mellitus, cardiac failure, hypoalbuminemia, serum creatinine, mean arterial pressure, or echocardiographic heart disease. For every 1-g/dL decrease in Hb, the relative risk (RR) of mortality increased by 18% (P = 0.019). Similarly, a large, retrospective, observational study of 75,283 hemodialysis patients showed an association between higher Hct levels and improved patient survival. 9 The authors concluded that, in a population of hemodialysis patients characterized during a 6-month entry period and then followed for a full year, there was an association between Hct level and survival. Patients whose Hct levels were maintained between 33% and 36% had the best chance of surviving into the next year. By comparison, patients whose Hct levels were <33% had a higher risk of all-cause and cardiac death. Additional data supporting this emerging body of evidence come from a 2 1/2 year retrospective analysis of 66,761 incident Medicare hemodialysis patients, which revealed that mortality risk was greatest in patients with Hct levels <30%. Patients with Hct levels of 33% to <36% had a lower risk of mortality compared with those with lower Hct levels. Mortality among patients with Hcts 36% was not significantly different from that of patients whose Hct was 33% to <36%. Anemia and Impaired Cognitive Function Anemia is a major contributor to decreased cognitive function in patients with renal disease. Several mechanisms have been suggested to explain the deleterious effect of anemia on cognitive function, including: (1) a compensatory rise in cerebral blood flow may result in increased delivery of toxins to the brain, (2) a decrease in cerebral oxygen delivery and consumption may decrease the effectiveness of brain functioning, and (3) Hb/Hct levels 17, may not be adequate to oxygenate the brain. One study showed that optimal delivery of oxygen to the brain requires a minimum Hb of 11 g/dl (Hct = 33%). 28 Another demonstrated a direct correlation between progressive increases in Hb and increased cerebral blood flow. 29 Anemia and Exercise Tolerance Patients with kidney disease typically have a low tolerance for exercise that can adversely affect their ability to walk independently, perform self-care, do housework, or pursue employment. The level of exercise tolerance in 13

16 patients with chronic kidney disease is low compared with age-predicted values. In fact, the energy required for occupational activities and those associated with daily living may preclude the performance of even simple tasks. 30 Studies have shown that patients with CRI and anemia have a significant decrease in exercise capacity. 31 Patients with anemia have peak VO 2 values as low as half those of healthy, sedentary, age-matched individuals by the time they reach ESRD. 30 Studies conducted in the CRI population indicate that partial correction of anemia with rhuepo 32, 33 results in significant improvements in energy levels 31, 34 and exercise capacity. These data suggest that appropriate management of anemia may be as important in the period before dialysis as during dialysis. The NIH observes that predialysis treatment of anemia may be critical to reduce cardiovascular morbidity and mortality, since complications such as long-standing LVH associated with anemia may be poorly reversible or irreversible if delayed until dialysis. 1 14

17 15 Major Points The anemia of CRI can have debilitating effects that are associated with significant morbidity and mortality over the course of disease progression. Many symptoms of uremia are partially or wholly attributable to anemia and are evident throughout the body. An emerging body of evidence suggests that anemia and its associated complications and comorbidities start well before the onset of ESRD. Data suggest that anemia should be appropriately managed early in the course of CRI.

18 CRI, Anemia, and Cardiac Disease LVH in Patients with CRI Cardiovascular disease is the leading cause of death in patients who progress from CRI to ESRD 50% of dialysis patients die of diseases of the cardiovascular system (excluding cerebrovascular disease). 1, 35 The most common cardiac abnormality found in patients with kidney disease is LVH, accompanied by an associated impairment of left ventricular filling While LVH has been shown to be a strong predictor of mortality in dialysis patients, 26,39,40,71 it is also a significant problem in the CRI population and appears to develop early in the course of the disease. 41,68 A prospective cohort study conducted in Canada revealed LVH in 74% of patients just starting dialysis (N=433). 26 Similarly, a study investigating the prevalence of comorbid conditions associated with CRI (N=175) found that while the overall prevalence of LVH was about 40%, the prevalence rose as kidney function declined: (1) 26.7% of patients whose creatinine clearance (Ccr) levels were >50 ml/min, (2) 30.8% of patients whose Ccr levels were 25 to 49 ml/min, and (3) 45.2% of patients whose Ccr was <25 ml/min (P= 0.05) (Figure 7). 41 LVH and Anemia Hypertrophy of cardiac muscle develops in response to increased workloads, such as those caused by hypertension and anemia. 37,68 Chronic anemia can cause a hyperdynamic state in which cardiac work and the cardiac index increase. When Hb and Hct levels decrease, there is 16 PREVALENCE OF LVH IN PATIENTS WITH CRI P=0.05 % of Patients with LVH Ccr>50 Ccr Ccr<25 Categories of Renal Function Creatinine Clearance (ml/min) Figure 7 The prevalence of LVH increases as renal function declines. 41

19 a concomitant rise in cardiac output as the body attempts to increase tissue oxygenation. Over time, this perpetual 35, 37, 38, 68 overwork results in hypertrophy of the left ventricle. The relationship between LVH and anemia has been well documented. In a study of 175 patients with CRI by Levin and colleagues, 41 for each 1-g/dL decrease in Hb, the risk of LVH increased by 6% (P= ). Similarly, a study reporting on 246 evaluable patients from a cohort of 446 patients with CRI found that for every 0.5-g/dL decrease in Hb, the RR of left ventricular growth increased by 32% (P= 0.004). 66 The effect of anemia on LVH has also been shown in patients who progress from CRI to ESRD. In a prospective study conducted by Foley and colleagues, patients (261 on hemodialysis and 171 on peritoneal dialysis) were followed for an average of 41 months. After adjusting for diabetes, ischemic heart disease, age, blood pressure, and serum albumin levels, each 1-g/dL decrease in mean Hb was independently associated with an increase in left ventricular dilatation (odds ratio = 1.46; P= 0.018), development of de novo (RR=1.28; P= 0.018) or recurrent (RR=1.20; P= 0.046) cardiac failure, and increased mortality (RR=1.14; P= 0.024). An analysis of 11 studies that investigated the effect of partial correction of anemia with rhuepo on left ventricular mass in dialysis patients showed that, in every study but one, an increase in Hct was associated with a reduction in left ventricular mass ranging from 11% to 35% ,72 In one study, blood pressure was not adequately controlled, and there was only a 2% reduction in left ventricular mass despite an increase in Hct, underscoring the need to adequately control blood pressure to fully realize the potential cardiovascular benefits associated with rhuepo-induced higher Hb/Hct levels. 48 These data demonstrate the potential negative cardiac sequelae associated with uncontrolled, chronic anemia in the CRI population and highlight the need for further research into the impact of anemia management interventions early in the course of CRI. 17 Major Points Cardiovascular disease is the leading cause of death in dialysis patients who progress from CRI to ESRD. LVH is the most common cardiovascular abnormality in patients with kidney disease and is an important predictor of mortality. Recent data correlating the progression of anemia with worsening of LVH may suggest approaches to early recognition and management of the cardiac comorbidities of CRI.

20 Benefits of Anemia Management with rruepo in CRI A large number of studies in patients with ESRD have suggested that partial correction of anemia with rhuepo to Hb levels of 11 to 12 g/dl may lead to decreased morbidity and may be associated with reduced hospitalization and mortality. A growing body of literature suggests similar results are possible in the CRI population. 73 Hb/Hct Levels and Left Ventricular Function Available published data involving small numbers of respondents suggest that correcting anemia with rhuepo can significantly reduce LVH; further research is needed to substantiate beneficial outcomes in early anemia treatment. In a study by Hayashi and colleagues, 53 the baseline left ventricular mass index (LVMI) of patients with a mean Hct level of 23.6% ± 0.5% was ± 12.1 g/m 2 (N = 9). After 4 months of rhuepo therapy, the mean Hct level had increased to 32.1% ± 1.8%, and LVMI decreased to ± 10.0 g/m 2. Additional improvements were seen after 12 months, when mean Hct level was 39.1% ± 2.4% and LVMI had decreased to ± 8.3 g/m 2. (All patients received antihypertensive medications before being treated.) Further research is warranted in this area. A study conducted by Portoles and colleagues 54 of 11 patients with CRI (8 of whom required antihypertensive medication for control of their blood pressure prior to 18 REGRESSION OF LVH IN CRI PATIENTS 220 P< LVMI (g/m 2 ) Basal Hb=9± 0.3 g/dl 6 Months Hb=11.7± 0.4 g/dl Figure 8 LVMI decreased significantly from baseline as Hb levels increased. 54

21 beginning rhuepo) observed a trend of decreased left ventricular thickness and a significant decrease in LVMI (from ± 20.6 g/m 2 to ± 20.6 g/m 2 ) as rhuepo increased Hb levels from a mean of 9.0 ± 0.3 g/dl to 11.7 ± 0.4 g/dl (Figure 8). The trend toward regression of LVH independent of blood pressure control confirms the role of anemia among the multiple factors associated with LVH in ESRD. These results are supported by larger patient populations. Data from a recent analysis of the Studies of Left Ventricular Dysfunction (SOLVD) database of more than 6,000 patients with left ventricular dysfunction found that Hct levels were significantly related to survival in patients with CRI. Mortality decreased progressively as Hct increased. 55 An additional study by Stewart and colleagues 56 evaluated cross-sectional echocardiographic results from 297 CRI patients and found that: (1) LVH develops early in the course of kidney disease and worsens as the disease progresses, and (2) Hb levels independently predict the elevation in LVMI, although blood pressure seems to be the major determinant. Although further studies are required to validate these results in CRI patients, more extensive evidence supporting the impact of partial correction of anemia with rhuepo is available in patients who have progressed to ESRD. It has been shown that correcting anemia with rhuepo to improve oxygen transport and reduce the cardiac index in these patients has a favorable impact on LVH. After partial rhuepo-induced correction of uremic anemia, a number of hemodynamic effects have been observed: Decreases in left ventricular end-diastolic diameter, left ventricular mass, left atrial diameter, and cardiac output Increases in venous tone, peripheral vascular resistance, blood viscosity, and tissue oxygenation Normalization of heart function and modifications in arteriolar and venous circulation Reductions in myocardial ischemia as indicated by normalization of ST-segment depression on electrocardiogram and improvements in symptomlimited exercise performance and duration In a study by Zehnder and colleagues 43 of 12 hemodialysis patients (8 of whom had a history of arterial hypertension treated with antihypertensive medication), baseline Hb concentrations of 8.6 ± 0.7 g/dl were increased to 11.4 ± 1.2 g/dl with rhuepo therapy. LVMI decreased from a baseline of ± 41 g/m 2 to ± 25.1 g/m 2 (P<0.001) after 18.8 ± 2.7 months of therapy (normal LVMI in adults is 98.9 ± 26.3 g/m 2 ). Subgroup analysis showed that LVH improvement required concomitant correction of anemia and control of blood pressure. 43 Similar results have been demonstrated in a wide range of studies that have consistently correlated rhuepo-induced correction of anemia with dramatic reductions (11% to 44-52, 72 35%) in left ventricular mass. Hb/Hct Levels and QOL For patients with chronic kidney disease, improvement in the overall QOL is perhaps the most welcome benefit associated with partial correction of anemia with rhuepo (Table 1). In a study of patients with CRI (N=14), partial correction of anemia with rhuepo was associated with subjective improvements in sense of well-being, angina, appetite, and physical activity, and objective improvements in the maximal work rate seen during exercise. 34 Likewise, a study by Revicki and colleagues 57 of 83 patients with CRI showed improvements in energy, physical function, home management, social activity, and cognitive functioning when rhuepo increased Hct levels. Similar improvements in QOL parameters were also reported in other studies of CRI patients treated with rhuepo. 31,33 A controlled study of 117 CRI patients evaluated the effect of treating anemia with rhuepo in patients whose baseline Hb was 13 g/dl for men or 11 g/dl for women. Among patients evaluated, 60% reported an increase in energy levels following correction of anemia, compared with 42% of those whose anemia was not corrected. Similarly, work capacity improved in 62% of patients in whom anemia was corrected with rhuepo, compared with 38% of those who remained anemic. 32 There is a considerable body of evidence demonstrating the benefits of anemia treatment with rhuepo on QOL parameters in patients with ESRD. Moreno and colleagues 58 used the Karnofsky scale and the Sickness 19

22 20 Impact Profile (SIP) to evaluate the effect of Hb level on QOL in 1,013 stable dialysis patients. Patients were divided into four groups based on Hb level: <8 g/dl, 8 to 10 g/dl, 10 to 12 g/dl, and >12 g/dl. Significant improvements were noted in physical dimension (P< 0.01) and global (P<0.05) SIP scores at each successive Hb level. QOL BENEFITS FROM ANEMIA TREATMENT WITH rhuepo Vitality Mental health Sexual satisfaction Functional ability Health status Well-being Happiness Physical and social functioning Social life Energy Sleep and eating behaviors Satisfaction with life Psychological effect Activity levels Table 1 Correction of anemia with rhuepo in patients with either CRI or ESRD has been associated with a wide variety of benefits. 57,62,64 Hb/Hct Levels and Exercise Capacity Anemia affects all facets of QOL but is often most apparent in the realm of physical activity. Clyne and colleagues 31 studied the effect of rhuepo-induced increases in Hb levels on physical exercise capacity in patients with CRI and uremia (N=12). In this study, an increase in Hb from 8.6 ± 0.8 g/dl to 11.7 ±1.1 g/dl resulted in a corresponding increase in exercise capacity evaluated by bicycle ergometer (from 128 ± 45 W to 147 ± 57 W, P<0.01). A study by Teehan and colleagues 65 examined the effect of correcting anemia with rhuepo on 23 patients with CRI who had a mean baseline Hct level of 28%. As Hct levels increased to 36%, improvements were observed in the duration of exercise, angina, and overall well-being. These results have been consistently duplicated in studies showing a direct correlation between rhuepo-induced increases in Hb/Hct levels and improved exercise capacity in patients with CRI. 31,34 Similar results have been seen in patients with ESRD. A number of studies have shown that partial correction of anemia with rhuepo is associated with increases in peak VO 2 and exercise capacity. 30,59-61 In general, these studies have reported that increasing Hb levels to between 10.0 and 11.7 g/dl (Hct between 30% and 35%) is associated with increases in peak VO 2 of 20% to 25%. 30 These data have shown that rhuepo-induced increases in Hb/Hct levels are associated with improvements in endurance, functional status, and physical performance. Hb/Hct Levels and Cognitive Function Data from a study including 27 patients with ischemic cerebrovascular disease indicate a direct correlation among higher Hb/Hct levels, increased cerebral blood flow, and cognitive function. 29 In a study by Marsh and colleagues, 17 rhuepo was used to increase mean Hct levels from a baseline of 23.7% to 36.5% (N=24), resulting in improved levels of sustained attention and enhanced learning and memory. It has been suggested that optimal delivery of oxygen to the brain requires a minimum Hb of 11 g/dl (Hct = 33%). 28 Hb/Hct Levels and Sexual Function in Dialysis Patients An increase in Hb following rhuepo therapy has been associated with improvement in sexual function. 62,63 In a study of nine female and seven male dialysis patients, an increase in mean Hb levels from a baseline of 7.3 ± 0.3 to 11.3 ± 0.4 g/dl was accompanied by a significant decrease in prolactin values in both men and women. 63 The authors concluded that improvements in sexual function appear to be linked to the normalization of elevated serum prolactin levels that accompanies the rhuepo-induced increase in Hb.

23 While additional data are required to confirm the benefits associated with correcting anemia in patients with CRI, current clinical results support early intervention to identify and appropriately manage anemia and other potential causes of morbidity and mortality in all patients diagnosed with CRI. 21 Major Points The management of anemia with rhuepo is associated with numerous clinical and QOL benefits. Although additional data are required, current clinical evidence supports early intervention to identify and appropriately manage the anemia associated with chronic kidney disease and to proactively improve patient outcomes.

24 The RAMP: Heightened Vigilance for Anemia Treatment Data indicate that anemia is a serious consequence of CRI associated with significant short- and long-term clinical and functional morbidities. Despite this preponderance of evidence, US Renal Data System and NIH reports indicate that anemia is often underrecognized and undertreated in this population. The information presented in this monograph provides support for establishing a Renal Anemia Management Period (RAMP) for patients with CRI. The RAMP is defined as the time following the onset of CRI when anemia develops and should be identified and managed appropriately (Figure 9). 74 On the basis of the preponderance of data illustrating the deleterious effects of anemia in CRI and ESRD populations, it follows that anemia should be identified early in the course of CRI and managed appropriately well before ESRD develops. This approach is supported by the corresponding benefits associated with rhuepo-induced anemia correction, including improvements in parameters such as LVH, QOL, exercise capacity, cognitive and sexual function, hospitalization, and mortality. 22 RENAL ANEMIA MANAGEMENT PERIOD Renal replacement therapy (RRT) Risk of Comorbid Conditions Anemia (can develop at any time after onset of CRI) RAMP Time CRI ESRD Figure 9 The onset of anemia, which often develops well before the need for renal replacement therapy (RRT) during CRI, marks the beginning of the Renal Anemia Management Period (RAMP). Adequate diagnosis and management of anemia during the RAMP may reduce those adverse sequelae related to anemia.

25 The RAMP concept was developed by a group of prominent nephrologists to designate a critical time during the evolution of CRI when the identification of and decision to treat anemia is linked to a number of benefits potentially having a positive impact on many of the comorbidities associated with the progression of kidney disease. It is important to note that the RAMP model illustrated in Figure 9 does not reflect data from a specific study. Rather, it depicts a compiled trend that became apparent from the analysis of many studies. The RAMP provides a conceptual framework for illustrating the spectrum of kidney disease from CRI to ESRD. In the model, the low end of the RAMP represents the onset of CRI, when patients have few comorbidities and QOL is only slightly affected. As the RAMP moves from CRI toward ESRD, anemia and its associated comorbidities can develop at any time, negatively affecting QOL while impacting future morbidity and survival over the course of disease progression. The RAMP model emphasizes the progressive nature of CRI and the need for early interventions to manage anemia and other comorbidities, thereby preventing or controlling the development of serious, potentially irreversible physiological damage. Nephrologists and the Renal Anemia Management Period A Call to Action Epidemiological data consistently demonstrate that patient outcomes improve when nephrologists are involved in caring for renal patients early in the course of kidney disease. Although the RAMP is currently a conceptual framework, specific action steps can be envisioned to help make appropriate management of the anemia of CRI a reality. Sample steps could include the following: Establish collaborative relationships with primary care physicians to ensure early evaluation of patients with CRI. While the primary care physician continues to provide everyday care, the nephrologist provides vital consultation on early guidelines for appropriately diagnosing and managing anemia and other comorbidities associated with CRI. Develop screening methods to identify chronic kidney disease early, stressing the need to use more accurate laboratory tests (such as calculated GFR). Follow trends in laboratory measurements. Isolated values within the normal range may otherwise go unrecognized as a possible marker of early disease. Treat conditions such as anemia appropriately early in the course of CRI with the goal of preventing and/or minimizing associated morbidities and improving patient outcomes. Develop a therapeutic approach tailored to meet patient and clinical needs. 23 Major Points The RAMP is a tool to increase awareness of the importance of early recognition and appropriate management of anemia during CRI. Early intervention to manage anemia and other progressive comorbidities of CRI has the potential to generate beneficial effects on the development of significant physiological sequelae. The nephrologist should take the lead in making management of the anemia of CRI a reality.

26 Summary This educational monograph provides scientific data supporting the need for a Renal Anemia Management Period (RAMP) presented as a clinical management tool to emphasize the need for early recognition and appropriate management of anemia in patients with CRI. Primary concepts outlined in this monograph are as follows: The prevalence of CRI is high, affecting as many as 6,200,000 patients in the United States. Serum creatinine alone does not accurately reflect the severity of kidney damage. Other physiological parameters including GFR (direct measurement or calculation) provide a more accurate assessment of kidney function. CRI is not receiving optimal medical management. 24 Cardiovascular disease (including LVH) is a major cause of morbidity and mortality that typically begins early in the course of CRI. Most patients with CRI have a deficiency of the hormone erythropoietin, which results in anemia. Anemia typically begins early in the course of CRI. Anemia of CRI is often underrecognized and undertreated. Anemia contributes to many comorbidities associated with CRI, including LVH and a decrease in QOL. The RAMP is a conceptual model illustrating the need for timely diagnosis of the anemia of CRI. Timely and appropriate management of the anemia of CRI can have a positive impact on patient outcomes and the quality and duration of life.

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