Complications of Chronic Kidney Disease: Anemia, Mineral Metabolism, and Cardiovascular Disease

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1 Med Clin N Am 89 (2005) Complications of Chronic Kidney Disease: Anemia, Mineral Metabolism, and Cardiovascular Disease Shona Pendse, MD, Ajay K. Singh, MB, MRCP(UK)* Renal Division, Brigham and Women s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA The publication of the Kidney Disease Outcome Quality Initiative (K/DOQI) clinical practice guidelines for chronic kidney disease (CKD) in 2002 heralded a focus on CKD. Public bodies have embraced the importance of CKD. The US Department of Health and Human Services has made CKD a national focus area in its Healthy People 2010 report [1,2]. There is now a National Kidney Disease Education Program in place. The National Kidney Foundation has embarked on an unprecedented national screening initiative termed Kidney Early Evaluation Program that has successfully screened over 40,000 individuals in the United States. Studies using the Third National Health and Nutrition Examination Survey (NHANES) estimate that 6.2 million Americans have serum creatinine greater than 1.5 mg/dl [3]. The K/DOQI work group more recently reassessed the NHANES III data and released estimates of the prevalence of each of the five stages of CKD [2,4 6]. Their repeat analysis suggests that 8.3 million individuals in the United States have CKD based on decreased glomerular filtration rate (GFR) (less than 60 ml/min/1.73 m 2 ) with an additional 11.2 million individuals who have persistent proteinuria with normal or mildly decreased GFR (60 ml/min/1.73 m 2 or higher). Their figures suggest that 3.3% of the population 20 years of age or older have CKD stage 1 disease; 3% have stage II; 4.3% have stage III; 0.2 have stage IV; and 0.2% have stage V (with stage V including those on dialysis) [2,4 6]. The early stages of CKD represent 10% of the United States population, as * Corresponding author. address: asingh@partners.org (A.K. Singh) /05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi: /j.mcna medical.theclinics.com

2 550 PENDSE & SINGH compared with less than 0.5% of the population with advanced (stages IV and V) disease. The impact of impaired kidney function on outcome has until recently been underappreciated. Recent work indicates emphatically that there is a graded relationship between the GFR and mortality, cardiovascular events, and hospitalizations [7,8]. Although a poor and relatively unchanged survival rate has been appreciated in the end-stage renal disease (ESRD) population for several decades (5- and 10-year survival rates of 38% and 21%, respectively) [9,10], mortality is also an important problem in pre- ESRD CKD patients [11 16]. As patients progress to more advanced stages of CKD, while the incidence of renal replacement therapy increases, there is a twofold to threefold higher mortality. Furthermore, the level of renal function seems to be one of the most important factors determining survival after a myocardial infarction. Collectively, these studies suggest that renalism, a term coined by Chertow et al [17], modulates outcome in a significant way and beyond the effect of a number of other factors [8]. In terms of public health dollars, kidney disease is an important problem. ESRD patients represent less than 0.5% of the Medicare population, but care of these patients necessitates more than 5% of the Medicare budget. Kidney disease becomes more costly as the patient approaches ESRD. The absence of optimal pre-esrd care, particularly if referral to a nephrologist has not occurred, accentuates the cost. Most patients with CKD are seen late in the course of CKD by a nephrologist and are frequently seen during the few months preceding the initiation of dialysis. Late referral to nephrology occurs despite the fact that factors associated with adverse outcomes in ESRD, such as bone disease, anemia, hypertension, and malnutrition, are present very early in the course of CKD, well before the development of ESRD and the need for initiation of dialysis [18,19]. Comorbidities in CKD patients seem to have a very significant effect on mortality [20 24]. Patients who have CKD in the presence of anemia, congestive heart failure, and/or diabetes mellitus have a mortality several fold higher than an otherwise uncomplicated CKD patient [12,14,15,20,24 26]. This article focuses on the importance of three major complications of CKD: (1) anemia, (2) calcium-phosphorous regulation and bone disease, and (3) cardiovascular risk profiling and treatment. The arguments for early and effective intervention have been amply made with respect to these three complications. Yet, substantive trial data are sorely needed to provide the definitive evidence that effective treatment of these complications results in better outcomes. Anemia of chronic kidney disease Anemia is usually observed when the GFR falls below 60 ml/min/ 1.73 m 2 and worsens as both renal function and erythropoietin production decline. In a multicenter study in Canada, the prevalence of anemia was

3 CKD: ANEMIA, MINERAL METABOLISM, & CVD 551 found to be approximately 25% in patients with creatinine clearance greater than 50 ml/min [27]. By the time a patient reaches a GFR of 15 to 29 ml/min/1.73 m 2, approximately 44% of patients are anemic (anemia defined as a hemoglobin of \ 12 g/dl in men and \ 11 g/dl in women), and by stage 5 CKD approximately 90% of patients are anemic [16,28,29]. NHANES survey data indicate that anemia is more common among non- Hispanic black men and women compared with other racial groups even after adjusting for renal function. Studies also suggest that diabetic CKD patients may have anemia that is more severe than in nondiabetics after adjusting for kidney function. CKD patients usually become symptomatic when the hemoglobin level falls below 11 g/dl. The most common symptoms are tiredness and fatigue. Anemia may also be associated with cardiovascular manifestations, however, such as left ventricular hypertrophy (LVH), worsening congestive heart failure, and myocardial ischemia. Several studies suggest that anemia in CKD patients is associated with reductions in health-related quality of life, impaired cognitive function, and abnormalities in immune responses. The role of anemia as a major risk factor in driving poor CVD outcomes has been suggested by several observational and a few small prospective interventional studies. The treatment of anemia in patients with kidney disease was transformed by the cloning of erythropoietin in 1986 and its commercial availability in Before this, anemia was either not being treated or various maneuvers, such as repeated blood transfusions or the use of anabolic steroids, were the mainstay, especially among dialysis patients. Presently, treatment for anemia in both pre-esrd and ESRD patients is strongly recommended. Anemia and its impact on mortality There are substantial observational data to support a relationship between anemia and mortality. A causal relationship between anemia and mortality, based on adequately powered randomized trials, however, has not been proven. Furthermore, data on the relationship between anemia and survival has been almost completely focused on the ESRD population. Among dialysis patients, several studies have documented that hemoglobin levels of 10 g/dl or less is associated with a higher risk of death when compared with levels greater than 10 g/dl. Indeed, hematocrit levels maintained between 33% and 36% has been suggested in a number of studies to be associated with the lowest risk of death. The argument favoring treatment of anemia is based on outcome benefits of meaningful magnitude based largely in observational studies with large sample size; careful modeling with adjustment for many factors; and the publication of smaller prospective studies using surrogate outcomes to show benefit (eg, improvement in LVH with the treatment of anemia).

4 552 PENDSE & SINGH Anemia and cardiovascular disease LVH has been proposed as a major consequence of the anemia of CKD. In a cross-sectional study by Levin et al [28], the prevalence of LVH detected by echocardiography was observed to be 26.7% in patients with creatinine clearance above 50 ml/min, 30.8% in patients with creatinine clearance 25 to 49 ml/min, and 45.2% in patients with clearances below 25 ml/min. In a multivariate analysis by the same investigators, hemoglobin concentration was found to be an independent risk factor for the development of LVH, with 32% increased risk for LVH for every 0.5 g/dl decrease in hemoglobin, as was creatinine clearance, with a 3% increase in risk of LVH for every 5 ml/min decline in GFR (P =.0168). Furthermore, only 15% of patients have normal left ventricular structure and function at the start of dialysis, and mortality caused by cardiovascular disease is 20- to 40-fold higher in patients with ESRD than in the general population [30,31]. These findings suggest that patients are exposed to anemia for a lengthy period of time before the development of ESRD, and that correction during this period may be critical to the optimization of outcomes for these patients. Fink et al [32] found that patients who received erythropoietin before initiation of dialysis had improvement in survival compared with patients who did not receive epoetin during this period. This work was based on data from Medical Evidence Forms (Health Care Financing Administration 2728, now the Centers for Medicare and Medicaid Services), which only specifies whether or not epoetin was given in the pre-esrd period, but does not specify the length of time of treatment. A study of 11 patients with CKD done by Portoles et al [13,33] demonstrated that partial improvement of anemia was associated with significant decrease in left ventricular mass index from g/m 2 to g/m 2 and a trend toward decreased left ventricular thickness. Another study by Hayashi et al [34] showed similar reduction in left ventricular mass with anemia correction. This study observed that left ventricular mass index tended to decrease after a partial correction of anemia (hematocrit 32.1% 1.8%) at 4 months (from a baseline of g/m 2 to g/m 2 after partial correction), whereas it tended to significantly decrease after normalization of hematocrit at 12 months (hematocrit 39.1% 2.4%) to g/m 2. A retrospective review of 89,193 Medicare patients with ESRD by Xue et al [11] showed that patients who received consistent predialysis therapy with erythropoietin had higher hematocrit at the start of dialysis and lower risk of mortality 1 year after the start of dialysis. The issue of the optimal target hemoglobin has been greatly debated over the past few years. The United States National Kidney Foundation Dialysis Outcomes Quality Initiative guidelines, initially published in 1997 and revised in 2001, recommend a target hematocrit between 33% and 36% or a hemoglobin concentration of 11 to 12 g/dl [35 37]. The European Best Practice Guidelines recommend a target hemoglobin of greater than 11 g/dl

5 CKD: ANEMIA, MINERAL METABOLISM, & CVD 553 or hematocrit greater than 33%, without a guideline for the upper limit [38,39]. The United States Normal Hematocrit study evaluated 1233 hemodialysis patients with clinical evidence of congestive heart failure or ischemic heart disease [40]. Of these, 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42%, and 615 were assigned to receive doses of epoetin adjusted to maintain a hematocrit of 30, for a median duration of 14 months. After 29 months of follow-up, there were 183 deaths and 19 first nonfatal myocardial infarctions in the normal-hematocrit group in contrast to 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group. The risk ratio for the normal-hematocrit group as compared with the low-hematocrit group was 1.3 with a 95% confidence interval of 0.9 to 1.9. The investigators halted the study prematurely given these unexpected results and concluded that normalization of hematocrit was not recommended for hemodialysis patients with evidence of congestive heart failure or ischemic heart disease [40]. In a study of nine predialysis patients, Hayashi et al [34] found a reduction in left ventricular mass with partial followed by full anemia correction. Despite evidence supporting the treatment of anemia, especially for the prevention of cardiovascular disease events and in reducing mortality, it is clear that anemia is not optimally being corrected in most CKD patients, both before and after referral to nephrologists. Valderrabano et al [41] in their predialysis survey on anemia management performed a retrospective chart review of 4333 new dialysis patients in 21 European countries, South Africa, and Israel. They found that, at first visit to a dialysis center, 68% had hemoglobin levels at or below 11 g/dl, and only 26.5% of patients received epoetin before the start of dialysis. Furthermore, they found that more than 30% of the patients had been followed by a nephrologist less than 6 months before initiation of dialysis. In a review of more than 150,000 dialysis patients in the United States, Obrador et al [41 44] observed that a similar percentage (23%) of patients had been given epoetin before initiation of dialysis. A review of more than 89,000 Medicare patients in the United States by Xue et al [11] found an even lower percentage (15.6%) of patients received erythropoietin in the pre-esrd period. Darbepoetin-a, the most recent therapeutic agent for renal anemia, was commercially launched in The premise for the introduction of darbepoetin-a is the observation that the greater the number of sialic acid residues on erythropoietin, the greater the in vivo stability, and hence longer the serum half-life [45]. Several clinical trials have demonstrated the effectiveness of darbepoetin-a, both intravenously and subcutaneously, at maintaining similar hemoglobin levels with less frequent dosing, usually once-weekly for patients on three times per week recombinant erythropoietin [46 53]. Notably, however, epoetin-a with a half-life one third of darbepoetin-a (8 hours versus nearly 24 hours) seems also to be amenable to extended dosing. In the PROMPT study, approximately 90% of patients

6 554 PENDSE & SINGH maintain their hemoglobin at greater than 11 g/dl after conversion from weekly subcutaneous administration epoetin-a to every other week administration. Interestingly, over 75% of patients maintain the target hemoglobin of greater than 11 g/dl dosed every 3 or 4 weeks. Mineral metabolism and renal bone disease The management of renal osteodystrophy and secondary hyperparathyroidism has undergone tremendous changes over the past several decades. Studies undertaken in the early 1970s by Slatopolsky et al [54,55] in uremic dogs demonstrated the effect of hypocalcemia in the development of hyperparathyroidism, and that restriction of phosphorous intake in the setting of advancing renal dysfunction prevented its occurrence. This was then followed by a study by Goldsmith et al [56] that showed that infusions of calcium could suppress parathyroid hormone (PTH) secretion in hemodialysis patients. This led to a newly acquired ability to manage secondary hyperparathyroidism with calcium repletion through supplementation of both calcium and calcitriol, phosphorous restriction in the diet, and the use of highly potent aluminum-based phosphate binders [57 60]. In the following decade, growing concern as to the toxic effects of aluminum, particularly in patients whose intrinsic ability to clear aluminum by the kidneys was impaired, led physicians to be wary of the use of these products as phosphate-binders, and once calcium-based binders became available in the 1980s, these became largely the agent of choice [61 63]. Although these agents were not quite as effective as their aluminum-based counterparts, they were considered safer given the risks of aluminum toxicity and aluminum-related bone disease, characterized by a low-turnover state with osteomalacia and adynamic bone [64 67]. Adequate binding of dietary phosphate with these calcium-based binders, however, because of their reduced potency in comparison to aluminum-based binders, necessitated large daily doses of calcium, which resulted in positive calcium balance and difficulties with hypercalcemia. Over the past decade the focus of calcium-phosphorous management in CKD has shifted to concerns regarding the significant increase in cardiovascular risk associated with extraskeletal calcification, particularly in the coronary vasculature. Several landmark studies have highlighted this issue. Braun et al [68] reported the prevalence of aortic and mitral valve calcification, as determined by electron-beam CT, to be 55% and 59%, respectively, in a series of patients on dialysis. In a later study, Block et al [69] found that elevated calcium-phosphorous product over 55 was associated with a significant increase in mortality in these patients, and those individuals in the highest quintile of the calcium-phosphorous product, greater than 72, had a relative mortality risk of 1.34 relative to those with products of 42 to 52. Goodman et al [70] used electron-beam CT to evaluate the presence of coronary calcification in 39 young patients on

7 CKD: ANEMIA, MINERAL METABOLISM, & CVD 555 dialysis and 60 normal subjects and found that 14 of the patients on dialysis had coronary calcification in contrast to only 3 of the normal subjects. Furthermore, those patients with coronary calcification were found to be older (26 3 versus 15 5 years, P \.001) and to have been on dialysis for a longer duration (14 5 versus 4 4 years, P \.001). In addition, elevated calcium-phosphorous product and use of calcium-based phosphate binders were both found to be correlated with coronary calcification. In a follow-up CT scan done in a subgroup of 10 of the patients with calcification, the calcification score was increased close to twofold ( initially to , P =.02), over a mean interval of 20 3 months [70]. These new concerns led to the search for non-aluminum and noncalcium based therapy for phosphate binding. Sevelamer hydrochloride (Renagel; Genzyme, Cambridge, MA), approved by the Food and Drug Administration in 1998, was found in numerous clinical trials to control serum phosphorous and calcium-phosphorous product effectively in dialysis patients, while avoiding the positive calcium balance and hypercalcemia induced by calcium-based binders [71 77]. In addition, sevelamer has been found to result in improvement in lipid profile, including reduction in total cholesterol and low-density lipoprotein along with increase in high-density lipoprotein levels [73,78]. This treatment was also found to result in fewer hospitalizations and a corresponding reduction in medical costs, as demonstrated by Collins et al [79] in a case-control study on Medicare patients. They evaluated 152 patients on hemodialysis treated with sevelamer with 152 non-sevelamer treated dialysis patients as their controls, and found a 46% to 54% decrease in relative risk of hospitalization in the sevelamer-treated patients compared with the control group, along with a reduction in cost of $3368 (Medicare expenditures per member, per month) in the sevelamer-treated patients compared with $4745 in the control patients. Vitamin D supplementation has been an essential element in the care of renal patients since the early 1980s, after studies by Slatapolsky et al [80 87] showed the benefit of 1,25-dihydroxyvitamin D 3 [1,25(OH)2D 3 ] on secondary hyperparathyroidism. Numerous studies have shown calcitriol and 1a-hydroxyvitamin D 3 to be effective in the prevention and treatment of secondary hyperparathyroidism in renal patients. In a prospective, doubleblind, placebo-controlled trial of patients with mild to moderate renal failure (creatinine clearances of 20 to 59 ml/min), however, bone biopsies done at baseline and 1 year posttreatment showed significant inhibition of bone turnover in the calcitriol-treated group compared with placebo [88]. In addition to this issue of precipitation of adynamic bone disease, also concerning was its ability to cause positive calcium balance and hypercalcemia. In response to these concerns, calcimimetic agents were developed that modulate the extracellular calcium-sensing receptors found on parathyroid cells, on calcitonin-secreting C-cells of the thyroid, in the kidneys, and in the brain and bone cells, causing these receptors to become

8 556 PENDSE & SINGH more sensitive to the inhibitory effects of calcium on PTH secretion [89 91]. One such agent is paricalcitol (19-nor-1,25-dihydroxyvitamin D 2 ), approved by the Food and Drug Administration in This was found to suppress PTH levels effectively while avoiding the changes in calcium and phosphorous levels associated with calcitriol [92,93]. In addition, this agent was found to suppress PTH levels in a prospective study of 39 patients with calcitriol-resistant secondary hyperparathyroidism. The mean ipth level decreased from a baseline of pg/ml during the initial 2 months to pg/ml at 16 months. Alkaline phosphatase levels decreased from IU at baseline to IU at 16 months. Mean calcium and phosphorus levels did not change significantly over the 16 months [92,93].In a recent large historical cohort study of hemodialysis patients done by Teng et al [94], the 36-month survival rate was compared among 29,021 patients on paricalcitol treatment and 38,378 patients on calcitriol between 1999 and Their findings revealed a significant survival advantage in the paricalcitol-treated patients (mortality rate of per person year in the paricalcitol group compared with in the calcitriol-treated patients), which was independent of baseline calcium, phosphorous, and PTH levels. In the adjusted analysis they found a 16% reduction in mortality in the paricalcitol-treated patients compared with the calcitriol-treated group. The difference in survival was significant at 12 months and increased with time. They also performed a subgroup analysis of patients who switched from one agent to the other, and found a significant survival advantage in those patients who transitioned from calcitriol to paricalcitol (73% 2-year survival rate) as opposed to those who switched to calcitriol from initial therapy with paricalcitol (64% survival at 2 years). Cardiovascular risk profiling and treatment The high prevalence of cardiovascular disease in dialysis patients has been well-described, particularly LVH [30,95 98]. Parfrey et al [99] found that the likelihood of de novo heart failure after the initiation of dialysis is approximately 80% within the first year, and that the combination of congestive heart failure and LVH is a predictor of poor survival [30,97,100]. This cardiovascular risk was observed to be 65-fold higher in dialysis patients in the 45- to 54-year age category compared with the general population [101,102]. In patients with very mild degrees of renal insufficiency, this increase in risk was found to be approximately threefold [103]. This increase in cardiovascular risk in patients with CKD is multifactorial, arising as a result of calcium-phosphorous dysregulation and extraskeletal calcifications; anemia with its associated increase risk of LVH; along with the well known associations with CKD of hypertension, diabetes, and dyslipidemia. Also included in this list of contributors is hyperhomocysteinemia, a common metabolic consequence of renal failure. A10lmol/L increase in plasma homocysteine concentration has been found

9 CKD: ANEMIA, MINERAL METABOLISM, & CVD 557 to be associated with a 1.8-fold increased risk of cardiovascular events. The plasma concentration of asymmetric dimethyl-l-arginine, an inhibitor of nitrous oxide synthase found endogenously, has been found to be increased early in the course of renal disease, even in the presence of a normal GFR [104]. A 2.7 lmol/l increase in plasma levels, which is the average difference in concentration between patients with CKD and normal subjects, has been associated with a greater than threefold increase in risk of cardiovascular events [105]. The future: the new arena of chronic kidney disease management, a focus on cardiovascular risk minimization CKD management has evolved a great deal over the past several years. There is now mounting evidence that suggests that patients have a much higher risk of cardiovascular disease than the general population even at the earliest stages of CKD. It is increasingly becoming evident that complications thought to exist only in advanced kidney disease, such as anemia and calcium-phosphorous dysregulation, are actually present much earlier in the course of renal dysfunction, and that correction of these factors in these early stages results in optimization of outcomes in these patients. It is critical, however, that knowledge in these arenas be increased, because many questions still remain unanswered. References [1] US Department of Health and Human Services. Office of Disease Prevention and Health Promotion Healthy People Nasnewsletter 2000;15:3. [2] Coresh J, et al. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 2003;41:1 12. [3] Jones CA, et al. Serum creatinine levels in the US population: third National Health and Nutrition Examination Survey. Am J Kidney Dis 1998;32: [4] Kidney Disease Outcome Quality Initiative. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39(2 Suppl 2):S [5] Hogg RJ, et al. National Kidney Foundation s Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics 2003;111(6 Pt 1): [6] Levey AS, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003;139: [7] Anavekar NS, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med 2004;351: [8] Go AS, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351: [9] Agodoa L. United States Renal Data System (USRDS). Nefrologia 2000;20(Suppl 5): [10] Cooper L. USRDS Annual data report. Nephrol News Issues 2001;15:31.

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