Resumative synthesis of contents: It is time for further renoprotection: Management of comorbidities in kidney disease in the 21st century: Anemia and bone disease

Abstract

Over the past decade, as industrialized nations struggled to cope with the fiscal stress imposed by a continuously expanding population of individuals with end-stage renal failure (ESRD), excitement over the concept of preventing or delaying uremia gained momentum. In the United States, for example, an estimated 20 to 25 million people currently have varying degrees of renal impairment that will, if not interrupted, deteriorate to ESRD within months to years. That ESRD may not be inevitable has been learned from success in slowing renal functional decline in both type 1 and type 2 diabetes by careful metabolic control using diet, oral hypoglycemic agents, and insulin. Multiple reports have indicated that pharmacologic interference with angiotensin-converting enzyme by either direct enzyme inhibition or receptor blockade retard progression of nephropathy. The concept of renoprotection has gained acceptance as the emblem for renal investigators sharing interest in interdicting the mounting toll extracted by kidney loss. Presently, several promising paths to stop the march toward ESRD are under intense inquiry, with special focus on the roles of anemia, bone disease, nutrition, and perturbed molecular biology. As the latest in a series of symposiums convened at the Avram Conference Center, Long Island College Hospital in Brooklyn, New York City, “Management of Comorbidities in Kidney Disease” was actually directed toward turning off the renal damage and improving the quality of life once on dialysis. This was accomplished by state-of-the-art lectures, workshops, and panels with lively debates. Each participant was asked to bring a manuscript for peer review, so that this huge body of new information could be made available worldwide. Indeed, it is neither possible nor desirable to disconnect the consequence of kidney malfunction, per se, from its wide-reaching impact on other vital organ systems. Launching the vital theme that anemia is more than a comorbid annoyance to those with renal insufficiency, Avram et al recount their unique 15-year single-center observational study of hemoglobin as a correlate of both prealbumin and survival in 529 hemodialysis and 326 peritoneal dialysis patients. For hemodialysis or peritoneal dialysis patients with a hemoglobin of 12 g/dL or higher at study enrollment, survival throughout their course of dialytic therapy, as well as after 15 years, was significantly (P = < 0.05) greater. The correlation discerned by Avram et al was greater for nondiabetic than diabetic patients, probably due to anemia induced by the adverse influence of multiple comorbidities in the diabetic cohort. Avram et al conclude that anemia is a modifiable risk factor, and this needs to be applied to current practice parameters. Reinforcing this view is the paper by Madhumathi Rao and Brian J.G. Pereira. Moreover, highlighting major recently launched multi-center, randomized, prospective trials designed to determine whether correction of anemia will reduce morbidity and mortality of patients with chronic kidney disease (CKD), they provide what amounts to a detailed prelude to the conference as a whole. Noting the “growing awareness” that raising hemoglobin levels in anemic CKD patients decreases the incidence of cardiovascular events, Rao and Pereira list what they term “issues needing resolution.” Key among the unresolved “many questions regarding optimal anemia management” are the relative and absolute benefits of partial versus full correction of anemia. It must be established by empirical trial, the authors comment, precisely which target hemoglobin concentration (hematocrit) to select as a treatment objective. Using the glomerular filtration rate (GFR) estimation equation from the Modification of Diet in Renal Disease (MDRD) study, Rao and Pereira underscore a prevalence of CKD, defined as a GFR <60 mL/min/1.73 m2, as approximately 8.3 million individuals, or 4.7% of the United States population. Also included in the MDRD study was the alarming inference that 85% of patients with impaired kidney function (GFR below 55 mL/min/1.73 m2) will continue to lose remaining kidney function at a rate of 4 mL/minute per year. Based on this progressive quality of CKD, and the improving survival of ESRD, kidney failure now has enormous impact on health care systems and national economic stability. Not only does CKD induce a decreased quality of life, but by its progression to ESRD results in a nearly eight-fold reduction in life span. A simple measure of the financial burden imposed by ESRD patients (who comprise 1.1% of Medicare beneficiaries but consume 5% of expenditures) is their total cost in the United States of $17.9 billion in 1999, representing a 7.2% increase over the previous year. Rao and Pereira sound a clear alarm for medicine to “Do Something!,” echoing the United States Renal Data System (USRDS) projection that by the year 2010, the United States will have to provide care for 661,330 ESRD patients, at an estimated Medicare ESRD cost of over $28 billion. To known strategies that may lessen the progression of CKD including normalization of hypertensive blood pressures, establishing euglycemia in diabetic patients, and modulating dietary protein consumption, treatment with erythropoietin (EPO) may well become a central component of an increasingly complex regimen. As suggested by the authors, the benefits of improving anemia, although expensive and labor-intensive, may gain the dual rewards of enhanced life quality plus increased longevity. Overall, it is the testing of this hypothesis that stands at the center of any regimen for comprehensive management of CKD. Furthermore, Avram et al call attention to the trend associating hemoglobin and prealbumin in their hemodialysis and peritoneal dialysis patients, which should gain statistical significance as cohort size increases. Derived from the Avram et al report, it follows that minimizing anemia before the start of renal replacement therapy maximizes the chance for survival. In his report, Toto continues this line of thought—that “anemia is a modifiable risk factor” in chronic kidney disease (CKD)—by first summarizing evidence indicting anemia to be a “powerful risk factor for cardiovascular disease.” He notes that it is cardiovascular disease that leads the causes of death in CKD with a mortality rate 30 to 50 times greater in hemodialysis patients than in age-matched normal individuals. Toto further states that anemia is a risk factor common to both renal and cardiovascular disease, but that it has not been carefully studied. Future studies of anemia in CKD should include evaluation of the effect of correcting anemia on both cardiovascular and renal outcomes. Updating the United States Renal Data System's Annual Report, Collins et al reported that diabetes, now fully recognized as the leading cause of ESRD, “is increasing in the general Medicare population at a rate of 4.4% per year.” Echoing the alert sounded by Toto, Collins et al noted that hospitalization for heart failure is five times more frequent in predialysis patients than in non-CKD patients. The USRDS continues to serve as the most reliable and extensive resource for all involved in management of kidney failure. With an ever-expanding data set, it is certain that mining the USRDS will prove fruitful in ultimately defining correlations with specific hemoglobin (hematocrit) levels in each age, diagnosis, and racial subset that is tallied nationwide. Focusing specifically on the “potential adverse effects of chronic anemia on the myocardium,” Pereira and Sarnak conclude that anemia is an independent risk factor for left ventricular hypertrophy and predict cardiovascular disease adverse outcomes in patients with CKD and heart failure. These investigators caution that, “although studies may demonstrate an association between anemia and cardiovascular disease outcomes,” the two may not be direct cause and effect. After exploring confounding factors such as anemia resulting from hemodilution associated with heart failure, Pereira and Sarnak recount evidence that anemia and systolic blood pressure were the clearest links to left ventricular hypertrophy. Citing a retrospective analysis of 78,974 Medicare beneficiaries 65 years or older hospitalized with acute myocardial infarction, the authors note that mortality was higher with lower hematocrits. These authors also underscore the need for further clinical studies and trials of the value of correcting anemia in CKD patients. Suggesting the utility of defining a Cardio Renal Anemia (CRA) Syndrome, Silverberg et al include congestive heart failure (CHF), chronic renal insufficiency, and anemia as its components. The lynch pin of CRA is CHF, which is found in “up to 64% of patients with CKD referred to nephrologists.” Silverberg et al make the important point that unless the anemia, constant in CRA, is corrected, the CHF will often not improve. The authors propose routine echocardiograms and “possibly measuring B-type natriuriteic peptide,” as well as exercising a responsibility to “recognize, investigate, or treat the anemia” that is present in CKD. There is no question that aggressive cardiac monitoring pays off in terms of ESRD patient survival. Our colleagues performing kidney transplants were the first to point out more than a decade ago that unless coronary artery disease is detected and treated in intended diabetic kidney transplant recipients, the post-transplant mortality would be unacceptably high. Characterizing anemia “as a prognostic factor” in all stages of heart failure, Mancini and Kunavarapu complete the examination of the strong contributing role of the incidence and prevalence of anemia in the genesis of morbidity and mortality in CKD. Employing a long-acting erythropoietin, darbopoietin alfa in 300 anemic patients with heart failure, the authors are supervising a double-blind, randomized, placebo-controlled, multicenter trial that may well produce needed answers, as end points of exercise tolerance and survival are weighed in both groups. From a subjective perspective, I have no doubt that correction of anemia in patients with chronic renal disease on or off dialysis results in better rehabilitation and strongly enhances life quality. Mushnick et al examine the importance of bioimpedance parameters as indicators of nutritional status and survival in peritoneal dialysis patients. Introducing the new-to-nephrology technique of bioelectrical impedance analysis (BIA), in a subgroup of 48 peritoneal dialysis patients, the investigators suggest that this simple, inexpensive physical measurement might yield as much information as that gained from laborious and expensive blood chemistry testing. BIA parameters, phase angle, and reactance were strongly correlated with prealbumin and other serum nutritional markers. They also reported that phase angle was an independent predictor of more than two years' survival in peritoneal dialysis patients. Addressing retinopathy, which is the major debilitating comorbidity accompanying diabetic nephropathy, Friedman and L'Esperance, Jr. presented a small yet intriguing series of azotemic diabetic patients whose macular edema remarkably improved upon raising their red cell mass by treatment with erythropoietin. Proposing that their experience in three patients might extrapolate to all diabetic patients with eye disease, the authors provide further reason to be intolerant of anemia in CKD. As is true for the need for frequent periodic collaboration between cardiologist and nephrologists, ophthalmologic guidance should be a routine practice in the management of every diabetic ESRD patient. Early laser photocoagulation coupled with blood pressure normalization and careful metabolic control will nearly always preempt blindness in diabetic ESRD patients. Erythrocyte synthesis is contingent on marrow stimulation by erythropoietin plus adequate stores of iron. Exploring this relationship, Nissenson and Charytan note that the first results of supplementation with oral iron were “disappointing” in hemodialysis patients. They then present recent results of the effect of administering “a new generation of oral iron product” termed heme-iron polypeptide (HIP). HIP, produced by hydrolysis of bovine hemoglobin, employs the heme porphyrin ring to deliver iron to key intestinal absorption sites with a bioavailability “up to 10 times higher than non-heme iron.” In a six-month trial of HIP (without parenteral iron), stable hemoglobin values were maintained. Until further larger trials of HIP are completed, treatment in hemodialysis facilities will be based on parenteral iron preparations. They believe that the currently available iron formulations, “both iron sucrose and iron gluconate, are safer than iron dextran,” which should be used only in “extraordinary circumstances.” Relying on “an accelerated regimen of high dose intravenous iron sucrose therapy,” Blaustein et al conducted a prospective study of CKD patients whose serum ferritin values were <500 ng/mL, while transferring saturation was <40%. They administered 500 mg of intravenous iron sucrose over three hours on two consecutive days to a study population consisting of 52 inpatients and 56 outpatients with CKD. Although iron sucrose for parenteral use has been available for more than 50 years, the present study affirmed both the drug's efficacy and low toxicity. Blaustein et al believe that the rapid dosing method utilized may hold an economic advantage, especially in terms of reduced expenditure for personnel. While no universal answer as to what to do in management of iron deficiency in CKD patients is on hand, this rapid, inexpensive manner of coping with a difficult problem holds substantial promise. Greenwood and Levin et al wrote about erythropoietin dose variation in different facilities in different countries and its relationship to drug resistance. Some United States facilities use nearly twice the EPO dose as is used in the United Kingdom. Factors related to inflammation, low albumin, the use of tunneled catheters, and low protein catabolic rate (nPCR) correlated with low hemoglobin and relative EPO resistance. Addressing the issue first raised in the literature by Avram's laboratory, Fein et al explore the role of prealbumin and inflammation as correlates of mortality in 63 peritoneal dialysis patients in whom C-reactive protein (CRP) and other nutritional markers were serially measured. Fein et al found that CRP was inversely correlated with BIA, prealbumin, and other nutritional markers at enrollment for ESRD therapy. Responding to the question of why serum albumin concentration may prove resistant to therapy in dialysis patients, Kaysen begins by noting that reduced protein and calorie intake does not cause hypoalbuminemia in otherwise healthy individuals. The genesis of reduced serum albumin levels in dialysis patients is the product of inflammation plus reduced protein intake, which blunts the defense of decreased albumin fractional catabolic rate and resting energy expenditure that are normal compensatory mechanisms. Inflammation in dialysis patients is caused by infections at the vascular access site and other more occult infections. Hypoalbuminemia is also strongly associated with chronic comorbid conditions such as chronic obstructive pulmonary disease, which may not be readily reversible even if clearly identified. Seeking an answer to why ESRD has a higher incidence in blacks than in whites, August and Suthanthiran explore the possible role of transforming growth factor-β (TFG-β) as a contributory factor to the renal fibrosis of progressive renal insufficiency. Testing the hypothesis that TFG-β may be more frequently expressed in blacks than in whites, blood levels were compared in cohorts of ESRD patients, those with hypertension, and normal patients. In all three subsets, TFG-β levels were higher in blacks. Preliminary genetic analysis supports the inference that TFG-β DNA polymorphisms may distinguish hypertensive from normal patients. Increasingly, nephrologists wishing answers to seminal dilemmas must turn to their colleagues conducting studies at the molecular biology level. It is probable that derivative studies may find that TFG-β and its molecular cousins may well lie at the root of why kidney disorders progress. Returning to the central importance of cytokines in the pathogenesis of CKD, Klahr and Morrissey present their findings in blocking fibrosis in a rat model in which ureteral ligation stimulates tubulointerstitial nephritis by stimulating both TFG-β and tumor necrosis factor-α (TNF-α). By utilizing both knockout mice and an orally active angiotensin-converting enzyme inhibitor, the investigators conclude that TNF-α is a factor in the genesis of myeloblast proliferation and nuclear factor kappa B (NK-κB) activation in the kidney during ureteral obstruction. In a complex series of studies, Klahr and Morrissey further demonstrate that a renal tubular developmental morphogenetic protein-7 (BMP-7) prevents tubulointerstitial nephritis after experimental ureteral obstruction. The underlying thrust of these fascinating experiments is that we will have to rely on molecular biology both to understand and treat at least some varieties of progressive CKD. During the early days of maintenance hemodialysis, various comorbid extrarenal complications were viewed as imposing absolute limits to the duration of life prolongation. First, it was coronary artery disease, which is now treated with diet modification and pharmacologic regulation of lipids and hypertension. Next, the grim entity of “renal osteodystrophy” gained center stage and gradually became clarified as an admixture of extrarenal calcification due to high Ca × P product plus bone demineralization, resulting from hyperparathyroidism and deficient vitamin D synthesis. With the advent of synthetic vitamin D formulations and a menu of phosphate binders, nephrologists face confusing choices in designing a therapy for each patient. Llach and Fernández provide a broad perspective on how bone lesions in renal patients have evolved while sketching their prediction of coming changes in therapy. Emphasizing “an increase in the calcium burden and hyperphosphatemia” as “major factors leading to the high mortality of ESRD patients,” these investigators analyze available drug choices. These investigators suggest that the use of calcimimetic agents, a novel method for stimulating the calcium-sensing receptor in the parathyroid gland, will lower parathormone secretion while controlling secondary hyperparathyroidism. A clinical trial of “Cinacalcet,” now in progress, has “resulted in a significant decrease of Ca × P product.” Long-term trials are needed to assess the effect of Cinacalcet on survival and life quality of ESRD patients. Central to all present strategies for preventing bone disease in both CKD and ESRD patients is precise, reliable measurement of parathyroid hormone (PTH). Goodman provides clarification in the selection of either a “first-generation” or “second-generation” immunometric assay of PTH. Assay reliability “depends largely on the extent to which results have been validated by bone histomorphometry.” Whether measuring “full-length biologically active PTH (1-84) exclusively” (second-generation), or detecting both “PTH (1-84) and other relatively large amino-terminally-truncated PTH-derived fragments (first generation), the relationship between bone histology and plasma PTH levels was equivalent. Goodman advises that the PTH target of 150 to 250 pg/mL for first-generation PTH assays should correspond to approximately 75 to 125 pg/mL in second-generation assays. Coburn writes a comprehensive paper that shows growing evidence for contributions of elevated levels of serum calcium and serum phosphorus as factors contributing to vascular and cardiac calcifications in ESRD patients. He raises questions about whether the current practice of vitamin D usage in ESRD patients might be a contributing factor to such vascular abnormalities. It is recommended that potential adverse vascular effects of vitamin D sterols related to the increments of serum calcium and phosphorus be carefully monitored and evaluated by practitioners. Affirming the report by Llach and Fernández, Block gives further details of the completed phase 2 clinical trial of Cinacalcet, a second-generation calcimimetic agent that exerts positive allosteric modulation of the calcium receptor, thereby increasing its sensitivity to extracellular calcium. Summarizing the case for preventing vascular calcification rather than treating after-the-fact, Block notes that in a 23-week double-blind, placebo-controlled, randomized trial, Cinacalcet induced a ≥30% reduction in mean PTH levels in 74% of subjects versus 11% of placebo-treated subjects (P < 0.001). The phase 3 trial is eagerly awaited. Overall, the pages that follow illustrate the breadth and accomplishment of investigators whose common bond is the extension of life, while maximizing quality, after onset of any of the still tragic disorders that comprise the hapless term of ESRD. Finally, this work was helped by an unrestricted educational grant from Amgen to Long Island College Hospital. My thanks to Dr. Robert Brenner for helping me make this very large body of new information available to nephrologists, cardiologists, and practitioners throughout the world.