Allen R. Nissenson

THE EFFECTS OF NORMAL AS COMPARED WITH LOW HEMATOCRIT VALUES IN PATIENTS WITH CARDIAC DISEASE WHO ARE RECEIVING HEMODIALYSIS AND EPOETIN

BACKGROUND In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis. METHODS We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction. RESULTS After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group. CONCLUSIONS In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States

BACKGROUND Hypertension is common in chronic hemodialysis patients, yet there are limited data on the epidemiology of hypertension in these patients in the United States. METHODS We assessed the prevalence, treatment, and control of hypertension in a cohort of 2535 clinically stable, adult hemodialysis patients who participated in a multicenter study of the safety and tolerability of an intravenous iron preparation. Hypertension was defined as an average predialysis systolic blood pressure >150 mm Hg or diastolic blood pressure >85 mm Hg, or the use of antihypertensive medications. RESULTS Hypertension was documented in 86% (n = 2173) of patients. The prevalence of hypertension, in contrast to that observed in the general population, did not increase linearly with age and was not affected by sex or ethnicity. Hypertension was controlled adequately in only 30% (n = 659) of the hypertensive patients. In the remaining patients, hypertension was either untreated (12% [252/2173]) or treated inadequately (58% [1262/2173]). CONCLUSION Control of hypertension, particularly systolic hypertension, in chronic hemodialysis patients in the United States is inadequate, despite recognition of its prevalence and the frequent use of antihypertensive drugs. Optimizing the use of medications and closer attention to nonpharmacologic interventions, such as adjustment of dry weight, a low-sodium diet, and exercise, may improve control.

Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients.

BACKGROUND Elements of malnutrition-inflammation complex syndrome (MICS) may blunt the responsiveness of anemia of end-stage renal disease (ESRD) to recombinant human erythropoietin (EPO). METHODS The authors examined cross-sectional associations between the required dose of EPO within a 13-week interval as prescribed by practicing nephrologists who were blind to the study and several laboratory values known to be related to nutrition and/or inflammation, as well as the malnutrition-inflammation score (MIS), which is a fully quantitative assessment tool based on the subjective global assessment of nutrition. RESULTS A total of 339 maintenance hemodialysis (MHD) outpatients, including 181 men, who were aged 54.7 +/- 14.5 years (mean +/- SD), who had undergone dialysis for 36.3 +/- 33.2 months, were selected randomly from 7 DaVita dialysis units in Los Angeles South/East Bay area. The average weekly dose of administered recombinant human EPO within a 13-week interval was 217 +/- 187 U/kg. Patients were receiving intravenous iron supplementation (iron gluconate or dextran) averaging 39.5 +/- 47.5 mg/wk. The MIS and serum concentrations of high-sensitivity C-reactive protein, interleukin 6 (IL-6), tumor necrosis factor-alpha, and lactate dehydrogenase had positive correlation with required EPO dose and EPO responsiveness index (EPO divided by hemoglobin), whereas serum total iron binding capacity (TIBC), prealbumin and total cholesterol, as well as blood lymphocyte count had statistically significant but negative correlations with indices of refractory anemia. Most correlations remained significant even after multivariate adjustment for case-mix and anemia factors and other relevant covariates. Similar associations were noticed across EPO per body weight tertiles via analysis of variance and after estimating odds ratio for higher versus lower tertile via logistic regression after same case-mix adjustment. CONCLUSION The existence of elements of MICS as indicated by a high MIS and increased levels of proinflammatory cytokines such as IL-6 as well as decreased nutritional values such as low serum concentrations of total cholesterol, prealbumin, and TIBC correlates with EPO hyporesponsiveness in MHD patients.

Understanding Sources of Dietary Phosphorus in the Treatment of Patients with Chronic Kidney Disease

In individuals with chronic kidney disease, high dietary phosphorus (P) burden may worsen hyperparathyroidism and renal osteodystrophy, promote vascular calcification and cardiovascular events, and increase mortality. In addition to the absolute amount of dietary P, its type (organic versus inorganic), source (animal versus plant derived), and ratio to dietary protein may be important. Organic P in such plant foods as seeds and legumes is less bioavailable because of limited gastrointestinal absorption of phytate-based P. Inorganic P is more readily absorbed by intestine, and its presence in processed, preserved, or enhanced foods or soft drinks that contain additives may be underreported and not distinguished from the less readily absorbed organic P in nutrient databases. Hence, P burden from food additives is disproportionately high relative to its dietary content as compared with natural sources that are derived from organic (animal and vegetable) food proteins. Observational and metabolic studies indicate nutritional and longevity benefits of higher protein intake in dialysis patients. This presents challenges to providing appropriate nutrition because protein and P intakes are closely correlated. During dietary counseling of patients with chronic kidney disease, the absolute dietary P content as well as the P-to-protein ratio in foods should be addressed. Foods with the least amount of inorganic P, low P-to-protein ratios, and adequate protein content that are consistent with acceptable palatability and enjoyment to the individual patient should be recommended along with appropriate prescription of P binders. Provision of in-center and monitored meals during hemodialysis treatment sessions in the dialysis clinic may facilitate the achievement of these goals.

Normalizing hematocrit in dialysis patients improves brain function

Recombinant human erythropoietin (rHuEPO) treatment has been shown to improve brain and cognitive function in anemic dialysis patients. Significant debate continues, however, regarding the appropriate target hematocrit (Hct) that will lead to the greatest benefits while considering possible side effects and costs of rHuEPO. Current practice results in an Hct averaging only 31% to 32% in dialysis patients, a level less than that achieved in the initial clinical trials and well less than normal. This study was designed to evaluate dialysis patients at the current practice Hct levels versus normal Hct levels (40% to 45%) to see if improvement in brain function resulted. Twenty patients with end-stage renal disease (ESRD) currently being treated with rHuEPO (mean Hct, 31.6%) were administered additional rHuEPO to reach normal Hct levels (mean, 42. 8%). Electroencephalogram (EEG) frequency analysis showed a significant decrease in EEG slowing at greater Hct values, and the auditory oddball and Continuous Performance Task tasks yielded significant electrode and time-by-electrode effects for P300 amplitude. Changes in P300 latency significantly correlated with increased Hct in the auditory oddball task. These findings suggest that further correction of anemia to normal Hct levels may result in continued improvement in neurocognitive function by improving the ability to sustain attention in easier tasks and by enhancing the ability to recognize, discriminate, and hold stimuli in memory for more difficult tasks.

The Obesity Paradox and Mortality Associated With Surrogates of Body Size and Muscle Mass in Patients Receiving Hemodialysis

OBJECTIVE To determine whether dry weight gain accompanied by an increase in muscle mass is associated with a survival benefit in patients receiving maintenance hemodialysis (HD). PATIENTS AND METHODS In a nationally representative 5-year cohort of 121,762 patients receiving HD 3 times weekly from July 1, 2001, through June 30, 2006, we examined whether body mass index (BMI) (calculated using 3-month averaged post-HD dry weight) and 3-month averaged serum creatinine levels (a likely surrogate of muscle mass) and their changes over time were predictive of mortality risk. RESULTS In the cohort, higher BMI (up to 45) and higher serum creatinine concentration were incrementally and independently associated with greater survival, even after extensive multivariate adjustment for available surrogates of nutritional status and inflammation. Dry weight loss or gain over time exhibited a graded association with higher rates of mortality or survival, respectively, as did changes in serum creatinine level over time. Among the 50,831 patients who survived the first 6 months and who had available data for changes in weight and creatinine level, those who lost weight but had an increased serum creatinine level had a greater survival rate than those who gained weight but had a decreased creatinine level. These associations appeared consistent across different demographic groups of patients receiving HD. CONCLUSION In patients receiving long-term HD, larger body size with more muscle mass appears associated with a higher survival rate. A discordant muscle gain with weight loss over time may confer more survival benefit than weight gain while losing muscle. Controlled trials of muscle-gaining interventions in patients receiving HD are warranted.

Hepcidin - A potential novel biomarker for iron status in chronic kidney disease

BACKGROUND AND OBJECTIVES Hepcidin is a key regulator of iron homeostasis, but its study in the setting of chronic kidney disease (CKD) has been hampered by the lack of validated serum assays. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study reports the first measurements of bioactive serum hepcidin using a novel competitive ELISA in 48 pediatric (PCKD2-4) and 32 adult (ACKD2-4) patients with stages 2 to 4 CKD along with 26 pediatric patients with stage 5 CKD (PCKD5D) on peritoneal dialysis. RESULTS When compared with their respective controls (pediatric median = 25.3 ng/ml, adult = 72.9 ng/ml), hepcidin was significantly increased in PCKD2-4 (127.3 ng/ml), ACKD2-4 (269.9 ng/ml), and PCKD5D (652.4 ng/ml). Multivariate regression analysis was used to assess the relationship between hepcidin and indicators of anemia, iron status, inflammation, and renal function. In PCKD2-4 (R(2) = 0.57), only ferritin correlated with hepcidin. In ACKD2-4 (R(2) = 0.78), ferritin and soluble transferrin receptor were associated with hepcidin, whereas GFR was inversely correlated. In PCKD5D (R(2) = 0.52), percent iron saturation and ferritin were predictors of hepcidin. In a multivariate analysis that incorporated all three groups (R(2) = 0.6), hepcidin was predicted by ferritin, C-reactive protein, and whether the patient had stage 5D versus stages 2 to 4 CKD. CONCLUSIONS These findings suggest that increased hepcidin across the spectrum of CKD may contribute to abnormal iron regulation and erythropoiesis and may be a novel biomarker of iron status and erythropoietin resistance.

Mid-Arm Muscle Circumference and Quality of Life and Survival in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES Maintenance hemodialysis (MHD) patients with larger body or fat mass have greater survival than normal to low mass. We hypothesized that mid-arm muscle circumference (MAMC), a conveniently measured surrogate of lean body mass (LBM), has stronger association with clinical outcomes than triceps skinfold (TSF), a surrogate of fat mass. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS The associations of TSF, MAMC, and serum creatinine, another LBM surrogate, with baseline short form 36 quality-of-life scores and 5-year survival were examined in 792 MHD patients. In a randomly selected subsample of 118 subjects, LBM was measured by dual-energy x-ray absorptiometry. RESULTS Dual-energy x-ray absorptiometry-assessed LBM correlated most strongly with MAMC and serum creatinine. Higher MAMC was associated with better short form 36 mental health scale and lower death hazard ratios (HRs) after adjustment for case-mix, malnutrition-inflammation-cachexia syndrome, and inflammatory markers. Adjusted death HRs were 1.00, 0.86, 0.69, and 0.63 for the first to fourth MAMC quartiles, respectively. Higher serum creatinine and TSF were also associated with lower death HRs, but these associations were mitigated after multivariate adjustments. Using median values of TSF and MAMC to dichotomize, combined high MAMC with either high or low TSF (compared with low MAMC/TSF) exhibited the greatest survival, i.e., death HRs of 0.52 and 0.59, respectively. CONCLUSIONS Higher MAMC is a surrogate of larger LBM and an independent predictor of better mental health and greater survival in MHD patients. Sarcopenia-correcting interventions to improve clinical outcomes in this patient population warrant controlled trials.

Systemic Lupus Erythematosus in Pregnancy

A retrospective analysis of the course of systemic lupus erythematosus in pregnant patients hospitalized at UCLA during a 15-year period provided important prognostic information. Women with systemic lupus erythematosus became pregnant if renal function was reasonably well preserved. Pregnancy infrequently posed a serious threat to the mother; the frequency of nonrenal complications in patients with systemic lupus erythematosus was very low, and the frequency of permanent deterioration of renal function was less than 10%. In contrast, the fetus was at high risk and was adversely affected even if mild renal involvement was detected in the mother. The prevalence of neonatal complications did not increase in the newborn; however, growth retardation did occur in the immediate neonatal period. The pharmacologic management of systemic lupus erythematosus does not require any important modifications in pregnant patients. During labor and in the postpartum period, however, an increase in the dosage of glucocorticoids may reduce postpartum exacerbations.

Race, Gender, and Socioeconomic Disparities in CKD in the United States

Chronic kidney disease (CKD) is a national public health problem beset by inequities in incidence, prevalence, and complications across gender, race/ethnicity, and socioeconomic status. As health care providers, we can directly address some factors crucial for closing the disparities gap. Other factors are seemingly beyond our reach, entrenched within the fabric of our society, such as social injustice and human indifference. Paradoxically, the existence of health inequities provides unique, unrecognized opportunities for understanding biologic, environmental, sociocultural, and health care system factors that can lead to improved clinical outcomes. Several recent reports documented that structured medical care systems can reduce many CKD-related disparities and improve patient outcomes. Can the moral imperative to eliminate CKD inequities inspire the nephrology community not only to advocate for but also to demand high-quality, structured health care delivery systems for all Americans in the context of social reform that improves the ecology, health, and well-being of our communities? If so, then perhaps we can eliminate the unacceptable premature morbidity and mortality associated with CKD and the tragedy of health inequities. By so doing, we could become global leaders not only in medical technology, as we currently are, but also in health promotion and disease prevention, truly leaving no patient behind.