Neal Mittman

Markers for survival in dialysis: A seven-year prospective study

Serum biochemical markers suggestive of undernutrition are directly correlated with mortality in hemodialysis and peritoneal dialysis patients. In particular, serum albumin is the most powerful predictor of survival. We have prospectively examined the relationship of single baseline measurements of serum albumin, cholesterol, creatinine, apoproteins, and prealbumin in 250 hemodialysis patients and 140 patients maintained on continuous ambulatory peritoneal dialysis (CAPD) monitored up to 7 years (1987 to 1994). Other variables studied included age, race, gender, diabetes, and number of months on dialysis. Observed survival was computed by the Kaplan-Meier method. Coxs proportional hazards model was used to determine independent predictors of mortality risk. Age, diabetes, prior months on dialysis, and low levels of serum albumin, creatinine, and cholesterol were important and independent predictors of mortality risk in hemodialysis patients. For peritoneal dialysis patients, the independent predictors of mortality risk were age, diabetes, and low serum albumin and serum creatinine. Prealbumin, a serum protein with rapid turnover and relatively small pool, was an important and independent risk predictor in both hemodialysis and CAPD patients. In addition, prealbumin was more highly correlated with other nutritional markers than was albumin. In summary, these findings suggest that biochemical measures associated with visceral and somatic protein depletion are predominant long-term mortality risk factors in patients maintained on hemodialysis and CAPD.

Prealbumin is the best nutritional predictor of survival in hemodialysis and peritoneal dialysis

Patients undergoing dialytic therapy for end-stage renal disease (ESRD) have greater morbidity and mortality than age-matched individuals with similar demographics in the general population. Risk factors for early death during treatment for ESRD include advanced age, diabetes, hypertension, and malnutrition. We questioned whether the level of serum prealbumin at the start of uremia therapy might serve as a marker of subsequent survival in patients treated with maintenance hemodialysis (HD) and peritoneal dialysis (PD). Study cohorts included 111 HD and 78 PD patients followed for up to 5 years. Selected demographic characteristics and biochemical variables were tested for correlation with survival in each cohort. Variables evaluated included age, race, gender, diabetic status, and serum concentrations of albumin, creatinine, cholesterol, and prealbumin. For comparison, expected survival was calculated with Cox proportional hazards analysis, which accounts for confounding variables. We found that a higher relative risk (RR) of death in HD patients correlated with older age, the diagnosis of diabetes, and a serum prealbumin < 30 mg/dL. In PD patients, older age and the presence of diabetes correlated with a higher RR of death than in the standard population. When nutritional variables were analyzed separately, prealbumin < 30 mg/dL was the strongest variable that predicted mortality in HD patients (RR = 2.64, P = 0.002) and also predicted increased risk of mortality in PD patients (RR = 1.8, P = 0.035). Observed and expected survival was significantly higher in patients with enrollment prealbumin greater than 30 mg/dL in both HD and PD. The serum prealbumin level correlated significantly with other measures of nutrition, including serum albumin, serum creatinine, and serum cholesterol, in both HD and PD patients. Among tested markers of nutritional status, prealbumin level appears to be the single best nutritional predictor of survival in ESRD patients.

Prealbumin and Lipoprotein(a) in Hemodialysis: Relationships With Patient and Vascular Access Survival

The high morbidity and mortality of hemodialysis patients has led to a search for early markers of risk. Because cardiovascular and nutritional risk are prevalent in this population, we examined the prognostic value of the serum levels of two markers of risk in the general population: (1) lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle linked to myocardial infarction and coronary bypass stenosis, and (2) prealbumin, a marker of visceral protein status, with a shorter half-life than that of serum albumin. Baseline demographics, clinical information, dialysis prescription, and serum biochemistry measurements of 125 hemodialysis patients followed for up to 14 months were recorded on enrollment. Vascular access events and deaths were recorded prospectively. The hypotheses tested were that increased serum Lp(a) levels would predict cardiovascular mortality and vascular access stenosis and thrombosis, and that reduced serum prealbumin levels would predict mortality risk independently of established risk predictors. Cross-sectional analysis of serum Lp(a) demonstrated a skewed distribution with a median value of 38.3 mg/dL (upper tertile, > or = 57 mg/dL). Lipoprotein(a) was significantly higher in black patients (P < 0.001) and was significantly correlated (P < 0.005) with total cholesterol and apoprotein B (apoB), but not with a history of prior coronary disease. Serum prealbumin was strongly correlated with serum albumin (r = 0.49, P < 0.001). However, prealbumin correlated (P < 0.001) more strongly with other serum nutrition markers (total cholesterol, apoB, creatinine, urea) than did serum albumin. Fourteen-month cumulative survival was 80%. Age, diabetes, and serum levels of albumin, prealbumin, creatinine, total cholesterol and apoB, but not Lp(a), were correlated with survival in univariate analysis. Using the Cox proportional hazards model, independent predictors of mortality risk were prealbumin less than 15 mg/dL versus higher values (relative risk [RR] = 4.48, P < 0.01), apoB (RR = 0.97 per 1 mg/dL increase, P < 0.02), creatinine less than 10 mg/dL versus higher values (RR = 3.51, P = 0.04), and age (RR = 1.04 per year, P = 0.10). Thirty-eight patients experienced at least one vascular access thrombosis (n = 33) or stenosis (n = 5) during the study. Patients with Lp(a) > or = 57 mg/dL had decreased vascular access event-free survival compared with patients with Lp(a) less than 57 mg/dL (56% v 73%, P < 0.06). This trend was increased in magnitude and statistically significant for white and Hispanic patients (31% v 79%, P < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

The Uremic Dyslipidemia: A Cross-Sectional and Longitudinal Study

Patients on maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) exhibit numerous disturbances of serum lipids and apoproteins that may contribute to their high cardiovascular mortality. Cross-sectional studies have found that lipid levels are inversely related to time on dialysis. However, it is not known whether this association is the result of the attrition of hyperlipidemic patients or a decrease in lipid levels over time in all patients. Additionally, few studies have investigated the effect of dialysis modality on the lipoprotein disturbances of uremia adjusting for the confounding influences of demographics, or nutritional and endocrine status. To address these issues, we undertook a cross-sectional and longitudinal study of lipids, apoproteins, and atherogenic risk ratios in patients maintained on HD and CAPD. Patients were enrolled in annual cohorts from 1987 to 1990 and monitored until 1991. A total of 196 HD and 77 CAPD patients were studied. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apoprotein (apo) A-I, and apo B were measured on enrollment and remeasured annually in survivors through 1990. Using multivariate methods, we examined the relationship of the lipids, apoproteins, their respective ratios, and their changes over time, to a broad range of clinical factors and to mortality. Compared with HD patients, CAPD patients had significantly higher TC, apo A-I, and apo B, and a significantly lower apo A-I/apo B ratio. Serum albumin correlated directly with TC and apo B and inversely with apo A-I/apo B. For patients with normal serum albumin (> or = 3.5 g/dL [35 g/L]), CAPD patients had a significantly higher TC/HDL-C than HD patients; otherwise the ratios were similar for CAPD and HD. Independent influences on lipoprotein levels in HD and CAPD patients were also demonstrated for race, gender, and diabetes, but not for parathyroid hormone (PTH) levels. For both dialysis modalities, patients who died had significantly lower TC and apo B, and significantly higher apo A-I/apo B throughout their entire courses compared with survivors. In the subset of patients followed longitudinally for 2 or more years, apo B tended to decrease with time, but TC, HDL-C, and apo A-I were stable. The longitudinal changes in lipoproteins did not correlate with outcome or other factors. In conclusion, CAPD patients have more atherogenic lipoprotein profiles than HD patients. Improved visceral protein nutritional status, as defined by serum albumin level, is associated with hyperlipidemia and, especially vor CAPD, worsened atherogenic risk ratios.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients

Diabetes is the most common cause of end-stage renal disease and an important risk factor for morbidity and mortality in dialysis patients. Glycemic control, utilizing serial measurement of glycosylated hemoglobin (HbA1c), is generally recommended to limit end-organ damage, including cardiovascular morbidity and mortality. We, along with others, have previously suggested that HbA1c may not be a reliable measure of glycemic control in dialysis patients, and have therefore explored the use of serum fructosamine (SF) as an alternative marker. The objective of this study was to compare HbA1c levels with SF in monitoring glycemic control and associated morbidity (infection and hospitalization) in diabetic patients in a large urban hemodialysis (HD) center. We enrolled 100 diabetic HD patients and followed them up prospectively for 3 years. Data on demographics, as well as biochemical and clinical data, including hospitalizations and infections, were recorded. The mean age was 63 years. In all 54% were women and the majority were African Americans (72%). As expected, HbA1c and albumin-corrected fructosamine (AlbF) levels were highly correlated and both were significantly associated with serum glucose. AlbF, however, was more highly correlated with mean glucose values when less than 150 mg/dl and was a more useful predictor of morbidity. By univariate logistic regression and by Poisson regression analysis, AlbF, but not HbA1c, was a significant predictor of hospitalization. Additionally, in patients dialyzed by arteriovenous (AV) access (that is, excluding those dialyzed via vascular catheters), AlbF, but not HbA1c, was a significant predictor of infection. In conclusion, AlbF is as reliable a marker as HbA1c for glycemic control in diabetic patients on HD, and may be advantageous for patients with serum glucose in a desirable therapeutic range (<150 mg/dl). In addition, AlbF, but not HbA1c, is associated with morbidity (hospitalizations and infections) in diabetic patients on HD.

Correlates of Vascular Access Occlusion in Hemodialysis

Vascular access occlusion results in significant morbidity in hemodialysis patients. Age, diabetes, and synthetic grafts (polytetrafluoroethylene [PTFE]) have been associated with vascular access occlusion in univariate analysis. However, the independent risk associated with each of these factors has not been assessed adjusting for confounding among the factors or by other variables, such as blood pressure (BP) or hematocrit. The influence of serum lipoprotein(a) [Lp(a)] and fibronectin on vascular access occlusion has not been widely studied despite their theoretical or demonstrated importance in vascular bypass occlusion. In a cohort study of 124 hemodialysis patients monitored for up to 14 months, we reported that Lp(a) values in the upper tertile (> or = 57 mg/dL) were associated with vascular access occlusion risk in white and Hispanic patients, but not in black patients. We now report an expanded analysis of this data set to determine the independent correlates of vascular access occlusion. Variables tested included age, race, gender, diabetes, access type (PTFE v endogenous), treatment time, systolic BP, hematocrit, heparin and erythropoietin dosage, and serum levels of Lp(a) and fibronectin. In univariate analysis, access occlusion was associated with age, diabetes, PTFE, Lp(a) > or = 57 mg/dL, serum fibronectin, and reduced BP. The independent correlates of first access occlusion were determined with the Cox proportional hazards model. Since the overall model included a significant race x Lp(a) interaction term, we stratified by race. In black patients, risk correlated directly with PTFE (P < 0.01) and inversely with systolic BP (P < 0.001), whereas for white and Hispanic patients, age (P = 0.04) and Lp(a) > or = 57 mg/dL (P = 0.05) were associated with increased risk. In summary, vascular access occlusion was found to be associated with a number of factors. Important independent correlates were PTFE and lower BP in black patients, and age and serum Lp(a) > or = 57 mg/dL in white and Hispanic patients. Diabetes mellitus and increased serum fibronectin may contribute additional risk.

The Changing Spectrum of Heroin-Associated Nephropathy

Thirty-five renal biopsies were performed on heroin abusers at our institution between January 1977 and June 1983 as part of the evaluation of unexplained heavy proteinuria. Twenty-eight patients (80%) had histopathologic diagnoses of either focal segmental glomerulosclerosis or renal amyloidosis. Patients having a diagnosis of renal amyloidosis were older (P = 0.025), had a longer history of heroin abuse (P = 0.05), and 13/14 demonstrated clear evidence of chronic subcutaneous suppurative lesions. The remaining seven patients demonstrated a spectrum of disease similar to that seen in the nonaddicted population. We compared the clinical and biopsy characteristics of patients evaluated between 1977 and 1980 with those seen between 1981 and 1983. The relative incidences of renal amyloidosis and focal glomerulosclerosis changed significantly (P = 0.025). Whereas 29% of patients in the early series had renal amyloidosis and 57% had focal glomerulosclerosis, the relative incidences in the later series were 48% and 29%, respectively. The development of renal amyloidosis in our patients appears to be related to a longer duration of heroin abuse with increased incidence of subcutaneous injection of the narcotic. Chronic, suppurative skin ulcerations tend to occur at the site of injection, resulting in a persistent acute-phase inflammatory state important for the initiation and potentiation of secondary amyloidosis.

Treatment of secondary hyperparathyroidism in ESRD: a 2-year, single-center crossover study.

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. The management of SHPT commonly involves vitamin D, either calcitriol or newer analogs (paricalcitol or doxercalciferol), along with dietary phosphorus restriction and phosphate binding agents. Published reports have suggested that treatment with paricalcitol in hemodialyzed (HD) patients offers a morbidity or mortality advantage in comparison with treatment with calcitriol. We have recently reported that switching from calcitriol to paricalcitol resulted in a lower serum calcium and calcium-phosphorus product (Ca x P product), as well as lower parathyroid hormone (PTH) and alkaline phosphatase during 6 months of serial treatment. We converted all HD patients in our large urban dialysis center from calcitriol to paricalcitol using a 1:3 conversion ratio, on the basis of published data. Comparisons of individual patient mean biochemical values, as well as episodes of hypercalcemia and elevated Ca x P product, were made after adjusting for equivalent doses. In addition, we recorded the number of missed doses during two years of therapy. No patient in this study had received a calcimimetic before or during the study period. Fifty-nine patients were treated with calcitriol for at least 12 months and then completed 12 months of paricalcitol. Conversion from calcitriol to paricalcitol resulted in lower serum calcium (P=0.0003), lower serum phosphorus (P=0.027), lower Ca x P product (P=0.003), reduced PTH (P=0.001) and reduced serum alkaline phosphatase (P=0.0005). Most dramatically, there was a highly significant difference in the number of missed doses (P<0.0001) during the treatments. This 2-year single-center study, comparing long-term calcitriol with paricalcitol treatment in the same HD patients, extends our previous findings, offers new information regarding single episodes of potentially adverse biochemical effects related to vitamin D therapy, and provides several clues that may explain the outcome advantages suggested by previously published retrospective analyses of large dialysis provider-pooled databases.

Glucose intolerance is a predictor of morbidity and long-term mortality in non-diabetic (NDM) hemodialysis (HD) patients (pts)

T induced dyslipidemia and oxidative stress is prevalent world over and is being managed through pharmacological treatment. There are some dietary components such as Zn, Cu, Mg Mn, vitaminE, C, omega-3 fatty acids which have shown to reduce the severity of oxidative stress associated with type-2 diabetes mellitus. In view of this information, the efficacy of modified poultry egg (Patent Application No 2264 Del-2005) enriched with optimum minerals, vitamin E and omega-3 fatty acids was studied on dyslipidemia and oxidative stress of type-2 diabetes mellitus induced rats. In this study, the type-2 diabetes mellitus in the rats was induced by increasing Zn concentration in semi-synthetic diet rich in fat and refined sugar according to Taneja et al., 2006. Accordingly, control diet-I (diet-I-C) consisted of basal diet containing 20mg Zn/kg diet was fed on control group-I and diabetes inducing diet (diet-II-ZS-DB) containing 80 mg/kg semisynthetic diet on group-II for a period of 180 days. The arterial blood pressure and heart rate was significantly higher in group-II than their control counterpart. The blood profile after 180 days of dietary treatment displayed a significant rise in glucose, total lipids, cholesterol, triglycerides, LDL-cholesterol, VLDLcholesterol whereas HDLcholesterol showed a reduction in their level. The estimation of minerals in this group of rats revealed a higher Zn and lower Cu, Mg and Mn levels in liver and kidney. Their lipid peroxidation products were higher and the enzyme activities of superoxide dismutase, catalase, glutathione-s-transferase, glutathione reductase, glutathione (reduced) and glucose -6phosphate dehydrogenase were significantly lower as compared to control group-I. In order to see the efficacy of the modified eggs, some type-2 diabetes mellitus induced rats from the Group-II were separated on day 90 and label as GroupIII and fed on modified eggs mixed diet (4 liquid eggs/kg diet mixed with diabetes inducing diet) for another 90 days completing 180 days from the start of the experiment. A significant reduction in the blood pressure and heart rates, serum glucose, serum lipid profile, the lipid peroxidation products and a significant increase in the activities of enzymes per se with reversal of Zn, Cu, Mg and Mn levels closer to the control group were recorded in the Group-III rats. The data suggest that the modified egg can ameliorate the dyslipidemia and oxidative stress in type-2 diabetes mellitus induced rats by improving the mineral status in their body.

209 Serum Fructosamine (SF), But Not Glycosylated Hemoglobin (HbA1C), Predicts Long-Term Survival in Nondiabetic (NDM) Hemodialysis (HD) Patients (PTS)

SERUM FRUCTOSAMINE (SF), BUT NOT GLYCOSYLATED HEMOGLOBIN (HbA1C), PREDICTS LONG-TERM SURVIVAL IN NONDIABETIC (NDM) HEMODIALYSIS (HD) PATIENTS (PTS) Neal Mittman, Brinda Desiraju, Swapna Vemulapalli, Jyotiprakas Chattopadhyay, Morrell M. Avram. Avram Division of Nephrology, Long Island College Hospital, Brooklyn, NY. We and others have reported that the level of SF, an alternative index of glycemic control, is elevated in NDM HD pts. Elevated levels of SF have been associated with increased cardiovascular mortality in elderly non-uremic, NDM women. We have previously reported that SF, but not HbA1c, predicts morbidity (infection and hospitalization) in NDM HD pts. The objective of this study was to investigate the prognostic importance of enrollment SF on long-term survival in NDM HD pts. We enrolled 72 NDM HD pts from February 2005 and followed them to November 2010. SF level was corrected for serum albumin (AlbF) as previously reported. Mean age was 54±16 (SD) yrs, fifty-four percent were women and the majority were African-Americans (81%). Mean values for enrollment SF, AlbF and HbA1c were 286μmol/l (range: 187-378μmol/l) and 742μmol/g (range:468-1076μmol/g) and 5.19% (range: 4.4-5.5%) respectively. During the study period, 21 pts (29%) expired. Pts who died during the study had significantly higher AlbF (810 vs. 721, p=0.004) compared to those who survived. Using Coxs multivariate regression analysis, adjusting for age, race, gender and dialysis vintage, AlbF was a significant independent predictor of mortality (Relative Risk=1.008, p=0.015) in these NDM HD pts. In contrast, HbA1c did not predict mortality (p=0.53) in this population. Variable Relative Risk p Age (years) 1.014 0.61 Gender (Male vs. Female) 2.17 0.25 Race (Others vs. AA) 1.14 0.91 Months on dialysis 1.004 0.37 AlbF (μmol/g) 1.008 0.015 AA= African American In conclusion, AlbF, but not HbA1c, the most commonly utilized measure of glycemic control, predicts long-term survival up to 6 years in these non-diabetic HD pts.