Background

The association between hepatitis C virus (HCV) infection and clinical and laboratory measures in maintenance haemodialysis (MHD) patients are poorly understood.

Methods

We analyzed data from over 37,000 MHD patients who underwent MHD for at least 3 months in DaVita dialysis clinics across USA in July 2001.

Results

The presence of HCV infection was determined using enzyme immunoassay (EIA), which was performed in 2778 MHD patients and was positive in 363 (13%) individuals. In a multivariate logistic regression model that adjusts for case-mix and available surrogates of malnutrition-inflammation complex syndrome (MICS), the following were independent predictors of HCV infection: younger age, male gender, Black race, Hispanic ethnicity, higher haemoglobin, lower serum albumin, higher total iron binding capacity, higher creatinine, and higher serum glutamic oxaloacetic transaminase (SGOT). Among receiver operating characteristics of commonly measured laboratory values in this population, the SGOT had the highest area. An SGOT > or =25 u/l had an adjusted odds ratio of 4.96 (95% confidence interval: 3.75-6.57) for HCV antibody positivity (sensitivity 50%, specificity 87%). HCV EIA positivity among MHD patients younger than 65 years was associated with 40-80% higher hazard ratio of all-cause and cardiovascular death during the 2 year follow-up (July 2001 to June 2003) after adjustment for case-mix and measures of MICS.

Conclusion

HCV infection, as diagnosed by EIA, has distinct racial, age and laboratory predilections in MHD patients. HCV positivity among MHD patients younger than 65 years is associated with significantly higher cardiovascular mortality. More diligent HCV detection and treatment may improve cardiovascular survival in MHD patients.

Background

Malnutrition-inflammation complex syndrome, an outcome predictor in maintenance hemodialysis (MHD) patients, may be related to anorexia.

Objectives

We examined whether subjectively reported appetite is associated with adverse conditions and increased morbidity and mortality in MHD patients.

Design

A cohort of 331 MHD outpatients was asked to rate their recent appetite status on a scale from 1 to 4 (very good, good, fair, and poor appetite, respectively). Anemia indexes and nutritional and inflammatory markers-including serum concentrations of C-reactive protein, tumor necrosis factor alpha, and interleukin 6-were measured. The malnutrition-inflammation score was used to evaluate the malnutrition-inflammation complex syndrome, and the SF36 questionnaire was used to assess quality of life (QoL). Mortality and hospitalization were followed prospectively for up to 12 mo.

Results

Patients were aged 54.5 +/- 14.4 y. Diminished appetite (fair to poor) was reported by 124 patients (38%). Hemoglobin, protein intake, and QoL scores were progressively lower, whereas markers of inflammation, malnutrition-inflammation scores, and the required erythropoietin dose were higher across the worsening categories of appetite. The adjusted odds ratios of diminished versus normal appetite for increased serum tumor necrosis factor alpha and C-reactive protein concentrations were significant. Significant associations between a poor appetite and an increased rate of hospitalization and mortality were observed. The hazard ratio of death for diminished appetite was 4.74 (95% CI: 1.85, 12.16; P = 0.001).

Conclusion

Diminished appetite (anorexia) is associated with higher concentrations of proinflammatory cytokines and higher levels of erythropoietin hyporesponsiveness and poor clinical outcome, including a 4-fold increase in mortality, greater hospitalization rates, and a poor QoL in MHD patients. Appetite status may yield significant insight into the clinical status of dialysis patients.

An increased level of total plasma homocysteine (tHcy) is a risk factor for poor cardiovascular outcome in the general population. However, a decreased, rather than an increased, tHcy concentration may predict poor outcome in maintenance hemodialysis (MHD) patients, a phenomenon referred to as reverse epidemiology. Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospective hospitalization and mortality in 367 MHD patients, aged 54.5 +/- 14.7 (mean +/- SD) years, who included 199 men and 55% individuals with diabetes. tHcy was 24.4 +/- 11.8 micro mol/L, and 94% of the patients had hyperhomocysteinemia (tHcy >13.5 micro mol/L). tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition (serum albumin, prealbumin, creatinine, and urea nitrogen) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines (IL-6 and TNF-alpha). During 12 mo of follow-up, 191 MHD patients were hospitalized, 37 died, nine underwent renal transplantation, and 38 transferred out. Hospitalization rates were significantly higher in patients with lower tHcy levels. Mortality rate in the lowest tHcy quartile (17.4%) was significantly higher compared with other three quartiles (6.5 to 9.8%; Kaplan-Meier P = 0.04). Relative risk of death for the lowest tHcy quartile, even after adjustment for case-mix and serum albumin, was 2.27 (95% confidence interval, 1.14 to 4.53; P = 0.02). Hence, tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures. Despite a very high prevalence of hyperhomocysteinemia in MHD patients, lower values of tHcy are paradoxically associated with increased hospitalization and mortality. The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia. The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome.

Objectives

Normalized protein nitrogen appearance (nPNA), also known as protein catabolic rate (nPCR), reflects the daily protein intake in maintenance hemodialysis (MHD) patients. Several studies indicate that nPNA and Kt/V correlate with clinical outcome and also with each other. Thus, the relationship between low nPNA and poor outcome could be due to uremia, low Kt/V or due to reported mathematical coupling between nPNA and Kt/V. We therefore investigated whether nPNA is associated with outcome in patients who have adequate or high Kt/V.

Design

Prospective cohort.

Settings

Outpatient dialysis unit affiliated with a tertiary-care community medical center.

Patients

From a pool of 135 MHD outpatients in one dialysis unit, 122 patients with a delivered, Kt/V(sp)>1.20, independent of their residual renal function, were evaluated. Patients (61 women, 61 men), aged from 23 to 89 years (53.4+/-14.0 years)(+/-SD), had been undergoing MHD for one month to 17 years.

Intervention

Review of laboratory values and clinical outcome.

Main outcome measures

Twelve-month mortality and hospitalization.

Results

Delivered Kt/V(sp) ranged from 1.23 to 2.71 (1.77+/-0.34), nPNA from 0.5 to 2.15 (1.13+/-0.29 g/kg/day), and serum albumin, from 1.9 to 4.6 (3.76+/-0.37 g/dL). During the 12-month follow-up, 55 patients were hospitalized overnight at least once; 12 patients died; 5 patients underwent renal transplantation, and 6 patients left the study. The nPNA and Kt/V(sp) did not correlate significantly (r=.09) except when analysis was limited to Kt/V values < 1.5 (r=.54). Serum nPNA and albumin were the only variables with statistically significant correlations with both mortality and 3 measures of hospitalization (H): total days of H (H(D)), total number of H (H(F)), and time to first H (H(T)). The case-mix adjusted correlations for serum albumin and nPNA versus total days (r(HD)) and frequency of H (r(HF)) were significant, and Cox analysis based on H(T) and time to death resulted in significant odds ratios for each standard deviation decrement for both serum albumin and nPNA. Serum total iron binding capacity (TIBC) and creatinine concentrations also correlated with some but not all outcome measures: lower serum concentrations of these values were each significantly associated with poor clinical outcomes.

Conclusions

Both nPNA and serum albumin predict prospective hospitalization and mortality in MHD patients with Kt/V > 1.20. Serum TIBC and creatinine concentrations appear to have association with some outcome measures as well. These data are consistent with the possibility that protein intake affects the clinical course even in the setting of an adequate to high hemodialysis dose. Studies based on randomized assignments to different protein intakes would be helpful to confirm these conclusions.

The independent association between the indices of iron stores or administered intravenous iron, both of which vary over time, and survival in patients who are on maintenance hemodialysis (MHD) is not clear. It was hypothesized that the observed associations between moderately high levels of three iron markers (serum ferritin, iron, and iron saturation ratio) or administered intravenous iron and all-cause and cardiovascular death is due to the time-varying confounding effect of malnutrition-inflammation-cachexia syndrome (MICS). Time-dependent Cox regression models were examined using prospectively collected data of the 2-yr (July 2001 to June 2003) historical cohort of 58,058 MHD patients from virtually all DaVita dialysis clinics in the United States. After time-dependent and multivariate adjustment for case mix, administered intravenous iron and erythropoietin doses, and available surrogates of MICS, serum ferritin levels between 200 and 1200 ng/ml (reference 100 to 199 ng/ml), serum iron levels between 60 and 120 microg/ml (reference 50 to 59 microg/ml), and iron saturation ratio between 30 and 50% (reference 45 to 50%) were associated with the lowest all-cause and cardiovascular death risks. Compared with those who did not receive intravenous iron, administered intravenous iron up to 400 mg/mo was associated with improved survival, whereas doses >400 mg/mo tended to be associated with higher death rates. The association between serum ferritin levels >800 ng/ml and mortality in MHD patients seems to be due mostly to the confounding effects of MICS. For ascertaining whether the observed associations between moderate doses of administered intravenous iron and improved survival are causal or due to selection bias by indication, clinical trials are warranted.

Background

Iron administration has been implicated as a cause of poor clinical outcome in maintenance hemodialysis (MHD) patients. However, the role of low iron levels in the clinical outcome of MHD patients is not clear.

Methods

We examined the predicting value of baseline serum iron level on prospective mortality and hospitalization in a cohort of all 1,283 MHD patients from 10 DaVita dialysis facilities in Los Angeles County, CA.

Results

Patients aged 57.8 +/- 15.2 years included 49% men, 45% Hispanics, 25% African Americans, and 53% patients with diabetes. During the first 3 months of the cohort, 97% of patients were administered erythropoietin (EPO) and 60% were administered intravenous iron (gluconate and/or dextran) at least once. During a 12-month follow-up, mortality was significantly greater (23%) in the lowest serum iron quartile (<45.3 microg/dL [<8.1 micromol/L]) compared with other quartiles (10% to 12%). Multivariate Poisson and Cox models adjusted for demographic features, dialysis dose and vintage, serum albumin and ferritin and blood hemoglobin concentrations, and administered EPO and iron doses showed that both serum iron level and iron saturation ratio had significant, but inverse, associations with prospective mortality and hospitalization. There was a statistically significant trend toward greater rates of mortality and hospitalization with lower serum iron levels. This reverse association remained significant in a subcohort of 322 MHD patients after additional adjustments for comorbid conditions and serum C-reactive protein level to reflect inflammation.

Conclusion

Low baseline serum iron indicators are associated with increased mortality and hospitalization in MHD patients independent of hemoglobin level, EPO and iron doses, indicators of nutrition and inflammation, and comorbid conditions. Clinical trials to examine the role of iron administration in improving morbidity and mortality by increasing serum iron levels in MHD patients are required.

Maintenance hemodialysis patients in the United States have a high prevalence (approximately 80%) of systolic hypertension and a high mortality (approximately 20% per year). Some reports indicate a paradoxical association between hypertension and mortality in hemodialysis patients (ie, a normal to low blood pressure is associated with poor outcome), whereas high pressure confers survival advantages, a phenomenon referred to as "reverse epidemiology." We hypothesized that malnutrition-inflammation complex syndrome may be a cause of this paradoxical association. We studied a 15-month cohort of 40 933 hemodialysis patients in the United States whose predialysis and postdialysis blood pressure values were recorded routinely during each hemodialysis treatment. Patients were 59.8+/-15.3 years old; 54% were women and 46% diabetics. Cox proportional hazard models were used for blood pressure categories (systolic <110, > or =190 mm Hg; diastolic <50, > or =110; and increments of 10 mm Hg in between). Unadjusted, case-mix and dialysis dose-adjusted, and additional malnutrition-inflammation-adjusted hazard ratios of all-cause and cardiovascular death showed progressively increasing all-cause and cardiovascular death risk for decreasing blood pressure values. The lowest mortality was associated with predialysis systolic pressure of 160 to 189 mm Hg, whereas normal to low predialysis pressure values were associated with significantly increased mortality. Adjustment for the malnutrition-inflammation mitigated only a small portion of paradoxical associations between the low blood pressure and mortality. Predialysis systolic hypertension remained a significant predictor of highest all-cause and cardiovascular survival rate. Although these associations may not be causal, they call into question whether treatment goals for the general population can be applied to dialysis patients or other similar populations.

Background

High doses of human recombinant erythropoietin (rHuEPO) to achieve hemoglobin levels greater than 13 g/dL in patients with chronic kidney disease appear to be associated with increased mortality.

Study design

We conducted logistic regression and survival analyses in a retrospective cohort of long-term hemodialysis patients to examine the hypothesis that the induced iron depletion with resultant relative thrombocytosis may be a possible contributor to the link between the high rHuEPO dose-associated hemoglobin level of 13 g/dL or greater and mortality.

Setting & participants

The national database of a large dialysis organization (DaVita) with 40,787 long-term hemodialysis patients during July to December 2001 and their survival up to July 2004 were examined.

Predictors

Hemoglobin level, platelet count, and administered rHuEPO dose during each calendar quarter.

Outcomes & other measurements

Case-mix-adjusted 3-year all-cause mortality and measures of iron stores, including serum ferritin and iron saturation ratio.

Results

Higher platelet count was associated with lower iron stores and greater prescribed rHuEPO dose. Compared with a hemoglobin level of 12 to 13 g/dL, a hemoglobin level of 13 g/dL or greater was associated with increased mortality in the presence of relative thrombocytosis, ie, platelet count of 300,000/microL or greater (case-mix-adjusted death-rate ratio, 1.21; 95% confidence limits, 1.02 to 1.44; P = 0.03) as opposed to the absence of relative thrombocytosis (death-rate ratio, 1.04; 95% confidence limits, 0.98 to 1.08; P = 0.1). A prescribed rHuEPO dose greater than 20,000 U/wk was associated with a greater likelihood of iron depletion (iron saturation ratio < 20%) and relative thrombocytosis (case-mix-adjusted odds ratio, 2.53; 95% confidence limits, 2.37 to 2.69; and 1.36; 95% confidence limits, 1.30 to 1.42, respectively; P < 0.001) and increased mortality during 3 years (death-rate ratio, 1.59; 95% confidence limits, 1.54 to 1.65; P < 0.001).

Limitations

Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different mortality predictability than targeted hemoglobin level.

Conclusions

Iron depletion and associated relative thrombocytosis might contribute to increased mortality when administering high rHuEPO doses to achieve hemoglobin levels of 13 g/dL or greater in long-term hemodialysis patients. Randomized trials are needed to test these observational associations.

Background

In maintenance hemodialysis (MHD) outpatients, a reverse epidemiology is described, ie, baseline obesity appears paradoxically associated with improved survival. However, the association between changes in weight over time and prospective mortality is not known.

Methods

Using time-dependent Cox models and adjusting for changes in laboratory values over time, the relation of quarterly-varying 3-month averaged body mass index (BMI) to all-cause and cardiovascular mortality was examined in a 2-year cohort of 54,535 MHD patients from virtually all DaVita dialysis clinics in the United States.

Results

Patients, aged 61.7 +/- 15.5 (SD) years, included 54% men and 45% with diabetes. Time-dependent unadjusted and multivariate-adjusted models, based on quarterly-averaged BMI controlled for case-mix and available time-varying laboratory surrogates of nutritional status, were calculated in 11 categories of BMI. Obesity, including morbid obesity, was associated with better survival and reduced cardiovascular death, even after accounting for changes in BMI and laboratory values over time. Survival advantages of obesity were maintained for dichotomized BMI cutoff values of 25, 30, and 35 kg/m2 across almost all strata of age, race, sex, dialysis dose, protein intake, and serum albumin level. Examining the regression slope of change in weight over time, progressively worsening weight loss was associated with poor survival, whereas weight gain showed a tendency toward decreased cardiovascular death.

Conclusion

Weight gain and both baseline and time-varying obesity may be associated with reduced cardiovascular mortality in MHD patients independent of laboratory surrogates of nutritional status and their changes over time. Morbidly obese patients have the lowest mortality. Clinical trials need to verify these observational findings.