Association of Growth Differentiation Factor 15 with Mortality in a Prospective Hemodialysis Cohort.

BACKGROUND/AIMS: Cardiovascular disease and protein-energy wasting are among the strongest predictors of the high mortality of dialysis patients. In the general population, the novel cardiovascular and wasting biomarker, growth differentiation factor 15 (GDF15), is associated with decreased survival. However, little is known about GDF15 in dialysis patients. METHODS: Among prevalent hemodialysis patients participating in a prospective study (October 2011 to August 2015), we examined the association of baseline GDF15 levels with all-cause mortality using unadjusted and case mix-adjusted death hazard ratios (HRs) that controlled for age, sex, race, ethnicity, diabetes, and dialysis vintage. RESULTS: The mean age ± SD of the 203 patients included in the study was 53.2 ± 14.5 years, and the cohort included 41% females, 34% African-Americans, and 48% Hispanics. GDF15 levels (mean ± SD 5.94 ± 3.90 ng/mL; range 1.58-39.8 ng/mL) were higher among older patients and were inversely associated with serum creatinine concentrations as a surrogate for muscle mass. Each 1.0 ng/mL increase in GDF15 was associated with an approximately 17-18% higher mortality risk in the unadjusted and case mix models (p < 0.05). Increments of about 1 SD (a 4.0 ng/mL increase in GDF15) were associated with a nearly 2-fold higher death risk. The highest GDF15 tertile was associated with higher mortality risk (reference: lowest tertile): the HRs (95% CI) were 3.19 (1.35-7.55) and 2.45 (1.00-6.00) in the unadjusted and the case mix-adjusted model, respectively. These incremental death trends were confirmed in cubic spline models. CONCLUSION: Higher circulating GDF15 levels are associated with higher mortality risk in hemodialysis patients. Future studies are needed to determine whether GDF15 may represent a novel therapeutic target for cardiovascular disease, wasting, and death in this population.

Seasonal variations in transition, mortality and kidney transplantation among patients with end-stage renal disease in the USA.

BACKGROUND: Seasonal variations may exist in transitioning to dialysis, kidney transplantation and related outcomes among end-stage renal disease (ESRD) patients. Elucidating these variations may have major clinical and healthcare policy implications for better resource allocation across seasons. METHODS: Using the United States Renal Data System database from 1 January 2000 to 31 December 2013, we calculated monthly counts of transitioning to dialysis or first transplantation and deaths. Crude monthly transition fraction was defined as the number of new ESRD patients divided by all ESRD patients on the first day of each month. Similar fractions were calculated for all-cause and cause-specific mortality and transplantation. RESULTS: The increasing trend of the annual transition to ESRD plateaued during 2009-2012 (n = 126 264), and dropped drastically in 2013 (n = 117 372). Independent of secular trends, monthly transition to ESRD was lowest in July (1.65%) and highest in January (1.97%) of each year. All-cause, cardiovascular and infectious mortalities were lowest in July or August (1.32, 0.58 and 0.15%, respectively) and highest in January (1.56, 0.71 and 0.19%, respectively). Kidney transplantation was highest in June (0.33%), and this peak was mainly attributed to living kidney transplantation in summer months. Transplant failure showed a similar seasonal variation to naïve transition, peaking in January (0.65%) and nadiring in September (0.56%). CONCLUSIONS: Transitioning to ESRD and adverse events among ESRD people were more frequent in winter and less frequent in summer, whereas kidney transplantation showed the reverse trend. The potential causes and implications of these consistent seasonal variations warrant more investigation.

Effect of high-protein meals during hemodialysis combined with lanthanum carbonate in hypoalbuminemic dialysis patients: findings from the FrEDI randomized controlled trial.

BACKGROUND: Inadequate protein intake and hypoalbuminemia, indicators of protein-energy wasting, are among the strongest mortality predictors in hemodialysis patients. Hemodialysis patients are frequently counseled on dietary phosphorus restriction, which may inadvertently lead to decreased protein intake. We hypothesized that, in hypoalbuminemic hemodialysis patients, provision of high-protein meals during hemodialysis combined with a potent phosphorus binder increases serum albumin without raising phosphorus levels. METHODS: We conducted a randomized controlled trial in 110 adults undergoing thrice-weekly hemodialysis with serum albumin <4.0 g/dL recruited between July 2010 and October 2011 from eight Southern California dialysis units. Patients were randomly assigned to receive high-protein (50-55 g) meals during dialysis, providing 400-500 mg phosphorus, combined with lanthanum carbonate versus low-protein (<1 g) meals during dialysis, providing <20 mg phosphorus. Prescribed nonlanthanum phosphorus binders were continued over an 8-week period. The primary composite outcome was a rise in serum albumin of ≥0.2 g/dL while maintaining phosphorus between 3.5-<5.5 mg/dL. Secondary outcomes included achievement of the primary outcome's individual endpoints and changes in mineral and bone disease and inflammatory markers. RESULTS: Among 106 participants who satisfied the trial entrance criteria, 27% ( n = 15) and 12% ( n = 6) of patients in the high-protein versus low-protein hemodialysis meal groups, respectively, achieved the primary outcome (intention-to-treat P-value = 0.045). A lower proportion of patients in the high-protein versus low-protein intake groups experienced a meaningful rise in interleukin-6 levels: 9% versus 31%, respectively (P = 0.009). No serious adverse events were observed. CONCLUSION: In hypoalbuminemic hemodialysis patients, high-protein meals during dialysis combined with lanthanum carbonate are safe and increase serum albumin while controlling phosphorus.

Predialysis Cardiovascular Disease Medication Adherence and Mortality After Transition to Dialysis.

BACKGROUND: Medication nonadherence is a known risk factor for adverse outcomes in the general population. However, little is known about the association of predialysis medication adherence among patients with advanced chronic kidney disease and mortality following their transition to dialysis. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 32,348 US veterans who transitioned to dialysis during 2007 to 2011. PREDICTORS: Adherence to treatment with cardiovascular drugs, ascertained from pharmacy database records using proportion of days covered (PDC) and persistence during the predialysis year. OUTCOMES: Post-dialysis therapy initiation all-cause and cardiovascular mortality, using Cox models with adjustment for confounders. RESULTS: Mean age of the cohort was 72±11 (SD) years; 96% were men, 74% were white, 23% were African American, and 69% had diabetes. During a median follow-up of 23 (IQR, 9-36) months, 18,608 patients died. Among patients with PDC>80%, there were 14,006 deaths (mortality rate, 283 [95% CI, 278-288]/1,000 patient-years]); among patients with PDC>60% to 80%, there were 3,882 deaths (mortality rate, 294 [95% CI, 285-304]/1,000 patient-years); among patients with PDC≤60%, there were 720 deaths (mortality rate, 291 [95% CI, 271-313]/1,000 patient-years). Compared with patients with PDC>80%, the adjusted HR for post-dialysis therapy initiation all-cause mortality for patients with PDC>60% to 80% was 1.12 (95% CI, 1.08-1.16), and for patients with PDC≤60% was 1.21 (95% CI, 1.11-1.30). In addition, compared with patients showing medication persistence, adjusted HR risk for post-dialysis therapy initiation all-cause mortality for patients with nonpersistence was 1.11 (95% CI, 1.05-1.16). A similar trend was detected for cardiovascular mortality and in subgroup analyses. LIMITATIONS: Large number of missing values; results may not be generalizable to women or the general US population. CONCLUSIONS: Predialysis cardiovascular medication nonadherence is an independent risk factor for postdialysis mortality in patients with advanced chronic kidney disease transitioning to dialysis therapy. Further studies are needed to assess whether interventions targeting adherence improve survival after dialysis therapy initiation.

Association of Slopes of Estimated Glomerular Filtration Rate With Post-End-Stage Renal Disease Mortality in Patients With Advanced Chronic Kidney Disease Transitioning to Dialysis.

OBJECTIVE: To investigate the association of estimated glomerular filtration rate (eGFR) slopes before dialysis initiation with cause-specific mortality after dialysis initiation. PATIENTS AND METHODS: In this retrospective cohort study of 18,874 US veterans who had transitioned to dialysis from October 1, 2007, through September 30, 2011, we examined the association of pre-end-stage renal disease (ESRD) eGFR slopes with all-cause, cardiovascular, and infection-related mortality during the post-ESRD period over a median follow-up of 2.0 years (interquartile range, 1.1-3.2 years). Associations were examined using Cox models with adjustment for potential confounders. RESULTS: Before the 18,874 patients transitioned to dialysis, 4485 (23.8%), 5633 (29.8%), and 7942 (42.1%) experienced fast, moderate, and slow eGFR decline, respectively, and 814 (4.3%) had increasing eGFR (defined as eGFR slopes of less than -10, -10 to less than -5, -5 to <0, and ≥0 mL/min per 1.73 m(2) per year). During the study period, a total of 9744 all-cause, 2702 cardiovascular, and 604 infection-related deaths were observed. Compared with patients with slow eGFR decline, those with moderate and fast eGFR decline had a higher risk of all-cause mortality (adjusted hazard ratio [HR], 1.06; 95% CI, 1.00-1.11; and HR, 1.11; 95% CI, 1.04-1.18, respectively) and cardiovascular mortality (HR, 1.11; 95% CI, 1.01-1.23 and HR, 1.13; 95% CI, 1.00-1.27, respectively). In contrast, increasing eGFR was only associated with higher infection-related mortality (HR, 1.49; 95% CI, 1.03-2.17). CONCLUSION: Rapid eGFR decline is associated with higher all-cause and cardiovascular mortality, and increasing eGFR is associated with higher infection-related mortality among incident dialysis cases.

Association of Adiponectin With Body Composition and Mortality in Hemodialysis Patients.

BACKGROUND: In the general population, circulating adiponectin is associated with a favorable cardiovascular risk profile (eg, lower triglycerides and body fat) and decreased mortality. Hemodialysis (HD) patients have comparatively higher adiponectin concentrations, but prior studies examining the adiponectin-mortality association in this population have not accounted for body composition or shown a consistent relationship. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: We examined baseline serum adiponectin concentrations in 501 HD patients across 13 dialysis centers from the prospective MADRAD (Malnutrition, Diet, and Racial Disparities in Chronic Kidney Disease) cohort (entry period, October 2011 to February 2013; follow-up through August 2013). PREDICTOR: Serum adiponectin concentration in tertiles (tertiles 1, 2, and 3 defined as ≤16.1, >16.1-<30.1, and ≥30.1-100.0 µg/mL, respectively). Adjustment variables included case-mix and laboratory test results (age, sex, race, ethnicity, vintage, diabetes, serum albumin, total iron-binding capacity, serum creatinine, white blood cell count, phosphate, hemoglobin, and normalized protein catabolic rate), body composition surrogates (subcutaneous, visceral, and total-body fat and lean body mass), and serum lipid levels (cholesterol, high-density lipoprotein cholesterol, and triglycerides). OUTCOMES: All-cause mortality using survival (Cox) models incrementally adjusted for case-mix and laboratory test results. RESULTS: Among 501 HD patients, 50 deaths were observed during 631.1 person-years of follow-up. In case-mix- and laboratory-adjusted Cox analyses, the highest adiponectin tertile was associated with increased mortality versus the lowest tertile (HR, 3.35; 95% CI, 1.50-7.47). These associations were robust in analyses that additionally accounted for body composition (HR, 3.18; 95% CI, 1.61-8.24) and lipid levels (HR, 3.64; 95% CI, 1.34-7.58). LIMITATIONS: Residual confounding cannot be excluded. CONCLUSIONS: Higher adiponectin level is associated with a 3-fold higher death risk in HD patients independent of body composition and lipid levels. Future studies are needed to elucidate underlying mechanisms and determine therapeutic targets associated with improved outcomes in HD patients.

Association of vascular access type with inflammatory marker levels in maintenance hemodialysis patients.

Aggressive NIH is a common histopathological lesion found at the sites of venous stenosis in arteriovenous fistula (AVF) and arteriovenous grafts (AVG). Inflammatory mediators have been proposed to play a pathogenic role in NIH, but there is paucity of data evaluating this hypothesis in clinical studies or in animal models. Serum levels of inflammatory mediators can potentially identify patients at high risk of AVF and AVG dysfunction. In a cross-sectional cohort study of 754 HD patients who were part of the NIED study cohort, we examined the associations between inflammatory markers including serum interleukin (IL) 1ß, IL-6, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) and type of vascular access. Unadjusted and multivariate-adjusted linear regression models were used. In addition, time-dependent regression model was used to assess the association between inflammatory markers and mortality. We observed that in the multivariate-adjusted model, inflammatory mediators interleukin-6 (IL-6), interleukin-1L-ß (IL-1ß), and C-reactive protein (CRP), the predicted value in hemodialysis patients, are lowest in patients with AVF and highest in central venous catheter (CVC) and AVG even in case-mix and malnutrition-inflammation complex syndrome (MICS)-adjusted models. IL-6 and CRP levels fall consistently in the same patients when AVG or CVC is changed to AVF and increase if the same patient changes access from AVF to AVG or CVC. Obesity is a risk factor for fistula failure and fistulas are associated with the lowest mortality compared with CVC and AVG. We did not find any statistically significant association between tumor necrosis factor-α (TNF- α) and vascular access outcomes. Higher levels of inflammatory mediators seen in CVC and AVG compared with AVF could potentially explain the higher mortality seen in patients with CVC and AVG compared with AVF.

Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration. METHODS: Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups. RESULTS: Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018). CONCLUSIONS: In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.

Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients.

OBJECTIVE: Hypo- and hyperphosphatemia have each been associated with increased mortality in maintenance hemodialysis (MHD) patients. There has not been previous evaluation of a differential relationship between serum phosphorus level and death risk across varying age groups in MHD patients. DESIGN AND SETTINGS: In a 6-year cohort of 107,817 MHD patients treated in a large dialysis organization, we examined the association between serum phosphorus levels with all-cause and cardiovascular mortality within 5 age categories (15 to <45, 45 to <65, 65 to <70, 70 to <75, and ≥75 years old) using Cox proportional hazards models adjusted for case-mix covariates and malnutrition inflammation complex syndrome (MICS) surrogates. MAIN OUTCOME MEASURE: All-cause and cardiovascular mortality. RESULTS: The overall mean age of the cohort was 60 ± 16 years, among whom there were 45% women, 35% Blacks, and 58% diabetics. The time-averaged serum phosphorus level (mean ± SD) within each age category was 6.26 ± 1.4, 5.65 ± 1.2, 5.26 ± 1.1, 5.11 ± 1.0, and 4.88 ± 1.0 mg/dL, respectively (P for trend <.001). Hyperphosphatemia (>5.5 mg/dL) was consistently associated with increased all-cause and cardiovascular mortality risks across all age categories, including after adjustment for case-mix and MICS-related covariates. In fully adjusted models, a low serum phosphorus level (<3.5 mg/dL) was associated with increased all-cause mortality only in elderly MHD patients ≥65 years old (hazard ratio [95% confidence interval]: 1.21 [1.07-1.37], 1.13 [1.02-1.25], and 1.28 [1.2-1.37] for patients 65 to <70, 70 to <75, and ≥75 years old, respectively), but not in younger patients (<65 years old). A similar differential cardiovascular mortality risk for low serum phosphorus levels between old and young age groups was observed. CONCLUSIONS: The association between hyperphosphatemia and mortality is similar across all age groups of MHD patients, whereas hypophosphatemia is associated with increased mortality only in elderly MHD patients. Preventing very low serum phosphorus levels in elderly dialysis patients may be associated with better outcomes, which needs to be examined in future studies.

Low protein nitrogen appearance as a surrogate of low dietary protein intake is associated with higher all-cause mortality in maintenance hemodialysis patients.

To determine the association between all-cause mortality and dietary protein intake in patients with chronic kidney disease, we performed a large-scale, 8-y prospective cohort study in 98,489 maintenance hemodialysis patients from a multicenter dialysis care provider. Compared with the reference level (60 to <70 g/d), low protein nitrogen appearance (PNA) levels [<30 g/d, HR: 1.40 (95% CI: 1.30, 1.50); 30 to <40 g/d, HR: 1.33 (95% CI: 1.28, 1.39)] was associated with higher all-cause mortality, and high PNA levels [≥110 g/d, HR: 0.92 (95% CI: 0.88, 0.97); 100 to <110 g/d, HR: 0.87 (95% CI: 0.82, 0.91)] were associated with lower all-cause mortality in all analyses. This association was also found in subanalyses performed among racial and hypoalbuminemic groups. Hence, using PNA as a surrogate for protein intake, a low daily dietary protein intake is associated with increased risk of death in all hemodialysis patients. Whether the association between dietary protein intake and survival is causal or a consequence of anorexia secondary to protein-energy-wasting/inflammation or other factors should be explored in interventional trials.

Mortality predictability of body size and muscle mass surrogates in Asian vs white and African American hemodialysis patients.

OBJECTIVE: To determine whether the association of body size and muscle mass with survival among patients undergoing long-term hemodialysis (HD) is consistent across race, especially in East Asian vs white and African American patients. PATIENTS AND METHODS: Using data from 20,818 patients from South Korea who underwent HD from February 1, 2001, to June 30, 2009, and 20,000 matched patients from the United States (10,000 whites and 10,000 African Americans) who underwent HD from July 1, 2001, to June 30, 2006, we compared mortality associations of baseline body mass index (BMI) and serum creatinine level as likely surrogates of obesity and muscle mass across the 3 races. RESULTS: In Korean HD patients, higher BMI together with higher serum creatinine levels were associated with greater survival, as previously reported from US and European studies. In the matched cohort (10,000 patients from each of the 3 races), mortality risks were lower across higher BMI and serum creatinine levels, and these associations were similar in all 3 races (reference groups: patients with BMI >25.0 kg/m(2) or serum creatinine >12 mg/dL in each race). White, African American, and Korean patients with BMI levels of 18.5 kg/m(2) or less (underweight) had 78%, 79%, and 57% higher mortality risk, respectively, and white, African American, and Korean patients with serum creatinine levels of 6.0 mg/dL or less had 108%, 87%, and 78% higher mortality, respectively. CONCLUSION: This study shows that race does not modify the association of higher body size and muscle mass with greater survival in HD patients. Given the consistency of the obesity paradox, which may be related to a mitigated effect of protein-energy wasting on mortality irrespective of racial disparities, nutritional support to improve survival should be tested in HD patients of all races.

Association of malnutrition-inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients.

BACKGROUND: Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis-stimulating agents (ESA) is often the cause of the refractory anemia. We hypothesized that the malnutrition-inflammation complex is an independent predictor of decreased responsiveness to ESAs in hemodialysis patients. METHODS: This cohort study of 754 hemodialysis patients was examined for an association between inflammatory and nutritional markers, including the malnutrition-inflammation score (MIS) and responsiveness to ESA. Cubic spline models were fitted to verify found associations. RESULTS: The mean (±SD) age of patients was 54 ± 15 years, 53% were diabetic and 32% blacks. MIS was worse in the highest quartile of ESAs responsiveness index (ERI, ESA dose divided by hemoglobin) when compared with 1st quartile (6.5 ± 4.5 versus 4.4 ± 3.4; P < 0.001). Both C-reactive protein (log CRP) (ß = 0.19) and interleukin-6 (log IL-6) (ß = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (ß = -0.30) and prealbumin levels (ß = -0.14) were inversely associated with ERI. Each 1 SD higher MIS, higher CRP and lower albumin were associated with 86, 44 and 97% higher likelihood of having highest versus three lowest ERI quartiles in fully adjusted models [odds ratio (and 95% confidence interval) of 1.86 (1.31-2.85), 1.44 (1.08-1.92) and 1.97 (1.41-2.78)], respectively. Cubic splines confirmed the continuous and incremental nature of these associations. CONCLUSIONS: Malnutrition-inflammation complex is an incremental predictor of poor responsiveness to ESAs in hemodialysis patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management.

Evaluation of diagnostic and therapeutic approaches for suspected influenza A(H1N1)pdm09 infection, 2009-2010.

To assess adherence to real-time changes in guidelines for influenza diagnosis and use of oseltamivir during the 2009 influenza A(H1N1) pandemic, we reviewed medical records of patients with confirmed or suspected influenza-like illness (ILI) and those with no viral testing in a large Los Angeles (California, USA) hospital. Of 882 tested patients, 178 had results positive for influenza; 136 of the remaining patients received oseltamivir despite negative or no results. Oseltamivir use was consistent with national recommendations in >90%. Of inpatients, children were less likely than adults to have ILI at testing and to receive oseltamivir if ILI was found. Of outpatients, children were more likely to have positive test results; 20% tested did not have ILI or other influenza signs and symptoms. Twenty-five of 96 test-positive patients and 13 of 19 with lower respiratory tract disease were, inappropriately, not treated. Variations between practice and national recommendations could inform clinical education in future influenza seasons.

Associations of pretransplant weight and muscle mass with mortality in renal transplant recipients.

BACKGROUND AND OBJECTIVES: The association between pretransplant body composition and posttransplant outcomes in renal transplant recipients is unclear. It was hypothesized that in hemodialysis patients higher muscle mass (represented by higher pretransplant serum creatinine level) and larger body size (represented by higher pretransplant body mass index [BMI]) are associated with better posttransplant outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Linking 5-year patient data of a large dialysis organization (DaVita) to the Scientific Registry of Transplant Recipients, 10,090 hemodialysis patients were identified who underwent kidney transplantation from July 2001 to June 2007. Cox regression hazard ratios and 95% confidence intervals of death and/or graft failure were estimated. RESULTS: Patients were 49 ± 13 years old and included 49% women, 45% diabetics, and 27% African Americans. In Cox models adjusted for case-mix, nutrition-inflammation complex, and transplant-related covariates, the 3-month-averaged postdialysis weight-based pretransplant BMI of 20 to <22 and < 20 kg/m(2), compared with 22 to <25 kg/m(2), showed a nonsignificant trend toward higher combined posttransplant mortality or graft failure, and even weaker associations existed for BMI ≥ 25 kg/m(2). Compared with pretransplant 3-month- averaged serum creatinine of 8 to <10 mg/dl, there was 2.2-fold higher risk of combined death or graft failure with serum creatinine <4 mg/dl, whereas creatinine ≥14 mg/dl exhibited 22% better graft and patient survival. CONCLUSIONS: Pretransplant obesity does not appear to be associated with poor posttransplant outcomes. Larger pretransplant muscle mass, reflected by higher pretransplant serum creatinine level, is associated with greater posttransplant graft and patient survival.

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.

Blood pressure and survival in long-term hemodialysis patients with and without polycystic kidney disease.

BACKGROUND: In maintenance dialysis patients, low blood pressure (BP) values are associated with higher death rates when compared with normal to moderately high values. This 'hypertension paradox' may be related to comorbid conditions. Dialysis patients with polycystic kidney disease (PKD) usually have a lower comorbidity burden and greater survival. We hypothesized that in PKD dialysis patients, a representative of a healthier dialysis patient population, high BP is associated with higher mortality. METHODS: Time-dependent survival models including after multivariate adjustment were examined to assess the association between prehemodialysis and posthemodialysis BP and all-cause mortality in a 5-year cohort of 67 085 non-PKD and 1579 PKD hemodialysis patients. RESULTS: In PKD patients, low prehemodialysis and posthemodialysis SBPs were associated with increased mortality, whereas high prehemodialysis DBP was associated with greater survival. Fully adjusted death hazard ratios (and 95% confidence levels) for prehemodialysis and posthemodialysis BP of less than 120 mmHg (reference 140 to <160 mmHg) were 1.30 (1.06-1.92) and 1.45 (1.04-2.02), respectively, and for prehemodialysis DBP of 80 mmHg or more (reference 70 to <80 mmHg) was 0.68 (0.49-0.93, all P values <0.05). Similar associations were observed in non-PKD patients. In pooled analyses, within each commensurate BP stratum, PKD patients exhibited superior survival to non-PKD patients. CONCLUSION: Among hemodialysis patients, those with PKD display a similar BP paradox as those without PKD, even though within each BP category PKD patients maintain superior survival. Randomized clinical trials are needed to define optimal blood pressure targets in the hemodialysis population.

Impact of race on hyperparathyroidism, mineral disarrays, administered vitamin D mimetic, and survival in hemodialysis patients.

Blacks have high rates of chronic kidney disease, are overrepresented among the US dialysis patients, have higher parathyroid hormone levels, but greater survival compared to nonblacks. We hypothesized that mineral and bone disorders (MBDs) have a bearing on survival advantages of black hemodialysis patients. In 139,328 thrice-weekly treated hemodialysis patients, including 32% blacks, in a large dialysis organization, where most laboratory values were measured monthly for up to 60 months (July 2001 to June 2006), we examined differences across races in measures of MBDs and survival predictabilities of these markers and administered the active vitamin D medication paricalcitol. Across each age increment, blacks had higher serum calcium and parathyroid hormone (PTH) levels and almost the same serum phosphorus and alkaline phosphatase levels and were more likely to receive injectable active vitamin D in the dialysis clinic, mostly paricalcitol, at higher doses than nonblacks. Racial differences existed in mortality predictabilities of different ranges of serum calcium, phosphorus, and PTH but not alkaline phosphatase. Blacks who received the highest dose of paricalcitol (>10 µg/week) had a demonstrable survival advantage over nonblacks (case-mix-adjusted death hazard ratio = 0.87, 95% confidence level 0.83-0.91) compared with those who received lower doses (<10 µg/week) or no active vitamin D. Hence, in black hemodialysis patients, hyperparathyroidism and hypercalcemia are more prevalent than in nonblacks, whereas hyperphosphatemia or hyperphosphatasemia are not. Survival advantages of blacks appear restricted to those receiving higher doses of active vitamin D. Examining the effect of MBD modulation on racial survival disparities of hemodialysis patients is warranted.

Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients.

Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001-9/2007) survival of 166 MHD patients, aged 53 +/- 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1-100, 101-400, and 400+. The 101-400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1-48.1, p = 0.02) and 13.3 (95% CI: 1.3-65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1-21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2-9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1-14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.

Predictors of hyporesponsiveness to erythropoiesis-stimulating agents in hemodialysis patients.

BACKGROUND: Identification of predictors of hyporesponsiveness to erythropoietin-stimulating agents (ESAs) in hemodialysis (HD) patients may help improve anemia management and reduce hemoglobin level variability. STUDY DESIGN: We conducted repeated-measure and logistic regression analyses in a retrospective cohort of long-term HD patients to examine the association of iron markers and measures of renal osteodystrophy with ESA responsiveness. The ESA response coefficient at the individual level, ie, the least confounded dose-response association, was separated from the population level, assumed to represent confounding by medical indication. SETTING/PARTICIPANTS: The national database of a large dialysis organization (DaVita Inc, El Segundo, CA) with 38,328 surviving prevalent HD patients during 12 months who received ESA for at least 3 consecutive calendar quarters was examined. PREDICTORS: Serum levels of ferritin, iron saturation ratio, intact parathyroid hormone, and alkaline phosphatase. OUTCOMES/OTHER MEASUREMENTS: The main outcome was case-mix-adjusted hemoglobin response to quarterly averaged ESA dose at the individual level. The odds ratio (OR) of the greatest versus poorest ESA-response quartile at the patient level was calculated. OR less than 1.0 indicated ESA hyporesponsiveness, and OR greater than 1.0, enhanced responsiveness. RESULTS: Mean ESA-response coefficients of the least to most responsive quartiles were 0.301 +/- 0.033 (SD), 0.344 +/- 0.004, 0.357 +/- 0.004, and 0.389 +/- 0.026 g/dL greater hemoglobin level per 1,000 U/wk greater ESA dose in each quarter, respectively. The ORs of greatest versus poorest ESA responsiveness at the patient level were serum ferritin level less than 200 ng/mL (0.77; 95% confidence interval [CI], 0.70 to 0.86; reference, 200 to 500 ng/mL), iron saturation ratio less than 20% (0.54; 95% CI, 0.49 to 0.59; reference, 20% to 30%), intact parathyroid hormone level of 600 pg/mL or greater (0.54; 95% CI, 0.49 to 0.60; reference, 150 to 300 pg/mL), and alkaline phosphatase level of 160 IU/L or greater (0.64; 95% CI, 0.58 to 0.70; reference, 80 to 120 IU/L). Lower estimated dietary protein intake and serum levels of nutritional markers were also associated with greater risk of ESA hyporesponsiveness. LIMITATIONS: Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different associations than targeted hemoglobin level. CONCLUSIONS: In long-term HD patients, low iron stores, hyperparathyroidism, and high-turnover bone disease are associated with significant ESA hyporesponsiveness. Prospective studies are needed to verify these associations.