Jennie Jing

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.

Serum and Dialysate Potassium Concentrations and Survival in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Controlling serum potassium is an important goal in maintenance hemodialysis patients. We examined the achievement of potassium balance through hemodialysis treatments and the associated fluctuations in serum potassium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A 3-yr (July 2001 to June 2004) cohort of 81,013 maintenance hemodialysis patients from all DaVita dialysis clinics across the United States were studied. Nine quarterly-averaged serum potassium groups (< 4.0, > or = 6.3 mEq/L and seven increments in-between) and four dialysate potassium concentration groups were created in each of the 12 calendar quarters. The death risk associated with predialysis potassium level and dialysate potassium concentration was examined using unadjusted, case-mix adjusted, and malnutrition-inflammation-adjusted time-dependent survival models. RESULTS Serum potassium correlated with nutritional markers. Serum potassium between 4.6 and 5.3 mEq/L was associated with the greatest survival, whereas potassium < 4.0 or > or = 5.6 mEq/L was associated with increased mortality. The death risk of serum potassium > or = 5.6 mEq/L remained consistent after adjustments. Higher dialysate potassium concentration was associated with increased mortality in hyperkalemic patients with predialysis serum potassium > or = 5.0 mEq/L. CONCLUSIONS A predialysis serum potassium of 4.6 to 5.3 mEq/L is associated with the greatest survival in maintenance hemodialysis patients. Hyperkalemic patients who undergo maintenance hemodialysis against lower dialysate bath may have better survival. Limitations of observational studies including confounding by indication should be considered when interpreting these results.

Serum Alkaline Phosphatase Predicts Mortality among Maintenance Hemodialysis Patients

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.

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.

Associations of Body Mass Index and Weight Loss with Mortality in Transplant-Waitlisted Maintenance Hemodialysis Patients

A body mass index (BMI) below morbid obesity range is often a requirement for kidney transplant wait‐listing, but data linking BMI changes to mortality during the waitlist period are lacking. By linking the 6‐year (7/2001–6/2007) national databases of a large dialysis organization and the Scientific Registry of Transplant Recipients, we identified 14 632 waitlisted hemodialysis patients without kidney transplantation. Time‐dependent survival models examined the mortality predictability of 13‐week‐averaged BMI, pretransplant serum creatinine as a muscle mass surrogate and their changes over time. The patients were on average 52 ± 13 years old, 40% women and had a BMI of 26.9 ± 6.3 kg/m2. Each kg/m2 increase of BMI was associated with a death hazard ratio (HR) of 0.96 (95%CI: 0.95–0.97). Compared to the lowest creatinine quintile, the 4th and 5th quintiles had death HRs of 0.75 (0.66–0.86) and 0.57 (0.49–0.66), respectively. Compared to minimal (< ± 1 kg) weight change over 6 months, those with 3 kg–<5 kg and ≥5 kg weight loss had death HRs of 1.31 (1.14–1.52) and 1.51 (1.30–1.75), respectively. Similar associations were observed with creatinine changes over time. Transplant‐waitlisted hemodialysis patients with lower BMI or muscle mass and/or unintentional weight or muscle loss have higher mortality in this observational study. Impact of intentional weight change remains unclear.

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.

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.

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.

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) (β = 0.19) and interleukin-6 (log IL-6) (β = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (β = -0.30) and prealbumin levels (β = -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.

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.