Glycemic Status and Mortality in Chronic Kidney Disease According to Transition Versus Nontransition to Dialysis.

OBJECTIVE: The impact of glycemic control in diabetic patients with chronic kidney disease (CKD) who may or may not transition to dialysis remains uncertain, given recent interest in the conservative management of advanced CKD without dialysis therapy, which may benefit from alternative glycemic control strategies. DESIGN AND METHODS: Among a national cohort of US Veterans, we examined the association of glycemic status, defined by averaged random blood glucose and hemoglobin A1c (HbA1c), with mortality after transitioning to dialysis over 2007-2011 (Transition Cohort) compared with patients in a one-to-one matched cohort of CKD patients with diabetes who did not transition to dialysis (Nontransition Cohort). RESULTS: Among 17,121 patients in the Transition Cohort, averaged random glucose ≥200 mg/dL was associated with higher mortality in expanded case-mix analyses (reference: 100-<120 mg/dL): adjusted hazard ratio (95% confidence interval) 1.26 (1.13-1.40). In the transition cohort, HbA1c 8-<10% and ≥10% were associated with higher mortality (reference: 6-<8%): adjusted hazard ratios (95% confidence interval) 1.21 (1.11-1.33) and 1.43 (1.21-1.69), respectively. Among 8,711 patients in the Nontransition Cohort, averaged random glucose <100 mg/dl and ≥160 mg/dl were associated with higher death risk, whereas HbA1c was not associated with mortality. CONCLUSION: In diabetic CKD patients transitioning to dialysis, higher averaged random glucose and HbA1c were associated with early dialysis mortality, whereas in matched CKD patients who did not transition, both lower and higher glucose levels were associated with higher mortality. These data suggest the need for different glycemic strategies based on whether there are plans to transition to dialysis versus pursue conservative management among diabetic patients with CKD.

Association of Ultrafiltration Rate with Mortality in Incident Hemodialysis Patients.

BACKGROUND/AIMS: Ultrafiltration rate (UFR) appears to be associated with mortality in prevalent hemodialysis (HD) patients. However, the association of UFR with mortality in incident HD patients remains unknown. METHODS: We examined a US cohort of 110,880 patients who initiated HD from 2007 to 2011. Baseline UFR was divided into 5 groups (<4, 4 to <6, 6 to <8, 8 to <10, and ≥10 mL/h/kg body weight [BW]). We examined predictors of higher baseline UFR using logistic regression and the association of baseline UFR and all-cause and cardiovascular (CV) mortality using Cox proportional hazard models with adjustments for demographics, comorbidities, and markers of malnutrition-inflammation-cachexia syndrome. RESULTS: Patients were 63 ± 15 years, with 43% women, 32% African Americans, and had a mean baseline UFR of 7.5 ± 3.1 mL/h/kg BW. In the fully adjusted logistic regression models, factors associated with higher UFR (≥7.5 mL/h/kg BW) included Hispanic ethnicity, diabetes, and higher dietary protein intake. There was a linear association between UFR and all-cause and CV mortality, where UFR ≥10 mL/h/kg BW (reference UFR 6-<8 mL/h/kg BW) conferred the highest risk in both unadjusted (HR 1.15 [95% CI 1.10-1.19]) and adjusted models (HR 1.23 [95% CI 1.16-1.31]). The linear association with all-cause mortality remained consistent across strata of age, urine volume, and treatment time. CONCLUSIONS: Higher UFR is independently associated with higher all-cause and CV mortality in incident HD patients. Clinical trials are warranted to examine the effects of lowering UFR on outcomes.

Association between Testosterone and Mortality Risk among U.S. Males Receiving Dialysis.

BACKGROUND: Among the general population, low circulating testosterone levels are associated with higher risk of cardiovascular disease and death. While testosterone deficiency is common in dialysis patients, studies of testosterone and mortality in this population are ambiguous and overlapping. We hypothesized that lower testosterone levels are associated with higher mortality in male dialysis patients. METHODS: We examined a nationally representative cohort of male dialysis patients from a large US dialysis organization who underwent one or more total testosterone measurements from 1/2007 to 12/2011. The association between total testosterone categorized as quartiles and all-cause mortality was studied using Cox models adjusted for expanded case-mix and laboratory covariates. We also examined total testosterone as a continuous predictor of all-cause mortality using restricted cubic splines. RESULTS: Among 624 male dialysis patients, 51% of patients demonstrated testosterone deficiency (total testosterone <300 ng/dL); median (IQR) total testosterone levels were 297 (190-424) ng/mL. In expanded case-mix + laboratory adjusted Cox analyses, we observed a graded association between lower testosterone levels and higher mortality risk (ref: quartile 3): adjusted hazard ratios (95% CI) 2.32 (1.33-4.06), 1.80 (0.99-3.28), and 0.68 (0.32-1.42) for Quartiles 1, 2, and 4, respectively. In adjusted spline analyses, the lower testosterone-higher mortality risk association declined with higher testosterone levels until the value reached a threshold of 400 ng/dL above which risk plateaued. CONCLUSION: Lower testosterone levels were independently associated with higher mortality risk in male dialysis patients. Further studies are needed to determine underlying mechanisms, and whether testosterone replacement ameliorates death risk in this population.

Pre-ESRD Depression and Post-ESRD Mortality in Patients with Advanced CKD Transitioning to Dialysis.

BACKGROUND AND OBJECTIVES: Depression in patients with nondialysis-dependent CKD is often undiagnosed, empirically overlooked, and associated with higher risk of death, progression to ESRD, and hospitalization. However, there is a paucity of evidence on the association between the presence of depression in patients with advanced nondialysis-dependent CKD and post-ESRD mortality, particularly among those in the transition period from late-stage nondialysis-dependent CKD to maintenance dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From a nation-wide cohort of 45,076 United States veterans who transitioned to ESRD over 4 contemporary years (November of 2007 to September of 2011), we identified 10,454 (23%) patients with a depression diagnosis during the predialysis period. We examined the association of pre-ESRD depression with all-cause mortality after transition to dialysis using Cox proportional hazards models adjusted for sociodemographics, comorbidities, and medications. RESULTS: Patients were 72±11 years old (mean±SD) and included 95% men, 66% patients with diabetes, and 23% blacks. The crude mortality rate was similar in patients with depression (289/1000 patient-years; 95% confidence interval, 282 to 297) versus patients without depression (286/1000 patient-years; 95% confidence interval, 282 to 290). Compared with patients without depression, patients with depression had a 6% higher all-cause mortality risk in the adjusted model (hazard ratio, 1.06; 95% confidence interval, 1.03 to 1.09). Similar results were found across all selected subgroups as well as in sensitivity analyses using alternate definitions of depression. CONCLUSION: Pre-ESRD depression has a weak association with post-ESRD mortality in veterans transitioning to dialysis.

Association of Glycemic Status During Progression of Chronic Kidney Disease With Early Dialysis Mortality in Patients With Diabetes.

OBJECTIVE: Although early trials suggested that intensive glycemic targets reduce the number of complications with diabetes, contemporary trials indicate no cardiovascular benefit and potentially higher mortality risk. As patients with advanced chronic kidney disease (CKD) transitioning to treatment with dialysis were excluded from these studies, the optimal glycemic level in this population remains uncertain. We hypothesized that glycemic status, defined by hemoglobin A1c (HbA--1c) and random glucose levels, in the pre-end-stage renal disease (ESRD) period is associated with higher 1-year post-ESRD mortality among patients with incident diabetes who have ESRD. RESEARCH DESIGN AND METHODS: Among 17,819 U.S. veterans with diabetic CKD transitioning to dialysis from October 2007 to September 2011, we examined the association of mean HbA--1c and random glucose levels averaged over the 1-year pre-ESRD transition period with mortality in the first year after dialysis initiation. All-cause mortality hazard ratios (HRs) were estimated using multivariable survival models. Secondary analyses examined cardiovascular mortality using competing risks methods. RESULTS: HbA--1c levels ≥8% (≥64 mmol/mol) were associated with higher mortality in the first year after dialysis initiation (reference value 6% to <7% [42-53 mmol/mol]): adjusted HRs [aHRs] 1.19 [95% CI 1.07-1.32] and 1.48 (1.31-1.67) for HbA--1c 8% to <9% [64-75 mmol/mol] and ≥9% [≥75 mmol/mol], respectively). Random glucose levels ≥200 mg/dL were associated with higher mortality (reference value 100 to <125 mg/dL): aHR 1.34 [95% CI 1.20-1.49]). Cumulative incidence curves showed that incrementally higher mean HbA--1c and random glucose levels were associated with increasingly higher cardiovascular mortality. CONCLUSIONS: In patients with diabetes and CKD transitioning to dialysis, higher mean HbA--1c and random glucose levels during the pre-ESRD prelude period were associated with higher 1-year post-ESRD mortality. Clinical trials are warranted to examine whether modulating glycemic status improves survival in this population.

Racial and Ethnic Differences in Mortality Associated with Serum Potassium in a Large Hemodialysis Cohort.

BACKGROUND: Hyperkalemia is observed in chronic kidney disease patients and may be a risk factor for life-threatening arrhythmias and death. Race/ethnicity may be important modifiers of the potassium-mortality relationship in maintenance hemodialysis (MHD) patients given that potassium intake and excretion vary among minorities. METHODS: We examined racial/ethnic differences in baseline serum potassium levels and all-cause and cardiovascular mortality using Cox proportional hazard models and restricted cubic splines in a cohort of 102,241 incident MHD patients. Serum potassium was categorized into 6 groups: ≤3.6, >3.6 to ≤4.0, >4.0 to ≤4.5 (reference), >4.5 to ≤5.0, >5.0 to ≤5.5, and >5.5 mEq/L. Models were adjusted for case-mix and malnutrition-inflammation cachexia syndrome (MICS) covariates. RESULTS: The cohort was composed of 50% whites, 34% African-Americans, and 16% Hispanics. Hispanics tended to have the highest baseline serum potassium levels (mean ± SD: 4.58 ± 0.55 mEq/L). Patients in our cohort were followed for a median of 1.3 years (interquartile range 0.6-2.5). In our cohort, associations between higher potassium (>5.5 mEq/L) and higher mortality risk were observed in African-American and whites, but not Hispanic patients in models adjusted for case-mix and MICS covariates. While in Hispanics only, lower serum potassium (<3.6 mEq/L) levels were associated with higher mortality risk. Similar trends were observed for cardiovascular mortality. CONCLUSIONS: Higher potassium levels were associated with higher mortality risk in white and African-American MHD patients, whereas lower potassium levels were associated with higher death risk in Hispanics. Further studies are needed to determine the underlying mechanisms for the differential association between potassium and mortality across race/ethnicity.

Blood Pressure Before Initiation of Maintenance Dialysis and Subsequent Mortality.

BACKGROUND: Mortality is extremely high immediately after the transition to dialysis therapy, but the association of blood pressure (BP) before dialysis therapy initiation with mortality after dialysis therapy initiation remains unknown. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 17,729 US veterans transitioning to dialysis therapy in October 2007 to September 2011, with a median follow-up of 2.0 years. PREDICTOR: Systolic (SBP) and diastolic BP (DBP) averaged over the last 1-year predialysis transition period as 6 (<120 to ≥160mmHg in 10-mmHg increments) and 5 (<60 to ≥90mmHg in 10-mmHg increments) categories, respectively, and as continuous measures. OUTCOMES & MEASUREMENTS: Postdialysis all-cause mortality, assessed over different follow-up periods (ie, <3, 3-<6, 6-<12, and ≥12 months after dialysis therapy initiation) using Cox regressions adjusted for demographics, comorbid conditions, medications, cardiovascular medication adherence, body mass index, estimated glomerular filtration rate, and type of vascular access. RESULTS: Mean predialysis SBP and DBP were 141.2±16.1 (SD) and 73.7±10.6mmHg, respectively. There was a reverse J-shaped association of SBP with all-cause mortality, with significantly higher mortality seen with SBP<140mmHg. Mortality risks associated with lower SBP were greatest in the first 3 months after dialysis therapy initiation, with multivariable-adjusted HRs of 2.40 (95% CI, 1.96-2.93), 1.99 (95% CI, 1.66-2.40), 1.35 (95% CI, 1.13-1.62), 0.98 (95% CI, 0.78-1.22), and 0.76 (95% CI, 0.57-1.00) for SBP <120, 120 to <130, 130 to <140, 150 to <160, and ≥160 (vs 140-<150) mmHg, respectively. No consistent association was observed between predialysis DBP and postdialysis mortality. LIMITATIONS: Results cannot be inferred to show causality and may not be generalizable to women or the general US population. CONCLUSIONS: Lower predialysis SBP is associated with higher all-cause mortality in the immediate postdialysis period. Predialysis DBP showed no consistent association with postdialysis mortality. Further studies are needed to clarify ideal predialysis SBP levels among incident dialysis patients as a potential means to improve the excessively high early dialysis mortality.

Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease.

BACKGROUND: Prior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors. METHODS: We examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes. RESULTS: Of the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from -6.0 to -16.3 mL/min/1.73 m2/year, P < 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from -5.6 to -4.1 mL/min/1.73 m2/year, P < 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models. CONCLUSIONS: The creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients.

Serum sodium and mortality in a national peritoneal dialysis cohort.

BACKGROUND: Sodium disarrays are common in peritoneal dialysis (PD) patients, and may be associated with adverse outcomes in this population. However, few studies of limited sample size have examined the association of serum sodium with mortality in PD patients, with inconsistent results. We hypothesized that both hypo- and hypernatremia are associated with higher death risk in a nationally representative cohort of US PD patients. METHODS: We sought to examine the association of serum sodium over time and mortality among 4687 adult incident PD patients from a large US dialysis organization who underwent one or more serum sodium measurements within the first 3 months of dialysis over January 2007 to December 2011. We examined the association of time-dependent and baseline sodium with all-cause mortality as a proxy of short- and long-term sodium-mortality associations, respectively. Hazard ratios were estimated using Cox models with three adjustment levels: minimally adjusted, case-mix adjusted, and case-mix + laboratory adjusted. RESULTS: In time-dependent analyses, sodium levels <140 mEq/L were associated with incrementally higher death risk in case-mix models (ref: 140 to <142 mEq/L); following laboratory covariate adjustment, associations between lower sodium and higher mortality remained significant for levels <136 mEq/L. In analyses using baseline values, sodium levels <140 mEq/L were associated with higher mortality risk across all models (ref: 140 to <142 mEq/L). CONCLUSIONS: In PD patients, lower time-dependent and baseline sodium levels were independently associated with higher death risk. Further studies are needed to determine whether correction of dysnatremia improves longevity in this population.

Racial-ethnic disparities in mortality and kidney transplant outcomes among pediatric dialysis patients.

BACKGROUND: Previous studies in adult hemodialysis patients have shown that African-American and Hispanic patients have a lower risk of mortality in addition to a lower likelihood of kidney transplantation. However, studies of the association between race and outcomes in pediatric dialysis are sparse and often do not examine outcomes in Hispanic children. The objective was to determine if racial-ethnic disparities in mortality and kidney transplantation outcomes exist in pediatric dialysis patients. METHODS: This was a retrospective cohort analysis of 2,697 pediatric dialysis patients (aged 0-20 years) from a large national dialysis organization (entry period 2001-2011) of non-Hispanic white, African-American, and Hispanic race-ethnicity. Associations between race-ethnicity with mortality and kidney transplantation outcomes were examined separately using competing risks methods. Logistic regression analyses were used to examine the association between race-ethnicity, with outcomes within 1 year of dialysis initiation. RESULTS: Of the 2,697 pediatric patients in this cohort, 895 were African-American, 778 were Hispanic, and 1,024 were non-Hispanic white. After adjusting for baseline demographics, competing risk survival analysis revealed that compared with non-Hispanic whites, African-Americans had a 64 % higher mortality risk (hazards ratio [HR] = 1.64; 95 % CI 1.24-2.17), whereas Hispanics had a 31 % lower mortality risk (HR = 0.69; 95 % CI 0.47-1.01) that did not reach statistical significance. African-Americans also had higher odds of 1-year mortality after starting dialysis (odds ratio [OR] = 2.08; 95 % CI 0.95-4.58), whereas both African-Americans and Hispanics had a lower odds of receiving a transplant within 1 year of starting dialysis (OR = 0.28; 95 % CI 0.19-0.41 and OR = 0.43; 95 % CI 0.31-0.59 respectively). CONCLUSION: In contrast to adults, African-American pediatric dialysis patients have worse survival than their non-Hispanic white counterparts, whereas Hispanics have a similar to lower mortality risk. Both African-American and Hispanic pediatric dialysis patients had a lower likelihood of kidney transplantation than non-Hispanic whites, similar to observations in the adult dialysis population.

Thyroid Functional Disease and Mortality in a National Peritoneal Dialysis Cohort.

CONTEXT AND OBJECTIVE: End-stage renal disease patients have a higher risk of thyroid disease compared with those without kidney disease. Although thyroid dysfunction is associated with higher death risk in the general population and those undergoing hemodialysis, little is known about the effect of thyroid disease upon mortality in patients treated with peritoneal dialysis (PD). DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME: We examined the association of thyroid status, assessed by serum TSH, with all-cause mortality among PD patients from a large national dialysis organization who underwent one or more TSH measurements over 5 years (January 2007 to December 2011). Thyroid status was categorized as overt-hyperthyroid, subclinical-hyperthyroid, low-normal, high-normal, subclinical-hypothyroid, and overt-hypothyroid range (TSH < 0.1, 0.1­<0.5, 0.5­<3.0, 3.0­<5.0, 5.0­<10.0, and ≥10.0 mIU/L, respectively). We examined the association between TSH and mortality using case mix­adjusted time-dependent Cox models to assess short-term thyroid function­mortality associations and to account for changes in thyroid function over time. RESULTS: Among 1484 patients, 7 and 18% had hyperthyroidism and hypothyroidism, respectively, at baseline. We found that both lower and higher time-dependent TSH levels were associated with higher mortality (reference: TSH, 0.5-<3.0 mIU/L): adjusted hazard ratios (95% confidence intervals) 2.09 (1.08-4.06), 1.53 (0.87-2.70), 1.05 (0.75-1.46), 1.63 (1.11-2.40), and 3.11 (2.08-4.63) for TSH levels, <0.1, 0.1-<0.5, 0.5-<3.0, 3.0-<5.0, 5.0-<10.0, and ≥10.0 mIU/L, respectively. CONCLUSION: Time-dependent TSH levels < 0.1 mIU/L and ≥ 5.0 mIU/L were associated with higher mortality, suggesting hyper- and hypothyroidism carry short-term risk in PD patients. Additional studies are needed to determine mechanisms underlying the thyroid dysfunction-mortality association, and whether normalization of TSH with treatment ameliorates mortality in this population.

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.

Changes in Markers of Mineral and Bone Disorders and Mortality in Incident Hemodialysis Patients.

BACKGROUND: Abnormalities in mineral and bone disorder (MBD) markers are common in patients with chronic kidney disease. However, previous studies have not accounted for their changes over time, and it is unclear whether these changes are associated with survival. METHODS: We examined the association of change in MBD markers (serum phosphorus (Phos), albumin-corrected calcium (Ca(Alb)), intact parathyroid hormone (iPTH) and alkaline phosphatase (ALP)) during the first 6 months of hemodialysis (HD) with all-cause mortality across baseline MBD strata using survival models adjusted for clinical characteristics and laboratory measurements in 102,754 incident HD patients treated in a large dialysis organization between 2007 and 2011. RESULTS: Across all MBD markers (Phos, Ca(Alb), iPTH and ALP), among patients whose baseline MBD levels were higher than the reference range, increase in MBD levels was associated with higher mortality (reference group: MBD level within reference range at baseline and no change at 6 months follow-up). Conversely, decrease in Phos and iPTH, among baseline Phos and iPTH levels lower than the reference range, respectively, were associated with higher mortality. An increase in ALP was associated with higher mortality across baseline strata of ALP ≥80 U/l. However, patients with baseline ALP <80 U/l trended towards a lower risk of mortality irrespective of the direction of change at 6 months follow-up. CONCLUSIONS: There is a differential association between changes in MBD markers with mortality across varying baseline levels in HD patients. Further study is needed to determine if consideration of both baseline and longitudinal changes in the management of MBD derangements improves outcomes in this population.

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.

Examining the robustness of the obesity paradox in maintenance hemodialysis patients: a marginal structural model analysis.

BACKGROUND: The inverse association between body mass index (BMI) and mortality observed in patients treated with maintenance hemodialysis (MHD), also known as the obesity paradox, may be a result of residual confounding. Marginal structural model (MSM) analysis, a technique that accounts for time-varying confounders, may be more appropriate to investigate this association. We hypothesize that after applying MSM, the inverse association between BMI and mortality in MHD patients is attenuated. METHODS: We examined the associations between BMI and all-cause mortality among 123 624 adult MHD patients treated during 2001-6. We examined baseline and time-varying BMI using Cox proportional hazards models and MSM while considering baseline and time-varying covariates, including demographics, comorbidities and markers of malnutrition and inflammation. RESULTS: The patients included 45% women and 32% African Americans with a mean age of 61(SD 15) years. In all models, BMI showed a linear incremental inverse association with mortality. Compared with the reference (BMI 25 to <27.5 kg/m(2)), a BMI of <18 kg/m(2) was associated with a 3.2-fold higher death risk [hazard ratio (HR) 3.17 (95% CI 3.05-3.29)], and mortality risks declined with increasing BMI with the greatest survival advantage of 31% lower risk [HR 0.69 (95% CI 0.64-0.75)] observed with a BMI of 40 to <45 kg/m(2). CONCLUSIONS: The linear inverse relationship between BMI and mortality is robust across models including MSM analyses that more completely account for time-varying confounders and biases.

Pre-dialysis serum sodium and mortality in a national incident hemodialysis cohort.

BACKGROUND: A consistent association between low serum sodium measured at a single-point-in-time (baseline sodium) and higher mortality has been observed in hemodialysis patients. We hypothesized that both low and high time-varying sodium levels (sodium levels updated at quarterly intervals as a proxy of short-term exposure) are independently associated with higher death risk in hemodialysis patients. METHODS: We examined the association of baseline and time-varying pre-dialysis serum sodium levels with all-cause mortality among adult incident hemodialysis patients receiving care from a large national dialysis organization during January 2007-December 2011. Hazard ratios were estimated using multivariable Cox models accounting for case-mix+laboratory covariates and incrementally adjusted for inter-dialytic weight gain, blood urea nitrogen and glucose. RESULTS: Among 27 180 patients, a total of 7562 deaths were observed during 46 194 patient-years of follow-up. Median (IQR) at-risk time was 1.4 (0.6, 2.5) years. In baseline analyses adjusted for case-mix+laboratory results, sodium levels <138 mEq/L were associated with incrementally higher mortality risk, while the association of sodium levels ≥140 mEq/L with lower mortality reached statistical significance only for the highest level of pre-dialysis sodium (reference: 138-<140 mEq/L). In time-varying analyses, we observed a U-shaped association between sodium and mortality such that sodium levels <138 and ≥144 mEq/L were associated with higher mortality risk. Similar patterns were observed in models incrementally adjusted for inter-dialytic weight gain, blood urea nitrogen and glucose. CONCLUSIONS: We observed a U-shaped association of time-varying pre-dialysis serum sodium and all-cause mortality in hemodialysis patients, suggesting that both hypo- and hypernatremia carry short-term risk in this population.

Association of Height with Mortality in Patients Undergoing Maintenance Hemodialysis.

BACKGROUND AND OBJECTIVES: Body mass index (BMI), determined as kilograms in body weight divided by the square of the height in meters (m(2)), is inversely associated with mortality in patients undergoing maintenance hemodialysis (MHD). It is commonly inferred that differences in the weight component of the BMI equation are responsible for this negative correlation. However, there are almost no data on the relationship between height and mortality in these patients. This study was conducted to examine the association between height and mortality in MHD patients and to evaluate the contribution of height to the BMI-mortality relationship. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A prospective study conducted from July 1, 2001, through June 30, 2006, enrolled a nationally representative cohort of 117,644 MHD patients receiving treatment in DaVita, Inc. outpatient dialysis facilities with (1) known height and weight, (2) age ≥18 years, (3) dialysis vintage ≥90 days, and (4) nonoutlying BMI values (≥12 to ≤60 kg/m(2)). The end date of follow-up was June 30, 2007, and median follow-up was 852 days (interquartile range, 504-1367 days). Mortality hazard ratios were computed within sex-standardized deciles of height and weight, and outcomes included all-cause mortality and cardiovascular, gastrointestinal, cancer, and infection mortality. Hazard models were unadjusted, adjusted for case-mix variables, or adjusted for case-mix variables plus laboratory variables. RESULTS: Mean age was 61±15 years; 45% of patients were women and 57% had diabetes. In adjusted models, height, also adjusted for weight, was directly associated with all-cause mortality and cardiovascular, infection, and cancer mortality. Compared with the median height decile, mortality risk in the highest height decile was 1.18 (95% confidence interval, 1.14 to 1.23) in fully adjusted analyses (P<0.001). Receiver-operating characteristic curves indicated that in adjusted analyses the contribution of height to the relationship between BMI and mortality was almost identical to that of weight. CONCLUSIONS: In MHD patients, height is positively associated with mortality risk and contributes similarly to weight with regard to the negative BMI-mortality relationship.

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.