Vanessa Ravel

Predictors of treatment with dialysis modalities in observational studies for comparative effectiveness research

BACKGROUND The Institute of Medicine has identified the comparative effectiveness of renal replacement therapies as a kidney-related topic among the top 100 national priorities. Given the importance of ensuring internal and external validity, the goal of this study was to identify potential sources of bias in observational studies that compare outcomes with different dialysis modalities. METHODS This observational cohort study used data from the electronic medical records of all patients that started maintenance dialysis in the calendar years 2007-2011 and underwent treatment for at least 60 days in any of the 2217 facilities operated by DaVita Inc. Each patient was assigned one of six dialysis modalities for each 91-day period from the date of first dialysis (thrice weekly in-center hemodialysis (HD), peritoneal dialysis (PD), less-frequent HD, home HD, frequent HD and nocturnal in-center HD). RESULTS Of the 162 644 patients, 18% underwent treatment with a modality other than HD for at least one 91-day period. Except for PD, patients started treatment with alternative modalities after variable lengths of treatment with HD; the time until a change in modality was shortest for less-frequent HD (median time = 6 months) and longest for frequent HD (median time = 15 months). Between 30 and 78% of patients transferred to another dialysis facility prior to change in modality. Finally, there were significant differences in baseline and time-varying clinical characteristics associated with dialysis modality. CONCLUSIONS This analysis identified numerous potential sources of bias in studies of the comparative effectiveness of dialysis modalities.

Uncorrected and Albumin-Corrected Calcium, Phosphorus, and Mortality in Patients Undergoing Maintenance Dialysis

Uncorrected serum calcium concentration is the first mineral metabolism metric planned for use as a quality measure in the United States ESRD population. Few studies in patients undergoing either peritoneal dialysis (PD) or hemodialysis (HD) have assessed the association of uncorrected serum calcium concentration with clinical outcomes. We obtained data from 129,076 patients on dialysis (PD, 10,066; HD, 119,010) treated in DaVita, Inc. facilities between July 1, 2001, and June 30, 2006. After adjustment for potential confounders, uncorrected serum calcium <8.5 and ≥10.2 mg/dl were associated with excess mortality in patients on PD or HD (comparison group uncorrected calcium 9.0 to <9.5 mg/dl). Additional adjustment for serum albumin concentration substantially attenuated the all-cause mortality hazard ratios (HRs) associated with uncorrected calcium <8.5 mg/dl (HR, 1.29; 95% confidence interval [95% CI], 1.16 to 1.44 for PD; HR, 1.17; 95% CI, 1.13 to 1.20 for HD) and amplified the HRs associated with calcium ≥10.2 mg/dl (HR, 1.65; 95% CI, 1.42 to 1.91 for PD; HR, 1.59; 95% CI, 1.53 to 1.65 for HD). Albumin-corrected calcium ≥10.2 mg/dl and serum phosphorus ≥6.4 mg/dl were also associated with increased risk for death, irrespective of dialysis modality. In summary, in a large nationally representative cohort of patients on dialysis, abnormalities in markers of mineral metabolism, particularly high concentrations of serum calcium and phosphorus, were associated with increased mortality risk. Additional studies are needed to investigate whether control of hypercalcemia and hyperphosphatemia in patients undergoing dialysis results in improved clinical outcomes.

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.

COMPARATIVE MORTALITY-PREDICTABILITY USING ALKALINE PHOSPHATASE AND PARATHYROID HORMONE IN PATIENTS ON PERITONEAL DIALYSIS AND HEMODIALYSIS

♦ Background: In hemodialysis (HD) patients, serum alkaline phosphatase (ALP) and parathyroid hormone (PTH) derangements are associated with mortality, but outcome-predictability using ALP and PTH in peritoneal dialysis (PD) patients remains uncertain. ♦ Methods: In a cohort of 9244 adult PD patients from a large national dialysis organization (entry period 2001 - 2006, with follow-up through 2009), we used multivariable Cox models adjusted for case-mix and laboratory covariates to examine the associations of time-averaged ALP and PTH with all-cause mortality. We then compared mortality-predictability using ALP and PTH in 9244 PD and 99 323 HD patients. ♦ Results: In PD patients, ALP concentrations exceeding 150 U/L were associated with increased mortality (reference ALP: 70 to <90 U/L). Hazard ratios (HRs) and 95% confidence intervals (CIs) were 1.18 (1.03 to 1.36), 1.27 (1.08 to 1.50), 1.49 (1.23 to 1.79), and 1.35 (1.19 to 1.53) for ALP concentrations of 150 to <170 U/L, 170 to <190 U/L, 190 to <210 U/L, and ≥210 U/L respectively. In contrast, we observed a U-shaped association between PTH concentration and death risk in PD patients, with PTH concentrations of less than 200 pg/mL and 700 pg/mL or more associated with increased mortality (reference PTH: 200 to <300 pg/mL). Hazard ratios and 95% CIs were 1.25 (1.12 to 1.41), 1.12 (1.02 to 1.23), 1.06 (0.96 to 1.18), 1.09 (0.97 to 1.24), 1.12 (0.97 to 1.29), 1.18 (0.99 to 1.40), and 1.23 (1.09 to 1.38) for PTH concentrations of <100 pg/mL, 100 to <200 pg/mL, 300 to <400 pg/mL, 400 to <500 pg/mL, 500 to <600 pg/mL, 600 to <700 pg/mL, and ≥700 pg/mL respectively. Compared with PD patients having serum concentrations of ALP and PTH within reference ranges, patients on HD experienced increased mortality across all ALP and PTH concentrations, particularly those in the lowest and highest categories. ♦ Conclusions: In summary, higher ALP concentrations are associated with increased mortality, and lower and higher PTH concentrations are both associated with death risk in PD patients. The utility of ALP in the management of chronic kidney disease mineral bone disorders in PD patients warrants further study.

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.

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.

Racial and Ethnic Disparities in Use of and Outcomes with Home Dialysis in the United States

Home dialysis, which comprises peritoneal dialysis (PD) or home hemodialysis (home HD), offers patients with ESRD greater flexibility and independence. Although ESRD disproportionately affects racial/ethnic minorities, data on disparities in use and outcomes with home dialysis are sparse. We analyzed data of patients who initiated maintenance dialysis between 2007 and 2011 and were admitted to any of 2217 dialysis facilities in 43 states operated by a single large dialysis organization, with follow-up through December 31, 2011 (n =: 162,050, of which 17,791 underwent PD and 2536 underwent home HD for ≥91 days). Every racial/ethnic minority group was significantly less likely to be treated with home dialysis than whites. Among individuals treated with in-center HD or PD, racial/ethnic minorities had a lower risk for death than whites; among individuals undergoing home HD, only blacks had a significantly lower death risk than whites. Blacks undergoing PD or home HD had a higher risk for transfer to in-center HD than their white counterparts, whereas Asians or others undergoing PD had a lower risk than whites undergoing PD. Blacks irrespective of dialysis modality, Hispanics undergoing PD or in-center HD, and Asians and other racial groups undergoing in-center HD were significantly less likely than white counterparts to receive a kidney transplant. In conclusion, there are racial/ethnic disparities in use of and outcomes with home dialysis in the United States. Disparities in kidney transplantation evident for blacks and Hispanics undergoing home dialysis are similar to those with in-center HD. Future studies should identify modifiable causes for these disparities.

Peritoneal Equilibration Test and Patient Outcomes

BACKGROUND AND OBJECTIVES Although a peritoneal equilibration test yields data on three parameters (4-hour dialysate/plasma creatinine, 4- to 0-hour dialysate glucose, and 4-hour ultrafiltration volume), all studies have focused on the prognostic value of dialysate/plasma creatinine for patients undergoing peritoneal dialysis. Because dialysate 4- to 0-hour glucose and ultrafiltration volume may be superior in predicting daily ultrafiltration, the likely mechanism for the association of peritoneal equilibration test results with outcomes, we hypothesized that they are superior to dialysate/plasma creatinine for risk prediction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We examined unadjusted and adjusted associations of three peritoneal equilibration test parameters with all-cause mortality, technique failure, and hospitalization rate in 10,142 patients on peritoneal dialysis treated between January 1, 2007 and December 31, 2011 in 764 dialysis facilities operated by a single large dialysis organization in the United States, with a median follow-up period of 15.8 months; 87% were treated with automated peritoneal dialysis. RESULTS Demographic and clinical parameters explained only 8% of the variability in dialysate/plasma creatinine. There was a linear association between dialysate/plasma creatinine and mortality (adjusted hazards ratio per 0.1 unit higher, 1.07; 95% confidence interval, 1.02 to 1.13) and hospitalization rate (adjusted incidence rate ratio per 0.1 unit higher, 1.05; 95% confidence interval, 1.03 to 1.06). Dialysate/plasma creatinine and dialysate glucose were highly correlated (r=-0.84) and yielded similar risk prediction. Ultrafiltration volume was inversely related with hospitalization rate but not with all-cause mortality. None of the parameters were associated with technique failure. Adding 4- to 0-hour dialysate glucose, ultrafiltration volume, or both did not result in any improvement in risk prediction with dialysate/plasma creatinine alone. CONCLUSIONS This analysis from a large contemporary cohort treated primarily with automated peritoneal dialysis validates dialysate/plasma creatinine as a robust predictor of outcomes in patients treated with peritoneal dialysis.

Extended-hours hemodialysis is associated with lower mortality risk in patients with end-stage renal disease.

Extended-hours hemodialysis offers substantially longer treatment time compared to conventional hemodialysis schedules and is associated with improved fluid and electrolyte control and favorable cardiac remodeling. However, whether extended-hours hemodialysis improves survival remains unclear. Therefore, we determined the association between extended-hours compared to conventional hemodialysis and the risk of all-cause mortality in a nationally representative cohort of patients initiating maintenance dialysis in the United States from 2007 to 2011. Survival analyses using causal inference modeling with marginal structural models were performed to compare mortality risk among 1206 individuals undergoing thrice weekly extended-hours hemodialysis or 111,707 patients receiving conventional hemodialysis treatments. The average treatment time per session for extended-hours hemodialysis was 399 minutes compared to 211 minutes for conventional therapy. The crude mortality rate with extended-hours hemodialysis was 6.4 deaths per 100 patient-years compared with 14.7 deaths per 100 patient-years for conventional hemodialysis. In the primary analysis, patients treated with extended-hours hemodialysis had a 33% lower adjusted risk of death compared to those who were treated with a conventional regimen (95% confidence interval: 7% to 51%). Additional analyses accounting for analytical assumptions regarding exposure and outcome, facility-level confounders, and prior modality history were similar. Thus, in this large nationally representative cohort, treatment with extended-hours hemodialysis was associated with a lower risk for mortality compared to treatment with conventional in-center therapy. Adequately powered randomized clinical trials comparing extended-hours to conventional hemodialysis are required to confirm these findings.