Gout Prevalence, Practice Patterns, and Associations with Outcomes in North American Dialysis Patients.

INTRODUCTION: Gout occurs frequently in patients with kidney disease and can lead to a significant burden on quality of life. Gout prevalence, and its association with outcomes in hemodialysis (HD) and peritoneal dialysis (PD) populations located in North America, is unknown. METHODS: We used data from North America cohorts of 70,297 HD patients (DOPPS, 2012-2020) and 5117 PD patients (PDOPPS, 2014-2020). We used three definitions of gout for this analysis: (1) having an active prescription for colchicine or febuxostat; (2) having an active prescription for colchicine, febuxostat, or allopurinol; or (3) having an active prescription for colchicine, febuxostat, or allopurinol, or prior diagnosis of gout. Propensity score matching was used to compare outcomes among patients with versus without gout. Outcomes included erythropoietin resistance index (ERI=erythropoiesis stimulating agent dose per week/(hemoglobin×weight)), all-cause mortality, hospitalization, and patient-reported outcomes (PROs). RESULTS: The gout prevalence was 13% in HD and 21% in PD; it was highest among incident dialysis patients. Description of previous history of gout was rare, and identification of gout defined by colchicine (2%-3%) or febuxostat (1%) prescription was less frequent than by allopurinol (9%-12%). Both HD and PD patients with gout (versus no gout) were older, were more likely male, had higher body mass index, and had higher prevalence of cardiovascular comorbidities. About half of patients with a gout history were prescribed urate-lowering therapy. After propensity score matching, mean ERI was 3%-6% higher for gout versus non-gout patients while there was minimal evidence of association with clinical outcomes or PROs. CONCLUSION: In a large cohort of PD and HD patients in North America, we found that gout occurs frequently and is likely under-reported. Gout was not associated with adverse clinical or PROs.

Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient.

INTRODUCTION: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. METHODS: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. RESULTS: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. DISCUSSION/CONCLUSION: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA - resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Etelcalcetide Utilization, Dosing Titration, and Chronic Kidney Disease-Mineral and Bone Disease (CKD-MBD) Marker Responses in US Hemodialysis Patients.

RATIONALE & OBJECTIVE: Clinical trial data have demonstrated the efficacy of etelcalcetide for reducing parathyroid hormone (PTH) levels in hemodialysis (HD) patients. We provide a real-world summary of etelcalcetide utilization, dosing, effectiveness, and discontinuation since its US introduction in April 2017. STUDY DESIGN: New-user design within prospective cohort. SETTING & PARTICIPANTS: 2,596 new users of etelcalcetide from April 2017 through August 2019 in a national sample of adult maintenance HD patients in the US Dialysis Outcomes and Practice Patterns Study (DOPPS). PREDICTORS: Baseline PTH, prior cinacalcet use, initial etelcalcetide dose. OUTCOME: Trajectories of etelcalcetide dose, chronic kidney disease-mineral and bone disease (CKD-MBD) medications, and levels of PTH, serum calcium, and phosphorus in the 12 months after etelcalcetide initiation. ANALYTICAL APPROACH: Cumulative incidence methods for etelcalcetide discontinuation and linear generalized estimating equations for trajectory analyses. RESULTS: By August 2019, etelcalcetide prescriptions increased to 6% of HD patients from their first use in April 2017. Starting etelcalcetide dose was 15 mg/wk in 70% of patients and 7.5 mg/wk in 27% of patients; 49% of new users were prescribed cinacalcet in the prior 3 months. Etelcalcetide discontinuation was 9%, 17%, and 27% by 3, 6, and 12 months after initiation. One year after etelcalcetide initiation, mean PTH levels declined by 40%, from 948 to 566 pg/mL, and the proportion of patients with PTH within target (150-599 pg/mL) increased from 33% to 64% overall, from 0 to 60% among patients with baseline PTH ≥ 600 pg/mL, and from 30% to 63% among patients with prior cinacalcet use. The proportion of patients with serum phosphorus > 5.5 mg/dL decreased from 55% to 45%, while the prevalence of albumin-corrected serum calcium < 7.5 mg/dL remained at 1%-2%. There were increases in use of active vitamin D (from 77% to 87%) and calcium-based phosphate binders (from 41% to 50%) in the 12 months after etelcalcetide initiation. LIMITATIONS: Data are unavailable for provider dosing protocols, dose holds, or reasons for discontinuation. CONCLUSIONS: In the 12 months after etelcalcetide initiation, patients had large and sustained reductions in PTH levels. These results support the utility of etelcalcetide as an effective therapy to achieve the KDIGO-recommended guidelines for CKD-MBD markers in HD patients.

Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

BACKGROUND: Reproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS). METHODS: To overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients. RESULTS: Comparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial. CONCLUSION: Our findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.

Associations between Hemodialysis Facility Practices to Manage Fluid Volume and Intradialytic Hypotension and Patient Outcomes.

BACKGROUND AND OBJECTIVES: Fluid overload and intradialytic hypotension are associated with cardiovascular events and mortality in patients on hemodialysis. We investigated associations between hemodialysis facility practices related to fluid volume and intradialytic hypotension and patient outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were analyzed from 10,250 patients in 273 facilities across 12 countries, from phase 4 of the Dialysis Outcomes and Practice Patterns Study (DOPPS; 2009-2012). Cox regression models (shared frailty) were used to estimate associations between facility practices reported by medical directors in response to the DOPPS Medical Directors Survey and all-cause and cardiovascular mortality and hospitalization, and cardiovascular events, adjusting for country, age, sex, dialysis vintage, predialysis systolic BP, cardiovascular comorbidities, diabetes, body mass index, smoking, residual kidney function, dialysis adequacy, and vascular access type. RESULTS: Of ten facility practices tested (chosen a priori), having a protocol that specifies how often to assess dry weight in most patients was associated with lower all-cause (hazard ratio [HR], 0.78; 99% confidence interval [99% CI], 0.64 to 0.94) and cardiovascular mortality (HR, 0.72; 99% CI, 0.55 to 0.95). Routine orthostatic BP measurement to assess dry weight was associated with lower all-cause hospitalization (HR, 0.86; 99% CI, 0.77 to 0.97) and cardiovascular events (HR, 0.85; 99% CI, 0.73 to 0.98). Routine use of lower dialysate temperature to limit or prevent intradialytic hypotension was associated with lower cardiovascular mortality (HR, 0.76; 99% CI, 0.58 to 0.98). Routine use of an online volume indicator to assess dry weight was associated with higher all-cause hospitalization (HR, 1.19; 99% CI, 1.02 to 1.38). Routine use of sodium modeling/profiling to limit or prevent intradialytic hypotension was associated with higher all-cause mortality (HR, 1.36; 99% CI, 1.14 to 1.63), cardiovascular mortality (HR, 1.34; 99% CI, 1.04 to 1.73), and cardiovascular events (HR, 1.21; 99% CI, 1.03 to 1.43). CONCLUSIONS: Hemodialysis facility practices relating to the management of fluid volume and intradialytic hypotension are associated with patient outcomes.

Functional Dependence and Mortality in the International Dialysis Outcomes and Practice Patterns Study (DOPPS).

BACKGROUND: Patients receiving long-term dialysis have among the highest mortality and hospitalization rates. In the nonrenal literature, functional dependence is recognized as a contributor to subsequent disability, recurrent hospitalization, and increased mortality. A higher burden of functional dependence with progressive worsening of kidney function has been observed in several studies, suggesting that functional dependence may contribute to both morbidity and mortality in dialysis patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 7,226 hemodialysis patients from 12 countries in the DOPPS (Dialysis Outcomes and Practice Patterns Study) phase 4 (2009-2011) with self-reported data for functional status. PREDICTOR: Patients' ability to perform 13 basic and instrumental activities of daily living was summarized to create an overall functional status score (range, 1.25 [most dependent] to 13 [functionally independent]). OUTCOME: Cox regression was used to estimate the association between functional status and all-cause mortality, adjusting for several demographic and clinical risk factors for mortality. Median follow-up was 17.2 months. RESULTS: The proportion of patients who could perform each activity of daily living task without assistance ranged from 97% (eating) to 47% (doing housework). 36% of patients could perform all 13 tasks without assistance (functional status = 13), and 14% of patients had high functional dependence (functional status < 8). Functionally independent patients were younger and had many indicators of better health status, including higher quality of life. Compared with functionally independent patients, the adjusted HR for mortality was 2.37 (95% CI, 1.92-2.94) for patients with functional status < 8. LIMITATIONS: Possible nonresponse bias and residual confounding. CONCLUSIONS: We found a high burden of functional dependence across all age groups and across all DOPPS countries. When adjusting for several known mortality risk factors, including age, access type, cachexia, and multimorbidity, functional dependence was a strong consistent predictor of mortality.

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing.

BACKGROUND AND OBJECTIVES: Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients' changes in ferritin over time. RESULTS: Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009-2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. CONCLUSIONS: In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of these changes in ferritin on health outcomes requires further investigation.

Association between allopurinol and mortality among Japanese hemodialysis patients: results from the DOPPS.

PURPOSE: Allopurinol, for treating hyperuricemia, is associated with lower mortality among hyperuricemic patients without chronic kidney disease (CKD). Greater allopurinol utilization in hemodialysis (HD) in Japan versus other countries provides an opportunity for understanding allopurinol-related HD outcomes. METHODS: Data from 6,252 Japanese HD patients from phases 1-3 of the Dialysis Outcomes and Practice Patterns Study (1999-2008) at ~60 facilities per phase were analyzed. Mortality was compared for patients prescribed (25 %) versus not-prescribed allopurinol using Cox regression, overall, and in patient subgroups. RESULTS: Patients prescribed allopurinol were more likely to be younger, male, and non-diabetic, and had higher serum creatinine and lower (treated) serum uric acid levels (mean = 7.0 vs. 8.0 mg/dL, p < 0.001). The inverse association between allopurinol prescription and mortality in unadjusted analyses (HR 0.65, 95 % CI 0.52-0.81) was attenuated by covariate adjustment (HR 0.84, 0.66-1.06). In subgroup analyses, allopurinol was associated with lower mortality among patients with no history of cardiovascular disease (CVD) (HR 0.48, 0.28-0.83), but not among patients with CVD (HR 1.00, 0.76-1.32). A similar pattern was seen outside Japan and for cardiovascular (CV)-related mortality. CONCLUSIONS: Allopurinol prescription was not significantly associated with case-mix-adjusted mortality in Japanese HD patients overall, but was associated with lower all-cause and CV-related mortality in the subgroup of patients with no prior CVD history. These findings in HD patients may be related to findings in non-dialysis CKD patients showing lower CV event rates and mortality, and improved endothelial function with allopurinol prescription. These results are useful for designing future trials of allopurinol use in HD patients.