Inflammation and Erythropoiesis-Stimulating Agent Response in Hemodialysis Patients: A Self-matched Longitudinal Study of Anemia Management in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

RATIONALE & OBJECTIVE: Previous studies of inflammation and anemia management in hemodialysis (HD) patients may be biased due to patient differences. We used a self-matched longitudinal design to test whether new inflammation, defined as an acute increase in C-reactive protein (CRP) level, reduces hemoglobin response to erythropoiesis-stimulating agent (ESA) treatment. STUDY DESIGN: Self-matched longitudinal design. SETTING & PARTICIPANTS: 3,568 new inflammation events, defined as CRP level > 10 mg/L following a 3-month period with CRP level ≤ 5 mg/L, were identified from 12,389 HD patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 6 (2009-2018) in 10 countries in which CRP is routinely measured. PREDICTOR: "After" (vs "before") observing a high CRP level. OUTCOMES: Within-patient changes in hemoglobin level, ESA dose, and ESA hyporesponsiveness (hemoglobin < 10 g/dL and ESA dose > 6,000 [Japan] or >8,000 [Europe] U/wk). ANALYTICAL APPROACH: Linear mixed models and modified Poisson regression. RESULTS: Comparing before with after periods, mean hemoglobin level decreased from 11.2 to 10.9 g/dL (adjusted mean change, -0.26 g/dL), while mean ESA dose increased from 6,320 to 6,960 U/wk (adjusted relative change, 8.4%). The prevalence of ESA hyporesponsiveness increased from 7.6% to 12.3%. Both the unadjusted and adjusted prevalence ratios of ESA hyporesponsiveness were 1.68 (95% CI, 1.48-1.91). These associations were consistent in sensitivity analyses varying CRP thresholds and were stronger when the CRP level increase was sustained over the 3-month after period. LIMITATIONS: Residual confounding by unmeasured time-varying risk factors for ESA hyporesponsiveness. CONCLUSIONS: In the 3 months after HD patients experienced an increase in CRP levels, hemoglobin levels declined quickly, ESA doses increased, and the prevalence of ESA hyporesponsiveness increased appreciably. Routine CRP measurement could identify inflammation as a cause of worsened anemia. In turn, these findings speak to a potentially important role for anemia therapies that are less susceptible to the effects of inflammation.

Predialysis anemia management and outcomes following dialysis initiation: A retrospective cohort analysis.

Whether and how anemia treatment with erythropoiesis stimulating agents (ESAs) before hemodialysis initiation may be associated with lower mortality after dialysis initiation is unknown. We compared all-cause and cardiovascular mortality in two groups of patients who experienced distinct anemia treatment patterns with ESAs before and after hemodialysis initiation. This retrospective cohort analysis included patients initiating hemodialysis April 1, 2012-June 30, 2013, identified from United States Renal Data System end-stage renal disease (ESRD) and pre-ESRD files. Patients treated with ESAs before and after hemodialysis initiation who maintained Hb ≥ 9.0 g/dL throughout (comparator group, n = 3662) were compared with patients with Hb < 9.0 g/dL before hemodialysis initiation (with or without ESAs) whose levels increased with ESAs after hemodialysis initiation (referent group, n = 4461). Cox proportional hazards models were used to calculate the hazard ratio of all-cause and cardiovascular mortality after hemodialysis initiation. Of 20,454 patients, 4855 (23.7%) had Hb < 9.0 g/dL upon hemodialysis initiation; of these 4855, 26.6% received ESAs before initiation. Comparator group Hb levels increased from 8.2 ± 0.8 mg/dL upon initiation to 10.9 ± 1.2 with ESAs afterward. Comparator patients were more likely than referent patients to be younger (76.3 ± 6.7 versus 77.2 ± 6.9 years), male (51.5% versus 49.8%), and black (24.6% versus 18.6%). Risk of all-cause mortality was lower for the comparator group versus the referent group at 3 (HR 0.83, 95% CI 0.68-1.00, P = 0.052), 6 (0.86, 0.74-1.00, P = 0.047), and 12 (0.88, 0.78-0.99, P = 0.036) months. The pattern was similar for cardiovascular mortality. Hb ≥ 9.0 with ESAs before and after hemodialysis initiation was generally associated with lower post-initiation all-cause and cardiovascular mortality compared with predialysis Hb < 9.0 g/dL in patients whose Hb levels subsequently improved with ESAs after hemodialysis initiation.

The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial.

BACKGROUND: Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels. STUDY DESIGN: 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. SETTING & PARTICIPANTS: Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders. INTERVENTION: 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). OUTCOMES: Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. MEASUREMENTS: Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. RESULTS: There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (-2.04±1.99 [SD] vs -2.18±2.25 mg/dL, respectively; P=0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22±0.90 vs 0.31±0.95 mg/dL; P=0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (-167.1±399.8 vs -152.7±392.1 pg/mL; P=0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. LIMITATIONS: Open-label study, few peritoneal dialysis patients. CONCLUSIONS: Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate.