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)

Abstract

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.

Keywords: inflammation, anemia management, erythropoiesis-stimulating agents, hemodialysis, DOPPS.

Graphical abstract

Figure 1

Illustration of before-after study design. For a given patient, average hemoglobin (Hgb) level and erythropoiesis-stimulating agent (ESA) dose were observed during the 3 months following an increase in C-reactive protein (CRP) level from low (≤5 mg/L) to high (>10 mg/L). Time-varying confounders were included during the month preceding the “before” period (C₁) and the month preceding the CRP level increase (C₂).

Figure 2

Flow chart illustrates inclusion/exclusion criteria. ∗Routine measurement of C-reactive protein (CRP) by a facility defined as ≥25% of patient-months with a CRP measurement, that is, CRP measured at least once every 4 months on average. Note that the 194,917 CRP measurements from 12,389 patients were used as the basis to report the distribution of CRP in Figure 3. Abbreviation: DOPPS, Dialysis Outcomes and Practice Patterns Study.

Figure 3

C-Reactive protein (CRP) level distribution, by country. Columns may not sum to 100% due to rounding. Abbreviations and Definitions: A/NZ, Australia/New Zealand; N obs, number of monthly CRP measurements available from these patients (denominators for the figure); N pats, number of patients with CRP measurements who are potentially eligible for inclusion (as described in Fig 2); UK, United Kingdom.

Figure 4

(A) Mean monthly hemoglobin level, (B) mean monthly erythropoiesis-stimulating agent (ESA) dose, and (C) percent ESA hyporesponsive in the 3 months before and after a C-reactive protein (CRP) level increase from ≤5 to >10 mg/L, by region. Mean hemoglobin level and ESA dose were calculated as the average across all patients at each time point. Months during which ESA was not prescribed are considered 0 U/wk. ESA hyporesponsive defined as hemoglobin level <10 g/dL and ESA dose > 6,000 (Japan) or >8,000 (Europe/ANZ) U/wk. Abbreviations: ANZ, Australia/New Zealand; CI, confidence interval.