Identifying Optimal Anemia Management Practices in Hemodialysis

Optimal anemia management strategies for end-stage kidney disease patients treated with hemodialysis are unknown, with controversies over how best to utilize erythropoiesis-stimulating agents (ESA) and intravenous iron to support hemoglobin levels and minimize adverse events. With large randomized trials rare in nephrology, it is thus crucial that research questions are clearly defined, study designs are appropriately selected, and analytic techniques are properly implemented when using observational data. The three aims of this dissertation attempt to address current controversies in anemia management using innovative statistical methods, leveraging data from the Dialysis Outcomes and Practice Patterns Study (DOPPS), an international prospective cohort study of hemodialysis patients. Aim 1 focused on anemia management during the transition period to hemodialysis. Among patients who initiated hemodialysis with hemoglobin =10 g/dL) four months later – was used to limit inclusion of patients whose low hemoglobin at hemodialysis initiation was likely confounded by poor health status. Even in this subset, anemia at hemodialysis initiation was common and associated with elevated mortality. A more proactive approach to anemia management prior to end-stage kidney disease may thus avoid aggressive correction of hemoglobin levels during the early dialysis period and improve survival. Aim 2 focused on how hemoglobin response to ESA therapy may be blunted by inflammation. Hemoglobin and ESA doses were compared over the 3 months before and after detection of new inflammation, defined as an acute C-reactive protein increase from 10 mg/L. Confounding due to baseline characteristics, whether measured (age, sex, comorbidity history) or unmeasured (genetic or environmental factors), was avoided by this longitudinal self-matched design. Patients experiencing new inflammation had both higher ESA doses and lower hemoglobin (vs. pre-inflammation levels), supporting the hypothesis that inflammation increases resistance to ESA treatment. Quicker recognition of new inflammation in hemodialysis patients could help identify the cause of worsening anemia and guide ESA and intravenous iron dosing decisions more proactively. Aim 3 focused on applying the parametric g-formula, an extension of standardization to longitudinal data, to replicate a randomized trial using observational data. DOPPS data were used to compare iron supplementation strategies, with the goal of mimicking the recently published PIVOTAL randomized trial. Comparing the proactive high-dose vs. reactive low-dose strategy, 1-year mortality risk was 20% greater under the parametric g-formula simulation, but similar in the PIVOTAL trial. Simulated differences for all secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial. Success in mimicking the PIVOTAL trial was mixed, and potential explanations for the divergent results include model misspecification and/or differences in the study populations. This example illustrates the potential of the parametric g-formula to evaluate many variations of complex interventions across different populations, which could prove enormously informative in the age of big data. This dissertation outlines critical gaps in the literature on anemia management in hemodialysis patients, and describes three studies that utilize innovative designs and complex statistical analyses to address these gaps. These studies attempt to advance both the optimization of anemia management strategies in hemodialysis patients and the use of causal inference principles to guide epidemiologic research using observational data.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/153463/1/akaraboy_1.pd

Association between serum ferritin and mortality : findings from the USA, Japan and European Dialysis Outcomes and Practice Patterns Study

Background: The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ. Methods: Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders. Results: Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region. Conclusion: The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed

Low hemoglobin at hemodialysis initiation : an international study of anemia management and mortality in the early dialysis period

Background. Anemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise. Methods. We included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4-5 (2009-15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb >= 10 g/dL 91-120 days after HD start (Month 4). Results. About 53% of these patients had Hgb = 10 g/dL). Month 1 Hgb was associated with first-year HD mortality (adjusted hazard ratio for 1 g/dL higher Hgb was 0.89; 95% confidence interval: 0.81-0.97), despite minimal differences in Month 4 Hgb. Patients with lower Hgb in Month 1 received higher doses of ESA, but not IV iron, over the first 3 months of HD. Results were consistent when excluding catheter users or adjusting for IV iron and ESA dose over the first 3 months. Conclusions. Even among patients with Hgb >= 10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed

Mortality risk in patients on hemodiafiltration versus hemodialysis : a 'real-world' comparison from the DOPPS

Background. With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes. Methods. In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume. Results. Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF > 20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities usingmore HDF (versus HD). Conclusions. Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices

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 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

The association of functional status with mortality and dialysis modality change : results from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS)

BACKGROUND: Little is known about the prevalence of functional impairment in peritoneal dialysis (PD) patients, its variation by country, and its association with mortality or transfer to hemodialysis. METHODS: A prospective cohort study was conducted in PD patients from 7 countries in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS) (2014 - 2017). Functional status (FS) was assessed by combining self-reports of 8 instrumental and 5 basic activities of daily living, using the Lawton-Brody and the Katz questionnaires. Summary FS scores, ranging from 1.25 (most dependent) to 13 (independent), were based on the patient's ability to perform each activity with or without assistance. Logistic regression was used to estimate the odds ratio (OR; 95% confidence interval [CI]) of a FS score < 11 comparing each country with the United States (US). Cox regression was used to estimate the hazard ratio (HR; 95% CI) for the effect of a low FS score on mortality and transfer to hemodialysis, adjusting for case mix. RESULTS: Of 2,593 patients with complete data on FS, 48% were fully independent (FS = 13), 32% had a FS score 11 to < 13, 14% had a FS score 8 to < 11, and 6% had a FS score < 8. Relative to the US, low FS scores (< 11; more dependent) were more frequent in Thailand (OR = 10.48, 5.90 - 18.60) and the United Kingdom (UK) (OR = 3.29, 1.77 - 6.08), but similar in other PDOPPS countries. The FS score was inversely and monotonically associated with mortality but not with transfer to hemodialysis; the HR, comparing a FS score < 8 vs 13, was 4.01 (2.44 - 6.61) for mortality and 0.91 (0.58 - 1.43) for transfer to hemodialysis. CONCLUSION: Regional differences in FS scores observed across PDOPPS countries may have been partly due to differences in regional patient selection for PD. Functional impairment was associated with mortality but not with permanent transfer to hemodialysis