Authors’ Reply
Authors: Murilo Guedes, Bruce Robinson, Brian Bieber, Roberto Pecoits-Filho
Journal: Journal of the American Society of Nephrology (2022)

We read with interest the Letter to the Editor by Rostoker and colleagues highlighting important aspects of our study on biomarkers of iron stores and clinical outcomes among patients with CKD.1 The authors suggest that, because biomarkers of iron stores are also acute-phase reactants, adjustment for C-reactive protein (CRP) would be preferred in our models. Indeed, Rostoker and colleagues are fundamentally correct when emphasizing the associations between inflammation and iron store biomarkers. Although we addressed these points in our manuscript, we would like to expand the discussion here. Inflammation increases hepcidin levels and thus results in reduced gastrointestinal iron absorption and triggers iron entrapment in the reticuloendothelial system. In fact, this iron restriction characterizes functional iron deficiency, a phenotype associated with worse clinical and patient-reported outcomes in heart failure2 and CKD.3 The extent to which the association between iron deficiency and mortality is primarily driven by the underlying inflammatory milieu or by tissue iron deficiency is currently unknown. However, tissue iron deficiency as the primary culprit is supported by a growing body of translational and clinical research.4 Of note, as suggested by our contour plots, even iron-deficient patients with low ferritin (who were, presumably, not as much burdened by inflammation) were at higher risk for all-cause mortality.1 It is well established that inflammation is involved in processes of iron deficiency and correlates with biomarkers of iron stores. It is also well appreciated that patients who are inflamed have higher risk for adverse clinical outcomes.4 Hence, not appropriately adjusting for inflammation may lead to bias when estimating the effect of iron deficiency on outcomes. Then, the question is for which inflammation surrogates should one choose to adjust? The Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) is a prospective cohort study reflecting nephrologists' real-world practices around the globe. Unfortunately, CRP is not routinely measured in clinical practice in most countries, and few patients in our study have CRP measurements available. Rather, patients with a CRP measurement are often being assessed "by indication," e.g., for acute clinical conditions such as suspected infection or autoimmune disease. We were able to adjust for inflammatory surrogates (white blood cells and albumin) that are routinely measured at CKDopps sites. Importantly, we also adjusted for transferrin saturation and ferritin. In models defining transferrin saturation (or ferritin) as the exposure, the inclusion of the other marker in the adjustment set assumes the latter is capturing information on biologic processes beyond iron deficiency—namely, inflammation. The question remains whether adjusting for the particular set of inflammatory surrogates available for our analysis sufficiently accounts for the potentially confounding influence of the chronic inflammatory milieu. This is one of the reasons why clinically relevant, event-driven randomized controlled trials for the treatment of iron deficiency in CKD are long overdue. Disclosures B. Bieber reports receiving research funding from the Dialysis Outcomes and Practice Patterns Study (DOPPS). R. Pecoits-Filho reports receiving grants (paid to employer) from Akebia, AstraZeneca, Bayer, Boehringer-Lilly, and Novo Nordisk (for participation in advisory boards and educational activities); receiving honoraria from Akebia, AstraZeneca, Bayer, Fresenius Medical Care, and Retrophin; serving on the editorial boards for American Journal of Kidney Diseases, Blood Purification, Hemodialysis International, International Society of Nephrology, Kidney Disease Improving Global Outcomes, Nephrology, and Peritoneal Dialysis International; being employed by Arbor Research Collaborative for Health (which runs the DOPPS studies); serving on speakers bureaus for AstraZeneca, Bayer, and Boehringer Ingelheim; receiving research funding from Fresenius Medical Care and National Council for Scientific and Technological Development; having consultancy agreements with George Clinical; and serving as a scientific advisor for, or member of, the Standardised Outcomes in Nephrology Initiative Executive Committee. B. Robinson reports serving on the editorial board of the American Journal of Kidney Diseases; receiving consultancy fees or travel reimbursement in the last 3 years from AstraZeneca, GlaxoSmithKline, and Kyowa Kirin Co., all paid directly to his institution of employment; and being the principal investigator of the DOPPS Program, which is funded by a consortium of private industry, public funders, and professional societies. The remaining author has nothing to disclose. Funding None.