Iron Sucrose and Blood Pressure Patterns During Hemodialysis

Abstract

Related Article, p. ∗∗∗ Related Article, p. ∗∗∗ Blood pressure management in persons receiving thrice-weekly hemodialysis is a perennial challenge. Intradialytic blood pressure management is particularly vexing, given the need to provide adequate volume removal during short treatment periods while avoiding excessively high or low blood pressures and minimizing extreme blood pressure changes.1Flythe J.E. Chang T.I. Gallagher M.P. et al.Blood pressure and volume management in dialysis: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.Kidney Int. 2020; 97: 861-876https://doi.org/10.1016/j.kint.2020.01.046Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Numerous physiologic perturbations affect blood pressure during hemodialysis. Intravascular volume removal and refilling, cardiac contractility, dialysate temperature, and dialysate osmolality and composition have all received much attention, yet the effects of the medications regularly administered during hemodialysis are also potentially important.2Reeves P.B. Mc Causland F.R. Mechanisms, clinical implications, and treatment of intradialytic hypotension.Clin J Am Soc Nephrol. 2018; 13: 1297-1303https://doi.org/10.2215/CJN.12141017Crossref PubMed Scopus (61) Google Scholar In this issue of AJKD, Singh et al report an investigation of the potential association of intravenous iron sucrose infusion with intradialytic blood pressure patterns in an observational cohort, driven by concern that iron sucrose may cause hypotension.3Singh AT, Yen TE, Mothi SS, Waikar SS, Mc Causland FR. Associations of iron sucrose and intradialytic blood pressure. Am J Kidney Dis. Published online December 29, 2022. https://doi.org/10.1053/j.ajkd.2022.11.007Google Scholar Intravenous iron is routinely infused during maintenance hemodialysis sessions as a central component of anemia management, and there is much interest in potential beneficial effects of maintaining adequate iron stores beyond red cell production.4Babitt J.L. Eisenga M.F. Haase V.H. et al.Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.Kidney Int. 2021; 99: 1280-1295https://doi.org/10.1016/j.kint.2021.03.020Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 5Batchelor E.K. Kapitsinou P. Pergola P.E. Kovesdy C.P. Jalal D.I. Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment.J Am Soc Nephrol. 2020; 31: 456-468https://doi.org/10.1681/ASN.2019020213Crossref PubMed Scopus (67) Google Scholar, 6Patino E. Akchurin O. Erythropoiesis-independent effects of iron in chronic kidney disease.Pediatr Nephrol. 2022; 37: 777-788https://doi.org/10.1007/s00467-021-05191-9Crossref PubMed Scopus (3) Google Scholar While evidence has accrued about the benefits and safety of intravenous iron in persons receiving dialysis,7Macdougall I.C. White C. Anker S.D. et al.Intravenous iron in patients undergoing maintenance hemodialysis.N Engl J Med. 2019; 380: 447-458https://doi.org/10.1056/NEJMoa1810742Crossref PubMed Scopus (218) Google Scholar,8Macdougall I.C. Bhandari S. White C. et al.Intravenous iron dosing and infection risk in patients on hemodialysis: a prespecified secondary analysis of the PIVOTAL Trial.J Am Soc Nephrol. 2020; 31: 1118-1127https://doi.org/10.1681/ASN.2019090972Crossref PubMed Scopus (39) Google Scholar questions about optimal usage remain, including questions surrounding different formulations.9Auerbach M. Gafter-Gvili A. Macdougall I.C. Intravenous iron: a framework for changing the management of iron deficiency.Lancet Haematol. 2020; 7: e342-e350https://doi.org/10.1016/S2352-3026(19)30264-9Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,10Gutierrez O.M. Treatment of iron deficiency anemia in CKD and end-stage kidney disease.Kidney Int Rep. 2021; 6: 2261-2269https://doi.org/10.1016/j.ekir.2021.05.020Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Iron sucrose is a widely studied and the predominantly used formulation of intravenous iron in the US dialysis setting. Hypotension is a known side effect of high-dose intravenous iron sucrose,11Chandler G. Harchowal J. Macdougall I.C. Intravenous iron sucrose: establishing a safe dose.Am J Kidney Dis. 2001; 38: 988-991https://doi.org/10.1053/ajkd.2001.28587Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar an effect attributed to its relatively weak iron binding—compared to some other iron formulations with iron tightly bound to the carbohydrate core—resulting in higher plasma levels of labile free iron.12Jahn M.R. Andreasen H.B. Futterer S. et al.A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications.Eur J Pharm Biopharm. 2011; 78: 480-491https://doi.org/10.1016/j.ejpb.2011.03.016Crossref PubMed Scopus (192) Google Scholar Although serious adverse events occurring with intravenous iron sucrose at moderate dosages appears comparable to other intravenous iron formulations, it remains possible that intravenous iron sucrose in commonly used doses would carry excess risk of more subtle blood pressure effects that could nevertheless be clinically important during hemodialysis sessions, given the risk of tenuous hemodynamics with hemodialysis. In this issue of AJKD, Singh et al examined the associations between intravenous iron sucrose administration and different intradialytic blood pressure patterns in a US cohort receiving thrice-weekly in-center hemodialysis. This observational cohort of persons was prospectively enrolled in selected units of a national dialysis provider between 2008 and 2014. Nine hundred fifty individuals, the majority new to dialysis, were studied, and the unit of analysis was the hemodialysis session, of which there were more than 135,000. The exposure for each hemodialysis session was receipt of intravenous iron sucrose for routine clinical indication, categorized as none, <100 mg, or ≥100 mg. No other intravenous iron formulation seems to have been given. Intravenous iron sucrose was given during 26% of the dialysis sessions, of which the administered dose was <100 mg in 56% and ≥100 mg in 44%. The primary outcome was the development of intradialytic hypotension, defined as nadir systolic blood pressure <90 mm Hg or <100 mm Hg (the higher threshold was for sessions with elevated pre-hemodialysis systolic blood pressure at ≥160 mm Hg). Perhaps surprisingly, contrary to the prespecified hypothesis, higher-dose intravenous iron sucrose (≥100 mg) versus no iron sucrose was found to be associated with reduced risk of intradialytic hypotension. Relative risk reduction was about 10% on unadjusted and adjusted analyses (adjustment was performed for several routinely collected clinical variables, including pre-hemodialysis systolic blood pressure, erythropoietin dose, and monthly hemoglobin level). Lower-dose intravenous iron sucrose (<100 mg) showed no association with intradialytic hypotension. Analyses of secondary outcomes further revealed that higher-dose intravenous iron sucrose was also associated with higher nadir systolic blood pressure values (point estimates 1.2-2.5 mm Hg higher depending on the model) and higher postdialysis systolic blood pressure (point estimates 1.0-2.8 mm Hg higher). No significant differences in these additional outcomes were found comparing lower-dose iron sucrose to no iron sucrose. These results add relevant evidence about the risks and benefits of intravenous iron sucrose use in maintenance hemodialysis. Although not providing causal evidence, the results may provide important qualitative information to guide further investigations. The results of the present study suggest that intravenous iron sucrose administration at currently used doses is likely not an important contributor to intradialytic hypotension. The distribution of iron doses given in the observational cohort high-dose group would be important to know, but it seems likely based on conventional hemodialysis dosing of intravenous iron sucrose that 100 mg and 200 mg doses made up the majority of the doses in this group. How is this new information to be interpreted in light of the meta-analysis cited by Singh et al in their introductory section, which reported that intravenous iron sucrose in randomized trials was associated with a 3-fold risk of hypotension?13Avni T. Bieber A. Grossman A. Green H. Leibovici L. Gafter-Gvili A. The safety of intravenous iron preparations: systematic review and meta-analysis.Mayo Clin Proc. 2015; 90: 12-23https://doi.org/10.1016/j.mayocp.2014.10.007Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar That meta-analysis combined studies of numerous different conditions in addition to chronic kidney disease, and included studies with intravenous iron sucrose doses up to 500 mg, much higher than what is currently used. When interpreted in light of the most relevant observational and experimental literature (limited to chronic kidney disease and to currently used doses, and ably surveyed by Singh et al in the discussion section), the present analysis provides additional support for the notion that hypotension during dialysis is not a major concern with intravenous iron sucrose. While alleviating concern about hypotension, do we now need to worry about intravenous iron sucrose causing intradialytic hypertension? The finding of a roughly 10% increase in the relative risk of intradialytic hypertension with high-dose intravenous iron sucrose in unadjusted and partially adjusted models (there was further decrease in the point estimate and loss of statistical significance with adjustment for hemoglobin and endothelin-1) could be clinically important. Singh et al speculate on potential reasons for this finding, such as requisite intravascular volume expansion or stimulation of endothelin-1 signaling through induction of reactive oxygen species formation by free iron. Singh et al downplay the endothelin-1 mechanism based on their adjustment for measured endothelin-1, but this was measured only at baseline for each participant and thus would not reflect treatment-related endothelin-1 increase occurring during any of the numerous follow-up dialysis sessions. Bias or residual confounding as a driver for the observed results cannot be excluded, especially for the intradialytic hypertension finding, which we believe has not been previously reported. Another shortcoming is the lack of adjustment for key drivers of the decision-making process toward iron administration, namely iron parameters. As the authors point out, much relevant data is not available in this study, such as the timing of blood pressure measurements and iron infusion, blood pressure medication use during dialysis, the volume status of the persons, the dialysate temperature, etc. Especially, the lack of information on the specific timing of the iron sucrose administration is potentially impactful when studying same-session effects of iron administration on blood pressure. In conclusion, this study, despite its limitations, has provided additional evidence that intravenous iron sucrose as presently dosed in maintenance hemodialysis is unlikely to be an important cause of intradialytic hypotension. However, it raises an additional question of whether iron sucrose may increase intradialytic blood pressure, a question that may warrant further investigation in other cohorts and using other methods. For investigating particular formulations of intravenous iron using observational data, addition of an active comparator group (ie, comparing different formulations of intravenous iron) could be particularly useful in reducing bias. Many questions remain about optimal intravenous iron use in persons on maintenance dialysis, including the choice of intravenous iron formulation, as nephrology works toward optimal, precision care of people with kidney failure. Jingyin Yan, MD, PhD, Wolfgang C. Winkelmayer, MD, MPH, ScD, and Carl P. Walther, MD, MS. Dr Winkelmayer is supported by the endowed Gordon A. Cain Chair in Nephrology at Baylor College of Medicine. Dr Walther is supported by National Institute of Diabetes and Digestive and Kidney Diseases grant, K23DK122131. Dr Yan has received consulting fees from Travere Therapeutics and serves as a medical director for a dialysis unit operated by DaVita Kidney Care. Dr Winkelmayer has received consulting fees from Akebia/Otsuka, Ardelyx, AstraZeneca, Bayer, Boehringer Ingelheim/Lilly, GlaxoSmithKline, Merck, Pharmacosmos, Reata, Unicycive, and Zydus. Dr Walther reports consulting fees from GlaxoSmithKline. Received January 9, 2023, in response to an invitation from the journal. Accepted January 25, 2023, after editorial review by an Associate Editor and a Deputy Editor. Associations of Iron Sucrose and Intradialytic Blood PressureAmerican Journal of Kidney DiseasesPreviewIntradialytic hypotension and intradialytic hypertension are associated with morbidity and mortality in hemodialysis (HD). Many factors can contribute to intra-HD blood pressure (BP) changes, such as drugs with vasoactive properties that can destabilize an already tenuous BP. Intravenous iron sucrose is commonly administered to correct iron deficiency; however, its reported associations with altered hemodynamics have not been consistent. Full-Text PDF