Anemia of CKD is multifactorial, with major contributors including erythropoietin deficiency, absolute and functional iron deficiency, and inflammation. Clinical management has largely neglected inflammation, administering erythropoiesis-stimulating agents (ESA) and iron instead. Most patients on chronic dialysis are inflamed, and inflammatory markers correlate with the severity of anemia, ESA dose requirements, muscle wasting, and death.1 Several inflammatory mediators, perhaps crucially IL-6, contribute to anemia and resistance to ESA.2 IL-6 levels are increased in patients with CKD, possibly due to effects of uremic toxins, and inversely correlate with GFR3 and ESA requirements.
In this issue of JASN, Pergola et al.4 report the results of a double-blind phase 1/2 trial of ziltivekimab, a novel anti–IL-6 ligand antibody. They identified patients on hemodialysis with ESA hyporesponsiveness and elevated IL-6 levels, and treated them with ziltivekimab or placebo for 12 weeks. They report dose-dependent improvements in markers of inflammation, increases in serum iron and transferrin saturation, and most importantly, dramatic reductions in ESA dose requirements.4
ESA hyporesponsiveness is prevalent in patients on hemodialysis. It has no universally accepted definition, but is ascribed to patients requiring high ESA doses relative to achieved hemoglobin,5 and reported as the ESA resistance index (weekly IU ESA dose/kg per hemoglobin value [g/dl]). Patients with a high ESA resistance index are at higher risk of cardiovascular events and death.6 These patients are also characterized by low serum iron, low transferrin saturation levels, and high ferritin levels, as seen in the anemia of inflammation.7 In 2011, in part due to safety issues about ESA, target hemoglobin and ESA doses were reduced in US patients on dialysis. Despite this, ESA hyporesponsiveness continues to associate with increased mortality.6 It is unclear whether higher ESA doses are causing the harm, are merely a sensitive marker of patients who are severely inflamed and at greater risk of death, or a combination of both. Consequently, interest is high in reducing both inflammation and ESA doses as a potential means to reduce the stubbornly high mortality rate of patients on dialysis.
IL-6 is a pleiotropic proinflammatory cytokine with a central role in the anemia of chronic disease.8 The deleterious effects of IL-6 on erythropoiesis are largely mediated by upregulation of the iron-regulatory hormone hepcidin.7 Hepcidin downregulates intestinal iron absorption and sequesters iron within macrophages, resulting in hypoferremia and anemia. This creates a functional iron deficiency despite adequate storage iron. Functional iron deficiency can be overcome in part by administering large amounts of intravenous iron, which is common clinical practice.7 Associations between transferrin saturation levels and ESA responsiveness show maximal responsiveness at saturations above 30%, with iron repletion protocols generally targeting 30%–50%.9 This relationship between transferrin saturation and ESA responsiveness might not be simply due to transferrin-mediated iron delivery for hemoglobin production. Iron-bound transferrin is also a ligand for the nonclassic transferrin receptor, which has been shown to associate with the erythropoietin receptor and modulate erythropoietin responsiveness. Possibly the improvement in ESA responsiveness with ziltivekimab was mediated in part by the increase in transferrin saturation. However, IL-6 appears to have additional effects on erythropoiesis in CKD.
The central role of IL-6 was clearly demonstrated in a murine model of CKD using IL-6 knockout mice. Decreased hepcidin levels, increased serum iron levels, and improved hematologic parameters were seen in the CKD mice with knockout of IL-6. Although the hypoferremia of CKD could be overcome with iron administration, the improvements in hematologic parameters were not as great as those seen with loss of IL-6. These observations support both iron-dependent and iron-independent contributions of IL-6 to anemia. The latter may include the effect of IL-6 on erythropoietin production, erythroblast maturation, and erythrocyte lifespan. Studies comparing IL-6 knockout and hepcidin knockout mice likewise demonstrate the contributions of the hepcidin-independent effects of IL-6 in anemia of inflammation.10 Perhaps these observations explain why the beneficial effect of ziltivekimab on ESA requirements was sustained, even though the effect on hepcidin levels was transient.4
In just 12 weeks, treatment with ziltivekimab altered several parameters that associate with increased mortality in patients on dialysis, including ESA dose and ESA resistance index, C-reactive protein, serum iron, transferrin saturation, and serum albumin. All these factors moved in a direction favoring better survival. Although association is not causation, these encouraging results support further investigation. To minimize genetic variability in iron metabolism, the authors limited enrollment to patients with the most common variant of the hepcidin regulator Tmprss6 gene, prevalent in 80% of the population. Whether these observations apply to individuals with other Tmprss6 polymorphisms remains to be determined.
The concept of inhibiting IL-6 signaling to improve anemia in inflamed patients is not new. Tocilizumab, an antibody to the soluble and membrane-bound IL-6 receptor, inhibits IL-6–mediated signaling and ameliorates anemia in patients with rheumatoid arthritis, and Castleman disease, which overproduces IL-6.7
The diverse actions of IL-6 include T-cell activation, induction of Ig secretion, and regulation of hematopoietic stem cell fate. Tocilizumab can cause neutropenia, thrombocytopenia, and increase risk of certain infections. Consequently, Pergola et al.4 excluded patients who recently received systemic antibiotics, had a positive blood test for tuberculosis, or active hepatitis B or C, or HIV 1 or 2.
The ziltivekimab trial also raises some safety concerns.4 Ziltivekimab produced dose-dependent rates of neutropenia and thrombocytopenia, although the severity and frequency were lower than observed with tocilizumab. Four patients died.4 Two deaths were due to sepsis, two were cardiac deaths, and all occurred in the higher dose arms of the trial.4 By selecting for patients with ESA hyporesponsiveness, the investigators selected patients at high risk of death from predominantly cardiac events and infections. Thus, these unfortunate deaths in a trial utterly underpowered to assess these risks should not be the final word on the safety of ziltivekimab.
This early-phase trial of ziltivekimab in patients on dialysis who were ESA hyporesponsive opens the window on the major contribution of elevated IL-6 levels to anemia and inflammation in our patients on dialysis. Ziltivekimab or other IL-6 signaling disruption may be a way to move beyond our stagnant anemia management of ESA therapy and parenteral iron, and finally target inflammation directly.
Disclosures
D. Coyne is a consultant to Fresenius Medical Care-Renal Therapies Group, which sells intravenous iron, Rockwell Medical, a maker of triferic, an iron added to dialysate, and Vifor, a maker of intravenous iron. D. Coyne reports consultancy agreements with MC-RTG, Medibeacon, Reata, GSK, Fibrogen, and AstraZeneca; research funding from GSK; and honoraria from FMC-RTG, Medibeacon, GSK, Fibrogen, and AstraZeneca. R. Fleming conducts research and is a consultant to Rockwell Medical, maker of triferic, an iron added to dialysate. R. Fleming reports research funding from Ultragenyx Pharmaceuticals; reports being a scientific advisor or membership as a Scientific Advisory Board Member for Silence Therapeutics, and Protagonist Therapeutics.
Funding
None.
Acknowledgments
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendations. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or JASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
See related article, “Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial,” on pages 211–222.
- Copyright © 2021 by the American Society of Nephrology