Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference

In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research. In chronic kidney disease, anemia and disordered iron homeostasis are prevalent and associated with significant adverse consequences. In 2012, Kidney Disease: Improving Global Outcomes (KDIGO) issued an anemia guideline for managing the diagnosis, evaluation, and treatment of anemia in chronic kidney disease. Since then, new data have accrued from basic research, epidemiological studies, and randomized trials that warrant a re-examination of previous recommendations. Therefore, in 2019, KDIGO decided to convene 2 Controversies Conferences to review the latest evidence, explore new and ongoing controversies, assess change implications for the current KDIGO anemia guideline, and propose a research agenda. The first conference, described here, focused mainly on iron-related issues, including the contribution of disordered iron homeostasis to the anemia of chronic kidney disease, diagnostic challenges, available and emerging iron therapies, treatment targets, and patient outcomes. The second conference will discuss issues more specifically related to erythropoiesis-stimulating agents, including epoetins, and hypoxia-inducible factor-prolyl hydroxylase inhibitors. Here we provide a concise overview of the consensus points and controversies resulting from the first conference and prioritize key questions that need to be answered by future research. Anemia and iron deficiency are prevalent in patients with chronic kidney disease (CKD)1Stauffer M.E. 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The multifaceted role of iron in renal health and disease.Nat Rev Nephrol. 2020; 16: 77-98Crossref PubMed Scopus (27) Google Scholar The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) anemia guideline provides recommendations on the diagnosis and treatment of anemia in CKD, including the use of iron agents, erythropoiesis-stimulating agents (ESAs), and red cell transfusions.16Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (481) Google Scholar Subsequently, based on evidence that full anemia correction with ESAs is associated with adverse outcomes,17Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1468) Google Scholar, 18Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1648) Google Scholar, 19Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2088) Google Scholar, 20Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1744) Google Scholar and consequent regulatory and reimbursement changes in many countries, practice patterns have shifted toward reduced ESA use and increased iron supplementation.21Gardiner R. Roshan D. 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In December 2019, KDIGO held its first of 2 Controversies Conferences on Optimal Management of Anemia focused on iron, to critically assess the latest evidence, to evaluate the need for guideline updates, and to identify key knowledge gaps for future research. The second conference, scheduled in 2021, will address ESAs and novel anemia therapies, including hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs), after data from ongoing long-term outcome studies become available. Iron is an essential component of hemoglobin for erythropoiesis. CKD is associated with several disturbances in systemic iron homeostasis resulting in an inadequate iron supply, broadly categorized as absolute iron deficiency and functional iron deficiency. Absolute iron deficiency is a deficit of total body iron manifest as reduced levels of both circulating and stored iron. Functional iron deficiency has been defined as a deficiency of circulating iron that limits erythropoiesis despite normal or elevated body iron stores. The distinction between absolute and functional iron deficiency is important for determining the etiology of anemia and the optimal therapeutic approach. In the last 2 decades, there have been new insights into the regulation of systemic iron homeostasis and the pathophysiology of both absolute and functional iron deficiency in CKD, including the discoveries of the hepcidin-ferroportin axis, erythroferrone, and the role of HIFs (Figure 127Wang C.Y. Babitt J.L. Liver iron sensing and body iron homeostasis.Blood. 2019; 133: 18-29Crossref PubMed Scopus (52) Google Scholar, 28Arezes J. Foy N. McHugh K. et al.Erythroferrone inhibits the induction of hepcidin by BMP6.Blood. 2018; 132: 1473-1477Crossref PubMed Scopus (0) Google Scholar, 29Wrighting D.M. Andrews N.C. Interleukin-6 induces hepcidin expression through STAT3.Blood. 2006; 108: 3204-3209Crossref PubMed Scopus (621) Google Scholar, 30Lee P. Peng H. Gelbart T. et al.Regulation of hepcidin transcription by interleukin-1 and interleukin-6.Proc Natl Acad Sci U S A. 2005; 102: 1906-1910Crossref PubMed Scopus (403) Google Scholar). Advanced CKD is associated with a negative iron balance due to reduced dietary intake, impaired enteral absorption, and increased losses.31Macdougall I.C. Bircher A.J. Eckardt K.U. et al.Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.Kidney Int. 2016; 89: 28-39Abstract Full Text Full Text PDF PubMed Google Scholar Functional iron deficiency is multifactorial, due in part to hepcidin excess (as a consequence of inflammation, decreased renal clearance, and reduced erythropoietin [EPO] production), leading to iron sequestration in macrophage stores.32van der Weerd N.C. Grooteman M.P. Nube M.J. et al.Hepcidin in chronic kidney disease: not an anaemia management tool, but promising as a cardiovascular biomarker.Neth J Med. 2015; 73: 108-118PubMed Google Scholar ESAs may also contribute to functional iron deficiency by causing a brisk iron demand that kinetically exceeds the iron supply. Other factors contributing to the anemia of CKD include reduced EPO production, poor bone marrow responsiveness, shortened red blood cell (RBC) survival, and direct bone marrow suppression. The definitions and diagnosis of iron deficiency and anemia in CKD are historically based on 3 parameters: hemoglobin (Hb); serum transferrin saturation (TSAT), an indicator of circulating iron; and serum ferritin, an indicator of stored iron. In CKD, absolute iron deficiency has been defined as TSAT <20% and ferritin <100 μg/l in patients not on hemodialysis therapy or <200 μg/l in hemodialysis (HDCKD) patients. Functional iron deficiency has been defined as TSAT <20% and ferritin >100 μg/l in patients not on dialysis therapy (NDCKD) or >200 μg/l in HDCKD patients.16Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int Suppl. 2012; 2: 279-335Abstract Full Text Full Text PDF Scopus (481) Google Scholar,33Fishbane S. Kowalski E.A. Imbriano L.J. et al.The evaluation of iron status in hemodialysis patients.J Am Soc Nephrol. 1996; 7: 2654-2657Crossref PubMed Google Scholar, 34Kalantar-Zadeh K. Hoffken B. Wunsch H. et al.Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era.Am J Kidney Dis. 1995; 26: 292-299Abstract Full Text PDF PubMed Google Scholar, 35Tessitore N. Solero G.P. Lippi G. et al.The role of iron status markers in predicting response to intravenous iron in haemodialysis patients on maintenance erythropoietin.Nephrol Dial Transplant. 2001; 16: 1416-1423Crossref PubMed Google Scholar, 36Stancu S. Barsan L. Stanciu A. et al.Can the response to iron therapy be predicted in anemic nondialysis patients with chronic kidney disease?.Clin J Am Soc Nephrol. 2010; 5: 409-416Crossref PubMed Scopus (0) Google Scholar However, these terms and definitions have come under scrutiny and discussion.37Batchelor E.K. Kapitsinou P. Pergola P.E. et al.Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment.J Am Soc Nephrol. 2020; 31: 456-468Crossref PubMed Scopus (7) Google Scholar,38Besarab A. Drueke T.B. The problem with transferrin saturation as an indicator of iron 'sufficiency' in chronic kidney disease [e-pub ahead of print]. Nephrol Dial Transplant.https://doi.org/10.1093/ndt/gfaa048Google Scholar The conference participants agreed that the presently used parameters are not reliable for estimating body iron stores or predicting response to therapy. Furthermore, there may be clinical utility in more precisely distinguishing subgroups of "functional iron deficiency" due to inflammation/hepcidin-mediated iron sequestration versus kinetic iron deficiency from ESA-stimulated bursts of erythropoiesis, to inform optimal treatment. These areas were identified as high priority for future research (Table 1).Table 1Research priorities for managing anemia in CKDEtiology and diagnosis of iron deficiency and anemia in CKD1.Describe the variability in Hb and iron parameters by levels of eGFR, disease states, age, and sex around the world to more accurately characterize "expected" Hb values for populations2.Define and implement optimal preanalysis and standardized assays on the various hematological platforms for RBC parameters (e.g., RetHb and % hypochromic cells) to allow uniform use of clinical decision limits and avoid reliance on ferritin and TSAT alone. Educate clinicians on the adoption of these tools to clinical practice3.Develop and validate novel diagnostic laboratory tools, possibly in partnership with industry4.Develop and validate tools to capture symptoms of anemia that are easy to administer and have clinical utility, such as wearable health devices (phone trackers, Fitbits), fatigue scales, and 6-min walk test. Use these patient-derived data to assess optimal quality of life information in relationship to improvement of Hb or iron parameters in clinical trials5.Determine the feasibility of redefining functional iron deficiency to more precisely describe specific etiologies (due to inflammation/hepcidin-mediated RES iron sequestration vs. kinetic iron deficiency due to bursts of erythropoiesis stimulated by ESAs) and the utility of this distinction for guiding clinical care. This would require validating additional diagnostic tests to discriminate between the 2 entitiesIron, anemia, and outcomes in CKD1.Conduct an RCT to evaluate the impact of different iron preparations (traditional oral iron preparations, ferric citrate, and i.v.) on hard clinical outcomes (major adverse cardiovascular events, mortality, infection) and patient-reported outcomes in patients with CKD with iron deficiency without anemia2.Conduct a large, pragmatic trial in hemodialysis patients examining the harms, benefits, and costs of protocolized iron therapy strategy (such as in PIVOTAL). Randomize patients to holding of iron if ferritin is 400 versus 700 versus 1200 μg/l (ng/ml). Compare hard clinical outcomes (major adverse cardiovascular events, infections, mortality), patient-reported outcomes, ESA use, and transfusions3.Conduct clinical trials to evaluate whether giving iron or ESAs to reach Hb targets leads to better clinical outcomes (and prevents transfusions). Data are needed for determining the optimal relative amount of iron and ESAs to reach Hb targetsUse of iron agents in CKD anemia management1.Conduct clinical trials to define optimal targets and treatment strategies for use of iron agents in patients with CKD at different eGFR values or etiologies of CKD, informed by epidemiology data above. Future studies should aim to more completely phenotype and genotype patients to enable the development of more personalized approaches2.Conduct clinical trials to compare newly available oral iron compounds to traditional oral and i.v. iron compounds in patients with CKD; investigate the appropriateness of an alternate day, single-dose administration of oral iron in patients with CKD; and investigate the proactive versus reactive oral iron therapy strategy in CKD (i.e., equivalent of PIVOTAL trial for oral iron therapy)3.Conduct head-to-head trials of different i.v. iron formulations, including iron similars, to evaluate relative efficacy and safety4.Conduct dedicated studies on biodistribution and bioavailability of iron compoundsESAs and novel therapies 1. Determine the ferrokinetic properties of HIF-PHIs and optimal iron management for HIF-PHI therapy, including:a. Optimal diagnostic parameters for initiating, monitoring, and optimizing HIF-PHI therapy, including novel diagnostic parameters such as retHb and % hypochromic RBCb. Upper limits of i.v. iron therapy (i.e., ferritin, TSAT, iron dose)c. Iron needs for successful therapy, e.g., oral versus i.v. preparation and i.v. iron dosing levelsd. Effects of HIF-PHI therapy on erythroferrone/hepcidin axise. Impact of HIF-PHIs on intestinal iron absorption using Fe-isotope labeling studiesf. Impact of HIF-PHIs on monoferric and diferric transferrin and how this affects hepcidin regulatory pathways and erythropoiesis 2. Conduct studies dedicated to specific populations to define the CKD populations that are suitable for HIF-PHI therapy and those that should be excluded from HIF-PHI therapy:a. Patients with diabetic nephropathy and retinopathyb. Patients with autosomal dominant polycystic kidney diseasec. Inflamed patients and ESA hyporespondersd. Pediatric patients with CKDe. Patients with vascular calcificationsf. Patients with pulmonary arterial hypertension 3. Explore the potential of combination therapies targeting the different pathogenetic mechanisms underlying CKD anemia development—take advantage of drugs, agents, or treatment that are being studied in other clinical settingsCKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HIF-PHI, hypoxia-inducible factor-prolyl hydroxylase inhibitor; i.v., intravenous; PIVOTAL, Proactive IV Iron Therapy in Haemodialysis Patients; RCT, randomized controlled trial; RES, reticuloendothelial system; retHb, reticulocyte hemoglobin; TSAT, transferrin saturation. Open table in a new tab CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HIF-PHI, hypoxia-inducible factor-prolyl hydroxylase inhibitor; i.v., intravenous; PIVOTAL, Proactive IV Iron Therapy in Haemodialysis Patients; RCT, randomized controlled trial; RES, reticuloendothelial system; retHb, reticulocyte hemoglobin; TSAT, transferrin saturation. The development and adoption of new tests to more accurately diagnose both absolute and functional iron deficiency, and to monitor response to therapy, is another high-priority research area. Several RBC parameters have been developed that are now more widely available in multiple hematology analyzers, including reticulocyte Hb content and percentage of hypochromic RBC.39Ullrich C. Wu A. Armsby C. et al.Screening healthy infants for iron deficiency using reticulocyte hemoglobin content.JAMA. 2005; 294: 924-930Crossref PubMed Scopus (130) Google Scholar,40Urrechaga E. Hoffmann J. Assessment of iron-restricted erythropoiesis in chronic renal disease: evaluation of Abbott CELL-DYN Sapphire mean reticulocyte hemoglobin content (MCHr).Scand J Clin Lab Invest. 2019; 79: 363-367Crossref PubMed Scopus (0) Google Scholar Reticulocyte Hb indicates whether iron is incorporated into reticulocytes within 3–4 days after starting iron administration and thus serves as a functional parameter that may be useful in guiding iron and ESA therapy.41Goodnough L.T. Nemeth E. Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis.Blood. 2010; 116: 4754-4761Crossref PubMed Scopus (281) Google Scholar, 42Piva E. Brugnara C. Spolaore F. et al.Clinical utility of reticulocyte parameters.Clin Lab Med. 2015; 35: 133-163Abstract Full Text Full Text PDF PubMed Google Scholar, 43Fishbane S. Shapiro W. Dutka P. et al.A randomized trial of iron deficiency testing strategies in hemodialysis patients.Kidney Int. 2001; 60: 2406-2411Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Mittman N. Sreedhara R. Mushnick R. et al.Reticulocyte hemoglobin content predicts functional iron deficiency in hemodialysis patients receiving rHuEPO.Am J Kidney Dis. 1997; 30: 912-922Abstract Full Text PDF PubMed Google Scholar, 45Brugnara C. Laufer M.R. Friedman A.J. et al.Reticulocyte hemoglobin content (CHr): early indicator of iron deficiency and response to therapy.Blood. 1994; 83: 3100-3101Crossref PubMed Google Scholar Percentage of hypochromic RBC reflects iron availability in the preceding 2–3 months, making it a sensitive long-term time-averaged functional parameter. However, widespread clinical use of both of these parameters is constrained by the absence of universal clinical decision limits. The requirement for fresh blood samples also limits the use of percentage of hypochromic RBC.46Brugnara C. Mohandas N. Red cell indices in classification and treatment of anemias: from M.M. Wintrobes's original 1934 classification to the third millennium.Curr Opin Hematol. 2013; 20: 222-230Crossref PubMed Scopus (37) Google Scholar Parameters to assess other functional consequences of iron deficiency or its correction, for example, in skeletal muscle and heart, may also be useful, but are not available. Hepcidin has not proved to be a consistent marker to distinguish absolute from functional iron deficiency or determine ESA responsiveness in patients with CKD.32van der Weerd N.C. Grooteman M.P. Nube M.J. et al.Hepcidin in chronic kidney disease: not an anaemia management tool, but promising as a cardiovascular biomarker.Neth J Med. 2015; 73: 108-118PubMed Google Scholar Other diagnostics related to novel mechanistic insights, for example, erythroferrone levels, are still under investigation. Data from multiple countries show that anemia and iron deficiency remain highly prevalent in patients with CKD. In NDCKD patients, the US Veteran study, REport of COmorbidities in non-Dialysis Renal Disease Population in Italy (RECORD-IT), and Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDoppS) report that 21%–62% of patients have anemia, defined as Hb <12 g/dl or <12 g/dl in females and <13.5 g/dl in males, with increasing prevalence in more advanced CKD.47Minutolo R. Locatelli F. Gallieni M. et al.Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics.Nephrol Dial Transplant. 2013; 28: 3035-3045Crossref PubMed Scopus (50) Google Scholar, 48Wong M.M.Y. Tu C. Li Y. et al.Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated.Clin Kidney J. 2020; 13: 613-624Crossref PubMed Google Scholar, 49Awan A.A. Walther C.P. Richardson P.A. et al.Prevalence, correlates and outcomes of absolute and functional iron deficiency anemia in nondialysis-dependent chronic kidney disease.Nephrol Dial Transplant. 2019; 36: 129-136Crossref Google Scholar Moreover, 15%–72.8% have either ferritin <100 μg/l or TSAT <20%, and 8%–20% have both parameters below the threshold.3Ryu S.R. Park S.K. Jung J.Y. et al.The prevalence and management of anemia in chronic kidney disease patients: result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).J Korean Med Sci. 2017; 32: 249-256Crossref PubMed Scopus (23) Google Scholar,47Minutolo R. Locatelli F. Gallieni M. et al.Anaemia management in non-dialysis chronic kidney disease (CKD) patients: a multicentre prospective study in renal clinics.Nephrol Dial Transplant. 2013; 28: 3035-3045Crossref PubMed Scopus (50) Google Scholar,48Wong M.M.Y. Tu C. Li Y. et al.Anemia and iron deficiency among chronic kidney disease Stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated.Clin Kidney J. 2020; 13: 613-624Crossref PubMed Google Scholar,50Iimori S. Naito S. Noda Y. et al.Anaemia management and mortality risk in newly visiting patients with chronic kidney disease in Japan: The CKD-ROUTE study.Nephrology. 2015; 20: 601-608Crossref PubMed Scopus (21) Google Scholar,51Fishbane S. Pollack S. Feldman H.I. et al.Iron indices in chronic kidney disease in the National Health and Nutritional Examination Survey 1988-2004.Clin J Am Soc Nephrol. 2009; 4: 57-61Crossref PubMed Scopus (102) Google Scholar For HDCKD patients, data from United States Renal Data System52United States Renal Data SystemSpecial analyses, USRDS ESRD Database.https://render.usrds.org/2017/view/img_v2_02.htmlDate accessed: November 2, 2020Google Scholar show that 64.5%, 14.4%, and 6.6% have Hb levels between 10–12 g/dl, 9 and 10 g/dl, or below 9 g/dl, respectively. Moreover, 15.8% have TSAT <20%, and 4.9% have ferritin <200 μg/l.53United States Renal Data SystemAnnual Data Report 2018.https://www.usrds.org/annual-data-report/previous-adrs/Date accessed: November 2, 2020Google Scholar Data from a Japanese registry show that 36.3%, 60.2%, and 28.0% of HDCKD patients have TSAT <20%, ferritin <100 μg/l, or both, respectively.54Hamano T. Fujii N. Hayashi T. et al.Thresholds of iron markers for iron deficiency erythropoiesis-finding of the Japanese nationwide dialysis registry.Kidney Int Suppl. 2015; 5: 23-32Abstract Full Text Full Text PDF Scopus (0) Google Scholar In peritoneal dialysis patients, the prevalence of iron deficiency anemia is reported in the range of 16%–23%.55Perlman R.L. Zhao J. Fuller D.S. et al.International anemia prevalence and management in peritoneal dialysis patients.Perit Dial Int. 2019; 39: 539-546Crossref PubMed Scopus (0) Google Scholar These observations may reflect poor adherence with oral iron prescriptions in NDCKD and peritoneal dialysis patients, as well as therapeutic inertia, that is, lack of adequate iron or ESA prescriptions despite low Hb and/or iron deficiency. Observational data indicate that anemia is associated with adverse outcomes in all disease states, including CKD7Hayashi T. Tanaka Y. Iwasaki M. et al.Association of circulatory iron deficiency with an enlarged heart in patients with end-stage kidney disease.J Ren Nutr. 2019; 29: 39-47Abstract Full Text Full Text PDF PubMed Google Scholar, 8Eisenga M.F. Nolte I.M. van der Meer P. et al.Association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease.BMC Nephrol. 2018; 19: 225Crossref PubMed Scopus (6) Google Scholar, 9Sato Y. Fujimoto S. Konta T. et al.Anemia as a risk factor for all-cause mortality: obscure synergic effect of chronic kidney disease.Clin Exp Nephrol. 2018; 22: 388-394Crossref PubMed Scopus (14) Google Scholar, 10Eriksson D. Goldsmith D. Teitsson S. et al.Cross-sectional survey in CKD patients across Europe describing the association between quality of life and anaemia.BMC Nephrol. 2016; 17: 97Crossref PubMed Scopus (31) Google Scholar, 11Shaker A.M. Mohamed O.M. Mohamed M.F. et al.Impact of correction of anemia in end-stage renal disease patients on cerebral circulati