Iron and Chronic Kidney Disease: Still a Challenge

Anemia is a clinical feature of chronic kidney disease (CKD). Most common causes are iron and erythropoietin deficiency. The last two decades have yielded significant advances in understanding iron balance's physiology, including iron trafficking and the crosstalk between iron, oxygen, and erythropoiesis. This knowledge sheds new light on the regulation and disturbance of iron homeostasis in CKD and holds the promise for developing new diagnostic and therapeutic tools to improve the management of iron disorders. Hepcidin–ferroportin axis has a central role in regulating body iron balance and coordinating communication between tissues and cells that acquire, store, and utilize iron. Recent research has revealed a bidirectional relationship between fibroblast growth factor 23 (FGF23) and iron status, anemia, and inflammation, as well as the role of erythroferrone (ERFE) in iron homeostasis. However, ERFE concentrations and actions are not well-characterized in CKD patients. Studies on ERFE in CKD are limited with slightly conflicting results. Despite general interest in iron metabolism in kidney diseases, studies on the less prevalent renal replacement therapy mode, such as peritoneal dialysis or hemodiafiltration, are scarce. Slightly more was published on hemodialysis. There are several novel options on the horizon; however, clinical data are limited. One should be aware of the potential risks and benefits of the novel, sophisticated therapies. An inhibition of hepcidin on the different pathways might be also a viable adjunctive therapeutic option in other clinical situations.

[1]  C. Kovesdy,et al.  Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment. , 2020, Journal of the American Society of Nephrology : JASN.

[2]  L. Silvestri,et al.  Iron metabolism and iron disorders revisited in the hepcidin era , 2020, Haematologica.

[3]  Celena B. Peters,et al.  An increased mortality risk is associated with abnormal iron status in diabetic and non-diabetic Veterans with predialysis chronic kidney disease. , 2019, Kidney international.

[4]  D. Swinkels,et al.  Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing , 2019, Pharmaceuticals.

[5]  C. Jacquelinet,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 , 2019, Clinical kidney journal.

[6]  T. Ganz,et al.  Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease. , 2019, Advances in chronic kidney disease.

[7]  D. Witcher,et al.  Targeting the hepcidin–ferroportin pathway in anaemia of chronic kidney disease , 2019, British journal of clinical pharmacology.

[8]  C. Zoccali,et al.  Serum Erythroferrone Levels Associate with Mortality and Cardiovascular Events in Hemodialysis and in CKD Patients: A Two Cohorts Study , 2019, Journal of clinical medicine.

[9]  D. Swinkels,et al.  First-in-human Phase I studies of PRS-080#22, a hepcidin antagonist, in healthy volunteers and patients with chronic kidney disease undergoing hemodialysis , 2019, PloS one.

[10]  I. Macdougall,et al.  Effects of Molidustat in the Treatment of Anemia in CKD. , 2018, Clinical journal of the American Society of Nephrology : CJASN.

[11]  Nupur K. Das,et al.  Hepatic hepcidin/intestinal HIF-2&agr; axis maintains iron absorption during iron deficiency and overload , 2018, The Journal of clinical investigation.

[12]  S. Taylor,et al.  Erythroferrone inhibits the induction of hepcidin by BMP6. , 2018, Blood.

[13]  I. Nolte,et al.  Association of different iron deficiency cutoffs with adverse outcomes in chronic kidney disease , 2018, BMC Nephrology.

[14]  T. Abe,et al.  Crossroads of metabolism and CKD. , 2018, Kidney international.

[15]  T. Ganz,et al.  Effects of erythropoietin on fibroblast growth factor 23 in mice and humans. , 2018, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[16]  C. Camaschella,et al.  Advances in understanding iron metabolism and its crosstalk with erythropoiesis , 2018, British journal of haematology.

[17]  C. Ahn,et al.  Circulating Fibroblast Growth Factor-23 Levels are Associated with an Increased Risk of Anemia Development in Patients with Nondialysis Chronic Kidney Disease , 2018, Scientific Reports.

[18]  T. Ganz,et al.  Levels of the erythropoietin-responsive hormone erythroferrone in mice and humans with chronic kidney disease , 2018, Haematologica.

[19]  T. Tamaki,et al.  The uremic toxin indoxyl sulfate interferes with iron metabolism by regulating hepcidin in chronic kidney disease , 2018, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[20]  K. Uhlig,et al.  Hemoglobin response to ferric citrate in patients with nondialysis‐dependent chronic kidney disease and iron deficiency anemia , 2018, American journal of hematology.

[21]  S. Fishbane,et al.  Update on Anemia in ESRD and Earlier Stages of CKD: Core Curriculum 2018. , 2018, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[22]  Gurinder K. Singh,et al.  Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia , 2018, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  P. Fu,et al.  Hypoxia Induced Factor in Chronic Kidney Disease: Friend or Foe? , 2018, Front. Med..

[24]  I. Macdougall Intravenous iron therapy in patients with chronic kidney disease: recent evidence and future directions , 2017, Clinical kidney journal.

[25]  Jodie L Babitt,et al.  Smad1/5 is required for erythropoietin-mediated suppression of hepcidin in mice. , 2017, Blood.

[26]  C. Ahn,et al.  Serum hepcidin may be a novel uremic toxin, which might be related to erythropoietin resistance , 2017, Scientific Reports.

[27]  K. Uhlig,et al.  Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia. , 2017, Journal of the American Society of Nephrology : JASN.

[28]  Jodie L Babitt,et al.  Overview of iron metabolism in health and disease , 2017, Hemodialysis international. International Symposium on Home Hemodialysis.

[29]  J. Lewis,et al.  The safety of achieved iron stores and their effect on IV iron and ESA use: post-hoc results from a randomized trial of ferric citrate as a phosphate binder in dialysis
. , 2017, Clinical nephrology.

[30]  I. Macdougall,et al.  Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients , 2017, American Journal of Nephrology.

[31]  V. Haase,et al.  Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. , 2016, Kidney international.

[32]  M. Wolf,et al.  Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. , 2016, Kidney international.

[33]  G. Navis,et al.  Iron deficiency, anemia, and mortality in renal transplant recipients , 2016, Transplant international : official journal of the European Society for Organ Transplantation.

[34]  James E. Novak,et al.  Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. , 2016, Clinical journal of the American Society of Nephrology : CJASN.

[35]  S. Hemmerich,et al.  Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients. , 2016, Journal of the American Society of Nephrology : JASN.

[36]  A. Rastogi,et al.  Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia. , 2016, Journal of the American Society of Nephrology : JASN.

[37]  Toshinori Yamamoto,et al.  Associations among Erythroferrone and Biomarkers of Erythropoiesis and Iron Metabolism, and Treatment with Long-Term Erythropoiesis-Stimulating Agents in Patients on Hemodialysis , 2016, PloS one.

[38]  L. Nilsson,et al.  Effect of a More Permeable Dialysis Membrane on ESA Resistance in Hemodialysis Patients - A Pilot Investigation , 2015, Blood Purification.

[39]  M. Wolf,et al.  Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production , 2015, Kidney international.

[40]  T. Okado,et al.  Anaemia management and mortality risk in newly visiting patients with chronic kidney disease in Japan: The CKD‐ROUTE study , 2015, Nephrology.

[41]  I. Slotki,et al.  The Labile Side of Iron Supplementation in CKD. , 2015, Journal of the American Society of Nephrology : JASN.

[42]  M. Wolf,et al.  A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD Stages 3-5. , 2015, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[43]  C. Tetta,et al.  High-volume online haemodiafiltration improves erythropoiesis-stimulating agent (ESA) resistance in comparison with low-flux bicarbonate dialysis: results of the REDERT study. , 2015, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[44]  Jodie L Babitt,et al.  The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. , 2014, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[45]  M. Stauffer,et al.  Prevalence of Anemia in Chronic Kidney Disease in the United States , 2014, PloS one.

[46]  C. Peyssonnaux,et al.  The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. , 2013, Blood.

[47]  Herbert Y. Lin,et al.  Mechanisms of anemia in CKD. , 2012, Journal of the American Society of Nephrology : JASN.

[48]  B. Haraldsson,et al.  Hemodiafiltration Improves Plasma 25-Hepcidin Levels: A Prospective, Randomized, Blinded, Cross-Over Study Comparing Hemodialysis and Hemodiafiltration , 2012, Nephron Extra.

[49]  C. Hong,et al.  Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats. , 2011, Blood.

[50]  P. Subramanian,et al.  Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. , 2011, Cell metabolism.

[51]  G. Sapkota,et al.  The specificities of small molecule inhibitors of the TGFß and BMP pathways. , 2011, Cellular signalling.

[52]  D. Scadden,et al.  Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation. , 2011, Blood.

[53]  T. Ganz,et al.  Detection, evaluation, and management of iron-restricted erythropoiesis. , 2010, Blood.

[54]  K. Yoshizaki,et al.  Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. , 2010, Blood.

[55]  S. Lonial,et al.  Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. , 2010, Journal of Clinical Oncology.

[56]  T. Ganz,et al.  Reduction of serum hepcidin by hemodialysis in pediatric and adult patients. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[57]  S. Bachmann,et al.  Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization. , 2010, Kidney international.

[58]  J. Małyszko,et al.  Type of Renal Replacement Therapy and Residual Renal Function May Affect Prohepcidin and Hepcidin , 2009, Renal failure.

[59]  S. Aronoff,et al.  The prevalence of anemia in patients with chronic kidney disease , 2004, Current medical research and opinion.

[60]  Jodie L Babitt,et al.  Ironing out the cross talk between FGF23 and inflammation. , 2017, American journal of physiology. Renal physiology.

[61]  T. Eleftheriadis,et al.  Kynurenine, by activating aryl hydrocarbon receptor, decreases erythropoietin and increases hepcidin production in HepG2 cells: A new mechanism for anemia of inflammation. , 2016, Experimental hematology.

[62]  V. Haase Regulation of erythropoiesis by hypoxia-inducible factors. , 2013, Blood reviews.