REVIEW www.jasn.org

Iron Deficiency in : Updates on Pathophysiology, Diagnosis, and Treatment

Elizabeth Katherine Batchelor,1 Pinelopi Kapitsinou,2,3 Pablo E. Pergola,4 Csaba P. Kovesdy ,5 and Diana I. Jalal6

1Department of Internal Medicine and 6Division of Nephrology, University of Iowa Hospitals and Clinics, Iowa City, Iowa; 2Feinberg Cardiovascular and Renal Research Institute and 3Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Renal Associates PA, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; and 5Division of Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee

ABSTRACT is a complication that affects a majority of individuals with advanced CKD. which impairs the body’s ability to appro- Although relative deficiency of production is the major driver of ane- priately utilize the sequestered in the mia in CKD, iron deficiency stands out among the mechanisms contributing to the tissues.8 Repletion of iron stores is often impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency necessary in patients with CKD for the plays a significant role in anemia in CKD. This may be due to a true paucity of iron treatment of IDA and to maximize the ef- stores (absolute iron deficiency) or a relative (functional) deficiency which prevents ficacy of ESAs. The traditional biomarkers the use of available iron stores. Several risk factors contribute to absolute and func- used to detect iron deficiency in CKD are tional iron deficiency in CKD, including losses, impaired iron absorption, and often unreliable, rendering the diagnostic chronic inflammation. The traditional biomarkers used for the diagnosis of iron- and monitoring processes difficult. To deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent best manage IDA in CKD, a thorough un- challenges in the detection and monitoring of IDA in these patients. Here, we review derstanding of its pathophysiology and the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the treatments is necessary. In this text, we literature that has informed the current practice guidelines for the treatment of IDA review the mechanisms of IDA, the poten- in CKD, and we summarize the available oral and intravenous (IV) iron formulations tial aids and pitfalls in the diagnosis of for the treatment of IDA in CKD. Two important issues are addressed, including the IDA, and the available treatment formu- potential risks of a more liberal approach to iron supplementation as well as the lations for IDA in patients with CKD. We potential risks and benefits of IV versus oral iron supplementation in patients furthermore provide an in-depth discus- with CKD. sion of the current literature as it pertains to target levels of Hgb and iron indices. JASN 31: 456–468, 2020. doi: https://doi.org/10.1681/ASN.2019020213

Anemia, defined as a (Hgb) ofanemia inpatientswith CKD (Figure 1). PATHOPHYSIOLOGY OF IDA concentration of ,13 g/dl in men and Several well conducted studies in patients ,12 g/dl in women, is an important with CKD indicate that use of ESAs to Iron metabolism is tightly regulated at complication of CKD.1 The prevalence normalize Hgb in patients with CKD multiple stages of the of anemia increases across the advancing mayworsencardiovascular(CV)out- (RBC) life cycle (Figure 2). Although stages of CKD, with estimates anywhere comes.3–6 Thus, the current guidelines from 7% to .50% in the more advanced advise a target Hgb below the definition 2 1 Published online ahead of print. Publication date stages of the disease. Multiple mecha- of normal in patients with CKD. available at www.jasn.org. nisms contribute to the development Many patients with anemia and CKD of anemia in CKD, the most important suffer from iron-deficiency anemia Correspondence: Dr. Diana Jalal, Division of Ne- phrology, Department of Medicine, Carver College fi 1,7 being relative de ciency of erythropoie- (IDA). This is due to both true paucity of Medicine, 200 Hawkins Drive, Iowa City, IA tin (EPO). As such, erythropoiesis- of iron stores (absolute IDA) and relative 52242. Email: [email protected] fi stimulating agents (ESAs) have been (functional) iron de ciency; the latter be- Copyright © 2020 by the American Society of considered a staple for the management ing due to underlying inflammation Nephrology

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recycling, a process influenced by EPO.11 Iron metabolism is further reg- ulated by hepcidin.12 Apeptidehor- mone synthesized predominately in the liver, hepcidin regulates the uptake of iron from the gut and the release of iron from the iron stores.13 Hepcidin production is stimulated by increased iron uptake, inflammation, and infec- tion; it is suppressed in the setting of iron deficiency and hypoxia.12,14 CKD is associated with increased hepcidin levels.15 Hypoxia-inducible factor (HIF) is an important transcription factor in the regulation of erythropoiesis, iron Figure 1. Mechanisms of Anemia in CKD. HIF-PHD, HIF prolyl-hydroxylase do- metabolism, and multiple other main–containing proteins. processes involved in the maintenance of homeostasis.16–19 HIF, a key media- the development of erythroid lineage iron is either transported to the liver tor of cellular adaptation to oxygen from a multipotential myeloid stem and spleen, where it is bound to deprivation, comprises an oxygen- cell is regulated by EPO, the differenti- for storage, or to the bone marrow sensitive a-subunit (HIF-1a,HIF-2a, ation from erythroblasts into reticulo- where it is used for erythropoiesis.10 Al- or HIF-3a)andastableb-subunit. cytesisaniron-dependentprocess. though dietary intake is typically suffi- HIF heterodimers activate the tran- Hence, iron deficiency will limit re- cient to replace most of the daily losses scription of genes whose promoters sponsiveness to EPO.9 Iron is absorbed of iron, the majority of iron stores are contain hypoxia response elements, in the gastrointestinal tract and bound replenished by macrophage phagocyto- whereas recruitment of coactivators to serum . Subsequently, sis of the destroyed RBCs and iron such as p300/CREB-binding protein is required in HIF-mediated transcrip- tion. HIF-a proteins are regulated by prolyl-4-hydroxylase domain–containing proteins 1–3(PHD1–3), ferrous- and 2- oxoglutarate-dependent oxygenases, whose activity is dependent on oxygen.20 Under normoxic conditions, PHDs hy- droxylate HIF-a at proline residues, al- lowing targeting for ubiquitination by the von Hippel-Lindau (pVHL)-E3- ubiquitin ligase complex and subse- quent proteasomal degradation.21 Under hypoxic conditions, HIF-a is sta- bilized and, after nuclear translocation, it dimerizes with the HIF-b subunit, forming heterodimers that activate 100–200 genes, including EPO and other genes involved in iron metabo- lism. Furthermore, HIF reduces serum levels of hepcidin indirectly through stimulation of EPO-induced erythro- Figure 2. Iron metabolism is a tightly regulated process. Iron is absorbed in the gut and poiesis.22 Compounds that pharmaco- bound to soluble transferrin. Iron is then moved to storage in the bone marrow and used for erythropoiesis. Additional stores are repleted by macrophage uptake of iron from RBC logically inhibit PHDs activate HIF sig- destruction. EPO induces RBC production, leading to the mobilization of iron stores from naling under normoxic conditions and the bone marrow. Hepcidin, which is produced by the liver and often stimulated by in- may represent effective treatments of flammation, leads to decreased iron uptake from the gut and decreased mobilization of anemia in CKD. These concepts are iron stores. Fe-Tf, iron-bound transferrin. summarized in Figure 3.

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DIAGNOSIS

Biomarkers traditionally used in the diagnosis of IDA include Hgb and he- matocrit, reticulocyte count, mean cor- puscular Hgb, and mean corpuscular volume, most of which are decreased in IDA.23 In the setting of absolute iron deficiency, iron studies typically show a decreased iron level, decreased ferritin, elevated transferrin and total iron binding capacity (calculated as transferrin 31.389), and decreased transferrin saturation (TSAT; calculated as serum iron/total iron binding capacity3100). However, there is evidence to indicate that the tra- # Figure 3. Hypoxia signaling controls erythropoiesis by coordinating EPO synthesis with ditional cutoffs of TSAT at 20% and # the expression of genes involved in iron metabolism. Under well oxygenated conditions, serum ferritin at 100 ng/ml are not sen- the three oxygen-labile HIF-a subunits (HIF-1a, HIF-2a, and HIF-3a) are hydroxylated at sitive to detect iron deficiency. In a study specific proline (Pro) residues by PHD enzymes. Prolyl hydroxylation targets HIF-a proteins of 100 patients with CKD (stages 3–5), for ubiquitination by the von Hippel-Lindau (pVHL)-E3-ubiquitin ligase complex with these indices identified only 17% of pa- subsequent proteasomal degradation. Under conditions of reduced PHD activity (for ex- tients with CKD as iron deficient whereas ample hypoxia or pharmacologic inhibition), HIF-a escapes hydroxylation and translocates approximately 50% were iron deficient b to the nucleus, where it forms a heterodimer with the constitutively expressed HIF- based on the gold standard of bone mar- a b subunit. The effective HIF- /HIF- complex activates the transcription genes whose pro- row iron staining.24 Consistent with moters contain hypoxia response elements. The HIF-mediated activation of transcription these findings, patients with iron studies requires the recruitment of coactivators such as p300/CREB-binding protein. An additional fi that are within what is considered the layer of regulation is due to factor-inhibiting HIF (FIH), which hydroxylates a speci cas- “ ” paragine (Asn) residue abrogating transcriptional cofactor recruitment. HIF-a stabilization normal range or at goal, may still results in the activation of genes in diverse biologic processes. For instance, HIF-2a in- show an increase in erythropoiesis to tri- duces EPO production from renal peritubular fibroblasts and hepatocytes, promoting als of iron therapy, whether they are on erythroid progenitors’ cell viability, proliferation, and differentiation through EPO receptor ESA therapy or not.24,25 (EPOR) signaling. Genes expressed in duodenum, duodenal cytochrome b reductase Another major limitation of these pa- (DCYTB)anddivalent metal transporter-1 (DMT1) along with ferroportin (FPN) are acti- rameters is that they do not differentiate vated by HIF-2, increasing iron uptake while HIF signaling also controls the expression of between absolute and functional IDA. iron transport genes transferrin (Tf)andtransferrin receptor (TfR). O2, oxygen; OH, Transferrin, for example, is increased in hydroxide. both absolute and functional IDA. In ad- dition, if functional iron deficiency exists ABSOLUTE VERSUS FUNCTIONAL iron stores, stemming from one or both due to a supply/demand mismatch, such of two main phenomena. The first of as with ESA supplementation, then iron these, anemia of chronic inflammation, maybe stripped from transferrin faster It is important to differentiate between ab- is known as reticuloendothelial cell iron than it can be mobilized from the iron solute (or storage) iron deficiency and blockade. This may occur in the absence stores, leading to a decrease in TSAT.10 functional (or relative) iron deficiency. In of EPO supplementation and can occur Bone marrow biopsy is considered by absolute iron deficiency, the total body iron in inflammatory diseases other than many to be the gold standard for diag- stores are depleted, limiting the production CKD. Specifically, reticuloendothelial nosis of IDA.26 A study of 303 children in of RBCs. Contributing factors to absolute cell iron blockade can be triggered by ac- Malawi with iron deficiency concluded iron deficiency include decreased gastroin- tive infection or inflammation, hypoxia, that the absence of iron fragments in a testinal absorption in patients with CKD or genetic deficiencies.11 The second pro- sample should be diagnostic of absolute and increased blood loss (for example in cess relates to the use of exogenous EPO. iron deficiency, whereas the absence of the setting of uremia-induced platelet dys- Because RBC production increases in re- erythroid progenitors (despite the pres- function and the iatrogenic loss from serial sponse to ESAs, the available iron may be ence of iron stores) should be diagnostic blood draws or access-site and circuit issues used faster than the existing iron stores of functional iron deficiency.27 Estimates during the dialysis procedure).8 are able to release it, leading to a supply/ conclude, however, that up to 30% of By contrast, functional iron deficiency demand mismatch and a “relative” iron bone marrow samples may be inaccurate occurs due to inefficient utilization of deficiency.10 or insufficient for diagnosis28 and the

458 JASN JASN 31: 456–468, 2020 www.jasn.org REVIEW number of fragments analyzed greatly responsiveness, leading some to pro- the potential ESA effects on NGAL. affects the yield of a correct diagnosis.29 pose their use in the evaluation of IDA Furthermore, two smaller studies of Other limitations include the invasive- in CKD.38,39 HRC%, especially, is seen patients with CKD were unable to ness of the procedure and the burdens as a cost-effective measure for esti- demonstrate that NGAL is an appro- of cost and travel for patients. Given mating iron responsiveness.39 How- priate marker of decreased iron avail- these limitations, there is a need for ever, both measurements are limited ability.46,47 Further research is needed novel serum biomarkers to differentiate by testing requirements. HRC% must before NGAL can be recommended as types of IDA in patients with CKD. Sev- be tested within 6 hours of collection a reliable marker of iron deficiency eral biomarkers have been proposed; and CHr is time sensitive to the mat- in CKD. they are summarized in Table 1 and uration of erythrocytes.40 Further- reviewed below. more, CHr cannot be used in the Based on the current literature, the setting of thalassemia, because thalas- use of the traditional biomarkers of c Serum ferritin: Ferritin is an acute- semia causes changes similar to iron IDA is reasonable, especially considering phase reactant and, as such, is fre- deficiency. the absence of other reliable biomarkers. quently elevated in patients with CKD, irrespective of their iron stores.30,31 c Hepcidin: Given its integral role in Increased ferritin levels in CKD are iron regulation, hepcidin has been MANAGEMENT likely the result of underlying systemic evaluated as a marker of iron stores inflammation because ferritin synthe- and iron responsiveness and to dif- The optimal management of iron defi- sis is responsive to inflammatory ferentiate absolute and functional ciency in patients with CKD remains un- cytokines.32,33 Hence, the specificity of IDA.41 Hepcidin has been shown to clear. Only a few large-scale randomized low ferritin is high for absolute iron correlate with ferritin levels in a subset trials had evaluated the safety of various deficiency, but normal or elevated of 61 patients with CKD from the iron formulations until recently. The ferritin levels to not exclude IDA in Ferinject assessment in patients with Kidney Disease: Improving Global Out- CKD.34,35 IDA and nondialysis-dependent CKD comes (KDIGO) work group guidelines (FIND-CKD) trial.42 However, no re- (2012) recommend balancing the poten- c Soluble transferrin receptor (sTfR): liable correlation was found between tial benefits of avoiding or minimizing The transferrin receptor binds ferric hepcidin and iron responsiveness.41 blood transfusions, ESA therapy, and iron and the complex is subsequently Similar findings have been reported in anemia-related symptoms against the internalized into the cell. sTfR is then patients with CKD receiving dialysis.38 potential risks of iron supplementation.1 shed from the membrane of erythroid These data suggest the measurement For adult patients with CKD and ane- progenitor cells into the circulation.36 of hepcidin levels is of limited utility in mia, KDIGO recommends a trial of Hence, sTfR has been evaluated as a the evaluation of IDA in CKD. iron repletion if the TSAT is #30% and potential indicator of iron deficiency. the serum ferritin is #500 ng/ml. The A study of 71 patients dependent on c Plasma neutrophil gelatinase- European Renal Best Practice guideline dialysis found that sTfR did not detect associated lipocalin (NGAL): NGAL (2013),48 on the other hand, recom- occult iron deficiency. Rather, it posi- has been implicated in AKI, as an in- mends a trial of iron for TSAT levels of tively correlated with hematologic dependent predictor of kidney-disease ,20% and ferritin levels of ,100 ng/ml parameters in the setting of EPO ad- progression, and as a biomarker of in- to increase Hgb while avoiding ESAs ministration, indicating sTfR is a flammation.43,44 Additionally, NGAL with the goal of remaining below the marker of erythropoiesis.36 Another affects sequestration of iron. In its free ceilingofTSATof30%andferritinof study of 91 patients on dialysis showed form, NGAL may increase the extra- 500 ng/ml during supplementation. similar results.37 Thus, the evidence cellular concentrations of iron, whereas Considering the more recent evidence does not support the use of sTfR in the the bound form of NGAL decreases it. that many patients with CKD have ferri- evaluation of IDA in CKD. The potential utility of NGAL as a tin levels .500 ng/ml,35 the most recent biomarker of iron stores in CKD was guidelines from the National Institute c Percentage of hypochromic RBCs evaluated in 419 patients with anemia, for Healthcare and Excellence (2015)49 (HRC%) and reticulocyte Hgb content of whom 288 had CKD. An NGAL and the Renal Association (2017)50 in- (CHr): Several other indirect mea- value of #394 ng/ml was found to creased the ferritin ceiling to 800 ng/ml surements have been considered in the correlate significantly with TSATand to during iron supplementation. evaluation of IDA. HRC% and CHr have a greater sensitivity and specificity both estimate Hgb content in RBCs, in the detection of decreased iron Risks of Iron Supplementation with thereby reflecting the iron available for stores in CKD than ferritin values of Elevated Ferritin erythropoiesis in the recent timescale. #500 ng/ml.45 Although these data are The concerns regarding HRC% and CHr are predictive of iron promising, the study did not evaluate are largely related to the potential for

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Table 1. Serum biomarkers for iron deficiency anemia in CKD Sensitivity/ Relation to Iron Treatment Predicts Response Name Measures (U) Specificity for Iron Drawbacks Deficiency Targeta to IV Iron Deficiencyb Ferritin Level of ferritin in the Decreases (,100 ng/ Uncertainc Not reliable ,100 ng/dl: 35%/ Acute-phase reactant, blood (ng/dl) dl diagnostic in 78%31 elevations not solely nondialysis- ,200 ng/dl: 41%/ related to iron status dependent CKD, 100%27 and upper limit of ,200 ng/dl ,500 ng/dl: 81%/ normal unclear diagnostic in CKD) 27%42 TSAT Amount of iron bound Decreases (,20% 30%–50% ,30% Predictive ,20%: 63%/80%21 TIBC affected by to transferrin diagnostic) inflammation and compared with total malnutrition body stores (%iron/ TIBC) CHr Absolute amount of Not reflective of Not ,29 pg predictive, 57%/93%31 Time sensitive to Hgb in circulating stores established more effective maturation of reticulocytes (pg) marker than reticulocytes ferritin or TSAT HRC% Concentration of Hgb Not reflective of Not .6% predictive 82%/95%31 Must be measured in RBCs (% relative stores established within 6 h of Hgb content relative collection to RBC size) sTfR Transferrin receptors May increase, can Not .1.5 mg/L 81%/71%31 Less reliable than CHr shed from the RBC potentially note established predictive and HRC%, may rise surface iron stores in the setting of EPO Hepcidin Level of hepcidin in Increases Not Not reliable Not applicable — blood applicable Plasma Level of NGAL in blood Increases Not #394 ng/ml 84%/50%42 — NGAL (ng/ml) established TIBC, total iron binding capacity. aThresholds take into account current evidence and are recommended based on these data. bSensitivity/specificity measurements are best estimates, but comparisons across biomarkers are difficult because most studies were done in sample sizes of ,100 patients and used different standards of comparison or diagnostic criteria (e.g., bone marrow stores versus response to iron). cCurrent recommendations 200–800 ng/dl and consider supplementation based on risk-benefit analysis for values $800 ng/m. free iron reactions, leading to damage or CV disease. Additionally, the study followed for 6 weeks after the comple- from oxidative stress, increased tissue- participants received iron and ESA per tion of treatment. Of note, ferritin levels iron deposition, and an increased risk the guidelines during the study period did not predict iron responsiveness. of infection.51–53 To address whether and, hence, the authors were unable to Rather, iron parameters showed greater chronic iron supplementation leads to evaluate the safety of higher ceilings of improvement in the group receiving fer- increased tissue-iron deposition, a pro- ferritin. ric gluconate and an associated signifi- spective study in France of 119 patients Several studies have evaluated the cant decrease in EPO doses.55 After the with CKD who were dialysis dependent safety of IV iron supplementation ac- additional 6-week follow-up period, the used magnetic resonance imaging to cording to different TSAT and ferritin patients who had received ferric gluco- quantify iron overload noninvasively. thresholds in patients with dialysis- nate continued to require lower EPO The authors reported no significant cor- dependent CKD and are summarized doses.56 Thesedatasupporttheuseof relation between iron dosing and iron in Table 2. The Dialysis Patients’ Re- iron supplementation as an ESA- deposition in the liver.54 Importantly, sponse to IV Iron with Elevated Ferritin sparing strategy, even in patients with cessation of IV iron supplementation re- (DRIVE) I and II trials investigated the elevated serum ferritin levels. sulted in a decline in iron deposition in safety of iron administration in patients The most compelling evidence in the liver, suggesting that the intermittent with dialysis-dependent CKD with ferri- support of a more liberal approach to administration of IV iron does not result tin levels ranging from 500 ng/ml to iron supplementation is derived from in long-term iron overload.54 Although 1200 ng/ml, with TSAT #25%.55,56 A the Randomized Trial Comparing Pro- the reported findings are reassuring, the total of 134 participants were random- active, High-Dose versus Reactive, studywaslimitedbecauseitmadeno ized to either 125 mg of ferric gluconate Low-Dose IV Iron Supplementation in observations regarding patient mortality or no treatment for 6 weeks, and then Hemodialysis (PIVOTAL).57 PIVOTAL

460 JASN JASN 31: 456–468, 2020 JASN Table 2. Summary of the clinical trials of iron supplementation in patients with CKD 31: n

456– Reference Title Year Population Follow-up Intervention Outcomes Safety Additional Coyne, et al.55 DRIVE I 2007 Patients undergoing 134 6 wk No iron (control) Patients receiving No difference in Ferritin levels 6,2020 468, hemodialysis with versus 125 mg IV ferric gluconate had adverse events ranged 500–1200 Hgb #11 g/dl, ferric gluconate higher Hgb and had no ferritin (P50.028), more correlation with 500–1200 ng/ml, rapid Hgb response outcomes TSAT #25%, and (P50.035) epoetin dosage $225 IU/kg per wk or $22,500 IU/wk Kapoian, DRIVE II 2008 Same as DRIVE I 112 12 wk (6 wk from No iron (control) Ferric gluconate group More adverse events in et al.56 DRIVE I) versus 125 mg IV had significantly control group (IRR ferric gluconate for lower EPO doses; 1.73, P50.041) the first 6 wk. For 84% of the the additional 6 wk, treatment arm treatment was per maintained Hgb center .11.0 versus 68% of the control (P,0.05) MacDougall, PIVOTAL 2019 Patients undergoing 2141 Median52.1 yr : high Composite outcome Similar rates of Rates of stroke were et al.57 hemodialysis dose (400 mg) (nonfatal myocardial infection and overall similar for both given monthly infarction, stroke, adverse events; groups but lower versus low dose heart failure vascular access rates of fatal or (0–400 mg) given hospitalization, any- thrombosis rates nonfatal reactively each mo cause death) was were 24% in the myocardial based on ferritin 29% versus 32% high-dose versus infarction were ,200 mcg/L or (P50.04) in the high- 21% in the low-dose noted in the high- TSAT ,20% dose versus low- group (P50.12); but dose group dose group; less lower rates of fatal or ESA use in the high- nonfatal myocardial dose group infarction were noted in the high- dose group (estimated treatment effect 0.69 [95% CI: 0.52- www.jasn.org 0.93])

D nCKD in IDA Agarwal, REVOKE 2015 Patients with stage 3 136 2 yr Open-label ferrous Similar decline in Infections: IRR 2.12 for Not powered for et al.58 or 4 CKD and IDA sulfate 325 mg TID eGFR; similar IV versus oral iron safety for 8 wk versus IV improvement in groups (P,0.006). iron sucrose Hgb; similar ESA CV events: IRR 2.51

200 mg every 2 wk dose for IV versus oral iron REVIEW (total dose 1 g) groups (P,0.001) 461 462

Table 2. Continued REVIEW

Reference Title Year Population n Follow-up Intervention Outcomes Safety Additional fi JASN Macdougall, FIND- 2017 Patients with 353 1 yr Oral iron (ferrous Time to initiation of No signi cant Ferritin levels were et al.59 CKD nondialysis- sulfate 304 mg additional anemia difference in significantly www.jasn.org dependent CKD twice daily) versus therapy: the primary adverse renal higher in the high- and IDA without FCM at high dose end point occurred outcomes dose FCM group ESA use (500 or 1000 mg in 23%, 32%, 32% in monthly based on the high-ferritin ferritin) versus FCM FCM, low-ferritin at low dose (2 mmg FCM and oral iron monthly based on groups, respectively ferritin) (HR, 0.65; 95% CI, 0.44 to 0.95; P50.026 for high- ferritin FCM versus oral iron) Charytan, 2013 Adult Patients with 416 NDD- 30 d Standard medical Safety of high-dose Primary end point: Not powered for et al.60 history of NDD- CKD, 97 HD- care (provider FCM: no difference high incidence of secondary end CKD of at least 3 CKD determined: no in safety events serious events in the points mo or HD-CKD of iron, oral iron, or IV between groups; no standard care group at least 6 mo with iron) versus FCM difference in the (notably iron sucrose IDA and no recent (15 mg/kg in NDD- proportion of or ferrous iron use CKD or 200 mg in patients with an gluconate), p,0.01 HD-CKD) increase of 1 g/dl in Hgb or Hgb .12 g/ dl Onken, et al.61 REPAIR- 2014 Patients with CKD 2584 56 d FCM (15 mg/kg32 Composite safety Composite (all-cause FCM noninferior for IDA and IDA with stable doses) versus IV outcome (all-cause mortality, nonfatal increases in TSAT, ESA dose (if iron sucrose (200 mortality, nonfatal myocardial ferritin applicable) mg35 doses) myocardial infarction, nonfatal infarction, nonfatal stroke, unstable stroke, unstable angina, CHF, angina, CHF, arrythmia, arrythmia, hypertension, hypertension, hypotension): no hypotension): no major difference; significant significant difference; mean difference in JASN change in Hgb from number of transient

31: baseline was higher hypertension in

456 in the FCM group FCM group and hypotension in iron – 6,2020 468, sucrose group IRR, incident risk ratio; TID, three times a day; NDD-CKD, non-dialysis dependent chronic kidney disease; HD-CKD, hemodialysis-dependent CKD; CHF, congestive heart failure. www.jasn.org REVIEW

Table 3. IV iron formulations Iron Concentration Test-Dose Black Box Molecular Weight (Da) Maximum Daily Dose (mg/ml) Required Warning Iron dextran 265,000 100 mg 50 Yes Yes Low mol wt iron dextran 165,000 low mol wt iron 100 mg 50 Yes Yes dextran Sodium ferric gluconate 289,000–444,000 125 mg 12.5 No No complex in sucrose injection Iron sucrose injection, 34,000–60,000 200 mg in CKD (100 mg 20 No No United States if on hemodialysis, Pharmacopeial 300–400 mg if on peritoneal dialysis) Ferumoxytol 750,000 510 mg 30 No Yes Iron isomaltoside, 150,000 20 mg/kg 100 No No FCM injection 150,000 750 mg if weight .50 kg 50 No No (15 mg/kg if weight ,50 kg)

is a randomized controlled trial of 2141 iron infusion; however, the clinical sig- patients on hemodialysis with 776,203 patients with dialysis-dependent CKD nificance of these findings is unclear. It unique iron exposure/follow-up periods randomized to either high-dose iron su- has been postulated that oxidative stress, with the goal of evaluating the safety crose (400 mg) given proscriptively each induced by IV iron, may lead to a higher of different IV-iron dosing strategies, month versus a reactive, lower-dosing risk of infection, atherosclerosis, and including bolus versus maintenance strategy that was adjusted based on fer- hospitalization. However, several obser- and high (.200 mg/mo) versus low ritin or TSAT. Notably, the investigators vational studies on the topic have yield- (#200 mg/mo) dosages. They observed set a ceiling of 700 ng/ml for ferritin and ed conflicting results. In one analysis no consistent associations between any 40% for TSAT as hard stops for holding of .32,000 patients with dialysis- of the evaluated dosing strategies and iron doses in the proactive, high-dose dependent CKD who were followed CV events.68 Although such data may arm. After a mean follow-up of 2.1 years, over 9 years, high doses of IV iron were be reassuring, considering the nature the group that was randomized to the found to associate with an increased risk and limitations of these observational proactive, high-dose arm had a lower in- of mortality, hospitalization, and CV studies, the long-term safety of IV iron cidence of death, nonfatal CV events, events.63 Although other analyses have remains unclear and caution should be and hospitalization, as well as signifi- yielded similar results,64 their findings applied when interpreting such studies. cantly lower ESAs and transfusion are at odds with those of several studies. Several randomized controlled trials requirements. Of note, there was no dif- For example, some have shown that the have been conducted to evaluate the ference in infection rates between both association between IV iron and mortal- potential benefits and safety of IV iron study arms. Results of PIVOTAL are con- ity is attenuated after adjusting for co- (Table 3). The Randomized Trial to Eval- sistent with the results of DRIVE I and II morbidities.65 Other studies have shown uate IVand Oral Iron in CKD (REVOKE) and indicate that a more liberal ap- more complex findings: IV iron use was was a single-center, randomized con- proach to iron supplementation is safe associated with a significantly lower in- trolled trial of 136 patients with and effective, specifically in patients un- cidence of death in 58,058 patients with nondialysis-dependent CKD that com- dergoingdialysis.However,giventhat CKDonhemodialysisaslongasthe pared IV iron sucrose to oral ferrous sul- the median serum ferritin level in the administered dosage of iron was fate. The primary end point of the study United States is higher than the safety #400 mg/mo, and with higher mortality was change in GFR. Secondary end points cutoff applied in PIVOTAL, further if the dosage was .400 mg/mo.66 A included albuminuria, Hgb response, and studies are needed to establish the safety larger observational study evaluated the kidney disease–related quality of life. Al- of iron supplementation in patients with potential association between IV iron though it was planned to last 2 years, the serum ferritin levels .700 ng/ml.62 and death in 72,114 patients with CKD study was stopped early due to the higher on hemodialysis. After adjusting for he- incidence of adverse events in the IV iron Risks of IV versus Oral Iron matocrit level and EPO dosing, the use group, including infection and heart fail- Administration of IV iron was associated with a 22% ure.58 The findings of REVOKE contrast Oxidative stress has been observed tran- lower mortality.67 The largest analysis with the reported results of the multicen- siently in both humans and animals after conducted, to date, evaluated 117,050 ter FIND-CKD trial, inwhich 626 patients

JASN 31: 456–468, 2020 IDA in CKD 463 REVIEW www.jasn.org with nondialysis-dependent CKD were postinfusion, hyper- and hypotensive use their judgment to weigh the risks of randomized to receive ferric carboxy- episodes in the FCM group; there was alternate treatment, including the risk of maltose (FCM) targeting one of two no significant difference in all-cause higher ESA dose and the patient’s medi- ferritin thresholds versus oral iron ther- mortality, nonfatal myocardial infarc- cal comorbidities, against the potential apy. In contrast to REVOKE, FIND-CKD tion, nonfatal stroke, unstable angina, risks of iron supplementation. A TSAT demonstrated no difference in the risk of or arrhythmia between the FCM and ceiling of 40% may be considered a rea- infection, CV events, or kidney toxicity iron sucrose groups.61 Although these sonable cutoff above which caution during 1 year of follow-up.59 When in- data suggest an overall similar safety should be exercised before continuing terpreting these conflicting results, r sev- profile to both formulations, both iron repletion. For patients with CKD eral factors.69,70 First, neither study was studies are limited by the short dura- who are at high risk of CKD progression, adequately powered to evaluate safety tion of follow-up. As such, the safety a trial of oral iron supplementation is outcomes. Second, REVOKE included of IV iron versus oral iron supplemen- warranted before the consideration of patients at risk of rapid CKD progres- tation remains debatable, especially in IV iron. sion, whereas FIND-CKD only included patients with nondialysis-dependent patients with stable CKD. As such, the CKD who are at high risk of CKD Iron Supplementation Formulations patients included in REVOKE may have progression. There is a variety of both IVand oral iron been at higher risk of infectious and CV preparations available for use, each with adverse events than those included in Anaphylaxis with IV Iron their own risks and benefits. FIND-CKD. Third, whereas REVOKE One additional concern which has been Oral agents include ferrous sulfate, considered each event within a trial par- noted with the administration of iron is ferrous gluconate, ferrous fumarate, ticipant as a separate reportable event, anaphylaxis. Anaphylaxis is most com- iron polysaccharide, and ferric citrate FIND-CKD reported only one type of monly reported with iron dextran formu- (FC). Ferrous preparations tend to be each event per participant even if there lations, although this cannot be reliably used most frequently as they are less ex- were multiple instances. FIND-CKD ad- confirmed due to inconsistencies with la- pensive and more widely available than ditionally only reported events up to the beling agents.52 Although dextrans confer other preparations,72 although their side point that the trial therapy was changed, a higher risk of anaphylaxis, most formu- effects limit the total daily dose tolerated. and so downstream events could not be lations of IV iron appear to have a better Additionally, there is evidence that IV directly attributed to their experimental safety profile in this regard and most for- ironmaybemoreeffectivethanoral intervention. Hence, it is difficult to rec- mulations do not require allergy testing iron in general. This was first demon- oncile the results of the two studies. before administration.51 Alargeretro- strated by Macdougall et al.73 in a ran- Two other studies were performed to spective cohort study of fee-for-service domized controlled trial of 37 patients evaluate the safety of IV iron as a primary Medicare patients followed for 10 years with CKD on ESAs comparing IV, oral, end point. As shown in Table 2, the first found the anaphylaxis risk is estimated and no iron supplementation. Further study evaluated IV versus oral iron sup- to range from 24 to 68/100,000 for all studies have confirmed the superiority plementation. A total of 508 patients combined IV iron formulations (dextran, of numerous different IV iron formula- with nondialysis-dependent CKD and gluconate, sucrose, and ferumoxytol) and tions to the common oral therapies in dialysis-dependent CKD were random- decreases with subsequent dosing.71 both patients who are dialysis dependent ized to receive either FCM or one of any Although these data indicate that the in- and those with CKD stages 3–5, both for treatment modality within the defined cidence of anaphylaxis remains small, pa- rapidity of improvement in Hgb and standard of care, including oral iron, tients receiving IV iron therapy should be quality of life.58,74–76 Regardless of for- IV iron (iron sucrose or sodium ferric monitored closely. mulation, it appears that using smaller gluconate), or no iron.60 There was no doses of IV iron with increased frequency significant difference between the Iron Administration Ceilings is a more effective approach, than the use groups in terms of overall adverse events Based on the current literature, we con- of larger doses less frequently, to main- or achievement of improvement in Hgb clude that drawing a ceiling for iron sup- tain Hgb levels and decrease the dose of after 30 days. The second study was the plementation for any patient with ferritin EPO.51,58 This approach of more- Randomized Evaluation of Efficacy and ,500 ng/ml and TSAT ,30% may lead frequent administration of smaller doses Safety of FCM in Patients with IDA and to the underutilization of iron supple- of IV iron is feasible and convenient in Impaired Renal Function (REPAIR- mentation in a large portion of patients patients with CKD receiving intermittent IDA) trial. This study similarly evaluated who would likely respond to treatment. A hemodialysis but not in patients receiv- the safety and efficacy of FCM compared trial of iron may be considered for those ing peritoneal dialysis or in patients with with iron sucrose. A total of 2584 pa- with ferritin levels .500 ng/ml in whom nondialysis-dependent CKD.51 In pa- tients with nondialysis-dependent CKD an increase in Hgb level and/or decrease tients with nondialysis-dependent CKD were followed over 60 days. Although in ESA dose is desired. Beyond a ceiling of who do require IV iron supplementation, there was an increase in transient, 800ng/ml,however,cliniciansshould larger doses with decreased frequency

464 JASN JASN 31: 456–468, 2020 www.jasn.org REVIEW may be preferred to reduce the number compared with placebo. The results of under investigation for the treatment of venipunctures (to preserve future he- this study are still pending. of anemia in CKD. Notably, agents modialysis vascular access sites) and to that inhibit HIF prolyl-hydroxylases minimize the burden of travel and the c Ferric pyrophosphate citrate (FPC): lead not only to increased production cost of the infusions. FPC was approved by the FDA in 2015 of EPO but also to increased iron store Several IV iron formulations are for use in patients on dialysis. It is availability and increased iron uptake available (reviewed in Table 3). Consid- a water-soluble, carbohydrate-free, com- from the gastrointestinal tract. HIF ering the large number of formulations plex iron salt administered via the prolyl-hydroxylase inhibitors (HIF- available, the choice of IV iron formula- dialysate to patients receiving hemo- PHIs) are oral formulations that have tion may be dictated not only by the dialysis. It donates iron directly to been shown to increase Hgb levels in safety profile but also by the cost and transferrin and may avoid iron se- patients with CKD. For example, a 20- ease of use (single versus multiple questration in the reticuloendothelial week phase 2b trial of illus- infusions). macrophages.82 FPC has been com- trated a significant improvement of Hgb pared with placebo in patients with compared with placebo in 138 patients ESKD receiving hemodialysis in the with CKD (stage 3–5).89 More recently, Continuous Replacement Using Iron NOVEL IRON THERAPIES was found to increase Hgb Soluble Equivalents (CRUISE) 1 and levels in a 9-week phase 3 trial of 154 2 trials. FPC delivered via dialysate The following is a summary of the novel patients with anemia of CKD not on di- was found to better maintain Hgb, fi iron therapies: alysis. Additional ndings included a re- TSAT, and ferritin as compared with duction in hepcidin levels and stable fi c FC: Iron replacement with an oral placebo, with signi cant reduction in iron indices (despite restricted IV iron 83 preparation like FC may be subject to ESA dosing. supplementation).90 In patients with a more physiologic regulation of iron ESKD on dialysis, 305 patients requiring c Liposomal/Sucrosomial iron: Liposo- absorption, thus potentially promis- ESA were randomized in a 2:1 ratio to mal iron surrounds the ferric pyro- ing to avoid the side effects of iron receive either roxadustat or epoetin phosphate core with a phospholipid overload that remain a concern with aalfa. During the 26 weeks of follow- bilayer and sucrososmial iron with IV formulations.77,78 FC is approved up, roxadustat increased Hgb and trans- an additional layer of sucrosomes as a phosphate binder in patients with ferrin levels, maintained serum iron (sucrester, a surfactant, and addi- ESKD. More recently, FC has been levels, and attenuated decreases in tional starchlike compounds).84 This approved by the Food and Drug Ad- TSAT.91 Similar to the data in patients allows for iron to bypass the gastro- ministration (FDA) for the treatment with CKD who were not on dialysis, intestinal tract and be taken up by of IDA in patients with CKD not on roxadustat reduced hepcidin levels.91 microfold cells through the lymphatic dialysis. This is based on recent data These findings suggest that HIF-PHIs system, thus avoiding the downregulating showing that FC improves Hgb (in may improve iron utilization.92 There effects of hepcidin and minimiz- addition to lowering phosphorus) in are currently at least six drugs from ing potential side effects.84 Prelimi- patients with CKD not on dialysis this family in various stages of clinical nary data suggest that liposomal iron (stage 3–5).79,80 Considering the high trials and investigation in the United improves Hgb in patients with CKD pill burden in CKD, FC may represent States and abroad: roxadustat, vadadu- while minimizing the risk of adverse an appealing approach for the treat- stat, , , enarodu- events.85 Sucrosomial iron has sim- ment of hyperphosphatemia and IDA stat, and .93,94 For example, ilarly been shown to improve anemia phase 3 studies to evaluate major ad- in CKD. 86 in patients with celiac disease, patients verse CV outcomes with roxadustat 87 c : Ferric maltol is ap- undergoing bariatric surgery, and in have been completed and the results 88 proved for the treatment of patients patients with malignancy. Whether are forthcoming. The entry of this novel fi with IDA and inflammatory bowel sucrosomial iron is ef cacious or safe class in our therapeutic armamentar- disease in the United Kingdom and in patients with CKD has not been ium is exciting. Although it is important the in the United States, having shown evaluated. to establish the long-term safety of HIF- rapid correction of anemia with a PHIs, especially considering their po- relatively low side-effect profile.81 A tential to promote neoplastic growth phase 3 trial in the Study with Oral and angiogenesis (particularly pertinent Ferric Maltol for the Treatment of IDA NONIRON THERAPIES OF to diabetic retinopathy),95 these agents in Subjects with CKD (AEGIS-CKD) ANEMIA OF CKD are likely to change the current algo- has been completed in patients with rithms for the treatment of anemia in CKD stages 3–4 to evaluate the po- There are several agents (outside of iron patients with CKD including the utili- tential effects of ferric maltol on Hgb supplementation) that are currently zation of iron supplementation.

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CONCLUSIONS chronic kidney disease. NEnglJMed355: of HIF-1 alpha. Cardiovasc Res 77: 463–470, 2085–2098, 2006 2008 fi 4. Pfeffer MA, Burdmann EA, Chen CY, Cooper 20. Schofield CJ, Ratcliffe PJ: Oxygen sensing by Iron de ciency is a common and treat- ME, de Zeeuw D, Eckardt KU, et al.; TREAT HIF hydroxylases. Nat Rev Mol Cell Biol 5: able cause of anemia in patients with Investigators: A trial of in 343–354, 2004 CKD. Given the limitations of TSAT type 2 diabetes and chronic kidney disease. 21. Kaelin WG Jr., Ratcliffe PJ: Oxygen sensing and ferritin in establishing iron defi- NEnglJMed361: 2019–2032, 2009 by metazoans: The central role of the HIF ciency in patients with anemia of CKD, 5. Levin A, Djurdjev O, Thompson C, Barrett B, hydroxylase pathway. Mol Cell 30: 393–402, Ethier J, Carlisle E, et al.: Canadian random- 2008 the KDIGO guidelines recommend bal- fi ized trial of hemoglobin maintenance to 22. Haase VH: Regulation of erythropoiesis by ancing the potential bene ts of avoiding prevent or delay left ventricular mass growth hypoxia-inducible factors. Blood Rev 27: or minimizing blood transfusions, ESA in patients with CKD. Am J Kidney Dis 46: 41–53, 2013 therapy, and anemia-related symptoms 799–811, 2005 23. Lopez A, Cacoub P, Macdougall IC, Peyrin- against the potential risks of iron supple- 6. Besarab A, Bolton WK, Browne JK, Egrie JC, Biroulet L: Iron deficiency anaemia. Lancet Nissenson AR, Okamoto DM, et al.: The ef- 387: 907–916, 2016 mentation. Multiple established agents fects of normal as compared with low he- 24. Stancu S, Stanciu A, Zugravu A, Bârsan L, exist for the treatment of IDA in CKD matocrit values in patients with cardiac Dumitru D, Lipan M, et al.: Bone marrow iron, including several oral and IV formula- disease who are receiving hemodialysis and iron indices, and the response to intravenous tions. For patients with stable CKD, IV epoetin. N Engl J Med 339: 584–590, 1998 iron in patients with non-dialysis-dependent formulations are acceptable and espe- 7. Fishbane S, Pollack S, Feldman HI, Joffe MM: CKD. Am J Kidney Dis 55: 639–647, 2010 Iron indices in chronic kidney disease in the 25. Stancu S, Bârsan L, Stanciu A, Mircescu G: cially convenient for patients requiring National Health and Nutritional Examination Can the response to iron therapy be pre- hemodialysis. The dose and the fre- Survey 1988-2004. Clin J Am Soc Nephrol 4: dicted in anemic nondialysis patients with quency of IV iron administration should 57–61, 2009 chronic kidney disease? Clin J Am Soc weigh patient comfort and accessibility. 8. Babitt JL, Lin HY: Mechanisms of anemia in Nephrol 5: 409–416, 2010 CKD. JAmSocNephrol23: 1631–1634, 26. Bahrainwala J, Berns JS: Diagnosis of iron- 2012 deficiency anemia in chronic kidney dis- 9. Yilmaz MI, Solak Y, Covic A, Goldsmith D, ease. 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Hung SC, Tarng DC: Bone marrow iron in Abbvie, Dr. Schar, Astra-Zeneca, and Takeda, 12. Ganz T: Hepcidin, a key regulator of iron CKD: Correlation with functional iron de- outside the submitted work. Dr. Jalal reports re- metabolism and mediator of anemia of in- ficiency. Am J Kidney Dis 55: 617–621, 2010 search support from Keryx Inc, during the conduct flammation. Blood 102: 783–788, 2003 30. Kim T, Rhee CM, Streja E, Obi Y, Brunelli SM, of the study. All remaining authors have nothing to 13. Panwar B, Gutiérrez OM: Disorders of iron Kovesdy CP, et al.: Longitudinal trends in disclose. metabolism and anemia in chronic kidney serum ferritin levels and associated factors in disease. Semin Nephrol 36: 252–261, 2016 a national incident hemodialysis cohort. 14. Basseri RJ, Nemeth E, Vassilaki ME, Basseri Nephrol Dial Transplant 32: 370–377, 2017 B, Enayati P, Shaye O, et al.: Hepcidin is a key 31. 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468 JASN JASN 31: 456–468, 2020