Introduction

Red cell production requires two ingredients––an erythropoietic stimulating agent (ESA) to produce, proliferate, mature and protect cells, and iron, so that hemoglobin can be synthesized within the post-erythroblast stages culminating in reticulocytes. A delivery of approximately 20-30 mg/d of iron per day is needed. 1

To accomplish this, transferrin-bound iron must be recycled 6-10 times daily  and even more often in patients with chronic kidney disease and end-stage renal disease. This review will focus on ESAs and iron preparations and delivery systems currently available worldwide, those under development in phase 3 studies, and those not yet brought to clinical development with a focus on how they might be more physiologic in correcting anemia of CKD.2

ESAs: The old compared to the new

Recombinant human erythropoietin (epoetin alfa) was introduced into clinical practice in 1989. It fundamentally changed anemia management, which had consisted of blood transfusions and supra pharmacologic androgen administration. All first generation, short acting epoetins (t1/2 of 4-10 hours) are produced in mammalian systems so that glycosylation can take place. The amino acid sequence of all first generation epoetins is identical to human erythropoietin but they differ in sialic acid residues. These differences in sialic acid are minor enough that no clear difference in action is noted among them. Biosimilars have proliferated so much (driven by economic cost issues) that all the Greek letters from “alfa” to omega have been used up. They are all administered at least twice weekly to hemodialysis patients and less often to continuous ambulatory peritoneal dialysis and non-dialysis CKD patients. The products produced under Good Manufacturing Practices in the United States and Europe are as “pure” as the original four epoetins (alfa, beta, omega and delta). However poor manufacturing practices in some parts of the world have been associated with outbreaks of pure red cell aplasia.

Types of ESAs

Short acting

Short acting ESAs must be administered frequently. Pharmacologic studies have shown that erythropoietin blood levels drop rapidly from levels of several thousand to basal levels < 30 mU/mL during the interdialytic period.3  This unphysiologic profile produces two effects: apotosis of developing cells in bone marrow and neocytolysis – hemolysis of young red blood cells (RBCs) less than 10 days old as plasma erythropoietin levels suddenly fall.4,5 One option to avoid supaphysiologic concentrations of erythropoietin in managing anemia is use of agents with intrinsically longer half lives.  

Longer-acting

A number of agents have been developed whose pharmacologic duration of action is longer, maintaining erythropoietic levels longer and minimizing peak levels. The second generation ESA, Darbepoetin alfa, has a serum half-life three times longer than first generation ESAs and can correct or maintain desired Hb levels in CKD-hemodialysis and CKD-nondialysis patients when administered weekly to once every 2 weeks. 6,7 In Europe, Asia, and the Pacific Rim, pegylated epoetin beta, (Mircera), with a half life of 130-140 hours, has been available since 2007 and can be dosed at still greater intervals of every 2-4 weeks.Phase III trials demonstrated that pegylated epoetin beta Q3W to QM corrects and maintains Hb levels in hemodialysis patients. 9  This agent may be available in the U.S. in mid 2014. Recently, a nonerythropoietic peptide, peginesatide linked to PEG (Omontys), again to increase circulating half-life, had been approved for once monthly use in the U.S. for hemodialysis patients10 but was voluntarily recalled by the manufacturer (Affymax) after three patient deaths due to hypersensitivity reaction.

Within limits, shorter or intermediate acting agents should not be dose-escalated to achieve less frequent administration as clearly shown by Carrera et al. 11 in hemodialysis patients maintained on Q2W dosing of darbepoetin. These patients could not be maintained on once monthly dosing of darbepoetin despite large escalations in total monthly dose. Dose escalation is counterproductive. It is not only cost-ineffective but such a strategy may be harmful if supaphysiologic peak levels of ESA from higher individual doses are in the pathway for harm.12

Although the exact mechanisms for harm are not known,13 increased shear stress from higher Hb, accentuated by hemodialysis-induced hemoconcentration,14 could produce endothelial injury or alter endothelial function, increasing risk for thrombosis in some susceptible patients. Recombinant erythropoietin increases platelet aggregability through a tyrosine phosphorylation–signaling pathway.15  In addition, epoetin has the following effects on vessels: increased endothelin,16 impaired endothelium-dependent nitric oxide–induced vasorelaxation,17 perturbed calcium homeostasis in vascular smooth muscle cells,18 and enhanced platelet serotonin release.19 These nonerythropoietic effects of ESA on platelet reactivity, seen only at concentrations of erythropoietin levels  > 1000 mU/ml, may produce ‘‘harm’’ from ‘‘non hemoglobin’’ effects of ESAs.

Dosing by regulation

Significant regulatory changes in the use of ESAs in general and the goals of therapy (i.e. hemoglobin levels) have been made in the United States, leading to restrictive use of ESAs. However we should remember that epidemiologic surveillance studies conducted by the U.S. Renal Data System through 2006 always showed that those who responded well to ESA therapy did well, whereas those who were hyporesponsive did not with an inverse relationship between ESA dose and achieved Hb level. Hyporesponsive patients received the largest doses and therefore would have the highest peak and intermediate plasma levels of ESA.

Although almost all RCTs clearly showed there was a danger in taking all comers to higher Hb levels; post hoc analyses of RCTs also identified hyporesponse as the major confounder. If high ESA levels from escalated doses given to hyporesponsive patients are part of mechanism of harm, how can these be minimized?

Hypoxia Inducible Factor (HIF) Prolyl-Hydroxylase Inhibitors (PHIs) act in a manner mechanistically distinct from ESAs. These agents are orally active and inhibit Proline Hydroxylase proteins, which are responsible for the hydroxylation, the ubiquitination, and the degradation of HIF-α. These compounds mimic a hypoxic stimulus, stabilize HIF-α permitting heterodimerization, nuclear translocation, and hypoxia responsive elements-mediated transcription of a multitude of genes. With respect to erythropoiesis, desired effects include stimulation of EPO release,20 inhibition of hepcidin transcription, amelioration of diabetic kidney disease, and protection from ischemia–reperfusion injury. Undesired effects include enhanced glycolysis, impaired mitochondrial respiration, aggravated tubulointerstitial injury, and increased vascular endothelial growth factor (VEGF)- mediated angiogenesis. The most advanced program is Fibrogen’s FG-4592 compound that has completed Phase 2 studies with phase 3 studies to begin this year.

Hypoxia Inducible Factor stabilization through proline hydroxylase inhibition (HIF- PHIs) represents a novel class of medications. Endogenous erythropoietin is produced with peak levels much lower than those resulting from exogenous ESA administration. The central question is whether the major differences in mechanisms of action between HIF- PHI agents and exogenous ESA can disconnect the risk between targeted and achieved hemoglobin in the most vulnerable patients. Possible mechanisms that could play such a role is the HIF-PHI induction of concomitant synergistic effects on iron metabolism and on sustained-controlled bone marrow stimulation of RBC precursors to the normoblast stage under conditions of “physiologic” levels of endogenous erythropoietin, i.e., levels seldom exceeding 200 mU/ml. By contrast, use of any ESA will always require concomitant exogenous iron (including parenteral agents) to optimize ESA dose.

Another technique currently under study in non-dialysis CKD is one of EPO gene therapy, in which dermal tissue structures are manipulated ex-vivo for autologous production and delivery of therapeutic proteins. The concept has been termed a biopump when implanted back into the original donor. Such “EPODURE” biopumps have been able to maintain HB of 10-11 g/dl for periods of 3-24 months in CKD patients.21

Still in the pipeline (i.e., animal studies) are GATA 2 inhibitors that act through the same pathway as HIFs, but distally. They have been found like HIF stabilizers to reverse the decreases in hemoglobin and erythropoietin concentrations, in reticulocyte counts, and the suppression of erythroid colony-forming units induced by IL-1 or TNF-α in animal models of anemia due to chronic inflammation.

Iron

Correction of iron deficiency and prevention of functional iron deficiency are crucial in the management of anemia, in part to avoid excessive ESA dose while achieving and maintaining the desired Hb level in any given individual. In addition, adequate iron supplementation seems to have nonhematologic benefits, such as improved cognition, thermoregulation, immune function, and exercise adaptation, as well as decreased restless legs syndrome.23  Two non-exclusionary models have been proposed for iron homeostasis. One model focuses on iron absorption and postulates that plasma iron is sensed by duodenal crypt enterocytes via the transferrin receptor 24 that is upregulated under conditions of iron deficit. A second, compatible regulatory model proposes that iron absorption is downregulated by hepcidin, a 25-amino acid polypeptide produced by hepatocytes when iron is abundant 25 but hepcidin also controls export of iron from storage sites.

Use of oral (PO) iron therapy, has inconsistent effects. PO iron includes the non-heme compounds as well as the relatively new heme iron polypeptide (HIP)26,27 Iron overload and toxicity with PO iron is much less likely than with IV iron, because hepcidin prevents GI absorption of excess iron in states of sufficiency. In advanced CKD, however, excess hepcidin levels and other acute phase and host defense molecules may limit iron absorption and movement from iron storage sites in the reticuloendothelial system and produce iron-restricted erythropoiesis. PO iron is usually ineffective in HD and PD patients.28  Use of HIP, which is absorbed from the GI tract 10 times more effectively than non-heme iron, initially showed promise in dialysis patients. This writer’s experience with HIP has been less successful.29 Also the HEMATOCRIT trial, a 6-month study of HIP in PD patients, reported that HIP was not superior to oral iron.30 Recently ferric citrate, initially developed as a phosphate binder, was reported to be highly efficacious for this role but also able to raise TSAT and ferritin, decrease IV iron and EPO use, and raise hemoglobin, compared to active control.31 It is possible that this agent could offer a highly advantageous new choice for a phosphate binder that can reduce iron costs for managing anemia.

Many formulations of IV iron are available and are useful in both CKD and ESRD patients.32 KDIGO recognizes that excessive use of iron has its own set of problems. Anaphylaxis can occur with any of the parenteral iron preparations. Hypotension can occur if the agents are given too rapidly. The risk of adverse events, including life-threatening episodes, exists with all but is highest with the HMW iron dextran.33 Until recently, a common clinical conundrum in ESRD HD patients had been whether to prescribe iron in low doses at regular intervals (maintenance dosing consisting of 22 to 65 mg of iron administered weekly or less often) or in high doses after iron deficiency develops (repletion dosing consisting of ~ 1 g of iron administered over 8-10 infusions). The former approach is recommended by the most current KDIGO guidelines.2

In patients with CKD not on HD where repeated venous access for iron infusions is problematic, the issue has been which agent not to use. Table 2 lists the agents currently available in the United States. Iron isomaltoside and ferric carboxymaltose are available in Europe. CKD patients not on dialysis and CAPD patients occasionally require parenteral iron to correct absolute or functional iron deficiency. This is best accomplished by Total Dose Infusion (TDI) of 1 gram of elemental iron. Both ferric gluconate and iron sucrose can be safely administered as a bolus or short infusion at doses up to 250 mg and 300 mg, respectively over 10-15 min. Higher doses of either drug as a bolus or short infusion is associated with unpleasant vasoactive and gastrointestinal symptoms.34,35 Accelerated regimens of high-dose IV iron sucrose (500 mg over 3 hours) have been demonstrated to be safe.36 Among IV iron formulations, iron isomaltoside, ferric carboxymaltose, and the iron dextrans (ID) were developed and tested for TDI of 1000 mg. Auerbach recently reported that accelerated TDI of iron dextran was safe. 37

We found that treatment of iron requiring on dialysis-CKD patients with 500-1000 mg of LMWID was efficacious; the serious ADE rate in this study was 0.06% per episode of  low molecular weight (LMW) iron dextran administered.38 However, TDI of iron is not FDA approved because of high incidence of delayed arthralgias and myalgias.39  By increasing our infusion duration of LMW iron dextran, our incidence was low. Recently Ferumoxytol has been given in doses of 510 mg in less than a minute.40 The dose has been increased to 1020 mg but infused over a longer time of several minutes (abstract, Am Soc Hematol 54th Annual Meeting, 2012.)

While properly powered studies may add clarity as to relative safety of the various parenteral formulations of iron, IV iron has been standard for two decades and millions of doses of IV iron have been administered to dialysis and non-dialysis patients. Clinicians should be aware that LMW iron dextran and high molecular weight (HMW) iron dextran are not clinically interchangeable with the later having a much higher adverse event rate.

Finally, a recent report indicated that soluble ferric phosphate (SFP), when added to the dialysate, is able to reduce EPO dose by about 30% compared to a regimen of IV maintenance therapy. 41

 

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