Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review.

Iron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.

Hypoxia-Inducible Factor Stabilization as an Emerging Therapy for CKD-Related Anemia: Report From a Scientific Workshop Sponsored by the National Kidney Foundation.

The National Kidney Foundation convened an interdisciplinary international workshop in March 2019 to discuss the potential role of a new class of agents for the treatment of anemia in patients with chronic kidney disease (CKD): the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). International experts with expertise in physiology, biochemistry, structural chemistry, translational medicine, and clinical management of anemia participated. Participants reviewed the unmet needs of current anemia treatment, the biology of hypoxia-inducible factor, the pharmacology of prolyl hydroxylase inhibitors, and the results of phase 2 clinical trials of HIF-PHIs among patients with CKD, both those treated by dialysis and those not receiving kidney replacement therapy. The results of key phase 3 clinical trials of HIF-PHIs available as of the time of writing are also included in this report, although they appeared after the workshop was completed. Participants in the workshop developed a number of recommendations for further examination of HIF-PHIs, which are summarized in this report and include long-term safety issues, potential benefits, and practical considerations for implementation including patient and provider education.

Difficult Patient Behavior in Dialysis Facilities.

Difficult behavior exhibited by dialysis patients is a spectrum that includes nonadherence, verbal or physical abuse, and threatening acts. Such behaviors may lead to harmful consequences to the patient, other patients, the facility, and staff and can culminate in involuntary discharge. It is important to recognize that these "difficult behaviors" may be due to underlying psychosocial or medical issues, which places an onus on care providers to explore further. According to the Conditions for Coverage (CfC) for dialysis facilities, it falls upon the medical director to coordinate and oversee policies for patient satisfaction, patient safety and rights, involuntary discharges, and adverse events and outcomes. Thus, medical directors are liable for their own actions, and their staff for which they have oversight, for harm or perceived harm to patients in response to difficult behaviors. Guidelines to deal with specific patient behavior scenarios have been published by the Decreasing Dialysis Patient Conflict National Task Force of the Forum of end-stage renal disease (ESRD) Networks. The common denominator for these difficult scenarios is impaired communication, and the majority of patient concerns involve issues with staff, policies, treatments, and diet. Involuntary discharge of a patient should always be viewed as a last resort, and there is a structured process described in the CfC that requires the involvement of the respective ESRD Network and the facility medical director. As physicians, we are bound by ethical and growing legal obligations to act in an appropriate, ethical, and fair manner to patients who are considered to be "difficult."

Erythropoietin mimetic peptides and erythropoietin fusion proteins for treating anemia of chronic kidney disease.

PURPOSE OF REVIEW: First generation erythropoiesis stimulating agents (ESAs) have short duration of action which requires administration once weekly or greater. Second generation ESAs were developed which have longer duration of action and can be administered one to two times monthly. Erythropoietin (EPO) mimetic peptides (EMPs) activate the EPO receptor but have no structural analogy to EPO, offering the potential for lower cost as they are not biologic drugs. The first approved EMP, peginesatide, was withdrawn from the market within a year of its approval because of fatal anaphylactic reactions. In this review, we summarize recent progress regarding the development of newer, possibly less toxic, EMPs. We also summarize the development of EPO fusion proteins which fuse EPO with a portion of an immunoglobulin molecule or another EPO molecule, achieving a longer duration of action and less frequent dosing. RECENT FINDINGS: AGEM400(hydroxyethyl starch) and pegolsihematide are EMPs in phase II clinical trials. Three EPO fusion proteins are under development, two in phase I and one in phase II. SUMMARY: The future success of EMPs is limited by the prior experience with peginesatide and EPO fusion proteins do not offer cost savings or longer duration of action than currently available ESAs.

Positive Iron Balance in Chronic Kidney Disease: How Much is Too Much and How to Tell?

BACKGROUND: Regulation of body iron occurs at cellular, tissue, and systemic levels. In healthy individuals, iron absorption and losses are minimal, creating a virtually closed system. In the setting of chronic kidney disease and hemodialysis (HD), increased iron losses, reduced iron absorption, and limited iron availability lead to iron deficiency. Intravenous (IV) iron therapy is frequently prescribed to replace lost iron, but determining an individual's iron balance and stores can be challenging and imprecise, contributing to uncertainty about the long-term safety of IV iron therapy. SUMMARY: Patients on HD receiving judicious doses of IV iron are likely to be in a state of positive iron balance, yet this does not appear to confer an overt risk for clinically relevant iron toxicity. The concomitant use of iron with erythropoiesis-stimulating agents, the use of maintenance iron dosing regimens, and the reticuloendothelial distribution of hepatic iron deposition likely minimize the potential for iron toxicity in patients on HD. Key Messages: Because no single diagnostic test can, at present, accurately assess iron status and risk for toxicity, clinicians need to take an integrative approach to avoid iron doses that impose excessive exposure while ensuring sufficient replenishment of iron stores capable of overcoming hepcidin blockade and allowing for effective erythropoiesis.

Do current quality measures truly reflect the quality of dialysis?

The US End Stage Renal Disease (ESRD) Program, which came into existence in 1973, was initially envisioned to provide needed financial coverage for about 50 000 patients through Medicare. Over the past 45 years the evolution of the ESRD program has been quite different, and it now serves over one half million dialysis and transplant patients. The Medicare Improvements for Patients and Providers Act (MIPPA) of 2008 Section 153(c) requires the Centers for Medicare and Medicaid Services (CMS) to develop and implement quality measures for dialysis patients as part of the ESRD Quality Incentive Program (QIP) beginning in payment year (PY) 2012. The annual ESRD Prospective Payment System (PPS) rulemaking process allows CMS to create ESRD QIP rules that specify the measures, scoring methods, and payment reduction ranges applicable to the respective PY. CMS assesses each facility's performance and calculates a score for each measure, according to the method detailed for that PY. Scores for each measure are combined to create the Total Performance Score (TPS) for each facility. If a facility's TPS does not meet or exceed the performance standards established during the earlier comparison period, the facility will incur a payment reduction of up to 2% for the entire PY. The QIP program has evolved over the several years since its inception. There have been deletions and additions of various measures. CMS uses additional measures in its Dialysis Facility Compare (DFC) website which is available to the public and forms the basis of the 5-star rating system for dialysis facilities. The evidence underlying inclusion many of these measures in the QIP and DFC remains an area of debate. In this review, we discuss the evolution of these measures and their appropriateness. We recommend that some of the current QIP and DFC measures should not be used for public reporting and/or payment as unintended consequences may occur. Nonetheless, all the current QIP and DFC measures and others are suitable for internal quality review.

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD.

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients.

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations.

Introduction of Biosimilar Therapeutics Into Nephrology Practice in the United States: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Biosimilars are biologic medicines highly similar to the reference product with no meaningful clinical differences in terms of safety, purity, and potency. All biologic medicines are produced by living cells, resulting in an inherent heterogeneity in their higher order structures and post-translational modifications. In 2010, the US Congress enacted legislation to streamline the approval process for biosimilars of products losing patent protection, with the goal of decreasing costs and improving patient access to therapeutically important but expensive biologic agents. In 2015, the US Food and Drug Administration approved the first biosimilar agent through this pathway. Approval of additional biosimilar agents in the United States, including those used by nephrologists, is anticipated. Given the relative lack of knowledge regarding biosimilars and their approval process and a lack of trust by the nephrology community regarding their safety and efficacy, the National Kidney Foundation conducted a symposium, Introduction of Biosimilar Therapeutics Into Nephrology Practice in the U.S., September 17 to 18, 2015. Issues related to manufacturing, the regulatory approval process, interchangeability, substitution/switching, nomenclature, and clinician and patient awareness and acceptance were examined. This report summarizes the main discussions at the symposium, highlights several controversies, and makes recommendations related to public policy, professional and patient education, and research needs.

A physician's perseverance uncovers problems in a key nephrology study.

The Normal Hematocrit Cardiac Trial, published in 1998, was a foundational study testing erythropoietin analog treatment to normal hematocrit targets. It served as a warning that erythropoietin replacement was not a panacea. Its large size gave it disproportionate weighting in evidence reviews and guideline development and thereby impacted treatment decisions. Coyne shows that the published results did not completely and clearly represent the study's actual results. We discuss the implications and make recommendations to prevent such occurrences.

Prevalence of arteriovenous fistulas in incident hemodialysis patients: correlation with patient factors that may be associated with maturation failure.

BACKGROUND: Lok et al previously reported a risk equation for arteriovenous fistula (AVF) maturation failure. It is unclear whether this model or a more comprehensive model correlates with incident AVF use in the US hemodialysis population. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 195,756 adult patients initiating outpatient hemodialysis therapy in the United States between July 1, 2005, and December 31, 2009, with 6 months or more prior nephrology care. PREDICTOR: Patient characteristics (age, peripheral vascular disease, coronary artery disease, and race) populating the AVF maturation failure risk equation and other demographic and clinical variables from the Centers for Medicare & Medicaid Services (CMS) Medical Evidence Report (CMS 2728). OUTCOMES & MEASUREMENTS: AVF use at first outpatient dialysis treatment as recorded on the CMS 2728. RESULTS: Using the risk categories defined by Lok et al, AVF use varied from 19.0% (very high risk) to 25.6% (low risk). In a model using only these risk categories, logistic regression showed lower ORs for moderate-, 0.90 (95% CI, 0.88-0.93); high-, 0.80 (95% CI, 0.78-0.83); and very high-risk patients, 0.68 (95% CI, 0.63-0.73) compared with low risk. In the expanded model, odds were lower for women, blacks, Hispanics, age older than 85 years, diabetes, peripheral vascular disease, congestive heart failure, other cardiac disease, and underweight. Odds were higher for hypertension, overweight, obesity, 12 months or more nephrologist care, most insurance types, and each successive year after 2005. Despite associations, the C statistic for the expanded model was 0.64. LIMITATIONS: This analysis is limited by lack of access creation history before dialysis therapy initiation and minimal external validation of CMS 2728 data. CONCLUSIONS: Clinical risk factors identified by Lok and expanded in this analysis have limited ability to predict incident AVF use. Even patients judged at highest risk can have successful AVF construction and initiate dialysis therapy through a functioning AVF.

Evolution of Mineralocorticoid Receptor Antagonists in the Treatment of Chronic Kidney Disease Associated with Type 2 Diabetes Mellitus.

Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin-angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.