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

Effects of bardoxolone methyl on body weight, waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease

AimsObesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.MethodsEligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to <30 mL/min/1.73 m2) were randomized 1:1 to receive once-daily oral dose of bardoxolone methyl (20 mg) or placebo.ResultsBEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p < 0.001). In patients randomized to bardoxolone methyl, rate and magnitude of body weight loss were proportional to baseline BMI. Bardoxolone methyl resulted in significant reductions in waist circumference and improved glycemic control.ConclusionsBardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI

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

Vascular and plaque imaging with ultrasmall superparamagnetic particles of iron oxide

Cardiovascular Magnetic Resonance (CMR) has become a primary tool for non-invasive assessment of cardiovascular anatomy, pathology and function. Existing contrast agents have been utilised for the identification of infarction, fibrosis, perfusion deficits and for angiography. Novel ultrasmall superparamagnetic particles of iron oxide (USPIO) contrast agents that are taken up by inflammatory cells can detect cellular inflammation non-invasively using CMR, potentially aiding the diagnosis of inflammatory medical conditions, guiding their treatment and giving insight into their pathophysiology. In this review we describe the utilization of USPIO as a novel contrast agent in vascular disease

Randomized Controlled Trial of Subcutaneous Epoetin Alfa-epbx Versus Epoetin Alfa in End-Stage Kidney Disease

© 2019 Introduction: This double-blind, randomized controlled trial compared the safety and efficacy of subcutaneous epoetin alfa-epbx, an epoetin alfa biosimilar, with the reference product, epoetin alfa, in hemodialysis patients with end-stage kidney disease (ESKD) and anemia who were receiving epoetin alfa maintenance treatment. Methods: Eligible patients (n = 320) were randomized (1:1) to subcutaneous epoetin alfa-epbx or epoetin alfa in a titration phase; patients who demonstrated stable subcutaneous dosing (n = 246) were re-randomized to receive subcutaneous epoetin alfa-epbx or epoetin alfa 1 to 3 times per week in a 16-week maintenance phase. Co-primary endpoints were least-squares mean difference between treatments in mean weekly hemoglobin concentration and mean weekly epoetin dose per kilogram body weight (BW) during the last 4 weeks of treatment in the maintenance phase. Results: The least-squares mean difference (95% confidence interval [CI]) between treatments in weekly hemoglobin was 0.04 g/dl (−0.17 to 0.24 g/dl) and weekly epoetin dose/kg BW was −2.34 U/kg per week (−14.51 to 9.82 U/kg per week). The 95% CIs were contained within the prespecified equivalence margins of ±0.5 g/dl (weekly hemoglobin) and ±45 U/kg per week (weekly epoetin dose/kg BW). In the epoetin alfa-epbx and epoetin alfa groups, respectively, 4.0% and 4.1% of patients required blood transfusions, 69.7% and 70.5% reported adverse events, 18.9% and 27.0% reported serious adverse events, and 3 and 2 deaths were reported. Five patients were confirmed positive for anti-recombinant human erythropoietin antibody, 2 of whom tested positive at baseline. All patients tested negative for neutralizing antibodies. Conclusions: This comparative clinical trial demonstrated equivalence in efficacy and similar safety of subcutaneously administered epoetin alfa-epbx to epoetin alfa

Alectinib (Alecensa)-induced reversible grade IV nephrotoxicity: a case report and review of the literature

Abstract Background Lung cancer is among the top causes of cancer-related mortality in men and is the second most common cancer after breast cancer in women. There are approximately 234,030 new cases of lung cancer and 154,050 deaths from lung cancer in 2018 as per the latest American Cancer Society’s report. Alectinib, a more potent orally active tyrosine kinase inhibitor which was approved by the US Food & Drug Administration for anaplastic lymphoma kinase-positive lung adenocarcinoma, has been shown to have a reasonable safety profile when compared with other anaplastic lymphoma kinase-targeted therapy. As per research studies, grade 1 or 2 renal impairment has been reported but grade 4 renal toxicity due to alectinib has not been reported so far. We report a case of acute renal failure caused by alectinib which necessitated emergency dialysis. This is the first case report describing the severe renal toxicity of alectinib. Case presentation We describe a case of 72-year-old Taiwanese man diagnosed with stage IV anaplastic lymphoma kinase-positive adenocarcinoma of the lung initially treated with crizotinib for over a year, which was switched to alectinib due to disease progression with brain metastasis. Within 6 weeks of starting alectinib, he developed acute renal failure needing emergency dialysis support. His renal failure was secondary to acute tubular necrosis and had a complete reversal within 7–10 days on withdrawing the medication. When he was re-challenged with alectinib, his creatinine started to worsen again which confirmed the renal toxicity of alectinib. Conclusions This case emphasizes the uncommon adverse effect of the anaplastic lymphoma kinase-targeted therapy alectinib causing acute renal failure manifesting as acute tubular necrosis. Recognition of alectinib nephropathy requires a thorough drug history and knowledge of risk factors that lessen its margin of safety at therapeutic ingestions. Frequent monitoring of renal functions and early nephrology referral significantly reduce the mortality and morbidity of these patients