Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Treating interdialytic hyperkalemia with fludrocortisone.

Hyperkalemia is a frequent and dangerous problem in dialysis patients. Many factors contribute to potentially life-threatening potassium elevation and most remedies used to treat hyperkalemia are handicapped by the consequences of the separate pools of intra- and extracellular potassium. Besides the kidney, the colon has the ability to excrete potassium, which can help lower total body potassium. Several prior authors have addressed the colon's ability to up-regulate potassium secretion, including the effect of aldosterone on fecal potassium content. Potentially dangerous intradialytic maneuvers to lower potassium levels may be avoidable with the use of the mineralocorticoid agonist fludrocortisone.

N-acetylcysteine in the prevention of radiocontrast-induced nephropathy.

N-acetylcysteine is a remarkably active agent shown to be useful in a variety of clinical settings. The drug has actions relevant to radiocontrast-induced nephropathy (RCIN) that include vasodilatation, enhancement of renal medullary blood flow, and antioxidant properties. The drug's pharmacokinetics are remarkable for almost complete first pass metabolism after oral administration, resulting in no free drug reaching the circulation. After intravenous administration, extensive reaction with tissue and plasma proteins greatly limits the amount of circulating free drug. Given the difficulty achieving free drug in the systemic circulation, it is highly likely that the drug works via its metabolites. The primary mechanism may be through L-cysteine as a cellular source for glutathione production. Clinical studies of N-acetylcysteine in the prevention of RCIN have yielded highly mixed results; five were dramatically positive, and eight others had no demonstrable efficacy at all. The following will review the individual studies, attempt to reconcile the divergent results, and propose future research needs.