Xanthine oxidase inhibitors may prevent or slow chronic kidney disease even in the absence of hyperuricemia

Abstract

In a recently published article, and based on the emerging evidence that suggests a causal link between hyperuricemia and the progression of chronic kidney disease (CKD), xanthine oxidase (XO) inhibitors were included in the list of promising medications for CKD.1Panchapakesan U. Pollock C. Drug repurposing in kidney disease.Kidney Int. 2018; 94: 40-48Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar However, these drugs may also act independently of the serum urate levels by decreasing the generation of intracellular reactive oxygen species (ROS) in endothelial cells. By transferring electrons to molecular oxygen, xanthine oxidase produces superoxide and hydrogen peroxide. Xanthine oxidase is one of the active catalytic forms of xanthine oxidoreductase, with xanthine dehydrogenase being the other one, which transfer electrons to nicotinamide adenine dinucleotide (NAD+). The 2 forms of xanthine oxidoreductase are interconvertible, yet under oxidative stress, the XO form prevails.2Pacher P. Nivorozhkin A. Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol.Pharmacol Rev. 2006; 58: 87-114Crossref PubMed Scopus (946) Google Scholar Hence, an initial ROS overproduction, induced by various stimuli, may activate XO, which afterward remains the major source of ROS. Two experimental studies evaluated this hypothesis in the context of the 2 main causes of CKD, hypertension and diabetes mellitus. In bovine aortic endothelial cells subjected to oscillatory shear stress, the initial ROS production by reduced NAD phosphate oxidase activates XO, which, as shown by the addition of oxypurinol, becomes the main source of ROS.3McNally J.S. Davis M.E. Giddens D.P. et al.Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress.Am J Physiol Heart Circ Physiol. 2003; 285: H2290-H2297Crossref PubMed Scopus (385) Google Scholar In human primary glomerular endothelial cells cultured under high-glucose conditions, the initial mitochondrial ROS production activates XO, which, as shown by using allopurinol, becomes the main source of ROS and responsible for endothelial dysfunction and activation.4Eleftheriadis T. Pissas G. Antoniadi G. et al.Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction.Int Urol Nephrol. 2018; 50: 179-186Crossref PubMed Scopus (24) Google Scholar Thus, XO inhibitors may be beneficial for preventing or slowing CKD even in the absence of hyperuricemia. Drug repurposing in kidney diseaseKidney InternationalVol. 94Issue 1PreviewDrug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Full-Text PDF Open ArchiveThe authors replyKidney InternationalVol. 94Issue 4PreviewWe thank Eleftheriadis and colleagues for their comments in the letter titled “Xanthine Oxidase Inhibitors May Prevent or Slow Chronic Kidney Disease Even in the Absence of Hyperuricemia.”1 The authors refer to in vitro studies in endothelial cells that provide mechanistic data to support that xanthine oxidase (XO) inhibition reduces the generation of reactive oxygen species. Confirmatory human clinical trials to demonstrate benefit independent of urate lowering with appropriate clinical renal endpoints are currently not available. Full-Text PDF Open Archive