Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury

Abstract

Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI.

Hyperpolarized 13C magnetic resonance evaluation of renal ischemia reperfusion injury in a murine model

“…In addition, there is increasing interest in the development of drugs that target the molecular and metabolic events in progressive kidney injury. For example, Skrypnyk et al have shown that pyridoxamine, a form of vitamin B6, interferes with oxidative macromolecular damage. Pyridoxamine reduced both short‐ and long‐term injury and fibrosis in a mouse model of IRI, and may prevent the transition of AKI to CKD .…”

“…For example, Skrypnyk et al have shown that pyridoxamine, a form of vitamin B6, interferes with oxidative macromolecular damage. Pyridoxamine reduced both short‐ and long‐term injury and fibrosis in a mouse model of IRI, and may prevent the transition of AKI to CKD . Bendavia, a mitochondrial‐targeted peptide, has been shown to protect mitochondrial structure and function in an IRI model .…”

“…Recent evidence has shown that renal tubules undergoing atrophy late after IRI display decreased mitochondrial pyruvate dehydrogenase (PDH) activity and oxidative phosphorylation, and increased glycolysis . The recognition of these cellular and molecular events, and metabolic alterations, following AKI has also motivated research into mechanistically targeted therapies to treat AKI and to prevent progression to CKD . Therefore, biomarkers that can non‐invasively inform on renal oxidative stress and mitochondrial dysfunction have the potential to improve the CKD risk stratification of patients following AKI and to aid in the determination of the efficacy of targeted therapies.…”

Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

“…PM treatment of db/db mice reduced kidney hypertrophy, proteinuria, mesangial expansion, podocyte loss [123] and the development of glucose intolerance [124]. In an ischemia/reperfusion model of acute kidney injury, pre-treatment of PM prior to nephrectomy reduced fibrosis and injury score [125]. PM pretreatment also reduced serum creatinine levels at 28 day post nephrectomy.…”

“…Limited efficacy in improving renal function in diabetic nephropathy in humans [135] [136] although improvements in renal function and plasma glucose handling are seen in several animals models [121–125]…”