Application of emerging biomarkers of acute kidney injury in development of kidney-sparing polypeptide-based antibiotics

Abstract

Polypeptide antibiotics, such as polymyxins and aminoglycosides, are essential for treatment of life-threatening Gram-negative infections. Acute kidney injury (AKI) attributed to treatment with these agents severely limits their clinical application. Because standard biomarkers (serum creatinine [sCRE] and blood urea nitrogen [BUN]) feature limited sensitivity, the development of novel biomarkers of AKI is important. Here, we compared the performance of standard and emerging biomarkers of AKI for the detection of nephrotoxicity caused by polymyxin B across multiple species (rat, dog and monkey). Further, we applied a biomarker-driven strategy for selection of new kidney-sparing polymyxin analogs. Polymyxin B treatment produced dose-dependent kidney injury observed as proximal tubular degeneration/regeneration and necrosis across all species. Dogs and monkeys had similar biomarker profiles that included increases of both standard (sCRE and BUN) and emerging (urinary neutrophil gelatinase-associated Lipocalin [NGAL] and urinary kidney injury molecule 1 [KIM-1]) biomarkers of AKI. In contrast, only urinary NGAL and urinary KIM-1 were sufficiently capable of detecting kidney injury in rats. Because rats provide a feasible model for screening compounds in drug development, we utilized urinary NGAL as a sensitive biomarker of AKI to screen and rank order compounds in a 2-day toxicity study. To our knowledge, this study provides a first example of successfully applying biomarkers of AKI in drug development.

Cisplatin nephrotoxicity in male beagle dogs: next-generation protein kidney safety biomarker tissue expression and related changes in urine

“…32,33 The US FDA, the EMA and the Pharmaceuticals Medical Devices Agency, Japan (PMDA) have qualified Ur TP as a biomarker to monitor drug-induced glomerular injury in rats only. 16 The biomarker profiles were capable of detecting acute DIKI at approximately 48 hours post the first dose. Recently, changes in traditional kidney safety urine-based proteins including Ur Cr, Ur NAG and Ur TP from beagle dogs treated with the polypeptide antibiotic polymyxin B which induced proximal tubule degeneration/regeneration and necrosis were reported.…”

“…These factors provide the basis for investigations that would reveal the predictive values and translatability for second generation kidney safety biomarkers for the early detection of DIKI as compared to sCr and BUN in dogs. 16 The biomarker profiles of rats, dogs and monkeys were similar and capable of detecting acute DIKI at approximately 48 hours post the first dose. A hallmark DIKI biomarker study in male beagle dogs treated by intravenous infusion with the nephrotoxic chemotherapeutic agent/tubular nephrotoxicant, CDDP (0.75 mg per kg per dose, single iv infusion for 5 consecutive days) was published.…”

Role of Urine Neutrophil Gelatinase-Associated Lipocalin in the Early Diagnosis of Amphotericin B-Induced Acute Kidney Injury

“…One promising application for biomarkers of AKI is monitoring of drug nephrotoxicity (23)(24)(25). In this setting, early knowledge of ongoing AKI may enable the physician to take measures to avoid additional damage before the progression to full-blown acute tubular necrosis.…”

Functional Assessments in Nonhuman Primate Toxicology Studies to Support Drug Development

“…Beside these qualified seven, novel exploratory biomarkers are being investigated for potential use in preclinical studies, such as specific microRNAs indicative of proximal or distal tubular injury. Although these qualified or emerging biomarkers have been primarily developed for rodent studies and remain less studied in NHPs, some investigators demonstrated the utility of urinary KIM-1 and lipocalin for early detection of acute injury in proximal tubules [82] and of clusterin and calbindin D28 to monitor the progression of distal nephron drug-induced kidney injury [83].…”