Performance Assessment of New Urinary Translational Safety Biomarkers of Drug-induced Renal Tubular Injury in Tenofovir-treated Cynomolgus Monkeys and Beagle Dogs

Abstract

Newer urinary protein kidney safety biomarkers can outperform the conventional kidney functional biomarkers blood urea nitrogen (BUN) and serum creatinine (SCr) in rats. However, there is far less experience with the relative performance of these biomarkers in dogs and nonhuman primates. Here, we report urine protein biomarker performance in tenofovir-treated cynomolgus monkeys and beagle dogs. Tenofovir intravenous daily dosing in monkeys for 2 or 4 weeks at 30 mg/kg/day resulted in minimal to moderate tubular degeneration and regeneration, and tenofovir disoproxil fumarate oral dosing in dogs for 10 days at 45 mg/kg/day resulted in mild to marked tubular degeneration, necrosis, and regeneration. Among biomarkers tested, kidney injury molecule 1 (Kim-1) and clusterin (CLU) clearly outperformed BUN and SCr and were the most reliable in detecting the onset and progression of tenofovir-induced tubular injury. Cystatin C, retinol binding protein 4, β2-microglobulin, neutrophil gelatinase-associated lipocalin, albumin, and total protein also performed better than BUN and SCr and added value when considered together with Kim-1 and CLU. These findings demonstrate the promising utility of these urinary safety biomarkers in monkeys and dogs and support their further evaluation in human to improve early detection of renal tubular injury.

Urinary Kidney Biomarker Panel Detects Preclinical Antisense Oligonucleotide-Induced Tubular Toxicity

“…As an example, urinary b2-microglobulin has frequently been used for the detection of kidney toxicity induced by both ASOs and other modalities. 32,43,51 As reported in Supplemental Material, in our study, this biomarker increased in a dose-dependent manner after tool ASO administration. Further work is needed to verify if the FDA-qualified kidney biomarker panel should be complemented by additional biomarkers in Figure 6.…”

“…The early KIM-1 increases in our study are in line with reports of similar rapid inductions seen in rodents with several nephrotoxins that are also known to target proximal tubules. 8,13,35,43,44 The expression of KIM-1 and NGAL has been shown to increase after kidney injury in proximal tubule epithelial cells, which initiate proliferation and migration to damaged areas, reflecting a regenerative response. [45][46][47] Unexpectedly, treatment with control ASO also induced elevations in several biomarkers, but to a lesser extent than a similar dose of the tool ASO.…”

“…Group 1 was dosed with phosphate-buffered saline (vehicle), group 2 with 50 mg/kg Ionis-860042 (control ASO), and groups 3 and 4 with 50 or 10 mg/kg of Ionis-860151 (tool ASO), respectively ( Table 1). All animals were dosed subcutaneously once a week for 8 consecutive weeks on days 1,8,15,22,29,36,43,50, and 57. Blood and urine samples were collected 48 hours after each dose.…”

Tenofovir disoproxil fumarate initiation and changes in urinary biomarker concentrations among HIV-infected men and women

“…Recent studies in animal models have demonstrated that several of these biomarkers outperformed traditional measures of kidney function in detecting the onset and progression of histologicallyconfirmed TDF-associated tubular injury. [59] Future studies exploring this methodology should include comparisons of the long-term renal impact of TDF and TAF to inform risk stratification and judicious allocation of the newer formulation of tenofovir. To distinguish tenofovir toxicity from other etiologies of kidney injury, future studies should also characterize longitudinal biomarker profiles associated with other kidney disease risk factors among HIV-infected persons.…”

Evaluation of 10 Urinary Biomarkers for Renal Safety With 5 Nephrotoxicants in Nonhuman Primates

“…7 Recent efforts have demonstrated the added value of novel kidney biomarkers in monitoring kidney injury, relative to the traditional blood biomarkers such as blood urea nitrogen (BUN) and serum creatinine (SCr). [8][9][10][11][12][13][14] Here, we provide a detailed characterization of drug-induced histomorphologic changes in the NHP kidney and conventional clinical chemistry alterations in blood following dosing with nephrotoxic pharmaceuticals and provide further insight to the corresponding performance of 10 urinary biomarkers. The urinary biomarkers selected included albumin, clusterin, cystatin C, KIM-1, livertype fatty acid-binding protein (L-FABP), N-acetyl-b-Dglucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), retinol binding protein 4 (RBP4), and total protein.…”