A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies

Abstract

A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients. This review is an introduction to alternative assays that can be utilized in chronic (>3 months duration) nonclinical safety studies to provide information on renal dysfunction and to demonstrate specific situations where these assays could be utilized in nonclinical drug development. Novel biomarkers such as symmetrical dimethyl arginine, dickkopf homolog 3, and cystatin C predict chronic renal injury in animals, act as surrogates for GFR, and may predict changes in GFR in patients over time, ultimately providing a bridge from preclinical to clinical renal monitoring.

Keywords: DKK3; SDMA; biomarkers; chronic renal injury; cystatin C; nonclinical safety; uromodulin.

Figure 1:

Renal Injury Biomarkers Along the Continuum of Animal Toxicity Studies. Acute renal injury biomarkers (KIM-1, NGAL, B2M, urine CysC) have shown some utility in monitoring the progression of acute to chronic injury, but often their successful usage in subacute to subchronic renal injury has been dependent upon type of injury and/or species (italicized). In addition to the standard renal functional biomarkers (ALB, Protein, mGFR), other biomarkers have shown promise in predicting and monitoring subacute to subchronic (SMDA, DKK3, serum CysC, UMOD) or chronic renal injury (SDMA, DKK3, serum CysC) in animal toxicity studies. u: urine, s: serum, p: plasma, kidney injury molecule 1: KIM-1, neutrophil gelatinase-associated lipocalin: NGAL, beta 2 macroglobulin: B2M, cystatin C: CysC, symmetrical dimethyl arginine: SDMA, dickkopf homolog 3: DKK3, uromodulin: UMOD, albumin: ALB, measured glomerular filtration rate: mGFR.