Urinary kidney biomarkers for early detection of nephrotoxicity in clinical drug development

Abstract

Early detection of drug-induced kidney injury is vital in drug development. Generally accepted biomarkers such as creatinine and blood urea nitrogen (BUN) lack sensitivity and early injury responses are missed. Many new biomarkers to detect nephrotoxicity for pre-clinical utilization have been described and their use is adopted in regulatory guidelines. However, guidance on appropriate biomarkers for clinical trials is minimal. We provide an overview of potentially useful kidney biomarkers that can be used in clinical trials. This includes guidance to select biomarkers suitable to capture specific characteristics of the (expected) kidney injury. We conclude that measurement of urinary kidney injury marker-1 (KIM-1) serves many purposes and is often an appropriate choice. Cystatin C captures effects on glomerular filtration rate (GFR), but this marker should preferably be combined with more specific markers to localize the origin of the observed effect. Untoward effects on tubules can be captured relatively well with several markers. Direct detection of glomerular injury is currently impossible since specific biomarkers are lacking. Indirect assessment of toxic effects on glomeruli is possible by using carefully selected panels of other injury markers. We conclude that it is possible to obtain appropriate information on nephrotoxicity in clinical drug development by using carefully selected panels of injury markers and suggest that identification and validation of specific glomerular biomarkers could be of great value.

Keywords: biomarkers; early clinical trials; nephrotoxicity.

Figure 1

Time course of serum creatinine and urinary kidney damage markers. Arrows denote drug administration on study days 1, 8 and 15. serum creatinine, urinary B2M, urinary αGST, urinary KIM-1, urinary NAG

Figure 2

Theoretical relationship between serum creatinine and glomerular filtration rate (GFR) calculated with creatinine clearance for a subject with normal muscle mass (12 mmol creatinine 24 h^–1). In the range of creatinine for healthy subjects large declines in GFR are associated with relatively small increases in serum creatinine. For example, if serum creatinine increases from 60 to 90 μmol l⁻¹ (blue arrow), which is a 50% increase (a cut off value for safety often used in clinical trials), GFR decreases to 50 ml min⁻¹, which reflects a considerable functional loss of over 35%. When the GFR decreases below 60 ml min⁻¹, further decrements are associated with larger increases in serum creatinine, which makes the marker more sensitive to change