Drug-induced rise in serum creatinine: cystatin C to the rescue? Evidence, pitfalls and knowledge gaps

Serum creatinine (SCr) concentration is a cheap biomarker of kidney function measured globally millions of times every day. It is part of the KDIGO definitions of both chronic kidney disease and acute kidney injury (AKI). However, SCr can be elevated following the introduction of a new medication, unrelated to reduced glomerular filtration rate (GFR) and may lead to medical misjudgment, with clinically significant consequences. Indeed, several antibacterial, antiviral, antifungal or antiparasitic agents, fibrates or corticosteroids have been linked to increases in SCr unrelated to kidney injury (pseudo-AKI). More recently, multiple classes of targeted anti-cancer treatments like tyrosine kinase inhibitors, PARP inhibitors or CDK 4/6 inhibitors have also been associated with pseudo-AKI. The mechanisms responsible are multiple and diverse, ranging from interference with the method of creatinine measurement to inhibition of renal tubular secretion of creatinine via various transporters. Cystatin C measurement can help discern between true and pseudo-AKI but some interactions also exist and data is lacking. In cases where a precise assessment of kidney function is needed, GFR can also be measured through plasma and urinary clearance of an exogenous marker, therefore removing the inaccuracies of the various eGFR equations. Here, we propose a narrative review, exploring for the first time in depth drugs associated with pseudo-AKI. Creatinine and cystatin C metabolism, methods of measurement and derived equations are discussed as well. We also propose a decision-making algorithm to help the clinician in daily practice.