[Polypharmacy and nephrotoxicity]

Polypharmacy is common among older adults. Renal effects can range from mild functional increases in creatinine to structural tubular injury.

The aim of the study was to systematically describe nephrotoxicity in the context of polypharmacy, identify typical pharmacokinetic and pharmacodynamic constellations, and introduce the concept of "nephrotoxic burden" as a potential tool for quantitative risk assessment.

A selective review of the literature on drug-induced nephrotoxicity and drug-drug interactions was performed.

Pharmacokinetic interactions leading to renal adverse drug reactions typically occur when dose-dependent nephrotoxic agents such as calcineurin inhibitors reach toxic concentrations through cytochrome P450 3A4 (CYP3A4) inhibition (e.g., by macrolides, azoles, or ritonavir). Pharmacodynamic interactions associated with renal effects are observed, for example, with the combination of nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, and diuretics, or with combinations of vancomycin and aminoglycosides or piperacillin. The concept of nephrotoxic burden addresses the risk of acute kidney injury (AKI) from concurrent use of multiple nephrotoxic drugs but currently lacks adequate differentiation between underlying mechanisms.

In patients receiving calcineurin inhibitors, any additional prescriptions should be carefully reviewed for potential interactions and accompanied by dose adjustment and close therapeutic drug monitoring where appropriate. The concurrent use of several agents with structural tubular toxicity generally increases risk, whereas functional mechanisms, such as those seen with combined ACE inhibitor and sodium-glucose cotransporter 2 inhibitor (SGLT2) inhibitor therapy, are usually well tolerated. The concept of nephrotoxic burden shows promise but requires further refinement and prospective validation before it can serve as a practical tool for risk stratification in polypharmacy.