Renal adverse events associated with cyclin-dependent kinase 4/6 inhibitors

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) have emerged as a standard of care for hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, significantly improving patient survival. While generally well-tolerated, their use is associated with a spectrum of adverse events, particularly impacting renal, cardiovascular, and metabolic systems. Clinical data indicate a higher incidence of nephrotoxic adverse reactions in patients receiving CDK4/6i compared to control groups, with abemaciclib showing the highest risk ratio. These renal effects can manifest as true acute kidney injury (AKI), including rare cases of acute tubular injury and acute interstitial nephritis, or as a more common "pseudo-AKI." The latter is characterized by an increase in serum creatinine due to the inhibition of renal organic cation transporters (OCT2/MATE), often without an actual decline in glomerular filtration rate (GFR). This highlights the importance of utilizing cystatin C alongside creatinine for accurate GFR assessment. Preclinical studies suggest a complex effect on renal health; while some data indicate acute nephroprotection, long-term rodent models treated with palbociclib after ischemic AKI demonstrated impaired recovery, increased renal fibrosis, and cellular senescence, indicating potentially detrimental long-term chronic effects. Beyond renal considerations, CDK4/6i are also associated with hypertension and electrolyte imbalance like hypokalemia and hyponatremia. Furthermore, these agents are susceptible to significant drug-drug interactions, particularly with CYP3A4 inhibitors/inducers and immunosuppressants, necessitating careful dose adjustments and monitoring, especially in solid organ transplant recipients. This review consolidates current evidence regarding the renal of CDK4/6i, emphasizing the need for vigilant monitoring and a multidisciplinary approach to optimize patient outcomes.