TKI-associated proteinuria and nephrotic syndrome: a narrative review with clinical illustration in radio-iodine-refractory thyroid cancer

OBJECTIVES: This article aims to highlight proteinuria and nephrotic syndrome as significant yet under-recognized adverse events of VEGF pathway inhibition by tyrosine kinase inhibitors (TKIs), illustrated in the treatment of radioiodine-refractory differentiated thyroid cancer. METHODS: This report presents a case of recurring (nephrotic range) proteinuria in a patient with radioiodine-refractory differentiated thyroid cancer treated sequentially with lenvatinib, sorafenib and cabozantinib. In the discussion, an overview of the existing literature is provided through a PubMed search. RESULTS: Reported incidence of proteinuria varies across VEGFR-targeted TKIs in clinical trials. However, direct comparisons between agents should be interpreted cautiously. The underlying pathophysiology is multifactorial, involving hypertension, endothelial injury, and direct podocyte damage, often resulting in focal segmental glomerulosclerosis, minimal change disease or non-thrombotic hyaline glomerular microangiopathy. Timely recognition and monitoring are essential, as early discontinuation or dose adjustment can lead to partial or full reversibility of renal damage. Switching to TKIs with a different nephrotoxic profile may be a feasible strategy to maintain oncological benefit while minimising renal risk. Nonetheless, given the limited evidence, this approach requires cautious implementation in selected cases. CONCLUSION: Proteinuria and nephrotic syndrome are an important class effect of VEGFR-directed TKIs. Regular monitoring, early detection, and timely dose adjustments or treatment switches are essential to minimize irreversible renal damage while maintaining oncological benefit.