From intracellular processing to renal phenotypes: a mechanism-informed framework for interpreting kidney injury and...

Antibody-drug conjugates (ADCs) have transformed solid-tumor therapy and are increasingly benchmarked directly against physician's-choice chemotherapy. However, kidney adverse events and electrolyte disturbances remain inconsistently captured across trials and are often interpreted without a unified pharmacological framework.

This review proposes a mechanism-informed narrative framework linking ADC architecture, intracellular processing, and payload exposure pathways to renal injury and electrolyte phenotype hypotheses while contextualizing these patterns against canonical renal-electrolyte programs of conventional cytotoxic chemotherapy.

We conducted a targeted literature review prioritizing randomized or registrational trials, regulatory labels, real-world or pharmacovigilance data when informative, and phenotype-defining case reports supported by urinary indices, biopsy, or both when available. Evidence is presented using explicit source-level stratification rather than quantitative pooling.

Intact ADCs are IgG-based macromolecules with limited glomerular filtration under an intact filtration barrier, whereas released small-molecule payloads or payload-containing catabolites may gain a filtration advantage and create proximal tubular exposure. Comparative studies support toxicity redistribution rather than uniform toxicity reduction. Enfortumab vedotin most often illustrates a systemic/prerenal acute kidney injury (AKI) axis driven by hyperglycemia, diabetic ketoacidosis, infection, and dehydration; sacituzumab govitecan combines gastrointestinal volume depletion with rare biopsy-proven acute tubulointerstitial nephritis; and trastuzumab deruxtecan has generated a hypothesis-defining Fanconi-like proximal tubule signal. Kidney tissue, especially the proximal tubule, contains protease-rich endolysosomal and apical brush-border systems that make renal processing of ADC-derived material biologically plausible, but kidney-specific proof remains limited. Because creatinine-based endpoints may miss mild tubular injury, future ADC programs should consider electrolyte-focused monitoring and the exploration of tubular injury biomarkers.

A trafficking-aligned taxonomy may improve the interpretation of ADC-associated renal and electrolyte events. Kidney Disease: Improving Global Outcomes (KDIGO)-aligned kidney endpoints, standardized electrolyte reporting, and prospective validation of tubular injury biomarkers should be priorities for future ADC trials.