Proximal tubular trap; radiation nephropathy risks from peptide reabsorption in peptide receptor radionuclide therapy for neuroendocrine tumors

Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs like 177Lu-DOTATATE) is highly effective for metastatic neuroendocrine tumors (NETs). However, a significant dose-limiting toxicity is radiation-induced nephropathy, primarily driven by a phenomenon termed the proximal tubular trap. Following glomerular filtration, radiolabeled peptides are avidly reabsorbed by proximal tubular epithelial cells (PTECs) via the megalin/cubilin receptor-mediated endocytosis pathway. This intracellular retention concentrates the radionuclide within the tubules, leading to prolonged, localized irradiation of renal tissue, particularly the radiosensitive proximal tubules and microvasculature. Cumulative radiation exposure causes DNA damage, oxidative stress, inflammation, and ultimately progressive tubular atrophy, interstitial fibrosis, and glomerulosclerosis, manifesting clinically as declining glomerular filtration rate (GFR), proteinuria, and potentially end-stage renal disease months to several years post-therapy.