Naeem Nikpour
1 
, Reza Farzaneh
2 , Mohammad Mehdi Darzi
3 , Simin Zeinadini
4 , Setare Sadeghi
5 , Zahra Eydizadeh
6 , Zahed Karimi
7 , Elham Kebriyaei
8 , Rasoul Jafari Arismani
9* 1 Department of Hematology and Medical Oncology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
2 Department of Nursing, Faculty of Nursing and Midwifery, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Urology, School of Medicine, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
4 Student Research Committee, Faculty of Nursing and Midwifery, Isfahan University of Medical Sciences, Isfahan, Iran
5 Department of Operating Room, Faculty of Nursing and Midwifery, Community of Health Research Center, Isf.C., Islamic Azad University, Isfahan, Iran
6 Department of Operating Room Nursing, Mother and Child Welfare Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
7 Department of Internal Medicine, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
8 Clinical Research Development Unit, Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran
9 Department of Urologic Surgery, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
Abstract
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.
Implication for health policy/practice/research/medical education:
Peptide receptor radionuclide therapy (PRRT) represents a targeted approach for treating neuroendocrine tumors (NETs) by delivering radiation specifically to somatostatin receptor-expressing cells using radiolabeled peptides like 177Lu-DOTATATE. Despite its efficacy, a major limitation is radiation nephropathy arising from unintended reabsorption of these peptides in the proximal tubules of the kidney, often termed the “proximal tubular trap,” where megalin-mediated endocytosis captures filtered radioligands, leading to prolonged radiation exposure and cellular damage. This phenomenon heightens risks particularly in patients with preexisting renal impairment, demanding protective strategies to mitigate long-term nephrotoxicity while preserving therapeutic benefits.
Please cite this paper as: Nikpour N, Farzaneh R, Darzi MM, Zeinadini S, Sadeghi S, Eydizadeh Z, Karimi Z, Kebriyaei E, Jafari Arismani R. Proximal tubular trap; radiation nephropathy risks from peptide reabsorption in peptide receptor radionuclide therapy for neuroendocrine tumors. J Nephropharmacol. 2026;15(2):e12854. DOI: 10.34172/npj.2026.12854.