Localisation and mechanism of renal retention of radiolabelled somatostatin analogues

Purpose: Radiolabelled somatostatin analogues, such as octreotide and octreotate, are used for tumour scintigraphy and radionide therapy. The kidney is the most important critical organ during such therapy owing to the reabsorption and retention of radiolabelled peptides. The aim of this study was to investigate in a rat model both the localisation and the mechanism of renal uptake after intravenous injection of radiolabelled somatostatin analogues. The multi-ligand megalin/cubilin receptor complex, responsible for reabsorption of many peptides and proteins in the kidney, is an interesting candidate for renal endocytosis of these peptide analogues. Methods: For localisation studies, ex vivo autoradiography and micro-autoradiography of rat kidneys were performed 1 - 24 h after injection of radiolabelled somatostatin analogues and compared with the renal anti-megalin immunohistochemical staining pattern. To confirm a role of megalin in the mechanism of renal retention of [In-111\-DTPA] octreotide, the effects of three inhibitory substances were explored in rats. Results: Renal ex vivo autoradiography showed high cortical radioactivity and lower radioactivity in the outer medulla. The distribution of cortical radioactivity was inhomogeneous. Micro-autoradiography indicated that radioactivity was only retained in the proximal tubules. The antimegalin immunohistochemical staining pattern showed a strong similarity with the renal [In-111-DTPA] octreotide ex vivo autoradiograms. Biodistribution studies showed that co-injection of positively charged D-lysine reduced renal uptake to 60% of control. Sodium maleate reduced renal [In-111-DTPA] octreotide uptake to 15% of control. Finally, cisplatin pre-treatment of rats reduced kidney uptake to 70% of control. Conclusion: Renal retention of [In-111-DTPA] octreotide is confined to proximal tubules in the rat kidney, in which megalin-mediated endocytosis may play an important part.