title: Nephroprotective effects of enalapril after [177Lu]-DOTATATE therapy using serial renal scintigraphies in a murine model of radiation-induced nephropathy.
abstract: BACKGROUND
  Radiation-induced nephropathy is still dose limiting in radionuclide therapy of neuroendocrine tumors. We investigated the nephroprotective potential of the angiotensine converting enzyme inhibiting drug enalpril after [177Lu]-DOTATATE therapy in a murine model of radiation-induced nephropathy by renal scintigraphy. At first, the appropriate therapy activity to induce nephropathy was identified. Baseline scintigraphy (n = 12) entailed 12-min dynamic acquisitions after injection of 25 MBq [99mTc]-MAG3, which was followed by radionuclide therapy at four escalating activities of [177Lu]-DOTATATE: group (Gp) 1: 10 MBq; Gp 2: 20 MBq; Gp 3: 40 MBq; Gp 4: 65 MBq. Follow-up [99mTc]-MAG3 scintigraphy was carried out at days 9, 23, 44, and 65. The treatment activity for the intervention arm was selected on the basis of histological examination and declining renal function. In the second part, daily administration by gavage of 10 mg/kg/d enalapril or water (control group) was initiated on the day of radionuclide therapy. Follow-up scintigraphy was carried out at days 9, 23, 44, 65, and 86. We also created a non-therapy control group to detect therapy-independent changes of renal function over time. For all scintigraphies, mean renogram curves were analyzed and the "fractional uptake rate" (FUR; %I.D./min ± SEM) of the tracer by the kidneys was calculated as an index of renal clearance.
  
  
  RESULTS
  At day 65 of follow-up, no significant change in the FUR relative to baseline (11.0 ± 0.3) was evident in radionuclide therapy groups 1 (11.2 ± 0.5) and 2 (10.1 ± 0.6), but FUR was significantly reduced in groups 3 (8.93 ± 0.6, p < 0.05) and 4 (6.0 ± 0.8, p < 0.01); we chose 40 MBq [177Lu]-DOTATATE (Gp 3) for the intervention study. Here, at the last day of follow-up (day 86), FUR was unaltered in enalapril-treated mice (11.8 ± 0.5) relative to the baseline group (12.4 ± 0.3) and non-therapy group (11.9 ± 0.8), whereas FUR in the control group had undergone a significant decline (9.3 ± 0.5; p < 0.01). Histological examination revealed prevention of kidney damage by enalapril treatment.
  
  
  CONCLUSIONS
  Treatment with enalapril is effective for nephroprotection during radionuclide therapy with [177Lu]-DOTATATE in mice. Although these results are only limitedly transferable to human studies, enalapril might serve as a promising drug in the mitigation of nephropathy following treatment with [177Lu]-DOTATATE.
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Harun
authors: H
authors: Ilhan
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Hao
authors: H
authors: Wang
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Franz J
authors: FJ
authors: Gildehaus
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.|Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany.
authors: Carmen
authors: C
authors: Wängler
authors: Department of Surgery, Campus Großhadern, University of Munich, Munich, Germany.
authors: Tanja
authors: T
authors: Herrler
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Andrei
authors: A
authors: Todica
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Julia
authors: J
authors: Schlichtiger
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Paul
authors: P
authors: Cumming
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.
authors: Peter
authors: P
authors: Bartenstein
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany.|Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, University of Vienna, Vienna, Austria.
authors: Marcus
authors: M
authors: Hacker
authors: Department of Nuclear Medicine, University of Munich, Munich, Germany. alexander.haug@meduniwien.ac.at.|Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, University of Vienna, Vienna, Austria. alexander.haug@meduniwien.ac.at.
authors: Alexander R
authors: AR
authors: Haug
keywords: Enalapril; Neuroendocrine tumors; Radiation-induced nephropathy; Tc-99m-MAG3 scintigraphy; [177Lu]-DOTATATE