Abstract
BackgroundRadiation-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.ResultsAt 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.ConclusionsTreatment 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0219-2) contains supplementary material, which is available to authorized users.
Highlights
Radiation-induced nephropathy is still dose limiting in radionuclide therapy of neuroendocrine tumors
We investigated the activity-dependent impairment of renal function in mice treated with four activities of [177Lu]-DOTATATE: group 1 (n = 6), 10 MBq; group 2 (n = 8), 20 MBq; group 3 (n = 7), 40 MBq, and group 4 (n = 7), 65 MBq
Identification of nephrotoxic activity of [177Lu]-DOTATATE Figure 2 illustrates the mean renograms for groups 1–4 at day 65
Summary
Radiation-induced nephropathy is still dose limiting in radionuclide therapy of neuroendocrine tumors. 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. Peptide receptor radionuclide therapy (PRRT) with [Y-90-DOTA0,TYR3]-octreotide ([90Y]-DOTATOC) and [177Lu-DOTA0,TYR3]-octreotate ([177Lu]-DOTATATE) has emerged as a well-established therapy option in the treatment of inoperable or metastasized neuroendocrine tumors (NET) expressing somatostatin receptors [1, 2]. An important factor limiting benefits of this therapy is the occurrence of radiation-induced nephropathy, which arises due to renal clearance and megalin-receptor mediated tubular reabsorption of the chelated somatostatin analogues [9, 10]. Histopathological findings in kidneys after PRRT present a pattern of tubular and glomerular damage which seems similar to that evoked by external beam radiation [21]
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