From outside to inside?: Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo 99mTc-DMSA-SPECT and molecular imaging

In peptide receptor radionuclide therapy (PRRT), the dose-limiting organ is, most often, the kidney. However, the precise mechanism as well,as the exact localization of kidney damage during PRRT have not been fully elucidated. We studied renal damage in rats after therapy with different amounts Of [Lu-177- DOTA(0),Tyr(3)]octreotate and investigated Tc-99m-DMSA (dimercaptosuccinic acid) as a tool to quantify renal damage after PRRT. Experimental Design: Twenty-nine (29) rats were divided into 3 groups and injected with either 0,278, or 555 MBq [Lu-177-DOTA(0),Tyr(3)]octreotate, leading to approximately 0,46, and 92 Gy to the renal cortex. More than 100 days after therapy, kidney damage was investigated using (TC)-T-99M-DMSA single-photon emission computed tomography (SPECT) autoradiography, histology, and blood analyses. Results: In vivo SPECT with Tc-99m-DMSA resulted in high-resolution (< 1.6-mm) images. The Tc-99m-DMSA uptake in the rat kidneys was inversely related with the earlier injected activity of [Lu-177- DOTA(0)'Tyr(3)]octreotate and correlated inversely with serum creatinine values. Renal ex vivo autoradiograms showed a dose-dependent distribution pattern of Tc-99m-DMSA. Tc-99m-DMSA SPECT could distinguish between the rats that were injected with 278 or 555 MBq [Lu-177-DOTA(0),Tyr(3)]octreotate, whereas histologic damage grading of the kidneys was nearly identicalfor these 2 groups. Histologic analyses indicated that lower amounts of injected radioactivity caused damage mainly in the proximal tubules, whereas as well the distal -tubules were damaged after high-dose radioactivity. Conclusions: Renal damage age in rats after PRRT appeared to start in a dose-dependent manner in the proximal tubules and continued to the more distal tubules with increasing amounts of injected activity. In vivo SPECT measurement of Tc-99m-DMSA uptake was highly accurate to grade renal tubular damage after PRRT.