From outside to inside? Dose-dependent renal tubular damage after high-dose peptide receptor radionuclide therapy in rats measured with in vivo (99m)Tc-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 [(177)Lu-DOTA(0), Tyr(3)]octreotate and investigated (99m)Tc-DMSA (dimercaptosuccinic acid) as a tool to quantify renal damage after PRRT.


METHODS
Twenty-nine (29) rats were divided into 3 groups and injected with either 0, 278, or 555 MBq [(177)Lu-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 (99m)Tc-DMSA single-photon emission computed tomography (SPECT) autoradiography, histology, and blood analyses.


RESULTS
In vivo SPECT with (99m)Tc-DMSA resulted in high-resolution (<1.6-mm) images. The (99m)Tc-DMSA uptake in the rat kidneys was inversely related with the earlier injected activity of [(177)Lu-DOTA(0), Tyr(3)]octreotate and correlated inversely with serum creatinine values. Renal ex vivo autoradiograms showed a dose-dependent distribution pattern of (99m)Tc-DMSA. (99m)Tc-DMSA SPECT could distinguish between the rats that were injected with 278 or 555 MBq [(177)Lu-DOTA(0), Tyr(3) ]octreotate, whereas histologic damage grading of the kidneys was nearly identical for 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 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 (99m)Tc-DMSA uptake was highly accurate to grade renal tubular damage after PRRT.
Forrer
Flavio
F
Department of Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands. fforrer@uhbs.ch
Rolleman
Edgar
E
Bijster
Magda
M
Melis
Marleen
M
Bernard
Bert
B
Krenning
Eric P
EP
de Jong
Marion
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D003404:Creatinine / Q000097:blood; D004307:Dose-Response Relationship, Radiation; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D018000:Receptors, Peptide / Q000378:metabolism*; D019783:Technetium Tc 99m Dimercaptosuccinic Acid / Q000009:adverse effects* / Q000494:pharmacology; D015899:Tomography, Emission-Computed, Single-Photon
D018000:Receptors, Peptide; D019783:Technetium Tc 99m Dimercaptosuccinic Acid; D003404:Creatinine