Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of 161Tb-folate and 177Lu-folate

Abstract

Background: The radiolanthanide 161Tb has, in recent years, attracted increasing interest due to its favorable characteristics for medical application. 161Tb exhibits similar properties to the widely-used therapeutic radionuclide 177Lu. In contrast to 177Lu, 161Tb yields a significant number of short-ranging Auger/conversion electrons (≤50 keV) during its decay process. 161Tb has been shown to be more effective for tumor therapy than 177Lu if applied using the same activity. The purpose of this study was to investigate long-term damage to the kidneys after application of 161Tb-folate and compare it to the renal effects caused by 177Lu-folate. Methods: Renal side effects were investigated in nude mice after the application of different activities of 161Tb-folate (10, 20, and 30 MBq per mouse) over a period of 8 months. Renal function was monitored by the determination of 99mTc-DMSA uptake in the kidneys and by measuring blood urea nitrogen and creatinine levels in the plasma. Histopathological analysis was performed by scoring of the tissue damage observed in HE-stained kidney sections from euthanized mice. Results: Due to the co-emitted Auger/conversion electrons, the mean absorbed renal dose of 161Tb-folate (3.0 Gy/MBq) was about 24 % higher than that of 177Lu-folate (2.3 Gy/MBq). After application of 161Tb-folate, kidney function was reduced in a dose- and time-dependent manner, as indicated by the decreased renal uptake of 99mTc-DMSA and the increased levels of blood urea nitrogen and creatinine. Similar results were obtained when 177Lu-folate was applied at the same activity. Histopathological investigations confirmed comparable renal cortical damage after application of the same activities of 161Tb-folate and 177Lu-folate. This was characterized by collapsed tubules and enlarged glomeruli with fibrin deposition in moderately injured kidneys and glomerulosclerosis in severely damaged kidneys. Conclusions: Tb-folate induced dose-dependent radionephropathy over time, but did not result in more severe damage than 177Lu-folate when applied at the same activity. These data are an indication that Auger/conversion electrons do not exacerbate overall renal damage after application with 161Tb-folate as compared to 177Lu-folate, even though they result in an increased dose deposition in the renal tissue. Global toxicity affecting other tissues than kidneys remains to be investigated after 161Tb-based therapy, however.