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

Abstract

Background: The radiolanthanide (161)Tb has, in recent years, attracted increasing interest due to its favorable characteristics for medical application. (161)Tb exhibits similar properties to the widely-used therapeutic radionuclide (177)Lu. In contrast to (177)Lu, (161)Tb yields a significant number of short-ranging Auger/conversion electrons (≤50 keV) during its decay process. (161)Tb has been shown to be more effective for tumor therapy than (177)Lu if applied using the same activity. The purpose of this study was to investigate long-term damage to the kidneys after application of (161)Tb-folate and compare it to the renal effects caused by (177)Lu-folate.

Methods: Renal side effects were investigated in nude mice after the application of different activities of (161)Tb-folate (10, 20, and 30 MBq per mouse) over a period of 8 months. Renal function was monitored by the determination of (99m)Tc-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 (161)Tb-folate (3.0 Gy/MBq) was about 24 % higher than that of (177)Lu-folate (2.3 Gy/MBq). After application of (161)Tb-folate, kidney function was reduced in a dose- and time-dependent manner, as indicated by the decreased renal uptake of (99m)Tc-DMSA and the increased levels of blood urea nitrogen and creatinine. Similar results were obtained when (177)Lu-folate was applied at the same activity. Histopathological investigations confirmed comparable renal cortical damage after application of the same activities of (161)Tb-folate and (177)Lu-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 (177)Lu-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 (161)Tb-folate as compared to (177)Lu-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 (161)Tb-based therapy, however.

Keywords: 161Tb; 177Lu; Auger/conversion electrons; Kidney; Radiofolate; Radionephropathy; Radionuclide therapy.

Fig. 1

Average relative body weights (RBW) (a) and median survival (b) of mice from each group after the injection of different activities of ¹⁶¹Tb-folate and ¹⁷⁷Lu-folate, respectively. RBWs are shown for each group for the time when at least two mice were alive (n ≥ 2)

Fig. 2

SPECT-based quantification of renal ^99mTc-DMSA uptake (% IA) in Week 15 (a), 22 (b), and 30 (c) after injection of ¹⁶¹Tb- and ¹⁷⁷Lu-folate. *P < 0.05, **P < 0.01, ***P < 0.001

Fig. 3

Histology (HE staining) of radiation-induced nephropathy in mice. Representative histological images (×20 magnification) of kidneys from untreated controls (final score 0) and progressively severe kidney damage (final scores 1–5) from mice injected with different activities of ¹⁶¹Tb-folate (▲ = localized tubular collapse; v = viable tubules; Δ = enlarged glomeruli with reduced numbers of capillaries; → = glomerulosclerosis). In the insets, cross sections of the kidneys are presented (×2 magnification) indicating gradual thinning of the cortex (↔) with increasing scores

Fig. 4

Correlation of individual results for kidney function tests and histological scores of the corresponding renal tissue sample. a Correlation of the histological scores and terminal blood urea nitrogen levels; b Correlation of the histological scores and terminal creatinine levels; c Inverse correlation of the histological scores and ^99mTc-DMSA uptake in the kidneys