title: 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.
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. stephanie.haller@psi.ch.
authors: Stephanie
authors: S
authors: Haller
authors: Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057, Zurich, Switzerland. giovanni.pellegrini@uzh.ch.
authors: Giovanni
authors: G
authors: Pellegrini
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. etienne.vermeulen@psi.ch.
authors: Christiaan
authors: C
authors: Vermeulen
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. nick.vandermeulen@psi.ch.|Laboratory of Radiochemistry, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. nick.vandermeulen@psi.ch.
authors: Nicholas P
authors: NP
authors: van der Meulen
authors: Institut Laue-Langevin, 38042, Grenoble, France. koster@ill.fr.
authors: Ulli
authors: U
authors: Köster
authors: Department of Radiation Physics, The Sahlgrenska Academy, University of Gothenburg, Sahlgrenska Universitetssjukhuset, 41345, Gothenburg, Sweden. peter.bernhardt@radfys.gu.se.
authors: Peter
authors: P
authors: Bernhardt
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. roger.schibi@psi.ch.|Department of Chemistry and Applied Biosciences, ETH Zurich, 8093, Zurich, Switzerland. roger.schibi@psi.ch.
authors: Roger
authors: R
authors: Schibli
authors: Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, 5232, Villigen-PSI, Switzerland. cristina.mueller@psi.ch.
authors: Cristina
authors: C
authors: Müller
keywords: 161Tb; 177Lu; Auger/conversion electrons; Kidney; Radiofolate; Radionephropathy; Radionuclide therapy