Kidney Radiation Doses Stay Low in Most Men After PSMA Therapy

Men with metastatic castration-resistant prostate cancer who received lutetium-177 PSMA radiopharmaceutical therapy rarely accumulated kidney radiation doses high enough to raise concern, according to a retrospective analysis published in EJNMMI Research. Among 127 patients followed for up to 36 months after starting treatment, only five exceeded a cumulative kidney absorbed dose of 20 Gy, and none of those developed severe, grade 3 or 4 nephrotoxicity on the CTCAE v5.0 scale.

The therapy, which uses radiolabeled ligands that target prostate-specific membrane antigen, is known to produce favorable clinical responses in metastatic castration-resistant prostate cancer. However, the kidneys are a vulnerable organ because the radiopharmaceutical accumulates there both specifically and nonspecifically, raising the possibility of radiation-induced kidney damage over time. The research team set out to evaluate the association between cumulative kidney absorbed doses and long-term kidney toxicity.

The retrospective analysis included 127 patients treated with 177Lu-based ligands. Twenty-five patients received [177Lu]Lu-PSMA-617 at 7.4 GBq per cycle, while 102 received [177Lu]Lu-PSMA-I&T at doses ranging from 3.6 to 9.5 GBq across their treatment courses. Kidney absorbed doses were calculated with MIM Software version 7.3.4 using CT-based segmentation, applying one of three validated dosimetry protocols depending on data availability: multiple timepoint acquisition, the Hänscheid approach at 48 hours, or the prior information approach.

Kidney function was monitored with two complementary methods. Tubular excretion rates were obtained from [99mTc]Tc-MAG3 scintigraphy scans, while serum-based sampling was used to quantify the estimated glomerular filtration rate, a standard measure of the kidneys’ filtering capacity. Chronic kidney disease was graded according to CTCAE v5.0 criteria for up to 36 months after treatment initiation.

At the first treatment cycle, the absorbed dose per unit of injected activity was significantly lower for [177Lu]Lu-PSMA-617 than for [177Lu]Lu-PSMA-I&T, at 0.26 plus or minus 0.09 Gy/GBq versus 0.32 plus or minus 0.13 Gy/GBq, a difference the authors reported as statistically significant with p equal to 0.01.

Kidney absorbed dose per cycle did not change significantly across successive treatment cycles for either ligand, although the number of patients contributing data shrank as cycles progressed. Median changes between consecutive cycles were small for both agents, ranging from minus 5 percent to 26 percent for [177Lu]Lu-PSMA-617 and from 0 to 5 percent for [177Lu]Lu-PSMA-I&T. Among the small subset who reached six cycles, the percent change in absorbed dose from cycle 1 to cycle 6 was 0.6 plus or minus 34.1 percent for [177Lu]Lu-PSMA-617 with three patients, and 12.2 plus or minus 32.8 percent for [177Lu]Lu-PSMA-I&T with nine patients, with wide variability in both groups.

Cumulative kidney absorbed dose exceeded 20 Gy in five of the 127 patients, about 4 percent, and every one of those patients had received at least six cycles of therapy. This finding links higher cumulative exposure to longer treatment courses, since patients who tolerate more cycles naturally accumulate more radiation dose to the kidneys.

Kidney function declined modestly over follow-up, with a slightly greater decrease observed in the [177Lu]Lu-PSMA-I&T group. At 24 months after treatment, the estimated glomerular filtration rate had fallen by a median of 13 percent in the [177Lu]Lu-PSMA-I&T group, with individual changes ranging from minus 76 percent to plus 40 percent, compared with a median decline of 10 percent in the [177Lu]Lu-PSMA-617 group, ranging from minus 26 percent to plus 13 percent. By 36 months after starting [177Lu]Lu-PSMA-I&T, one patient had developed CTCAE grade 3 chronic kidney disease and another grade 4. Follow-up of the [177Lu]Lu-PSMA-617 cohort at 36 months was not yet mature, meaning that long-term data for that group remain incomplete.

The authors concluded that radiation-induced nephrotoxicity remains rare within three years of treatment, with only five of 127 patients exceeding a kidney absorbed dose of 20 Gy and none of those developing grade 3 or 4 nephrotoxicity. They noted that while the eGFR decrease was slightly greater with [177Lu]Lu-PSMA-I&T than with [177Lu]Lu-PSMA-617, the clinical repercussions of that difference remain unknown. As a retrospective single-cohort analysis with decreasing patient numbers at later cycles and immature long-term follow-up for one of the two ligands, the study describes associations within its observed population rather than establishing thresholds or predicting outcomes for individual patients.

Subject of Research: Long-term kidney toxicity and cumulative absorbed dose after lutetium-177 PSMA radiopharmaceutical therapy for metastatic castration-resistant prostate cancer

Article Title: Long-term effects of [177Lu]Lu-PSMA therapy on the kidneys based on cumulative absorbed dose

Article References: Ells, Z., Wu, M., Hempel, L., Scheifele, M., Siegmund, S. C., Ells, J., Zacherl, M., Böning, G., Casuscelli, J., Werner, R. A., Calais, J., Dahlbom, M., Holzgreve, A., Delker, A., & Unterrainer, L. M. (2026). Long-term effects of [177Lu]Lu-PSMA therapy on the kidneys based on cumulative absorbed dose. EJNMMI Research. https://doi.org/10.1186/s13550-026-01534-5

Image Credits: AI Generated

DOI: 10.1186/s13550-026-01534-5

Keywords: 177Lu-PSMA, radiopharmaceutical therapy, prostate cancer, kidney absorbed dose, nephrotoxicity, dosimetry, eGFR, mCRPC, EJNMMI Research, retrospective study, Long-term, effects