Longitudinal renal function following [¹⁷⁷Lu]Lu-PSMA I&T in metastatic castration-resistant prostate cancer

The kidneys are recognised organs at risk during prostate-specific membrane antigen (PSMA)–targeted radioligand therapy. While clinically overt nephrotoxicity appears uncommon in late-line metastatic castration-resistant prostate cancer (mCRPC), the longitudinal trajectory of renal function following [¹⁷⁷Lu]Lu-PSMA I&T remains incompletely characterised. We aimed to quantify longitudinal changes in renal function in a treated mCRPC cohort and explore clinical factors associated with renal decline. This retrospective cohort study included patients with mCRPC treated with [¹⁷⁷Lu]Lu-PSMA I&T between November 2018 and July 2024. Longitudinal renal analyses were performed in patients with baseline and post-treatment estimated glomerular filtration rate (eGFR) measurements, calculated using the 2021 CKD-EPI creatinine equation (race-free version). Changes in eGFR over time were modelled using linear mixed-effects models with random intercepts and slopes. Fixed effects included time since first treatment, estimated cumulative renal absorbed dose (derived from a population-based conversion factor in the absence of patient-specific dosimetry), and a predefined Renal Risk Index (RRI) capturing baseline chronic kidney disease, hypertension, and diabetes mellitus. Additional analyses examined reconstructed pre-treatment trajectories using piecewise modelling, restricted 12-month analyses, and non-linearity testing. Clinically significant renal decline was defined as a ≥ 25% reduction in eGFR from baseline and evaluated using time-to-event analyses. A total of 105 patients were included, contributing 238 post-treatment eGFR measurements over follow-up of up to 48 months. Renal function declined over time with an estimated mean decrease of 0.85 mL/min/1.73 m² per month (95% CI − 1.30 to − 0.40; p < 0.001). Baseline renal vulnerability was independently associated with lower absolute eGFR values (− 6.76 mL/min/1.73 m² per RRI unit; p < 0.001) but did not modify the rate of decline. Within the administered activity range and using population-based dose estimates, no clear dose–response relationship was detected; this finding should be interpreted in the context of the narrow activity range studied and the absence of patient-specific dosimetry. Reconstructed pre-treatment trajectories demonstrated stable renal function prior to therapy (β = +0.06 mL/min/month; p = 0.30), whereas post-treatment eGFR declined significantly (β = −0.60 mL/min/month; p < 0.001). Restricted analyses limited to the first 12 months showed similar slopes, with no evidence of non-linearity. Clinically significant renal decline occurred in 16 patients (15%), most frequently within the first year following treatment initiation. In this retrospective mCRPC cohort treated with [¹⁷⁷Lu]Lu-PSMA I&T, a measurable decline in renal function was observed over time, although the observational design precludes causal attribution to radioligand therapy. Clinically significant renal deterioration remained relatively uncommon. Baseline renal vulnerability influenced overall renal reserve but not the rate of decline, and no clear dose–response relationship was detected within the administered activity range. Extrapolation of these findings to earlier-line settings should be considered hypothesis-generating. These findings support baseline renal assessment and longitudinal monitoring as PSMA-targeted radioligand therapy expands to earlier disease settings.