Split Renal Function Estimation Using [18F]F-Flotufolastat PET/CT: Comparison with [68Ga]Ga-PSMA-11 and [99mTc]Tc-MAG3 Scintigraphy

Abstract Background: Physiological prostate-specific membrane antigen (PSMA) expression in renal proximal tubules results in radiopharmaceutical uptake in PSMA-PET, suggesting the potential to assess renal function. Thus, we evaluated whether PSMA-PET/CT allowed estimation of split renal function (SRF), potentially replacing [99mTc]Tc-MAG3 scintigraphy. We retrospectively analyzed 302 patients with metastatic castration-resistant prostate cancer undergoing PSMA-PET/CT using either [¹⁸F]F-flotufolastat ([¹⁸F]F-rhPSMA-7.3) (n=221) or [⁶⁸Ga]Ga-PSMA-11 (n=81), along with [99mTc]Tc-MAG3 scintigraphy, prior to PSMA radioligand therapy. SRF was calculated from PSMA-PET/CT using mean standardized uptake values and CT-derived renal volumes. SRF was calculated from [99mTc]Tc-MAG3 using standard integral analysis. Correlations between PET-derived SRF (PET-SRF) and [99mTc]Tc-MAG3 -derived SRF ([99mTc]Tc-MAG3-SRF) were assessed using Pearson correlation and Bland–Altman analysis. Receiver operating characteristic (ROC) analyses were conducted to evaluate diagnostic performance in detecting impaired renal function (SRF ≤ 25% and ≤40%). A PET-based accumulation index (ACI) was explored for correlation with estimated glomerular filtration rate (eGFR). Results: Strong correlations were found between PET-SRF and [99mTc]Tc-MAG3-SRF (r=0.88 for [¹⁸F]F-flotufolastat, r=0.85 for [⁶⁸Ga]Ga-PSMA-11; both p<0.0001). Bland–Altman analysis showed a smaller mean bias and narrower limits of agreement for [¹⁸F]F-flotufolastat(-0.56%; -11.88% to +10.75%) compared with [⁶⁸Ga]Ga-PSMA-11 (-1.18%; -15.3% to +12.95%), with 92% versus 83% of values within ± 10%, respectively. ROC analysis confirmed excellent accuracy for identifying [99mTc]Tc-MAG3-SRF ≤ 25% (area under the curve [AUC] = 0.997 for [¹⁸F]F-flotufolastat; AUC = 0.942 for [⁶⁸Ga]Ga-PSMA-11). ACI and eGFR were not significantly correlated (Spearman’s ρ=0.048; p=0.49]). Conclusion: PSMA-PET/CT provides reliable estimates of SRF, with [¹⁸F]F-flotufolastatshowing slightly superior agreement with [99mTc]Tc-MAG3 scintigraphy. This may potentially eliminate the need for additional renal scintigraphy for SRF assessment in the future and may simplify workflows and reduce patient burden.