Society of Diabetic Nephropathy Prevention Journal of Nephropharmacology 2345-4202 16 1 2027 01 01 Therapeutic windows and renal rescue; evaluating prophylactic complement modulation and dose fractionation strategies to mitigate thrombotic microangiopathy in high-risk patients receiving 177Lu-PSMA-based combination therapies e12903 e12903 10.34172/npj.12903 EN Maryam Aghabozorgi https://orcid.org/0000-0002-4203-6584 Milad Eskandari https://orcid.org/0009-0007-5304-9544 Ahmadreza Maghsoudi https://orcid.org/0000-0002-0173-1222 Journal Article 10.34172/npj.12903 2026 06 20 2026 08 14 The integration of 177Lu-PSMA radioligand therapy with systemic agents has transformed the management of metastatic castration-resistant prostate cancer, yet the emergence of thrombotic microangiopathy (TMA) in high-risk cohorts remains a critical barrier to optimal dosing and long-term efficacy. Recently, utilizing a translational framework combining preclinical models, pharmacokinetic/pharmacodynamic simulations, and retrospective clinical data from high-risk patients demonstrated that unchecked complement activation following radiopharmaceutical delivery exacerbates endothelial injury and precipitates microvascular thrombosis. Prophylactic administration of complement inhibitors significantly attenuated early glomerular damage and preserved filtration capacity without compromising tumor uptake, while strategic dose fractionation reduced peak renal radiation exposure and allowed for dynamic endothelial repair intervals. Recent studies revealed that combined approaches yielded synergistic renal protection, delaying TMA onset in susceptible populations. These findings emphasize the feasibility of proactive complement modulation and precision dosing as complementary renal rescue paradigms in 177Lu-PSMA-based combination regimens.