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Background Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) is highly effective for HIV prevention, although concerns about potential nephrotoxicity may influence long-term use. We evaluated the incidence, timing and determinants of renal toxicity within the Italian national PrIDE cohort.Methods We conducted a retrospective observational study among TDF/FTC-based oral PrEP users enrolled in the PrIDE national cohort with at least one estimated glomerular filtration rate (eGFR) measurement. Follow-up started at PrEP initiation and ended at renal event occurrence or at switching, discontinuation, or December 31, 2025 (cut date), whichever came first. Renal toxicity was defined as eGFR<60 ml/min/1.73m 2. Cox proportional hazards models were used to identify factors associated with renal toxicity; in stratified analysis by age-group, to address potential small-sample bias and sparse event limitations, Firth -penalized likelihood Cox models were applied. Non-renal adverse events, PrEP discontinuation, co-medication and substance use were also assessed.Results Among 1,583 PrEP users included, 15 participants (0.9%) developed renal toxicity ( table 1). Incidence rate per 100 person-years was 1.22 (95%CI 0.68–2.01), 0.70 (0.28–1.43) in <50 years and 3.54 (1.53–6.89) in ≥50 years. The Kaplan Meier curve (figure 1) shows the cumulative probability of renal toxicity during follow-up. Median time from PrEP initiation to event was 127 days (IQR 106.5–136). No definitive PrEP discontinuations occurred among individuals experiencing renal events, and only one temporary interruption was reported.Non-renal adverse events were uncommon (diarrhoea 5.9%, fatigue 1.5%, headache 1.3%, insomnia/nightmares 0.3% and skin rash 0.2%), with no age-group differences.In multivariable Cox analysis, age ≥50 years (aHR 4.44, 95%CI 1.59–12.35; p=0.004) and use of physical performance-enhancing substances (aHR 8.41, 95%CI 2.31–30.60; p=0.001) were independently associated with renal toxicity (table 2), in particular in the older group after stratification with Firth penalized likelihood Cox models.Conclusions In this large national real-world PrEP cohort, renal toxicity during TDF/FTC use was rare and occasionally led to interruption. Older age and physical performance-enhancing substances use identify individuals who may benefit from targeted renal monitoring supporting the overall favourable safety profile of oral PrEP.Abstract SC1 Figure 1Kaplan Meier curve showing the cumulative probability of renal toxicity during follow-upAbstract SC1 Table 1–2