*Purpose: Kidney transplant recipients (KTR) have an elevated risk of cancer. We sought to estimate to what extent does the immunosuppression regimen increase KTRs’ susceptibility to cancer, and if this risk is modified by age and sex.

*Methods: We reconstructed a retrospective 20-year Quebec province-wide cohort including first time kidney only transplant recipients by linking two provincial administrative healthcare databases. Immunosuppression prescription data (date, form, dose, and duration) along with pertinent effect modifiers and confounders were obtained from the Régie de l’assurance maladie du Québec. Incident cancer cases were identified in Quebec’s clinical and administrative database (Med-ECHO) using the World Health Organization International Disease Classification ICD-10 codes. We computed hazard ratios and 95% confidence intervals [HR (95%CI)] for the associations between risk of cancer and time-varying unweighted cumulative doses of prednisone, MMF and tacrolimus administered over the last 8 years. Exposure to immunosuppression agents was lagged by 2 years as very recent exposure is unlikely to affect the immediate risk of cancer. In addition, we assessed the recency-Weighted Cumulative Exposure (WCE) for the same immunosuppression agents in multivariable models adjusted for sex, age at transplant, era, and the unweighted cumulative doses of the other two immunosuppression agents. Interactions between the main exposures and age, using a 50-year threshold, and sex, were also assessed.

*Results: A total of 3,112 KTR experienced 423 cancer events. Cumulative prednisone dose (5mg per day over 8 years, the median follow-up) was associated with an increased risk of cancer [HR 1.28 (95% CI, 1.01-1.64)] while MMF (1000mg per day over 8-years) and tacrolimus (2mg per day over 8-years) were not [0.94 (0.74-1.21) and 0.96 (0.82-1.12), respectively]. We observed a significant interaction between cumulative prednisone dose and age (p<0.01), with a higher risk of cancer observed among recipients >50 years of age [1.51 (1.15-1.97)]. We also observed a statistically significant interaction between the cumulative dose of MMF and age (p=0.03) with patients ≤50 years experiencing a lower risk [0.67 (0.44-1.01)]. No significant interaction was observed between the cumulative dose of tacrolimus and age or between the cumulative dose of prednisone, MMF or tacrolimus and sex. A similar trend was observed in WCE models for prednisone, MMF and tacrolimus use over an 8-year period vs. non-use with HRs 1.26; 0.91; and 0.95, respectively.

*Conclusions: An increased risk of cancer was observed the higher the cumulative dose of prednisone. The cancer risk by cumulative prednisone dose was further accentuated in older KTR. Whether lower intensity regimens may help mitigate risk of cancer warrants further study.

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