Host and Pathogen Pharmacogenetics in Pneumocystis jirovecii Pneumonia After Kidney Transplantation: A Retrospective Cohort and Case–Control Study

BACKGROUND: Kidney transplant recipients are at risk for Pneumocystis jirovecii pneumonia (PJP), particularly under profound immunosuppression. Mycophenolic acid (MPA) is widely used after transplantation and is associated with interindividual variability in exposure and hematologic toxicity. Genetic variation affecting MPA metabolism and pharmacodynamics may contribute to lymphopenia and PJP. METHODS: We performed a matched 1:2 case-control study to assess risk factors for PJP in kidney transplant recipients (1993-2022) using multivariable logistic regression. In addition, a retrospective cohort study restricted to PJP cases evaluated recipient polymorphisms in UGT1A9, IMPDH2, and IMPDH1, and their associations with bone marrow toxicity. P. jirovecii DNA from bronchoalveolar lavage samples was genotyped for IMPDH variants potentially associated with MPA resistance. RESULTS: Thirty-nine PJP cases and 78 controls were included. Posttransplant cytomegalovirus infection and lymphopenia were independently associated with PJP. Among PJP cases, carriers of the IMPDH1 rs2278294 variant had a significantly higher incidence of lymphopenia, independent of MPA dose. P. jirovecii genotyping was obtained for 24 patients. The IMPDH Ala261Thr variant was detected in 16.7% and the Ala261Ser variant in 22.2% of MPA-treated patients, which is substantially lower than previously reported. CONCLUSIONS: In kidney transplant recipients with PJP, host genetic variation in IMPDH1, rather than polymorphisms affecting MPA metabolism, appears to be associated with lymphopenia and infection susceptibility. In contrast to prior reports, no clear enrichment of MPA resistance-associated P. jirovecii IMPDH variants was observed. These findings underscore the complexity of host-pathogen interactions under immunosuppressive therapy and highlight the need for larger, well-controlled studies integrating pharmacogenetics and microbial genomics.