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. MPA has demonstrated in vitro antifungal activity against several fungal species, although its effect on P. jirovecii remains uncertain. In two independent studies the IMPDH gene was analyzed in P. jirovecii detected in bronchoalveolar lavage (BAL) samples from SOT recipients treated with MPA and non-SOT patients not exposed to MPA. Nine SNPs in the fungal IMPDH gene were identified. Notably, the G1020A mutation, resulting in an Ala261Thr substitution, was detected in the majority of MPA-treated SOT recipients and in none of the non-treated control patients. A second missense variant, G1020T (Ala261Ser), was detected in P. jirovecii in BAL samples from three SOT recipients, including two who had received MPA. The predominance of Ala261Thr/Ala261Ser IMPDH mutations in MPA-exposed SOT recipients suggests that MPA acts as a selective pressure on P. jirovecii, favoring resistant strains that may circulate within this population and contribute to PJP case clusters.
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. Additionally, a retrospective cohort study restricted to renal transplant PJP cases evaluated recipient polymorphisms in UGT1A9, IMPDH2, and IMPDH1 and their associations with hematotoxicity. 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 (Table 1). Post-transplant cytomegalovirus infection (P= 0.0097) and lymphopenia (P=0.0004) were independently associated with PJP. Among PJP cases, carriers of the IMPDH1 rs2278294 variant had a significantly higher incidence of lymphopenia (P=0.0133), independent of MPA dose. P. jirovecii genotyping was obtained in 24 patients. The IMPDH Ala261Thr variant was detected in 16.7% and the Ala261Ser variant in 22.2% of MPA-treated patients, 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 gene variants was observed (39% of lavage samples from MPA treated patients). 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.