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Host and Pathogen Pharmacogenetics in Pneumocystis jirovecii Pneumonia After Kidney Transplantation: A Retrospective
Nathalie Henskens1, Katrien Lagrou2,3, Henriette de Loor4
1Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
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.
Insights
Host genetic variations in IMPDH1 are linked to lymphopenia and Pneumocystis pneumonia (PJP) risk in kidney transplant patients. This suggests host genetics, not MPA metabolism, influences PJP susceptibility.
Area of Science:
- Transplantation immunology
- Medical genetics
- Infectious diseases
Background:
- Kidney transplant recipients face high Pneumocystis jirovecii pneumonia (PJP) risk, especially with intense immunosuppression.
- Mycophenolic acid (MPA) use varies in exposure and causes toxicity, potentially influenced by genetic factors.
- Genetic variations may impact MPA metabolism, leading to lymphopenia and PJP.
Purpose of the Study:
- To identify risk factors for PJP in kidney transplant recipients.
- To investigate the association between recipient genetic polymorphisms (UGT1A9, IMPDH2, IMPDH1) and PJP.
- To explore the link between IMPDH variants, MPA resistance, and bone marrow toxicity.
Main Methods:
- A matched 1:2 case-control study analyzed PJP risk factors from 1993-2022.
- Multivariable logistic regression identified independent risk factors for PJP.
- Recipient polymorphisms and P. jirovecii IMPDH variants were genotyped in PJP cases.
Main Results:
- PJP was associated with posttransplant cytomegalovirus infection and lymphopenia.
- IMPDH1 rs2278294 variant carriers showed higher lymphopenia rates, irrespective of MPA dose.
- P. jirovecii IMPDH variants linked to MPA resistance were found at lower frequencies than previously reported.
Conclusions:
- Host genetic variation in IMPDH1, not MPA metabolism genes, is associated with lymphopenia and PJP susceptibility in kidney transplant recipients.
- No significant enrichment of MPA resistance-associated P. jirovecii IMPDH variants was observed.
- Findings highlight complex host-pathogen interactions and the need for integrated pharmacogenetic and microbial genomic studies.
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