Influence of mycophenolate mofetil dosage and plasma levels on the occurrence of chronic lung allograft dysfunction in lung transplants: a retrospective cohort analysis

Abstract

INTRODUCTION: Development of chronic lung allograft dysfunction is a limiting factor for post-lung transplant survival. We evaluated whether the dose of the immunosuppressant mycophenolate mofetil or plasma concentrations of the active metabolite mycophenolic acid affect the development of chronic lung allograft dysfunction. METHODS: In this retrospective cohort study we recruited 71 patients with a lung transplant between 2010 and 2014 which survived the first year after transplantation up to 1 July 2021. An event-time-analytical Cox proportional-hazards regression model with time-varying-covariates (18,431 measurements for MPA, mycophenolate mofetil dosage, lymphocytes) was used to predict chronic lung allograft dysfunction, with adjustment for sociodemographic factors and lung function at baseline. RESULTS: 37 patients did not develop chronic lung allograft dysfunction (age 41.3 ± 15.6 years, baseline FEV1 95.5 ± 19.1% predicted) and 34 patients developed chronic lung allograft dysfunction (age 50.9 ± 13.3 years, baseline FEV1 102.2 ± 25.4% predicted). Mean mycophenolic acid did not differ significantly between the groups (2.8 ± 1.7 and 3.0 ± 2.3 mg/l; p = 0.724). In the first 4 post-transplant years the death rate was 25%. A total of 50% of the patients died by the ninth post-transplant year. There was a dose-effect relationship between mycophenolate mofetil dosage, mycophenolic acid (r2 = 0.02, p <0.001), as well as lymphocyte levels (r2 = –0.007, p <0.001), but only the traditional risk factor age predicted chronic lung allograft dysfunction. Continuously measured mycophenolic acid did not predict chronic lung allograft dysfunction (hazard ratio 0.98, 95% confidence interval 0.90–1.06, p = 0.64 over a period of 382.97 patient-years). CONCLUSION: Mycophenolate mofetil dosage and mycophenolic acid were not associated with chronic lung allograft dysfunction development. Thus, the mycophenolate mofetil dose or mycophenolic acid plasma concentration are not a primary factor related to organ rejection, but chronic lung allograft dysfunction may be influenced by other components of immunosuppression or other factors.