The Burden of Gastrointestinal Complaints in Kidney Transplant Recipients Using Tacrolimus With and Without Mycophenolate Mofetil: A Randomized Controlled Study

Abstract

BackgroundTacrolimus (TAC) combined with mycophenolate mofetil (MMF) is the immunosuppressive regimen in the majority of solid organ transplant recipients. Gastrointestinal complaints are frequent, which is considered predominantly a side effect of MMF. However, systematic research in this field is lacking. The aim of this study is to systematically investigate the burden of gastrointestinal complaints in TAC-treated kidney transplant recipients with and without MMF.MethodsIn a single-center, open-label, randomized controlled trial, low immunological risk recipients were randomized to either TAC and MMF or to TAC monotherapy from 6 months after kidney transplantation onwards [NTR4672],. They filled in the Gastrointestinal Symptom Rating Scale questionnaire, which covers five dimensions (abdominal pain, reflux, indigestion, constipation, and diarrhea), 6, 12, and 15 months after transplantation.ResultsSeventy-nine recipients were randomized and 72 completed all questionnaires (34 TACmono and 38 TAC/MMF). At baseline, the mean age was 59 years with 72% male, mean BMI 28 kg/m2, eGFR 55 ml/min/1.73m2, mean daily dose MMF 1200 mg and TAC 5.8 mg, with trough levels of 2.1 mg/L and 7.4 ug/L. Six months after transplantation, 75% of recipients reported troublesome symptoms (score ≥3). Diarrhea was the most troublesome (mean 3.3) and discontinuing MMF significantly reduced it (mean Δ score between month 6 and 15 TAC/MMF -0.9 vs. TACmono -1.8, p=0.03). In recipients with troublesome symptoms, abdominal pain (2.7 to 1.8, p=0.003), indigestion (2.8 to 2.3, p=0.012), and reflux (2.9 to 1.7, p=0.007) significantly decreased over time, independent of MMF use.ConclusionThe majority of kidney transplant recipients with TAC and MMF experienced troublesome gastrointestinal symptoms 6 months after transplantation. While constipation remained troublesome, indigestion, abdominal pain, and reflux improved over time by month 15. Diarrhea only improved after discontinuing MMF.

Tacrolimus Monotherapy is Safe in Immunologically Low-Risk Kidney Transplant Recipients: A Randomized-Controlled Pilot Study

“…In addition, with an average tacrolimus trough level of 6 ng/L the graft function remained stable, no DSA developed and adherence to the once daily immunosuppressive regimen in the TACmono group was significantly better than in the TAC/MMF group (23). Another benefit TACmono recipients experienced, was improvement in diarrhea complaints after discontinuing MMF, as assessed with standardized questionnaires on gastro-intestinal symptoms (24). The benefits of TACmono in terms of less adverse events is of course difficult to quantify in a pilot study.…”

Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots

“…MMF has replaced azathioprine in current immune suppressive regimens. MMF use may cause serious gastrointestinal side effects and severely lower the antibody response to vaccination, e.g., COVID-19 vaccines ( 111 – 113 ). In general, the use of MMF is associated with more infections, particularly viral infections, but it does not seem to increase the risk for cancer significantly and may even have therapeutic potential as an anticancer drug ( 114 – 116 ).…”

“…An RCT based on this concept was recently published with 5-year follow-up data and indeed showed that this may be a feasible approach as the results showed no development of DSA, no increased rejection rate, significantly fewer infections, and a much better serological response after COVID vaccination ( 112 , 146 ). Tacrolimus was given as a once-daily formulation, increasing medication adherence, and there were fewer gastrointestinal symptoms after MMF discontinuation ( 83 , 113 , 147 ). Of note, the mean age of the recipients in this trial was 59 years, and recipients with a TCMR treated with T cell-depleting therapy were excluded from randomization.…”