Inadequate mycophenolic acid exposure and acute rejection in kidney transplantation.

INTRODUCTION: The clinical utility of predose levels of mycophenolic acid (MPA) monitoring among patients treated with mycophenolate mofetil (MMF) has been questioned. The aim of this study was to evaluate the impact of adequate MPA levels in the incidence of acute rejection episodes among a cohort of kidney transplant recipients. MATERIAL AND METHODS: In this retrospective study of 314 consecutive cases treated with tacrolimus, MMF, and steroids, evaluated 12-hour trough MPA samples during the first week as well as at 1, 3, 6, and 12 months as median values. RESULTS: During the first week, the median values of MPA were 1.6 microg/mL (p25-75 0.7-2.7 microg/mL) on mean doses of 1.84 +/- 0.38 g/d. The incidence of acute rejection was 28%. The mean MPA levels during the first week were significantly lower among patients who developed rejection than in nonrejectors (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001). There were no significant differences in trough tacrolimus levels between rejectors and nonrejectors (11.2 +/- 0.4 vs 11.6 +/- 1.2 microg/mL; P < .78). Logistic regression analysis showed that one of the predictive factors of acute rejection was a 12-hour trough MPA <1.6 microg/mL (relative risk [RR] 2.6; CI [confidence interval] 95% 1.6-4.3; P < .001). CONCLUSIONS: Adequate MPA exposure is important to prevent acute rejection. Taking into account that the routine measurement of the area under the curve of MPA is impractical, at least the follow-up of trough MPA levels may help in the management of renal transplant recipients.

Graft outcome and mycophenolic acid trough level monitoring in kidney transplantation.

BACKGROUND: Large inter- and intrapatient variabilities have been observed in the pharmacokinetics of mycophenolic acid (MPA). As a consequence, the efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic drug monitoring. MATERIALS AND METHODS: In this retrospective study we analyzed; 7536 12-hour trough MPA samples obtained during the first year posttransplantation among 314 kidney recipients treated with tacrolimus, MMF, and corticosteroids. RESULTS: Despite taking similar MMF doses, patients with delayed graft function (DGF) showed lower 12-hour trough MPA levels than patients without DGF 1.4 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P = .001). There was a significant correlation between 12-hour trough MPA levels and creatinine clearance (r = .32; P < .001). Logistic regression analysis showed that creatinine clearance was a predictive factor of adequate 12-hour trough MPA levels (>1.6 microg/mL) at 7 days posttransplantation. Twelve-hour trough MPA levels at 7 days posttransplantation were lower among patients who developed an acute rejecton episode (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001), whereas those with gastrointestinal side effects showed high levels (4.1 +/- 0.5 microg/mL). CONCLUSIONS: In patients with delayed or poor graft function, MMF doses greater than 2 g/d may be necessary to achieve adequate MPA levels. Therapeutic drug monitoring of MPA may be useful to prevent acute rejection episodes or toxicity.

Sirolimus and everolimus induced pneumonitis in adult renal allograft recipients: experience in a center.

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.