Higher Mycophenolate Mofetil Research Articles

Alternative lineage B cells utilizing fatty acid oxidation predict response to third dose COVID vaccination in solid organ transplant recipients

Abstract Solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates following standard two dose mRNA vaccination against SARs-CoV-2. However, within a prospective cohort of SOTRs, the majority of patients (72%) developed a positive anti-Spike (S) IgG following a third vaccine dose, compared to only 15% following two doses. Those who failed to respond to vaccination uniformly received mycophenolate mofetil (MMF). To better understand mechanisms underlying divergent vaccine responses, both global and S-specific B cells were evaluated using flow cytometry to assess immunologic and metabolic phenotypes. Prior to the third dose, 76% of SOTRs demonstrated detectable S-specific B cells even though only 15% had positive anti-S IgG titers. However, B cells were skewed towards a non-class switched phenotype in SOTRs compared to healthy controls. Response to a third dose was predicted by expanded populations of germinal center (GC)-like B cells and CD11c+ alternative lineage B cells with upregulation of carnitine palmitoyltransferase 1a (CPT1a), the rate limiting enzyme for fatty acid oxidation (FAO), a preferred energy source of GC B cells. SOTRs receiving high dose MMF demonstrated significantly lower expression of CPT1a compared to healthy controls, indicating an energetic deficit associated with MMF and failure to respond. Further, in vitro treatment of B cells with MMF reduced the ability to oxidize fatty acids and induced an accumulation of intracellular lipid droplets. Together, these data define alternative lineage B cells present in those who respond to a third vaccine dose, outlining FAO as a metabolic pathway that could be targeted to improve vaccine responses.

The Optimal MMF Dose in Tacrolimus Treated Patients

To the Editor: We appreciate the opportunity to respond to the Letter to the Editor of Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). In their letter they propose a novel immunosuppressive strategy, aimed at treating de novo kidney transplant recipients with (very) low-dose tacrolimus and a higher mycophenolate mofetil (MMF) dose. The hypothesis of their prospective study is that reduced exposure to tacrolimus will result in an improved histology in 1-year protocol biopsies (less interstitial fibrosis and tubular atrophy), while the higher MMF dose (3 g daily) compensates for the lower tacrolimus exposure and will maintain efficacy. We feel that the observations in our analysis of three large, randomized-controlled trials (2Bouamar R Shuker N Hesselink DA et al.Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: A pooled analysis from three randomized-controlled clinical trials.Am J Transplant. 2013; 13: 1253-1261Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) suggest that the currently targeted tacrolimus predose concentrations may be too high and that a further reduction of the target levels is possible without compromising efficacy. We agree that optimizing MMF exposure is likely to further improve the outcome. What the optimal MMF dose would be has been a matter of debate for some time. In the registration trials, MMF doses of 2 or 3 g per day were compared with placebo or azathioprine treatment. Patients in these studies were on full-dose cyclosporine (CsA) treatment. It may well be that in a setting of low-dose tacrolimus treatment (say target predose concentrations in the range of 3 ng/mL) higher MMF doses would offer a benefit. It is known that in tacrolimus-treated patients an MMF dose of 2 g/day will result in mycophenolic acid (MPA) exposure below the target in 25% of patients in the first month after transplantation (and in CsA co-treated patients this occurs in no less than 50%). Temporary intensified dosing has been suggested to avoid reduced MPA exposure in the early posttransplant phase (3Gourishankar S Houde I Keown PA et al.The CLEAR study: A 5-day, 3-g loading dose of mycophenolate mofetil versus standard 2-g dosing in renal transplantation.Clin J Am Soc Nephrol. 2010; 5: 1282-1289Crossref PubMed Scopus (48) Google Scholar). Knotek et al (1Knotek M Galešić Ljubanović D Mihovilović K Maksimović B Tacrolimus or mycophenolate in kidney transplantation—Less, or more?.Am J Transplant. 2014; 14: 1220Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) propose a 3 g MMF dose in the first week, and in half of the patients this dose is maintained thereafter. Whether or not a prolonged duration of higher MMF dosing would offer a benefit when very low tacrolimus concentrations are targeted remains to be seen. One could expect more MMF-related toxicity in a substantial proportion of patients, as observed in an older MMF dose finding study in tacrolimus-treated patients (4Squifflet JP Bäckman L Claesson K et al.Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.Transplantation. 2001; 72: 63-69Crossref PubMed Scopus (122) Google Scholar). Therapeutic drug monitoring for MPA may identify patients with over-exposure, and in such patients, dose reductions may improve tolerability to the proposed regimen (5van Gelder T Therapeutic drug monitoring for mycophenolic acid is value for (little) money.Clin Pharmacol Ther. 2011; 90: 203-204Crossref PubMed Scopus (15) Google Scholar). The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Hesselink has received lecture fees from Astellas Pharma. Dr. van Gelder has received lecture fees from Astellas Pharma, and Roche. Dr. Bernasconi has received consulting fees from F. Hoffmann-La Roche Ltd, Basel, Switzerland. All other authors have no conflicts to declare.

Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years.

Accelerated atherosclerosis is a major cause of mortality in SLE. Mycophenolate mofetil (MMF) has been shown to suppress growth factor-induced proliferation of vascular smooth muscle and endothelial cells in animal models. We hypothesized that MMF might modify the inflammatory component of atherosclerosis in SLE. We examined the effect of MMF on atherosclerosis as measured by changes in carotid intima-media thickness (IMT) or coronary artery calcium (CAC) over 2 years. CAC and carotid IMT were measured at baseline and 2 years later in a cohort of 187 patients with SLE. The cohort was 91% women, 59% Caucasian, and 35% African-American, with a mean age of 45 ± 11 years. Of these, 12.5% (n = 25) received MMF during follow-up. The daily dose ranged from 500 to 3,000 mg/day, and duration ranged from 84 days to the entire 2 years. We divided MMF users into three groups: low exposure (<1,500 mg average daily dose), high exposure (≥1,500 average daily dose), and any exposure of MMF (<1,500 or ≥1,500 average daily dose) for 2 years. The mean CAC increased in all four groups: no MMF: 1.17-1.28, low MMF: 1.02-1.13, high MMF: 1.44-1.61, and any MMF: 1.21-1.34 log-Agatston units. Compared to no MMF, there was no statistically different change between the three groups (p = 0.99, 0.87, and 0.91). Similarly, mean carotid IMT increased in all four groups: no MMF: 0.58-0.66, low MMF: 0.55-0.60, high MMF: 0.56-0.71, and any MMF: 0.56-0.66. We then adjusted for statin use, lupus nephritis, body mass index, systolic blood pressure, cholesterol, and age during the 2-year follow-up. The association between MMF exposure and change in CAC or carotid IMT was not statistically significant (p = 0.63 for CAC, and p = 0.085 for carotid IMT). There was no evidence that MMF slowed or decreased the progression of atherosclerosis as measured by carotid IMT or CAC. Because the number of patients taking MMF was only twenty-five, larger studies for longer time periods are needed to explore any effect of MMF on subclinical atherosclerosis in SLE.

Complicated Lymphoceles After Kidney Transplantation

Lymphocele is a common surgical complication after renal transplantation. The incidence of lymphocele ranges from 0.6% to 18%. The aim of this study was to determine incidence, risk factors and prognosis of complicated lymphocele in the era of modern immunosuppression. We retrospectively reviewed 311 renal transplants from January 2003 to September 2008, we excluding patients who received sirolimus or underwent multiorgan transplantations. A complicated lymphocele was defined by the requirement for a surgical procedure for cure. Of the 311 transplant recipients, we included 269 in the study with 49 (18.9%) presenting a complicated lymphocele after transplantation. Cold ischemia time, waiting time on dialysis, gender, donor source, induction therapy (thymoglobulin vs basiliximab), and dialysis modality were similar between the 2 groups. Mycophenolate mofetil (MMF) doses were higher among the lymphocele than the nonlymphocele group (2.7 ± 0.54 g/d vs 2.36 ± 0.68 g/d; P < .05). However, the areas under the concentration-time curves of mycophenolic acid were not significally different between the 2 groups (43.7 ± 15.3 h · mg/L vs 48 ± 21 h · mg/L; P = .33). However, a multivariate analysis showed complicated lymphocele to be associated with greater MMF doses (odds ratio [OR] 2.75; P < .01), warm ischemia time (OR 1.035; P < .05), and recipient age (OR 1.04; P < .05). In conclusion, we identified high MMF doses as an independent risk factor for lymphocele formation after renal transplantation.

Severe Relapsing Goodpasture's Disease Successfully Treated with Mycophenolate Mofetil

Goodpasture's disease is a rare autoimmune disorder characterised by the development of antiglomerular basement membrane autoantibodies, which typically presents with rapidly progressive crescentic glomerulonephritis and pulmonary haemorrhage. Even with aggressive nonspecific immunosuppression and plasma exchange, mortality remains high. We report a case of life-threatening Goodpasture's disease with relapsing pulmonary haemorrhage refractory to conventional therapy. Second line treatment was based on mycophenolate mofetil 1 g every 12 hours and prednisolone 60 mg/day. In this case, the use of a low-dose mycophenolate mofetil regimen turned out to be insufficient. However, in our opinion higher mycophenolate mofetil doses should be considered an alternative treatment, mainly in relapsing disease, due to its mechanism of action and current insufficient therapeutic weapons.

Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation

Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 +/- 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61-0.89; p < 0.004). IMPDH activity above the cut-off value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.

Treatment by Mycophenolate Mofetil of Advanced Graft Vascular Disease in Non‐Human Primate Recipients of Orthotopic Aortic Allografts

Failure to control chronic graft dysfunction [e.g. graft vascular disease (GVD)] is the primary cause of immunologic graft failure. This is the first study of mycophenolate mofetil (MMF) for the treatment of GVD in non-human primate recipients of aortic allografts. Abdominal aortic allografts were exchanged between mixed leukocyte reaction (MLR) -mismatched, blood-group-compatible cynomolgus monkeys. Six control recipients were untreated. Individualized treatment with frequent dose adjustments of MMF insured that treatment was close to the maximum tolerated dose (mean 99.2 mg/kg/day). Immune-mediated injury proceeded unhindered until day 45, after which MMF treatment began. Changes in intimal volume (IV) were quantified by intravascular ultrasound (IVUS) and compared to histology on day 105. Serial IVUS measurements of IV (mm(3)) in controls showed progressive GVD. In four out of six animals, MMF was well tolerated, thus enabling optimum treatment; in all these animals, IV was significantly less than in the control animals (p = 0.02). In the two remaining animals, high doses were not tolerated; at day 105, there was no significant difference in IV between them and the controls. We found a significant correlation between the mean MMF tolerated dose and the inhibition of progression of IV (r = -0.88, p = 0.015). When high MMF doses were tolerated, MMF slowed progression of GVD.