AZA/Tacrolimus Is Associated with Similar Outcomes as MMF/Tacrolimus among Renal Transplant Recipients

There have been several retrospective studies indicating benefits associated with mycophenalate mofetil (MMF) compared to azathioprine (AZA) for renal transplant recipients. However, these analyses evaluated outcomes prior to changes in utilization patterns of concomitant immunosuppression. Recent prospective trials have indicated similar outcomes among patients treated with MMF and AZA. The aim of this study was to evaluate outcomes in a broad group of patients in the more recent era. We evaluated adult solitary renal transplant recipients from 1998 to 2006 with the national SRTR database. Primary outcomes were time to patient death and graft loss, complications and renal function. Models were adjusted for potential confounding factors, propensity scores and stratified between higher/lower risk transplants and concomitant immunosuppression. Adjusted models indicated a modest risk among AZA patients for graft loss (AHR = 1.14, 95% CI 1.07–1.20); however, this was not apparent among AZA patients also treated with tacrolimus (AHR = 0.97, 95% CI 0.85–1.11]. One-year acute rejection rates were reduced for patients on MMF versus AZA (10 vs. 13%, p < 0.01); there were no statistically significant differences of malignancies, renal function or BK virus at 1 year. The primary findings suggest the association of MMF with improved outcomes may not be apparent in patients also receiving tacrolimus.     

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.     

Uncommon Side Effect of MMF in Renal Transplant Recipients

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used in renal transplantation. Gastrointestinal and hematological side effects are commonly observed, but hepatotoxicity has not been reported. In this study, we assessed MMF-related hepatotoxicity in renal transplant recipients. A total of 124 renal transplantation recipients (RTRs) were evaluated for elevated liver enzymes associated with MMF, and 79 patients were enrolled to the study. Patients used MMF 2 g/day. The patients who had progressive increase in liver enzymes after renal transplantation and their AST, ALT, GGT, ALP, bilirubin levels, hepatitis, cytomegalovirus (CMV), abdominal ultrasonography, duration of hepatotoxicity, and decreased dosage or withdrawal of MMF were recorded. Also, we evaluated their liver enzymes while the patients were on the waiting list. Of the 79 patients, 11 patients (13.9%) had a progressive increase in liver enzymes. The median (min–max) age of the patients with MMF-hepatotoxicity was 29 (19–54) and 72.7% of them were male. None of the patients had hepatitis B or C, CMV infection, or other possible causes for elevated liver enzymes and their abdominal ultrasonography were normal. High liver enzyme levels regressed after the withdrawal (n = 6) or reduce dosage (n = 5) of MMF. The median time of the increase in liver enzymes was 28 (4–70) days and after 50% reduction or withdrawal of MMF, returned to normal values in 16 (4–210) days. The median levels of ALT in waiting list (I), before (II), and after (III) reduction dosage or withdrawal of MMF were 22.0 (3–22), 222.0 (51–508), and 33.0 (21–64) U/L, respectively (p I–II = 0.004, p I–II = 0.013, and p II–III = 0.005). There were no differences for ALP, GGT, total bilirubin, and direct bilirubin levels. Also, the correlation between recovery time of ALT and persistence time of ALT elevation before adjustment of MMF was significant (r = 0.739, p = 0.009). Consequently, after renal transplantation, hepatotoxicity can occur due to a lot of reason including MMF usage. If hepatotoxicity related to MMF is not considered, especially in the early period of renal transplantation, resolution of hepatotoxicity can be required long term.     

Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant population. We prospectively evaluated 94 first solitary kidney transplant patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was also given to 72 recipients. MPA exposure was measured by HPLC using a limited sampling estimate of 12 h area under the curve (AUC [0-12]) within the first week. Efficacy was determined by the occurrence of acute rejection and toxicity by the need to reduce MMF doses within the first 3 months post-transplantation. Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver operator curve analysis shows that MPA AUC [0-12] on day 3 was predictive of efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate analysis of only patients on basiliximab shows that the MPA AUC [0-12] on day 3 was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate exposure to MPA by day 3 is associated with low acute rejection but cannot predict toxicity. Adequate MPA exposure is also important with basiliximab induction therapy.     

Equivalent Pharmacokinetics of Mycophenolate Mofetil in African-American and Caucasian Male and Female Stable Renal Allograft Recipients

African-American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end-points of dose-adjusted PK parameters AUC0-12 and Cmax of MPA using log-transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back-transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose-adjusted AUC0-12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race-by-gender effects (p-values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.     

Cytochrome P450 3A4 and P-glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.     

The Use of Daclizumab, Tacrolimus and Mycophenolate Mofetil in African-American and Hispanic First Renal Transplant Recipients

Limited data are available on the use of tacrolimus and mycophenolate mofetil in conjunction with anti-IL-2 receptor antibody, in groups of kidney transplant recipients considered to be at higher risk. This study compared the incidence of acute rejection between African-American (AA), Hispanic (H), and non-African-American, non-Hispanics (non-AA, non-H) first renal transplant recipients. We studied 233 sequential first renal transplants. Of the 233, 37 recipients (16%) were AA, 85 (36.5%) were H and 111 (47.5%) were non-AA, non-H. All received daclizumab induction therapy (1 mg/kg) on the day of surgery, and every other week for a total of 5 doses, as well as mycophenolate mofetil, tacrolimus, and steroids. At 1 year, patient and graft survival were 97% and 95% in AA, 98% and 98% in H, and 96% and 95% in non-AA, non-H, respectively (not statistically different). Biopsy-proven acute rejection episodes were 8.1% in AA, 4.7% in H, and 4.5% in non-AA, non-H (also not statistically different). This immunosuppressive protocol appears to be safe and effective in helping to minimize biopsy-proven acute rejection and optimize renal allograft survival in African-American and Hispanic renal transplant recipients in the first year post transplantation.     

Pharmacokinetic Studies of Mycophenolate Mofetil in Rat Kidney Allograft Recipients

Background A pharmacokinetic estimation of the immunosuppressive activity of mycophenolate mofetil (MPM) was performed in rats with transplanted kidney allografts.
Methods Kidney allografts from Brown Norway rats were transplanted into Lewis rats using a microsurgical technique. MPM, at doses of 5, 10, 15 and 25mg/kg/day, was administered orally every day after transplantation. Pharmacokinetic studies were performed on days 7 and 14, and thereafter every 2 weeks.
Results After the administration of MPM, the plasma concentration of mycophenolic acid (MPA) increased rapidly, peaking at 15 to 30 minutes, and then decreased biexponentially. The peak concentration of MPA and the area under the plasma MPA concentration versus time curves (AUC) significantly correlated with the dosage. MPM administration at 5 and 10mg/kg/day significantly prolonged the graft survival time from 7.1 days to 18.5 days and 85.0 days, respectively. The AUC values on day 7 after transplantation were 32.7,ug-h/mL and 38.6/ig-h/mL in rats receiving 5 and 10mg/kg/day, respectively. However, in rats receiving 1 5mg/kg/day of MPM or more, the AUC value at 7 days was 78.8,ug-h/mL, and almost all of these rats died from gastrointestinal toxicity.
Conclusion MPM monotherapy significantly prolonged rat kidney allograft survival, however, high dosages of MPM caused gastrointestinal toxicity. AUC measurements of the MPA concentration are suitable for the pharmacokinetic monitoring of MPM.     

Differential Effect of Diarrhea on FK506 Versus Cyclosporine A Trough Levels and Resultant Prevention of Allograft Rejection in Renal Transplant Recipients

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.     

Lack of Benefit of Early Protocol Biopsies in Renal Transplant Patients Receiving TAC and MMF: A Randomized Study

We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct)> 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score >or= 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 +/- 21.7 in the Biopsy and 68.90 mL/min +/- 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.     

Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p<0.001) and death-censored graft survival (p<0.001) as compared to TAC/MMF (N=27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI=1.32, 1.63) and for CsA/SRL 1.38 (95% CI=1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5-12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.     

Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin

Hiwarkar P, Shaw BE, Tredger JM, Brown NW, Kulkarni S, Saso R, Evans S, Treleaven J, Davies FE, Ethell ME, Morgan GJ, Potter MN. Mycophenolic acid trough level monitoring: relevance in acute and chronic graft versus host disease and its relation with albumin.
Clin Transplant 2011: 25: 222–227. © 2010 John Wiley & Sons A/S. Abstract: Mycophenolate mofetil (MMF) is used to treat acute and chronic graft versus host disease (GvHD). There is scant evidence in the literature about mycophenolic acid (MPA) trough level monitoring in GvHD. We therefore reviewed 32 patients treated with MMF for acute (n = 19) or chronic GvHD (n = 13). Twelve (63%) of 19 patients with acute GvHD and nine (69%) of 13 with chronic GvHD showed a good response. In all 21 patients who responded to MMF, their mean total MPA levels were therapeutic (1–3.5 mg/L), whereas five of 11 patients who did not respond had sub‐therapeutic mean MPA levels (p = 0.002). Sixteen (66%) of 24 steroid refractory or dependent patients responded to MMF. Associations between the mean total MPA level for each patient and the corresponding mean serum albumin concentration showed therapeutic mean total MPA levels for all 23 patients with mean albumin ≥31 g/L but sub‐therapeutic mean total MPA levels in five of nine patients with mean albumin <31 g/L (p = 0.0006). In conclusion, MMF is efficacious in steroid refractory and dependent acute or chronic GvHD with statistically significant correlation between therapeutic plasma total MPA trough levels and clinical response. Serum albumin levels should be taken into account when considering MMF dose adjustments.     

Enteric-Coated Mycophenolate Sodium is Therapeutically Equivalent to Mycophenolate Mofetil in de novo Renal Transplant Patients

The introduction of mycophenolate mofetil (MMF) represented a major advance in transplant medicine, although optimal use may be limited by gastrointestinal (GI) side-effects. An enteric-coated formulation of mycophenolate sodium (EC-MPS; myfortic) has been developed with the aim of improving the upper GI tolerability of mycophenolic acid. Therapeutic equivalence of EC-MPS (720 mg b.i.d.) and MMF (1000 mg MMF b.i.d.), with concomitant cyclosporine microemulsion (Neoral) and corticosteroids, was assessed in 423 de novo kidney transplant patients recruited to a 12-month, double-blind study. Efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow up) at 6 months (EC-MPS 25.8% vs. MMF 26.2%; 95% CI: [-8.7, +8.0]) demonstrated therapeutic equivalence. At 12 months, the incidence of BPAR, graft loss or death was 26.3% and 28.1%, and of BPAR alone was 22.5% and 24.3% for EC-MPS and MMF, respectively. Among those with BPAR, the incidence of severe acute rejection was 2.1% with EC-MPS and 9.8% with MMF (p=ns). The safety profile and incidence of GI adverse events were similar for both groups. Within 12 months, 15.0% of EC-MPS patients and 19.5% of MMF patients required dose changes for GI adverse events (p=ns). Enteric-coated-MPS 720 mg b.i.d. is therapeutically equivalent to MMF 1000 mg b.i.d. with a comparable safety profile.     

Enteric-Coated Mycophenolate Sodium can be Safely Administered in Maintenance Renal Transplant Patients: Results of a 1-Year Study

With the objective of enhancing upper gastrointestinal (GI) tolerability, enteric-coated mycophenolate sodium (EC-MPS, myfortic, Novartis Pharma AG, Basel, Switzerland) has been developed. This double-blinded, 12-month study investigated whether renal transplant patients taking mycophenolate mofetil (MMF) can be safely converted to EC-MPS. Stable kidney transplant patients were randomized to receive EC-MPS (720 mg b.i.d.; n=159) or continue receiving MMF (1000 mg b.i.d.; n=163). The incidence of GI adverse events (AEs) was similar at 3 months (primary endpoint: EC-MPS 26.4%; MMF 20.9%; p=NS) and at 12 months (EC-MPS 29.6%; MMF 24.5%; p=NS). The increase from baseline in mean GI AE severity score, adjusted for duration, tended to be lower in EC-MPS patients (3 months: 0.15 vs. 0.20; 12 months: 0.23 vs. 0.47; p=NS). Neutropenia (<1500 cells/mm3) within the first 3 months (coprimary endpoint) was low in both groups (EC-MPS 0.6%; MMF 3.1%; p=NS). Although the overall incidence of infections was similar, the number of serious infections was significantly lower in EC-MPS patients (8.8% vs. 16.0%; p<0.05). Similar rates of efficacy failure (EC-MPS 2.5%; MMF 6.1%; p=NS), biopsy-proven acute rejection (EC-MPS 1.3%; MMF 3.1%; p=NS) and biopsy-proven chronic rejection (EC-MPS 3.8%; MMF 4.9%; p=NS) were observed in both groups. In conclusion, renal maintenance patients can be converted from MMF to EC-MPS without compromising the safety and efficacy profile associated with MMF.     

Differential Effects of Donor Age in Liver Transplant Recipients Infected With Hepatitis B, Hepatitis C and Without Viral Hepatitis

The variable impact of specific risk factors on survival outcomes based on pre-transplantation diagnosis was analyzed in adult liver transplant recipients reported to the Scientific Registry of Transplant Recipients: 778 with hepatitis B (HBV), 3463 with hepatitis C (HCV) and 7429 without viral hepatitis. Graft and patient survival for the HBV and no viral hepatitis groups did not differ significantly. The HCV group had significantly lower graft (p = 0.0019) and patient survival (p < 0.0001) than the no viral hepatitis group. Patient survival was significantly lower (p = 0.0011) for HCV compared to HBV patients; differences in graft survival approached significance (p = 0.0561). Donor age, which was not a risk factor in patients with HBV, was the strongest predictor of graft loss and death in patients with HCV, starting with donors >40 years. Donor age >60 years was the strongest predictor of graft loss and death in patients without viral hepatitis. The risks of graft loss and death were reduced for patients on tacrolimus-based immunosuppression with mycophenolate mofetil, regardless of disease etiology. There are clear differences in risk factors for poor outcomes based on underlying liver disease, particularly with regard to the impact of donor age.     

The Influence of Calcineurin Inhibitors on Pulse Wave Velocity in Renal Transplant Recipients

Background. Pulse wave velocity (PWV) is a marker of the arterial wall stiffness and independent cardiovascular risk factor in hemodialysis patients. Cyclosporine A (CyA) and tacrolimus (TAC) are known to differ in the influence on cardiovascular risk factors in renal transplant recipients. Recent studies suggest that CyA may decrease arterial compliance. The aim of the study was to assess the influence of CyA and TAC on the PWV and arterial wall stiffness in renal transplant recipients. Methods. The study population consisted of two groups of cadaveric renal transplant recipients, 76 patients each, matched for age, sex, blood pressure, body mass index, and length of the post-transplant follow-up. PWV between carotid and femoral artery was measured using a Complior device. Fasting blood was sampled for serum creatinine, lipid profile, uric acid, glucose, and C-reactive protein. Results. Aortic pulse wave velocity—a marker of increased arterial stiffness—was significantly higher in CyA group compared with TAC group (9.33 ± 2.10 vs. 8.54 ± 1.35, respectively; p < 0.01). Uric acid, total cholesterol, triglycerides, and LDL-cholesterol concentrations were significantly higher in CyA group. Significant correlations were found between PWV and age, systolic and diastolic blood pressure, and fasting glucose in the CyA group, but only between PWV and age in TAC group. Conclusion. CyA-based immunosuppressive therapy is associated with an unfavorable profile of cardiovascular risk factors and increased arterial stiffness in renal transplant recipients.     

Mycophenolic Acid 12-h Trough Level Monitoring in Renal Transplantation: Association with Acute Rejection and Toxicity

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection. In this study, 5600 12-h trough MPA samples from 121 renal transplant recipients immunosuppressed with mycophenolate mofetil (MMF) and tacrolimus in a steroid sparing protocol (steroids for 7 days only) were sequentially analyzed. Higher MPA levels were associated with lower hemoglobin concentrations and anemia (hemoglobin <10 g/dL). Similarly, higher MPA levels were associated with lower total white cell counts and an increased incidence of leucopenia (total white cell count <4.0 x 10(9)/L). Hypoalbuminemia and renal impairment were also associated with hemotoxicity. MMF-associated diarrhea and viral infection were associated with higher MPA levels. Conversely, biopsy-proven acute rejection within the first month post-transplantation was associated with lower MPA levels. Anti-CD25 antibody induction was also associated with reduced rejection rates. No association was seen between MPA levels and platelet count, thrombocytopenia or bacterial infection. An MPA level of 1.60 mg/L early post-transplantation best discriminated patients with and without rejection, and an MPA level of 2.75 mg/L best discriminated patients with and without toxicity later post-transplantation.     

Mycophenolic acid (MPA) and its glucuronide metabolites interact with transport systems responsible for excretion of organic anions in the basolateral membrane of the human kidney.

BACKGROUND: Mycophenolic acid (MPA), the active moiety of the prodrug mycophenolate mofetil, is widely used in immunosuppressive regimens after kidney, liver or heart transplantation. MPA is metabolized predominantly to the inactive 7-O-glucuronide (MPAG). A minor fraction is converted to the pharmacologically active acyl glucuronide (AcMPAG). All compounds ultimately are eliminated via the kidneys. Due to their structures, MPA and its metabolites are candidate substrates for the human organic anion transporters 1 (OAT1) and 3 (OAT3) as well as for the Na+-dicarboxylate cotransporter 3 (NaDC3). METHODS: Human (h)OAT1, hOAT3 and hNaDC3 were expressed from in vitro synthesized cRNA in collagenase-defolliculated Xenopus laevis oocytes. On day 3 post-injection, measurements were made of (i) substrate-associated currents using MPA and MPAG (only in hNaDC3-expressing oocytes) and (ii) uptake of [3H]p-aminohippurate (hOAT1) or [3H]estrone sulfate (hOAT3) in the absence or presence of either MPA, MPAG or AcMPAG. RESULTS: In hNaDC3-expressing oocytes at -60 mV, MPA (0.1 mM) as well as MPAG (0.1 mM) induced inward currents that were 17 and 25% of the currents evoked by succinate (1 mM). Vice versa, currents induced by succinate (1 mM) were partially inhibited by MPA and MPAG. hOAT1 and hOAT3 were potently inhibited by MPA (IC50 1.24 and 0.52 microM, respectively). Human OAT3, but not hOAT1, was additionally inhibited by both glucuronide metabolites of MPA in a concentration-dependent manner (IC50 15.2 microM for MPAG and 2.88 microM for AcMPAG), consistent with a preference of hOAT3 for more bulky substrates compared with hOAT1. CONCLUSIONS: MPA and its metabolites potently interact with renal organic anion transporters hOAT1 and hOAT3, and thereby may interfere with the renal secretion of antiviral drugs, cortisol and other organic anions.     

Impact of Early or Delayed Cyclosporine on Delayed Graft Function in Renal Transplant Recipients: A Randomized, Multicenter Study

The benefit of delayed cyclosporine in reducing risk of delayed graft function (DGF) is not clearly established. This study compared early vs. delayed cyclosporine microemulsion (CsA-ME) in de novo renal transplant patients. Patients were randomized to early (day 0, n = 97) or delayed (day 6, n = 100) CsA-ME at an initial dose of 8 mg/kg/day with dose adjusted according to C₂ level. All patients received enteric-coated mycophenolate sodium (EC-MPS), steroids and an anti-interleukin-2 receptor antibody. In both groups, 33% of patients were at high risk of DGF; 26 patients (26.8%) in the early CsA-ME group and 23 patients (23.0%) in the delayed CsA-ME group experienced DGF (n.s.). Renal function at 3 months was comparable (creatinine clearance 51.1mL/min with early CsA-ME and 53.8 mL/min with delayed CsA-ME), and remained similar to 12 months. Treatment failure, defined as biopsy-proven acute rejection, graft loss or death, did not differ significantly at 12 months (23.7% with early CsA-ME vs. 29.0% with delayed CsA-ME). Biopsy-proven acute rejection occurred in 15.5% of early CsA-ME and 26.5% of delayed CsA-ME patients (n.s.). Both regimens were well tolerated. These data suggest that early or delayed introduction of CsA-ME results in similar renal function in renal transplant patients regardless of DGF risk level.     

Pre-Transplant IFN-γ ELISPOTs Are Associated with Post-Transplant Renal Function in African American Renal Transplant Recipients

Final crossmatch testing is routinely used to assess the risk of antibody-mediated graft injury/rejection post-transplant. Analogously, we postulated that quantitative measurements of anti-donor effector/memory T cells pre-transplant would independently assess post-transplant risk. To address this hypothesis, we determined the frequencies of pre-transplant, donor-specific interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spots (ELISPOTs) and correlated the results with post-transplant outcomes in 37 African American recipients of deceased donor kidney transplants treated with tacrolimus- and sirolimus-based immunosuppression. A positive ELISPOT test (>25 spots/300,000 cells) was detected in 14 (38%) of 37 patients. The incidence of biopsy-proven acute rejection was 50% (7/14) in ELISPOT-positive versus 17% (4/23) in ELISPOT-negative patients (p=0.036). Calculated glomerular filtration rate (MDRD) at 12 months was 37+/-16 mL/min in ELISPOT-positive versus 55+/-20 mL/min in ELISPOT-negative patients (p=0.01). ELISPOT status remained a correlate of allograft function at 12 months by linear regression analysis (p=0.001), independent of rejection and other contributing variables. Pre-transplant donor-directed IFN-gamma ELISPOT assessment of anti-donor cellular immunity may function as a 'cellular crossmatch' and independently correlates with renal allograft function in African Americans receiving tacrolimus- and sirolimus-based immunosuppression.