Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus.

A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3-8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients. TRIAL REGISTRATION: NCT01025817.

Efficacy and Safety of Everolimus Plus Low-Dose Tacrolimus Versus Mycophenolate Mofetil Plus Standard-Dose Tacrolimus in De Novo Renal Transplant Recipients: 12-Month Data.

In this 12-month, multicenter, randomized, open-label, noninferiority study, de novo renal transplant recipients (RTxRs) were randomized (1:1) to receive everolimus plus low-dose tacrolimus (EVR+LTac) or mycophenolate mofetil plus standard-dose Tac (MMF+STac) with induction therapy (basiliximab or rabbit anti-thymocyte globulin). Noninferiority of composite efficacy failure rate (treated biopsy-proven acute rejection [tBPAR]/graft loss/death/loss to follow-up) in EVR+LTac versus MMF+STac was missed by 1.4%, considering the noninferiority margin of 10% (24.6% vs. 20.4%; 4.2% [-3.0, 11.4]). Incidence of tBPAR (19.1% vs. 11.2%; p < 0.05) was significantly higher, while graft loss (1.3% vs. 3.9%; p < 0.05) and composite of graft loss/death/lost to follow-up (6.1% vs. 10.5%, p = 0.05) were significantly lower in EVR+LTac versus MMF+STac groups, respectively. Mean estimated glomerular filtration rate was similar between EVR+LTac and MMF+STac groups (63.1 [22.0] vs. 63.1 [19.5] mL/min/1.73 m2 ) and safety was comparable. In conclusion, EVR+LTac missed noninferiority versus MMF+STac based on the 10% noninferiority margin. Further studies evaluating optimal immunosuppression for improved efficacy will guide appropriate dosing and target levels of EVR and LTac in RTxRs.

Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT): the phase III randomized MELT trial.

Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.

Chain transplantation: initial experience of a large multicenter program.

We report the results of a large series of chain transplantations that were facilitated by a multicenter US database in which 57 centers pooled incompatible donor/recipient pairs. Chains, initiated by nondirected donors, were identified using a computer algorithm incorporating virtual cross-matches and potential to extend chains. The first 54 chains facilitated 272 kidney transplants (mean chain length = 5.0). Seven chains ended because potential donors became unavailable to donate after their recipient received a kidney; however, every recipient whose intended donor donated was transplanted. The remaining 47 chains were eventually closed by having the last donor donate to the waiting list. Of the 272 chain recipients 46% were ethnic minorities and 63% of grafts were shipped from other centers. The number of blood type O-patients receiving a transplant (n = 90) was greater than the number of blood type O-non-directed donors (n = 32) initiating chains. We have 1-year follow up on the first 100 transplants. The mean 1-year creatinine of the first 100 transplants from this series was 1.3 mg/dL. Chain transplantation enables many recipients with immunologically incompatible donors to be transplanted with high quality grafts.

Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.

Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m(2) , p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation.

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6-month, multicenter, randomized, open-label study of three ascending concentration-controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low-risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic-pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low-dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high-dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r(2) = 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6-month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low- and medium-exposure groups, and potentially associated with a reduced incidence of NODAT.

Fixed- or controlled-dose mycophenolate mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept trial.

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMF(CC)) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF(CC) and reduced-level calcineurin inhibitor (MMF(CC)/CNI(RL)); (B) MMF(CC) and standard-level CNI (MMF(CC)/CNI(SL)); or (C) fixed-dose MMF and CNI(SL) (MMF(FD)/CNI(SL)). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (alpha= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p < or = 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMF(CC) with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF(FD), indicating potential utility of MMF(CC) in CNI-sparing regimens.

Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients.

This randomized, pilot study compared the Janus kinase inhibitor CP-690,550 (15 mg BID [CP15] and 30 mg BID [CP30], n = 20 each) with tacrolimus (n = 21) in de novo kidney allograft recipients. Patients received an IL-2 receptor antagonist, concomitant mycophenolate mofetil (MMF) and corticosteroids. CP-690,550 doses were reduced after 6 months. Due to a high incidence of BK virus nephropathy (BKN) in CP30, MMF was discontinued in this group. The 6-month biopsy-proven acute rejection rates were 1 of 20, 4 of 20 and 1 of 21 for CP15, CP30 and tacrolimus groups, respectively. BKN developed in 4 of 20 patients in CP30 group. The 6-month rates of cytomegalovirus disease were 2 of 20, 4 of 20 and none of 21 for CP15, CP30 and tacrolimus groups, respectively. Estimated glomerular filtration rate was >70 mL/min at 6 and 12 months (all groups). NK cells were reduced by

Establishing pharmacokinetic bioequivalence of valganciclovir oral solution versus the tablet formulation.

Dosing with valganciclovir tablets may not be appropriate in some patients, such as those on hemodialysis or children. A "tutti-frutti" flavored oral valganciclovir solution has been developed to provide flexibility in dosage needed to accommodate these patients. An adult, multicenter, open-label randomized trial was conducted to establish bioequivalence between valganciclovir oral solution and valganciclovir tablets. Pharmacokinetic profiles and safety of the oral solution versus the tablet formulation were determined in 23 renal transplant recipients with estimated creatinine clearance>or=60 mL/min who had been receiving cytomegalovirus prophylaxis with valganciclovir for >or=4 days prior to the administration of the study drug. Patients received two doses of 900 mg valganciclovir either by tablet or oral solution in random order once daily over 6 days. Plasma concentrations of ganciclovir were assessed on days 2, 4, and 6 predose and at 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12 hours after the dose. Maximum mean plasma concentrations (Cmax) were 6.73 microg/mL and 6.39 microg/mL for the valganciclovir tablet and oral solution, respectively, with identical mean AUC0-24 of 51.2 microg.h/mL. For both the AUC0-24 and Cmax ratio, the 90% Cl of the mean ratios of the oral solution relative to the tablet formulation lies within the acceptance region (80% to 125%) required by the US Food and Drug Administration and European Agency for the Evaluation of Medicinal Products. With the demonstration of bioequivalence and no differences in the incidence of adverse effects, it will be possible to interchangeably use the oral formulation.

Characteristics and Evaluation of Geographically Distant vs Geographically Nearby Living Kidney Donors.

BACKGROUND: Living donor kidney transplant (LDKT) can be impeded by multiple barriers. One possible barrier to LDKT is a large physical distance between the living donor's home residence and the procuring transplant center. METHODS: We performed a retrospective, single-center study of living kidney donors in the United States who were geographically distant (residing ≥150 miles) from our transplant center. Each distant donor was matched to 4 geographically nearby donors (<150 miles from our center) as controls. RESULTS: From 2007 to 2010, of 429 live kidney donors, 55 (12.8%) were geographically distant. Black donors composed a higher proportion of geographically distant vs nearby donors (34.6% vs 15.5%), whereas Hispanic and Asian donors composed a lower proportion (P = .001). Distant vs nearby donors had similar median times from donor referral to actual donation (165 vs 161 days, P = .81). The geographically distant donors lived a median of 703 miles (25% to 75% range, 244 to 1072) from our center and 21.2 miles (25% to 75% range, 9.8 to 49.7) from the nearest kidney transplant center. The proportion of geographically distant donors who had their physician evaluation (21.6%), psychosocial evaluation (21.6%), or computed tomography angiogram (29.4%) performed close to home, rather than at our center, was low. CONCLUSIONS: Many geographically distant donors live close to transplant centers other than the procuring transplant center, but few of these donors perform parts of their donor evaluation at these closer centers. Black donors comprise a large proportion of geographically distant donors. The evaluation of geographically distant donors, especially among minorities, warrants further study.

Withdrawal of mycophenolate mofetil in stable renal transplant recipients.

BACKGROUND: Mycophenolate mofetil (MMF) has been demonstrated to decrease episodes of acute rejection in renal transplant recipients during the first year after transplantation. The utility of MMF after 1 year is less clear. METHODS: Forty-five stable renal transplant recipients on maintenance therapy of cyclosporine microemulsion, MMF, and prednisone had MMF withdrawn at approximately 1 year after transplantation. A matching concurrent group of 45 stable renal transplant recipients served as the case control group. RESULTS: Two of 45 patients in the MMF withdrawal group suffered an acute rejection episode as opposed to 1 of 45 in the control group. Both patients who rejected in the withdrawal group had adequate cyclosporine levels and had no recent decrease in prednisone dose. There was no evidence of an increased incidence of proteinuria or increased creatinine levels in the MMF withdrawal group. CONCLUSION: In general, withdrawal of MMF in stable renal transplant recipients is well tolerated. No increased risk of rejection could be demonstrated in this patient group. A larger study will be needed to confirm our result.

Infectious complications in geriatric renal transplant patients: comparison of two immunosuppressive protocols.

BACKGROUND: It has been well documented that a regimen of mycophenolate mofetil (MMF), cyclosporine (CsA), and prednisone (Pred) reduces the incidence of acute rejection in renal transplant recipients, as compared with previous regimens based on azathioprine (AZA), CsA, and Pred. In the general renal transplant patient population, immunosuppressive regimens that include MMF are usually well tolerated. It is not clear whether this holds true for older transplant recipients, who may be more susceptible to complications from the greater immunosuppression conferred by MMF. METHODS: We retrospectively analyzed our geriatric renal transplant population (age >60 years, 1990-1998) and compared a cohort of 46 patients treated with AZA, Pred, and CsA to a cohort of 45 patients treated with MMF, Pred, and CsA. RESULTS: There were no significant differences between the groups with regard to pretransplantation demographics. Patient and graft survival during the first year was not significantly different between the groups. During the first year of follow-up, we observed 27 infections requiring hospitalization in 15 patients in the MMF-treated group as compared with 10 infections in 7 patients in the AZA-treated group. A Cox proportional hazard model accounting for the above mentioned covariates isolated MMF versus AZA as a significant risk factor for the occurrence of serious infectious events (all: P<0.01; cytomegalovirus, fungal: P<0.01). CONCLUSION: We conclude that an immunosuppressive regimen of MMF, CsA, and Pred seems to be correlated with an increased incidence of infectious adverse events as compared with AZA, CsA, and Pred in elderly patients.

Unmasking of primary hyperaldosteronism by renal transplantation.

BACKGROUND: Primary hyperaldosteronism is an uncommon cause of hypertension in the general population. Given the mechanism of action of aldosterone clinical manifestations may not occur in the setting of end stage renal disease. However, if a successful renal transplant is performed clinical manifestations may occur. METHODS: We present a case of a patient with a preexisting adrenal adenoma who only presented with clinical signs of hyperaldosteronism after renal transplantation. Patients' work-up included plasma aldosterone, plasma renin activity, serum cortisol, and estimation of trans tubular potassium gradient. RESULTS: The patient's serum aldosterone was markedly elevated with a relatively suppressed plasma renin activity. Trans tubular potassium gradient was high in the presence of hypokalemia. CONCLUSION: Previously silent hyperaldosteronism may be unmasked by a successful renal transplant.

Potential interaction of troglitazone and cyclosporine.

BACKGROUND: Troglitazone (Rezulin) is a promising new oral hypoglycemic agent recently approved by the Federal Drug Administration for use in type II diabetes mellitus. Although troglitazone is not metabolized by the cytochrome p450 3A isozyme family, it is a potential inducer of this system. Other medications, e.g., rifampin and phenobarbital, which also induce p450 3A activity, have been reported to significantly decrease cyclosporine (CsA) concentrations. METHODS: We report a case of a stable renal transplant patient who had a decrease in CsA concentration after beginning troglitazone and who subsequently developed an acute rejection episode. We then reviewed all stable renal patients begun on troglitazone over the previous 6 months. RESULTS: The seven transplant patients who had been started on troglitazone therapy experienced a statistically and clinically significant decrease in CsA 12-hr trough levels immediately after the institution of troglitazone therapy. CONCLUSION: A potential interaction exists between troglitazone and CsA. Transplant patients on CsA who receive troglitazone therapy should be monitored closely.

Evaluation of voiding cystourethrography prior to renal transplantation.

In many centers, voiding cystourethrography is a routine part of pretransplantation assessment of the lower urinary tract. To assess the value of this investigation, a retrospective review of transplant candidates evaluated in our center over 2 years was undertaken. A total of 517 patients were fully evaluable. Only 13 voiding cystourethrograms (VCUGs) (2.5%) of 517 were found to be abnormal. Three patients with reflux alone did not require intervention before transplantation. Four patients with decreased bladder capacity underwent hydrodistention. Two patients increased their capacity to over 150 ml and two patients failed distention, one requiring an ileal conduit and the other requiring an augmentation cystoplasty. Three patients had increased postvoid residual (PVR). Two patients started clean intermittent catheterization. One required prostate resection for benign prostatic hypertrophy. One patient with reflux and decreased bladder capacity refused treatment. One patient with reflux combined with increased PVR started clean intermittent catheterization and was cleared for transplant surgery. One patient with decreased bladder capacity and increased PVR had a stroke and was excluded from transplantation. All 13 patients with abnormal VCUGs had a prior urologic history. In total, only 56 of 517 patients evaluated had a prior urological history. Each VCUG costs approximately $500. Limiting VCUG studies to those patients with a prior urological history would have resulted in a significant cost savings. Hence, we recommend that only patients with a prior urological history should undergo this costly and often distressing examination.

Allograft loss in renal transplant recipients with Fabry's disease and activated protein C resistance.

INTRODUCTION: Fabry's disease is associated with an increased incidence of thrombotic events and rejection. Spontaneous thrombosis of a functioning cadaveric renal allograft in a recipient with Fabry's disease prompted prospective evaluation of all transplant candidates with Fabry's disease for hypercoagulability. MATERIALS AND METHODS: Transplant candidates with Fabry's disease were tested for hypercoagulability, analyzed for HLA-type and ABO group, and comorbid conditions suggestive of hypercoagulability. RESULTS: A unique association of Fabry's disease with activated protein C Resistance was documented in a cohort of Caucasian male renal transplant recipients with Fabry's disease. Four of five patients were blood group A and had no significant comorbid conditions suggestive of hypercoagulability. The resistance to activation of protein C (APCR)(+) patients shared HLA loci-B8 and Dr3, although the APCR(-) patients shared HLA loci-B27 and -B38. CONCLUSIONS: Due to the observed increase in the incidence of APCR in our Fabry's cohort, we suggest screening all patients with Fabry's disease for APCR. Because factor V and factor Va receptors are found on vascular endothelium and peripheral blood monocytes, APCR in the presence of Fabry's disease may be a nonimmunological stimulus for rejection. Analysis of HLA typing in patients with Fabry's disease may further elucidate HLA-based association of Fabry's disease and resistance to activated protein C with the risk of thrombosis and rejection.

Hypercoagulable states in renal transplant candidates: impact of anticoagulation upon incidence of renal allograft thrombosis.

INTRODUCTION: Although multiple studies of demographic variables have been associated with allograft thrombosis, these results are not routinely reproducible. Are ESRD patients with hypercoagulable states (HCS) (antithrombin III deficiency, protein S or C deficiency, activated protein C resistance, and anticardiolipin antibodies) at predictably greater risk for allograft thrombosis? METHODS: Between 1996 and 1999, all renal transplant candidates were screened for hypercoagulability risk factors [HRF] (multiple arteriovenous access thromboses, prior deep vein thrombosis, prior allograft thrombosis, collagen vascular disease, multiple miscarriages, diabetes, autoimmune disease, and Fabry's disease). HRF(+) candidates were then tested for HCS status. We administered preemptive posttransplant i.v. Heparin in HCS(+) patients and observed the impact of this intervention upon the incidence of allograft thrombosis. We compared demographic data and incidence of allograft thrombosis in an historic control (346 patients transplanted between June 31, 1992, and March 5, 1996) not tested for HCS and a study cohort (502 patients transplanted between March 6, 1996, and June 31, 1999) prospectively screened for HRF. HRF(+) patients who were HCS(+) in the study cohort received i.v. heparin immediately after transplant and p.o. warfarin as outpatients. RESULTS: Demographic characteristics previously implicated in allograft thrombosis were equivalently distributed in both cohorts with the exceptions that more living-donor transplants (33.1% vs. 15.3%) were performed in study cohort, CIT>24 hr occurred in more control patients (37.3% vs. 22.1%) and more study patients (16.7% vs. 0%) received tacrolimus. Hypercoagulable states were found upon reevaluating five of seven controls (71.4%), who lost prior allografts to thrombosis. Hypercoagulable states were prospectively detected in 10 study patients with hypercoagulability risk factors. Most (9 of 10) study patients receiving anticoagulation have achieved long-term allograft function. Study group allograft thrombosis incidence was reduced (1.59% vs. 4.05%). Hypercoagulable states were demonstrated in most episodes of allograft thrombosis. Control patients who lost prior allografts to thrombosis were anticoagulated after retransplantation and 100% achieved long-term allograft function. CONCLUSIONS: Long-term allograft function has been achieved in 90% of study patients when prophylactically anticoagulating study patients with hypercoagulable states. A 2.6-fold reduction in the expected incidence of allograft thrombosis was observed in anticoagulated patients with hypercoagulable states.

Prevalence of cytomegalovirus in the gastrointestinal tract of renal transplant recipients with persistent abdominal pain.

Abdominal pain occurs frequently in renal transplant recipients receiving mycophenolate mofetil (MMF) therapy. The cause of this abdominal pain has not been fully elucidated, but may involve local irritation, as well as inhibition of rapidly dividing cells of the gastrointestinal (GI) tract. This milieu of inflammation and added immunosuppression is conducive to activation of cytomegalovirus (CMV). We therefore sought to find the prevalence of active CMV in patients presenting with abdominal pain on maintenance MMF therapy. All patients receiving a renal transplant at our center from March 1, 1997, to September 1, 1997, were studied. Any patient presenting with midepigastric pain for greater than 3 days underwent esophagogastroduodenoscopy (EGD) with biopsy. CMV was diagnosed by the presence of inclusion bodies and immunohistochemical studies. Ten patients presented with persistent midepigastric pain; nine of these patients had evidence of GI CMV. Patients who were CMV negative and received an allograft from CMV-positive donors and those with leukopenia were at significantly increased risk for the development of abdominal pain. In our study population, the majority of patients on maintenance MMF therapy who presented with persistent midepigastric pain had evidence of active CMV infection in the upper gastrointestinal tract.

The effect of renal insufficiency on mycophenolic acid protein binding.

Mycophenolate mofetil (MMF) is commonly used in solid organ transplant recipients. MMF is converted to mycophenolic acid (MPA) upon reaching the systemic circulation. Many acidic drugs have altered protein binding in renal failure, and it is possible that MPA protein binding may be decreased. The authors studied 23 renal transplant recipients: 8 transplant patients (7 kidney, 1 kidney/pancreas) with chronic renal insufficiency (CRI) and 15 renal transplant patients with preserved renal function. Plasma was obtained for kinetic profiles of total MPA, free MPA, and its glucuronide metabolite (MPAG). Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding. Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function (5.8 +/- 2.7 vs. 2.5 +/- 0.4, p < 0.01). Free MPAAUC was almost doubled in the patients with chronic renal insufficiency versus controls (2.04 +/- .08 vs. 1.03 +/- 0.6, p < 0.01). MPA protein binding is decreased, and free MPA concentrations are increased in patients with chronic renal failure.

Stress dose steroids in renal transplant patients undergoing lymphocele surgery.

The requirement for perioperative stress dose steroids (SDS) in patients on long-term steroid therapy is controversial, but SDS are given during perioperative care. Studies focusing on surrogate outcomes like cortisol levels indicate a possible requirement for SDS, but clinical results are sparse. We retrospectively compared outcomes of renal or pancreas/kidney transplant patients undergoing surgical lymphocele drainage who did (n=20) or did not (n=38) receive SDS. Patients had similar demographic characteristics (P=NS). No patient developed hypotension (SBP < 80 mmHg), mental status change, unexplained arthralgias, or ileus. Impaired wound healing occurred in one patient in each group (P=NS), and lymphocele recurrence occurred in 25% of the SDS group and 10.5% of the other group (P=.25). SBP decreased from baseline in both groups (P <.001) but did not differ between groups, and maximum blood glucose was higher in the SDS group (P=.04). No difference was observed in other measured parameters. These data indicate that SDS increased the risk of hyperglycemia and provided no apparent benefit. A prospective study is warranted to confirm these findings.