Effect of Treatment With Tabalumab, a B Cell-Activating Factor Inhibitor, on Highly Sensitized Patients With End-Stage Renal Disease Awaiting Transplantation.

B cell-activation factor (BAFF) is critical for B cell maturation. Inhibition of BAFF represents an appealing target for desensitization of sensitized end-stage renal disease (ESRD) patients. We conducted a Phase 2a, single-arm, open-label exploratory study investigating the effect of tabalumab (BAFF inhibitor) in patients with ESRD and calculated panel reactive antibodies (cPRAs) >50%. The treatment period duration was 24 weeks. Eighteen patients received tabalumab, at doses of 240-mg subcutaneous (SC) at Week 0 followed by 120-mg SC monthly for 5 additional months. Patients were followed for an additional 52 weeks. Immunopharmacologic effects were characterized through analysis of blood for HLA antibodies, BAFF concentrations, immunoglobulins, T and B cell subsets, as well as pre- and posttreatment tonsil and bone marrow biopsies. Significant reductions in cPRAs were observed at Weeks 16 (p = 0.043) and 36 (p = 0.004); however, absolute reductions were small (<5%). Expected pharmacologic changes in B cell subsets and immunoglobulin reductions were observed. Two tabalumab-related serious adverse events occurred (pneumonia, worsening of peripheral neuropathy), while the most common other adverse events were injection-site pain and hypotension. Three patients received matched deceased donor transplants during follow-up. Treatment with a BAFF inhibitor resulted in statistically significant, but not clinically meaningful reduction in the cPRA from baseline (NCT01200290, Clinicaltrials.gov).

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log(10) copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36-0.99) and month 12 (OR 0.33; 95% CI 0.16-0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

Analysis and clinical correlation of genetic variation in cytomegalovirus.

BACKGROUND: Cytomegalovirus (CMV) displays genetic polymorphisms in multiple genes, which may result in important virulence differences. Glycoprotein N (gN) and immediate early 1 (IE1) are key viral genes and immune targets. We aimed to characterize the molecular epidemiology of gN and IE1 genotypes in organ transplant patients with CMV disease in the context of clinical and virologic endpoints. METHODS: A total of 240 patients with CMV disease had genotyping analysis by nested polymerase chain reaction assays and sequencing using blood samples obtained at disease onset. Results were correlated with viral clearance kinetics and recurrence. RESULTS: Complex patterns of gN and IE1 genotypes were present with no clear genetic linkages. No single genotype of IE1 or gN was associated with poorer outcome. For example, different gN or IE1 genotypes had comparable baseline viral load, clearance half-lives, time to clearance, and rates of virologic recurrence. Mixed infection was present at IE1 in 15.8% and gN in 21.9%, but analysis of a single gene was insufficient to detect all mixed infections. Infections caused by multiple strains, as opposed to single strains, were associated with higher baseline viral loads (P = 0.011), delayed viral clearance (P = 0.033), and higher rates of virologic recurrence (P = 0.008). CONCLUSIONS: Genetic diversity in CMV is complex. Specific gN or IE subtypes do not seem to affect in vivo viral virulence patterns in single-strain infections. Mixed infections demonstrate associations with virologic outcomes that single-strain infections do not.

Effect of class II antigen matching on renal allograft survival in miniature swine.

The benefit of class II major histocompatibility complex (MHC) antigen matching to renal allograft survival, in the absence of immunosuppression, has been studied in partially inbred miniature swine. Permanent (greater than 6 mo) renal allograft survival was found in 30% of recipients of either class II only or fully matched grafts. Analysis of the survival of the class II-only matched grafts by specific recipient/donor haplotype combinations indicated that survival was regulated by at least three genetic factors, including antigen gene dose, a class I MHC allele-dependent effect, and non-MHC-linked immune response phenomenon. Animals accepting class II-matched kidneys developed spontaneous tolerance to the graft, despite mounting an initial immune response marked by renal damage and the development of serum cytotoxic antibodies directed at the donor MHC antigens. The antibodies were only of the IgM class, suggesting that conversion of the humoral response to IgG was blocked. After acceptance of the kidney, three out of five animals showed specific prolongation of donor skin grafts. At the time of rejection of these skin grafts, no decrease in renal function nor reappearance of anti-donor antibodies was observed.

Valganciclovir: recent progress.

In 2001 valganciclovir was approved by the FDA for treatment of HIV associated retinitis and in 2003 for prevention of post transplant CMV. This review provides an update on the status of its use and areas of controversy: How long should prophylaxis be given?; What is the appropriate dose for prophylaxis?; Can it be used in children, and at what dose?; Can it be used to treat CMV disease? The question of optimal dosing will probably not be settled as the sample size for controlled trials would be prohibitive. Other trials clearly show that extended therapy provides added benefit, the drug is safe and an appropriate dose has been identified in children and oral therapy of CMV disease is effective.

Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients.

An effective host immune response, critical for successful control of Cytomegalovirus (CMV) disease in solid organ transplant recipients, is affected by intensity and type of immunosuppressive therapy. We used information prospectively captured in the VICTOR-trial to investigate the impact of immunosuppressive therapy on short- and long-term outcomes of CMV treatment in organ transplant recipients. Dual, as compared to triple, immunosuppressive therapy ([odds ratios] OR of 2.55; 95% CI: 1.51-4.60; p = 0.002), lower blood concentrations of calcineurin inhibitors (OR of 5.53; CI: 1.04-29.35; p = 0.045), and longer time since transplantation (OR of 1.70; CI: 1.01-2.87; p = 0.047) all showed better early (Day 21) CMV DNAemia eradication. We observed no effect of the intensity of the immunosuppressive therapy on overall rates of viral eradication or recurrence. The type of calcineurin inhibitor (tacrolimus/cyclosporine) or use of mycophenolate did not affect treatment efficacy, although both tacrolimus and mycophenolate treated patients showed a lower rate of virological recurrence OR 0.51 (95% CI: 0.26-0.98; p = 0.044) and OR 0.45 (95% CI: 0.22-0.93; p = 0.031), respectively. Lower total intensity of immunosuppressive therapy was associated with more effective early, but not overall, CMV DNAemia eradication by valganciclovir/ganciclovir therapy. Both mycophenolate and tacrolimus (rather than cyclosporine) therapy seem to be associated with reduced risk of recurrence.

Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients.

In an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral (p.o.) valganciclovir when normalized for body surface area (BSA) in pediatric liver (n=20) and renal (n=26) transplant patients Reference doses for IV GCV (200 mg/m(2)) and p.o. valganciclovir (520 mg/m(2)) were based on adult doses, and adjusted for BSA initially, and BSA and renal function (estimated via creatinine clearance [CrCL]) thereafter. Renal transplant patients received GCV on days 1-2, valganciclovir 260 mg/m(2) on day 3, and valganciclovir 520 mg/m(2) on day 4. Liver transplant patients received twice daily GCV from enrollment to day 12, and then valganciclovir twice daily on days 13-14. GCV pharmacokinetics were described using a population pharmacokinetic approach. Type of solid organ transplant (kidney or liver) had no effect on GCV pharmacokinetics. Median GCV exposure following valganciclovir 520 mg/m(2) was similar to that with IV GCV, and to that reported in adults. Patients <5 years of age had AUC values approximately 50% of those compared with older age ranges; dosing based on both BSA and CrCL increased drug exposure in younger patients. A dosing algorithm based on BSA and CrCL should be tested in future studies.

A randomized, double-blind, pharmacokinetic study of oral maribavir with tacrolimus in stable renal transplant recipients.

Maribavir is being developed as a novel agent for the prevention or treatment of cytomegalovirus infections after stem cell and organ transplantation. This was a randomized, double-blind, placebo-controlled study designed to evaluate the potential pharmacokinetic interaction of concomitant administration of maribavir and tacrolimus. Twenty-five adult renal transplant recipients with stable renal function and stable dosing regimens of tacrolimus were randomized (20 maribavir 400 mg p.o. q12 h: 5 placebo). Tacrolimus whole blood concentration profiles were determined before and after 7 days of co-administration with maribavir. When co-administered with maribavir, tacrolimus mean C(max) increased 38%, tacrolimus trough concentrations (12 h post-dose) increased 57% and tacrolimus AUC((0-tau)) increased 51%. Apparent oral clearance of tacrolimus decreased 34% and T(max) was delayed by 0.5 h. There were no serious adverse events and no subject prematurely discontinued treatment. Because of the limited 7-day dosing course, the adverse event profile could not be adequately assessed. However, as seen with other maribavir studies, dysgeusia was common (90% of maribavir subjects and 20% of placebo subjects). In conclusion, co-administration of maribavir 400 mg twice daily increases exposure to tacrolimus. Routine therapeutic drug monitoring of tacrolimus blood concentrations should be included both at initiation and completion of maribavir treatment.

An assessment of herpesvirus co-infections in patients with CMV disease: correlation with clinical and virologic outcomes.

The effect of herpesvirus co-infections (HHV-6, HHV-7) on cytomegalovirus (CMV) disease and its response to therapy is unknown. We prospectively analyzed herpesvirus co-infections in transplant recipients with CMV disease. All patients received 3 weeks of antiviral therapy. Samples were collected at baseline (day 0) and then day 3, 7, 14 and 21 poststart of therapy. Viral load testing for CMV, HHV-6 and HHV-7 was done using quantitative PCR assays in 302 patients of whom 256 had documented symptomatic CMV viremia. In this subset, day 0 HHV-6 co-infection was present in 23/253 (9.1%) and HHV-7 in 17/253 (6.7%). Including those positive at any time point raised the prevalence to 79/256 (30.9%) for HHV-6 and 75/256 (29.3%) for HHV-7. Viral co-infection did not influence the response of CMV disease to antiviral therapy. Baseline CMV viral loads, time to eradication and risk of recurrence were similar in patients with and without HHV-6 or HHV-7 co-infection. Ganciclovir and valganciclovir had no clear effect on HHV-6 and HHV-7 viremia. In conclusion, herpesvirus co-infections are common in patients with CMV disease but with standard antiviral therapy, no clear clinical effects are discernable. Routine monitoring for viral co-infection in patients with CMV disease is not indicated.

Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients.

Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3-11.3], p = 0.012; virological: OR 5.6 [2.5-12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.

Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics.

CP-690 550 inhibits Janus kinase 3 with nanomolar potency. In this dose-escalation study, we assessed the safety, tolerability, effects on lymphocyte subsets, and pharmacokinetics of CP-690 550 when coadministered with mycophenolate mofetil in stable renal allograft recipients for 28 days. Twenty-eight patients were enrolled. Six patients received CP-690 550 5 mg twice daily (BID), 6 patients received 15 mg BID, 10 patients received 30 mg BID, and 6 patients received placebo. The most frequent adverse events were infections and gastrointestinal (abdominal pain, diarrhea, dyspepsia, and vomiting). CP-690 550 15 mg BID and 30 mg BID were associated with a mean decrease in hemoglobin from baseline of 11% and a mean decrease in absolute natural killer cell counts of 50%. CP-690 550 30 mg BID was also associated with a mean increase in absolute CD19(+) B-lymphocytes of 130%. There were no changes in the number of neutrophils, total lymphocytes, platelets, or CD4(+) or CD8(+) T cells; clinical chemistry; vital signs; or electrocardiograms from the pretreatment baseline. Administration of CP-690 550 without a concomitant calcineurin inhibitor resulted in CP-690 550 exposures consistent with previous studies in nontransplant subjects. Additional dose-ranging studies are warranted to evaluate the safety and efficacy of CP-690 550 in renal transplant recipients over longer treatment duration.

Organ acceptance and rejection.

During the past year, transplantation scientists have continued the quest for their version of the Holy Grail, developing and expanding model systems aimed at improving allograft survival. The highlights include further analyses of tolerance induction by intrathymic inoculation of allogeneic tissue, the use of oral tolerance to MHC antigens to improve graft survival, and expansion of the model of bone marrow transplantation to achieve solid organ tolerance in a large animal model and humans. Immunogeneticists have provided data on improved graft survival when MHC matching was performed at the molecular level.

Pharmacokinetics of neoral in stable renal transplant recipients with long-term diabetes mellitus.

Therapeutic drug monitoring (TDM) of Neoral has been studied widely and C2 monitoring has been shown to be superior to C0 monitoring in predicting outcomes. However, data are scarce in diabetic renal transplant recipients who may have gastroparesis. We studied 0 to 8 hour pharmacokinetic profiles (AUC(0-8h)) of Neoral on 3 consecutive days in 18 diabetic adults who had stable renal function for at least 6 months after transplantation and no overt symptoms of diabetic gastroparesis. All patients had diabetes mellitus (DM) for at least 5 years. Intrapatient variability of C2 levels was 28% (range, 6%-68%); it was < or =20% in 9 patients (50%) and >60% in 2 patients. Correlation coefficients between AUC(0-8h) and AUC(0-4h), between C2 and AUC(0-8h), and between C0 and AUC(0-8h) were 0.95, 0.86, and 0.77, respectively. Exposure phase (85% of AUC(0-8h)) was longer than 4 hours in all completed (48/54; 89%) profiles; it was longer than 6 hours in 20 profiles. C4 levels had good correlation with AUC(0-8h) (0.86) and low intrapatient variability (16% +/- 11%; range, 2%-39%). Thirteen of 18 patients (72%) had intrapatient variability of C4 < or = 20%. We conclude that the exposure phase of Neoral is prolonged more than 4 hours in adult renal transplant recipients with long-term diabetes, even in the absence of symptoms of gastroparesis. Because of very high intrapatient variability in this group of patients, C2 levels may not be reliable for TDM of Neoral despite high correlation with AUC(0-8h). C4 level may be a valid alternative for these patients.

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.

Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus.

OBJECTIVE: We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen. METHODS: This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. RESULTS: At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL. CONCLUSIONS: Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.

In vitro monitoring of in vivo development of human anti-thymoglobulin antibodies by ELISA.

Thymoglobulin (rATG), polyclonal immunoglobulin, is prepared from rabbits immunized with human thymocytes. It is effective in prevention and treatment of renal allograft rejection. Human antibodies against antilymphocyte preparations can reduce efficacy by accelerating drug clearance or by inducing serum sickness. We developed an enzyme-linked immunosorbent assay (ELISA) to study posttreatment development of anti-rATG. In an Institutional Review Board-approved trial, we tested 101 allograft recipients for anti-rATG antibodies. Patients received rATG intravenously at 1.25 to 2.0 mg/kg/d for 2 to 14 days. Serum samples were obtained pretreatment and at weeks 1, 2, 4, 6, and months 3 and 6 post-rATG. ELISA plates were coated with rATG (10 microg/mL). Samples were diluted 1:100 and tested in quadruplicate. Positive samples were titrated. Horseradish peroxidase-conjugated (HRPO) affinity-purified goat anti-human immunoglobulin G (H&L) antibody reacted with bound human antibody. A chromagenic substrate for HRPO was added and optical density (OD, 490 nm) was read. An OD of twice the negative control was considered positive. Mean ODs of negative and positive controls were 0.113 +/- 0.030 and 1.042 +/- 0.196, respectively. Ten patients had detectable anti-rATG before rATG administration (1:100). Thirty-five of 101 patients (35%) developed anti-rATG antibody. Patients showed an initial positive anti-rATG antibody from days 8 to 59 after infusion and titers from 1:100 to 1:4000. In spite of rATG's postulated anti-B-cell activity, this study confirms that rATG induces sensitization at a frequency and titer seen with other xenogeneic antilymphocyte antibodies. Formation of such antixenoantibodies can have a negative impact on treatment response and hence warrant monitoring.

Follow-up experience using histidine-tryptophan ketoglutarate solution in clinical pancreas transplantation.

In May 2003, at Indiana University, the standard cold preservation solution University of Wisconsin (UW) solution was replaced by histidine-tryptophan ketogluatarate (HTK) solution. Earlier, we presented our initial experience with HTK in pancreas preservation with an analysis of the first 10 pancreas transplants. Here we report updated results with HTK in pancreas transplantation over the past 18 months. Between May 2003 and March 2005, a total of 87 pancreas transplants were performed with 78 of these organs utilizing HTK. Seventy five patients received 78 organ transplants. Surgical procedures performed were: simultaneous kidney pancreas transplantation (n = 50, 64%), pancreas after kidney transplantation (n = 19, 24%), solitary pancreas transplantation (n = 9, 12%). Donor and recipient data were collected with primary outcomes as primary nonfunction and 30-day graft and patient survivals, and compared to the UW cohort from our original report. Donor and recipient demographics were similar. Mean follow-up time is 12 +/- 6 months. The mean cold ischemia time was 9 +/- 3 hours. There were no cases of primary graft nonfunction. Thirty-day and 1-year patient survivals were 99% and 93%. The 30-day and 1-year graft survivals were 96% and 93%. There were five grafts lost, including three within the first month (two venous and one arterial thrombosis). There was one case of chronic rejection and one noncompliance. All other patients were insulin-independent by discharge. Serum fasting blood glucose and serial amylase remained comparable at all intervals posttransplantation. Within this range of cold ischemia time, HTK appears to provide effective pancreas preservation.

Comparison of histidine-tryptophan ketoglutarate and University of Wisconsin solutions as primary preservation in renal allografts undergoing pulsatile perfusion.

INTRODUCTION: University of Wisconsin (UW) solution is the standard preservation solution for organ transplantation. Histidine-tryptophan ketogluatarate (HTK) solution has been used increasingly for kidney, pancreas, and liver transplantation. This study compared HTK and UW used during kidney procurement with subsequent pulsatile perfusion. METHODS: Between January and October 2003, 91 deceased renal and simultaneous kidney pancreas transplants were performed (UW, n = 41, and HTK, n = 50). There were no differences with regard to donor and recipient demographics or cold ischemia. RESULTS: Delayed graft function occurred in 3 (7%) of UW and 4 (8%) of HTK-preserved kidneys (P = NS). There were no significant differences between patient or graft survival. There was an anticipated difference between total preservative volumes used (HTK: 4.1 +/- 1.0 vs UW: 3.0 +/- 0.5; P < .005). CONCLUSION: UW and HTK appear to have similar efficacy in kidney preservation with pulsatile perfusion. HTK preservation solution can be used safely in conjunction with pulsatile preservation for cold storage of renal allografts.

Simultaneous liver and pancreas transplantation in patients with cystic fibrosis.

BACKGROUND: Improved survival in patients with cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, cirrhosis and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality. Liver transplantation is the treatment of choice for cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CFRD has not been reported. METHODS: Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both had pancreatic insufficiency, CFRD, cirrhosis, and preserved renal function. In each case, the liver and pancreas were procured from a single cadaveric donor. The liver transplant was performed first. A lower midline extension was added for improved exposure of the iliac vessels. The donor pancreas transplant was performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and early steroid withdrawal. RESULTS: Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, they are now independent of supplemental pancreatic enzymes. CONCLUSIONS: Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CFRD who require liver transplants.