Enteric-coated mycophenolate sodium versus mycophenolate mofetil maintenance immunosuppression: outcomes analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network database.

BACKGROUND: A large, retrospective database analysis was conducted to evaluate the long-term outcomes of patients who received enteric-coated mycophenolate sodium (EC-MPS) versus mycophenolate mofetil (MMF) maintenance immunosuppression at the time of discharge. METHODS: All primary kidney transplant patients who received either EC-MPS or MMF at time of discharge in the United Network for Organ Sharing/Organ Procurement and Transplantation Network database from 2004 to 2007 were included. Patients were excluded if they had received a previous kidney transplant, multiple organs, or combination therapy with everolimus at the time of discharge. Outcomes included graft failure, death-censored graft failure, and death with functioning graft, biopsy-proven acute rejection (BPAR), new-onset diabetes mellitus, and renal function. The propensity score method was used to adjust for nonrandomized treatment selection. A total of 48,458 patients were included in the analysis. RESULTS: At time of discharge, 10.4% of patients received EC-MPS (n=5057) and 89.6% received MMF (n=43,401). Propensity score-adjusted regression analysis showed that patients who received EC-MPS were at increased risk of BPAR (hazards ratio, 1.167; 95% confidence interval, 1.056-1.129; P=0.002). CONCLUSIONS: The adjusted BPAR rate difference at 3 years posttransplantation was less than 2% (13.6% vs. 11.7%); statistically significant because of the large number of patients included in the analysis, but a difference that may not be clinically meaningful. No differences in graft survival, new-onset diabetes mellitus, or renal function were observed between the treatment groups.

Defining the risks for cytomegalovirus infection and disease after solid organ transplantation.

Cytomegalovirus continues to be one of the most clinically significant infections after solid organ transplantation. Classic definitions of patients at high risk for infection and tissue-invasive disease are focused on recipient-donor serostatus, type of organ transplanted, and overall level of immunosuppression. However, recent trends in clinical practice call for a reevaluation of cytomegalovirus infection risks after solid organ transplantation. Indeed, whereas early-onset cytomegalovirus infection is usually controlled by antiviral prophylaxis with ganciclovir and derivatives, delayed- and late-onset cytomegalovirus infection can develop after the completion of a course of preventive therapy. In addition, indirect effects of cytomegalovirus infection may occur as a result of persistent low-level viremia. Suboptimal dosing of antiviral drugs due to specific drug toxicities may result in the development of ganciclovir-resistant cytomegalovirus disease. The relationship between organ allograft rejection and cytomegalovirus infection and disease has been recognized for some time. Transplantation of increasing numbers of extended-criteria donor organs increases the risk of delayed graft function and acute rejection, prompting the use of more intensive immunosuppression. In addition, the trend to spare long-term exposure to calcineurin inhibitors has contributed to a resurgence in the use of polyclonal T-cell induction immunosuppressive agents, which may reduce host anticytomegalovirus immunity. We discuss the current trends in solid organ transplantation that provide a foundation for defining risks for cytomegalovirus infection and disease, including identification of patients who would benefit from more aggressive cytomegalovirus monitoring and prevention strategies.

No difference between smokers, former smokers, or nonsmokers in the operative outcomes of laparoscopic donor nephrectomies.

The laparoscopic donor nephrectomy has revolutionized the living donation process for kidney transplantation. Because this surgery is elective and altruistic and smoking has been associated with greater technical difficulty and increased risk for postoperative complications for other types of surgeries, the potential risk of smoking must be addressed with regard to surgical complications. We reviewed 221 laparoscopic kidney donors with known smoking status. Forty-two (19%) were smokers, 39 (18%) were former smokers, and 140 (63%) were nonsmokers. Important donor demographics were similar between groups. There was no difference between the 3 groups for mean operative time (4.5 h vs. 4.6 h vs. 4.4 h), median or mean length of stay (2 days for all groups), estimated blood loss (173+/-137 mL vs. 209+/-184 mL vs. 188+/-198 mL), narcotic use (0.57+/-0.48 mg/kg vs. 0.49+/-0.26 mg/kg vs. 0.53+/-0.36 mg/kg of total 4 morphine equivalents), or postoperative complications. Smoking status does not seem to impact perisurgical patient outcomes in patients undergoing laparoscopic nephrectomies.

Use of bivalirudin to prevent thrombosis following orthotopic liver transplantation in a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia.

Type II heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome that may arise in a time-dependent manner following heparin therapy, placing patients at significant risk for thromboembolic events. Therapy includes anticoagulation with a direct thrombin inhibitor and avoidance of heparin. We report a patient with Budd-Chiari syndrome and a history of heparin-induced thrombocytopenia who presented for orthotopic liver transplant and required postoperative anticoagulation with bivalirudin. During the post-transplant graft function improvement, we observed a significant dose-effect alteration manifested by an increased bivalirudin dose requirement as factor V activity increased. This observation is an important consideration in the attempt to maintain an optimal balance between effective anticoagulation and a reduced risk of postoperative bleeding.

Use of bone health protocol to identify and prevent bone disease in kidney and pancreas transplant recipients.

BACKGROUND: Posttransplant bone disease is a well recognized and undertreated problem. The use of protocols within other populations has been shown to improve recognition and treatment of common disease states, but outcome studies involving the use of protocols within transplant patients are lacking. OBJECTIVE: To compare the appropriate screening for and the prevention and treatment of osteopenia and osteoporosis in transplant patients before and after a bone health protocol was implemented. METHODS: A retrospective analysis in a single institution was designed to determine whether the development and implementation of a comprehensive bone health protocol impacted disease outcomes in posttransplant kidney and simultaneous kidney-pancreas patients. RESULTS: There were 132 patients in the historical control group and 76 in the treatment group. The groups were well matched, with no statistically significant differences noted for any of the baseline characteristics that were compared, including the modifiable and nonmodifiable risk factors known to put a patient at increased risk for osteopenia or osteoporosis. Significantly more patients in the treatment group received proper screening and prevention compared with the historical control group (p < 0.001). Although more patients in the treatment group received proper bone disease treatment, this did not reach statistical significance (81% vs 66%; p < 0.22). Additionally, the dual energy X-ray absorptiometry scans were performed, on average, 19 days earlier in the treatment group, although this also did not achieve statistical significance (p = 0.149). CONCLUSIONS: The multidisciplinary development and implementation of a comprehensive bone health protocol improves the screening and prevention of osteopenia and osteoporosis within kidney and pancreas transplant recipients.

Prevention of cytomegalovirus disease in solid organ transplant patients: prophylactic versus preemptive therapy.

PURPOSE: The advantages and disadvantages of universal prophylaxis and preemptive therapy and current evidence-based recommendations for preventing cytomegalovirus (CMV) disease in solid organ transplant recipients are discussed. SUMMARY: Advantages of universal prophylaxis include the ease of implementation, a reduced incidence of CMV disease, and possibly fewer indirect effects of CMV infection. Disadvantages of universal prophylaxis may include prolonged antiviral drug exposure, resistance, toxicity, the development of late-onset CMV disease, and greater drug costs. Advantages of preemptive therapy may include reduced drug exposure and decreased risk for toxicity and resistance. Disadvantages include the logistic demands of laboratory testing, uncertainty about the impact on the indirect effects of CMV disease, and the costs associated with failure to prevent CMV disease. Evidence-based guidelines call for universal prophylaxis for patients at highest risk for CMV disease. Preemptive therapy may be most appropriate for those at a moderate or low risk of CMV. Antiviral drug regimens used for universal prophylaxis depend on the type of organ transplanted and the donor-recipient CMV serostatus. The optimal preemptive drug regimen and laboratory monitoring strategy are unknown. CONCLUSION: Selection of a strategy for preventing CMV disease in solid organ transplant patients requires consideration of patient-specific risk factors as well as practical considerations, such as available resources.

Does bioequivalence between modified cyclosporine formulations translate into equal outcomes?

Neoral was replaced with a generic cyclosporine formulation on our hospital formulary. We compared outcomes for de novo kidney transplant recipients who either received Gengraf (n=88) or Neoral (n=100) in a single-center, retrospective review. As compared to patients who received Neoral, patients who received Gengraf were significantly more likely to have an acute rejection episode (39% vs. 25%, P=0.04), more likely to have a second rejection episode (13% vs. 4%; P=0.03), or to have received an antibody preparation to treat acute rejection (19% vs. 8%; P=0.02). Patients treated with Gengraf had a higher degree of intrapatient variability for cyclosporine trough concentrations as determined by %CV (P<0.05). The incidence of acute rejection at 6 months posttransplant was significantly higher in patients who received Gengraf compared to Neoral. A larger, prospective analysis is warranted to compare these formulations of cyclosporine in de novo kidney transplant recipients.

Heparin-induced thrombocytopenia in a renal transplant recipient.

Heparin-induced thrombocytopenia (HIT) type II is an immunologically mediated reduction in platelets that increases the risk of arterial or venous thrombosis. It has been reported in up to 5% of patients receiving unfractionated heparin. Unlike other thrombocytopenic coagulopathies, HIT is associated with a high risk of thromboembolic events if not treated with an appropriate anticoagulant alternative. Diagnosis is dependent on assessment of platelet reduction, identification of previous heparin exposure, detection of thrombotic complications and evaluation of laboratory assays. HIT has been well described in surgical patient populations; however, the abdominal organ transplant population is an exception. HIT should be included in the differential diagnosis of patients presenting with thrombocytopenia after transplantation in order to prevent or treat thrombotic complications that can pose a risk to patient or graft survival.

Pharmacokinetics of antiviral agents for the treatment of cytomegalovirus infection.

PURPOSE: The mechanism of action, pharmacokinetics, and other advantages and disadvantages of ganciclovir and valganciclovir are discussed. SUMMARY: Shortcomings of oral ganciclovir include low bioavailability, large pill burden, patient nonadherence, and the emergence of resistance. Valganciclovir, an oral prodrug of ganciclovir, has a nearly tenfold greater absolute bioavailability than ganciclovir. Dosage adjustment is required for both drugs in patients with renal impairment. CONCLUSION: The pharmacokinetic profile of valganciclovir offers significant advantages for its use in cytomegalovirus (CMV) prophylaxis.

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation.

Sirolimus (SRL) rescue in kidney-pancreas transplantation has not been well described. We reviewed 112 KPTxs performed at our institution between December 3, 1995 and June 27, 2002. All patients received antibody induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. In 35 patients, SRL was substituted for MMF for the following reasons: acute rejection (AR) of kidney or pancreas despite adequate TAC levels, MMF intolerance, increasing creatinine levels, and TAC-induced hyperglycemia. Three-year kidney and pancreas graft survivals were 97% and 90%, respectively. Of 10 patients who were switched to SRL because of AR, one kidney failed because of antibody-resistant AR, and one kidney developed borderline AR; the other eight patients remain AR-free. AR developed in seven other patients despite therapeutic SRL levels; six had TAC levels less than 4.5 ng/mL. The mean creatinine levels overall and for the group with increasing creatinine remained stable. All patients who were switched to SRL for TAC-induced hyperglycemia or MMF intolerance improved. Kidney-pancreas transplant recipients can be safely switched to SRL with excellent graft and patient survival.

Fatty acid synthase blockade protects steatotic livers from warm ischemia reperfusion injury and transplantation.

Cerulenin has been shown to reduce body weight and hepatic steatosis in murine models of obesity by inhibiting fatty acid synthase (FAS). We have shown that attenuating intrahepatocyte lipid content diminished the sensitivity of ob/ob mice to ischemia/reperfusion injury and improved survival after liver transplantation. The mechanism of action is by inhibition of fatty acid metabolism by downregulating PPARalpha, as well as mitochondrial uncoupling protein 2 (UCP2), with a concomitant increase in ATP. A short treatment course of cerulenin prior to I/R injury is ideal for protection of steatotic livers. Cerulenin opens the potential for expanding the use of steatotic livers in transplantation.

Influence of mild obesity on outcome of simultaneous pancreas and kidney transplantation.

The influence of body mass index (BMI) on outcome of simultaneous pancreas-kidney transplantation (SPK) has not been well described. We retrospectively reviewed 88 consecutive primary SPKs performed at our institution between March 15, 1995 and August 28, 2001. All patients received antibody induction and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids. Systemic-enteric implantation was performed in all patients. Primary end points were patient, pancreas, and kidney survival. Secondary end points were rates of anastomotic leakage, pancreas thrombosis, major infection, rejection, repeat laparotomy, and length of hospital stay. Values are shown as mean+/-standard deviation, range, or percentage. Fifty-two patients (59.1%) were nonobese with a BMI < or =24.9 (mean 21.7+/-2.2, range 15.4 to 24.9). Thirty-six patients were mild to moderately obese with a BMI > or =25 (mean 27.7+/-2.2, range 25 to 35.1). Distribution of recipient age, sex, and ethnicity was similar between groups. Kidney and pancreas preservation times were similar between nonobese and obese patients. One-, three-, and five-year actuarial patient (nonobese: 95%, 95%, 95% vs. obese: 95%, 95%, 89%), kidney graft (nonobese: 91%, 91%, 87% vs. obese: 97%, 91%, 85%), and pancreas graft (nonobese: 78%, 78%, 73% vs. obese: 70%, 62%, 62%) survival were comparable between nonobese and obese (P=NS). The mean rates of pancreas thrombosis, major infection, pancreas rejection, kidney rejection, relaparotomy, and length of hospital stay were similar in the two groups. The overall duodenojejunal anastomotic leakage rate was 8%. Obese patients had a 17% incidence of leakage (6 of 36) compared to a 2% incidence of leakage in nonobese patients (P=0.012). Six of seven leaks occurred in obese patients. Mean BMI in the seven patients with a leak (27+/-1.9) was significantly higher than in patients who did not develop a leak (24+/-3.7; P=0.05). Although obesity had no effect on patient or graft survival, it was associated with a significantly higher leakage rate. There should therefore be a higher degree of suspicion for the presence of duodenojejunal anastomotic leaks in obese SPK recipients.

Effect of ethnicity on outcome of simultaneous pancreas and kidney transplantation.

The influence of ethnicity on outcome of simultaneous pancreas-kidney transplantation (SPK) is poorly defined. After excluding technical failures, we retrospectively reviewed 96 consecutive SPKs (63 Caucasians [C], 33 African-Americans [AA]). All patients received antibody induction, tacrolimus, mycophenolate mofetil, and steroids. One-, 3-, and 5-year actuarial patient survival was similar between C (98%, 95%, 87%) and AA (90%, 90%, 81%), p=NS. One-, 3-, and 5-year kidney graft survival was similar between C (98%, 86%, 81%) and AA (85%, 85%, 78%), p =NS. One-, 3-, and 5-year pancreas graft survival was significantly worse in AA (71%, 68%, 46%) than in C (90%, 85%, 81%), p = 0.008. The cumulative incidence of kidney and pancreas acute rejection (AR) was higher in AA compared with C. Distribution of kidney and pancreas rejection grade was similar between C and AA. AA experienced more pancreas graft losses from early death with functioning graft, AR, and late chronic rejection. The higher incidence of AR and resistance to currently employed induction, maintenance, and antirejection immunosuppression therapies in AA may account for their inferior pancreas graft survival. More aggressive immunosuppression strategies may improve pancreas graft survival in AA but may be associated with increased morbidity and mortality. Further study is warranted.

Chylous ascites secondary to laparoscopic donor nephrectomy.

Live donor renal transplantation offers many significant advantages over cadaveric donor transplantation. Yet living donation continues to be underused, accounting for less than 30% of all donor renal transplants. In an attempt to remove the disincentives to live donation, Ratner et al. developed laparoscopic donor nephrectomy (LDN). LDN is gaining acceptance in the transplant community. The overriding concern must always be the safety and welfare of the donor. To this end, potential complications of LDN must be identified and discussed. We present a patient who developed the complication of chylous ascites from LDN. To improve the laparoscopic technique further, a discussion of its successes and complications needs to be encouraged. To this end, we present chylous ascites as a potential complication after LDN. We also offer suggestions to minimize the likelihood of this complication.