G. Mark Baillie

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 PPARα, 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.

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.

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.

Phaeohyphomycosis from Exophiala jeanselmei with Concomitant Nocardia asteroides Infection in a Renal Transplant Recipient: Case Report and Review of the Literature

A 59‐year‐old black man who received a cadaveric renal transplant 15 months earlier developed subcutaneous nodules on his right upper extremity that were identified as phaeohyphomycosis caused by Exophiala jeanselmei. The man was admitted 4 weeks later with a swollen left arm and had Nocardia asteroides in this area and in the apex of his left lung. He was treated with surgical excision, and itraconazole, imipenem‐cilastatin, and trimethoprimsulfamethoxazole. With the potential presence of more than one microorganism in an immunocompromised patient, it is important to identify and differentiate them correctly to direct appropriate therapy.

Hematologic complications of anti-CMV therapy in solid organ transplant recipients.

Abstract:  Cytomegalovirus (CMV) infection complicates the post‐operative course of patients receiving solid organ transplants. While ganciclovir has significantly reduced the direct effects of CMV infection, some patients cannot tolerate the optimal therapeutic exposure required for CMV prevention and treatment. Few reports directly address the incidence, consequences, and risk factors for hematologic toxicities related to ganciclovir therapy. Nevertheless, leukopenia, thrombocytopenia, and anemia occur in 5–50% of patients. Current strategies, focused on ganciclovir dose reduction, may increase the risk of CMV reactivation and drug‐resistant disease. The current article reviews the incidence, risk factors, and consequences of ganciclovir‐associated hematologic adverse events in transplant recipients. Management strategies, including ganciclovir dose reduction, and the addition of CMV hyperimmune globulin are discussed. Exposing this relatively frequently occurring, but uncommonly discussed, toxicity should lead to better avoidance and treatment strategies, without placing patients at increased risk of CMV disease.

Cyclosporine‐induced hemolytic uremic syndrome and hemorrhagic colitis following renal transplantation

Nephrotoxicity remains one of the most common side‐effects of cyclosporine in the setting of transplantation. Acute reversible decreases in glomerular filtration rate and chronic irreversible renal damage are the most common manifestations, but hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported. Prognosis of cyclosporine‐associated de novo hemolytic uremic syndrome (CyA‐HUS) is poor, with nearly half of affected patients losing function in the transplanted kidney. Therapeutic options are limited, but good outcomes have been reported by switching patients from cyclosporine to tacrolimus. We report an unusual presentation of CyA‐HUS associated with hemorrhagic colitis following renal transplantation. The patient was successfully managed by switching from cyclosporine to tacrolimus.

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.

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. Systemicenteric 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 ≦24.9 (mean 21.7 ± 2.2, range 15.4 to 24.9). Thirty-six patients were mild to moderately obese with a BMI ≧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.

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.

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.