Pilot Randomized Trial of Tacrolimus/Everolimus vs Tacrolimus/Enteric-Coated Mycophenolate Sodium in Adult, Primary Kidney Transplant Recipients at a Single Center.

BACKGROUND: Recent studies suggest that the combination of tacrolimus (TAC) and everolimus (EVL) could become a viable option for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients. METHODS: We conducted a single-center, open-label, randomized pilot trial comparing two maintenance immunosuppression regimens in non-highly sensitized, adult, primary kidney transplant recipients: (TAC/EVL, Group A) vs our standard maintenance regimen of TAC plus enteric-coated mycophenolate mofetil (TAC/EC-MPS, Group B). In both treatment arms, dual induction therapy consisting of anti-thymocyte globulin (Thymoglobulin) and basiliximab was given. Early corticosteroid withdrawal (by 7-10 days posttransplantation) was also planned in both arms. There were 30 study participants, 15 per treatment arm. Results during the first 12 months posttransplantation are reported here. RESULTS: Between 1 month and 12 months posttransplantation, mean TAC trough levels ranged between 5 and 8 ng/mL in both arms. Mean trough EVL level in Group A ranged between 4 and 6 ng/mL, and mean EC-MPS dose in Group B ranged from 1440 mg at 1 month to 945 mg at 12 months. One patient in Group A vs three patients in Group B experienced a first biopsy-proven acute rejection during the first 12 months posttransplantation (P = .32). Four patients in each group experienced biopsy-proven chronic allograft injury (interstitial fibrosis/tubular atrophy) (P = .99). There was a slight trend toward more favorable renal function in Group A at months 1-3 posttransplantation (P = .06, .10, and .18 for estimated glomerular filtration rate, respectively). No graft failures or deaths were observed in either group during the first 12 months posttransplantation. Four patients in each group developed an infection during the first 12 months posttransplantation. Two patients in Group A developed new-onset diabetes after transplant during the 12-month follow-up period, vs no patients in Group B (P = .13). CONCLUSION: TAC/EVL may be a viable alternative to TAC/EC-MPS for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients and should be given further consideration.

Kidney allograft survival of African American and Caucasian American recipients with lupus.

BACKGROUND: African Americans with lupus who receive kidney transplants have high prevalence of predictors of allograft failure, which can explain their poor outcomes. METHODS: Of 1223 African Americans and 1029 Caucasian Americans with lupus who received kidney transplants from deceased donors between 1987 and 2006 with complete records in the UNOS program, 741 pairs were matched in 16 predictors employing a predicted probability of group membership. The primary outcome was allograft failure. Main secondary outcomes were rejection, allograft failure due to rejection, and mortality. RESULTS: Matched pairs were predominantly women (82%) with a mean age of 39 years. Twenty-four percent of recipients received kidneys from expanded criteria donors. African Americans and Caucasian Americans matched well (p ≥ 0.05): donor age, gender and race; recipient age, gender, education and insurance; dialysis prior to transplant, kidneys from expanded criteria donors, cold ischemia time, history of prior kidney transplant, panel reactive antibodies, human leukocyte antigens mismatch, blood type compatibility, transplant Era, and follow-up time. Contrary to the unmatched cohort with significantly higher allograft failure rate (events per 100 patient-years) in African Americans compared to Caucasian Americans (10.49 vs 6.18, p<0.001), matched pairs had similar allograft failure rates (8.41 vs 7.81, p=0.418). Matched pairs also had similar rates of rejections (9.82 vs 9.39, p=0.602), allograft failure due to rejection (6.19 vs 5.71, p=0.453), and mortality (2.79 vs 3.52, p=0.097). CONCLUSION: In lupus recipients of kidney transplants from deceased donors, African American and Caucasian Americans have similar allograft failure rates when predictors are matched between groups.

Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single-center trial at 10 years.

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent.

Predisposing factors of diminished survival in simultaneous liver/kidney transplantation.

Since the adoption of the Model for End-Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death-censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow-up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1-7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1-7.2) and female donor gender (HR 2.9, 95% CI 1.1-7.9). For death-censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5-27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death-censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6-21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long-term outcomes.

Absorbable cyanoacrylate surgical sealant in kidney transplantation.

As the proportion of older recipients increases, the vascular anastomoses can be challenging with significant atherosclerosis, and patients with comorbidities may be on an anticoagulation therapy, potentially increasing the risk of hemorrhagic complications. We report a case of kidney transplantation in which an absorbable cyanoacrylate surgical sealant was used. A 32-year-old white male received a kidney transplant from his wife. Two renal arteries of the donor's left kidney were reconstructed on the back table and anastomosed to the right iliac artery of the recipient. After the sealant was applied to the suture lines, the vascular clamps were released without significant bleeding from the anastomoses. The recipient demonstrated a stable graft function without an immediate complication. This case illustrates the potential benefits of the cyanoacrylate sealant in selected kidney transplant recipients.

Technical modification for laparoscopic donor nephrectomy to minimize testicular pain: a complication with significant morbidity.

The laparoscopic approach to donor nephrectomy is becoming increasingly common. While it is felt that the recovery from laparoscopic nephrectomy is quicker and less painful, a number of complications have been reported. A rarely reported on complication in the literature with significant morbidity is ipsilateral orchalgia. From 1998 to 2008, 257 hand-assisted laparoscopic donor nephrectomies were performed at our institution. Eight of 129 (6.2%) men complained of de novo ipsilateral orchalgia postoperatively. The average duration of pain was 402 days. Patients reported significant morbidity related to this complication. None, however, required further treatment. Three patients reported that they would reconsider organ donation as a result of testicular pain. Our technique originally included dissection and ligation of the gonadal vein en bloc with the ureter at the level of the left common iliac artery. Since recognizing this complication, we have adopted a gonadal vein sparing approach so as not to disturb the vessel below its point of ligation at the renal vein. To date, 50 patients have undergone the modified technique without experiencing orchalgia. In conclusion, ipsilateral testicular pan is a relatively frequent complication of laparoscopic donor nephrectomy and may be a source of significant morbidity. Using a modified surgical technique, this complication can be reduced or eradicated.

Combined pancreas and en bloc kidney transplantation using a bladder patch technique from very small pediatric donors.

Very small pediatric donors are underutilized for pancreas and kidney transplantation for the fear of inadequate islet mass and higher incidence of technical complications, and the lower age limit for such donors is not well defined. We present here two cases of combined pancreas and en bloc kidney transplantation from very small pediatric donors (14 and 18 months old) to adult type 1 diabetic and uremic patients. The conventional surgical procedure for simultaneous pancreas and kidney transplantation with systemic venous and bladder exocrine drainage was successfully applied to very small organs. For both, we utilized the recently described bladder patch technique for ureteral reconstruction. One patient developed venous thrombosis (partial thrombosis of the splenic and mesenteric veins) and the other urine leak (from a midportion of the medial ureter without compromising the bladder patch) after the transplants; both were successfully managed and the patients demonstrated immediate and sustained pancreas and kidney graft functions for 12 and 2 months posttransplantation. These cases illustrate the feasibility of combined pancreas and en bloc kidney transplantation from very small pediatric donors using a bladder patch technique to avoid small ureteral anastomosis.

Insulin protein and proliferation in ductal cells in the transplanted pancreas of patients with type 1 diabetes and recurrence of autoimmunity.

AIM/HYPOTHESIS: We investigated whether beta cell neoformation occurs in the transplanted pancreas in patients with type 1 diabetes who had received a simultaneous pancreas-kidney transplant (SPK) and later developed recurrence of autoimmunity. METHODS: We examined pancreas transplant biopsies from nine SPK patients with or without recurrent autoimmunity or recurrent diabetes and from 16 non-diabetic organ donors. Tissues were analysed by immunohistochemistry and immunofluorescence. RESULTS: Numerous cytokeratin-19 (CK-19)(+) pancreatic ductal cells stained for insulin in six SPK recipients with recurrent autoimmunity, in five of whom diabetes requiring insulin therapy recurred. These cells also stained for the transcription factor pancreatic-duodenal homeobox-1 (Pdx-1), which is implicated in pancreatic development and beta cell differentiation. The number of insulin(+) ductal cells varied, being highest in the patient with the most severe beta cell loss and lowest in the normoglycaemic patient. In the patient with the most severe beta cell loss, we detected insulin(+)CK-19(+)Pdx-1(+) cells staining for the proliferation-related Ki-67 antigen (Ki-67), indicating proliferation. We were unable to detect Ki-67(+) beta cells within the islets in any SPK patient. Some insulin(+)CK-19(-) ductal cells contained chromogranin A, suggesting further endocrine differentiation. Insulin(+) cells were rarely noted in the pancreas transplant ducts in three SPK patients without islet autoimmunity and in six of 16 non-diabetic organ donors; these insulin(+) cells were never CK-19(+). CONCLUSIONS/INTERPRETATION: Insulin(+) pancreatic ductal cells, some apparently proliferating, were found in the transplanted pancreas with recurrent islet autoimmunity/diabetes. Replicating beta cells were not detected within islets. The observed changes may represent attempts at tissue remodelling and beta cell regeneration involving ductal cells in the human transplanted pancreas, possibly stimulated by hyperglycaemia and chronic inflammation.

Clinical application of the two-layer (University of Wisconsin solution/perfluorochemical plus O2) method of pancreas preservation before transplantation.

BACKGROUND: The two-layer method [University of Wisconson solution (UW)/perfluorochemical plus O2] for pancreas preservation has been demonstrated to be superior to simple UW storage alone in the canine model. For the first time, we applied the two-layer method to clinical whole-pancreas transplantation. METHODS: Pancreases were placed in the two-layer method in 10 cases and UW alone in 44 cases before transplant. The mean cold ischemic time was 16.5 hr in the two-layer group versus 18.1 hr in the UW group (P=NS). We compared the condition of graft at the time of reperfusion, and then 3 months posttransplant graft function and complications. RESULTS: At the time of reperfusion, no grafts in the two-layer group were edematous, compared with 10(23.3%) of 43 in the UW group (P=0.18). Seven (70%) of 10 grafts in the two-layer group obtained the best overall quality score, compared with 24(57.1%) of 42 in the UW group (P=0.72). Nine (90%) of 10 recipients in the two-layer group became insulin-independent during hospitalization, compared with 31(70.5%) of 44 in the UW group (P=0.26). Time to insulin independence was no different between the two groups. No pancreas grafts preserved by the two-layer method suffered acute rejection. Conclusions. The two-layer preservation method is feasible in human clinical transplantation. It was at least equivalent and may be superior to UW alone in both morphologic and functional assessment of the transplanted pancreas.

Clinical application of vascular closure staple clips for blood access surgery.

We investigated the usefulness of nonpenetrating titanium vascular closure staple (VCS) clips developed for anastomosis of peripheral blood vessels. VCS clip applier systems (Autosuture; United States Surgical Corporation, Norwalk, CT) were used for 10 patients on hemodialysis who needed peripheral vascular anastomoses for blood access. Two arteriovenous (AV) fistulas, one closure of a fistula with reconstruction of the radial artery, six vascular graft implantations, and one vascular graft closure were performed. Medium clips were used for AV fistulas and large clips for vascular graft implantation. It took 12 min, on average, for vascular access graft anastomoses and 8.5 min, on average, for the AV fistulas. In two patients, bleeding from the anastomosed site occurred after declamping and additional sutures were required; however, neither hematoma nor wound infection occurred at 9 to 12 months after surgery. In one patient, stenosis of the graft-venous junction was found and was successfully treated by percutaneous transluminal angioplasty. The VCS clip applier is easy to manipulate, is as safe as hand-suture methods, and has time saving potential. We conclude that these VCS clips are useful for vascular anastomoses of blood access.