Rescue therapy with tacrolimus in simultaneous pancreas/kidney transplantation

Tacrolimus has been effective both in primary and rescue therapy following steroid and OKT3-resistant acute rejection in liver and kidney transplantation. Due to the effects of tacrolimus on glucose metabolism, there has been concern about its use in simultaneous pancreas/kidney transplantation. We report on the results of six patients (three female, three male, age 35.2 ± 7.3 years) converted from cyclosporin A to tacrolimus following simultaneous pancreas/kidney transplantation in steroid-resistant acute rejection. Tacrolimus was induced 2.8 ± 1.7 months (range 1–4.8 months) after transplantation; follow-up was 3–18 months. Following conversion, creatinine levels declined in all patients [3.5 ± 1.2 mg/dl before conversion, 3.0 ± 1.9 mg/dl (n = 6) at three months, 1.4 ± 0.1 mg/dl at 1 year (n = 3)]. Before conversion, fasting blood glucose levels averaged 154 ± 33 mg/dl, with three patients receiving insulin. Three months later no patient required insulin, the mean glucose level being 107 ± 23 mg/dl (n = 6); at 1 year it was 92 ± 9 mg/dl (n = 3). One patient lost his pancreatic graft after 4 months due to a mycotic aneurysm. We conclude that conversion to tacrolimus is a safe and effective treatment in cases of steroid-resistant rejections following pancreas/kidney transplantation.     

Pancreas-specific protein (PASP), serum amyloid A (SAA), and neopterin (NEOP) in the diagnosis of rejection after simultaneous pancreas and kidney transplantation

A reliable, noninvasive indicator of pancreatic allograft rejection is urgently needed. In this study, serum (S), plasma (P), and urine (U) levels of pancreas-specific protein (P-PASP, U-PASP), neopterin (S-NEOP, U-NEOP), amylase (U-AMYL), and amyloid A (SAA) were measured daily in ten type I diabetic patients following simultaneous pancreas and kidney transplantation (SPK). Rejection episodes occurred in three isolated pancreas, nine isolated kidney, and five simultaneous pancreas and kidney transplants. In the case of the eight pancreas rejections, SAA was the rejection marker with the highest diagnostic accuracy (94 %). Using P-PASP and U-PASP, an accuracy of 81 % and 79 %, respectively, was achieved. During viral infections, U-NEOP levels increased to a maximum level of 1904 μmol/mol creatinine, whereas during bacterial infections, SAA levels increased to a maximum value of 43 mg/dl. SAA, measured for the first time in SPK, appears to be a valuable rejection parameter. In combination with U-NEOP and U-AMYL, a differential diagnosis between rejection, bacterial infection, and viral infection was possible. Neither U-PASP nor P-PASP monitoring led to a significant improvement in the results. Received: 23 July 1996 Received after revision: 31 December 1996 Accepted: 3 January 1997     

Impact of Portal Venous Pancreas Graft Drainage on Kidney Graft Outcome in Simultaneous Pancreas-Kidney Recipients Reported to UNOS

Clinical data on the potential immunologic impact of portal (PD) vs. systemic (SD) venous pancreas graft drainage on outcome remains controversial. We reviewed the UNOS database to study the effect of PD vs. SD on the incidence of kidney graft rejection and survival in first cadaveric simultaneous pancreas-kidney (SPK) recipients transplanted 1994-2001. We studied three groups: all SPK (n=6629, 13% PD) (group I), SPK on tacrolimus (n=3563, 17% PD) (group II), and SPK on tacrolimus performed at centers with significant PD experience (n=948, 46% PD) (group III). The cumulative kidney graft rejection incidence for PD vs. SD was only significantly different in group I (for PD vs. SD, respectively: at 6 months, 31% vs. 36% [p=0.015]; at 1 year, 37% vs. 43% [p=0.006]). Kidney graft survival was similar in all groups for PD vs. SD. Multivariate analysis of group III showed only transplantation during the earlier era (1994-96), but not SD, to be an independent risk factor for kidney graft rejection. Portal venous pancreas graft drainage does not affect kidney graft rejection and survival in SPK recipients on tacrolimus. Our data suggests that the efficacy of current immunosuppressive protocols and increasing center experience are clinically much more relevant than any potential immunologic advantage of portal venous drainage in SPK recipients.     

胰肾联合移植的排斥反应

目的　探讨胰肾联合移植术后的排斥反应。方法　对我院施行的 3例胰肾联合移植的病人 ,采用FK5 0 6 MMF Perid Zenapax四联免疫治疗方案 ,通过床边彩超及Cr、BUN、血糖等来监测移植物的排斥反应。对排斥反应采用激素冲击疗法 ,对激素不敏感者采用OKT3治疗。结果　3例患者中有 2例出现排斥反应 ,其发生率达 6 6 % ;在出现排斥反应时 ,首先表现为低热、全身不适 ,尿量减少 ,血Cr、BUN升高 ,彩超示移植物血流阻抗升高 ,之后才是血糖升高。结论　胰肾联合移植中 ,排斥反应与多种因素有关 ,移植肾对移植胰具有保护作用 ,肾脏可以作为监测胰腺排异的窗口 ,彩超检查可以作为筛选移植物排异反应的手段。     

Everolimus with low‐dose tacrolimus in simultaneous pancreas and kidney transplantation

The efficacy and safety of everolimus (EVR) in simultaneous pancreas and kidney transplantation (SPKT) is unclear. We retrospectively evaluated 25 consecutive SPKT recipients at our center from November 2011 to March 2013. All patients received dual induction (Thymoglobulin/basiliximab) and low‐dose tacrolimus plus corticosteroids. Nine patients who received EVR were compared with 14 patients who received enteric‐coated mycophenolate sodium (EC‐MPS); two patients who received sirolimus were excluded from the analysis. With a median follow‐up of 14 months, the pancreas graft survival rate was 100% in both groups, and the kidney graft survival rate was 100% and 93% in EVR and EC‐MPS patients, respectively. One EC‐MPS patient lost her kidney graft from proteinuric kidney disease. Another EC‐MPS patient received treatment for clinically diagnosed pancreas and kidney graft rejection. No rejection was observed in EVR patients. Serum creatinine and HbA1c levels were similar between the groups. There was no significant difference of surgical or medical complications. In conclusion, EVR seems to provide comparable short‐term outcome to EC‐MPS when combined with low‐dose tacrolimus/steroids and dual induction therapy. A larger study with a longer follow‐up is required to further assess this combination.     

BKV in Simultaneous Pancreas-Kidney Transplant Recipients: A Leading Cause of Renal Graft Loss in First 2 Years Post-Transplant

With the introduction of more potent immunosuppressive agents, rejection has decreased in simultaneous pancreas/kidney transplant (SPK) recipients. However, as a consequence, opportunistic infections have increased. The purpose of this report is to outline the course of SPK patients who developed polyomavirus-associated nephropathy (PVAN). A retrospective review of 146 consecutive SPK recipients from January 1, 1996 to December 31, 2002 was performed. Immunosuppression, rejection and development of PVAN were reviewed. Nine patients were identified. All received induction with either OKT3 or thymoglobulin. Immunosuppression included tacrolimus/cyclosporine, MMF/azathioprine and sirolimus/prednisone. Two patients were treated for kidney rejection prior to the diagnosis of PVAN. Time to diagnosis was an average of 359.3 days post-transplantation. Immunosuppression was decreased but five ultimately lost function. However, none developed pancreatic abnormalities as demonstrated by normal glucose and amylase. Two underwent renal retransplantation after PVAN diagnosis and both have normal kidney function. PVAN was the leading cause of renal loss in SPK patients in the first 2 years after transplantation and is a serious concern for SPK recipients. The pancreas, however, is spared from evidence of infection, and no pancreatic rejection occurred when immunosuppression was decreased.     

Tacrolimus‐ versus sirolimus‐based immunosuppression after simultaneous pancreas and kidney transplantation: 5‐year results of a randomized trial

Tacrolimus, the cornerstone immunosuppression after simultaneous pancreas and ‐kidney (SPK) transplantation, may exert nephrotoxic and diabetogenic effects. We therefore prospectively compared in an open‐label, randomized, monocentric, 5‐year follow‐up study, a tacrolimus‐ and a sirolimus‐based immunosuppressive regimen. Randomization using the block method allowing a blind allocation was done at the time of surgery. All patients received anti‐thymocyte globulin and maintenance therapy with tacrolimus, mycophenolate mofetil, and steroids. At month 3, tacrolimus was continued or replaced by sirolimus. The primary endpoint was kidney and pancreas graft survival at 1 and 5 years. Fifty patients were included in the final analysis in each group. At 1 year, differences for kidney and pancreas graft survival between sirolimus and tacrolimus were 0% (90% confidence interval ?4.61% to 4.61%) and 6% (90% confidence interval ?6.32% to 18.32%), respectively. There was no difference in renal and pancreas graft survival at 5 years. Thirty‐four patients (68%) in the sirolimus group vs three (6%) in the tacrolimus group needed definitive withdrawal of the study drug. Despite noninferiority of sirolimus compared to tacrolimus for kidney and pancreas graft survival, the high rate of sirolimus discontinuation does not favor its use as cornerstone therapy after SPK transplantation (NCT00693446).     

Kidney retransplantation following graft loss to polyoma virus-associated nephropathy: an effective treatment option in simultaneous pancreas and kidney transplant recipients.

Polyomavirus-associated nephropathy (PVAN) has emerged as an important cause of graft loss following kidney transplantation. Experience with kidney retransplantation (reKT) in PVAN is very limited, especially in the setting of uninterrupted immunosuppression protecting the still functioning pancreatic graft after simultaneous pancreas/kidney transplantation (SPK). We present a review of five cases of reKT in four SPK recipients with Type 1 diabetes mellitus from a single centre (a second reKT was performed in one patient following first reKT failure due PVAN recurrence). Pre-emptive nephrectomy of the failed graft was performed in three of the cases and all kidney grafts for reKT were harvested from cadaveric donors. All patients are dialysis- and insulin-independent at 30 (9-55), median (range), months following last reKT with maintenance immunosuppression consisting of tacrolimus/sirolimus in three and cyclosporine A/mycophenolate mofetil in one patient. In conclusion, reKT represents an effective treatment option in SPK patients with kidney failure on account of PVAN. Use of interventions designed to reduce active viral replication, including pre-emptive nephrectomy of the failed graft, should be considered before reKT.     

Long-term results of pancreas transplantation under tacrolius immunosuppression

BACKGROUND: The long-term safety and efficacy of tacrolimus in pancreas transplantation has not yet been demonstrated. The observation of prolonged pancreatic graft function under tacrolimus would indicate that any potential islet toxicity is short-lived and clinically insignificant. We report herein the results of pancreas transplantation in patients receiving primary tacrolimus immunosuppression for a minimum of 2 years. METHODS: From July 4, 1994 until April 18, 1996, 60 patients received either simultaneous pancreas-kidney transplant (n=55), pancreas transplant only (n=4), or pancreas after kidney transplantation (n=1). Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Azathioprine was used as a third agent in 51 patients and mycophenolate mofetil in 9. Rejection episodes within the first 6 months occurred in 48 (80%) patients and were treated with high-dose corticosteroids. Antilymphocyte antibody was required in eight (13%) patients with steroid-resistant rejection. RESULTS: With a mean follow-up of 35.1+/-5.9 months (range: 24.3-45.7 months), 6-month and 1-, 2-, and 33-year graft survival is 88%, 82%, 80%, and 80% (pancreas) and 98%, 96%, 93%, and 91% (kidney), respectively. Six-month and 1-, 2-, and 3-year patient survival is 100%, 98%, 98%, and 96.5%. Mean fasting glucose is 91.6+/-13.8 mg/dl, and mean glycosylated hemoglobin is 5.1+/-0.7% (normal range: 4.3-6.1%). Mean tacrolimus dose is 6.5+/-2.6 mg/day and mean prednisone dose 2.0+/-2.9 mg/day at follow-up. Complete steroid withdrawal was possible in 31 (65%) of the 48 patients with functioning pancreases. CONCLUSIONS: These data show for the first time that tacrolimus is a safe and effective long-term primary agent in pancreas transplantation and provides excellent long-term islet function without evidence of toxicity while permitting steroid withdrawal in the majority of patients.     

Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression

PURPOSE: The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed. METHODS: From July 4, 1994 until April 30, 1998, 147 pancreas transplantations were performed in 141 patients, including 126 simultaneous pancreas-kidney transplantations, 13 pancreas after kidney transplantation, and 8 pancreas transplantations alone. Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Twenty-three patients were excluded from analysis because of early graft loss in 17 cases, retransplantation in 5 cases, and simultaneous pancreas-kidney transplantation after heart transplantation in 1 patient. RESULTS: With a mean follow-up of 2.8+/-1.1 years (range 1.0 to 4.8 years), complete steroid withdrawal was achieved in 58 (47%) patients with a mean time to steroid withdrawal of 15.2+/-8 months (range 4 to 40 months after transplantation). Of the entire cohort of 141 patients, overall 1-, 2-, and 4-year patient survival rates were 98%, 95.5%, and 86%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 83%, 80%, and 71% (pancreas) and 95%, 91%, and 84% (kidney), respectively. Of the 124 patients analyzed for steroid withdrawal, 1-, 2-, and 4-year patient survival rates were 98%, 97%, and 92%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 98%, 91.5%, 83% (pancreas) and 97%, 95%, and 91% (kidney). Patient, pancreas, and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids) versus 97%, 91%, and 96% (on steroids, all NS) and at 4 years were 100%, 94%, and 95% (off steroids) versus 78%, 68%, and 85% (on steroids, P = 0.01, 0.002, and NS, respectively). The cumulative risk of rejection at the time of follow-up was 76% for patients on steroids versus 74% for patients off steroids (P = NS). Seven patients originally tapered off steroids were treated for subsequent rejection episodes, which were all steroid sensitive, and two of these seven patients are currently off steroids. Thirteen patients received antilymphocyte therapy for steroid-resistant rejection, five of whom are now off steroids. Tacrolimus trough levels were 9.3+/-2.4 ng/ml (off steroids) and 9.7+/-4.3 (on steroids, P = NS). Mean fasting glucose levels were 98+/-34 mg/dl (off steroids) and 110+/-41 mg/dl (on steroids, P = NS). Mean glycosylated hemoglobin levels were 5.2+/-0.9% (off steroids) and 6.2+/-2.1% (on steroids, P = 0.02), and mean serum creatinine levels were 1.4+/-0.8 mg/dl (off steroids) and 1.7+/-1.0 mg/dl (on steroids, P = 0.02). CONCLUSION: These data show for the first time that steroid withdrawal can be safely accomplished in pancreas transplant recipients maintained on tacrolimus-based immunosuppression. Steroid withdrawal is associated with excellent patient and graft survival with no increase in the cumulative risk of rejection.     

Use of tacrolimus and mycophenolate mofetil as induction and maintenance in simultaneous pancreas‐kidney transplantation

Abstract Clinical trials using quadruple immunosuppression that include the combination of tacrolimus and mycophenolate mofetil have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas‐kidney (SPK) transplantation. In an attempt to obtain a low rejection rate without antibody induction therapy, we undertook a prospective study of combined tacrolimus and mycophenolate mofetil and steroids as primary immunosuppression for SPK transplantation. In this study, we analyzed 17 patients who received low‐dose intravenous tacrolimus as induction therapy. This was combined with oral tacrolimus, mycophenolate mofetil, and steroids as the primary immunosuppression regimen. There was a significant reduction of empirically and biopsy‐proven rejection with an incidence of 23 % (4 patients). Leukopenia, gastroparesis, and gastrointestinal side‐effects were the cause of discontinuation of mycophenolate mofetil, or low tacrolimus trough level in those patients who developed rejection. All rejection episodes were easy to treat, and none of them required antibody therapy. The combination of tacrolimus with mycophenolate mofetil without antibody induction therapy is effective in preventing early acute rejection. This combination is safe and effective as an alternative immunosuppressive regimen after SPK transplantation.     

Conversion to tacrolimus after liver transplantation

We have reviewed our experience with conversion to tacrolimus after 435 liver transplantations. Tacrolimus was administered as a rescue agent in 33 patients until October 1993. Indications for rescue therapy were: cholestatic forms of severe, steroid-resistant cellular rejection (n=8), OKT3-resistant cellular rejections (n=6), cellular rejections in patients suffering from cyclosporin malabsorption (n=4), late onset cellular rejections (n=4), early chronic rejections (n=3), and chronic vascular or ductopenic rejections (n=8). Response was evident in 29 of the 33 patients (88%), whereas 4 patients (12%) were nonresponsive. Patient and graft survival were 76% and 70%, respecitively. Graft loss with or without patient death occurred in three of eight patients suffering from severe, steroid-resistant cellular rejection, in two of six patients with OKT3-resistant cellular rejections, and in five of eight patients undergoing chronic rejection. In severe steroid-resistant cellular rejection, successful tacrolimus rescue therapy corresponded to a significantly lower total serum bilirubin than unsuccessful therapy (12.0±5.6 mg% vs 29.7±5.9 mg%, P(0.05). We conclude that tacrolimus rescue therapy is a safe and efficient alternative for high-risk cases that do not respond to conservative treatment. In severe, steroid-resistant cellular rejection and in chronic ductopenic rejection, conversion to tacrolimus is beneficial only in a limited number of cases. A predictive parameter, which total serum bilirubin may prove to be in severe, steroid-resistant cellular rejection, is needed to select those cases that might benefit more from retransplantation than from conversion to tacrolimus.     

Alemtuzumab Induction and Steroid‐Free Maintenance Immunosuppression in Pancreas Transplantation

Alemtuzumab is a humanized anti‐CD52 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation. The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated, with particular reference to steroid avoidance in maintenance. A total of 100 patients who received 102 pancreas transplants (83 simultaneous kidney–pancreas [SPK], 15 pancreas after kidney transplantation [PAK] and 4 pancreas transplant alone [PTA]) were included. All patients received two doses of 30‐mg alemtuzumab i.v. with tacrolimus (trough level 8–12 ng/mL) and mycophenolate mofetil (MMF,1g/day) with no maintenance steroids. This analysis included 62 male and 38 female recipients, with mean (±SD) age of 42 (±7.6) years. Median follow‐up was 17 months (range 8–41 months). One‐year patient, pancreas and kidney graft survival (actuarial) was 97%, 89% and 94%, respectively. Overall incidence of rejection was 25%. Side effects of alemtuzumab administration included thrombocytopenia (14%), pulmonary edema (2%) and rash (1%). Twenty‐five percent required reoperations (12% for bleeding). Infectious complications included Cytomegalovirus (CMV,6.8%) BK viruria (3.8%), fungal infections (4%), primary varicella (1%) and posttransplant lymphoproliferative disorders (PTLD,1%). Eighty‐three percent did not require any steroids posttransplant. These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83% of cases and acceptable rejection rate.     

Prospective, Randomized, Multi-Center Trial of Antibody Induction Therapy in Simultaneous Pancreas-Kidney Transplantation

A randomized, multicenter, prospective study was conducted at 18 pancreas transplant centers in the United States to determine the role of induction therapy in simultaneous pancreas-kidney (SPK) transplantation. One hundred and 74 recipients were enrolled: 87 recipients each in the induction and noninduction treatment arms. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. There were no statistically significant differences between treatment groups for patient, kidney, and pancreas graft survival at 1-year. The 1-year cumulative incidence of any treated biopsy-confirmed or presumptive rejection episodes (kidney or pancreas) in the induction and noninduction treatment arms was 24.6% and 31.2% (p = 0.28), respectively. The 1-year cumulative incidence of biopsy-confirmed, treated, acute kidney allograft rejection in the induction and noninduction treatment arms was 13.1% and 23.0% (p = 0.08), respectively. Biopsy-confirmed kidney allograft rejection occurred later post-transplant and appeared to be less severe among recipients that received induction therapy. The highest rate of Cytomegalovirus (CMV) viremia/syndrome was observed in the subgroup of recipients who received T-cell depleting antibody induction and received organs from CMV serologically positive donors. Decisions regarding the routine use of induction therapy in SPK transplantation must take into consideration its differential effects on risk of rejection and infection.     

Reduced dose Thymoglobulin,tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes

BACKGROUND: Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas-kidney transplants. Thymoglobulin (TMG), a polyclonal rabbit-derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1-yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate. PATIENTS AND METHODS: Eighteen pancreas after kidney and four pancreas transplants alone were performed between January 1998 and October 2000 at McGill University. Induction therapy with TMG at a starting dose of 1.5 mg/kg/d was started 12 h post-operatively. The daily dose of TMG was held if the total leukocyte count was <2,500/mm3 or if the lymphocyte count was <100/mm3. Maintenance therapy was initiated with steroids (tapered to 20 mg prednisone orally once a day) tacrolimus (2 mg twice a day), and mofetil mycophenolate (1 g daily). RESULTS: Patients received three to seven doses of TMG over the first seven post-operative days at a dose of 0.85 +/- 0.27 mg/kg/d (mean +/- SD). The mean follow-up was 1.28 +/- 0.14 yr. The 1-yr patient and graft survival was 100% (22 of 22) and 96% (21 of 22), respectively. The 1 yr acute rejection rate was 27.3% (six of 22). Five of the six rejections responded to steroid boluses. One was refractory to steroids and TMG resulting in graft loss. Presumed rejections were diagnosed on the basis of decreasing urine amylase and/or hyperglycemia. DISCUSSION: Monitoring the total leukocyte and lymphocyte count resulted in a 43% reduction in the amount of TMG used compared with the recommended dosing. Despite the reduced amounts, patient and graft survival were excellent with acute rejection rates comparing favorably to other published series.     

Early steroid withdrawal in solitary pancreas transplantation results in equivalent graft and patient survival compared with maintenance steroid therapy

Although steroid withdrawal in simultaneous kidney pancreas transplantation has been shown to be feasible, the results of early steroid withdrawal in immunologically solitary pancreas transplantation are not well known. This study evaluated an early steroid withdrawal protocol in this group. The results of steroid withdrawal at 21 d post-transplant in solitary pancreas transplant recipients was compared with a control group consisting of solitary pancreas transplant recipients maintained on steroids (MG). Additional immunosuppression consisted of rabbit anti-thymocyte globulin induction followed by tacrolimus and mycophenolate mofetil in both groups. The withdrawal group (WG, n = 22) consisted of 11 pancreas transplant alone (PTA), six pancreas after kidney (PAK), and five simultaneous cadaveric pancreas living kidney (SPLK) recipients. The steroid maintenance group (MG, n = 32) consisted of 8 PTA, 11 PAK, and 13 SPLK recipients. Recipient and donor demographic characteristics were similar. Seventy eight percent of MG patients had infection-related complications in the first year compared with 50% of the WG patients (p = 0.04). The one-yr rejection, pancreas graft, and patient survival rates were 27.3% 95.5%, and 100% in the WG, and 37.5%, 81.3%, and 93.8% in the MG respectively and not significantly different. We conclude that early corticosteroid withdrawal in isolated pancreas transplantation results in fewer infections and can be achieved without an increased risk of rejection or graft loss over the first year.     

Efficacy of tacrolimus in patients with steroid-resistant cardiac allograft cellular rejection.

BACKGROUND: Tacrolimus is an immunosuppressive agent that is gaining widespread use in solid organ transplantation. This study was undertaken to evaluate the efficacy of tacrolimus in treating steroid-resistant cellular myocardial rejection. METHODS: We retrospectively analyzed the incidence of rejection and clinical outcome of 21 heart transplant recipients who were electively converted from cyclosporine to tacrolimus for recurrent episodes of steroid-resistant cellular rejection. These were compared to a historic group of 6 hemodynamically stable patients who were treated electively with Orthoclone OKT3 (Muromonab/CD3) for recurrent rejection. RESULTS: Eighty five percent (56/66) of the episodes of rejection occurred within the first 3 months after heart transplantation. Tacrolimus was started 2. 4 +/- 2.0 months post-transplant, and the mean follow-up duration on tacrolimus was 11.0 +/- 7.0 months. After conversion, a significant decline was noted in both the number of episodes of acute rejection per patient (3.14 +/- 0.85-0.57 +/- 0.87, p < 0.0001), and the incidence of acute rejection per 100 patient-days (6.39 +/- 3.96-0. 25 +/- 0.47, p < 0.0001). In comparison, OKT3 was started 5.25 +/- 9. 20 months post-transplant. Similarly, there was a significant decrease in the incidence of acute rejection per 100 patient-days (8. 69 +/- 5.65-0.20 +/- 0.23, p < 0.0001). The average hospital charges per patient for the OKT3-treated group was $33,339 +/- $10,511. There was no significant difference in the actuarial 1-year survival between the tacrolimus and OKT3-treated groups (93% vs 80%, p = 0.5). CONCLUSIONS: Outpatient conversion to tacrolimus is safe, well tolerated, and an effective therapeutic strategy for the treatment of steroid-resistant cellular rejection in heart transplant recipients. It is more cost-effective than OKT3 in the hemodynamically stable patient and outcomes are similar.     

Long-term use of FK 506 in living related liver transplantation

Abstract FK 506 (Tacrolimus) was used with steroids to treat 61 pediatric patients who received living related partial liver transplantation. Fifty-two recipients survived and 9 died between 6 months and 3 years after transplantation. In the surviving patients, oral doses of Tacrolimus were tapered from 0.298 ± 0.277 mg/kg daily at 1 month after transplantation to 0.078 ± 0.054 at 24 months after transplantation. The 12 h trough levels of Tacrolimus were 12.6 ± 7.1 ng/ml and 4.1 ± 2.4 at 1 and 24 months after transplantation, respectively. The percentage of recipients free from steroids was 77%, 97%, and 94% at 6, 12, and 24 months after transplantation, respectively. Liver allograft rejection was encountered in seven recipients, five of whom were treated by steroid pulse therapy and a dose increase of Tacrolimus; the remaining two required OKT3. However, there was no episode of rejection that required retransplantation. Infectious complications encountered in 34 patients included 12 bacterial, 3 fungal, and 19 viral infections. Two recipients died one of fungal pneumonia and one of Epstein-Barr virus-associated lymphoproliferative disorder. Regarding adverse reactions of Tacrolimus, hypertension was observed in 28 patients, diabetes mellitus in 3, pancreatitis in 3, convulsion in 1, tremor in 12, itching in 5, and pigmentation in the oral mucosa in 2. Slightly increased values of creatinine were observed in most of the patients; however, an abnormal increase of serum of serum creatinine (> 1.0 mg/dl) was confined to the complicated cases. Improvement of somatic growth was observed in 21 patients (62%) and 13 (75%) at 12 and 24 months after transplantation, respectively. The long-term use of Tacrolimus is highly effective in terms of its immunosuppressive potential and reduced adverse reaction. Steady growth development can be expected in pediatric recipients free from steroids.     

The case for pancreas after kidney transplantation

Abstract:  Pancreas after kidney (PAK) transplantation has historically demonstrated inferior pancreas allograft survival compared to simultaneous pancreas and kidney (SPK) transplantation. Under our current immunosuppression protocol, we have noted excellent outcomes and rare immunological graft loss. The goal of this study was to compare pancreas allograft survival in PAK and SPK recipients using this regimen. This was a single center retrospective review of all SPK and PAK transplants performed between January 2003 and November 2007. All transplants were performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included induction with rabbit anti-thymocyte globulin (thymoglobulin), early steroid withdrawal, and maintenance with tacrolimus and sirolimus or mycophenolate mofetil. Study end points included graft and patient survival and immunosuppression related complications. Transplants included PAK 61 (30%) and SPK 142 (70%). One-yr patient survival was PAK 98% and SPK 95% (p = 0.44) and pancreas graft survival was PAK 95% and SPK 90% (p = 0.28). Acute cellular rejection was uncommon with 2% requiring treatment in each group. Survival for PAK using thymoglobulin induction, early steroid withdrawal and tacrolimus-based immunosuppression is at least comparable to SPK and should be pursued in the recipient with a potential living donor.     

Glucose metabolism after pancreas transplantation: cyclosporine versus tacrolimus

BACKGROUND: The results of the new immunosuppressants in simultaneous pancreas-kidney transplantation (SPK) concerning organ survival and rejection rates are excellent. Tacrolimus as well as cyclosporine are assumed to be diabetogenic; however, there are no comparative studies investigating their effects on glucose metabolism. METHODS: One hundred thirty-six type 1 diabetic patients who had undergone successful SPK were investigated. Glucose and insulin levels during an oral glucose tolerance test as well as hemoglobin (Hb) A1c were analyzed. Investigations were performed early (3 months, n = 136) and late (3 years, n = 83) after transplantation. Graft recipients were grouped according to the first-line immunosuppression: group 1, cyclosporine; group 2, tacrolimus. There were no differences concerning age, gender, body mass index, and renal function between the groups. RESULTS: Early after transplantation, there was no difference between the groups concerning fasting glucose, HbA1c levels, basal and stimulated insulin secretion, and incidence of normal glucose tolerance. Late after transplantation, the incidence of a normal glucose tolerance tended to be lower (70% vs. 78%), whereas HbA1c (5.3% vs. 5.0%) and fasting glucose (81 vs. 78 mg/dL) levels tended to be higher in tacrolimus-treated patients. However, these differences were not significant. Insulin secretion was not reduced in the tacrolimus group. CONCLUSIONS: Concerning glucose metabolism and secretory capacity of the pancreas graft, no significant differences were found comparing tacrolimus- versus cyclosporine-treated graft recipients.