The best magazine
What's new concerning immunosuppression in pancreas transplantation? Find out in this easy-to-navigate collection of recent MEDLINE abstracts compiled by the editors at Medscape Transplantation.
Kidney transplantation is preferred over dialysis for management of end-stage renal disease complicating type 1 or type 2 diabetes mellitus. Pancreas transplantation is the only treatment of type 1 diabetes that consistently achieves an insulin-independent, normoglycemic state, and has been shown to decrease progression of or improve most diabetic end-organ complications using current immunosuppression regimens. Currently, long-term insulin independence is achieved in > 80% of simultaneous pancreas-kidney (SPK) transplant recipients, in > 70% of pancreas after kidney (PAK) transplant recipients, and in nonuremic pancreas transplantation alone (PTA) recipients.
Stratta RJ, Alloway RR, Lo A, Hodge E
Transplantation. 2003;75:1260-1266
Background: Controversy exists about the optimal immunosuppressive regimen in simultaneous kidney-pancreas transplant (SKPT) recipients. This study determined the safety and efficacy of two dosing regimens of daclizumab compared with no antibody induction in SKPT recipients receiving tacrolimus, mycophenolate mofetil, and steroids.
Methods: A total of 297 SKPT patients were enrolled in this prospective, multicenter, randomized, open-label study. The patients were randomized into three groups: daclizumab 1 mg/kg per dose every 14 days for five doses (group I, n=107), daclizumab 2 mg/kg per dose every 14 days for two doses (group II, n=112), and no antibody induction (group III, n=78). All patients received tacrolimus, mycophenolate mofetil, and steroids as maintenance immunosuppression.
Results: Demographic and transplant characteristics were similar among the groups. At 6 months, there were no differences in patient, kidney, and pancreas graft survival rates among the three groups. The probability of either kidney or pancreas allograft rejection at 6 months was 21%, 17%, and 32% in groups I, II, and III, respectively (P=0.042). The median time to first acute rejection of either the kidney or pancreas was 23 days in group I, 44 days in group II, and 20 days in group III (group I vs. II, P=0.078; group II vs. III, P=0.016). At 6 months, the actuarial event-free survival (no acute rejection, allograft loss, or death) rates were 66%, 77%, and 56% in groups I, II, and III, respectively (group I vs. III, P=0.119; group II vs. III, P=0.002). There were no differences in the incidence of serious adverse events including infectious complications among the groups. All three groups demonstrate excellent kidney and pancreas function at 6 months.
Conclusions: Daclizumab is safe and effective in reducing the incidence of acute rejection in SKPT recipients compared with no antibody induction. Moreover, the two-dose regimen of daclizumab (2 mg/kg on days 0 and 14) compares favorably with the standard five-dose regimen.
Kaufman DB, Iii GW, Bruce DS, et al
Am J Transplant. 2003;3:855-864
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.
Vincenti F, Stock P
Transplant Proc. 2003;35(3 Suppl):S183-S186
At UCSF, we have used sirolimus in several immunosuppression regimens and protocols, and this article will summarize our experience in four areas. The purpose of the first study was to assess the efficacy of a sirolimus-based, calcineurin inhibitor-free regimen for the first 3 months after transplantation. Patients were treated with a calcineurin inhibitor-free regimen that consisted of daclizumab, sirolimus, mycophenolate mofetil (MMF), and conventional corticosteroids. Of nine patients, one (case #7) had an acute rejection episode (type IA) at 2 months after transplantation, which was fully reversed with corticosteroids. The second study was a prospective trial of calcineurin inhibitor-free regimen in patients with severe delayed graft function (DGF) (requiring dialysis). The immunosuppression regimen consisted of daclizumab, sirolimus, MMF, and corticosteroids. This immunosuppressive regimen was effective in patients with DGF; however, it was effective only in non-African American (non-AA) patients (AA had a significantly higher acute rejection rate at 1 year than non-AA, 63% vs 23%, P = .025). In some patients sirolimus was associated with a prolonged recovery from DGF. The addition of sirolimus to immunosuppressive agents provides the opportunity for safe steroid withdrawal (at day 5). We participated in a sirolimus-based, multicenter open-label trial of very early corticosteroid withdrawal. Primary renal transplant patients were enrolled in an immunosuppression regimen that consisted of basiliximab, sirolimus (target levels 8 to 15 ng/mL, 0 to 5 months, and 6 to 12 ng/mL, 6 to 12 months) and tacrolimus in a dose of 0.05 mg/kg BID (target levels 6 to 9 ng/mL). Two of 14 enrolled patients had an episode of acute rejection before steroids were withdrawn. No acute rejection episodes have occurred after steroids were withdrawn (6-month follow-up). The regimen of sirolimus and tacrolimus was well tolerated. Wound complications were not noted. Another important use of sirolimus has been its incorporation in the immunosuppressive regimens in kidney-pancreas transplantation. Our current protocol consists of thymoglobulin induction, combined with MMF, sirolimus, and low-dose tacrolimus, for maintenance therapy. Steroids are only utilized during the first 5 to 6 days following the transplant. This steroid-free maintenance regimen has been used in the last 30 enteric-drained, simultaneous pancreas-kidney transplants. Using this immunosuppressive approach, rejection rates are less than 10% for either the kidney or the pancreas.
Knight RJ, Kerman RH, Zela S, et al.
Transplantation. 2003;75:1301-1306
Background: We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection.
Methods: A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL.
Results: The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5±1 (mean±standard deviation). With a mean follow-up of 13.6±4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9±3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2±0.3 mg/dL, fasting glucose was 88±15 mg/dL, and sirolimus dose at month 3 was 6.3±3 mg per day and at month 12 2.7±1 mg per day. The average total daily cyclosporine A dose at month 3 was 208±62 mg per day and 133±13 mg per day at 1 year.
Conclusions: This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.
Bonatti H, Berger N, Kafka R, et al.
Ann Transplant. 2002;7:22-27
Background: New immunosuppressive protocols and advanced surgical technique resulted in a major improvement in the outcome of pancreatic transplantation.
Patients and Methods: 112 enteric drained whole pancreas transplants (PTx) performed at the Innsbruck University Hospital between 3.1997 and 10.2001 were retrospectively analysed. Prophylactic immunosuppression consisted of FK506, MMF and steroids. A short course of high dose ATG induction was given additionally. Perioperative antimicrobial prophylaxis consisted of Amoxicillin/Clavulanic (32 PTx), Piperacillin/Tazobactam (68 PTx), quinolones (10 PTx) or macrolide (2 PTx). 64 patients additionally received fluconazole.
Results: Actuarial patient, pancreas and kidney graft survival at one year were 96.4%, 86.7% and 95.3%, surgical complication rate was 28%, rejection rate 40%. Eight grafts were lost due to intraabdominal infection, seven due to rejection. Median perioperative observation days (OD) were 29 (range 14-125), patients were on antibiotics for 68% of OD, and developed fever on 33% of OD. Incidence of CMV infection was 42% (but only five patients developed CMV disease), HSV 24%, intraabdominal infection 22%, UTI 11%, wound infection 9% and pneumonia: 5%.
Conclusion: ATG short course induction is well tolerated after enteric drained PTx. Infection represents a frequent and at least for IA sepsis serious complication after PTx with enteric drainage.
Tan M, Cantarovich M, Mangel R, Paraskevas S, Fortier M, Metrakos P
Clin Transplant. 2002;16:414-418
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.
Trofe J, Stratta RJ, Egidi MF, et al
Clin Transplant. 2002;16(Suppl 7):34-44
Purpose: To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil.
Methods: Retrospective, single centre analysis of 45 patients transplanted between 1995 and 2000 who received 54 courses of thymoglobulin, including 36 courses in 29 solitary pancreas transplant recipients (16 pancreas alone, 13 pancreas after kidney transplants) and 18 courses in 16 simultaneous kidney-pancreas transplant patients. Thirty-two patients (71%) were primary pancreas transplants, 10 (22%) were second transplants and three (7%) were third transplants. Of the 54 treatment courses, 19 (35%) were for induction, 27 (50%) were for primary rejection and eight (15%) were rescue therapy for rejection. All rejection episodes were biopsy-proven in at least one organ.
Results: The median thymoglobulin dose was 1.5 mg/kg/d with a mean of six doses (range 3-10). Dose reduction or interruption was required in 28 courses (52%), most often due to leukopenia (n = 24), fever (n = 2) and thrombocytopenia (n = 2). Thymoglobulin was resumed in all but three patients, two with persistent fever and one with infection. Infectious complications (n = 25) occurred in 17 patients (38%) within 30 days and included bacterial (n = 16), cytomegalovirus (n = 4), polyoma (n = 1), fungal (Candida albicans, n = 1), toxoplasmosis (n = 1) and ehrlichiosis (n = 2). Post-transplant lymphoproliferative disease occurred in two patients (4%) at a mean of 70 d post-thymoglobulin treatment. In the 19 patients that received thymoglobulin induction, one simultaneous kidney-pancreas transplant, two pancreas alone and four pancreas after kidney transplant recipients developed rejection (37% incidence), while all remaining patients followed by surveillance protocol biopsies were rejection-free. In the 35 patients that received thymoglobulin for rejection, reversal occurred in 26 of the patients (74%). Rejection recurred within 30 d in five patients and post-treatment biopsies revealed persistent rejection in three of 20 pancreas and two of eight renal biopsies. After a mean follow-up of 6 months, the actual patient and pancreas graft survival rates were 93% and 71%, respectively.
Conclusion: Thymoglobulin was effective as induction therapy in high-risk pancreas transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population.
Trofe J, Gaber LW, Stratta RJ, et al
Transpl Infect Dis. 2003;5:21-28
Purpose: To report the incidence and clinical characteristics of polyomavirus (PV) nephritis in kidney (KTX) and kidney-pancreas transplant (KPTX) recipients.
Methods: Single center retrospective analysis of all cases of PV nephritis in KTX and KPTX patients transplanted between 1994 and 1999.
Results: Thirteen (5 KTX and 8 KPTX) patients (2.1%) had PV nephritis diagnosed on multiple biopsies (n = 22) among 504 KTX and 106 KPTX recipients. The incidence of PV nephritis was higher in cadaver donor transplants (2.6% cadaver vs. 0.7% living donors), after KPTX (1% KTX vs. 7.5% KPTX), in males (3.3% male vs. 0.7% female), and in diabetic patients (4.4% diabetic vs. 0.8% nondiabetic). The mean time to diagnosis of PV nephritis was 18 (range 6-48) months after KTX and 17 (range 9-31) months after KPTX. Three KTX patients and 5 KPTX patients had calcineurin inhibitor toxicity on biopsy prior to developing PV nephritis. Reduction in immunosuppression occurred in 100% of KTX and 63% of KPTX patients. Three patients (23%) developed rejection within 3 months of diagnosis of PV, 1 after a reduction in immunosuppression. Despite multiple antiviral treatment regimens, renal allograft failure requiring dialysis occurred in 60% of KTX and 50% of KPTX patients. All KPTX patients remain insulin independent and 2 were successfully retransplanted with living donor kidneys. 2 patients (15%) died but there was no mortality directly related to the virus.
Conclusions: Polyomavirus nephritis may be increasing in incidence and appears to be unresponsive to either conventional antiviral agents or a reduction in immunosuppression. Most of our cases occurred in male diabetic patients undergoing cadaveric donor transplantation and were preceded by biopsy-proven nephrotoxicity. Further studies are needed to better define the pathogenesis of PV and effective antiviral treatment.
Haririan A, Hamze O, Drachenberg CB, Ramos E, Weir MR, Klassen DK
Transplantation. 2003;75:1186-1190
Background: Polyomavirus infection is common in childhood, with a seroprevalence of 60% to 100%. These viruses remain latent mostly in the kidney. Impairment in cellular immunity can allow reactivation of the virus. Reactivation can occur in 10% to 45% of renal allografts. A higher intensity of immunosuppression and the allogeneic microenvironment of the graft have been suggested to predispose to reactivation. There are limited data on the status of viral activity in the native kidneys of non-renal solid organ recipients.
Methods: Thirty-eight recipients of pancreas transplant alone were evaluated for evidence of polyomavirus reactivation by urine cytology. All had received induction therapy and were maintained on tacrolimus, mycophenolate mofetil, and prednisone. The renal function and degree of exposure to immunosuppressive agents of patients shedding polyomavirus-infected renal tubular cells were compared with those of patients with negative urine cytology.
Results: Screening cytology was performed 16 months (mean) after transplantation. Four subjects (11%) had polyomaviruria. The renal function at baseline and time of screening was comparable between the two groups. The 12-hour trough levels of tacrolimus were significantly higher in patients with positive cytology compared with those without viruria. The doses of mycophenolate mofetil and prednisone were not different between the two groups.
Conclusion: This study shows that polyomavirus reactivation in native kidneys and urinary tract of pancreas transplant alone patients is not uncommon. In these recipients, viral reactivation was not associated with significant renal functional impairment. The results also suggest that patients who are exposed to higher blood levels of tacrolimus are at higher risk of viral reactivation.
Al-Jedai AH, Honaker MR, Trofe J, et al
Transplantation. 2003;75:490-494
Background: Polyomavirus (PV) infection in kidney transplant patients has been reported to cause interstitial nephritis and subsequent graft loss. The cornerstone of current therapy is a reduction in immunosuppression, which can subsequently lead to kidney allograft rejection. This dilemma becomes even more challenging in the setting of simultaneous kidney-pancreas transplantation, because a reduction in immunosuppression may result in rejection of the pancreas allograft. Antiviral therapy has not been shown to be clinically successful in decreasing the risk of graft loss secondary to PV infection. Furthermore, because of limited experience, the decision to perform retransplantation in patients who lost their primary kidney grafts to PV interstitial nephritis becomes a difficult one.
Methods: Retrospective review and case studies.
Results: We report two successful living donor kidney retransplants in simultaneous kidney-pancreas transplant patients who lost their first kidney grafts to PV infection. Both patients are receiving rimantadine therapy and performing well, with functioning kidney and pancreas grafts and no evidence of recurrent PV interstitial nephritis 22 and 37 months after retransplantation.
Conclusions: Although follow-up is limited, our initial experience would indicate that graft loss secondary to PV interstitial nephritis is not an absolute contraindication for kidney retransplantation.
Source: ...