Early outcome of different steroid-free regimens in small bowel transplantation: a large-animal study

The intestine is a highly immunogenic organ that requires heavy immunosuppression (IS); therefore corticosteroid withdrawal after clinical small bowel transplantation (SBT) has not been standardized. In this study, we compared different immunosuppressive regimens (none with steroid or induction treatment) in a SBT pig model. Large White unrelated piglets were transplanted and divided into four groups as follow: group 1 (n = 3): no IS; group 2 (n = 10): IS with tacrolimus only; group 3 (n = 10): IS with tacrolimus and mycophenolate mofetil; group 4 (n = 5): IS with tacrolimus and rapamycin. Follow-up time was 30 days. All IS drugs were given orally; tacrolimus whole blood levels ranged between 5 and 15 ng/mL in all groups except for group 2 whose tacrolimus whole blood levels ranged between 15 and 25 ng/mL. Group 1 pigs died of graft acute rejection (ACR) after a median of 12 days. Overall survival in groups 2, 3, and 4 at day 30 was 40%, 80%, and 60%, respectively. Biochemical parameters, including glycemia and cholesterol, were into the normal range with no significant differences between groups. At the end of the study, one animal in group 2 and another one in group 4 showed histological signs of moderate to severe ACR. The incidence of infection was higher in group 2 (2.1 episodes/pig) compared to group 3 (1.25) and group 4 (1.6). This large-animal study demonstrates that tacrolimus-based IS without corticosteroids allows, in the early postoperative period (30 days) after SBT, good survival rates without an increased risk in the incidence of rejection.     

Pilot study of early corticosteroid elimination after pancreas transplantation

Early corticosteroid withdrawal has recently been shown to be possible in recipients of simultaneous pancreas kidney transplants; however, its feasibility in solitary pancreas recipients has not been documented. In the present study, we provide evidence that early withdrawal can be achieved in pancreas as well as pancreas-kidney recipients. METHODS: Twenty type I diabetics underwent 13 pancreas-kidney transplants and 7 pancreas-only transplants with early withdrawal (methylprednisone 6-day taper). Additional immunosuppression consisted of tacrolimus, mycophenolate mofetil, and thymoglobulin induction (five doses). RESULTS: Transplants included 13 pancreas-kidney, 6 pancreas after kidney transplant, and 1 pancreas after islet transplant. Overall mean follow-up was 7.3 months. One episode of pancreas transplant rejection after pancreas-only transplant was detected on protocol biopsy without biochemical abnormalities. One renal allograft rejection occurred 65 days posttransplant in a pancreas-kidney recipient and was graded as a Banff IA rejection. A single pancreas graft loss occurred due to thrombosis 6 days after pancreas-kidney transplantation. CONCLUSIONS: These results indicate that relatively short thymoglobulin induction (five doses) with tacrolimus and mycophenolate mofetil can allow early withdrawal in both pancreas-kidney and pancreas-only transplant recipients.     

Polyomavirus nephropathy after renal transplantation: a single centre experience

BACKGROUND: Polyomavirus associated nephropathy (PVN) in renal transplant recipients has been observed with increasing frequency recently and has emerged as a cause of allograft failure linked to highly potent new immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). METHODS: Polyomavirus associated nephropathy was identified in nine out of 182 patients who received renal transplantation between October 1998 and July 2003. PVN was confirmed by allograft biopsy. The clinical records of these nine patients were reviewed, as were all of the allograft biopsies. Electron microscopy was performed in all nine cases. After the diagnosis of PVN, maintenance immunosuppression was reduced. The clinical course and outcome of the PVN patients were reviewed in relation to manipulation of immunosuppressive agents. RESULTS: There were nine cases of PVN in renal transplant recipients and the incidence of PVN was 4.9%. All patients with PVN were under triple immunosuppression comprising tacrolimus and MMF. The mean time to a diagnosis of PVN was 7.8 months after transplantation. Three of the nine patients received antirejection therapy prior to PVN. Seven out of nine PVN patients presenting acute allograft dysfunction were initially treated with high-dose intravenous steroid pulse or OKT3 before reduction of the immunosuppression. After reduction of the immunosuppression, seven patients stabilized their renal function. Two (22%) lost their grafts due to persistent PVN and chronic rejection. Two (22%) patients later developed acute rejection after reduction of the immunosuppression. CONCLUSION: PVN can cause allograft dysfunction and graft loss. Renal allograft recipients who are at risk of PVN should be routinely screened with urine cytology and quantitative measurements of viral load in the blood, particularly patients who had graft dysfunction. Early diagnosis and judicious alteration of immunosuppressive agents might permit a superior prognosis and reduce the graft loss from PVN in renal transplant recipients.     

Simultaneous kidney-pancreas transplantation without antilymphocyte induction

BACKGROUND: The introduction of potent new immunosuppressive agents may allow simultaneous kidney-pancreas transplantation to be performed without antilymphocyte induction. METHODS: We analyzed 30 simultaneous kidney-pancreas transplantations receiving tacrolimus, mycophenolate mofetil, and steroids without without antilymphocyte induction. Eighteen patients underwent pancreas transplantation with portal-enteric (P-E) drainage and the remaining 12 had systemic bladder (S-B) drainage. Target 12 hr trough tacrolimus levels for the first 3 months after simultaneous kidney-pancreas transplantation were 15-20 ng/ml. The oral mycophenolate mofetil dose was 2-3 g/day begun immediately posttransplant in two to four divided doses. Steroids were tapered according to protocol. RESULTS: All patients experienced immediate function of both kidney and pancreas grafts. One-year actuarial patient, kidney, and pancreas graft survival rates are 93, 93, and 90%, respectively. Nine patients (30%) had a total of 13 rejection episodes (12 biopsy proven) including 4 within 2 weeks, 6 between 2 weeks and 3 months, and 3 beyond 3 months after simultaneous kidney-pancreas transplantation. Three rejection episodes were treated with steroids alone and 10 were treated with antilymphocyte therapy (5 OKT3 and 5 ATGAM). A total of seven patients (23%) received antilymphocyte therapy. Three patients (10%) had more than one rejection episode. Two pancreas grafts (7%) and one kidney graft (3%) were lost from rejection. Four patients (13%) developed cytomegalovirus infection, but none had tissue-invasive cytomegalovirus. At present, 22 surviving patients (81%) remain on triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone with excellent dual graft function. CONCLUSION: Tacrolimus, mycophenolate mofetil, and prednisone immunosuppression without without antilymphocyte induction is safe and effective after simultaneous kidney-pancreas transplantation.     

Decreased incidence of acute rejection in adolescent kidney transplant recipients using antithymocyte induction and triple immunosuppression

BACKGROUND: Acute rejection is a frequent event in pediatric renal transplantation; it can diminish allograft function and affect long-term outcome. Recent data from the North American Pediatric Renal Transplant Cooperative Study indicates that the rate of acute rejection remains high despite current immunosuppressive regimens. METHODS: In this retrospective series, we examined 37 pediatric renal transplant recipients who received induction doses of antithymocyte globulin combined with maintenance immunotherapy using tacrolimus, mycophenolate mofetil, and prednisone. The postoperative course was reviewed for initial and total hospital stay, number of rehospitalizations, evidence of posttransplant complications, graft fibrosis, and overall patient and graft survival. RESULTS: Three episodes of acute rejection (8.1%) were recorded in the first year posttransplant. The median initial hospital stay for patients receiving a kidney transplant was 8 days. Patient and graft survival were 100% and 91.9% at 1 year, respectively. The incidence of viral infection (cytomegalovirus, BK virus, and Epstein-Barr virus) and posttransplant lymphoproliferative disease remained low. Urinary tract infection and fluid and electrolyte complications were the main causes of posttransplant hospitalization. CONCLUSIONS: We conclude that induction with antithymocyte globulin and maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone should be considered a valuable tool in the management of children undergoing renal transplantation.     

Compromised kidney graft rejection response in Vervet monkeys after withdrawal of immunosuppressants tacrolimus and sirolimus

BACKGROUND: In nonprimates, organ allografts are often not rejected after withdrawal of immunosuppression. In this study, we examined whether such a phenomenon also occurs in primates. METHODS: Vervet monkeys were transplanted with renal allografts and treated for 60 days with tacrolimus, or tacrolimus plus sirolimus. The drugs were totally withdrawn on day 61. The survival of the monkeys was monitored, and their response to donor- or third party-derived alloantigens was examined in vivo and in vitro. RESULTS: The majority (80-100%) of the grafts survived for at least additional 30 days with no signs of acute rejection. The compromised rejection is donor-specific, because recipient monkeys failed to reject a donor-derived skin graft, but a third-party skin graft was rejected. In vitro mixed lymphocyte reaction and interleukin-2 production in the mixed lymphocyte reaction between the recipients and their donors or between the recipients and a third party had no discernable patterns, and thus did not reflect the in vivo status of the immune system. Although the recipients could not reject the graft acutely after drug withdrawal, the kidney grafts and the donor-derived skin grafts had pathological findings of chronic rejection. CONCLUSIONS: The rejection response of the monkeys to an established graft after withdrawal of immunosuppression is compromised. The compromised rejection is specific and is not due to a permanent alteration of the immune system by the initial drug treatment. The allografts are not inert but have low levels of interaction with the recipient immune system.     

Immunologic benefits of longer graft in rat allogenic small bowel transplantation

BACKGROUND: The effect of graft length on rejection reaction in small bowel transplantation (SBT), which is poorly understood, is tested using rat allogenic SBT models with a short course of tacrolimus. MATERIALS AND METHODS: Inbred Brown Norway rats (major histocompatibility complex: RT1) and Lewis rats (RT1) were used as donors and recipients, respectively. The intestinal tract of the recipient was partially or totally replaced by segmental (15 cm) or whole (70 cm) donor intestine, using two different SBT models. With tacrolimus treatment (0.64 mg/kg per day, 0-13 postoperative days, intramuscularly), recipients' body weights and their survival were evaluated. To compare the extent of peripheral chimerism, donor passenger leukocytes were followed using flow cytometry with a donor-specific monoclonal antibody, OX-27. For the periodical histologic analysis, heterotopic SBT and protocol biopsies of the graft were also performed with short or long intestinal grafts. RESULTS: In a classical Monchik and Russell orthotopic SBT model, whole SBT recipients survived more than 60 days. However, all of the allogenic segmental SBT recipients died within 14 days without histologic sign of graft rejection. In the modified orthotopic SBT model using a cuff technique without systemic clamping, all recipients with segmental allograft survived longer than 29 days. However, recipients with whole graft tended to survive longer than those with segmental graft. The suffering period, lasting from the onset of rejection to death, was significantly shorter in the segmental group than in the whole group. Flow cytometric analysis showed that recipients with whole intestinal grafts had significantly higher ratio of donor passenger leukocytes in peripheral blood. Histologic studies of the protocol biopsies showed that the shorter graft tended to be more severely rejected than the longer graft. CONCLUSIONS: We have demonstrated experimentally that long intestinal grafts have immunologic advantage over short grafts.     

Tacrolimus monotherapy in adult cardiac transplant recipients: intermediate-term results.

Background: Tacrolimus (FK506) is a macrolide antibiotic that inhibits T-cell activation and proliferation. To date, all published trials have used tacrolimus and steroids in combination with either azathioprine or mycophenolate mofetil. Previous experience with pediatric cardiac transplant patients at our institution suggested that use of tacrolimus alone provides an adequate level of immunosuppression and that withdrawal of steroids is readily achieved in most recipients.Between January 1, 1996, and July 7, 1999, we performed 77 adult cardiac transplants. Forty-three of these patients received tacrolimus and prednisone as primary immunosuppression, without azathioprine or mycophenolate mofetil. Thirty-two of the 43 patients started on tacrolimus have been weaned off steroids and are maintained on monotherapy. These latter patients form the basis of this report.The mean time for achieving monotherapy was 246 +/- 127 days (range, 106 to 730). Grade > or = 2 rejection occurred at 0.40 episodes per patient in the first 90 days (a combination of Grades 2 and 3A/3B rejections). The freedom from treated rejection (includes all 3A/3B and Grade 2 rejection in the first 90 days) was 69% at 90 days and 52% at 1 year. One patient (of 32) had documented cytomegalovirus infection (gastritis) diagnosed at 8 months post-transplant. We observed 1 case of transplant vasculopathy and 1 case of post-transplant lymphoproliferative disorder during the follow-up period.Our results show that use of tacrolimus alone after steroid weaning provides effective immunosuppression with low incidence of rejection, cytomegalovirus infection, transplant arteriopathy, or post-transplant lymphoproliferative disease.     

Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.     

Steroid withdrawal or steroid avoidance in renal transplant recipients: focus on tacrolimus-based immunosuppressive regimens

Steroid-induced adverse effects after transplantation include cosmetic, metabolic, and cardiovascular complications. Steroid withdrawal or avoidance with cyclosporine-based regimens have been hampered by an unacceptably high rate of acute rejections and increased rates of graft loss. Recently the results of several large, randomized trials of steroid withdrawal/avoidance with tacrolimus-based immunosuppression in renal transplant recipients became available. A review of these trials appeared to be of clinical interest. Data from the THOMAS trial clearly indicate that steroid withdrawal from a regimen of tacrolimus, mycophenolate mofetil (MMF), steroids after 3 months after transplantation is safe with regard to acute rejection rate and graft survival. If an induction therapy with daclizumab is used in combination with tacrolimus and MMF (CARMEN trial), even steroid avoidance is safe with regard to acute rejection rate and graft survival. Finally, in the ATLAS trial, steroid avoidance with basiliximab in combination with tacrolimus (resulting in tacrolimus monotherapy) or alternatively with tacrolimus and MMF both resulted in similar graft survival, but higher rates of acute rejection. In conclusion, steroid withdrawal is safe from a triple-drug regimen of tacrolimus, MMF, and steroids after 3 months after transplantation, and steroid use may completely be avoided with tacrolimus, and MMF combined with daclizumab induction. Tacrolimus monotherapy may be achieved using basiliximab induction at the price of higher rates of acute rejection, but with unaffected graft survival. Thus tacrolimus-based immunosuppression with or without interleukin-2 receptor antagonist induction has made steroid withdrawal or avoidance a realistic option in renal transplantation.     

Maintenance immunosuppression: new agents and persistent dilemmas

Since the approval of cyclosporine in 1983, only 3 drugs, mycophenolate mofetil, tacrolimus, and sirolimus, have been approved for maintenance immunosuppression in renal transplant recipients. All 3 agents decrease the incidence of early acute allograft rejection. An increase in intermediate and long-term graft survival has not been shown. However, survival data from these clinical trials should be interpreted with caution because the studies were not designed for this purpose. All 3 drugs have significant, albeit different, safety profiles. It remains to be seen whether, the lower incidence of hypertension and hyperlipidemia seen in tacrolimus-treated patients will reduce the incidence and severity of the cardiovascular disease experienced by renal transplant recipients. Sirolimus causes severe hyperlipidemia, and the long-term consequences both on the pathogenesis of cardiovascular disease and on lipid-associated renal injury have yet to be determined. Tacrolimus and mycophenolate mofetil appear to increase graft survival in pancreas-kidney recipients but their efficacy in another high-risk group, African-American recipients, has not yet been clearly shown. However, the trend toward improved graft survival in African-American recipients treated with tacrolimus is encouraging. Steroid-withdrawal remains a goal in the posttransplant period. The available data from steroid-withdrawal and steroid-avoidance clinical trials are mixed. Steroid withdrawal can be achieved in about 50% of patients on a cyclosporine-based immunosuppression regimen. Steroid-withdrawal under coverage of tacrolimus, mycophenolate mofetil or Neoral (Novartis Pharmaceuticals, East Hanover, NJ) may be more successful than that achieved in patients receiving Sandimmune (Novartis Pharmaceuticals). Further studies are needed in this area.     

BK virus infection in kidney transplant recipients

INTRODUCTION: Nephropathy associated with the polyomavirus type BK virus (BKV) has emerged as a cause of allograft failure linked to immunosuppressive regimens containing tacrolimus or mycophenolate mofetil (MMF). The outcome in BKV nephropathy is generally unfavorable, namely 50% of patients lose graft function. We herein report nine cases of BKV nephropathy after kidney transplantation. METHODS: From October 1998 to May 2003, 138 of 169 consecutive kidney transplant patients received tacrolimus-based immunosuppression, and 31 received cyclosporine-based immunosuppression. Additionally, 88.2% of the patients received mycophenolate mofetil (MMF). The diagnosis of BK infection was made by the presence of decoy cells in the urine and by allograft biopsy. RESULTS: There were nine cases of BKV nephropathy in kidney transplant recipients, an incidence of 5.3%. All patients with BKV nephropathy received tacrolimus, MMF, and steroids. The median time to diagnosis of BKV infection was 7.8 months after transplantation. All patients experienced an elevated serum creatinine, which stabilized or decreased in seven patients with altered or decreased immunosuppression. After a mean follow-up of 11.1 months, 2 (22.2%) of nine patients lost the graft. CONCLUSION: Because BKV nephropathy is a rare but serious complication after kidney transplantation, it should be included in the clinical differential of transplant dysfunction. In the absence of documented antiviral treatment, early diagnosis and judicious use of immunosuppressive agents is indicated to minimize the occurrence of BKV infection.     

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.     

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective,randomized clinical trial

In a phase 2 multicenter open‐label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas‐kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)–based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low‐dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy‐proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.     

Bone marrow augmentation in kidney transplantation: a large animal study

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days –2, –1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45 % of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression – irrespective of indefinite or short-term administration – was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosuppression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants. Received: 6 June 2000 Accepted: 28 December 2000     

Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.     

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis

BACKGROUND: Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. METHODS: Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. RESULTS: There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5-40%) compared with 6% (range, 0-10%) in those with acute rejection (P=0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2-15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15-30%) in those patients who had acute rejection (P=0.0159). CONCLUSION: Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.     

Corticosteroid weaning in the tacrolimus and mycophenolate era in heart transplantation: clinical and neurohormonal benefits

BACKGROUND: Compared with cyclosporine, tacrolimus-based immunosuppression yields improved metabolic outcomes in heart transplantation. Whether corticosteroid freedom provides incremental metabolic benefits in tacrolimus and mycophenolate mofetil immunoprophylaxis remains uncertain. METHODS: In a prospective trial, 41 heart transplant patients treated with tacrolimus and mycophenolate mofetil underwent steroid weaning immediately after transplantation until weaning was complete. Weaning was interrupted only for treated rejection with or without hemodynamic compromise. Benefits of steroid weaning assessed following the first year included B-type natriuretic peptide (BNP), late infections, lipids, blood pressure, hyperglycemia, and body mass index (BMI). RESULTS: Of this 41 patient cohort (age 53 +/- 9 years, 50% black American, 35% women) followed for a total of 47 +/- 5 months, 25 had corticosteroids discontinued (62%) by an average of 20 +/- 11 months. No differences between the two groups were noted in baseline characteristics. Significant predictors of failure to wean steroids included higher rejection, BNP, and lower dose of mycophenolate mofetil. No significant benefits of steroid weaning were noted on lipids, blood pressure, hyperglycemia, and BMI. However, late infections (after 1 year) requiring hospitalizations were more frequent in the failure to wean group (0.60.4 vs 0 infections/patient/y, P <.001). INFERENCES: Unlike known metabolic benefits of steroid withdrawal with cyclosporine, heart transplant recipients treated with tacrolimus and mycophenolate mofetil demonstrate no incremental metabolic benefits, but instead experience benefits of decreased serious late infections. Furthermore, failure to discontinue corticosteroids in this series is predicted by early allograft rejection, use of lower doses of mycophenolate mofetil, and higher BNP levels suggesting poor cardiac adaptation.     

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.     

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.