tacrolimus and Substance-Withdrawal-Syndrome

Diagnosis of immunologic injury (acute and chronic) is much more difficult in pancreas transplants when compared with transplants of other organs. Currently, the immunosuppressive regimen for induction involves calcineurin inhibitors (CNI), antimetabolites and corticosteroids (Cs). This strong and nonspecific regimen does not take into consideration pancreas specificities (i.e. the need to avoid diabetogenic compounds). For obvious reasons, CNI might be calling for review, if permanently indicated in recipients of solitary pancreas with mild renal dysfunction. CNI as well as corticosteroids may induce hyperglycemia and contribute to differential diagnosis of a rejection process. However, in spite of the benefits accruing from withdrawal of above immunosuppressive agents, minimization or avoidance of these drugs could be dangerous and may end up with graft loss (i.e. antibody-mediated process). Long-term results of pancreas transplantation are now achieving comparable survival rates similar to the transplant of traditional organs such as kidney and liver. As a consequence, the physicians' objectives are to prolong the patient's quality of life and organ function as long as possible. Weaning strategies in regard to CNI and steroids are tested. Sirolimus, everolimus, CTLA-4 Ig, etc, are agents known to be either both nonnephrotoxic and nondiabetogenic or less so when compared with CNI. Their impact on pancreas transplantation is beginning to be evaluated. Large randomized trials in all pancreas categories, with long-term clinical and histologic results, are mandatory to establish new guidelines for immunosuppressive regimens for pancreas transplantation.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Sirolimus; Substance Withdrawal Syndrome; Tacrolimus

Introduction of new innovative immunosuppressive strategies has been the milestone of the recent evolution of intestinal and multivisceral transplantation. With new insights into the mechanisms of organ engraftment and acquired tolerance, the Pittsburgh tolerogenic protocol was recently introduced and consisted of two main therapeutic principles: recipient pretreatment with lymphoid ablating antibodies and minimal post-transplant immunosuppression with tacrolimus monotherapy. The reported herein improved survival and the striking ability to wean immunosuppression among the intestinal and multivisceral recipients pretreated with a single-dose of Thymoglobulin (rATG) or Campath-1H (alemtuzumab) supports our working hypothesis with successful induction of variable tolerance. It is important, however, that careful monitoring of subtle histologic changes in serial endoscopic-guided mucosal biopsies be carried out for early diagnosis of allograft immune activation with prompt restoration of the baseline immunosuppressive therapy. Future scientific discoveries with better understanding of the mechanisms of immune tolerance and clinical introduction of reliable assays will increase the chance and safety of achieving complete tolerance among the intestinal and other solid organ recipients. This review will focus on the historic evolution of the immunosuppressive and other management strategies utilized for the intestinal and multivisceral recipients at the University of Pittsburgh with special reference to allograft immunity and the successful achievement of partial tolerance.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Calcineurin Inhibitors; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestines; Opportunistic Infections; Substance Withdrawal Syndrome; Tacrolimus; Transplantation Conditioning; Transplantation Tolerance; Transplantation, Homologous

BK virus (BKV) is a significant post-transplant infection. Mammalian target of rapamycin inhibitors (mTORis) reduce BKV large T antigen expression in vitro and are associated with lower rates of BKV infection when used as de novo immunosuppression in clinical studies.. Forty patients were enrolled and randomized in a 1:1 manner; 11 (55%) and 8 patients (40%) reached the primary endpoint in the everolimus group and the MMF group, respectively (P = .53). Of those with BK viremia at the time of enrollment, 8 of 16 (50%) and 5 of 15 (33.3%) cleared the viremia by month 3 in the everolimus conversion and MMF dose reduction groups, respectively (P = .47).. Conversion from MMF to everolimus in BKV infection demonstrated a trend toward improved viral clearance but did not reach statistical significance.

Topics: Adult; Aged; BK Virus; Drug Substitution; Everolimus; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Polyomavirus Infections; Postoperative Complications; Prospective Studies; Substance Withdrawal Syndrome; Tacrolimus; Tumor Virus Infections; Viremia

Calcineurin inhibitors (CNIs) have an unfavorable cardiovascular risk profile in renal transplant recipients. The aim of this substudy was to assess the effects of late CNI or mycophenolate mofetil (MMF) withdrawal on ambulatory blood pressure monitoring and carotid intima media thickness.. A total of 119 stable renal transplant recipients on triple regimen with steroids, a CNI and MMF were randomized into either the concentration-controlled CNI or MMF withdrawal groups. Patients were treated for traditional cardiovascular risk factors according to predefined targets. Ambulatory blood pressure monitoring and measurements of intima media thickness were performed at baseline and after 1, 2, and 3 years after randomization.. CNI withdrawal resulted in a significant decline in both ambulatory day- and nighttime blood pressures (daytime: systolic blood pressure, -1.6 mm Hg/y, P=0.018; diastolic blood pressure, -1.3 mm Hg/y, P=0.002; nighttime systolic blood pressure: -1.9 mm Hg/y, P=0.008; diastolic blood pressure: -1.3 mm Hg/y, P=0.014), which was not observed after MMF withdrawal. There was no difference in the proportion of nocturnal nondippers (both groups, 69%, P=0.95). Despite the reduction in ambulatory blood pressure, no effect of CNI withdrawal on carotid intima media thickness was found.. In stable renal transplant recipients, late CNI withdrawal from a triple drug regimen decreased blood pressure in comparison with MMF withdrawal but had no specific impact on carotid intima media thickness. Considering the high prevalence of hypertension in patients on CNI therapy, most stable renal transplant recipients may benefit from late CNI withdrawal by improved blood pressure control.

Topics: Adult; Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcineurin Inhibitors; Carotid Intima-Media Thickness; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Steroids; Substance Withdrawal Syndrome; Tacrolimus; Treatment Outcome

Prospective, long-term data on corticosteroid withdrawal (CSW) versus corticosteroid continuation (CSC) following kidney transplantation are scarce.. The Mycophenolic Renal Transplant (MORE) Registry was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA) and standard of care. Adult patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at time of transplant were analyzed to 4 years according to CSW by month 3 (n=363) or CSC (n=509).. In the CSW and CSC groups, 3.3% and 13.0% had undergone retransplantation (p<0.001), 89.9% and 77.0% had panel reactive antibodies <30% (p<0.001), and 72.5% and 87.2% received pretransplant dialysis (p<0.001), respectively. Rabbit antithymocyte induction was used in 62.3% of CSW patients and 58.6% of CSC patients (p=0.015), and alemtuzumab in 23.7% and 4.7%, respectively (p=0.002). At all time points to 3 years post-transplant, significantly fewer CSW patients were maintained on the full recommended dose of MPA versus CSC patients. Biopsy-proven acute rejection occurred in 10.1% and 14.3% of CSW and CSC patients (p=0.12), graft survival was 96.9% versus 93.7% (p=0.030), and patient survival was 95.6% versus 95.0% (p=0.65), respectively. Adverse events were similar except for leukopenia (CSW 60.6%, CSC 29.9%; p<0.001) and neutropenia (CSW 17.4%, CSC 11.4%; p=0.013), with infections in 24.8% and 30.8% of CSW and CSC patients, respectively (p=0.057).. CSW patients were less likely to receive the full dose of MPA than CSC patients, possibly due to induction-related hematological toxicity. Graft survival to 4 years post-transplant was superior in CSW patients.

Topics: Abdomen, Acute; Adrenal Cortex Hormones; Adult; Aged; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Registries; Substance Withdrawal Syndrome; Tacrolimus; Treatment Outcome

Islet transplantation has been reported to induce allosensitization in the majority of type 1 diabetic recipients of fresh or shortly incubated islet grafts prepared from one to three donors.. We examined the appearance of human leukocyte antigen (HLA) antibodies after withdrawal of immunosuppressants in 35 type 1 diabetic recipients of islet cell grafts prepared from a median of 6 donors (range, 2-11), cultured for longer periods, and characterized for their cellular composition. Immunosuppression consisted of antithymocyte globulin induction followed by mycophenolate mofetil plus calcineurin inhibitors (n=28, with 7 also receiving steroids) or sirolimus with (n=3) or without calcineurin inhibitors (n=4). Both the complement-dependent cytotoxicity (CDC) assay (class I) and the solid-phase flow-based Luminex method (class I and II) were used to identify HLA antibodies.. Immunosuppressant withdrawal resulted in CDC positivity for class I antibodies in only 6% of patients. However, the majority became positive for class I antibodies (72%) or class II antibodies (72%) in the Luminex assay; positivity was not correlated to a higher number of donors or HLA mismatches, but with a lower β-cell purity; use of steroids reduced de novo positivity for Luminex class I antibodies.. Allosensitization to cultured human islet cell grafts was low when assessed by CDC assay but high in Luminex. No correlation was found with the number of donors but risk was higher for grafts with lower β-cell purity.

Topics: Adult; Antilymphocyte Serum; Calcineurin Inhibitors; Cells, Cultured; Cytotoxicity Tests, Immunologic; Diabetes Mellitus, Type 1; Female; Graft Rejection; Graft Survival; Histocompatibility Antigens Class I; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Isoantibodies; Isoantigens; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Seroepidemiologic Studies; Substance Withdrawal Syndrome; Tacrolimus

Tumor lysis syndrome usually occurs after Initiation of chemotherapy or radiation therapy in cancer patients with a moderate to high tumor burden. To our knowledge, the occurrence of this syndrome after discontinuation or reduction of an immunosuppressive regimen has not been reported in the literature. We describe a patient who had undergone lung transplantation and who was receiving immunosuppression and experienced an episode of acute pancreatitis. During the course of the work-up, the patient was found to have a B-cell lymphoma (posttransplantation lymphoproliferative disease). His tacrolimus dosage was decreased, and azathioprine was discontinued. The patient subsequently developed tumor lysis syndrome. Other than the decrease in immunosuppression, we found no other factor that could have accounted for this syndrome.

Topics: Aged; Azathioprine; Fatal Outcome; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Substance Withdrawal Syndrome; Tacrolimus; Tumor Lysis Syndrome

FK506 is an immunophilin-binding ligand that inhibits calcineurin and decreases nitric oxide (NO) production in the nervous tissues. We examined the effects in mice of systemic treatment with FK506 on the induction and expression of morphine (s.c.) tolerance and dependence and compared them with the effects of the non-specific NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and specific inducible NO synthase inhibitor, aminoguanidine. FK506 (0.5-10 mg/kg, s.c.) exerted inhibitory effects on both development and expression of tolerance to morphine-induced antinociception. FK506 also significantly decreased the expression of morphine dependence, as assessed by naloxone-precipitated (2 mg/kg, i.p.) withdrawal syndrome, but a similar effect was not found for the development of morphine dependence. A similar pattern of effects was observed with L-NAME (3-20 mg/kg, i.p.), while aminoguanidine (50-100 mg/kg, i.p.) did not alter tolerance or dependence. Examining the possible interaction between their inhibitory effects on tolerance and dependence, we combined the subeffective doses of FK506 (0.5 or 1 mg/kg) with L-NAME (3 mg/kg) or aminoguanidine (100 mg/kg). The combination of FK506 with L-NAME, but not with aminoguanidine, significantly decreased the development and expression of tolerance and expression of dependence. These data show the effectiveness of FK506 on morphine tolerance and dependence and suggest an additive effect between FK506 and the inhibition of constitutive NO synthesis in this regard.

Topics: Analgesics; Animals; Dose-Response Relationship, Drug; Drug Tolerance; Enzyme Inhibitors; Guanidines; Immunophilins; Injections, Intraperitoneal; Injections, Subcutaneous; Ligands; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain Measurement; Substance Withdrawal Syndrome; Tacrolimus

Administration of corticosteroids to kidney recipients has hampered the complete clinical success of kidney transplantation. Because most organ transplantation in Japan is living-related, we had the experience of performing kidney transplantation (KT) after liver transplantation (LT) from the same donor in four patients and successfully withdrew corticosteroid administration.. Three pediatric and one adult patient received kidney allografts from 3 to 10 months after LT from the same donor. The immunosuppressive regimen consisted of a corticosteroid and tacrolimus. The steroid was withdrawn after KT in all four patients. After complete withdrawal of the steroid, DNA was extracted from two recipients and examined by polymerase chain reaction to detect microchimerism. A mixed lymphocyte reaction (MLR) and cell-mediated lymphocytotoxicity assay (CML) were performed to test for donor-specific hyporesponsiveness.. Steroid withdrawal was successfully accomplished after KT in every patient. No steroid-withdrawal-associated complications were observed. In the three pediatric patients, remarkable catch-up growth was observed after steroid withdrawal. In the two patients tested, donor DNA was not detected by polymerase chain reaction, suggesting the absence of microchimerism. MLR and CML showed that recipient lymphocytes reacted against donor lymphocytes at the same level as against the third-party lymphocytes.. Steroid withdrawal was successfully achieved in four kidney recipients who had received a liver allograft from the same donor. The MLR and CML findings indicated the absence of donor-specific hyporesponsiveness in vitro. Although the precise mechanism is not yet clear, KT after LT from the same donor should be considered as a method that allows steroids to be withdrawn from the immunosuppressive regimen of KT.

Topics: Adrenal Cortex Hormones; Adult; Bilirubin; Child, Preschool; Creatinine; Cytotoxicity, Immunologic; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Living Donors; Lymphocyte Culture Test, Mixed; Male; Nuclear Family; Substance Withdrawal Syndrome; Tacrolimus; Transplantation Chimera

The hamster-to-rat xenotransplantation model is a useful model to investigate the features of extended host response to long-surviving xenografts. Early xenoantibody responses are T-cell independent and resistant to tacrolimus. Treatment with the combination of mofetil mycophenolate plus FK506 avoids acute xenograft rejection completely, but after withdrawal of immunosuppression hamster grafts are rejected by a process called late xenograft rejection (LXR).. Hamster hearts and livers were transplanted into Lewis rats. Grafted rats were treated with mofetil mycophenolate (25 mg/kg/day) for 8 days and FK506 (0.2 mg/kg/day) for 31 days. Serum IgM and IgG levels were determined by flow cytometry and interferon-gamma levels by ELISA. IgM, IgG, and C3 deposits were measured in tissue by immunofluorescence, and leukocyte infiltration was measured by immunoperoxidase staining. Results. Survival of heart and liver xenografts in the rats was 48+/-4 days and 63+/-8 days, respectively. After cessation of all immunosuppression, hearts were rejected in 18+/-4 days and livers in 33+/-8 days. Production sequences of xenoantibodies in the two organs differed substantially, especially 7 days after transplantation and at the moment of rejection. Quantification of interferon-gamma levels indicated that there were no significant changes after transplantation. Histological and immunohistochemical studies showed signs of humoral mechanism of LXR in rats undergoing heart transplantation and cellular mechanism of LXR in those that received a liver transplant. Conclusions. These observations suggest that rejection in the hamster-to-rat heart xenotransplantation model is mediated by a T cell-independent B-cell response to which a T cell-dependent B-cell response is added in LXR. In the liver xenotransplantation model, our hypothesis is that LXR is mediated by a mixed cell mechanism, involving lymphocytes CD4+ CD45RC+, macrophages, and cytotoxic T lymphocytes. In summary, we have demonstrated and compared the peculiar features of LXR in two different organs.

Topics: Animals; Antibodies, Heterophile; Antibody Formation; Cricetinae; Dose-Response Relationship, Drug; Graft Rejection; Graft Survival; Heart Transplantation; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Liver Transplantation; Male; Mesocricetus; Rats; Rats, Inbred Lew; Substance Withdrawal Syndrome; Tacrolimus; Transplantation, Heterologous

The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed.. 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.. 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).. 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.

Topics: Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Pancreas Transplantation; Steroids; Substance Withdrawal Syndrome; Survival Rate; Tacrolimus; Time Factors

Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression.. Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF --> ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59 +/- 23 months.. The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF --> ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF --> ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF --> ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn from steroids earlier (median: 5 months) than those who had one or more episodes of acute rejection (median: 7.6 months, P=0.001). There was no effect of donor age, race, sex, recipient race, sex, cadaveric versus living donor, 48-hr graft function, panel reactive antibody, and total HLA mismatches or matches on the likelihood of being weaned off steroids. Serum creatinine at most recent follow-up in the OFF group was 1.2 +/- 0.5 mg/dl; in the OFF --> ON group, it was 1.8 +/- 0.9 mg/dl, and in the ON group it was 2.0 mg/dl (P<0.003). The incidence of rejection in the OFF, OFF --> ON, and ON groups was 39%, 77%, and 100%, respectively (P<0.05).. These data suggest that steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression is associated with reasonable short- and medium-term patient and graft survival, and acceptable renal function. Patients who discontinue and then resume steroids had patient and graft survival rates comparable with those in patients who discontinue and stay off steroids, but had a higher serum creatinine and a higher incidence of rejection.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Middle Aged; Multivariate Analysis; Substance Withdrawal Syndrome; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome