tacrolimus and Diabetes-Mellitus--Type-1

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation.. We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment.. The percentages of cells expressing the T. This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain T

Topics: Child; Diabetes Mellitus, Type 1; Diarrhea; Forkhead Transcription Factors; Gastrointestinal Tract; GATA3 Transcription Factor; Genetic Diseases, X-Linked; Humans; Immune System Diseases; Immunohistochemistry; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Mucosa; Kidney; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Rituximab; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Tacrolimus; Th1 Cells; Th17 Cells; Th2 Cells

The feasibility and timing of corticosteroid elimination and its impact on lipid metabolism in simultaneous pancreas and preemptive kidney transplantation were examined.. A retrospective study was conducted on 14 recipients of pancreas and preemptive kidney grafts transplanted form April 2003 to March 2004. All recipients received ATG induction. Tacrolimus (Tac) was administered according to trough concentration 8-15 ng/ml. Mycophenolate mofetil (MMF) was administered at doses of 2 g per day with subsequent dosage adjustment based on tolerability. All recipients received corticosteroids with subsequent dose tapering. Total cholesterol and triglyceride levels before transplantation and after steroid withdrawal were assessed.. One year recipient survival rate was 100%. Cumulative one year panaceas and kidney survival rates were: 85% and 100%, respectively. After transplantation of fasting glycemia and HbAIC were normalized. Serum creatinine decreased from 4.35 +/- 1.61 mg/dl before transplantation to 1.1 + 0.25 mg/dl after surgery (p < 0.05). Corticosteroids were eliminated between the 2nd and 16th month (mean 6 months) after transplantation. Cholesterol and triglyceride levels were wiyhin normal range, in addition significantly decreased after transplantation and steroid withdrawal, from 194.5 +/- 35.6 mg/dl to 162.4 +/- 36.8 mg/dl and 142.5 +/- 65 94.8 +/- 42.5 mg/dl, respectively (p < 0.05).. It is possible to eliminate steroids 6 months after transplantation using immunossupression based on MMF and Tac. Withdrawal of steroids could be partially contributed to the normalization of lipid metabolism.

Topics: Adrenal Cortex Hormones; Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Diabetes Mellitus, Type 1; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Prognosis; Sirolimus; Tacrolimus; Tissue Donors

New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment. Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis. New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n=1636) or cyclosporine (n=1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p<0.00001), an effect observed in renal (9.8% vs. 2.7% p<0.00001) and nonrenal (11.1% vs. 6.2%; p<0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p<0.00001). The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.

Topics: Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Humans; Immunosuppressive Agents; Organ Transplantation; Prospective Studies; Retrospective Studies; Tacrolimus; Time Factors

Despite early obstacles impacting the success of pancreatic transplantation, the introduction of new procedures and new immunosuppressive therapies during the past 2 decades has improved outcomes for pancreatic transplant recipients. For example, the use of bladder drainage and better human leukocyte antigen matching has helped overcome some of the early obstacles of pancreatic transplantation. In addition, the introduction of tacrolimus in 1994 and mycophenolate mofetil in 1996 has helped lower rates of acute rejection and increase graft survival, with less nephrotoxicity than treatment with cyclosporine. Regimens allowing the tapering of corticosteroids have also helped reduce the rates of acute pancreas rejection. To further improve therapeutic options for patients with type 1 diabetes or end-stage renal disease, pancreatic islet transplantation and organ and islet xenotransplantation should be further explored.

Topics: Diabetes Mellitus, Type 1; Glucocorticoids; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Pancreas Transplantation; Tacrolimus

Topics: Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glucose; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Metabolic Clearance Rate; Tacrolimus; Tremor

Topics: Animals; Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Muromonab-CD3; Pancreas Transplantation; T-Lymphocytes; Tacrolimus

Islet cell transplantation can potentially normalize blood glucose levels and stop the progression of clinical complications, and if the transplant is done early in the course of the disease complications may be prevented. Remarkable progress has been made in recent years and islet cell transplantation has resulted in normalization of metabolic control in several patients with Type 1 diabetes in the absence of hypoglycemia. Only a few patients, however, have achieved insulin independence. Issues relating to islet cell engraftment within the liver, prevention of rejection and recurrent autoimmunity, and identification of alternative immunosuppressive drugs that do not adversely affect islet cell function remain to be solved. Thus far, the need for chronic, generalized immunosuppression to prevent rejection of the islets has limited the indication to those patients who have already received another transplant or to those who simultaneously receive islets and another organ (generally a kidney). Identification of immunointervention protocols that allow for engraftment in the absence of deleterious effects on the islets and prevent rejection and recurrent autoimmunity would make this procedure suitable for all patients, including children who have not yet developed long-term complications of the disease.

Topics: Clinical Trials as Topic; Cyclosporine; Diabetes Mellitus, Type 1; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Tacrolimus; Tissue Donors

Topics: Adult; Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cholangitis; Cyclosporine; Diabetes Mellitus, Type 1; Digestive System Diseases; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Female; Humans; Kidney Diseases; Male; Mice; Multiple Sclerosis; Nephrotic Syndrome; Psoriasis; Rats; Swine; Tacrolimus

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 μg/L) and low-level sirolimus (SIR, 3-7 μg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 μg/L) and high-level SIR (8-12 μg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisone; Prospective Studies; Sirolimus; Steroids; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Topics: Adolescent; Adult; Aged; Australia; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Insulin; Islets of Langerhans Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus; Treatment Outcome; Young Adult

Islet transplantation can improve metabolic control for type 1 diabetes (T1D), an effect anticipated to improve insulin sensitivity. However, current immunosuppression regimens containing tacrolimus and sirolimus have been shown to induce insulin resistance in rodents.. The objective of the study was to evaluate the effect of islet transplantation on insulin sensitivity in T1D using euglycemic clamps with the isotopic dilution method to distinguish between effects at the liver and skeletal muscle.. Twelve T1D subjects underwent evaluation in the Clinical and Translational Research Center before and between 6 and 7 months after the transplant and were compared with normal control subjects.. The intervention included intrahepatic islet transplantation according to a Clinical Islet Transplantation Consortium protocol under low-dose tacrolimus and sirolimus immunosuppression.. Total body (M/Δinsulin), hepatic (1/endogenous glucose production ·basal insulin) and peripheral [(Rd - endogenous glucose production)/Δinsulin] insulin sensitivity assessed by hyperinsulinemic (1 mU·kg(-1)·min(-1)) euglycemic (∼90 mg/dL) clamps with 6,6-(2)H2-glucose tracer infusion were measured.. Glycosylated hemoglobin was reduced in the transplant recipients from 7.0% ± 0.3% to 5.6% ± 0.1% (P < .01). There were increases in total (0.11 ± 0.01 to 0.15 ± 0.02 dL/min·kg per microunit per milliliter), hepatic [2.3 ± 0.1 to 3.7 ± 0.4 × 10(2) ([milligrams per kilogram per minute](-1)·(microunits per milliliter)(-1))], and peripheral (0.08 ± 0.01 to 0.12 ± 0.02 dL/min·kg per microunit per milliliter) insulin sensitivity from before to after transplantation (P < .05 for all). All insulin sensitivity measures were less than normal in T1D before (P ≤ .05) and not different from normal after transplantation.. Islet transplantation results in improved insulin sensitivity mediated by effects at both the liver and skeletal muscle. Modern dosing of glucocorticoid-free immunosuppression with low-dose tacrolimus and sirolimus does not induce insulin resistance in this population.

Topics: Adult; Diabetes Mellitus, Type 1; Female; Glucose Clamp Technique; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Islets of Langerhans Transplantation; Liver; Male; Middle Aged; Muscle, Skeletal; Sirolimus; Tacrolimus

We investigated the safety and efficacy of Campath induction and tacrolimus (TAC) maintenance therapy compared to ATG induction with TAC +MMF + steroids in de novo kidney-pancreas transplanted patients.. 14 patients (Group A) received Campath 30 mg + methylprednisolone 500 mg before revascularization followed by TAC monotherapy, and 16 patients (Group B) ATG 8 mg/kg with TAC + MMF+ steroids (withdrawn at month 3). TAC trough levels (ng/mL) of 12-15 were aimed for in both groups until month 6 and thereafter 6-12.. 1-year patient survival was 100% in both groups; kidney and pancreas survival in Group A was 93% each. In Group B 1-year kidney and pancreas survival was 100% and 87%, respectively. A total of three pancreas grafts were lost due to thrombosis of the graft vein within the first month. The only kidney loss was due to initial non-function. All biopsy-proven acute rejections of renal transplants (n=3 in Group A, n=0 in Group B) were reversible. No acute pancreas graft rejection was demonstrated. Infectious complications, lipid metabolism and blood pressure were comparable in both groups, as were other adverse events. No tumor occurred. At 12 months 13 patients in each group were steroid-free; the mean serum creatinine level was 1.44 mg/dL in Group A and 1.33 mg/dL in Group B. All patients were exogenous insulin-free.. At one year efficacy and safety of Campath +TAC monotherapy were comparable to those of ATG + TAC + MMF + steroids in a limited number of combined kidney-pancreas transplant recipients.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Transplantation; Maintenance Chemotherapy; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

OBJECTIVE To investigate the influence of primary graft function (PGF) on graft survival and metabolic control after islet transplantation with the Edmonton protocol. RESEARCH DESIGN AND METHODS A total of 14 consecutive patients with brittle type 1 diabetes were enrolled in this phase 2 study and received median 12,479 islet equivalents per kilogram of body weight (interquartile range 11,072-15,755) in two or three sequential infusions within 67 days (44-95). PGF was estimated 1 month after the last infusion by the beta-score, a previously validated index (range 0-8) based on insulin or oral treatment requirements, plasma C-peptide, blood glucose, and A1C. Primary outcome was graft survival, defined as insulin independence with A1C < or =6.5%. RESULTS All patients gained insulin independence within 12 days (6-23) after the last infusion. PGF was optimal (beta-score > or =7) in nine patients and suboptimal (beta-score < or =6) in five. At last follow-up, 3.3 years (2.8-4.0) after islet transplantation, eight patients (57%) remained insulin independent with A1C < or =6.5%, including seven patients with optimal PGF (78%) and one with suboptimal PGF (20%) (P = 0.01, log-rank test). Graft survival was not significantly influenced by HLA mismatches or by preexisting islet autoantibodies. A1C, mean glucose, glucose variability (assessed with continuous glucose monitoring system), and glucose tolerance (using an oral glucose tolerance test) were markedly improved when compared with baseline values and were significantly lower in patients with optimal PGF than in those with suboptimal PGF. CONCLUSIONS Optimal PGF was associated with prolonged graft survival and better metabolic control after islet transplantation. This early outcome may represent a valuable end point in future clinical trials.

Topics: Adult; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Male; Middle Aged; Portal Vein; Tacrolimus; Treatment Outcome

The aim of this study was to evaluate the efficiency and safety of simultaneous islet and kidney transplantation in patients with type 1 diabetes and end-stage renal disease using a glucocorticoid-free immunosuppressive regimen with alemtuzumab induction.. Seven patients with type 1 diabetes and end-stage renal failure were transplanted with allogenic islets and kidneys procured from brain-dead donors. To prevent organ rejection, patients received alemtuzumab for induction immunosuppression, followed by sirolimus and tacrolimus. No glucocorticoids were given at any time.. The median duration of follow-up was 18.3 months (range 13-31). Kidney survival was 100%. Four patients became insulin independent at 1 year. The other three reduced insulin use to less than 25% of the amount required before transplantation. Serum C-peptide levels were significantly greater posttransplant in all patients, indicating continued islet function. No major procedure-related complications were observed.. Our results demonstrate that a steroid-free immunosuppressive regimen consisting of alemtuzumab, sirolimus, and tacrolimus is feasible for simultaneous islet and kidney transplantation. The question of whether this induction regimen is superior to more standard induction deserves large studies.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Diabetes Mellitus, Type 1; Feasibility Studies; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Function Tests; Male; Middle Aged; Pilot Projects; Sirolimus; Tacrolimus

One year survival of islet cell grafts has been reproducibly achieved under combination immune therapy including tacrolimus (TAC). However, the use of TAC causes beta-cell and renal toxicity. Because sirolimus (SIR) monotherapy was successful in kidney transplantation under antithymocyte globulin (ATG), we undertook a pilot study comparing SIR monotherapy with SIR-TAC combination therapy.. Nonuremic type 1 diabetics received a cultured beta-cell graft under ATG and were randomly assigned to SIR or SIR-TAC-maintenance therapy; a second graft was implanted during posttransplantation month 3 without ATG. The planned number of patients per group (n=10) was reduced to five in view of the observed side effects.. At posttransplant month 6, three SIR-patients had lost graft function and two presented marginal function; among SIR-TAC-patients, there were two early graft failures but three became insulin-independent. These three patients maintained metabolically relevant function (C-peptide >1 ng/ml and coefficient of variation fasting glycemia <25%) for more than 2 years but low-dose insulin therapy was needed from 8, 18, and 26 months posttransplant; this was still the case in two of them after reducing and stopping TAC dose. In both groups, incapacitating adverse events were attributed to sirolimus requiring its discontinuation in 4 of 10 patients; in the 3 patients with pretransplant microalbuminuria, macroalbuminuria developed which resolved when sirolimus was stopped.. SIR monotherapy is not sufficient to suppress rejection after transplantation under ATG, but it can maintain survival of established beta-cell grafts. However, the risk for a SIR-induced proteinuria remains a concern.

Topics: Adult; Albuminuria; Autoantibodies; C-Peptide; Cell Transplantation; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocyte Count; Male; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus

Simultaneous pancreas-kidney (SPK) transplantation is an effective treatment for patients suffering from type 1 diabetes mellitus. Conventional immunosuppressive treatments include steroids that may induce insulin resistance and are responsible for many side effects. In de novo SPK, early withdrawal of corticosteroids may be an important issue.. A total of 24 consecutive patients with type 1 diabetes mellitus had been treated by SPK transplantation. All of them had a short induction therapy with anti-thymoglobulin (ATG) and steroids for only 4 days, association with CellCept and tacrolimus. The rate of acute rejection, graft and patient survival and side effects have been analysed.. Patient and kidney survival was 100% and the pancreas survival was 95.6% at 1 year. The rate of acute rejection of kidney and pancreas was 4.2% and 8.3% at 6 months, respectively. The mean serum creatinine was 98.9+/-19.6 micromol/l and the mean HbA1c concentration was 5.1%+/-0.5% at 6 months. Only four patients developed a cytomegalovirus primo-infection, associated in one case with pneumonia, whereas 75% of patients developed a bacterial infection. Because of the occurrence of leucopenia and/or diarrhoea, CellCept has been dramatically decreased in 33% of cases and required the re-introduction of steroids.. A short induction with ATG and steroids associated with a chronic therapy with CellCept and tacrolimus is safe and efficient in preventing acute renal rejection in SPK.

Topics: Acute Disease; Adult; Autoantibodies; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Prodrugs; Prospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Blood Chemical Analysis; Chromatography, High Pressure Liquid; Creatinine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 1; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Leukocyte Count; Liver Function Tests; Male; Mass Spectrometry; Metabolic Clearance Rate; Middle Aged; Models, Biological; Polymorphism, Genetic; Sirolimus; Tacrolimus; Time Factors

Simultaneous pancreas-kidney (SPK) transplantation is an accepted therapy for type 1 diabetic patients with end-stage renal disease. This study analyses the occurrence of rejection episodes in patients undergoing SPK.. The study population was obtained from 205 patients enrolled in the Euro-SPK 001 study and randomized to receive tacrolimus- (n = 103) or cyclosporin microemulsion (ME)-based (n = 102) immunosuppressive therapy. All patients received concomitant antibody induction therapy, mycophenolate mofetil and short-term corticosteroids.. After 3 years of follow-up, rejection episodes occurred in 41 patients receiving tacrolimus and in 51 patients receiving cyclosporin-ME. The majority of first rejection episodes in both groups occurred during the first 6 months (93 and 90%, respectively) and in most cases were treated with corticosteroids alone (88 vs 90%). Actuarial rejection-free kidney and/or pancreas graft survival was similar for tacrolimus (54%) and cyclosporin-ME (44%). Human leukocyte antigen (HLA) compatibility (P = 0.003) and graft vessel extension (P = 0.000001) had a significant influence on rejection-free graft survival. Also, rejection influenced pancreas graft survival (P = 0.01), and pancreas graft loss due to rejection influenced patient survival (P = 0.02). In the intent-to-treat analysis of early rejection, significantly fewer tacrolimus- than cyclosporin-ME-treated patients had (i) more than one rejection episode (11 out of 40 vs 24 out of 47; P = 0.03); (ii) first moderate to severe rejection (one out of 40 vs 12 out of 47; P = 0.004); and (iii) refractory rejection (two out of 40 vs 10 out of 47; P = 0.03). Pancreas survival was lower in late rejectors (53%) than non-rejectors (86%; P = 0.002). Also, serum creatinine was highest in late rejectors.. Tacrolimus-based immunosuppressive therapy demonstrates significant advantages over cyclosporin-ME in terms of the severity of acute rejection in SPK transplant patients.

Topics: Adolescent; Adult; Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease-Free Survival; Drug Therapy, Combination; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Postoperative Complications; Tacrolimus

Single-centre and retrospective studies suggest superiority of tacrolimus over cyclosporin as cornerstone immunosuppressive therapy for simultaneous pancreas-kidney (SPK) transplantation. This open-label, multicentre trial compared the efficacy and safety of tacrolimus with cyclosporin microemulsion (ME) in diabetic patients with end-stage renal disease undergoing their first cadaveric SPK transplantation. The 3-year results are reported.. Patients were recruited from 10 centres in Europe and one centre in Israel: 103 were randomized to receive tacrolimus (initial dose: 0.2 mg/kg/day p.o.) and 102 to cyclosporin-ME (7 mg/kg/day p.o.). All patients received concomitant rabbit anti-T-cell globulin induction, mycophenolate mofetil (MMF) and short-term corticosteroids.. Fewer patients receiving tacrolimus (36.9%) than cyclosporin-ME (57.8%) were discontinued from treatment (P = 0.003). The initial episodes of biopsy-proven rejection were moderate or severe in just one out of 31 (3%) tacrolimus-treated patients compared with 11 out of 39 (28%) patients receiving cyclosporin-ME (P = 0.009). While 3-year patient and kidney survival rates were similar in the two treatment groups, pancreas survival was superior with tacrolimus (89.2 vs 72.4%; P = 0.002). Thrombosis resulted in pancreas graft loss in 10 patients receiving cyclosporin-ME and in only two treated with tacrolimus (P = 0.02). Overall adverse event frequency was similar in both groups, but MMF intolerance was more frequent with tacrolimus and hyperlipidaemia more frequent with cyclosporin-ME.. In this 3-year study, tacrolimus was more effective than cyclosporin-ME in preventing moderate or severe kidney or pancreas rejection after SPK transplantation. It also provided superior pancreas survival and reduced the risk of pancreas graft thrombosis.

Topics: Adolescent; Adult; Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Emulsions; Europe; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Israel; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Prospective Studies; Safety; Tacrolimus; Treatment Outcome

This report examines the early and late secondary effects of tacrolimus, cyclosporin microemulsion (ME), mycophenolate mofetil (MMF) and rabbit anti-thymocyte globulin (rATG) in simultaneous pancreas-kidney (SPK) recipients.. Of the 205 patients participating in the Euro-SPK 001 study, 103 were randomized to tacrolimus (0.2 mg/kg) and 102 to cyclosporin-ME (7 mg/kg). All patients received rATG for 4 days [ATG-Fresenius (ATG-F) 4 mg/kg/day or Thymoglobulin (Thymo-S) 1.25 mg/kg/day] plus MMF and short-term corticosteroids.. Thymo-S induction therapy was associated with a lower white cell count in the first 3 months than was seen with ATG-F, while ATG-F caused a lower initial nadir in platelet count. Both polyclonal preparations were well tolerated and no clinically relevant differences were observed with respect to side effects such as infections and malignancies. High cyclosporin-ME trough levels were associated with pancreas graft thrombosis, and concentrations >150 ng/ml were associated with poor renal allograft function. Treatment discontinuation was higher with cyclosporin-ME (57.8%) than with tacrolimus-based therapy (36.9%) due to more frequent toxicity, graft loss and lack of efficacy requiring a switch to tacrolimus. The main reason for withdrawal in the tacrolimus group was MMF discontinuation; MMF-related side effects resulted in more frequent dose reductions to <2 g/day and discontinuations in the tacrolimus group, and indirectly indicate a higher dose-corrected exposure to mycophenolic acid, as previously observed in kidney transplant patients.. Short-term induction therapy is effective and well tolerated in patients undergoing SPK transplantation. Tacrolimus was the preferred immunosuppressive agent, resulting in fewer cases of pancreas graft loss and drug discontinuation compared with cyclosporin-ME.

Topics: Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Leukocyte Count; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Time Factors; Treatment Outcome

Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice for selected diabetic patients. Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patients' health, necessitating eventual discontinuation.. This prospective study evaluated the safety and feasibility of corticosteroid withdrawal in 205 SPK transplant recipients randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporin microemulsion (ME) and MMF (n = 102).. Corticosteroid withdrawal was successful in the majority of in-study patients (66% tacrolimus, 73% cyclosporin-ME). Compared with out-of-study patients or those continuing corticosteroid therapy, in-study patients withdrawn from corticosteroids experienced fewer pancreas or kidney graft losses, fewer episodes of acute rejection and were less likely to be withdrawn from the study. Acute rejection occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection-free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in the dose of both MMF and tacrolimus.. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate the positive effects on glucose metabolism and hypertension.

Topics: Biopsy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Europe; Feasibility Studies; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Israel; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Safety; Tacrolimus; Time Factors; Treatment Outcome; Withholding Treatment

Simultaneous pancreas-kidney transplantation (SPK) has evolved as an effective treatment for patients with end-stage nephropathy due to type 1 diabetes mellitus. This report analyses the spectrum of surgical complications among patients receiving tacrolimus and cyclosporin microemulsion (ME)-based therapy for SPK transplantation.. The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporin-ME (n = 102) in the Euro-SPK 001 study. Surgical complications were defined as any intervention in the 3-month post-operative course related to the transplant procedure.. In the tacrolimus vs cyclosporin-ME group, repeat laparotomy was required by fewer patients (26 vs 43%, respectively; P = 0.01) and at a later stage post-transplant (26+/-26 vs 14+/-17 days; P = 0.05). Also, thrombosis of graft vessels (2 vs 9%; P = 0.03) and repeat laparotomy for intra-abdominal haemorrhage within the first 3 months (8 vs 22%; P = 0.005) occurred significantly less frequently with tacrolimus vs cyclosporin-ME. A donor age of > or =45 years was a significant determinant for surgical complications requiring repeat laparotomy, regardless of the type of immunosuppression. Portal anastomosis was the safest method of endocrine venous drainage, and Roux-en-Y loop for enteric exocrine drainage was associated with a higher re-operation rate than duodenoenterostomy. Repeat laparotomy had no impact on patient survival, but significantly reduced kidney and pancreas graft survival in the cyclosporin-ME group (kidney: P<0.01; pancreas: P<0.001) and in both groups combined (P < or = 0.05 and P<0.001, respectively).. The immunological benefits of tacrolimus compared with cyclosporin-ME treatment result in a lower incidence of repeat laparotomies post-transplant and a reduced in-hospital stay. Fewer repeat laparotomies translate into improved pancreas and kidney graft survival.

Topics: Adult; Age Factors; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Europe; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Israel; Kidney Failure, Chronic; Kidney Transplantation; Laparotomy; Middle Aged; Pancreas Transplantation; Postoperative Complications; Prospective Studies; Reoperation; Survival Rate; Tacrolimus; Treatment Outcome

Islet transplantation is gaining recognition as a therapeutic option for selected diabetic patients. The immunosuppressive regimen based on sirolimus/low-dose tacrolimus is considered a major breakthrough that allowed considerable improvement in graft survival. A high incidence of side effects associated with such a regimen has been reported in the literature, but this immunosuppressive protocol is generally considered safe or even protective to the kidney. Herein, we analyze the impact of the sirolimus/low-dose tacrolimus-based protocol on kidney function.. Five islet-after-kidney and 5 islet-transplant-alone patients were enrolled and followed up. Renal function was assessed by the periodic measurement of serum creatinine and by the presence of albuminuria. Metabolic control markers and graft function were followed, as well as immunosuppressive whole blood trough levels.. Kidney function significantly decreased in 6 of 10 patients. Neither metabolic markers nor immunosuppressive drugs levels were significantly associated with the decreased kidney function.. Although a specific etiology was not identified, subsets of patients presented a higher risk for decrease of kidney function. The presence of low creatinine clearance, albuminuria, and long-established kidney graft were associated with poorer outcomes.

Topics: Creatinine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Kidney Function Tests; Sirolimus; Tacrolimus; Treatment Outcome

Following the success obtained with transplantation of fresh human islets under steroid-free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF-alpha) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33+/-6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; C-Peptide; Daclizumab; Diabetes Mellitus, Type 1; Female; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Tacrolimus; Tissue Culture Techniques; Tumor Necrosis Factors

Simultaneous pancreas-kidney transplantation (SPK) transplantation has become an accepted therapy for type 1 diabetic patients with end-stage renal disease. This open-label, multicenter study compared the efficacy and safety of tacrolimus with the microemulsion (ME) formulation of cyclosporine in a clinical setting. The 1-year results are reported here.. The study was conducted in 10 European centers and one center in Israel. One hundred three patients were randomly assigned to tacrolimus and 102 to cyclosporine-ME. All patients received concomitant rabbit anti-T-cell globulin induction therapy, mycophenolate mofetil (MMF), and short-term cortico-steroids. The initial daily oral doses were 0.2 mg/kg for tacrolimus, 7 mg/kg for cyclosporine-ME, and 2 to 3 g for MMF.. The 1-year incidence of biopsy-proven kidney or pancreas acute rejection was lower with tacrolimus (27.2%) than with cyclosporine-ME (38.2%; P = 0.09). Pancreas graft survival at 1 year was 91.3% with tacrolimus and 74.5% with cyclosporine-ME (P <0.0005). Renal graft survival was similar in the two study groups. There were no significant treatment-related differences in pancreatic or renal graft function. In total, 34 patients switched treatment from cyclosporine-ME to tacrolimus, but only 6 patients receiving tacrolimus required alternative therapy. Mean doses of MMF at 1 year were also lower in the tacrolimus group (1.36 vs. 1.67 g/day; P = 0.007).. These findings support the use of tacrolimus therapy for uremic patients with type 1 diabetes who are undergoing SPK transplantation.

Topics: Acute Disease; Adult; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Emulsions; Europe; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Israel; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Safety; Tacrolimus

The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned.. Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus.. All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function.. We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Reproducibility of Results; Sirolimus; Tacrolimus; Time Factors

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Middle Aged; Postoperative Complications; Spain; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Daclizumab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Cholesterol; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Pancreas Transplantation; Pilot Projects; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year.. Seven consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization.. All seven patients quickly attained sustained insulin independence after transplantation of a mean (+/-SD) islet mass of 11,547+/-1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors to achieve sustained insulin independence. The mean glycosylated hemoglobin values were normal after transplantation in all recipients. The mean amplitude of glycemic excursions (a measure of fluctuations in blood glucose concentrations) was significantly decreased after the attainment of insulin independence (from 198+/-32 mg per deciliter [11.1+/-1.8 mmol per liter] before transplantation to 119+/-37 mg per deciliter [6.7+/-2.1 mmol per liter] after the first transplantation and 51+/-30 mg per deciliter [2.8+/-1.7 mmol per liter] after the attainment of insulin independence; P<0.001). There were no further episodes of hypoglycemic coma. Complications were minor, and there were no significant increases in lipid concentrations during follow-up.. Our observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; C-Peptide; Daclizumab; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Cadaver; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Tacrolimus; Tissue Donors

Topics: Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Prospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Azathioprine; Cyclosporine; Diabetes Mellitus, Type 1; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Mycophenolic Acid; Pancreas Transplantation; Prospective Studies; Tacrolimus; Transplantation, Homologous

Topics: Blood Pressure; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclosporine; Diabetes Mellitus, Type 1; Follow-Up Studies; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Lipids; Prevalence; Tacrolimus

Topics: Bias; Black People; Cadaver; Cross-Over Studies; Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppression Therapy; Immunosuppressive Agents; Insulin; Kidney Transplantation; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; United States; White People

Topics: Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Premedication; Tacrolimus

This follow-up multicenter analysis is based on 362 pancreas allograft recipients at 14 institutions who were given tacrolimus between 1 May 1994 and 15 November 1995. Three groups were studied: (1) recipients given tacrolimus initially for induction and maintenance therapy (n = 250; 215 without, 35 with, a concurrent bone marrow transplant), (2) recipients who converted to tacrolimus for rescue or rejection therapy (n = 89), and (3) recipients who converted to tacrolimus for other reasons (n = 23). Of 215 recipients without a bone marrow transplant in the induction group, 166 (77%) underwent a simultaneous pancreas-kidney transplant (SPK), 29 (14%) a pancreas transplant alone (PTA), and 20 (9%) a pancreas after previous kidney transplant (PAK). Initial antibody therapy was given to 185 (86%) recipients. All 215 received tacrolimus and prednisone; 202 (94%) also received azathioprine (AZA) and 11 (5%) mycophenolate mofetil (MMF). The most common side effects of tacrolimus were neurotoxicity in 21%, nephrotoxicity in 21%, gastrointestinal (GI) toxicity in 13%, and diabetogenicity in 13% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. Of 89 recipients in the rescue group, 71 (79%) had an SPK, 11 (13%) a PTA, and 7 (8%) a PAK. Before conversion, all had been on cyclosporine (CsA)-based immunosuppression; 74% of them had 2 or more rejection episodes previously. The most common side effects were nephrotoxicity in 27%, neurotoxicity in 26%, GI toxicity in 18%, and diabetogenicity in 8% of these recipients. No recipient in this group developed new-onset insulin-dependent diabetes mellitus. In the induction group patient survival at 1 yr was 98% for SPK, 79% for PTA, and 100% for PAK recipients. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 1 yr was 88% with tacrolimus vs. 73% with CsA (p = 0.002); for PTA recipients, 68% vs. 70% (p > 0.35); and for PAK recipients, 85% vs. 65% (p = 0.13). Graft loss from rejection was not different with tacrolimus vs. CsA in all 3 pancreas recipient categories. At 1 yr, 17% of recipients had converted from tacrolimus to CsA for diabetogenicity, nephrotoxicity, or rejection; 23% had converted from AZA to MMF. The incidence of post-transplant lymphoma was < 2%. In the rescue group, patient survival rates at 1 yr were 96% for SPK, 100% for PTA, and 86% for PAK recipients (p < 0.08). Pancreas graft survival at 1 yr was 89% for SPK, 58% for

Topics: Adult; Anti-Inflammatory Agents; Azathioprine; Bone Marrow Transplantation; Case-Control Studies; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Lymphoma; Male; Muromonab-CD3; Mycophenolic Acid; Nervous System Diseases; Pancreas Transplantation; Prednisone; Prospective Studies; Randomized Controlled Trials as Topic; Survival Rate; Tacrolimus; Transplantation, Homologous

Simultaneous pancreas-kidney transplantation has become a widely accepted treatment option for selected uremic patients with insulin-dependent diabetes mellitus (IDDM). Patient survival rates at 1 year exceed 90%, and rates of pancreas graft survival, 70%. However, solitary pancreas transplantation for nonuremic patients with IDDM has been controversial because of the less favorable outcome and the need for long-term immunosuppression with its associated morbidity and mortality.. We studied the outcome of 225 solitary pancreas transplants during three immunosuppressive eras: the precyclosporine (CsA) era (n=83), the CsA era (n=118), and the tacrolimus era (n=24). Only patients with labile IDDM (e.g., hypoglycemic unawareness, insulin reactions, > or = 2 failed attempts at intensified insulin therapy for metabolic control) underwent solitary pancreas transplantation. Using univariate and multivariate analyses, we looked at patient and graft survival, the risk of surgical complications, and native kidney function during these three eras.. Pancreas graft survival improved significantly over time: 34% at 1 year after transplantation in the pre-CsA era, 52% in the CsA era, and 80% in the tacrolimus era (P=0.002). Pancreas graft loss due to rejection decreased from 50% at 1 year in the pre-CsA era, to 34% in the CsA era, to 9% in the tacrolimus era (P=0.008). The rate of technical failures (i.e., the risk of surgical complications) decreased from 30% in the pre-CsA era, to 14% in the CsA era, to 0% in the tacrolimus era (P=0.001). Patient survival rates at 1 year have ranged between 88% and 95% in the three eras (P=NS). Matching for at least one antigen on each HLA locus and avoiding HLA-B mismatches significantly decreased the incidence of rejection. The incidence of native kidney failure due to drug-induced toxicity decreased significantly over time, in part because only recipients with pretransplant creatinine clearance > or = 80 ml/min received transplants.. Solitary pancreas transplantation has become a viable alternative for nonuremic patients with labile IDDM. The risks of surgical complications and drug-induced nephrotoxicity have significantly decreased over time. Using tacrolimus as the mainstay immunosuppressant, patient and graft survival rates now no longer trail those of simultaneous pancreas-kidney transplantation.

Topics: Adolescent; Adult; Azathioprine; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Prednisone; Tacrolimus; Uremia

This study was designed to evaluate the results of solitary pancreas transplantation in a protocol that uses the new immunosuppressant tacrolimus (FK) and liberally applies ultrasound-guided percutaneous pancreas biopsy to diagnose rejection.. Pancreas graft survival in patients who simultaneously receive a kidney transplant (SPK) historically has been 75% to 90% at 1 year, approaching that of cadaveric kidney transplantations. In sharp contrast, graft survival rates in patients who receive a pancreas atone (PA) have remained static over the past decade, with approximately 50% functional at 1 year. It was hypothesized that the results of PA transplantations would improve with newer maintenance immunosuppressants and biopsy techniques.. Twenty-seven PA recipients prospectively were treated with FK-based immunosuppression (PA-FK). Percutaneous biopsy was performed for hyperamylasemia, hyperlipasemia, hypoamylasuria, or unexplained fever. One year pancreas graft survival in these patients was compared to 15 cyclosporine treated PA cases (PA-CsA) and 113 SPK recipients.. The 1-year pancreas graft survival rate of 90.1% in technically successful PA-FK patients was significantly better than the 53.4% rate in PA-CsA recipients (p = 0.002) and no different than the 87.4% rate in SPK recipients. The only graft lost to acute rejection in the PA-FK group was because of acknowledged patient noncompliance. Percutaneous biopsy substantially improved the diagnostic certainty in cases of suspected rejection and was associated with a low complication rate (3/178 = 1.5%).. Modern immunosuppression and biopsy techniques have improved the success of solitary pancreas transplantations to the point where outcome is now equivalent to that of SPKs.

Topics: Adult; Biopsy, Needle; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pancreas; Pancreas Transplantation; Prospective Studies; Tacrolimus; Ultrasonography, Interventional

Topics: Adult; Amylases; Biomarkers; Blood Glucose; Cadaver; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreas Transplantation; Recurrence; Tacrolimus; Time Factors; Tissue Donors; Urine

Topics: Adult; Arteriosclerosis; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Lipids; Male; Pancreas Transplantation; Risk Factors; Tacrolimus

Topics: Blood Glucose; C-Peptide; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation; Tacrolimus

Long-term renal function was compared in 49 liver recipients [25 patients received cyclosporin (CyA) and 24 patients received FK 506] followed for a period of 1 year. Creatinine (CR) and glomerular filtration rate (GFR) pretransplantation (pre-Tx) and at 1, 3, 5, and 12 months post-Tx were recorded, as well as incidences of hyperkalemia, post-Tx hypertension, and insulin-dependent diabetes mellitus (IDDM) in the two groups. At 1 year post-Tx, the mean Cr had risen from baseline by 56% and 60% in the FK and CyA groups, respectively; the mean GFR had dropped by 32% in FK patients and by 27% in CyA patients. Acute nephrotoxicity occurred in 7/25 CyA patients (2/7 required dialysis) and 9/26 FK patients (7/9 required dialysis; 2/7 were switched to CyA). None remained on dialysis at 3 months. Renal insufficiency persisted at 1 year in 7/16 patients with early toxicity (CyA, 4; FK, 3) and in 3 of the remaining 36 pts (P < 0.001). Hyperkalemia occurred in 4/25 CyA, and in 12/24 FK patients (P < 0.025), post-Tx hypertension occurred in 15 CyA, and 7 FK patients (P < 0.05), and IDDM occurred in 4 CyA and 7 FK patients (P = ns). FK 506 and CyA, thus, exerted similar chronic renal effects. Although acute renal insufficiency improved upon dose reduction, renal impairment was permanent in some cases.

Topics: Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Postoperative Complications; Tacrolimus; Time Factors

Topics: Adult; Anti-Bacterial Agents; Diabetes Mellitus, Type 1; Female; Graft Rejection; Heart; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Kidney; Male; Middle Aged; Opportunistic Infections; Prospective Studies; Survival Analysis; Tacrolimus

Topics: Adolescent; Adult; Anti-Bacterial Agents; Child; Child, Preschool; Creatinine; Diabetes Mellitus, Type 1; Female; Heart Transplantation; Humans; Hypertension; Immunosuppression Therapy; Infant; Infant, Newborn; Kidney; Male; Middle Aged; Oliguria; Prospective Studies; Tacrolimus; Uremia

Topics: Adolescent; Adult; Diabetes Mellitus, Type 1; Female; Humans; Male; Research Design; Tacrolimus

Pancreatic islet transplantation holds great potential as a curative therapy for treating type 1 diabetes. However, the need for lifelong systemic immunosuppression with inevitable side effects is an obstacle to clinical success. Here we devised a strategy for the site-specific delivery of an immunosuppressant (tacrolimus) using layer-by-layer assembly of polymeric particles and collagen on the islet surface. This approach aims to provide a continuous and sustained supply of tacrolimus in the vicinity of transplanted cells while avoiding systemic drug exposure. The dose and release rate of tacrolimus can be tunable to achieve therapeutic windows by varying layer-by-layer construction and chemistry of polymers. Transplanting 400 IEQ of pancreatic islets coated with particles containing ∼3 μg of TAC per recipient provided controlled drug release and rectified diabetes for up to 5 months in a xenogeneic rodent model of type 1 diabetes. We anticipate that the findings of this study will be found useful by those developing local immunomodulation strategies aimed at improving the outcomes and safety of cell therapies for curing type 1 diabetes.

Topics: Collagen; Diabetes Mellitus, Type 1; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Polymers; Tacrolimus

This study aimed to assess posttransplant changes in insulin sensitivity and β-cell function of pancreas transplant recipients according to the type of diabetes mellitus (DM) and the pretransplant insulin sensitivity measured by the Matsuda Index (MI).. We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant.. At 1 month posttransplant, insulin sensitivity did not show significant improvement; particularly, the MI was significantly lower after transplant in recipients with type 1 DM (T1DM) and those with pretransplant MI of 5 or greater. β-cell function was significantly improved after transplant in all recipients regardless of the type of DM and pretransplant MI values. Glucose control was significantly improved in recipients with T1DM and in all recipients regardless of the pretransplant MI values. Additional oral glucose tolerance test at 1 year posttransplant revealed that insulin sensitivity remained unimproved and β-cell function was higher compared with pretransplant. Glucose control had partially reverted to pretransplant levels in recipients with T1DM and those with pretransplant MI of 5 or greater.. Unlike β-cell function and glucose control, insulin sensitivity did not significantly improve until posttransplant 1 year after pancreas transplantation regardless of the type of DM or the degree of pretransplant insulin sensitivity.

Topics: Adult; Blood Glucose; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Insulin-Secreting Cells; Kaplan-Meier Estimate; Male; Middle Aged; Pancreas Transplantation; Tacrolimus

Topics: Caliciviridae Infections; Diabetes Mellitus, Type 1; Diagnosis, Differential; Diarrhea; Disease Progression; Drug Tapering; Feces; Fluid Therapy; Gastroenteritis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Sapovirus; Tacrolimus

The need for chronic immune suppression (IS) is one of the hurdles precluding widespread use of islet cell transplantation to restore glycemic control in patients with type 1 diabetes. We report the case of a healthy nonhuman primate (NHP) treated on and off for over 2.5 years with steroid-free IS, consisting of daclizumab induction and maintenance therapy with rapamycin and low dose tacrolimus. Treatment for 1 year resulted in a striking destabilization of glycemic control, with concomitant decreases in fasting c-peptide and insulin levels. Although these changes gradually reversed during a wash out period of 7 months, retreatment with the same therapy led to accelerated deterioration in glycemic control. Intravenous glucose tolerance and percentage of glycosylated hemoglobin testing further supported a dramatic effect on metabolic control. IS also led to decreases in weight during treatment. Histological evaluation of the pancreas revealed islet hyperplasia, with varying sizes and endocrine cell ratios that differed from normal islet composition, and parenchymal infiltration with adipose tissue. These deleterious effects of IS on glucose control and endocrine components in the native pancreas of a healthy NHP suggest that IS agents commonly utilized for islet transplantation may contribute to failure in islet allograft function in long-term transplant patients.

Topics: Animals; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Glucose Tolerance Test; Graft Survival; Immunosuppression Therapy; Islets of Langerhans; Islets of Langerhans Transplantation; Macaca fascicularis; Male; Sirolimus; Tacrolimus; Transplantation, Homologous

Solid organ transplant patients are well established to be at risk of herpes simplex virus and varicella zoster virus infection and reactivation. We present a case of a 41-year-old woman with a history of pancreas and renal transplant who presented with what appeared to be disseminated herpes simplex virus or varicella zoster virus induced rash, but who was ultimately diagnosed and treated as linear IgA bullous dermatosis. This case alerts physicians to other non-infectious dermatoses as a cause of vesiculobullous rash in solid organ transplant patients.

Topics: Adult; Dermatitis Herpetiformis; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Linear IgA Bullous Dermatosis; Pancreas Transplantation; Prednisone; Skin; Tacrolimus

Successful simultaneous pancreas and kidney transplantation (SPK) or pancreas transplantation alone (PTA) restores glycemic control. Diabetes and impaired kidney function are common side effects of immunosuppressive therapy. This study addresses glucometabolic parameters and kidney function during the first year.. We examined 67 patients with functioning grafts (SPK n = 30, PTA n = 37) transplanted between September 2011 and November 2016 who underwent repeated oral glucose tolerance tests (OGTTs) 8 and 52 weeks after transplantation. Another 19 patients lost their graft the first year post-transplant and 28 patients did not undergo repeated OGTTs and could not be studied. All patients received ATG induction therapy plus tacrolimus, mycophenolate and prednisolone. Glomerular filtration rate was measured before and 8 and 52 weeks after transplantation by serum clearance methods.. From week 8 to 52 after transplantation, mean fasting glucose decreased (SPK: 5.4 ± 0.7 to 5.1 ± 0.8 mmol/L, PTA: 5.4 ± 0.6 to 5.2 ± 0.7 mmol/L; both P < 0.05), and also 120-min post-OGTT glucose (SPK: 6.9 ± 2.9 to 5.7 ± 2.2 mmol/L; P = 0.07, PTA: 6.5 ± 1.7 to 5.7 ± 1.2 mmol/L; P < 0.05). Fasting C-peptide levels also decreased (SPK: 1500 ± 573 to 1078 ± 357 pmol/L, PTA: 1210 ± 487 to 1021 ± 434 pmol/L, both P < 0.005). Measured GFR decreased from enlistment to 8 weeks post transplant in PTA patients (94 ± 22 to 78 ± 19 mL/min/1.73 m2; P < 0.005), but did not deteriorate from week 8 to week 52 (SPK: 55.0 ± 15.1 vs 59.7 ± 11.3 ml/min/1.73 m²; P = 0.19, PTA: 76 ± 19 vs 77 ± 19 mL/min/1.73 m²; P = 0.74).. Glycemic control and kidney function remain preserved in recipients with functioning SPK and PTA grafts 1 year after transplantation.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Glucose Tolerance Test; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Insulin Secretion; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prospective Studies; Tacrolimus

Induction therapy with a T cell-depleting agent followed by mycophenolate mofetil and tacrolimus is presently the most frequently used immune suppression (IS) regimen in islet transplantation. This study assesses its safety and tolerability in nonuremic type 1 diabetic recipients.. Fifty-one patients (age, between 29 and 63 years) with high glycemic variability and problematic hypoglycemia received intraportal islet grafts under anti-thymocyte globulin-mycophenolate mofetil-tacrolimus protocol. They were followed up for over 48 months for function of the implant and adverse events.. Severe hypoglycemia and diabetic ketoacidosis were absent in patients with functioning graft. Immune suppressive therapy was maintained for 48 months in 29 recipients with sustained function (group A), whereas 16 patients stopped earlier due to graft failure (group B) and in 6 for other reasons. Group A was significantly older at the time of implantation and achieved higher graft function at posttransplantation month 6 under similar dose of IS. Prevalence of IS-related side effects was similar in groups A and B, occurring predominantly during the first year posttransplantation. IS-related serious adverse events (SAE) were reported in 47% of patients, with 4 presenting with cytomegalovirus infection and 4 (age, 42-59 years) diagnosed with cancer. Except in 1 patient with cancer, all SAEs resolved after appropriate treatment.. These risk/benefit data serve as a basis for clinical decision-making before entering an intraportal islet transplantation protocol. A longer benefit is observed in recipients of higher age (≥40 years), but it is not associated with more side effects and SAE.

Topics: Adult; Antilymphocyte Serum; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Condyloma acuminata (CA) are warty lesions caused by human papilloma virus (HPV) that generally affect the external genitalia and mucocutaneous junctions. Involvement of the urinary tract is rare, and involvement of the urinary bladder is thought to be due to immunosuppression. A 30-year-old woman was diagnosed with urethral CA 12 months after renal transplantation. She underwent transurethral resection (TUR) of the urethral lesions. During the operation, multiple sessile warty lesions were found incidentally inside the bladder and were also removed by TUR. The patient's postoperative course was uneventful. Pathological examination confirmed that the lesions were CA. Multiplex real-time polymerase chain reaction was performed to confirm the HPV genotype and revealed type 45 HPV DNA. CA of the urethra are uncommon, and bladder involvement is extremely rare. This case is the first reported, to our knowledge, to involve HPV type 45 in bladder condyloma. TUR may be the preferred option for the management of CA in the urinary bladder.

Topics: Adult; Condylomata Acuminata; Cystoscopy; Diabetes Mellitus, Type 1; Female; Genotype; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidental Findings; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Papillomaviridae; Prednisolone; Real-Time Polymerase Chain Reaction; Tacrolimus; Transplant Recipients; Urethra; Urinary Bladder

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus, Type 1; Dyslipidemias; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prevalence; Prospective Studies; Risk Factors; Severity of Illness Index; Spain; Survival Analysis; Tacrolimus; Transplant Recipients

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet-after-kidney transplantation in patients with type 1 diabetes using an alemtuzumab-based induction regimen leads to considerable islet allograft function and improvement in glycemic control.

Topics: Alemtuzumab; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Glucose Tolerance Test; Glycemic Index; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Function Tests; Kidney Transplantation; Maintenance Chemotherapy; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Prognosis; Risk Factors; Tacrolimus

Topics: Adolescent; Diabetes Mellitus, Type 1; Humans; Male; Necrobiosis Lipoidica; Skin; Tacrolimus

The maintenance or expansion of regulatory T (Treg) cells has a fundamental role in the achievement of immunological tolerance after transplantation. Here we aimed to determine mechanisms of human Treg cell depletion and reconstitution after anti-CD25 monoclonal antibody (mAb) treatment.. Seventeen patients with type 1 diabetes who received pancreatic islet transplantation and anti-CD25 mAb as induction therapy were studied.. We observed an almost complete depletion of Treg cells after injection of anti-CD25 mAb. The kinetic of Treg cell depletion did not parallel the disappearance of CD25+ T cells as CD25 is also rapidly downregulated and internalized. Regulatory T cell reconstitution is completed within 6 months posttransplantation and appeared to be driven by IL-7-mediated homeostatic T cell proliferation. Anti-CD25 mAb treatment sensitizes Treg cell to the biological effect of IL-7, possibly rendering more common γc-chain available to interact with CD127. Homeostatic Treg cell proliferation is resistant to the inhibitory effect of rapamycin and FK506 but can be blocked by the presence of mycophenolate mofetil.. Our data suggest that a compensatory mechanism of IL-7-mediated homeostatic proliferation can restore the inhibitory network of Treg cell after anti-CD25 induction therapy in islet allotransplantation.

Topics: Adult; Allografts; Antibodies, Monoclonal; Basiliximab; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Forkhead Transcription Factors; Humans; Immunologic Memory; Immunosuppressive Agents; Interleukin Receptor Common gamma Subunit; Interleukin-2 Receptor alpha Subunit; Interleukin-7; Interleukin-7 Receptor alpha Subunit; Islets of Langerhans Transplantation; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Signal Transduction; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Time Factors; Treatment Outcome

Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent TRPC6 activation underlies glomerular diseases. Here, we developed a murine model in which a constitutively active Gq α subunit (Gq(Q209L), referred to herein as GqQ>L) is specifically expressed in podocytes and examined the effects of this mutation in response to puromycin aminonucleoside (PAN) nephrosis. We found that compared with control animals, animals expressing GqQ>L exhibited robust albuminuria, structural features of FSGS, and reduced numbers of glomerular podocytes. Gq activation stimulated calcineurin (CN) activity, resulting in CN-dependent upregulation of TRPC6 in murine kidneys. Deletion of TRPC6 in GqQ>L-expressing mice prevented FSGS development and inhibited both tubular damage and podocyte loss induced by PAN nephrosis. Similarly, administration of the CN inhibitor FK506 reduced proteinuria and tubular injury but had more modest effects on glomerular pathology and podocyte numbers in animals with constitutive Gq activation. Moreover, these Gq-dependent effects on podocyte injury were generalizable to diabetic kidney disease, as expression of GqQ>L promoted albuminuria, mesangial expansion, and increased glomerular basement membrane width in diabetic mice. Together, these results suggest that targeting Gq/TRPC6 signaling may have therapeutic benefits for the treatment of glomerular diseases.

Topics: Albuminuria; Animals; Calcineurin; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Gene Deletion; Genes, Reporter; Glomerulosclerosis, Focal Segmental; GTP-Binding Protein alpha Subunits, Gq-G11; HEK293 Cells; Humans; Kidney Glomerulus; Kidney Tubules; Mice; Mice, Mutant Strains; Mice, Transgenic; NFATC Transcription Factors; Podocytes; Point Mutation; Puromycin Aminonucleoside; Recombinant Fusion Proteins; Signal Transduction; Tacrolimus; TRPC Cation Channels; TRPC6 Cation Channel

Necrobiosis lipoidica presents with a distinctive appearance making it an important clinical diagnosis.. To describe a case of necrobiosis lipoidica in a patient with type 1 diabetes mellitus, and to discuss differential diagnoses and management.. Necrobiosis lipoidica is most commonly found on the shins, presenting as a well-defined plaque. Management is challenging and options are discussed. Avoiding ulceration is a key concern.

Topics: Adult; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Leg Ulcer; Necrobiosis Lipoidica; Risk Factors; Tacrolimus

Transplant patients on tacrolimus therapy exhibit a reduced glomerular filtration rate (GFR). The type of graft and immune treatment protocol may influence the extent and reversibility of this side effect.. The present single-center study is conducted in 48 nonuremic type 1 diabetic recipients of an intraportal islet-cell graft under maintenance immunosuppression (IS) with tacrolimus and mycophenolate mofetil. Estimated GFR (eGFR) and albuminuria were followed up to 5 years posttransplantation.. Mean eGFR values decreased by 19 mL/min/1.73 m after 1 to 2 weeks of IS (P<0.0001) and then remained stable throughout the complete treatment period. The decrease was related to predose trough tacrolimus concentrations or doses and disappeared upon its discontinuation; it was also associated with the presence of albuminuria at the time of transplantation. Tacrolimus treatment resulted in a reduction of albuminuria; its discontinuation restored albuminuria to the initial levels.. The use of tacrolimus in our islet-cell transplant protocol caused an initial 20% reduction in eGFR, which was reversible following its discontinuation, at least within the 5-year follow-up period. The associated reduction in albuminuria was also reversible, compatible with a tacrolimus-induced preglomerular vasoconstriction. These observations support further use of our tacrolimus regimen in this patient population.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

We report a case of a 57-year-old woman with type I diabetes who had received a simultaneous pancreas-kidney (SPK) transplant maintained on tacrolimus, mycophenolic acid (MPA) and prednisolone. Her renal allograft failed 6 years post-transplant but she continued to have a normal functioning pancreatic allograft. Over the course of 5 years, she developed progressive bone marrow failure with repeat bone marrow aspirates demonstrating an evolution from erythroid hypoplasia to hypocellular marrow and eventual aplastic anaemia despite discontinuation of MPA and reduction of tacrolimus. She was transfusion-dependent and had frequent admissions for sepsis. Despite treatment with antithymocyte globulin and cyclosporine for aplastic anaemia, she developed fatal invasive pulmonary aspergillosis within 3 weeks of treatment. Even though the cause of aplastic anaemia is likely multifactorial, this case highlights the difficulty in balancing the need for versus the risk of ongoing immunosuppression in a SPK transplant recipient who continues to have normal pancreatic graft function.

Topics: Anemia, Aplastic; Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Tacrolimus

The Clinical Islet Transplantation 07 (CIT07) protocol uses antithymocyte globulin and etanercept induction, islet culture, heparinization, and intensive insulin therapy with the same low-dose tacrolimus and sirolimus maintenance immunosuppression as in the Edmonton protocol. To determine whether CIT07 improves engrafted islet β-cell mass, our center measured β-cell secretory capacity from glucose-potentiated arginine tests at days 75 and 365 after transplantation and compared those results with the results previously achieved by our group using the Edmonton protocol and normal subjects. All subjects were insulin free, with CIT07 subjects receiving fewer islet equivalents from a median of one donor compared with two donors for Edmonton protocol subjects. The acute insulin response to glucose-potentiated arginine (AIRpot) was greater in the CIT07 protocol than in the Edmonton protocol and was less in both cohorts than in normal subjects, with similar findings for C-peptide. The CIT07 subjects who completed reassessment at day 365 exhibited increasing AIRpot by trend relative to that of day 75. These data indicate that engrafted islet β-cell mass is markedly improved with the CIT07 protocol, especially given more frequent use of single islet donors. Although several peritransplant differences may have each contributed to this improvement, the lack of deterioration in β-cell secretory capacity over time in the CIT07 protocol suggests that low-dose tacrolimus and sirolimus are not toxic to islets.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Insulin Secretion; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Male; Middle Aged; Sirolimus; 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

Topics: Adolescent; Diabetes Mellitus, Type 1; Diagnosis, Differential; Eye; Facial Dermatoses; Female; Giant Cells; Granuloma; Histiocytes; Humans; Immunosuppressive Agents; Necrobiosis Lipoidica; Necrobiotic Xanthogranuloma; Plasma Cells; Tacrolimus

Tacrolimus, a reversible calcineurin inhibitor, is known for its diabetogenic potential. The incidence of diabetes is less frequent among the patients of nephrotic syndrome in comparison to organ transplant recipients. Diabetic ketoacidosis (DKA) is even rarer. DKA as the first presentation of new onset tacrolimus induced transient type 1 diabetes despite a lower dose range and low trough level of the drug is being reported in a 12-y-old girl with steroid resistant nephrotic syndrome.

Topics: Child; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

Controversy persists over the safety and efficacy of pancreas transplantation in patients with insulin-dependent diabetes mellitus who have received a prior kidney transplant.. We compared the outcomes of recipients who received either Synchronous-Pancreas Kidney-Transplantation (SPK, n=123) or Pancreas-After-Kidney-Transplants(n=49)at our institution between August 2002 to January 2010.. Donor and recipient demographics were similar. Time interval between kidney and pancreas transplantation was 5.9 ± 3.8 (4.8 [1.6-12.2]) years. The majority of kidney-recipients in PAK group were transplanted at outside institutions and referred to us for PAK. Most patients received thymoglobulin induction and were maintained on tacrolimus, MMF, and prednisone. For SPK versus PAK recipients, there was no difference in median of length of hospital stay or incidence of overall complications. All PAK recipients are alive with functioning kidney grafts, whereas the 1-, 3-, and 5-year SPK patient survival rates were 98%,96%,and 94%, P=0.09. The 1-,3-, and 5-yr uncensored pancreas survival rates for SPK versus PAK were 93% vs. 90%, 90% vs. 90%, and 82% versus 85%, respectively (P=0.4).. Glycemic control and intermediate survival outcomes were similar in both groups. Pancreas-graft outcomes in SPK and PAK were equivalent in our study, but our specific population entailed among other factors a long K to PAK time interval; PAK could be a comparable option to SPK for patients with access to kidney grafts.

Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome; Young Adult

Topics: Area Under Curve; Blood Glucose; C-Peptide; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Immune Tolerance; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Middle Aged; Tacrolimus

The effects of a water-soluble tacrolimus-PEG conjugate (KI-102) on insulin-dependent diabetes mellitus and systemic lupus erythematosus were investigated. KI-102 was stable at pH 4.0-4.5 and 4°C. The area under the concentration-time curve, the time of maximum concentration, and the maximum concentration were 43.4 ng·h/mL, 0.85 h, and 8.1 ng/mL, respectively, similar to those of FK506. Mice that administered KI-102 at 4.32 mg/kg had the plasma glucose concentrations that decreased to 7.5 mmol/L after 170 days, similar to that of mice administered FK506 at 0.6 mg/kg. There were no incidences of diabetes when KI-102 was administered at 86.4 mg/kg after 24 weeks. The group that administered 43.2 mg/kg had decreases in the concentrations of β-hydroxybutyrate (60%), triglyceride (24%), and cholesterol (30%). KI-102 administered at 180 mg/kg reduced serum anti-dsDNA antibody activity by 64% compared with a control. Urinary albumin concentration in the same group decreased 81% compared with the control. These results indicate that KI-102 may be practically applicable as prodrug of FK506.

Topics: Administration, Oral; Albumins; Animals; Antibodies, Antinuclear; Blood Glucose; Capsules; Cholesterol; Diabetes Mellitus, Type 1; DNA; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Compounding; Drug Delivery Systems; Drug Evaluation, Preclinical; Drug Stability; Female; Freeze Drying; Hydrogen-Ion Concentration; Immunosuppressive Agents; Insulin; Lupus Erythematosus, Systemic; Mice; Polyethylene Glycols; Prodrugs; Rats; Rats, Sprague-Dawley; Tacrolimus; Triglycerides

Pancreas transplantation involves a set of procedures that, in some cases, lead to different complications and outcomes. The aim of this study was to analyze the long-term effects of pancreas transplantation regarding carbohydrate and lipid metabolism parameters to determine differences between simultaneous pancreas-kidney (SPK) transplantation and pancreas transplantation alone (PTA).. Sixty-four patients (46 SPK and 18 PTA), with an immunosuppression protocol based on tacrolimus plus mycophenolate mofetil and prednisone, were evaluated for at least 1 year after transplantation. No patient made use of any hypoglycemic or hypolipidemic drugs. Comparisons were performed between SPK and PTA patients using the chi-square test, Fischer's exact test, and unpaired Student's t test, as appropriate.. Patients were 39.8+/-9.3 years old, predominantly male (60.9%), with a mean follow-up of 25.4+/-10.4 months after transplantation. The PTA group exhibited worse renal function and higher tacrolimus levels than the SPK group. Fasting glucose, 2 hr plasma glucose after overload, C-peptide, and HbA1C were within the normal range, with no statistically significant differences between the PTA and SPK groups. Insulin (INS) and the homeostasis model assessment of INS resistance index were above the normal range in both the groups. Lipids were also similar between groups.. The majority of patients with long-term functioning pancreas transplant achieved good glucose control without use of exogenous INS or oral antidiabetic drugs, although they were hyperinsulinemic. There were no significant differences concerning glucose and lipid parameters between the SPK and PTA groups, even though the PTA patients exhibited higher tacrolimus levels and worse renal function.

Topics: Adult; Blood Glucose; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Patient Selection; Prednisone; Reproducibility of Results; Tacrolimus; Time; Time Factors; Treatment Outcome

Topics: Acute Disease; Antibodies, Monoclonal; Antilymphocyte Serum; Calcineurin Inhibitors; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Pancreas Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Tacrolimus

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen-1 antibody efalizumab which permits long-term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single-islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long-term follow-up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid-free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long-term islet allograft survival.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Blood Glucose; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppression Therapy; Islets of Langerhans Transplantation; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Islet or beta cell transplantation provides a promising cure for type 1 diabetes patients, but insulin-independency decreases frequently over time. Immunosuppressive regimens are implemented attempting to cope with both auto- and alloimmunity after transplantation. We analysed the influence of different immunotherapies on autoreactive and alloreactive T cell patterns and transplant outcome. Patients receiving three different immunosuppressive regimens were analysed. All patients received anti-thymocyte globulin induction therapy. Twenty-one patients received tacrolimus-mycophenolate mofetil maintenance immunosuppression, whereas the other patients received tacrolimus-sirolimus (SIR, n = 5) or SIR only (n = 5). Cellular autoreactivity and alloreactivity (CTL precursor frequency) were measured ex vivo. Clinical outcome in the first 6 months after transplantation was correlated with immunological parameters. C-peptide levels were significantly different between the three groups studied (P = 0.01). We confirm that C-peptide production was correlated negatively with pretransplant cellular autoreactivity and low graft size (P = 0.001, P = 0.007 respectively). Combining all three therapies, cellular autoimmunity after transplantation was not associated with delayed insulin-independence or C-peptide production. In combined tacrolimus-SIR and SIR-treated patients, CTL alloreactivity was associated with less insulin independence and C-peptide production (P = 0.03). The percentage of donors to whom high CTLp frequencies were measured was lower in insulin-independent recipients (P = 0.03). In this cohort of islet cell graft recipients, clinical outcome in the first 6 months after transplantation correlates with the applied immunosuppressive regimen. An association exists between insulin-independence and lower incidence of CTL alloreactivity towards donor human leucocyte antigen. This observational study demonstrates the usefulness of monitoring T cell reactivity against islet allografts to correlate immune function with graft survival.

Topics: Adult; Autoimmunity; C-Peptide; Cells, Cultured; Cytotoxicity, Immunologic; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocyte Activation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Sirolimus; T-Lymphocytes, Cytotoxic; Tacrolimus; Treatment Outcome

We encountered an unexpectedly high rate of ovarian cysts in premenopausal women receiving sirolimus and tacrolimus following islet transplantation. The goal of this retrospective chart review was to determine the frequency of ovarian cysts found on pelvic ultrasound examinations of female islet transplant recipients and to look for potential causal factors. Fifty-seven women with a median age of 42.5 years underwent islet transplantation at the University of Alberta. Ovarian cysts were found in 31 out of 44 (70.5%) premenopausal and two out of 13 (15.4%) postmenopausal women (P = 0.001). No women using combined oral contraception developed ovarian cysts. Eight women required surgery; in four women undergoing cystectomy or unilateral oophorectomy, ovarian cysts recurred. Sirolimus withdrawal was associated with a reduction in cyst size and resolution of cysts in 80% of subjects. The risk of ovarian cysts should be discussed with female islet transplant candidates and pelvic ultrasounds performed routinely post-transplant.

Topics: Abdomen; Adult; Canada; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Ovarian Cysts; Postmenopause; Premenopause; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Treatment Outcome; Ultrasonography

Pancreatic islet transplantation has the potential to be an effective treatment for type 1 diabetes mellitus. While recent improvements have improved 1-year outcomes, follow-up studies show a persistent loss of graft function/survival over 5 years. One possible cause of islet transplant failure is the immunosuppressant regimen required to prevent alloimmune graft rejection. Although there is evidence from separate studies, mostly in rodents and cell lines, that FK506 (tacrolimus), rapamycin (sirolimus), and mycophenolate mofetil (MMF; CellCept) can damage pancreatic beta-cells, there have been few side-by-side, multiparameter comparisons of the effects of these drugs on human islets. In the present study, we show that 24-h exposure to FK506 or MMF impairs glucose-stimulated insulin secretion in human islets. FK506 had acute and direct effects on insulin exocytosis, whereas MMF did not. FK506, but not MMF, impaired human islet graft function in diabetic NOD*scid mice. All of the immunosuppressants tested in vitro increased caspase-3 cleavage and caspase-3 activity, whereas MMF induced ER-stress to the greatest degree. Treating human islets with the GLP-1 agonist exenatide ameliorated the immunosuppressant-induced defects in glucose-stimulated insulin release. Together, our results demonstrate that immunosuppressants impair human beta-cell function and survival, and that these defects can be circumvented to a certain extent with exenatide treatment.

Topics: Animals; Apoptosis; Cells, Cultured; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Glucose; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Mice, SCID; Mycophenolic Acid; Sirolimus; Tacrolimus

The metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function.. Thirty nonuremic C-peptide-negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus-mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model.. Patients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive beta-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability.. Higher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus-mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.

Topics: Adult; Anticoagulants; Antilymphocyte Serum; Biopsy; C-Peptide; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Liver; Lymphocyte Count; Male; Middle Aged; Mycophenolic Acid; Reference Values; Reoperation; T-Lymphocytes; Tacrolimus; Treatment Outcome

After decades of controversy surrounding the therapeutic validity of pancreas transplantation, the procedure has become accepted as the preferred treatment for selected patients with type 1 diabetes mellitus. Between January 2001 and January 2008, 100 patients underwent pancreatic transplantation at our center: 88 simultaneous pancreas-kidney transplantation and 12 pancreas transplantations alone. Pancreas graft management of the exocrine drainage technique involved enteric drainage in 8 (all simultaneous pancreas-kidney) and the bladder in 92 cases. The recipient systemic venous system was used for the pancreas graft venous effluent in all cases. Our overall results have shown that the number of functioning pancreatic grafts was 64 of 100. Graft losses were: rejection (n = 8), venous thrombosis (n = 9), arterial thrombosis (n = 1), or surgical complications such as anastomotic leak (n = 3), perigraft infection (n = 10), pancreatitis of the graft (n = 5). Most cases of pancreatitis (80%) had preservation times exceeding 18 hours. Despite surgical and immunosuppressive complications, our impression was that pancreas transplantation was a highly effective therapy for diabetes mellitus. After 7 years of the program and 100 transplantations, we believe that there is a major role for transplantation in diabetes management.

Topics: Adolescent; Adult; Brazil; Cadaver; Child; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Registries; Retrospective Studies; Tacrolimus; Tissue Donors; Treatment Outcome; United States

The rate of mycophenolic acid (MPA) absorption after oral administration of mycophenolate mofetil (MMF) is delayed in patients with diabetes. Cyclosporine (CsA) decreases MPA exposure by inhibiting enterohepatic recirculation of MPA/MPA glucuronide, and tacrolimus (TRL) may alter the rate and extent of MPA absorption due to its prokinetic properties especially in patients with diabetic gastroparesis. This study evaluated the effect of changing from CsA to TRL on pharmacokinetics of MPA in stable renal transplant recipients with long-standing diabetes. Eight patients were switched from a stable dose of CsA to TRL while taking MMF 1 g twice daily. The 12-hour steady-state total plasma concentration-time profiles of MPA and MPA glucuronide were obtained after oral administration of MMF on 2 occasions: first while taking CsA and second after changing to TRL. Pharmacokinetic parameters of MPA were calculated by the noncompartmental method. Changing from CsA to TRL resulted in significantly increased MPA exposure (area under the concentration-time curve from 0 to 12 hours, AUC0-12) by 46 +/- 32% (P = 0.012) and MPA predose concentration (C0) by 121 +/- 67% (P = 0.008). The magnitude of change in MPA exposure did not correlate well with MPA-C0 or CsA trough concentration. Switching to TRL had minimal impact on peak concentration of MPA (15.0 +/- 6.9 mg/L with CsA versus 16.1 +/- 9.7 mg/L with TRL, P = 0.773) and time to reach the peak concentration (1.0 +/- 0.4 hours with CsA versus 1.2 +/- 0.8 hours with TRL, P = 0.461). Highly variable and unpredictable changes in MPA exposure among renal transplant patients with diabetes do not support a strategy of preemptively adjusting MMF dose when switching calcineurin inhibitors in this population.

Topics: Adult; Cross-Over Studies; Cyclosporine; Diabetes Mellitus, Type 1; Drug Interactions; Female; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation

Topics: Adult; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Mycophenolic Acid; Pancreas Transplantation; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Only a minority of islet transplant recipients maintain insulin independence at 5 years under the Edmonton protocol of immunosuppression. New immunosuppressive strategies are required to improve long-term outcomes.. Three subjects with unstable type 1 diabetes mellitus underwent islet transplantation with alemtuzumab induction and sirolimus-tacrolimus maintenance for 3 months and then sirolimus-mycophenolic acid maintenance thereafter. Follow-up was more than 2 years. Comparison was with 16 historical subjects transplanted under the Miami version of the Edmonton protocol.. Insulin independence was achieved in 2 of 3 alemtuzumab and 14 of 16 historical subjects. Those who did not achieve insulin independence only received a single islet infusion. Insulin-independence rates remained unchanged in the alemtuzumab group, but decreased from 14 of 16 (88%) to 6 of 16 (38%) in the historical group over 2 years. Insulin requirements increased in the historical group while remaining stable in the alemtuzumab group. Comparison of functional measures at 3 months suggested better engraftment with alemtuzumab (P=NS). Further comparison of alemtuzumab versus historical groups, up to 24 months, demonstrated significantly better: Mixed meal stimulation index (24 months, 1.0+/-0.08 [n=3] vs. 0.5+/-0.06 pmol/mL [n=6], P<0.01), mixed meal peak C-peptide (24 months, 5.0+/-0.5 [n=3] vs. 3.1+/-0.3 nmol/mL [n=6], P<0.05), HbA1c (24 months, 5.4+/-0.15 [n=3] vs. 6.3+/-0.12 pmol/mL [n=10], P<0.01). Administration of alemtuzumab was well tolerated. There was no increased incidence of infections in alemtuzumab subjects despite profound, prolonged lymphocyte depletion.. Islet transplantation with alemtuzumab induction was well tolerated and resulted in improved short- and long-term outcomes. Further investigation is underway for validation.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Blood Glucose; Body Mass Index; C-Peptide; Calcineurin; Diabetes Mellitus, Type 1; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Sirolimus; Tacrolimus; Treatment Outcome

A pancreas transplant alone (PTA) in a nonuremic patient with brittle diabetes mellitus remains a rare procedure because the tradeoff for insulin independence is lifelong immunosuppression.. Herein we report our results at the University of Minnesota of 513 PTAs from December 17, 1966, through December 31, 2006. Of these recipients, 87% had previously experienced hypoglycemic unawareness and 23% experienced coma and/or seizures. These transplants spanned four immunosuppressive eras: pre-cyclosporine A (pre-CsA) era (16%), CsA era (23%), tacrolimus (TAC) era (47%), and calcineurin-inhibitor (CNI)-free era (14%).. The overall patient survival rate at 1 year posttransplant was about 95%; at 5 years, it was 90%. The pancreas graft survival rate at 1 year increased significantly from the pre-CsA era (31%) to the TAC era (75%), thanks to a significant decline in immunologic and technical failures. The CNI-free protocol, because of its high infection and hematologic infection rate, did not further improve outcome. Risk factors for subsequent kidney failure (13% at 5 years posttransplant) were serum creatinine levels>1.5 mg/dl at the time of the pancreas transplant and recipient age<30 years.. A technically successful PTA is currently the only treatment option that allows nonuremic patients with brittle diabetes to become insulin-independent in the long term.

Topics: Adolescent; Adult; Cyclosporine; Diabetes Mellitus, Type 1; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Pancreas Transplantation; Renal Dialysis; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome

Topics: Animals; Diabetes Mellitus, Type 1; Humans; Immunosuppressive Agents; Insulin; Insulin-Secreting Cells; Mice; Mice, Transgenic; Sirolimus; Tacrolimus

Successful transplantation requires the prevention of allograft rejection and, in the case of transplantation to treat autoimmune disease, the suppression of autoimmune responses. The standard immunosuppressive treatment regimen given to patients with autoimmune type 1 diabetes who have received an islet transplant results in the loss of T cells. In many other situations, the immune system responds to T cell loss through cytokine-dependant homeostatic proliferation of any remaining T cells. Here we show that T cell loss after islet transplantation in patients with autoimmune type 1 diabetes was associated with both increased serum concentrations of IL-7 and IL-15 and in vivo proliferation of memory CD45RO(+) T cells, highly enriched in autoreactive glutamic acid decarboxylase 65-specific T cell clones. Immunosuppression with FK506 and rapamycin after transplantation resulted in a chronic homeostatic expansion of T cells, which acquired effector function after immunosuppression was removed. In contrast, the cytostatic drug mycophenolate mofetil efficiently blocked homeostatic T cell expansion. We propose that the increased production of cytokines that induce homeostatic expansion could contribute to recurrent autoimmunity in transplanted patients with autoimmune disease and that therapy that prevents the expansion of autoreactive T cells will improve the outcome of islet transplantation.

Topics: Adult; Animals; Diabetes Mellitus, Type 1; Homeostasis; Humans; Immunosuppressive Agents; Interleukin-15; Interleukin-7; Islets of Langerhans Transplantation; Male; Mice; Mycophenolic Acid; Sirolimus; T-Lymphocyte Subsets; T-Lymphocytes; Tacrolimus

Tight glycemic control can reduce progression of diabetic nephropathy (DN) while the histological changes may regress after pancreas transplantation. Clinical islet transplantation (CIT) can restore euglycemia but the effects of CIT and concomitant immunosuppression on renal function are not known. Renal function (modification of diet in renal disease estimated glomerular filtration rate [GFR]) is reported in 41 type 1 diabetes subjects followed for 29.8 (6-57) months after CIT who received sirolimus and tacrolimus. HbA(1c) improved by 3 months (6.1 +/- 0.5 vs. 8.1 +/- 1.3%, p < 0.001) and was sustained. Over 4 years estimated GFR (eGFR) declined (repeated measures ANOVA: p = 0.0011). The median rate of change in eGFR was -0.39 mL/min/1.73 m(2)/month but was highly variable (range: +1.62 to -2.79 mL/min/1.73 m(2)/month). Progression of albuminuria was observed in ten individuals while regression of microalbuminuria was observed in only one (chi square = 22.51, df = 4, p = 0.0002). Despite improved glycemia, CIT and concomitant immunosuppression, was associated with a fall in eGFR and progression of albuminuria over 4 years of observation. The rate of decline in eGFR was extremely variable and difficult to predict. The risk of progressive nephrotoxicity with decline in eGFR should be discussed with prospective CIT candidates and the risk: benefit ratio carefully considered in individuals with pre-existing renal impairment.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Immunosuppression Therapy; Islets of Langerhans Transplantation; Kidney; Male; Middle Aged; Sirolimus; Tacrolimus

Islet transplantation alone is an alternative for the replacement of pancreatic endocrine function in patients with type 1 diabetes. The aim of our study was to assess the impact of the Edmonton immunosuppressive protocol (tacrolimus-sirolimus association) on kidney function.. Nineteen patients with type 1 diabetes and metabolic instability received islet transplantation alone and immunosuppressive therapy according to the Edmonton protocol. Serum creatinine (sCr), creatinine clearance (CrCl), and 24-h urinary protein excretion (UPE) were assessed at baseline and during a follow-up of 339 patient-months.. After islet transplantation we observed 1) sCr within the normal range in all but two patients in whom sCr increased immediately after islet transplantation, and despite withdrawal of immunosuppression, patients progressed to end-stage renal disease (ESRD); 2) CrCl remained within the normal range for those patients who had normal baseline values and decreased, progressing to ESRD in two patients with a decreased baseline CrCl; and 3) 24-h UPE worsened (>300 mg/24 h) in four patients. In the two patients who progressed to ESRD, the worsening of 24-h UPE occurred immediately after islet transplantation. In one patient 24-h UPE worsening occurred at 18 months, and, after withdrawal of immunosuppression, it returned to the normal range. In another patient 24-h UPE increased at 24 months and remained stable while immunosuppression was continued.. In type 1 diabetic patients receiving islet transplantation alone, the association of tacrolimus and sirolimus should be used only in patients with normal kidney function. Alternative options for immunosuppressive treatment should be considered for patients with even a mild decrease of kidney function.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Daclizumab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Disease Progression; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Immunoglobulin G; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Kidney Function Tests; Retrospective Studies; Sirolimus; Tacrolimus

Topics: Albuminuria; Blood Glucose; Diabetes Mellitus, Type 1; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Islets of Langerhans Transplantation; Sirolimus; Tacrolimus

Tacrolimus is an immunosuppressive agent used in solid organ and islet transplantation. Its topical form has shown benefit in the treatment of inflammatory skin conditions. Although tacrolimus has a wide spectrum of side effects, dermatological complications related to systemic tacrolimus therapy are limited in the literature. Atopic dermatitis (AD) is a chronic pruritic cutaneous condition that usually begins in infancy and is characterized by an increased Th2 response. We report the case of a patient with type 1 diabetes mellitus (T1DM) and history of AD latent for 10 years who developed severe dermatitis and alopecia 5 months after undergoing allogeneic islet transplantation and initiating a steroid-free immunosuppressive regimen with sirolimus and tacrolimus maintenance. After exclusion of other possible causes for the progression and exacerbation of the clinical presentation of AD, discontinuation of tacrolimus and introduction of mycophenolate mofetil resulted in full remission of the symptoms. The beneficial effects of tacrolimus withdrawal suggest a cause-effect relationship between this adverse event and the utilization of the drug. Islet graft function remained stable after modification of the therapeutic regimen (stable glycemic control and unchanged C-peptide).

Topics: Adult; Alopecia Areata; Dermatitis, Atopic; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The effect of diabetes mellitus on the pharmacokinetics of tacrolimus is not well characterized. We have compared tacrolimus 12-hour steady-state concentration-time profiles in diabetic (n = 11) and demographically matched nondiabetic (n = 9) stable kidney transplant recipients and derived a limited sampling strategy for the estimation of tacrolimus area under the concentration-time curve (AUC(0-12)). Tacrolimus concentration was measured by liquid chromatography tandem mass spectrometry and acetaminophen absorption method was used to characterize gastric emptying time. Demographic and biochemical characteristics were comparable between the two groups with the exception of significantly higher glycated hemoglobin levels in patients with diabetes (P = 0.02). Time to maximum concentration (T(max)) of acetaminophen was significantly longer in diabetics [D: 74.1 minute versus nondiabetics (ND): 29.3 minutes, P = 0.02]; however, tacrolimus T(max) was not significantly different (D: 121 minutes versus ND: 87 minutes, P = 0.15). Median (interquartile range) of tacrolimus AUC(0-12) was 114 (101-161) microg*hr/L in patients with diabetes and 113 (87-189) microg*hr/L in nondiabetics (P = 0.62). The following limited sampling equation [AUC(pred) (microg*hr/L) = 18.70 - 1.72 C(1 hr) - 4.09 C(2 hr) + 14.40 C(3 hr)] was derived from a training data set that included 10 patients. The correlation coefficient between model-predicted and observed AUC0-12 values was 0.999. Mean prediction error and root mean square error of the model-predicted values derived from the patients in validation data set were 0.04 and 17.48 microg*hr/L, respectively. In conclusion, it appears that diabetes has a modest effect on the rate but not the extent of tacrolimus absorption, and a three-point abbreviated sampling strategy common to both groups may prove useful for the estimation of tacrolimus exposure in kidney transplant recipients.

Topics: Adolescent; Adult; Aged; Area Under Curve; Chromatography, Liquid; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Monitoring; Gastric Emptying; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Models, Biological; Regression Analysis; Sampling Studies; Tacrolimus; Tandem Mass Spectrometry

This case report describes the successful treatment of severe plaque psoriasis with etanercept in a patient who underwent a liver transplant. It also addresses the concerns that arise in the treatment of chronic inflammatory dermatologic disease accompanied by multiple organ disorders.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Diabetes Mellitus, Type 1; Etanercept; Graft Rejection; Humans; Immunocompromised Host; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Psoriasis; Receptors, Tumor Necrosis Factor; Renal Insufficiency; Sirolimus; Tacrolimus

Adverse effects associated with calcineurin inhibitors may impact their clinical utility in some patients. This study characterizes the clinical outcomes of liver transplanted (LT) patients who experienced diabetes mellitus (DM) on tacrolimus-based regimen and were converted to cyclosporine-based therapy. Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Clinical and laboratory data related to the clinical course of the patients were recorded. Twenty-five patients were included after a median delay of 54 months after LT [seven women and 18 men, 51 years (range 30-69)]. There were 11 patients with insulin-treated DM (ITDM), 14 patients with noninsulin-treated DM (NITDM), and the glycemic control was poor (HbA1c > 6.5%) in 13/25 patients (52%). After a median follow-up of 20 months after conversion, there were four patients with ITDM, 17 patients with NITDM, and four patients without DM, and the glycemic control was poor in 3/25 patients (12%). Four patients returned to tacrolimus because of arterial hypertension or digestive side-effects. In conclusion, our results suggest that conversion from tacrolimus to cyclosporine in stable LT patients with DM is well tolerated and beneficial on glycemic control.

Topics: Adult; Aged; Blood Glucose; Cyclosporine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Treatment Outcome

To determine whether pancreatic islet transplantation can control diabetes and prevent severe life-threatening hypoglycaemia.. A single-arm observation study of six patients undergoing islet transplantation. All patients had had type 1 diabetes mellitus for over 5 years and documented episodes of repeated severe hypoglycaemia. Islets were isolated from donor pancreases digested by Liberase. Separated islets were infused into the recipient's liver via the portal vein. Patients were immunosuppressed with daclizumab, sirolimus and tacrolimus. The transplants were performed at Westmead Hospital, NSW, between October 2002 and February 2005.. Normal blood glucose control without administration of exogenous insulin; demonstration of islet function and abolition of hypoglycaemia.. Five of the patients received two islet infusions, and the sixth was withdrawn after one infusion following a portal vein thrombosis. Three patients became insulin-independent, with excellent glycaemic control. Two had islet function with circulating C-peptide, improved glycaemic control, reduced insulin requirement and abolition of severe hypoglycaemia. However, over a 2-year period, graft function deteriorated. Recipients who were initially insulin free remained C-peptide positive but required supplemental insulin. Complications included one postoperative bleed, two portal vein thromboses (which resolved completely), presumed recurrence of tuberculosis in one patient, and deterioration in renal function in one patient.. Islet transplantation is effective at improving glycaemic control and hypoglycaemia unawareness in the short to medium term. However, problems with long-term safety of immunosuppression, islet-induced thrombosis and early detection of loss of islet function remain to be addressed.

Topics: Adult; Age Factors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Australia; Blood Glucose; Daclizumab; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypoglycemia; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Middle Aged; Postoperative Complications; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

We report on a 30-year-old man, with type 1 diabetes mellitus, who developed generalized allergy to insulin consisting of several bouts of tremor, tachycardia, breathlessness and syncope. Strong positive reactions to protamine and metacresol were demonstrated by skin-prick testing. Symptoms persisted despite the use of antihistamine therapy, Actrapid HM Paraben and Monotard (insulin without protamine and metacresol) and immunosuppression (tacrolimus). He underwent a cadaver pancreas transplantation with portal-enteric drainage in June 2003. Following the antithymocyte globulin induction, immunosuppression consisted in tacrolimus and sirolimus without steroids. The patient subsequently reported a complete resolution of his symptoms and excellent glycaemic control. Thirteen months after transplantation, the patient developed oral ulcerations and severe leucopoenia initially attributed to sirolimus, which was subsequently stopped. A hyperglycaemic episode following corticosteroid therapy for acute rejection therapy required the reintroduction of insulin. Allergic manifestations reappeared promptly. Currently, 2 years after transplantation, the patient is euglycaemic without insulin (glycated haemoglobin 5.8%) and he is free of allergic reactions.

Topics: Adult; Diabetes Mellitus, Type 1; Homeostasis; Humans; Hypersensitivity; Hypersensitivity, Immediate; Immunosuppressive Agents; Insulin; Insulin Resistance; Male; Pancreas Transplantation; Protamines; Sirolimus; Tacrolimus

Despite the availability of immunosuppressive drugs such as prednisone, cyclophosphamide, cyclosporine A (CyA) and mycophenolate mofetil for the treatment of steroid-dependent idiopathic nephrotic syndrome (SDNS), medication-free remission is not achieved in a number of patients. To avoid excessive steroid toxicity, the use of tacrolimus (Tac) has been discussed. We report on five children diagnosed with SDNS on the histological basis of minimal change glomerulopathy or focal segmental glomerulosclerosis. Following the failure of other medications to achieve sustained remission, Tac was administered to these patients who varied in age from 10.5 to 13.5 years. Only one patient showed a substantial reduction in the number of relapses with the Tac treatment. Two boys, after 9 and 44 months on therapy, respectively, developed insulin-dependent diabetes mellitus (IDDM), necessitating the withdrawal of Tac and the daily use of insulin for 3 and 6 months. In both patients hyperglycemia had occurred during prednisone-based relapse therapy of SDNS. The patients had low serum protein concentrations, presumably increasing the free active Tac fraction, while trough levels of the drug remained unchanged. Both of the affected patients had additional risk factors for impaired glucose tolerance, such as morbid obesity (patient 1; BMI: 41.6 kg/m(2)) and African American origin (patient 2). Our case reports demonstrate that the use of Tac in patients with SDNS may be associated with an increased risk for IDDM, especially during relapse of NS, and particularly if additional risk factors are present. Moreover, Tac does not appear to substantially increase the success of treatment.

Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Prognosis; Recurrence; Risk Factors; Tacrolimus

We report a case of severe ulcerative colitis complicated with primary diabetes mellitus that was effectively treated with oral tacrolimus. A 36-year-old man suffered his first attack of ulcerative colitis. Because it was difficult to control the patient's diabetes, we instituted tacrolimus and azathioprine without a corticosteroid regimen as the initial treatment. Within two weeks, the ulcerative colitis activity went into remission and the patient's diabetes did not worsen.

Topics: Administration, Oral; Adult; Colitis, Ulcerative; Diabetes Mellitus, Type 1; Humans; Immunosuppressive Agents; Male; Tacrolimus

We performed the world's first successful living donor islet transplantation for unstable diabetes. A total of 408,114 islet equivalents were isolated from half a living pancreas and transplanted immediately to the recipient who was a 27-year-old female. The donor was a 56-year-old female in good health, mother of the recipient. The islets functioned immediately, and the recipient was weaned completely from insulin on the 22nd posttransplant day, and has maintained excellent glycemic control since. The donor was discharged on the 18th postoperative day with normal oral glucose tolerance test and without complications. Living donor islet transplantation could cure one insulin-dependent diabetes mellitus patients with a single donor. There are some advantages in the living donor islet transplantation: (a) living donor can alleviate the issue of donor shortage; (b) highly potent islets can be isolated from a living donor; and (c) the recipient can be treated with immunosuppressant and controlled blood glucose level tightly prior to the transplantation. These are important factors in overcoming the obstacles limiting islet transplantation. We believe that the living donor islet transplantation may become an additional option in treating insulin-dependent diabetes.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Glucose Tolerance Test; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Infliximab; Insulin; Islets of Langerhans Transplantation; Living Donors; Middle Aged; Postoperative Period; Preoperative Care; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Calcineurin inhibitors such as tacrolimus have well-recognized efficacy in organ transplantation but side effects of nephrotoxicity, neurotoxicity, and beta-cell toxicity that can be particularly detrimental in islet transplantation. Neuro- and nephrotoxicity have been demonstrated in multiple islet transplant recipients despite the relatively low serum maintenance levels typically used (3-5 ng/ml). We describe a single patient in whom symptoms and signs of neurotoxicity necessitated substitution of tacrolimus with mycophenolate mofetil (MMF), which resulted in complete symptom resolution over the subsequent 9 months. Concomitantly noted were an almost immediate improvement in glycemic control and an improved response to stimulation testing, suggesting remission of tacrolimus-induced beta-cell toxicity and insulin resistance. At 18 months post-"switch," 30 months posttransplant, the patient remains insulin independent with good glycemic control. The goal to remove calcineurin inhibitors from regimens of islet transplantation is a worthy one.

Topics: Adult; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Insulin Resistance; Insulin-Secreting Cells; Islets of Langerhans Transplantation; Mycophenolic Acid; Neurotoxicity Syndromes; Risk Factors; Sirolimus; Tacrolimus

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 1; Female; Glomerulonephritis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Proteinuria; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

The immunosuppressive (IS) regimen based on sirolimus/low-dose tacrolimus is considered a major determinant of success of the Edmonton protocol. This regimen is generally considered safe or even protective for the kidney. Herein, we analyzed the impact of the sirolimus/low-dose tacrolimus combination on kidney function. The medical charts of islet transplant recipients with at least 6 months follow up were reviewed. There were five islet-after-kidney and five islet transplantation alone patients. Serum creatinin, albuminuria, metabolic control markers and graft function were analyzed. Impairment of kidney function was observed in six of 10 patients. Neither metabolic markers nor IS drugs levels were significantly associated with the decrease of kidney function. Although a specific etiology was not identified, some subsets of patients presented a higher risk for decline of kidney function. Low creatinin clearance, albuminuria and long-established kidney graft were associated with poorer outcome.

Topics: Adult; Biopsy; Creatinine; Delayed Graft Function; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Islets of Langerhans Transplantation; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sirolimus; Tacrolimus

To determine the prevalence of diabetes and its glycemic control in the renal transplant population of northeast England (Newcastle, Sunderland, Middlesborough, and Carlisle).. All renal transplant notes in northeast England were reviewed. Data on patient details, type of diabetes, time of onset of diabetes, diabetes medications, time of insulin commencement, date of renal transplant, immunosuppressive medications, and HbA(1C) were recorded.. Living renal transplant patients (n = 1073) transplanted between March 1982 and November 5, 2003 were identified. One hundred and nine (10.2%) patients had diabetes, of whom 39 were type 1 and 70 were type 2. Median HBA(1C) in patients with type 1 diabetes on tacrolimus was 10.1% +/- 1.94% (SD) versus 7.8% +/- 1.98% (SD) for patients not on tacrolimus. Among patients with type 2 diabetes, 25 had diabetes prior to transplant and 45 (4.5%) developed posttransplant diabetes (PTDM). Those who developed PTDM and were taking tacrolimus were more likely to require insulin for blood glucose control (0.39 U/kg/24 hours vs 0 U/kg/24 hours; P = .05) compared to those not on tacrolimus. Both type 1 and type 2 diabetics on tacrolimus showed better preservation of renal function as measured by mean serum creatinine (type 1: 145 +/- 53 vs 196 +/- 74, P = .02; type 2 pretransplant: 159 +/- 73 vs 172 +/- 59, P = .35; type 2 posttransplant: 123 +/- 35 vs 167 +/- 63, P = .01).. Tacrolimus use in renal transplant patients with diabetes appeared to be associated with more problematic blood glucose control; however, it seemed to be better at preserving renal function. Intensive blood glucose monitoring is recommended for this group.

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; England; Glycated Hemoglobin; Humans; Immunosuppressive Agents; Kidney Transplantation; Medical Audit; Retrospective Studies; Tacrolimus

The effects of tacrolimus on insulin-dependent diabetes mellitus (IDDM) induced by the D-variant of encephalomyocarditis virus (D-EMCV) have been investigated. Male BALB/c mice were treated with tacrolimus before viral inoculation, and then were inoculated with 10 plaque forming units (PFU) of DEMCV. The mice continued to be treated with tacrolimus until the animals were sacrificed. D-EMCV-infected mice, which were treated with saline as controls, showed abnormal glucose tolerance test (GTT) values, whereas all infected mice with tacrolimus pretreatment were normal on 7 days-post inoculation (DPI). Histological observations revealed that non-treated tacrolimus D-EMCV-infected mice and which developed diabetes showed severe insulitis in their islets of Langerhans. On the other hand, D-EMCV-infected mice treated with tacrolimus were normal. In D-EMCV-infected mice, viruses in the pancreata were detected at the same level regardless of treatment with tacrolimus or saline. Expressions of TNF-alpha and IFN-gamma mRNA in spleens of tacrolimus-treated D-EMCV-infected mice were lower than that of non-treated tacrolimus DEMCV-infected mice on 7 DPI. The results suggest that tacrolimus suppresses expressions of TNF-alpha and IFN-gamma mRNAs to prevent the onset of D-EMCV-induced IDDM.

Topics: Animals; Blood Glucose; Cardiovirus Infections; Diabetes Mellitus, Type 1; Encephalomyocarditis virus; Gene Expression; Glucose Tolerance Test; Immunosuppressive Agents; Interferon-gamma; Islets of Langerhans; Male; Mice; Mice, Inbred BALB C; Pancreas; RNA, Messenger; Spleen; Tacrolimus; Tumor Necrosis Factor-alpha; Viral Load

Leflunomide is a low molecular weight immunosuppressive drug which inhibits the enzymes dehydroorotate dehydrogenase and protein tyrosine kinase, both of which are important components in the immune response. As the mechanisms of action of leflunomide and tacrolimus are different, we postulated an additive or synergistic effect of the two drugs and investigated the effects of leflunomide alone, or in combination with a suboptimal dose of tacrolimus, on xenogeneic islet transplantation in a rat-to-mouse model. A total of 1200-1500 rat islets were transplanted under the left kidney capsule of streptozotocin-induced diabetic BALB/c mice. The median survival time (MST) of the untreated group was 6 days. Leflunomide at 5, 10 and 20 mg/kg/d administrated for 10 days significantly prolonged MST to 10, 16 and 20 days. A dose of tacrolimus (2 mg/kg/d) was associated with a graft survival of 9 (range 6-12) days; most grafts rejected during ongoing therapy. When tacrolimus (2 mg/kg/d) was combined with leflunomide (10 mg/kg/d), the survival time of the islet xenografts was increased further to 22 days, significantly longer than with leflunomide or tacrolimus alone. In summary, our findings demonstrate that leflunomide prolonged xenogeneic islet graft survival, and that its immunosuppressive effect was improved when combined with tacrolimus.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Synergism; Graft Rejection; Histocytochemistry; Immunosuppressive Agents; Interleukin-2; Islets of Langerhans Transplantation; Isoxazoles; Leflunomide; Lymphocyte Subsets; Male; Mice; Mice, Inbred BALB C; Rats; Rats, Wistar; T-Lymphocytes; Tacrolimus; Transplantation, Heterologous

Among the numeruos adverse side effects of tacrolimus (TAC), de novo thrombotic microangiopathy stands out as an infrecuente but severe complication. Renal dysfunction is the only alteration that should lead to suspicion of thrombotic microangiopathy, because the clinical features of intravascular hemolysis are not always found. The definitive diagnosis can usually be made with kidney biopsy. Patientes with TAC induced thrombotic microangiopathy usually promptly recover after treatment withdrawal or reduction in the dose of TAC and a short course of plasma therapy, but the risk of rejection increases. Switching from TAC to cyclosporine has also been tried with resolution of the hemolysis but thrombotic microangiopathy has been noted with both and this condition may later recur. We present a 29-year-old man who received a kidney-pancreas transplant for end-stage diabetic nephropathy. After initial induction with basiliximab, the immunosuppression consisted of prednisone, tacrolimus and mycophenolate mofetil. Twenty four days posttransplantation his renal function declined with a peak creatine level of 2.35 mg/dl. Laboratory studies showed thrombocytopenia and features of intravascular hemolysis. TAC associated hemolytic uremic syndrome was suspected and drug was immediately stopped and converted to sirolimus. Also he was treated with plasma infusion. The allograft biopsy showed focal glomerular and arteriolar acute thrombosis without evidence of rejection. Our experience demostrate that switching from tacrolimus to sirolimus could be an adecuate strategy for patients who develop FK506-associated de novo thrombotic microangiopathy without increase risk of acute rejection.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Duodenostomy; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Jejunostomy; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Male; Mycophenolic Acid; Pancreas Transplantation; Pancreatic Fistula; Plasma; Postoperative Complications; Prednisone; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

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.. 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.. 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.. Concerning glucose metabolism and secretory capacity of the pancreas graft, no significant differences were found comparing tacrolimus- versus cyclosporine-treated graft recipients.

Topics: Adult; Blood Glucose; Cyclosporine; Diabetes Mellitus, Type 1; Female; Glucose; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreas Transplantation; Postoperative Period; Tacrolimus; Time Factors

Topics: Adult; Antihypertensive Agents; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diagnosis, Differential; Diltiazem; Drug Interactions; HIV Infections; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Protease Inhibitors; Tacrolimus

Diabetes mellitus derives from either insulin deficiency (type I) or resistance (type II). Homozygous mutations in the insulin receptor (IR) gene cause the rare leprechaunism and Rabson-Mendenhall syndromes, severe forms of hyperinsulinemic insulin resistance for which no therapy is currently available. Systems have been developed that allow protein-protein interactions to be brought under the control of small-molecule dimerizer drugs. As a potential tool to rescue glucose homeostasis at will in both insulin and insulin receptor deficiencies, we developed a recombinant chimeric insulin receptor (LFv2IRE) that can be homodimerized and activated by the small-molecule dimerizer AP20187. In HepG2 cells transduced with adeno-associated viral (AAV) vectors encoding LFv2IRE, AP20187 induces LFv2IRE homodimerization and transphosphorylation minutes after drug administration, resulting in the phosphorylation of a canonical substrate of the insulin receptor tyrosine kinase, IRS-1. AP20187 activation of LFv2IRE is dependent on the dose of drug and the amount of chimeric receptor expressed in AAV-transduced cells. Finally, AP20187-dependent activation of LFv2IRE results in insulin-like effects, such as induction of glycogen synthase activity and cellular proliferation. In vivo LFv2IRE transduction of insulin target tissues followed by AP20187 dosing may represent a therapeutic strategy to be tested in animal models of insulin resistance due to insulin receptor deficiency or of type I diabetes. This system may also represent a useful tool to dissect in vivo the independent contribution of insulin target tissues to hormone action.

Topics: Blotting, Western; Cell Line; Cell Line, Tumor; Cell Proliferation; Dependovirus; Diabetes Mellitus, Type 1; Dimerization; Dose-Response Relationship, Drug; Fibroblasts; Gene Transfer Techniques; Genetic Vectors; Glycogen Synthase; Homozygote; Humans; Immunoprecipitation; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Mutation; Phosphoproteins; Phosphorylation; Protein Structure, Tertiary; Receptor, Insulin; Signal Transduction; Tacrolimus; Time Factors; Tyrosine

Campath-1H preconditioning with tacrolimus monotherapy is an effective immunosuppressive regimen for pancreas transplantation, with acceptable patient and graft survival rates early after transplantation. Rejection rates are low under this protocol if the tacrolimus level is kept consistently >10 ng/ml. This immunosuppressive protocol, combined with recent technical refinements, has resulted in lower rates of thrombosis and overall complications. Pancreatic transplantation en-bloc with visceral grafts has the following unique features: Diabetes is a rare indication, and HLA matching is not required. The gland is immunologically protected by the simultaneously transplanted visceral organs. Disease gravity, surgical complexity and gut alloimmunity influence the overall pancreatic allograft survival. The current UNOS listing criteria and data registry should be modified for obvious logistic and scientific reasons.

Topics: Adolescent; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Child; Diabetes Mellitus, Type 1; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Middle Aged; Pancreas; Pancreas Transplantation; Pennsylvania; Survival Rate; Tacrolimus; Tissue Donors; Transplantation Conditioning

Advances in surgical techniques and clinical immunosuppression have led to steadily improving results in pancreas transplantation (PTX). The purpose of this study was to analyze retrospectively the outcomes in patients undergoing solitary PTX with portal-enteric (P-E) drainage and contemporary immunosuppression. From June 1998 through December 2000, we performed 28 solitary PTXs with antibody induction and tacrolimus/mycophenolate mofetil maintenance therapy. The first 13 patients received daclizumab (DAC) induction, while the next 15 received thymoglobulin (rabbit anti-human thymocyte gamma globulin; Thymo) induction. The study group included 13 pancreas alone (PA) and 15 sequential pancreas-after-kidney-transplantations (PAKT). Solitary PTX was performed with P-E drainage in 18 patients and systemic-enteric (S-E) drainage in ten. Patient and pancreas graft survival rates were 96% and 79%, respectively, with a mean follow-up of 22 (range 1-39) months. The 1-year actual death-censored pancreas graft survival rate was 89%. One PAKT patient died with a functioning graft at 1 month; three patients (11%) experienced early graft loss due to thrombosis and were excluded from the immunological analysis, leaving 24 evaluable patients. The incidence of acute rejection was 54%, including 50% in PA and 58% in PAKT recipients ( P=NS). In patients receiving Thymo induction, the rate of acute rejection was slightly lower (43% Thymo vs 70% DAC). Moreover, P-E drainage was associated with a slightly lower rate of acute rejection (44% P-E vs 75% S-E; P=NS). In patients with both Thymo induction and P-E drainage ( n=11), there was a tendency toward less rejection (the incidence of acute rejection was 36%). Two immunological graft losses occurred (one due to non-compliance), both in patients with P-E drainage. Only one patient had a cytomegalovirus (CMV) infection. Event-free survival (no rejection, graft loss, or death) was slightly higher in patients receiving Thymo (47%) than in those on DAC (23%) induction ( P=NS). We can conclude that solitary PTX with P-E drainage and Thymo induction may be associated with improved intermediate-term outcomes and a possible immunological advantage.

Topics: Adult; Animals; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Drainage; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppression Therapy; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Portal System; Rabbits; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Nonobese diabetic (NOD) mice develop autoimmune diabetes with features similar to those observed in the human disease. The concurrence of allorecognition and recurrence of autoimmunity might explain why most of the treatments successful in preventing islet allograft destruction in other nonautoimmune combinations often fail in NOD recipients. To assess the value of the NOD mouse model for the evaluation of treatments relevant to clinical islet transplantation, the authors have tested the effect of a protocol closely resembling the one successfully used in the Edmonton clinical trial on the survival of islet allografts in NOD mice.. C57BL/6 islets were transplanted under the kidney capsule of spontaneously diabetic NOD mice. Treatment consisted of a combination of rapamycin, tacrolimus, and anti-interleukin (IL)-2 monoclonal antibody. Control groups received each treatment alone, a combination of two agents, or no treatment.. Untreated animals invariably lost their graft within 13 days. Administration of rapamycin and tacrolimus significantly prolonged graft survival, with two of seven animals bearing a functional graft longer than 100 days. Addition of anti-IL-2 antibody therapy further improved graft survival, with six of eight grafts functioning longer than 100 days and two of eight grafts functioning longer than 200 days.. In view of the limited success obtained with other treatments in this model, the dramatic prolongation of graft survival observed in the authors' study, by using a therapy that mimics one successfully used in clinical trials, seems to validate the NOD mouse as a meaningful model for the study of therapeutic interventions for the prevention of islet graft loss.

Topics: Animals; Antibodies, Monoclonal; Body Weight; Cytokines; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Survival; Immunophenotyping; Immunosuppressive Agents; In Vitro Techniques; Interleukin-2; Islets of Langerhans; Islets of Langerhans Transplantation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Sirolimus; Tacrolimus; Transplantation, Homologous

Simultaneous pancreas and kidney transplantation (SPK) from cadaveric donors has become a widely accepted therapeutic option for insulin-dependent uremic patients. In 1996 the first SPK from a live donor was performed. This procedure offers the advantage of a better immunologic match, reduced cold ischemia injury, and decreased waiting time. As such, it is an attractive alternative treatment for diabetic patients with end-stage nephropathy with an available living donor.. We performed six SPKs from living-related donors. There were four men and two women among the recipients; median age was 34 (range, 29-39) years. All donors were recipients' siblings with excellent HLA matching. Donors underwent standardized metabolic workup, anti-insulin and anti-islet antibody assays, and computed tomography of the abdomen. Both donors and recipients were treated with octreotide for 5 days perioperatively. After transplantation, the patients were maintained on tacrolimus-based immunosuppression, with the exception of one recipient of SPK from an identical twin, who received cyclosporine monotherapy.. All the donors are doing well and have normal renal function and blood glucose levels. One-year patient, renal, and pancreatic graft survival rates were 100%, 100%, and 83%, respectively. Acute kidney rejection was documented in two patients, and both recovered completely after OKT3 therapy. No rejection of pancreatic graft has been documented. Except for one patient who lost the graft because of hemorrhagic pancreatitis, all recipients maintained serum glucose levels at less than 130 mg/dL without insulin therapy. No major surgical complications such as graft thrombosis, intra-abdominal infection, or abscess were reported.. Living donor SPK can represent a successful alternative to cadaveric donor SPK. The procedure can be performed safely in the donor and with low morbidity in the recipient.

Topics: Adult; Blood Glucose; Cadaver; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Muromonab-CD3; Pancreas Transplantation; Tacrolimus; Tissue Donors; Treatment Outcome; Uremia

Employing tacrolimus (Tac) for routine immunosuppression in renal transplantation (RT), produced an incidence of new-onset, insulin-treated, diabetes mellitus (newDM) as high as 20%. More recently, several large multicenter kidney studies using Tac as the primary immunosuppressant have been reported in Europe. Between 1997 and 2001, we performed 155 RTs using Tac (0.2 mg/k/per day, targeting whole blood trough levels <15 ng/mL) with a rapid steroid taper. The acute rejection rate was 13%, and 89% of grafts are still functioning. Only 5 Tac-treated patients not previously requiring insulin needed insulin therapy for > or =30 days (3.2%). Eight separate studies employing Tac in at least one arm (N=2728) have been reported between 1997 and 2002. Tac was combined with azathioprine or MMF, and/or steroids. The incidence of new DM at study end ranged from 2.3% to 8.3%. The only trial with >6% incidence was the first one, using an initial dose of 0.3 mg/kg per day. The most recent studies utilized an initial dose of 0.2 mg/kg per day, targeting whole blood trough levels of <15 ng/mL and a steroid taper, with newDM at <6%. On the basis of these data, we confirm in that the use of Tac as a first-line immunosuppressant in renal transplant patients affords protection against acute rejection with a low level of newDM. The tendency to employ lower oral doses of Tac, lower blood target levels, and a reduced steroid dose appear to minimize glucose disturbances in RT.

Topics: Diabetes Mellitus, Type 1; Europe; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Retrospective Studies; Tacrolimus

Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience.. All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart.. Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression.. The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Topics: Abnormalities, Multiple; Adolescent; Adult; Anti-Inflammatory Agents; Birth Weight; Diabetes Mellitus, Type 1; Female; Fludrocortisone; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant, Newborn; Kidney; Liver; Liver Diseases; Liver Transplantation; Pre-Eclampsia; Prednisone; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy Outcome; Prospective Studies; Survival Rate; Tacrolimus; Transplantation, Homologous

Topics: Adult; Diabetes Mellitus, Type 1; Female; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Islets of Langerhans Transplantation; Kidney Transplantation; Sirolimus; Tacrolimus

Topics: Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Antilymphocyte Serum; Azathioprine; Creatinine; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Prednisolone; Prednisone; Tacrolimus; Time Factors; Treatment Failure; Treatment Outcome

The use of immunosuppressive agents is becoming more widespread, especially in the context of organ transplantation. We report a child with a complication, new-onset diabetes mellitus with diabetic ketoacidosis, associated with the use of one such agent, FK506 (tacrolimus).

Topics: Adolescent; Diabetes Mellitus, Type 1; Diabetic Ketoacidosis; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

A successful immunosuppression regimen for combined kidney and pancreas transplants is tacrolimus, mycophenolate mofetil, and prednisone. However, not all patients tolerate these immunosuppressants especially tacrolimus.. To evaluate the efficacy of cyclosporine as a rescue agent for tacrolimus toxicity in combined kidney and pancreas transplants.. Retrospective.. Single center.. Thirty-five combined kidney and pancreas transplants were performed between July 1994 and January 1999. All patients were insulin dependent diabetics with end-stage renal disease. Twenty-eight (mean age: 36 years and 57% female) were available with at least 12 month follow-up.. Conversion to cyclosporine following renal (biopsy proven) or pancreatic dysfunction.. Toxicity, rejection rate, and patient/transplant organ survival.. Nineteen transplant recipients (68%) were continuously maintained on tacrolimus while nine (32%) required conversion to cyclosporine 75 +/- 20 days post-transplant. Reasons for conversion included: hyperglycemia (n=2), hemolytic-uremic syndrome (n=1), and severe tacrolimus nephrotoxicity (n=6). By 12 months post-transplant, the 19 patients maintained on tacrolimus had 5 rejections (26%). Three of the 9 patients (33%) converted to cyclosporine had an acute rejection prior to conversion. Seven of these 9 patients (78%; P=0.017 vs. patients maintained on tacrolimus) had rejections an average of 25 +/- 4 days post-conversion. Four of the 7 patients had no previous rejections prior to conversion. In spite of increased rejections, the 1- and 2-year patient/graft survivals were unchanged by converting.. Converting to cyclosporine from tacrolimus was associated with an increased risk of acute rejection especially within the first 30 days post conversion.

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Drug Tolerance; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Pancreas Transplantation; Retrospective Studies; Salvage Therapy; Survival Rate; Tacrolimus

Sirolimus and tacrolimus are immunosuppressive drugs that prevent rejection of pancreatic islet allografts transplanted into patients with Type I (insulin-dependent) diabetes mellitus. This study aimed to determine whether sirolimus and tacrolimus can prevent autoimmune beta-cell destruction, and if so, what the mechanisms of action are.. Sirolimus and tacrolimus were given separately and together to female non-obese diabetic (NOD) mice from age 12 to 35 weeks. Diabetes incidence was determined and pancreatic insulitis and insulin content were measured. Sirolimus and tacrolimus were also given separately and together to diabetic NOD mice from the time of syngeneic islet transplantation until the reappearance of hyperglycaemia. Islet grafts were examined by RT-PCR assay for expression of interferon (IFN)- gamma, interleukin (IL)-2, IL-4, IL-10 and transforming growth factor (TGF)- beta1.. Low doses of sirolimus (0.1 mg/kg) and tacrolimus (0.1 mg/kg) were synergistic in reducing insulitis, preserving pancreatic insulin content and preventing diabetes in female NOD mice (8 % diabetes incidence at 35 weeks vs 66 % in vehicle-treated mice). Also, the combination of sirolimus and tacrolimus prolonged syngeneic islet graft survival (median 34 days vs 13 days for vehicle-treated mice). Islet grafts from sirolimus plus tacrolimus-treated mice expressed significantly decreased mRNA contents of Th1-type cytokines (IFN- gamma and IL-2) and the highest ratio of TGF- beta1/IFN- gamma mRNA.. These findings suggest that combination therapy with sirolimus and tacrolimus prevent autoimmune beta-cell destruction by upregulating expression of the immunoregulatory cytokine, TGF- beta1 and reducing Th1 cytokines (IFN- gamma and IL-2) expressed in the islets. Low-dose sirolimus and tacrolimus combination therapy could warrant consideration for prevention or early treatment of human Type I diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Drug Synergism; Female; Immunosuppressive Agents; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Recurrence; Sirolimus; Tacrolimus

There are two types of indications for Langerhans islets transplantation, patients with type 1 diabetes mellitus who have a functional kidney graft but who cannot be candidates for total pancreas transplantation, and soon, patients without renal failure who develop particularly uncontrollable diabetes mellitus.. Several conditions are required for the success of Langerhans islet transplantation: a laboratory with demonstrated skill is isolating islets, a sufficiently large number of islets for injection (600,000 for a 60-kg patient), fresh islets harvested within less than 24 hours before transplantation, effective immunosuppressive treatment with no toxic effect on Langerhans islets. The injection is a simple procedure performed under local anesthesia via transhepatic catheterization of the portal vein.. Through 2000, 10% to 20% of implanted grafts were functional at 1 year. Islets survival has exceeded 80% at 1 year. The gold standard for success is withdrawal of insulin therapy and normal glucose control. Islets grafts will undoubtedly become the next important step in the treatment of type 1 diabetes mellitus, but other techniques are also envisaged for the future.

Topics: Age Factors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Clinical Protocols; Cyclosporine; Daclizumab; Diabetes Mellitus, Type 1; Everolimus; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Islets of Langerhans Transplantation; Prodrugs; Receptors, Interleukin-2; Recombinant Fusion Proteins; Sirolimus; Tacrolimus

When tacrolimus side effects persist despite dose reduction, conversion to cyclosporine-based immunosuppression (CyA) is necessary. We characterized tacrolimus side effects that warranted discontinuation of the drug, and outcomes after conversion. Of 388 liver recipients who received tacrolimus as primary immunosuppression, 70 required conversion to CyA. We recorded indication for conversion, whether conversion was early or late after transplantation, tacrolimus dose and trough blood level at conversion, and incidence of rejection after conversion. Conversion was early in 29 patients (41.4%) and late in 41 (58.6%). Indications for early conversion were neurotoxicity (20), (insulin-dependent) diabetes mellitus (IDDM) (5), nephrotoxicity (3), gastrointestinal (GI) toxicity (6), and cardiomyopathy (1), and for late conversion were neurotoxicity (15), IDDM (12), nephrotoxicity (3), GI toxicity (5), hepatotoxicity (6), post-transplant lmphoproliferate disease (PTLD) (2), cardiomyopathy (1), hemolytic anemia (1), and pruritus (1). All early-conversion patients showed improvement/resolution of symptoms. Among late-conversion patients, 37 (90.2%) had improvement/resolution; in 4 (9.8%), adverse effects persisted. The overall rejection rate was 30%. Sixty-two patients (88.6%) are alive with functioning grafts 686 +/- 362 days (range, 154-1433 days) after conversion. When tacrolimus side effects are unresponsive to dose reduction, conversion to CyA can be accomplished safely, with no increased risk of rejection and excellent long-term outcome.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Nervous System Diseases; Retrospective Studies; Tacrolimus

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Sirolimus; Tacrolimus

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Ischemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Pancreas Transplantation; Postoperative Complications; Prednisolone; Radiography; Splanchnic Circulation; Tacrolimus

Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, asp

Topics: Adult; Anticoagulants; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Heparin; Humans; Immunosuppressive Agents; Kidney Transplantation; Mesenteric Vascular Occlusion; Mesenteric Veins; Pancreas Transplantation; Platelet Aggregation Inhibitors; Postoperative Complications; Receptors, Interleukin-2; Retrospective Studies; Risk Factors; Splenic Vein; Tacrolimus; Time Factors; Transplantation, Homologous; Venous Thrombosis

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Biopsy, Needle; Chemical and Drug Induced Liver Injury; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Inflammation; Insulin; Liver Function Tests; Liver Transplantation; Male; Neutrophils; Tacrolimus

Topics: Adolescent; Adult; Chronic Disease; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreas Transplantation; Pancreatitis; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Child; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus

The aims of this study were to determine 1) changes in lipids after solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2) factors that influence those changes.. Lipids were evaluated prospectively in 24 patients who underwent SPTX. Three were excluded because of early graft failure. The remaining patients (n = 21; 13 men, 8 women) were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12 months). Glycohemoglobin, serum creatinine, BMI, and medications were also analyzed for their effects on lipid changes.. Cholesterol, HDL, and LDL decreased in the immediate postoperative period (0-2 months), whereas triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After 12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05). During the study, systolic and diastolic blood pressure increased, renal function decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The same pattern of lipids occurred in patients prescribed or not prescribed hypolipidemic agents.. Lipids do not improve within the 1st year after SPTX, despite improved glycemic control and blood pressure control, and renal function is worse. These results are in contrast to those reported for combined kidney-pancreas transplantation, where lipids, blood pressure, and renal function improved immediately after transplant. Further studies are needed to determine whether lipids continue to change with time after SPTX. The impact of these changes after SPTX on overall cardiovascular risk is unknown.

Topics: Blood Pressure; Cholesterol; Cholesterol, HDL; Cyclosporine; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lipids; Lipoproteins, HDL; Lipoproteins, LDL; Male; Pancreas Transplantation; Tacrolimus; Time Factors; Triglycerides

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Humans; Kidney Transplantation; Tacrolimus

Difficulty in preventing rejection of fetal pig islet-like cell clusters (ICCs) transplanted into pigs using traditional forms of immunotherapy has been reported. An in vitro study of the efficacy of seven different immunosuppressive agents to inhibit proliferation of pig peripheral blood mononuclear cells (PBMC) was performed, and a comparison was made between the human and pig to determine if the efficacy of these agents differed between species. The efficacy of cyclosporine (CsA), azathioprine (Aza), methylprednisolone (MP), FK506, rapamycin (RAP), mycophenolate mofetil (MMF) and deoxymethylspergualin (MeDSG) to inhibit pig and human PBMC proliferation in mitogenic experiments using phytohaemagglutinin (PHA) as a stimulus was performed. Further, allogeneic pig mixed lymphocyte reactions (MLR) were used to determine the activity of these agents in a model more comparable to the allograft rejection process. It was found that pig PBMC stimulated with PHA or in a MLR were inhibited by the agents tested, with the exception of MeDSG that was ineffective in mitogenic experiments. The inhibitory effects of these agents differed between PHA and MLR, the respective (50% inhibitory concentration) IC50 values for pig PBMC being 1.7 and 0.08 microg/ml for CsA, 1.4 and 4.4 microg/ml for Aza, 0.11 and 0.002 microg/ml for MP, 3.0 and 2.8 ng/ml for FK506, 2.1 and 0.3 ng/ml for RAP and 10.8 and 454 ng/ml for MME Pig PBMC were less sensitive than human PBMC to the antiproliferative effects of CsA, Aza, FK506, RAP and MMF, but not MP on PHA stimulation, the ratio of the pig to human IC50 values being 19, 11, 13, 2.3, 1.4, and 0.4, respectively. These data suggest that the doses of most immunosuppressive agents administered to prevent rejection in pigs need to be higher than those used to achieve therapeutic benefit in humans.

Topics: Animals; Azathioprine; Cell Division; Cyclosporine; Diabetes Mellitus, Type 1; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; In Vitro Techniques; Islets of Langerhans Transplantation; Leukocytes, Mononuclear; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Methylprednisolone; Mycophenolic Acid; Phytohemagglutinins; Sirolimus; Species Specificity; Swine; Tacrolimus; Transplantation, Homologous

The aim of this study was to report the results of 50 transplantations of kidney and pancreas performed in the same surgical centre for chronic renal insufficiency of patients with insulino-dependent diabetes.. From 1989 to 1999, 50 pancreatic transplantations were consecutively performed, 48 combined with a kidney transplantation and two in patients having a functioning kidney graft. The whole pancreas was transplanted in the right iliac fossa through an extraperitoneal approach with duodeno-vesical bypass of exocrine secretion. The kidney was transplanted in the left iliac fossa through a different extraperitoneal approach. Immunosuppression protocol included Azathioprine replaced by Mycophenolate Mofetil since 1996, associated with corticotherapy and Ciclosporine replaced by FK 506 since 1997. Recipients were 32 women and 18 men (mean age: 37 +/- 5 years) treated by insulinotherapy since 23 +/- 6 years and receiving 35 +/- 10 insulin units per day. Peptide C was 0.33 +/- 0.35 mg/mL and serum creatinin 726 +/- 260 mumol/L.. One patient died on d10 from pulmonary artery thrombosis due to unknown drepanocytosis. The most frequent postoperative complications were leakage of duodeno-vesical anastomosis (n = 9) decreasing in frequency with experience, reoperated with preservation of the pancreatic graft in all cases and venous thrombosis of the pancreatic graft (n = 5) with a definitive loss of function. Secondary deaths occurred at 24, 36, 48, 50, 72 months with functioning grafts in two patients. With a mean 5-year follow-up, 44 patients were alive (88% of the whole series), 34 of them with two functional grafts (68% of the whole series) Sixteen pancreas grafts were lost: three by death of the patients, eight from surgical complications, four by rejection and one by transplantectomy of a functional graft.. Combined kidney and pancreas transplantation is now very efficient in the treatment of diabetic renal insufficiency. Total pancreas transplantation through an extraperitoneal approach seems to be the safest method. A very strict selection of both donors and recipients is necessary.

Topics: Adult; Azathioprine; Combined Modality Therapy; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Survival Analysis; Tacrolimus; Treatment Outcome

Analysis of the SPK program at the University of Pittsburgh has led to a number of observations: 1. Under tacrolimus-based immunosuppression, without antibody induction, it has been possible to achieve (a) One- and 3-year actuarial patient survival rates of 98% and 95% (b) One- and 3-year actuarial kidney survival rates of 95% and 87% (c) One- and 3-year actuarial pancreas survival rates of 86% and 80% 2. Steroid withdrawal has been achieved in over half of the successfully transplanted recipients, with excellent outcomes and a low rate (4.7%) of subsequent rejection. 3. Bone marrow augmentation has been associated with (a) less rejection (b) less pancreatic graft loss to rejection (c) an increased ability to withdraw steroids 4. Rejection has been associated with a rising serum lipase. 5. Renal allograft rejection in SPK patients with elevated serum lipase levels has been seen in the setting of normal renal function. 6. Enteric drainage has been associated with a reasonably low complication rate. 7. SPK transplantation is a successful therapeutic option in selected type I diabetics with end-stage renal disease.

Topics: Adult; Bone Marrow Transplantation; Cause of Death; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Therapy, Combination; Graft Rejection; Graft Survival; Hospitals, University; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Pennsylvania; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Previous studies have shown that anti-gamma-interferon (IFN-gamma) antibody reduces the frequency of autoimmune IDDM in the DP-BB rat. We tested the effects of systemically administered recombinant rat IFN-gamma in both DP-BB and DR-BB rats. Unexpectedly, IFN-gamma markedly reduced the incidence of IDDM as compared with control rats when administered six times per week at a dosage of 280,000 U between ages 30-35 to 105 days or ages 60-64 to 105 days. A lower dosage (28,000 U on alternate days) was also protective when administered to DP-BB rats between birth and age 60 days. However, long-lasting protection against IDDM development over the 1-year study period was achieved only by the highest dosage of IFN-gamma administered from age 30 to 105 days. Ex vivo production of tumor necrosis factor-alpha from splenic lymphoid cells (SLCs) and peritoneal macrophages of the rats treated with IFN-gamma was comparable with that of controls; however, SLCs from the IFN-gamma-treated animals secreted lower amounts of IFN-gamma after stimulation with concanavalin A. IFN-gamma treatment also markedly reduced the frequency of phenotypically activated SLC-expressing class II antigens and interleukin-2 receptor. Finally, in agreement with the observed antidiabetogenic effects, exogenously administered IFN-gamma induced neither insulitis nor IDDM development in DR-BB rats, a subline of DP-BB rats in which autoimmune diabetes rarely occurs spontaneously but can be induced by administration of polyinosinic-polycytidilic acid.

Topics: Aging; Animals; Concanavalin A; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Histocompatibility Antigens Class II; Hypoglycemic Agents; Immunosuppressive Agents; Incidence; Injections, Intraperitoneal; Interferon-gamma; Macrophages, Peritoneal; Male; Phenotype; Random Allocation; Rats; Rats, Inbred BB; Receptors, Interleukin-2; Recombinant Proteins; Spleen; Tacrolimus; Tumor Necrosis Factor-alpha

In this study, we compare cholesterol levels during the first year after renal transplantation in FK506 (Prograf)- and cyclosporine-treated patients matched for cumulative first-year steroid dose and hypercholesterolemia risk factors. All patients had pretransplant cholesterol levels < 200 mg/dl. At 3 months posttransplant, 68% of the cyclosporine-treated patients had at least one cholesterol level greater than 200 mg/dl compared with 30% of the FK506-treated patients (P < 0.05). At the end of the year, 26% of FK506- and 67% of cyclosporine-treated patients remained hypercholesterolemic (P < 0.05). We conclude that cyclosporine has inherently more effect on cholesterol levels than FK506 during the first year after kidney transplantation.

Topics: Adult; Age Factors; Cholesterol; Cyclosporine; Diabetes Mellitus, Type 1; Female; Furosemide; Humans; Hypercholesterolemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sex Factors; Tacrolimus

Use of tacrolimus (FK506), a potent immunosuppressive agent, has been reported to have a 10-20% incidence of insulin-dependent diabetes mellitus (IDDM) in adults, but the incidence of IDDM in pediatric renal transplant recipients treated with this agent is unknown. In this article, we report our single-center experience with FK506-induced IDDM in children.. Five consecutive living related donor pediatric renal transplants were reviewed retrospectively.. All five patients developed IDDM lasting longer than 6 months. Mean follow-up time was 18.6 months.. Pediatric patients may be at high risk for developing FK506-induced IDDM.

Topics: Adolescent; Child; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Humans; Kidney Transplantation; Tacrolimus

Topics: Adult; Cholesterol; Cyclosporine; Diabetes Mellitus, Type 1; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Pancreas Transplantation; Tacrolimus; Transplantation, Homologous

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Tacrolimus

Topics: Administration, Oral; Adult; Biological Availability; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fasting; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Metabolic Clearance Rate; Middle Aged; Postprandial Period; Premedication; Tacrolimus

Topics: Adult; Age Factors; Aged; Child; Creatinine; Diabetes Mellitus, Type 1; Follow-Up Studies; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant; Liver Transplantation; Postoperative Complications; Prednisone; Survival Rate; Tacrolimus; Time Factors

Topics: Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus

Topics: Administration, Oral; Azathioprine; Cyclosporine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Tacrolimus

Topics: Administration, Oral; Adolescent; Blood Glucose; Child; Child, Preschool; Cyclosporine; Diabetes Mellitus, Type 1; Emulsions; Follow-Up Studies; Humans; Hyperglycemia; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Organ Preservation; Pancreas; Pancreas Transplantation; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Most recipients of simultaneous pancreas-kidney transplants experience acute rejection in the early postoperative course. We report our experience with four recipients of simultaneous pancreas-kidney transplants with acute rejection who were effectively treated with the combination of intravenous and oral FK506 therapy. This spared these patients an extra course of monoclonal or polyclonal antibody.

Topics: Administration, Oral; Adult; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Injections, Intravenous; Kidney Transplantation; Male; Pancreas Transplantation; Tacrolimus

Tacrolimus has a negative effect on the pancreatic beta islet cell, and both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid organ transplant recipients.. To determine the association between tacrolimus and new-onset diabetes mellitus in childhood, we reviewed data on 78 pediatric heart and heart-lung/lung recipients receiving tacrolimus-based immunosuppression. Trough tacrolimus levels, fasting and random blood glucose levels, and corticosteroid requirements were reviewed. Diabetes was defined as glucose intolerance requiring long-term insulin treatment more than 30 days after transplantation.. No patient had diabetes before introduction of tacrolimus. In heart-lung/lung recipients, 12 of 28 (43%) had development of diabetes at a median follow-up of 7 months (range 1 to 39). In this group diabetes developed in three of eight (38%) patients with cystic fibrosis and nine of 20 (45%) without (p = NS). In contrast, only two of 50 (4%) heart transplant recipients had development of diabetes. Of the 14 patients with diabetes, 10 had development of diabetes during augmentation of immunosuppression with pulsed corticosteroids. Tacrolimus trough levels were significantly lower in heart compared with heart-lung/lung transplant recipients (9.4 +/- 3.3 versus 15.3 +/- 0.9 ng/ml) (p < 0.01), and at latest follow-up significantly fewer heart transplant recipients were treated with maintenance corticosteroids (28% versus 75%; p < 0.01). In the heart-lung/lung group, no significant difference in tacrolimus levels was found between patients with and without diabetes, nor was there a significant difference in the average corticosteroid dose or number of pulses of corticosteroids per patient.. New-onset diabetes mellitus is rare in pediatric heart transplant recipients receiving tacrolimus-based immunosuppression, but it occurs with a high incidence after pediatric heart-lung/lung transplantation and usually develops during pulsed corticosteroid therapy. However, it is currently not possible to predict which heart-lung/ lung transplant recipients will have development of this serious complication.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cystic Fibrosis; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucose Tolerance Test; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Infant; Islets of Langerhans; Lung Transplantation; Male; Postoperative Complications; Risk Factors; Tacrolimus

We report a successful en bloc pancreas and kidney transplantation on a type I diabetic patient with advanced peripheral arterial calcific disease, who had frequent life-threatening episodes of hypoglycemia. The en bloc double organ, created by joining the graft renal artery to the arterial Y graft of the pancreas, was implanted to the proximal left common iliac artery, which was the only site available for an arterial anastomosis. Under appropriate circumstances, this procedure would be an option for potential combined pancreas-kidney transplant recipients with severe calcific arterial disease.

Topics: Adult; Anastomosis, Surgical; Arteriovenous Anastomosis; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Graft Rejection; Humans; Iliac Artery; Iliac Vein; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Mycophenolic Acid; Pancreas Transplantation; Postoperative Period; Radionuclide Imaging; Regional Blood Flow; Tacrolimus; Technetium Tc 99m Pentetate

The data show that with careful surgical technique, modern immunosuppression with MMF and FK506, and pancreatic allograft biopsy, it should be possible to achieve: 1) a low rate of technical complications, 2) improved long-term graft survival, particularly in solitary pancreas recipients improving the risk/benefit ratio of this option for nonuremic diabetics, 3) a high safety profile with combined MMF and FK506 immunosuppression, 4) safe transplantation using enteric drainage without increased risk of rejection, infection or graft loss, and 5) successful pancreas transplantation without induction therapy.

Topics: Adolescent; Adult; Child; Child, Preschool; Diabetes Mellitus, Type 1; Graft Rejection; Graft Survival; Hospitals, University; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Patient Selection; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; Wisconsin

Three cases of insulin-requiring diabetes mellitus associated with tacrolimus (FK506) therapy in pediatric renal transplant patients are presented. New-onset diabetes mellitus has been reported with tacrolimus therapy post liver and kidney transplants in up to 12% of adult patients, but is thought to be rare in pediatrics. Although insulin requirement with tacrolimus therapy has been occasionally reported in adolescent patients post liver transplant, only a single case in a pediatric kidney transplant recipient has been previously documented. These cases illustrate the significant diabetogenic effect of tacrolimus in pediatric renal transplant patients. As the use of tacrolimus becomes more prevalent in pediatric kidney transplantation, pediatric nephrologists should be aware of this potential complication.

Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 1; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Tacrolimus

Topics: Adult; Antilymphocyte Serum; Cyclosporine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Pancreas Transplantation; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adolescent; Adult; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glucose Tolerance Test; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Risk Factors; Tacrolimus; Time Factors

Diabetes-prone (DP) BB rats (RT1(u), RT6.1) spontaneously develop insulin-dependent diabetes mellitus (IDDM) and the disease manifestation resembles that in human IDDM. DP rats are immunodeficient with severe T lymphocytopenia due to the absence of T cells expressing the RT6 differential alloantigen, which have immunoregulatory functions. MHC- and non-MHC-compatible Wistar Furth (WF; RT1(u), RT6.2) pancreases were transplanted into DP rats. WF pancreas grafts were destroyed by IDDM recurrence (insulitis), but not by rejection, with a mean survival time of 65.3 +/- 21.7 days. To prevent the recurrence of IDDM in the grafts, monoclonal antibodies to intercellular adhesion molecule-1 and leukocyte function-associated antigen-1 were administered. WF pancreas grafts were indefinitely accepted (>108.0 +/- 26.8 days) in monoclonal antibody-treated DP recipients. The number of T cells was increased and cellular immune responses restored only in the DP rats that had accepted grafts. The increased number of T cells was due to the peripheral appearance of donor-type RT6.2+ T cells, which represented 34.3 +/- 7.0% of total splenic T cells. The cytotoxicity of splenic T cells to WF islet cells was suppressed in the presence of RT6+ T cells in vitro. These findings demonstrated that stable macrochimerism of donor-derived RT6+ T cells could restore the immune responses and prevent the recurrence of IDDM in the DP recipients.

Topics: ADP Ribose Transferases; Animals; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Autoimmunity; Chimera; Diabetes Mellitus, Type 1; Flow Cytometry; GPI-Linked Proteins; Lymphocyte Activation; Male; Membrane Glycoproteins; Mice; Pancreas Transplantation; Rats; Rats, Inbred BB; Rats, Inbred WF; T-Lymphocytes; Tacrolimus

Topics: Adult; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Safety; Tacrolimus

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 1; Glucose Tolerance Test; Islets of Langerhans Transplantation; Kidney; Organelles; Rats; Rats, Inbred Strains; Tacrolimus; Transplantation, Heterotopic; Transplantation, Isogeneic

Delayed administration of tetrandrine, a novel broad-spectrum anti-inflammatory agent, to BB rats at a dosage schedule of 20 mg kg-1 day-1 from 79 days of age reduced the cumulative incidence of diabetes from 73.1 to 41.7% (p < 0.01). Brief treatment with the potent immunosuppressive agent FK506 at a dosage schedule of 0.5 mg kg-1 day-1 from 79 days of age for 5 days had no significant effect on the cumulative incidence of diabetes (66.7%, p > 0.1). However, the combination of tetrandrine and FK506 in the afore-mentioned dosage schedules reduced the incidence of diabetes to only 3.6% (p < 0.001). These results suggest that the strong synergy between tetrandrine and FK506 may offer a safe and effective therapeutic strategy for the treatment of patients with recent onset or imminent IDDM.

Topics: Alkaloids; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzylisoquinolines; Diabetes Mellitus, Type 1; Drug Synergism; Female; Male; Rats; Rats, Inbred BB; Tacrolimus

Topics: Actuarial Analysis; Diabetes Mellitus, Type 1; Female; Follow-Up Studies; Graft Survival; Humans; Hypertension; Kidney; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Potassium; Tacrolimus

Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Hospitals, Veterans; Humans; Insulin; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Pennsylvania; Tacrolimus

Topics: Adult; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Graft Survival; Humans; Islets of Langerhans Transplantation; Kidney Transplantation; Portal Vein; Tacrolimus

We investigated the preventive effect of the immunosuppressive agent FK506 on autoimmune insulitis in nonobese diabetic mice. The mice were given FK506 in a dose of 1.0 mg/kg, every other day, from age 2 to 12, 2 to 6, and 4 to 12 weeks, respectively; after which, the incidence of insulitis and overt diabetes was monitored. Effects of FK506 on immune reactions to beta cells were also investigated by using both syngeneic and allogeneic islet transplants. Treatment with FK506 in mice from age 2 weeks prevented completely the onset of overt diabetes, and the incidence of insulitis was reduced to less than 10% at age 30 weeks. Treatment of mice with FK506 from age 4 weeks was less effective in preventing insulitis and the onset of diabetes. In case of islet transplantation, FK506 treatment of NOD mice from age 2 to 6 weeks prevented autoimmune responses both in syngeneic islets and in allogeneic islets, which share the same H-2 antigen with the nonobese diabetic mouse. These results also indicate that the recognition of islet antigens and the generation of autoimmune-reactive T lymphocytes start between 2 and 4 weeks of age, and FK506 prevents an autoimmune reaction.

Topics: Animals; Diabetes Mellitus, Type 1; Islets of Langerhans Transplantation; Lymphocyte Subsets; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Pancreas Transplantation; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic

FK506, a agent extracted from a streptomyces, has more potent immunosuppressive properties compared with cyclosporin in vitro. We compared the preventive effect of FK506 on the development of diabetes mellitus with that of cyclosporin in BB rats, which are regarded as a useful model of insulin-dependent diabetes mellitus. BB rats aged 30 days were treated intramuscularly with FK506 (0.1 mg/kg/day and 0.32 mg/kg/day) or with cyclosporin (10 mg/kg, alternate days) until 150 days of age. Diabetes developed in 2 (10.5%) of 19 rats treated with the lower dose of FK506 and none of 20 rats with the higher dose of FK506; on the other hand, 1 (5.3%) of 19 rats treated with cyclosporin developed diabetes. In contrast, 9 (36.0%) of 25 control rats became diabetic. The cumulative incidence of diabetes mellitus in the group treated with FK506 (0.32 mg/kg) showed a decrease similar to or more than that of the cyclosporin-treated group. Histological examination showed that FK506 and cyclosporin prevented the reduction in the average size of islets and in the area of beta cells. The analysis of lymphocyte subsets proved the decrease of W3/25: OX8 ratio in both FK506- and cyclosporin-treated groups. These data suggest that the administration of FK506 might be a more useful tool for preventing the development of insulin-dependent diabetes mellitus.

Topics: Aging; Animals; Cyclosporine; Diabetes Mellitus, Type 1; Female; Fluorescent Antibody Technique; Lymphocyte Subsets; Male; Pancreas; Rats; Rats, Inbred BB; Tacrolimus

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Diabetes Mellitus, Type 1; Graft Survival; Islets of Langerhans; Mice; Mice, Inbred NOD; Pancreas; Pancreas Transplantation; Pancreatic Diseases; Tacrolimus

Topics: Anti-Bacterial Agents; Blood Glucose; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Graft Rejection; Humans; Immunosuppressive Agents; Insulin; Liver Transplantation; Tacrolimus

Topics: Adolescent; Child; Cyclosporine; Diabetes Mellitus, Type 1; Female; Humans; Male; Tacrolimus; Transplantation Immunology

Topics: Adolescent; Adult; Aged; Child; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans Transplantation; Kidney Transplantation; Liver Transplantation; Tacrolimus; Transplantation, Homologous

The effect of the immunosuppressant FK-506 on the development of diabetes in BB/Wor rats was investigated. Using a treatment schedule (25 micrograms i.m. from day 27 to 120), not associated with detectable general ill effects, this drug was found to completely inhibit the appearance hyperglycemia and to reduce the histological signs of pancreatic insulitis. The treatment was also able to reduce the percentages of Ia+ T-lymphocytes and to block the appearance of detectable serum levels of gamma interferon (IFN).

Topics: Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Female; Interferon-gamma; Lymphocyte Activation; Male; Rats; Rats, Inbred BB; T-Lymphocyte Subsets; Tacrolimus

A novel immunosuppressive compound, FK-506, isolated from Streptomyces has potent immunosuppressive activities. To investigate the effect of FK-506 on the course of diabetes in nonobese diabetic (NOD) mice, we gave this drug to these animals, from the age of 8 weeks, intraperitoneally, in doses of 0.1 mg (2.5 mg/kg/day) or 0.01 mg (0.25 mg/kg/day) three times a week. Overt diabetes were observed in 75.5% of control mice by the age of 20 weeks. In contrast, no diabetes occurred in mice given 0.1 mg of FK-506. Sixteen percent of mice treated with 0.01 mg of the drug became diabetic. Administration of this drug prevented the progression of insulitis in NOD mice. The mice given 0.1 mg of FK-506 lost weight, but this was reversible.

Topics: Animals; Anti-Bacterial Agents; Antigens, Surface; Diabetes Mellitus, Type 1; Female; Immunosuppressive Agents; Mice; Mice, Obese; Spleen; Tacrolimus; Weight Loss