mycophenolic-acid and Cadaver

The myfortic Prospective Multicenter Study (myPROMS) utilizes a core protocol in which renal transplant patients receive enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion. Substudies investigate specific aspects of the immunosuppressive regimen.. A pooled analysis of three 12-month myPROMS substudies in de novo renal transplant patients was undertaken. Patients in the US01 and DE01 substudies were randomized to higher or lower cyclosporine C(2) target ranges; patients in FR01 were randomized to early or delayed introduction of cyclosporine. All patients received steroids and interleukin-2 receptor antagonist induction.. In total, 456 patients were included in the pooled analysis. Treatment failure (biopsy-proven acute rejection, graft loss, or death) occurred in 118 patients (25.9%) by month 12, with biopsy-proven acute rejection reported in 101 patients (22.1%). Fourteen patients (3.1%) lost their graft, and six patients died (1.3%). Median calculated creatinine clearance was 62.9 mL/min at month 12 (median serum creatinine, 138 +/- 51 mumol/L). Gastrointestinal (GI) adverse events were reported in 354 patients (77.6%); these were mild or moderate in 323 patients. Within 12 months, 16.2% of patients required EC-MPS dose changes for GI adverse events. GI disorders led to EC-MPS discontinuation in only 10 patients (2.2%). Over the 12-month study, mean EC-MPS dose was 1352 +/- 230 mg/d (94% of recommended dose).. Cyclosporine, EC-MPS, and steroids with interleukin-2 antagonist induction offers effective and well-tolerated immunosuppression following renal transplantation. Graft survival was excellent and renal function was stable. High EC-MPS dosing was sustained throughout (>90% recommended dose) and dose modifications due to EC-MPS-related adverse events or infections were infrequent.

Topics: Adult; Cadaver; Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Patient Selection; Racial Groups; Safety; Tablets, Enteric-Coated; Tissue Donors; Treatment Failure; Treatment Outcome

The availability of a number of new immunosuppressive drugs has resulted in significant improvements in the outcome of kidney transplantation. Currently 1-year graft survival rate for cadaver kidney transplants is approximately 85%. A number of new agents are presently in clinical studies. This article reviews the currently available agents and examines various aspects of induction and maintenance immunosuppressive therapy, and the treatment of acute rejection episodes. In addition, the agents currently in clinical trials and future directions in immunosuppressive therapy are discussed.

Topics: Acute Disease; Cadaver; Cyclosporine; Forecasting; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tacrolimus; Tissue Donors; Treatment Outcome

Human parvovirus B19 disease is an infrequent but recognized rare cause of anemia in immunocompromised patients. A few cases of parvovirus B19 infections have been reported in transplant recipients, of those only four patients underwent renal transplantation. The primary immunosuppressive therapy in these patients included prednisone with either cyclosporine or tacrolimus. In one patient the disease was self-limiting, while in three others the hematocrit improved following 10-15 d of treatment with commercial intravenous immunoglobulin (IVIG). Herein, we report the fifth case of pure red cell aplasia due to parvovirus B19 infection in a renal transplant recipient who responded to a 5-d course of IVIG. To our knowledge, this is the first case of parvovirus B19 infection in a patient with solid-organ transplantation whose immunosuppressive regimen included both mycophenolate mofetil and tacrolimus and in whom an excellent clinical response was achieved with a short course of IVIG infusion.

Topics: Adult; Anti-Inflammatory Agents; Cadaver; Cyclosporine; DNA, Viral; Hematocrit; Humans; Immunoblotting; Immunocompromised Host; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infusions, Intravenous; Kidney Transplantation; Male; Mycophenolic Acid; Parvoviridae Infections; Parvovirus B19, Human; Polymerase Chain Reaction; Prednisone; Red-Cell Aplasia, Pure; Remission Induction; Tacrolimus

Graft failure due to chronic rejection is greater among renal transplant patients with donor-specific antibody (DSA) than among DSA-free patients. For patients dependent on deceased donor transplantation, preoperative desensitization to eliminate DSAs may be impractical. We speculated that perioperative desensitization might eliminate preexisting DSAs and prevent de novo DSAs and improve graft outcomes. We report that brief perioperative desensitization using either intravenous immunoglobulin (IVIG) or plasmapheresis/IVIG (PP/IVIG) treatment improves clinical outcomes among patients with positive crossmatches.. Immediately following deceased donor transplantation, 235 renal recipients were assigned points for PRA and flow crossmatches (FCXM): delayed graft function (DGF) ≤ 1 point received standard therapy; 2 points received high-dose IVIG; and ≥3 points received PP/IVIG. The DSAs were serially monitored by single antigen bead luminex for 1 year. Five-year clinical outcomes were determined from the chart review.. All desensitized patients had preoperatively positive FCXM with DSA. Rejection was more common (P < .05) among desensitized than nonsensitized groups. However, overall graft survivals were similar between the groups (P = not significant) and superior to historic untreated patients (P < .05). Treatment with PP/IVIG more effectively eliminated preexisting DSAs (67% vs 33%, P < 0.05) than IVIG, but neither regimen prevented de novo formation of DSA (20%, P = not significant). Graft survival was >90% in all desensitizated patients with DSA elimination as well as PP/IVIG patients with residual DSA. In contrast, IVIG patients with persistent DSA had poorer graft survival (45%, P < .05).. Preemptive perioperative desensitization improved overall graft survival of sensitized patients compared to historic untreated patients. Plasmapheresis/IVIG had greater impact on DSA eradication and graft survival than IVIG alone.

Topics: Adult; Antibodies; Antilymphocyte Serum; Cadaver; Cohort Studies; Delayed Graft Function; Desensitization, Immunologic; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone Hemisuccinate; Middle Aged; Mycophenolic Acid; Perioperative Care; Plasmapheresis; Tacrolimus

In searching for an optimal induction regimen, we conducted two separate randomized trials of 38 living donor and 90 deceased donor adult, primary kidney transplant recipients comparing antithymocyte globulin (Thymoglobulin) (group A, N=43) versus alemtuzumab (group B, N=43) versus daclizumab (group C, N=42), using exactly the same three treatment arms in each trial.. For the purpose of maximizing statistical power, results from the two randomized trials were combined. Groups A and C received standard maintenance dosing with tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids. Because of intense lymphodepletion expected with alemtuzumab use (and hoped-for achievement of a truer immunoregulatory state), group B received lower TAC and MMF dosing and corticosteroid avoidance. Long-term target TAC trough level and MMF dosing were 5 to 7 ng/mL and 1,000 mg b.i.d. in groups A and C; 4 to 6 ng/mL and 500 mg b.i.d. in group B.. With median follow-up of 95 months, biopsy-proven cute rejection incidence was similar in the three groups (8/43, 14/43, and 12/42, P=0.34), but biopsy-proven chronic allograft injury incidence was significantly higher in group B (19/43) in comparison with groups A (9/43) and C (7/42) combined (P=0.0008). Mean calculated creatinine clearance was significantly lower in group B versus the average of groups A and C means throughout 60 months posttransplant (62.9±4.2 vs. 83.6±6.9 and 79.8±5.9 at 60 months, P=0.01), and death-censored graft failure was significantly higher in group B (13/43) versus groups A (5/43) and C (5/42) combined (P=0.009). Total infection and new-onset diabetes after transplant rates were not significantly different. Ad hoc analysis suggested that the inferior results in group B were specifically a result of reduced dosing and greater withholding of TAC and MMF occurring in that group.. Long-term results clearly indicate inferior clinical outcomes in group B.

Topics: Adrenal Cortex Hormones; Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Cadaver; Creatinine; Daclizumab; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Treatment Outcome

Although cyclosporine maintenance therapy reduces the risk of acute rejection and increases short-term graft survival in renal transplant recipients, its associated nephrotoxicity increases the risk of chronic graft dysfunction. The dose that allows an optimal risk-to-benefit ratio has not been established.. This multicentre study enrolled stable renal allograft recipients receiving cyclosporine and mycophenolate mofetil without corticosteroids in their second year post-transplant. Patients were randomized to a cyclosporine dose targeted to a standard area under the concentration-time curve (AUC)(0-12 h) (usual exposure, n = 104) or 50% of the study standard AUC(0-12 h) (low exposure, n = 108) using a three-point pharmacokinetic sampling. The primary endpoint was the percentage of patients with treatment failure at 24 months (graft loss/acute rejection/nephrotoxicity/>15% serum creatinine level increase).. Treatment failure was reported in 37 out of 101 (37%) patients in the usual-exposure and 19 out of 106 (18%) patients in the low-exposure groups (P = 0.003). Mean estimated glomerular filtration rate decreased from baseline to 2 years with usual exposure and increased with low exposure (P < 0.001). Mean systolic and diastolic blood pressures were lower with low exposure (P = 0.03 and P = 0.008, respectively).. In renal transplant recipients receiving maintenance therapy without corticosteroids, a minimization strategy using three-point pharmacokinetic sampling to reduce and maintain cyclosporine exposure to 50% of the usual levels is safe and reduces the risk of graft dysfunction.

Topics: Adolescent; Adult; Aged; Area Under Curve; Cadaver; Creatinine; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Survival Rate; Tissue Distribution; Tissue Donors; Treatment Outcome; Young Adult

We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event.. We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66+/-22 mL/min in the study group and 67+/-23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections.. We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD; Antigens, CD19; Antigens, CD20; Cadaver; Double-Blind Method; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Placebos; Reoperation; Rituximab; Safety; Survival Analysis; Tissue Donors; Treatment Outcome

Living-donor liver transplantation (LDLT) has been considered an alternative method for treatment of patients with end-stage liver disease. However, the characteristics of pharmacokinetics of mycophenolic acid (MPA) in patients who underwent LDLT were not clear. This study was designed to compare the pharmacokinetics of MPA and its metabolites between LDLT patients and deceased donor liver transplant (DDLT) patients after oral administration of mycophenolate mofetil (MMF). Thirteen patients who underwent LDLT and 14 patients who underwent DDLT were enrolled prospectively. All patients received oral MMF administration (1.0 g, twice daily) in combination with tacrolimus (TAC). The plasma concentrations of MPA, free MPA, glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by high-performance liquid chromatography method. There was a wide variation in various pharmacokinetic parameters of MPA and its metabolites in patients who underwent LDLT and DDLT after oral MMF administration. Although mean MPA area under the plasma concentration time curve for 0-12 hours (AUC(0-12h)) of MPA and MPAG in DDLT patients were higher than those in LDLT patients, there was no significant difference between the two groups. MPA concentration at 6 hours (C(6h)), C(10h), C(12h), and MPA AUC(6-12h) were significantly higher in DDLT group than those in LDLT group (P < 0.05). Inversely, higher free MPA AUC(0-12h) and significant free MPA fraction (P < 0.05) in LDLT patients were observed in DDLT patients when compared with DDLT group. AcMPAG concentrations at 4, 8, and 10 hours and AcMPAG AUC(0-12h) were significantly higher in the DDLT group (P < 0.05). In conclusion, after a fixed oral dose of MMF, DDLT patients had higher enterohepatic recycling contributing to total MPA exposure compared with LDLT patients. The function of glucuronide conjugation in LDLT patients was decreased compared with that in DDLT patients. Higher free MPA AUC(0-12h) and a significantly higher fraction of free MPA in LDLT patients suggested that a lower oral dose of MMF may be administered for patients who underwent LDLT.

Topics: Administration, Oral; Adult; Cadaver; Enzyme Inhibitors; Female; Graft Rejection; Humans; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Young Adult

We recently reported a randomized study in renal transplant patients (RTP) receiving tacrolimus, mycophenolate mofetil, and prednisone in which patients who had early protocol biopsies (PBx) derived no benefit compared with controls (no PBx) at 6 months, likely due to the low prevalence of subclinical rejection. We report on the follow-up of these patients to 24 months at which time a repeat PBx and tests of renal function were performed.. Of the 240 RTP randomized, 22 were excluded for a protocol violation. Approximately 75% of the remaining 218 (111 PBx and 107 controls) completed the study.. At 24 months, graft function was excellent with a mean creatinine clearance of approximately 74 mL/min and negligible proteinuria; however, the prevalence of interstitial fibrosis and tubular atrophy (IF/TA)-ci + ct more than or equal to 2-increased from approximately 3% at baseline to up to 40% to 50%. By logistic regression analysis, the only independent positive correlate of IF/TA was transplantation with a deceased donor. However, by post hoc analysis, use of angiotensin-II-converting enzyme inhibitors or angiotensin II receptor blockers was negatively correlated with both the prevalence of IF/TA at 24 months and its progression between 6 and 24 months in RTP that had paired biopsies.. A regimen of tacrolimus, mycophenolate mofetil, and prednisone results in excellent renal function at 24 months posttransplant but with a progressive increase in IF/TA. A potential inhibitory effect of angiotensin-II-converting enzyme inhibitor/angiotensin II receptor blockers on IF/TA is suggested that requires confirmation in a randomized study.

Topics: Adult; Biopsy; Cadaver; Disease Progression; Female; Fibrosis; Graft Rejection; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prednisone; Regression Analysis; Tacrolimus; Tissue Donors

Tolerance to immunosuppresant treatment has considerable impact on adherence to therapy and on the outcome of renal transplantation. Recent data indicate better gastrointestinal tolerance to enteric-coated mycophenolate sodium (EC-MPS) than to the classic mycophenolate mofetil (MMF) formulation.. This study assessed the effect of conversion therapy from MMF to EC-MPS on gastrointestinal tolerance and quality of life in renal transplant recipients.. This open observational study analyzed the outcomes of conversion from MMF to EC-MPS among renal transplant patients with gastrointestinal complaints. At baseline (B) and at 8 weeks postconversion patients were assessed by the Gastrointestinal Quality of Life Index (GIQLI) questionnaire as well as by clinical evaluation (acute rejection, infection) and analytical determinations.. We analyzed 18 recipients of cadaveric renal transplants of mean age of 54 +/- 9 years including 61% men and one retransplant. Our patients had stable renal function with mean creatinine of 1.9 +/- 0.7 mg/dL. Baseline treatment included cyclosporine-MMF-prednisone (33%) or FK-MMF-prednisone (66%). Bioequivalent conversion was carried out at 50 +/- 29 months posttransplantation. Conversion to EC-MPS resulted in an improvement in overall quality of life (total score: baseline 106.61 vs 8 weeks 116.89; P < .01). Improvements were observed in the following GIQLI subscales: gastrointestinal symptoms (3.12 vs 3.48, P < .001), physical function (2.54 vs 2.76, P = .003), medical treatment (2.17 vs 2.50, P = .031), and emotion (3.08 vs 3.39, P = .001). No changes were observed in the social function subscale. The hemogram and renal function remained stable; there were no episodes of rejection or infection.. Conversion from MMF to an EC-MPS formulation was associated with improvements in gastrointestinal complaints and quality of life among renal transplant recipients.

Topics: Adult; Cadaver; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Quality of Life; Tablets, Enteric-Coated; Tissue Donors

In liver transplantation, mycophenolate mofetil (MMF) is habitually administered using fixed doses. We assessed whether mycophenolic acid (MPA) monitoring could be advisable in liver transplant patients.. In 15 liver transplant patients receiving tacrolimus, daclizumab and MMF (1 g bid, orally), we determined the 12-hour plasma MPA pharmacokinetic profile after one dose of MMF at days 6, 10, and 16, and months 3 and 6. The inhibitory capacity of serum MPA on proliferation of CEM cells, a cell line insensitive to other immunosuppressants, was also determined.. A large interindividual variability in MPA profiles was observed at any time. Regardless of a gradual increase in individual MPA AUC and C(0) over time following transplantation, a substantial proportion of patients had these parameters below the ranges recommended in other organ transplantations throughout the study. When MPA AUC and C(0) were within the recommended ranges, CEM proliferation was inhibited by almost all serum samples, but when these pharmacokinetic parameters were below the recommended ranges, CEM proliferation was very variable and, therefore, unpredictable. No relationship between MPA pharmacokinetics and the efficacy of MMF could be established (only one patient developed rejection), probably due to the concomitant administration of tacrolimus and daclizumab. Gastrointestinal symptoms were the only adverse events with a significant relationship with MPA levels.. During the first postoperative months, exposure to MPA is low in a considerable proportion of liver transplant patients receiving MMF at a fixed dose of 1 g bid. MPA monitoring appears necessary in these patients.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cadaver; Cell Division; Daclizumab; Drug Therapy, Combination; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Tacrolimus; Tissue Donors

This study compared early postoperative complications in kidney transplant recipients treated with either a sirolimus-based calcineurin inhibitor (CNI)-free regimen or a tacrolimus-based steroid-free regimen. We used a single-center, prospective, sequential but nonrandomized study design. Consecutive recipients of primary cadaveric or non-HLA identical kidney transplant recipients received either a CNI-free regimen, consisting of sirolimus 5 mg daily beginning postoperative day 3, mycophenolate mofetil 1 gm twice a day, and methylprednisolone 500 mg intraoperatively, then prednisone 30 mg daily tapered to 10 mg daily at 3 months, or a prednisone-free regimen, consisting of methylprednisolone 500 mg, 250 mg, and 125 mg from days 0 to 2, then no further steroids, tacrolimus 0.075 mg/kg twice a day, and mycophenolate mofetil 1 g twice a day. All patients received thymoglobulin induction 6 mg/kg total dose. Outcome measures were patient and graft survival, BPAR, surgical and wound complications, viral infections and posttransplant diabetes mellitus (PTDM). Both groups had excellent early outcomes with no significant difference in patient or graft survival, early renal function, BPAR, surgical or wound complications, or viral infections between the two groups. Patients in the sirolimus-based CNI-free group had a significantly higher incidence of PTDM and a trend toward more discontinuation due to drug toxicity. Whether either regimen improves long-term outcomes awaits longer follow-up.

Topics: Adrenal Cortex Hormones; Adult; Cadaver; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Graft Survival; Histocompatibility Testing; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Postoperative Complications; Racial Groups; Survival Analysis; Tacrolimus; Tissue Donors; Treatment Outcome

The increasing number of patients on waiting lists and the relatively stable organ procurement rate provide the groundwork for the use of expanded criteria deceased donors. While calcineurin-inhibitors (CNI) are excellent immunosuppressive drugs, their nephrotoxicity is largely responsible for the lack of improvement in long-term graft survival. The objective of this study was to analyze the results obtained with the use of a calcineurin inhibitor-free immunosuppressive protocol (polyclonal antibody induction, plus sirolimus, mycophenolate mofetil, and low doses of steroids) in terms of graft and patient survival as well as posttransplant clinical complications over 2 years. Under this immunosuppressive protocol, 78.04% of the patients completed the follow-up. A protocol biopsy was performed on 17 patients (53.1%) within 2 years posttransplant of which 82.31% were diagnosed as chronic allograph nephropathy grade I. The incidence of clinical complications was low and not significantly different from that reported with other immunosuppressive schemes. Death-censored graft survival was 95.12%. In conclusion, the use of a calcineurin inhibitor-free protocol in renal-transplant recipients of expanded criteria deceased donors was associated with excellent graft and patient survival rates and a low incidence of adverse events.

Topics: Adrenal Cortex Hormones; Aged; Antilymphocyte Serum; Cadaver; Calcineurin Inhibitors; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Sirolimus; Survival Analysis; Time Factors; Tissue Donors

Basiliximab is a monoclonal antibody directed to the interleukin-2 receptor. Several studies have demonstrated both its efficacy and safety. Even with the use of polyclonal antibodies in renal pediatric transplant recipients, the local incidence of steroid-resistant rejections has been close to 10% of the total incidence of acute rejection episodes (AREs). An open, multicenter prospective study was performed to assess the safety tolerability, and efficacy of induction with basiliximab in renal pediatric transplant patients receiving cyclosporine, mycophenolate, and steroids.. Eighteen patients (8 boys) of mean age 11.9 +/- 4.5 years and body weight 32 +/- 15 kg received cadaveric (n = 7) or living (n = 11) donor grafts. Simulect was administered on days 0 and 4. Efficacy was assessed by the incidence of biopsy-proven acute rejection (BPAR). Safety assessment consisted of a description of the adverse events (AEs).. Six BPAR (Banff I and II) occurred in 5, (27.7%) children all of which were steroid responsive. Creatinine levels at day 7 and months 3, 6, and 12 were 1.6 +/- 1.5 mg/dL, 1.0 +/- 0.4 mg/dL, 1.0 +/- 0.5 mg/dL, and 1.0 +/- 0.4 mg/dL, respectively. Schwartz calculation at 12 months was 71 +/- 15 mL/1.73 m2 AEs were hypertension (12), anemia (9), abdominal pain (8), metabolic acidosis (8), nausea (7), diarrhea (2), gingival hypertrophy (2), hirsutism (2), lymphocele (2), and infections (15). No deaths, graft losses, PTLDs, or malignancies were observed.. No steroid-resistant AREs, were observed in this pediatric group using basiliximab. The Schwartz calculation at 12 months was 71 +/- 15 mL/min/1.73 m2.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Basiliximab; Biopsy; Cadaver; Child; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Safety; Tissue Donors

Effect of early steroid withdrawal protocol using basiliximab in kidney transplantation (KTx) on the clinical outcomes was investigated as compared with triple regimen.. Kidney transplant patients in group 1 (n = 62) were treated with 8 mg/kg of cyclosporine (CsA), 2000 mg of MMF, two bolus IV injections of 20 mg of basiliximab and 500 mg of methylprednisolone (MP) rapidly tapered and withdrawn at 14 postoperative days (POD). Group 2 (n = 56) was treated with same dose of CsA and MMF, and 250 mg of MP tapered and continued. Acute rejection (AR) episodes were treated with MP pulse therapy followed by muromonab CD3 (OKT3) in case of steroid-resistant rejection.. In 46 of 62 cases (74.2%) in group 1, steroid was successfully withdrawn at 13.7 +/- 1.7 POD. Graft survival at 3, 6, and 12 months in group 1 was 100%, 100%, and 98.4% (one death with functioning graft), and 100%, 98.2%, and 96.4% in group 2, respectively. The incidence of AR was 12.9% for group 1 and 42.9% for group 2, among which 21 cases in group 2 were treated with ALG or OKT3; no patient needed ALG or OKT3 in group 1. Fifteen cases in group 1 and 13 cases in group 2 developed CMV antigenemia, among which febrile episode was exhibited in 3 cases (4.8%) in group 1 and 5 cases (8.9%) in group 2.. Early steroid withdrawal protocol using basiliximab is promising for reducing the incidence of AR (especially steroid-resistant rejection), CMV diseases, and steroid-related complications.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Cadaver; Calcineurin; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Muromonab-CD3; Mycophenolic Acid; Recombinant Fusion Proteins; Tissue Donors; Treatment Outcome

Immunosuppressive regimens including mycophenolate mofetil (MMF, Cellcept) were used in a renal transplant transplant program since May 2000 including 67 patients in whom it was the primary drug. Acute rejection (AR) occurred in 9 cases (13%) with 1-year graft survival rate of 96.8%. Pharmacokinetic (PK) studies of mycophenolic acid (MPA) were performed in 46 recent patients (total, 127 times). There was no correlation between dose (mg/kg) and blood concentration (AUC0-9: r2= 0.27). AUC0-9 was well correlated with AUC0-4 (r2= 0.91), but not with a single timepoint concentration. MPA AUC0-9 level was significantly higher among the AR-negative group (n = 33; 34.2 +/- 16.8 ng.hr/mL) compared with AR-positive group (n = 3; 28.2 +/- 1.9 ng.hr/mL; P = .04085) over the 2 weeks after transplantation. MPA AUC0-9 level was higher among the adverse event (AE-positive) group (n = 15; 39.2 +/- 22.8 ng.hr/mL) compared with the negative group (n = 21; 30.1 +/- 8.0 ng.hr/mL; P = .08772) within 2 weeks after transplantation. These results suggest the necessity of measuring AUC for therapeutic drug monitoring (TDM) of MMF-containing immunosuppressive therapy. The possible target level of MPA AUC0-9 would be approximately 30 ng.hr/mL using the present immunosuppressive regimen.

Topics: Adolescent; Adult; Cadaver; Child; Cyclosporine; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Survival Analysis; Tissue Donors

Our goal was to evaluate the efficacy and safety of basiliximab (Simulect) as immunosuppressive induction therapy for the prevention of acute allograft rejection among sensitized kidney recipients.. Fifty-six adult recipients receiving cadaveric kidney transplant with panel reactive antibody class I ranging from 30% to 50% and or class II 30% to 80% were randomized at about a 2:1 ratio to the Simulect group (36 patients) or matching control group (20 patients). All patients received baseline triple immunosuppressive therapy with cyclosporine (Neoral), mycophenolate mofetil, and steroids. Simulect was given in two doses of 20 mg each on day 0 (2 hours before operation) and day 4 after transplantation.. There was no hyperacute rejection in either group and delayed graft function occurred in three control patients. The incidence of acute rejection during the first 3 months was 11.1% in the Simulect group compared with 50% in the placebo group (77.8% reduction, P < .01). No apparent adverse and toxic events were recorded in the Simulect group. The mean daily dose of steroids was significantly higher in the control group 2 to 4 weeks posttransplantation. No clinically meaningful differences in the mean dose of cyclosporine were observed between the two groups; in addition, there were no statistically significant differences in the rate of patient or graft survival.. On the basis of appropriate selection of the donor and recipient, Simulect is effective and safety for the sensitized recipients as immunosuppressive induction therapy.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Basiliximab; Cadaver; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunization; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Recombinant Fusion Proteins; Tissue Donors; Transplantation, Homologous

With the aim to improve the inferior outcomes in elderly recipients of kidneys from elderly cadaver donors, we applied and investigated a therapeutic regimen consisting of calcineurin inhibitor (CNI)-free, mycophenolate mofetil (MMF)-based immunosuppressive (i.s.) induction/maintenance protocol. In this article, we report the long-term results of this clinical trial.. A total of 89 recipients (mean age: 63.8 yr) of kidneys from cadaver donors (mean age: 66.8 yr) were consecutively recruited for this 5-yr, prospective, open, single centre, pilot trial. Induction therapy consisted of MMF and steroids in conjunction with a short course (4-10 d) of rabbit antithymocyte globulin (ATG). Maintenance treatment was performed with MMF/steroids or MMF alone under strict therapeutic drug monitoring by aiming target mycophenolic acid (MPA)-trough levels between 2 and 6 mg/mL.. Cumulative 5-year patient and renal allograft survival was 87.69% and 69.81%, respectively. Acute rejection episodes occurred in 23.6% (21 patients). Long-term function of the old renal allografts proved to be satisfactory as reflected by serum creatinine-values of 1.53 mg/dL and urea-values of 57.9 mg/dL at 5 yr.. Application of a nephrotoxicity- and atherogenicity-free, MMF-based i.s. induction/maintenance protocol in elderly recipient of kidneys from elderly cadaver donors leads to improved long-term outcomes which are comparable with data from young recipients who have received allografts from young cadaver donors.

Topics: Aged; Cadaver; Calcineurin Inhibitors; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Prospective Studies; Tissue Donors

We carried out a prospective study of the safety and efficacy of daclizumab combined with triple immunosuppression in adult recipients of at least one HLA-mismatched cadaveric renal allograft. All studied patients received the same immunosuppression: a daclizumab infusion of 1 mg/kg immediately before transplantation, and at 2, 4, 6, and 8 weeks following the transplantation. Infusion of cyclosporine (CsA) (0.08 mg/kg/h) was started at the time of the operation and continued by CsA microemulsion (CsA-Neoral), 3 mg/kg twice daily on day 2, methylprednisolone, 0.4 mg/kg intravenously at operation, and mycophenolate mofetil started on day 1. The dose of CsA-Neoral was adjusted to maintain target blood trough levels. Oral methylprednisolone was tapered by 4 mg per week to achieve a maintenance dose of 0.08 mg/kg/day. Fifty-five patients, with a mean age of 48 +/- 11 years, were studied. Six of them received a second renal allograft. The mean donor age was 38 +/- 14 years. Mean cold ischemia time was 19.5 +/- 6.5 h, mean value of HLA-antigen mismatches was 2.7 +/- 0.9, mean latest PRA value was 3 +/- 7%. Fifteen patients experienced delayed graft function. During a follow-up period of 3 months three acute rejection episodes occurred. One patient died because of systemic aspergillosis. After 3 months mean serum creatinine was 104 +/- 38 micromol/L. Five renal allografts failed, one of them due to rejection. Patient and graft survival was 98.2% and 90.9%, respectively. Daclizumab with this triple therapy represents safe and efficient immunosuppression strategy, demonstrated with low incidence of early acute rejection episodes and an acceptable adverse event profile in cadaveric renal allograft recipients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cadaver; Cyclosporine; Daclizumab; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunoglobulin G; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Prospective Studies; Safety; Transplantation, Homologous; Treatment Outcome

To reduce long-term nephrotoxic calcineurin inhibitor dosage, adjunctive sirolimus or mycophenolate mofetil (MMF) was used in a 150-patient, randomized, three-armed trial in cadaveric or human leukocyte antigen non-identical living-donor first renal transplant recipients (n=50/group).. Group A received tacrolimus and sirolimus. Target tacrolimus trough levels postoperatively were 10, 8, and 6 ng/mL at 1 month, 6 months, and 1 year, respectively. Group B received tacrolimus and MMF. Target tacrolimus trough levels were 10 and 8 ng/mL at 1 month and 1 year, with a targeted dose of MMF of 1 g twice daily. Group C received cyclosporine A (CsA) (Neoral, Novartis, Basel, Switzerland) and sirolimus with target CsA trough levels of 225 and 175 ng/mL at 1 month and 1 year. Maintenance sirolimus target trough levels were 8 ng/mL in groups A and C. Each group received daclizumab induction and methylprednisolone maintenance. This first of two companion 1-year reports details demographics, drug-dosing interactions, and rejection.. There were no notable differences in group demographics, but a somewhat less favorable course occurred in group C, despite higher bioavailability of sirolimus in group C versus group A (P<0.001). Acute rejection rates were lower in groups A (4%) and B (4%) combined versus group C (14%) (P=0.03). Histopathologic findings were supported by comparing perioperative with 1-year postoperative protocol biopsies.. This 1-year interim analysis indicates that a decreasing dosage of tacrolimus with either adjunctive sirolimus or MMF may optimize future graft survival versus a less favorable outcome using a similar algorithm with CsA and sirolimus.

Topics: Adult; Area Under Curve; Biological Availability; Cadaver; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors; Tissue Donors

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Basiliximab; Cadaver; Cytomegalovirus Infections; Cytotoxicity, Immunologic; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Recombinant Fusion Proteins; Tissue Donors

This study examines the efficacy and toxicity of sirolimus used as primary immunosuppression in combination with reduced dose tacrolimus (calcineurin inhibitor [CI]-sparing regimen) or mycophenolate mofetil (CI-free regimen) in high-risk cadaveric renal transplantation.. Seventy subjects were treated in a quadruple sequential protocol in which 41 were treated with a CI-sparing regimen and 29 were treated with a CI-free regimen. The efficacy and toxicity profiles of these regimens were prospectively monitored and compared.. The study consisted of African Americans (71%), cadaveric donors (100%), donors aged more than 50 years (30%), and patients with delayed graft function (47%). At 1 year, patient survival, graft survival, and incidence of biopsy-proven acute rejection were 98%, 80%, and 10%, respectively, in the CI-sparing group and 100%, 89%, and 7%, respectively, in the CI-free group. Three-month protocol biopsies were performed in 41% (17/41) and 67% (20/29) of the subjects in the CI-sparing and CI-free groups, respectively. Subclinical rejection was detected in 6% (1/17) and 15% (3/20) of the subjects in the CI-sparing and CI-free groups, respectively. Histologic evidence of chronic allograft nephropathy was more prevalent in the CI-sparing group. At 1 year, the mean estimated creatinine clearance was higher in the CI-free group than in the CI-sparing group (72.4 +/-20.0 mL/min vs. 50.5 +/-20.8 mL/min, P <0.01). The two regimens had similar toxicity profiles (hospital readmission, infection, wound complications, and metabolic complications).. Both sirolimus-based CI-sparing and CI-free regimens are safe and effective in a population with high immunologic risk. The CI-free regimen is associated with better renal function at 1 year post-transplant. Long-term follow-up will aid in determining the risk and benefit ratio of these regimens.

Topics: Adult; Cadaver; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Safety; Sirolimus; Tacrolimus

In an attempt to reduce both initial and long-term (nephrotoxic) calcineurin inhibitor maintenance dosage and totally eliminate maintenance corticosteroids, alemtuzumab (Campath-1H) was used as induction therapy in first cadaver and non-HLA-identical living donor renal transplantation.. Forty-four de novo renal allograft recipients were treated with Campath-1H (0.3 mg/kg) on days 0 and 4 postoperatively, preceded by methylprednisolone boluses. Maintenance target 12-hr tacrolimus trough levels of 5 to 7 ng/mL were operational from the outset as well as (reduced) mycophenolate mofetil dosage of 500 mg twice daily. No corticosteroids were planned to be given after the first week postoperatively.. With a median follow-up of 9 (range, 1-19) months, patient and graft survival rates are each at 100%. Biopsy-proven acute rejection was diagnosed in four patients. Infections requiring hospitalization developed in four patients. Thirty-eight recipients remain without the need for long-term corticosteroid therapy.. In an early assessment, the combination of Campath-1H, low dosing of tacrolimus and mycophenolate mofetil, and avoidance of maintenance corticosteroid use seems to be safe and effective for kidney transplant recipients. Long-term outcomes will be reported in the future.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cadaver; Creatinine; Drug Therapy, Combination; Ethnicity; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Injections, Intravenous; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Tissue Donors

Topics: Adult; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Time Factors; Treatment Failure; Treatment Outcome

Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years.. The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF.. All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Topics: Acute Disease; Azathioprine; Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Florida; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperglycemia; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Probability; Racial Groups; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

Kidney grafts from suboptimal donors are more likely to suffer the nephrotoxic side-effects of cyclosporine than kidneys from standard donors. In an attempt to avoid the use of cyclosporine, we carried out a prospective study in low-immunological risk recipients of suboptimal kidneys, using an immunosuppressive protocol combining Thymoglobuline in induction with a bi-therapy of mycophenolate mofetil (MMF) and steroids. Patients with panel reactive antibodies (PRA) <50% receiving a first renal transplant from a suboptimal donor (age >or=50, non heart beating, arterial hypertension, or acute renal failure) or a kidney at risk of delayed graft function (DGF) because of a prolonged cold ischaemia time (CIT) of 24 h or more, were eligible for this trial. Between September 1996 and December 1999, 30 patients were enrolled for the trial and treated with MMF 2 g orally, pre-operatively, and 3 g daily, post-operatively; Thymoglobuline 2 mg/kg IV pre-operatively, 1.5 mg/kg IV the next day, and for doses of 1 mg/kg IV given on alternate days; and prednisolone 0.25 mg/kg per day, reduced progressively from the end of the first month to 0.1 mg/kg per day by 3 months post-transplant. Cyclosporine was added only if rejection grade II or higher, or a reduction in MMF below 1 g daily, occurred. Ten patients (30%) suffered from DGF, and one kidney suffered primary non function. Seven patients (24%) suffered acute rejection (six were biopsy proven, 3 grade I and 3 grade II). MMF dosage was reduced in 28 patients because of adverse events, and calcineurin inhibitors were introduced in 16 patients. There were 14 episodes of opportunistic infection (cytomegalovirus (CMV 10), Herpes zoster 2, Listeria monocytogenes 1, Pseudomonas aeuruginosa 1), and 7 malignancies (skin 2, thyroid 1, lung 1, Kaposi's sarcoma 2, post-transplantation lymphoproliferative disorder 1). Mean serum creatinine was 178, 199, 213, and 218 micromol/l at 1, 2, 3 and 5 years after transplantation, respectively. Actuarial patient and graft (after censoring for death) survival was 94% and 83% after 1 year and 79% and 65% after 5 years, respectively. These results show that with the combination of MMF, Thymoglobuline and steroids the use of cyclosporine can be delayed, and in a few cases completely avoided, with good efficacy in terms of prevention of rejection and recovery of renal function. Regardless of acceptable patient and graft survival, side-effects of MMF at the doses used in this protocol were common

Topics: Adult; Aged; Antilymphocyte Serum; Cadaver; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Opportunistic Infections; Prospective Studies; Survival Analysis; Tissue Donors

Topics: Adrenal Cortex Hormones; Cadaver; Creatinine; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Prospective Studies; Tacrolimus; Time Factors; Tissue Donors

Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients.. Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months.. At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05).. Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Topics: Adrenal Cortex Hormones; Adult; Cadaver; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years.. Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years.. The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF.. All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

Topics: Administration, Oral; Adolescent; Adult; Antilymphocyte Serum; Azathioprine; Black People; Cadaver; Child; Cross-Over Studies; Cyclosporine; Diabetes Mellitus; Drug Monitoring; Drug Therapy, Combination; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Insulin; Kidney Function Tests; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Mycophenolic Acid; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; United States; White People

Topics: Acute Disease; Acyclovir; Antiviral Agents; Cadaver; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Emulsions; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Muromonab-CD3; Mycophenolic Acid; Prednisone; Reoperation; Time Factors; Treatment Outcome

Topics: Age Factors; Aged; Aged, 80 and over; Cadaver; Cytomegalovirus Infections; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Pilot Projects; Postoperative Complications; Prospective Studies; Survival Rate; Tissue Donors; Transplantation, Homologous

Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation.. A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year.. There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups.. All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.

Topics: Adult; Azathioprine; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Prospective Studies; Tacrolimus

Tacrolimus (FK506) is a safe and effective treatment for the prevention of rejection of renal allografts. Mycophenolate mofetil (MMF) has been used as adjunct immunosuppressive therapy with cyclosporine and corticosteroids for the same purpose. The objective of this study was to investigate the safety and efficacy of FK506 and MMF in renal transplant recipients.. After cadaveric renal transplant, patients were randomized to receive tacrolimus in combination with either azathioprine (AZA, n=59), MMF 1 g/day (n=59), or MMF 2 g/day group (n=58). Patients were followed for 1 yr posttransplant for the incidence of biopsy-confirmed acute rejection, patient and graft survival, and adverse events.. Tacrolimus doses and trough concentrations were similar between treatment groups at all time points; 80% of patients were maintained within a range of 5.0-13.9 ng/ml at 12 months posttransplant. The mean dose of MMF decreased in the 2 g/day group to 1.5 g/day by 6 months posttransplant, primarily due to gastrointestinal GI-related disorders. The incidence of biopsy-confirmed acute rejection at 1 year was 32.2%, 32.2%, and 8.6% in the AZA, MMF 1 g/day, and MMF 2 g/day groups, respectively (P<0.01). The use of antilymphocyte antibodies for the treatment of rejection was comparable across treatment groups. The incidence of most adverse events was similar across treatment groups and comparable with previous reports. The overall incidence of posttransplant diabetes mellitus was 11.9%, with the lowest rate observed in the MMF 2 g/day group (4.7%), and was reversible in 40% of patients. The incidence of malignancies and opportunistic infections was low and not different across treatment groups.. Tacrolimus in combination with an initial dose of MMF 2 g/day is a very effective and safe regimen in cadaveric kidney transplant recipients.

Topics: Acute Disease; Adult; Azathioprine; Cadaver; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Treatment Failure; Treatment Outcome

Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post-transplant month in the converted group and after the 12th month in the control. During the 20-month observation period, biopsy-proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.

Topics: Adult; Azathioprine; Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Tissue Donors

Topics: Adolescent; Adult; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Survival Rate; Tacrolimus; Tissue Donors

Topics: Adult; Azathioprine; Cadaver; Chronic Disease; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Time Factors; Tissue Donors

This report extends the randomized, double-blind, multicenter trial at 14 centers in the United States that compared triple-therapy regimens containing mycophenolate mofetil (MMF), 2 or 3 g, with a similar regimen containing azathioprine (AZA) in recipients of cadaveric renal allografts. We investigated the continued long-term use of MMF with respect to graft and patient survival, graft function, and safety. All patients who received the study drug (MMF, 2 g, n = 165; MMF, 3 g, n = 166; AZA, n = 164) were included in the 3-year intent-to-treat evaluation of graft and patient survival. At 3 years posttransplantation, the weighted pairwise difference was 6.5%, and 95% confidence interval in graft and patient survival (ie, patients alive with a functioning graft) was -2.1 to 15.1 (P = 0.17) numerically in favor of MMF, 2 g, compared with AZA. Similar to the 1-year data, the principal adverse events were limited to the gastrointestinal and hematologic systems. Although cytomegalovirus (CMV) tissue-invasive disease occurred more often in the MMF-treated groups, most instances occurred during the first year posttransplantation. One patient in the AZA group and one patient in the MMF 2-g group developed lymphoma, whereas three patients in the MMF 3-g group developed lymphoma at 3 years posttransplantation. In conclusion, although the design of the study did not afford adequate statistical power to address survival end points, at 3 years posttransplantation, graft survival, patient survival, renal function, and safety were similar among the AZA, MMF 2-g, and MMF 3-g groups. There was an increased incidence of infection caused by invasive CMV and Aspergillus spp and mucormycosis seen in the MMF groups, but the long-term data confirm MMF is a safe and valuable addition to the range of drugs available to prevent rejection.

Topics: Azathioprine; Cadaver; Double-Blind Method; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Opportunistic Infections; Survival Rate

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: Adolescent; Adult; Aged; Cadaver; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Tacrolimus; Time Factors; Tissue Donors

Three large-scale clinical trials conducted in North America, Europe, and Australia showed that mycophenolate mofetil (MMF) decreases the incidence of acute renal allograft rejection in the first 6 months after transplant compared with placebo or azathioprine. This study extends the randomized, prospective, double-blind trial of MMF conducted by the Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group.. Patients (n=503) were randomized to receive 100-150 mg of azathioprine (AZA) (n=166), 2 g of MMF (n=173), or 3 g of MMF (n=164) per day, in conjunction with cyclosporine and prednisone from the time of transplantation.. During the first 6 months, the incidence of biopsy-proven acute graft rejection (BPR) was reduced by approximately 50% in the MMF 2 g (19.7%) and MMF 3 g (15.9%) groups compared with the AZA group (35.5%). The incidence of treatment failure during the first 6 months, including BPR, death, graft loss, and early withdrawal without prior BPR, was significantly decreased: AZA, 50%, compared with MMF 2 g, 38.2% (P=0.0287), and MMF 3 g, 34.8% (P=0.0045). At 3 years after transplant, both intent-to-treat and on-study (censoring at 90 days after treatment) analyses of graft and patient survival showed a trend toward advantage for MMF 2 g and 3 g vs. AZA (intent-to-treat: 81.9% and 84.8% vs. 80.2%; on-study: 84.0% and 86.4% vs. 82.7%), although this trend did not reach statistical significance. Rejection was the principal cause of graft loss in all groups: AZA, 9.9%; MMF 2 g, 5.8%; and MMF 3 g, 3.0%. Graft function (intent-to-treat and on-study) was comparable in all three groups at 3 years. Gastrointestinal toxicity, leukopenia, and tissue-invasive cytomegalovirus disease were more common in the MMF 3 g group both during and after the first posttransplant year. Lymphoproliferative disorders were diagnosed in one AZA (0.6%), two MMF 2 g (1.2%), and three MMF 3 g (1.8%) patients. Other (non-lymphoproliferative disorders, noncutaneous) malignancies occurred in six AZA (3.7%), four MMF 2 g (2.3%), and nine MMF 3 g (5.5%) patients. Mortality was comparable in all three groups (AZA, 8.6%; MMF 2 g, 4.7%; MMF 3 g, 9.1%) by 3 years of follow-up.. MMF significantly reduced the incidence of rejection in the first 6 months, but there was not a significant improvement in graft survival throughout the 3 years after cadaver kidney transplantation.

Topics: Cadaver; Double-Blind Method; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Longitudinal Studies; Mycophenolic Acid; Survival Analysis

Topics: Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Survival Rate; Tissue Donors

Mycophenolate mofetil (MMF) has been shown to reduce the incidence of acute graft rejection in three controlled trials of cadaveric renal transplantation. In a U.S. trial using quadruple sequential induction therapy as control, the MMF 2-g treatment group had an acute rejection rate 40.6% lower than control in the first posttransplant year (27.9% MMF-treated versus 47.0% control). The purpose of this analysis is to evaluate the economic implications of these clinical differences. The analysis relies on resource use data from the trial and other sources. Medical costs were estimated using a societal perspective and excluded the cost of the transplant procedure and organ acquisition. The two groups were compared in terms of treatment for acute rejection and opportunistic infection, graft survival, dialysis use, and maintenance immunosuppression. The results suggest that, on average, when compared with standard therapy, patients treated with MMF are likely to have lower rejection-related treatment costs because of a lower incidence of rejection ($6237 versus $3702), lower dialysis and graft failure costs because of improved graft survival ($20,104 versus $16,972), no difference in opportunistic infection treatment costs ($1962 versus $1962), and higher additional immunosuppression costs ($855 versus $5170). Taken together, these results suggest that patients treated with MMF are, on average, likely to have slightly lower first-year costs ($29,158 versus $27,807) compared with control, indicating that MMF treatment is cost-effective in the first year. These results remained stable under sensitivity analyses, with plausible variation in the rates of acute rejection, graft survival, and infection.

Topics: Acute Disease; Azathioprine; Cadaver; Cost-Benefit Analysis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Opportunistic Infections; Time Factors

Mycopehenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multi-center trial to compare the efficacy and safety of MMF and azathioprine within standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3g group (P=0.0045) and 38.2 % in the MMF 2g group (P=0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1 %, 10.4% and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were tested for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. I

Topics: Adult; Aged; Azathioprine; Cadaver; Double-Blind Method; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies

Since the advent of cyclosporine-based immunosuppression for cadaveric kidney transplants in 1983, several changes have been made in immunosuppressive management at the University of Wisconsin. Since 1986, OKT3 has been available to treat steroid-resistant rejection; since 1992, OKT3 has been used as an induction agent replacing antilymphocyte globulin; and since 1993, mycophenolate mofetil has been used in 104 patients.. The impact of different immunosuppressive strategies on overall and immunologic graft survival (defined as graft loss caused by rejection) was evaluated in 1210 primary cadaveric renal transplants at the University of Wisconsin. Covariables, including degree of human leukocyte antigen matching, age, gender, cause of kidney failure, and early graft dysfunction, were evaluated. The series was subdivided into four eras according to immunosuppressive regimen, and the results were analyzed by era.. Our principal findings are that immunologic graft survival has improved significantly during this series whereas overall graft survival has not. Mycophenolate was associated with a significant decrease in acute rejection. For a given patient, graft loss from rejection becomes less likely over time. Late rejection poses a greater risk than early rejection for graft loss.. Improving outcomes may be related to improving immunosuppressive treatment, increasing degree of human leukocyte antigen matching, and better early graft function.

Topics: Adult; Age Factors; Antilymphocyte Serum; Cadaver; Cohort Studies; Cyclosporine; Demography; Evaluation Studies as Topic; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tissue Donors; Transplantation, Homologous

Mycophenolate mofetil (MMF), a new immunosuppressant that selectively inhibits proliferation of T and B lymphocytes, may reduce the frequency and severity of acute graft rejection. Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation. The purpose of this randomized, double-blind, multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation. A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were randomized to receive MMF 1.0 g b.i.d. (MMF 2 g treatment group), MMF 1.5 g b.i.d. (MMF 3 g treatment group), or azathioprine 1-2 mg/kg/day. CsA, corticosteroids, and antithymocyte globulin (ATGAM) were administered as part of a quadruple sequential induction protocol. The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason) during the first 6 months after transplant. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. The 495 patients who received study drug were included in the safety and secondary efficacy analyses. Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6% of patients in the azathioprine group compared with 31.1% (P = 0.0015) and 31.3% (P = 0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine (P = 0.0036) and MMF 3 g versus azathioprine (P = 0.0006). First biopsy-proven rejection alone occurred in 38.0% of patients who received azathioprine compared with 19.8% and 17.5% of patients who received MMF 2 g and 3 g, respectively. Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups (44.5%, 24.8%, and 21.1%, respectively). The use of antilymphocyte agents to treat rejection was greater in the azathioprine group (20.1%) compared with the MMF 2 g group (10.3%) and the MMF 3 g group (5.4%). At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Antilymphocyte Serum; Biopsy; Cadaver; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Treatment Failure

To assess the effect of pretransplant blood transfusions on the outcome of cadaveric kidney transplantation, a single-centre analysis was performed of 171 patients randomly assigned to receive no pretransplant transfusion (n = 85) or to receive at least three random blood transfusions (n = 86). After transfusion 18 of the latter patients developed circulating lymphocytotoxic T-cell antibodies, but the sensitization was only transient. At the time of transplantation, none was still sensitized. In both groups 60 patients have been transplanted. Patient and graft survival rates were significantly higher in the transfused group than in the non-transfused group. In the non-transfused patients the higher mortality was due to complications related to repeated anti-rejection therapy. Non-transfused patients had more repeated acute rejection episodes than the transfused patients. The present study indicates that pretransplant blood transfusions still facilitate graft acceptance even in the setting of good HLA matching and with cyclosporine as the basic immunosuppressant. The risk of sensitization is very low.

Topics: Adult; Blood Transfusion; Cadaver; Cyclosporine; Double-Blind Method; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Middle Aged; Mycophenolic Acid; Postoperative Complications; Preoperative Care; Survival Rate; Time Factors; Tissue Donors

Topics: Adult; Cadaver; Dose-Response Relationship, Drug; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Mycophenolic Acid

RS-61443, the morpholinoethyl ester of mycophenolic acid (mPA), is a potent, noncompetitive, reversible inhibitor of eucaryotic inosine monophosphate (IMP) dehydrogenases. Because of the importance of the guanosine and deoxyguanosine nucleotides in activating phosphoribosyl pyrophosphate (PRPP) synthesis and ribonucleotide reductase, respectively, it was postulated that depletion of GMP (and consequently GTP and GDP) would have antiproliferative effects on lymphocytes. Furthermore, since lymphocytes rely on de novo pruine synthesis whereas other cell types do not, antiproliferative effects produced in this way are more selective for lymphocytes than other cell types.

Topics: Adrenal Cortex Hormones; Cadaver; Drug Therapy, Combination; Enzyme Inhibitors; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Living Donors; Muromonab-CD3; Mycophenolic Acid; Tissue Donors

To describe the clinical outcome of allogenic simple limbal epithelial transplantation (alloSLET) utilising tissue from cadaveric donor eyes after failed re-epithelialisation of the corneal surface.. Medical records of 14 eyes from 14 patients treated for persistent corneal epithelial defects with alloSLET were reviewed. The primary outcome measure was complete epithelialisation of the corneal surface. Secondary outcome measures were best corrected visual acuity (BCVA) and postoperative side effects due to surgery or medical therapy.. Of the 14 eyes, 7 received alloSLET only and 7 alloSLET together with penetrating keratoplasty (PK). Thirteen (92.9%) of 14 eyes had an epithelialised corneal surface 3 and 6 months after surgery and 10 (71.4%) of 14 eyes displayed an epithelialised corneal surface 12 months after surgery. In both subgroups, alloSLET only and alloSLET with PK, respectively, 5 (71.4%) of 7 eyes had a stable corneal epithelium 12 months after surgery, respectively. Postoperatively, BCVA improved markedly in the whole patient collective. However, the increase was not significant when looking at the two individual subgroups. One patient lost his bandage contact lens several times within the first postoperative month and had a partial detachment of the amniotic membrane. The ocular surface of this patient failed to epithelialise. In three patients, limbal donor pieces translocated to the centre of the cornea, which possibly prolonged the improvement of BCVA.. AlloSLET appears to be an effective treatment option in eyes with non-healing corneal epithelial defects when autologous limbal tissue is not available.

Topics: Adult; Aged; Aged, 80 and over; Allografts; Cadaver; Corneal Diseases; Epithelium, Corneal; Female; Humans; Immunosuppressive Agents; Limbus Corneae; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Re-Epithelialization; Retrospective Studies; Tissue Donors; Treatment Outcome; Visual Acuity

In kidney transplantation, immunotherapy with thymoglobulin (rATG) has been used to down-regulate the patient immune system. rATG is a powerful immunobiologic drug used to deplete lymphocytes to prevent early acute rejection. The aim of this research was to evaluate the effects of immunotherapy by rATG on graft suvival during a 9-year period in kidney-transplanted patients with different immunological profiles.. A sample of 469 patients were allocated into four groups (G) based on immunological risk of rejection: G1, low risk, not sensitized recipients, solid-phase immunoassay with single antigen beads (SPI-SAB) < 10%; G2, medium risk I, sensitized recipients, SPI-SAB ≥ 10 < 50%; G3, medium risk II sensitized (SPI-SAB ≥50%); and G4, high risk, sensitized recipients, SPI-SAB- donor-specific antibody positive (DSA+). Only patients from G3 and G4 received immunotherapy.. Of 255 patients who received a kidney from a living donor (LD), 42 (16.47%) from all groups (G) had T-cell-mediated rejection (TCMR) and four (G1) lost their grafts, 8 (3.14%) had antibody-mediated rejection (AMR), and two lost their graft in G1 and G4. Of 214 patients who received a kidney from deceased donors (DD), 37 (17.29%) had TCMR with one lost graft in G1. AMR was shown in 13 (6.07%) patients, with three losses observed in G2. Statistical differences between the groups in the 9-year graft survival rate were found only in the comparison of G1 versus G2 (P = 0.005) and G2 versus G4 (P = 0.047) for DD. For LD, no statistical differences were found.. This clinical retrospective study shows that immunotherapy induction was associated with improvement of outcomes, graft function, and survival in patients treated with immunotherapy in comparison with patients who did not received induction therapy. These findings strongly suggest that immunotherapy should be used for all patients transplanted with kidneys from deceased donors.

Topics: Adult; Age Factors; Antilymphocyte Serum; Cadaver; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Immunotherapy; Kidney Transplantation; Living Donors; Maintenance Chemotherapy; Male; Methylprednisolone; Mycophenolic Acid; Retrospective Studies; Risk; Sex Factors; Sirolimus; Survival Rate; T-Lymphocytes; Tacrolimus; Time Factors; Treatment Outcome

Type 2 diabetes mellitus (DM) is the commonest cause of end-stage renal disease (ESRD) worldwide. Renal transplantation (RTx) is the best therapeutic modality for such patients. First-degree relatives of patients with type 2 DM have high risk of diabetes/pre-diabetes. Parents are often too old to be suitable donors, and siblings/children/spouse are either not suitable/acceptable or do not come forward for organ donation. This leaves deceased donation (DD) as only suitable donors. Data scarcity on DDRTx outcome in diabetic nephropathy (DN) prompted us to review our experience. This retrospective single-center 10-year study was undertaken to evaluate patient/graft survival, graft function, rejection episodes, and mortality in these patients.. Between January 2001 and March 2011, thirty-five DN-ESRD patients underwent DDRTx in our center following cardiac fitness assessment of recipients. All patients received single-dose rabbit-anti-thymocyte globulin for induction and steroids, calcineurin inhibitor, and mycophenolate mofetil/azathioprine for maintenance immunosuppression. Mean recipient age was 49.66 ± 6.76 years, and 25 were men. Mean donor age was 50 ± 16.45 years, 23 were men.. Over a mean follow-up of 2.28 ± 2.59 years, patient and graft survival rates were 68.5% and 88.5%, respectively, with mean SCr of 1.9 ± 0.62 mg/dl. Delayed graft function was observed in 34.3% patients, and 25.7% had biopsy-proven acute rejection; 31.5% patients died, mainly because of infections (22.8%), coronary artery disease (2.86%), and cerebrovascular events (5.7%).. DDRTx in patients with DN has acceptable graft function and patient/graft survival over 10-year follow-up in our center and, therefore, we believe it should be encouraged.

Topics: Adult; Aged; Antilymphocyte Serum; Azathioprine; Cadaver; Calcineurin Inhibitors; Creatinine; Delayed Graft Function; Developing Countries; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; India; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Steroids; Treatment Outcome

Over last several years, alemtuzumab induction has been increasingly used in kidney transplantation especially in patients maintained on steroid-free immunosuppression. It is unclear which induction agent is associated with better graft and patient outcomes in these patients.. Using Organ Procurement and Transplant Network/United Network of Organ Sharing database, graft and patient survivals were compared with multivariate analysis for deceased donor kidney transplant recipients from January 2000 to December 2008 who received induction with rabbit-antithymocyte globulin (r-ATG), alemtuzumab, or an interleukin-2 (IL-2) receptor blocker and were discharged on a calcineurin inhibitor/mycophenolate mofetil/steroid-free immunosuppression.. When compared with r-ATG (n=5348), adjusted graft survival was inferior with alemtuzumab (n=2428, hazards ratio [HR] 1.26, 95% confidence interval [CI] 1.10-1.43, P=0.001) and IL-2 receptor blocker (n=1396, HR 1.19, 95% CI 1.01-1.39, P=0.04) inductions and patient survival was inferior with alemtuzumab (HR 1.29, 95% CI 1.08-1.55, P=0.006). Alemtuzumab induction was associated with higher adjusted graft failure risks in patients with panel reactive antibody more than 20% (HR 1.30, 95% CI 1.01-1.68, P=0.04), recipients of expanded criteria donor kidneys (HR 1.58, 95% CI 1.23-2.02, P<0.001), and kidneys with cold ischemia time more than 24 hr (HR 1.31, 95% CI 1.04-1.65, P=0.02) and higher patient death risks in recipients of expanded criteria donor kidney (HR 1.66, 95% CI 1.20-1.30, P=0.002) and kidneys with cold ischemia time more than 24 hr (HR 1.44, 95% CI 1.04-2.00, P=0.03). Adjusted graft survival rates were similar for different induction agents in the low-immune risk group.. When compared with alemtuzumab and IL-2 receptor blocker, r-ATG induction seems to be associated with superior outcomes in deceased donor kidney transplant recipients maintained on calcineurin inhibitor/mycophenolate mofetil/steroid-free regimen.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Cadaver; Calcineurin Inhibitors; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Receptors, Interleukin-2; Steroids; Survival Rate; Treatment Outcome; Young Adult

The success of an immunosuppressive drug therapy depends on the extent of exposure to the drugs (the blood levels and duration), which is measured as the area under the curve (AUC). Tacrolimus shows considerable variability in its pharmacokinetics, with poor correlation between the tacrolimus trough level and systemic exposure, as measured by the AUC of concentration time. Monitoring trough levels helps not only in reducing nephrotoxiicity but also in reducing the chances of acute rejection; although there is no international consensus, the trough concentration is used to determine dosing and the AUC for calculating the exposure of the patient to the drug. The major objective of this study was to find the best sampling time for an abbreviated AUC0-6 (area under the concentration time curve) to predict the total body exposure to tacrolimus in adult renal transplantation recipients.. The study involved retrospective analysis of 14 renal transplant patients (2 female and 12 male) that were on triple immunosuppressive therapy, methyl prednisolone, mycophenolate mofetil and tacrolimus. To determine trough concentrations, blood samples were collected before administration of tacrolimus (0 h) and at fixed time points of 2 h, 4 h and 6 h after administration of oral tacrolimus and analyzed in duplicate by microparticle enzyme immunoassay. AUC0-6 was determined using the linear trapezoidal rule. The association between the blood concentration and AUC6 were evaluated by the Pearson correlation coefficient. All statistical analyses were performed using the SPSS software (IBM Corp., NY, USA) program.. Trough levels were fairly consistent at 7.9-18 ng·h/mL in all the patients included in this study, and this did not show variation with age or sex. The AUC0-6 was higher [202-290 ng/mL at 3-8 mg bis-daily (b.d.) dosage] in patients who received kidneys from cadavers compared to recipients from live donors (60.5-171 ng/mL at 3-8 mg b.d. dosage), but the clinical significance of this is not known. The highest AUC0-6 was 246 ng/mL, observed at 4.5 mg b.d. dosage. Dosages higher than 2 mg b.d. did not result in a noticeable increase in AUC0-6. Peak blood levels of tacrolimus were obtained 4 h after administration.. Trough level determination and a C2, C4 two-point limited sampling strategy may be useful to plan the dosing strategy and estimate the exposure of renal transplant patients to tacrolimus.

Topics: Administration, Oral; Adult; Area Under Curve; Cadaver; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

In our Universitary Hospital of Canarias we iniciated in May 2008 a induction therapy protocol for sensitized patients receiving cadaveric renal graft using intravenous immunoglobulins, plasmapheresis and rituximab plus immunosuppression with prednisone, tacrolimus and mycophenolate mofetil. We present the results of four patients. Everyone had anti-HLA antibodies rate (PRA by CDC) more than 75%, were on a waiting list during 4 to 17 years and follow-up time was 10-14 months after transplantation. Patient and graft survival in this period was 100%. Only one patient suffered a humoral acute rejection and another one cellular rejection, in both cases reversible with treatment. During the first year, no evidence of de novo donor-specific antibodies was detected. All patients had significantly reduced the CD19+ cells percentage after infusion of rituximab. Neurological symptoms suggestive of progressive multifocal leukoencephalopathy or serious viral infections after transplantation have not been observed. Additionally, no immediate side effects were observed after administration of medication. In summary, induction therapy by combining immunoglobulin, plasmapheresis and rituximab in hypersensitive patients allows the realization of deceased kidney transplantation with good results in the short and medium-term without serious side effects. It remains to know whether this success will continue in the long term.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cadaver; Combined Modality Therapy; Female; Graft Rejection; Histocompatibility; HLA Antigens; Humans; Immunization; Immunoglobulins, Intravenous; Immunosuppressive Agents; Isoantibodies; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Plasmapheresis; Prednisone; Premedication; Reoperation; Rituximab; Tacrolimus; Tissue Donors

Mycophenolate mofetil (MMF) is routinely used at a fixed dose, but several factors interact to alter the blood level of mycophenolic acid (MPA), resulting in toxicity or treatment failure.. From January 2007 to December 2008, 85 kidney transplantation patients were given a fixed dose of 1.5 g/d of MMF in 12-hour intervals. MPA trough levels were measured on postoperative 1 week, 1 month, 3 months, 6 months, and 12 months.. Mean age of patients was 41 years. Thirty five cases were deceased donor kidney transplantations and 50 were living donor kidney transplantations. Mean trough levels of MPA were 1.04 microg/mL, 1.09 microg/mL, 1.28 microg/mL, 1.83 microg/mL, and 1.69 microg/mL at postoperative 1 week, 1 month, 3 months, 6 months, and 12 months, respectively. Mean trough levels of the subgroup of patients taking cyclosporine were 0.82 microg/mL, 0.94 microg/mL, 1.01 microg/mL, 1.56 microg/mL, and 1.46 microg/mL (n=36). Mean trough levels of the subgroup of patients taking tacrolimus were 1.19 microg/mL, 1.21 microg/mL, 1.56 microg/mL, 2.13 microg/mL, and 2.20 microg/mL (n=49). At 12 months, 31% of all patients experienced one or more opportunistic infections. Eight patients (9.4%) had cytomegalovirus infections, 14 patients (16.5%) had polyomavirus infections, and four patients (4.7%) had parvovirus infections. Ten patients (11.8%) experienced biopsy-proven acute rejection during the follow-up period.. Mean MPA trough levels of patients on 1.5 g/d of MMF reached 1.0 microg/mL within 1 week. Thirty one percent of patients experienced opportunistic infections, and 11.8% of patients had biopsy-proven acute rejections.

Topics: Adult; Cadaver; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Opportunistic Infections; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P=.000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates.

Topics: Adult; Cadaver; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Endemic Diseases; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Korea; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Tissue Donors

Three randomized-controlled trials have examined the utility of mycophenolic acid (MPA) therapeutic drug monitoring in kidney transplant recipients. Each used a different methodology to estimate MPA exposure (predose concentrations [C(0)], multiple regression-derived limited sampling strategies [LSSs], and Bayesian estimation in Opticept, FDCC [fixed dose versus concentration controlled] and APOMYGERE [adaption de Posologie du MMF en Greffe Renale] trials, respectively). Results were conflicting. This study aimed to compare the ability of these methodologies to predict AUC(0-12) in an independent cohort of kidney transplant recipients.. Sixty-nine full AUC (AUCf) profiles were collected from 45 subjects. C(0) and AUC(0-12) predicted by the LSSs and Bayesian estimation (AUCp) were compared with AUCf.. Correlation between C(0) and AUCf was poor. There was better correlation between LSSs and AUCf, and correlation was higher again between Bayesian estimates and AUCf. Bias and precision associated with the LSS and Bayesian-forecasting methods fell close to the level considered acceptable in clinical studies (<15%). However, neither method quite achieved this, and regardless of whether LSSs or Bayesian forecasting were applied, only 45% to 47% of AUCp values fell within 15% of AUCf. Discordance between C(0) and AUCp and AUCf occurred in 15% to 27% of cases.. This study highlights the difficulties of MPA therapeutic drug monitoring. Bayesian estimations showed slight superiority over C(0) and LSS predictions, suggesting that this may be the preferable methodology.

Topics: Adult; Anti-Bacterial Agents; Area Under Curve; Bayes Theorem; Cadaver; Cyclosporine; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Randomized Controlled Trials as Topic; Sampling Studies; Tissue Donors

IL2 receptor antagonist (IL2ra) induction therapy has gained favor due to an excellent safety profile and improved outcomes in randomized trials using cyclosporine-based immunosuppression. However, there have been no large randomized trials or retrospective analyses examining the effect of IL2ra versus no induction using tacrolimus and mycophenolate (TAC/MPA)-based therapy.. A retrospective analysis from the Scientific Renal Transplant Registry of adult, primary kidney transplant recipients from 2000 to 2008 with initial immunosuppression of TAC/MPA and prednisone, who received IL2ra induction therapy or no induction therapy (n=28,686) was performed. The primary outcome was acute rejection at 1 year, and secondary outcomes were graft and patient survival at 1 and 3 years. Multivariable analysis was used to control for factors shown to influence the incidence of acute rejection, and separate analyses were performed for deceased versus living donors.. Acute rejection at 1 year was significantly lower with IL2ra (11.6%) versus no induction therapy (13.0%; P=0.001). One-year (95.7% vs. 95.8%) and 3-year (87.5% vs. 87.8%) graft survival, and 1-year (97.4% vs. 97.5%) and 3-year (92.8% vs. 93.2%) patient survival, was not different between those receiving IL2ra and no induction therapy. On multivariable analysis, the relative risk of acute rejection with IL2ra was 0.90 (95% CI, 0.85-0.96; P=0.001), and the effect was greater in living donors (relative risk, 0.82; P<0.001) than deceased donors (relative risk, 0.95; P=0.23).. The benefit of IL2ra induction with TAC/MPA/prednisone maintenance immunosuppression is less than previously reported due to a low baseline incidence of acute rejection.

Topics: Adult; Cadaver; Cohort Studies; Female; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prednisone; Registries; Retrospective Studies; Tacrolimus; Tissue Donors

Registry analyses suggest that tacrolimus (TAC)/mycophenolate (MPA) immunosuppression is associated with superior kidney graft survival versus TAC/sirolimus (SRL). Large single-center experience can assist in clarifying these findings, by examining outcomes related to specific utilization practice.. We retrospectively examined the outcomes of 518 consecutive first renal transplants at a single center treated with TAC/SRL (n=307) or TAC/MPA (n=211) with prednisone. Graft and patient survival, acute rejection, and 1-year glomerular filtration rate (GFR) were analyzed by era of transplant (2000-2002 vs. 2003-2006). Changes in TAC/SRL utilization between eras included elimination of the SRL loading dose and a reduction in TAC target trough concentrations.. Three-year graft survival with TAC/SRL was lower when first used (2000-2002) because of a higher incidence of patient death, primarily due to cardiovascular causes. Survival improved from 85.3% to 95.9% between 2000 to 2002 and 2003 to 2006 (P=0.001), with comparable graft and patient survival between TAC/SRL and TAC/MPA cohorts, confirmed following multivariable analysis controlling for donor and recipient factors. Rates of BK virus and acute rejection were comparable, but a higher incidence of hyperlipidemia, anemia, posttransplant diabetes, and a lower 1-year GFR (57.6 vs. 63.1 mL/min, P=0.008) was noted in the TAC/SRL cohort.. These data, as the largest long-term single-center report comparing TAC/SRL with TAC/MPA in kidney transplantation, demonstrate worse patient survival initially with TAC/SRL, with improved outcomes in a later era that were temporally associated with reduced TAC exposure. Differences in cardiovascular risk factors and 1-year GFR highlight the need for further investigation of the optimal utilization of SRL in kidney transplantation.

Topics: Adult; Cadaver; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate; Tacrolimus; Tissue Donors

To clarify the demographic data, outcomes and complications of renal transplantation in children at Srinagarind (university) Hospital.. The authors reviewed the medical records of children with end-stage renal disease (ESRD) who received renal transplantation at Srinagarind Hospital, Khon Kaen, between August 2001 and July 2008.. Eight male and seven female patients were identified Their mean age was 12.8 +/- 3.2 years (range, 5.0-17.6). The major cause of ESRD was a congenital anomaly of the kidneys (53%). All of the children received cadaveric transplantations and none received induction therapy. Triple immunosuppressive drugs comprising cyclosporine, prednisolone and mycophenolate mofetil were administered to 12 patients. Tacrolimus, instead of cyclosporine, was given to three patients who had received a renal transplant since January 2008. The median follow-up time was 15 months (3 to 82 months). The most frequent complication was urinary tract infection (40%). Acute graft loss was found in one patient (6.7%) due to graft infarction. Other complications included herpes viral infection, chronic rejection, acute rejection, severe gingival hyperplasia, myopathy, lymphocele and transitional cell carcinoma of the bladder. Two patients returned to dialysis due to graft infarction and chronic rejection, respectively. The mean serum creatinine at the last follow-up of the remaining cases was 1.2 +/- 0.5 mg/dL (range, 0.6-2.3). All of the patients survived. The 1- and 5-year graft survival rates were 93.3% and 86.7%, respectively.. The present study demonstrates the potential for successful outcomes of pediatric renal transplantation in this resource-limited area.

Topics: Adolescent; Age Factors; Cadaver; Child; Child, Preschool; Cyclosporine; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Intensive Care Units, Pediatric; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Retrospective Studies; Tacrolimus; Thailand

To assess the significance of antibodies detected by complement-dependent cytotoxicity (CDC), solid phase (SPA) and flow cytometry (FC) assays we compared their predictive value in 354 consecutive cases of deceased-donor kidney transplantation. Pre-transplantation screening of anti-HLA class I and class II antibodies was performed by CDC and SPA. The direct crossmatch between recipients' sera and donors' T and B cells was performed by CDC followed by FC and SPA ("virtual cross-match"). The past history of antibodies displayed by the recipient was not considered a contraindication for transplantation even when it showed DSA. A side-by-side comparison of the correlation between graft loss, history of DSA and cross-match results indicated that sensitivity was 5%, 16% and 17% while specificity was 99%, 93% and 86% in CDC, SPA, FC crossmatches respectively. There was no significant difference between the 3 year survival of primary and secondary kidney allografts. We conclude that screening and cross-matching the sera by CDC provides reliable results and optimizes the patient's chances to receive a transplant. SPA and FC, however, are of great importance for identifying patients which require close monitoring by biopsy and serology for early diagnosis and treatment of acute antibody mediated rejection (AAMR).

Topics: Adrenal Cortex Hormones; Adult; Aged; Cadaver; Cytotoxicity Tests, Immunologic; Female; Flow Cytometry; Graft Rejection; Graft Survival; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Histocompatibility Testing; Humans; Immunosuppression Therapy; Isoantibodies; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Predictive Value of Tests; Sensitivity and Specificity; Tacrolimus

Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis readily relapses after renal transplantation; the recurrence often causes graft losts. We have reported herein a 53-year-old cadaveric renal allograft recipient. His original disease was ANCA-associated microscopic polyangiitis (MPA), which was proven by renal biopsy. On postoperative day 4, the patient developed dyspnea, hemoptysis, and gross hematuria; the serum p-ANCA titer increased from 1:40 to 1:80. The patient was immediately treated with 5 sessions of plasma exchange. Five days later, the hemoptysis and gross hematuria both disappeared. Serum p-ANCA titer recovered to 1:40. The patient showed stable graft function for 2 months, until mycophenolate mofetil (MMF) was converted to mizoribine (150 mg/d). Seven days after the conversion, the serum creatinine increased from 1.27 to 1.7 mg/dL. Serum p-ANCA increased to 1:160. When mizoribine was converted to MMF, 2 days later the renal function and p-ANCA titer recovered. This case report suggested that early use of plasma exchange combined with MMF was effective to prevent the relapse of ANCA-associated systemic vasculitis after transplantation, and may be helpful to improve transplant outcomes.

Topics: Antibodies, Antineutrophil Cytoplasmic; Cadaver; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Plasma Exchange; Tissue Donors; Vasculitis

The purpose of this study was to describe the initial experience with alemtuzumab as induction followed by steroid-free immunosuppression in kidney transplantation.. One hundred patients who received renal transplants from living and deceased donors were followed for a median period of 12 months (range = 1 to 12). A 30-mg intravenous dose of Alemtuzumab was administered on the transplant day, preceded by a 500-mg methylprednisolone dose. Maintenance immunosuppression consisted in the use of a calcineurin inhibitor in association with mycophenolic acid. Maintenance C2 levels of cyclosporine were between 400 and 600 ng/dL; or of tacrolimus, between 4 and 7 ng/dL. Prophylaxis included valgancyclovir, trimethoprim-sulfamethoxasole, and nystatin. All patients were evaluated for acute rejection episodes, adverse events, or death.. The cumulative incidences of acute rejection at 1, 3, 6, and 12 months were 0%, 4% (n = 4), 5% (n = 5), and 8% (n = 8), respectively. Most episodes were Banff 1 a or b (88%). The infectious complication rate was 23%. There was no case of cytomegalovirus infection or posttransplant lymphoproliferative disease. Three patients died: one due to tuberculosis; one, sepsis; and one, an acute coronary event. No patient was lost to follow-up.. This study suggested the safety and efficacy of Campath-1H as an induction agent in renal transplant recipients.

Topics: Adolescent; Adult; Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Cadaver; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Tissue Donors

The association of tacrolimus (TAC) and mycophenolate mofetil (MMF) in renal transplant patients has diminished the incidence of acute rejection. We evaluated the use of generic TAC and MMF as primary immunosuppression in 6 living related (LR) and 11 cadaveric (C) donor renal transplant recipients (9 men, 8 women) of mean age 37 +/- 12 years (range, 17-56 years) between May 2006 and June 2007. From day 0 all patients received TAC, MMF, and prednisone without antibody induction. They were followed for the development of acute rejection, graft loss, side effects, and mortality. Mean follow-up was 7.6 months (range, 2-15 months). No biopsy-proven acute rejection episodes, graft loss, or recipient deaths were observed. Creatinine levels at the end of the study were 1.90 +/- 1.0 mg/dL (range, 0.62-4.25 mg/dL for C recipients and 1.19 +/- 0.15 mg/dL (range, 0.91-1.35 mg/dL) for LR recipients. Mean systolic and diastolic blood pressures were 130/73 mm Hg with 12 patients (70.5%) on antihypertensive therapy with calcium antagonists and beta-blockers. Mean (range) of total cholesterol, triglycerides, and glucose were 172 (110-244) mg/dL, 139 (69-277) mg/dL, and 89 (63-129) mg/dL, respectively. MMF was suspended in 1 patient due to diarrhea and 1 other because of leukopenia. We observed that generic TAC and MMF yielded effective and safe immunosuppression in terms of mortality, biopsy-proven acute rejection, and graft loss with a low incidence of adverse effects during the study period.

Topics: Adult; Cadaver; China; Drug Administration Schedule; Drug Therapy, Combination; Drugs, Generic; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Prednisone; Survival Analysis; Tacrolimus; Tissue Donors

The aim of this study was to compare the graft survival after kidney transplantation in patients treated with azathioprine (AZA) or mycophenolate mofetil (MMF) and analyze the significance of different risk factors for graft survival.. A total of 137 patients, transplanted between January 1996 and June 2001, were retrospectively divided into two groups: patients who received AZA together with cyclosporine A and methylprednisolone (AZA group, n=72) and patients who received MMF either immediately or were switched from AZA to MMF during 3 months (MMF group, n=65).. According to Kaplan-Meier analysis, a 1-year graft survival was 79% in the AZA group and 85% in the MMF group; a 6-year graft survival was 51% and 67%, respectively (P=0.046). Multivariate Cox survival model demonstrated that MMF therapy reduced the risk of graft loss by 34% (P=0.028), while delayed graft function increased the risk of graft loss (risk ratio 2.26, P=0.009). A statistically significant difference in total cholesterol level (6.7 vs. 5.7 mmol/L, respectively; P=0.002), mean systolic blood pressure (145 vs. 134 mmHg, P=0.009), and cyclosporine A daily dose (238 vs. 203 mg, P=0.015) between the AZA and MMF groups at 1 year was revealed.. MMF rescue therapy improves the long-term graft survival compared to AZA despite high early rejection rate and avoids the negative impact of acute rejections on graft survival.

Topics: Adult; Azathioprine; Cadaver; Case-Control Studies; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Retrospective Studies; Risk Factors; Time Factors; Tissue Donors

This study was designed to investigate the relationship between clinical events and the pharmacokinetics of mycophenolic acid (MPA) in adult renal transplant patients.. Thirty-seven adult kidney transplant recipients received a cyclosporine, mycophenolate mofetil, and steroids. MPA-AUC(0-12) was obtained before and 12 days after grafting by RP-HPLC. Predose blood samples were measured for MPA-C(0) were gathered from all the recipients at 4, 12, and 21 days as well as 1, 1.5, 2, 2.5, 3, and 6 months after grafting. The clinical events at corresponding time points were recorded to correlate with each MPA-C(0) value.. In addition to single-dose and multidose MPA-AUC(0-12), 357 MPA-C(0) values were obtained from 37 patients. The 357 units were divided into three subgroups: group A patients, including 239 units (66.9%), experienced uneventful outcomes; group B of 100 units (28.0%) showed MPA-related side effects, and group C, 18 units (5.0%) of acute rejection episodes. MPA-C(0) for groups A, B, and C were 0.8416 +/- 0.1373 mg/L, 1.5903 +/- 0.3741 mg/L and 0.6057 +/- 0.2338 mg/L, respectively (P < .001 between groups A and B, groups B and C, and P = .021 between groups A and C). The three groups were also divided into an initial phase (< or =1 month, 251 units) and a stable phase (>1 month, 106 units). The relationship between MPA-C(0) and associated clinical events was also investigated.. Our results suggested a relationship between MPA pharmacokinetics and clinical events. The MPA-C(0) might be an appropriate pharmacokinetic monitoring parameter for kidney transplantation.

Topics: Adolescent; Adult; Cadaver; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; ROC Curve; Tissue Donors

In order to evaluate whether immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine would differently influence the outcome of the renal transplants, we prospectively analyzed the incidence of acute rejection episodes, cytomegalovirus infection within the first 6 months following renal transplantation and 5 yr graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. There was no significant difference in sex, HLA mismatch, cold ischemic time, and patients' weight between the two groups. Contrary to the previous studies which demonstrated that MMF could lower the incidence of acute rejection episodes and improved graft survival rate, the two groups showed no significant difference in the incidence of acute rejection episodes and 5-yr graft survival rate as well. This discrepancy in these results might explain that donor factors could be important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical studies of cadaveric renal transplantation.

Topics: ABO Blood-Group System; Adult; Azathioprine; Body Weight; Cadaver; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunophenotyping; Immunosuppressive Agents; Ischemia; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Tissue Donors; Treatment Outcome

Early adequate cyclosporine exposure has been shown to predict low acute rejection rate in kidney transplantation. The aim of this study is to determine the importance of exceeding the early cyclosporine therapeutic exposure threshold with basiliximab induction. A retrospective analysis of 166 first cadaveric and non-identical live donor transplant recipients treated with or without basiliximab induction, Neoral, mycophenolate mofetil and prednisone, was performed. Adequate exposure was defined as a 2-h post-Neoral dose cyclosporine level (C2) >1700 ng/mL at day 3. The primary outcome was acute rejection within the first 6 months. In the no basiliximab (control) group (n = 74), rejection occurred in 23% (17 of 74) of recipients and was strongly associated with low cyclosporine exposure on day 3. Acute rejection occurred in 38% (11 of 29) with C2 <1700 ng/mL compared with 13% (six of 45) with C2 >/=1700 ng/mL (p = 0.014). In the basiliximab group (n = 92), rejection occurred in only 11% (10 of 92) of recipients and did not correlate with cyclosporine exposure. Acute rejection occurred in 10% (four of 40) with C2 <1700 ng/mL compared with 12% (six of 52) with C2 >/=1700 ng/mL (p = 0.81). Therefore achieving cyclosporine therapeutic targets by day 3 may not be required when anti-IL2 receptor antibody induction is used.

Topics: Acute Disease; Antibodies, Monoclonal; Basiliximab; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Retrospective Studies

Although most of the published papers had not found increase in the incidence of CMV disease in kidney transplant recipients treated with mycophenolate mofetil (MMF), we had feeling from everyday practice that after its introduction number of patients with CMV disease has increased. To test this hypothesis, we performed retrospective analysis of our database, comparing the incidence of CMV disease in patients treated with azathioprine (AZA) and patients treated with MMF. CMV disease was defined as CMV antigenemia (positive CMV pp65 determined by ELISA test) plus any of the following: decrease leucocytes or platelets, increased transaminases, increase in serum creatinine. The azathioprine treated group (AZA group) included 280 patients (132 female) treated for 17,672 months with AZA + Cyclosporine A (CyA) + steroid, or AZA + steroid, while the MMF group included 219 patients (112 female) treated for 5079 months with MMF + CyA + steroid, or MMF + steroid. There was no difference in acute rejection episodes between the AZA and the MMF group. The AZA group had 51 CMV disease episodes (1 episode per 346.5 treatment months), and the MMF group experienced 43 episodes (1 per 118.1 months) (P < .01). Mean onset of CMV disease was 32.65 +/- 47.69 (SD) months after transplantation in the AZA group, and 3.72 +/- 4.43 in the MMF group. There was no difference between two treatment groups regarding the donor-recipient CMV status mismatch. Despite having the increased incidence of CMV disease, MMF group had less severe disease compared to AZA group with decrease in leukocyte count in 11.6% vs 15.7% of episodes, decrease in platelet count in 20.9% vs 21.6%, elevation of transaminases in 18.6% vs 29.4% respectively, and finally increase in serum creatinine greater than 20% in 51.2% in MMF vs 74.5% in AZA group. Five patients from the AZA group experienced CMV pneumonitis with the mortality rate of 80%. Only one patient from the MMF group had CMV pneumonitis, and he survived. According to our results, patients treated with MMF have increased risk for development of CMV disease. However, the disease course is less severe, and less frequently accompanied with deterioration of renal function in comparison to the AZA group.

Topics: Adrenal Cortex Hormones; Azathioprine; Cadaver; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Time Factors

HLA mismatches have a strong impact on acute rejection and renal allograft survival. The objective of this study was to evaluate the effectiveness of antibody induction according to the degree of HLA mismatches.. Of 20,429 deceased donor (DD) transplantations and 12,859 living donor (LD) transplantations reported to the United Network for Organ Sharing (UNOS) between 1999 and 2001, 51% of DD and 45% of LD transplant recipients received induction therapy. Propensity scores (PS) were calculated to indicate independent factors associated with the use of induction. Levels of HLA match examined for DD transplant recipients were 0 ABDR (n = 3239), 0 DR (n = 4210), and DR mismatched transplants (n = 12,980), and 0 (n = 1133), 1 (n = 3836), and 2 (n = 7890) haplotype mismatches for LD transplant recipients. Outcome parameters were reported as hazard ratios (HR) for graft loss and odds ratios (OR) for first-year acute rejection.. Recipients with HLA mismatches were more likely to receive induction antibody for DR mismatch in DDs (PS = 1.11, 95% confidence interval [CI] 1.04-1.19) and for haplotype mismatch in LDs (PS = 1.36, 95% CI 1.22-1.52). Induction reduced the likelihood of acute rejection for DD transplant recipients regardless of the level of HLA mismatch (OR = 0.70; 95% CI 0.57-0.85 in 0 ABDR MM; OR = 0.76, 95% CI 0.64-0.89 in 0 DR MM; and OR = 0.69, 95% CI 0.62-0.77 in DR MM), and for 2 haplotype mismatched LD transplant recipients (OR = 0.82, 95% CI 0.70-0.96); in other LD transplant recipients, reductions in acute rejection rates were observed but not statistically significant. Induction reduced the risk of graft loss for DR mismatched DD transplant recipients by about 12% (HR = 0.88; 95% CI 0.80-0.97).. Antibody induction resulted in a significant reduction of acute rejection and graft loss for patients with HLA mismatch.

Topics: Antibody Formation; Cadaver; Graft Rejection; Histocompatibility Testing; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Multivariate Analysis; Mycophenolic Acid; Odds Ratio; Regression Analysis; Tissue Donors; Treatment Failure

Acute rejection is a major problem in kidney transplantation. To reduce its likelihood, we investigated the efficacy and safety of an immunosuppressive regimen including tacrolimus, basiliximab, mycophenolate mofetil, and low-dose steroids.. Fifty-seven patients, including 14 pediatric patients, were enrolled in this study. The mean age at the time of transplantation was 33.5 years, and the mean observation period was 8.2 months. The mean trough concentrations of FK at 1, 6, and 12 months posttransplant were 10.2, 6.6, and 6.0 ng/mL, respectively.. All recipients survived without graft loss. The cumulative incidence of acute rejection in adults was 2.3% and 8.4% at 6 and 12 months posttransplant, respectively. Of the adverse events, 11 recipients (19.3%) were positive for CMV antigenemia or had CMV infections. Four recipients (7.0%) exhibited mild hyperglycemia.. Our immunosuppressive regimen demonstrated favorable results, reducing the incidence of acute rejection without causing severe adverse events, especially in adults.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Cadaver; Child; Child, Preschool; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Living Donors; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Tacrolimus; Tissue Donors

We evaluated the influence of different immunosuppressive regimens on delayed renal graft function and progression of renal function in the first year after transplantation.. Patients were divided into four groups according to the immunosuppressive regimen received: (1) rapamycin (Rap) + mycophenolate mofetil (MMF) + methylprednisolone (MP) + daclizumab (Dmab); (n = 44); (2) tacrolimus (Tac) + MMF + MP + Dmab (n = 39); (3) cyclosporine (CsA) + MMF + MP + basiliximab (Bmab); (n = 30); (4) antithymocyte globulin (ATG) + MMF + MP and CsA after ATG withdrawal (n = 40). Data were analyzed using ANOVA and linear regression. Delayed graft function was defined as the need for hemodialysis posttransplantation.. There were no statistically significant differences between the four groups in terms of gender, time on dialysis before transplantation, histocompatibility, donor age, and cold ischemia time. However, age (49.8, 50.4, 49.8, and 43.5 years, P < .05), panel reactive antibodies (22%, 39%, 27%, 34%, P < .05) and time of delayed graft function (12, 7, 3, 6 days, P < .05) were significantly different between the four groups. The time of delayed graft function depended on the immunosuppressive regimen, as well as donor and recipient age (P < .05). The creatinine clearance demonstrated a statistically significant difference between the four groups in the first month after transplantation (45, 46, 61, 53 mL/min, P < .05), though no further difference was observed at the month 12th.. The type of immunosuppressive therapy seems to substantially influence the time of recovery from delayed renal graft function, even though it does not seem to affect future graft function. Especially Rap, probably due to its potent antiproliferative effects, seems to prolong the length of graft recovery after renal transplantation.

Topics: Adolescent; Adult; Analysis of Variance; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Cadaver; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Regression Analysis; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

Living donors represent 30% of our kidneys for renal transplantation. Laparoscopic nephrectomy is the best surgical procedure to obtain them due to its clear advantages such as low morbidity, less blood supply and donor time in hospital. From March 2002 to August 2004 we performed 50 laparoscopic nephrectomies for renal transplantation. Kidneys were transplanted to recipients receiving tacrolimus 0.1 mg/kg/bid, mycophenolate mofetil 1 g/bid and prednisone 0.5-1 mg/kg/day p.o 48 hours before transplantation. Mean time for surgery was 170 minutes (120-260), warm ischaemia time 3.1 minutes (1.5-10) and cold ischaemia time 1.27 hours (0.85-4). Mean bleeding was 270 cc (100-900) and donor time in hospital 5.5 days (3-9). Four cases required conversion of the laparoscopic procedure to open surgery because of bleeding. 72 hours post-transplant mean plasmatic creatinine was 170 micromol/l. None of the patients suffered delayed graft function. 18% presented acute rejection. Survival of donor and recipient was 100% at 1 year and graft survival was 94% at 1 year (kidney losses were due to acute rejection, severe acute pancreatitis and surgical problem).

Topics: Anti-Inflammatory Agents; Cadaver; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Laparoscopy; Length of Stay; Living Donors; Middle Aged; Mycophenolic Acid; Nephrectomy; Prednisone; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p<0.001) and death-censored graft survival (p<0.001) as compared to TAC/MMF (N=27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI=1.32, 1.63) and for CsA/SRL 1.38 (95% CI=1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5-12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.

Topics: Adolescent; Adult; Aged; Cadaver; Child; Child, Preschool; Clinical Trials as Topic; Cohort Studies; Databases as Topic; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Living Donors; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Proportional Hazards Models; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Transplantation Conditioning; Treatment Outcome

The anti-allograft immune response may have a cellular and a humoral component. Lymphocytotoxic antibodies (Ab) and anti-human leucocyte antigen (HLA) Ab present before kidney transplantation carry an enhanced risk of acute rejection. Current immunosuppressive drugs act predominantly upon the cellular immune pathway which may leave unopposed the humoral mechanisms of anti-allograft response. We studied the production of lymphocytotoxic Ab and anti-HLA Ab after kidney transplantation under different drug therapies. Two hundred and sixty-four consecutive kidney transplant recipients treated with different immunosuppressive drugs, either stable and or with previous acute rejection or acute urologic obstruction, entered this study. Lymphocytotoxic Ab and anti-HLA Ab were evaluated by complement-dependent cytotoxicity and by ELISA. Ab donor-specificity was determined by flow cytometry. Both lymphocytotoxic Ab and anti-HLA Ab were significantly increased in acute rejection whatever the immunosuppressive regimen and almost significantly in urologic obstruction treated with azathioprine (AZA) groups. The presence of antidonor-specific Ab was associated with a significantly higher rate of graft loss. Mycophenolate mofetil (MMF) therapy significantly down-regulated Ab synthesis in all patients groups when compared with AZA. The development of humoral antidonor response post-transplantation is associated with a dismal graft prognosis. This is the first report that acute urologic obstruction may be followed by unspecific lymphocytotoxic and anti-HLA Ab synthesis, surmising that a protracted obstruction may promote renal fibrosis through antibody mediation. The significant down-regulation of the humoral response by MMF when compared with AZA may herald a lower risk to mount a chronic rejection process.

Topics: Acute Disease; Antibody Formation; Antilymphocyte Serum; Azathioprine; Cadaver; Down-Regulation; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Mycophenolic Acid; Risk Factors; Urologic Diseases

Mycophenolate mofetil (MMF) is an immunosuppressant that is widely used for prophylaxis of rejection in solid organ transplantation. In this study, we examined the effect of renal insufficiency on the pharmacokinetics of MMF, particularly on the free fraction of drug in renal transplant patients. Our study was performed on 10 patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min), and 10 control patients with preserved renal function (CrCl >90 mL/min). All the patients had received a cadaveric donor graft at least 1 year prior and were clinically stable under treatment with MMF and cyclosporine. For each patient, we determined 12-hour areas under the curve (AUC(0-12 h)) for the metabolites: mycophenolic acid (MPA), 7-O-mycophenolic acid glucuronide (MPAG), and the free non-protein-bound fraction of MPA (f-MPA). The two groups were matched for age, sex, and MMF dose. Mean AUC(0-12 h) values for MPA were similar in both groups. The renal insufficiency group showed a significantly increased AUC(0-12 h) for MPAG (1550 +/- 392 vs 3527 +/- 1130 microg.h/mL, P < .001) and increased trough and AUC(0-12 h) values for f-MPA (0.023 +/- 0.02 vs 0.094 +/- 0.07 microg/mL, P = .003, and 0.87 +/- 0.3 vs 1.52 +/- 0.8 microg . h/mL, P = .016, respectively). We proposed that these differences should be taken into account when deciding upon the dose of this drug for the subset of patients with impaired transplant function.

Topics: Area Under Curve; Biotransformation; Cadaver; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Tissue Donors

Though mycophenolate mofetil has markedly reduced the incidence of acute rejection in renal transplantation, a significant improvement in graft survival has been more difficult to demonstrate. This retrospective study compares an historical control group of 210 consecutive renal transplant patients, who had received ATG induction associated with cyclosporin, prednisolone and azathioprine, with 187 patients receiving mycophenolate instead of azathioprine. The incidence of acute rejection was decreased with mycophenolate. In rejection-free patients, the 3-year graft survival rates were equivalent. In contrast, graft survival at 3 years improved significantly for patients who experienced a rejection crisis and remained under the initial triple drug regimen with mycophenolate compared to the patients of the historical group who were kept on azathioprine after a rejection episode. In conclusion, mycophenolate mofetil is not only able to reduce the incidence of acute rejection but could also improve the prognostic significance of acute rejection crises.

Topics: Adult; Azathioprine; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Survival Analysis; Time Factors

Topics: Adult; Area Under Curve; Cadaver; China; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Selection; Retrospective Studies; Tissue Donors

To evaluate the association between a regimen of cyclosporine microemulsion (CsA) + sirolimus (Rapa) treatment versus CsA and mycophenolate mofetil (MMF) and renal allograft survival, we analyzed 23 016 primary recipients reported to the Scientific Registry of Transplant Recipients between January 1, 1998 and July 26, 2003. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models correcting for demographic and clinical covariates were used to estimate the relative risks for CsA+Rapa versus CsA+MMF-treated patients reaching study endpoints. Subgroup analyses were conducted for recipient ethnicity and donor type. CsA+Rapa was associated with significantly lower graft survival (74.6% vs. 79.3% at 4 years, p = 0.002) and death-censored graft survival (83.7% vs. 87.2%, p = 0.003) compared to CsA+MMF. In multivariate analyses, CsA+Rapa was associated with a significantly increased risk for graft loss, death-censored graft loss and decline in renal function (HR = 1.22, p = 0.002; HR = 1.22, p = 0.018 and HR = 1.25, p < 0.001, respectively). Similar results were obtained in recipient ethnicity and donor type subgroups. In summary, CsA+Rapa was associated with significantly worse graft survival and death-censored graft survival compared to CsA+MMF, and likely reflects full-dose CsA +Rapa. Outcomes regarding alternative strategies of Rapa utilization with reduced CsA, with alternative agents or with no calcineurin inhibitor cannot be extrapolated from these data.

Topics: Adult; Cadaver; Cyclosporine; Female; Graft Survival; Humans; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Registries; Retrospective Studies; Sirolimus; Survival Analysis; Tissue Donors; Transplantation, Homologous; Treatment Outcome

Mycophenolate mofetil (MMF) is a new immunosuppressive agent that blocks de novo purine synthesis in T and B lymphocytes via a potent selective inhibition of inosine monophosphate dehydrogenase. MMF has been shown to significantly reduce the incidence of acute rejection in both adult and pediatric renal transplantation. The impact of MMF on routine antibody induction therapy in pediatric renal transplantation has not been defined. Remarkably, a recent North American Pediatric Transplant Cooperative Study concluded that T-cell antibody induction therapy was deleterious for patients who received MMF. Our study examines the use of MMF in an evolving immunosuppressive strategy to avoid antibody induction in both living (LD) and cadaver (CAD) donor pediatric renal transplantation. We retrospectively analyzed the records of 43 pediatric renal transplants that received MMF-based triple therapy without antibody induction therapy between November 1996 and April 2000. We compared CAD (n = 17) with LD (n = 26). The two groups were similar demographically except that CAD had significantly younger donors than LD, 26.1 +/- 13.7 vs. 36.2 +/- 9.2 yr (p = 0.006). All the patients received MMF at 600 mg/m2/b.i.d. (maximum dose of 2 g/d) and prednisone with cyclosporine (86%) or tacrolimus (14%). Mean follow-up was >36 months for each group. Acute rejection rate at 6 months was 11.8% (CAD) vs. 15.4% (LD) (p = 0.999) and at 1 yr was 23.5% (CAD) vs. 26.9% (LD) (p = 0.999). Mean estimated glomerular filtration rate (ml/min/1.73 m2) at 6 months was 73.3 +/- 15.3 (CAD) vs. 87.6 +/- 24.2 (LD) (p = 0.068). Patient survival at 1, 2, and 3 yr was 100, 100, and 100% for CAD vs. 100, 96, and 96% for LD, respectively. Graft survival at 1, 2, and 3 yr was 100, 100, and 94% for CAD vs. 96, 88, and 71% for LD, respectively. Graft loss in CAD was because of chronic rejection (n = 2) while in LD it was because of non-compliance (n = 6), post-transplant lymphoproliferative disorder (n = 1), and sepsis (n = 1). In conclusion, MMF without antibody induction in both CAD and LD pediatric renal transplantation provides statistically similar and effective prophylaxis against acute rejection at 6 months and 1 yr post-transplant. The short-term patient and graft survival rates are excellent, however, non-compliance remains a serious challenge to long-term graft survival. Additional controlled studies are needed to define the role of MMF without antibody induction therapy in pediatric renal transplan

Topics: Adolescent; Cadaver; Chi-Square Distribution; Child; Cyclosporine; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mycophenolic Acid; Prednisone; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

A previous study has argued that mycophenolate mofetil (MMF) is associated with a reduced incidence of death with function when compared to azathioprine (AZA) in cadaveric renal transplantation. This study was designed to verify this result because methodological issues bring these findings into question.. The data used in this study was derived from records of renal transplants performed in 1995 and 1996 as recorded in the UNOS Scientific Renal Transplant Registry and supplied by the United States Renal Data System (USRDS). Univariate and multivariate survival analysis was used to compare rates of death with function. Covariate characteristics of the donor, recipient, procedures, early outcomes and the transplant centre were considered.. 12,251 recipients of cadaveric renal transplants were identified as having received either MMF or AZA, but not both. The relative risk of death with function calculated by the Kaplan-Meier method was 21% less for MMF patients (P=0.005). MMF had from 21% (P=0.008) to 24% (P=0.001) reductions in relative risk by multivariate methods.. The use of MMF is associated with a reduction in the incidence of death with a functioning graft in cadaveric renal transplantation. These results verify previous analyses.

Topics: Adolescent; Adult; Analysis of Variance; Azathioprine; Cadaver; Child; Child, Preschool; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Risk Factors; Survival Analysis

Finding the best combination of immunosuppression is an important challenge in kidney transplantation. Current short-term (1- and 3-year) allograft survival is quite good, making it difficult to determine differences in therapeutic regimens without large sample sizes. Using data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network database, the current study provides substantial statistical power to analyze the outcomes for different immunosuppressive regimens.. To compare the effects of four discharge regimens (cyclosporine and azathioprine [CYA+AZA], CYA and mycophenolate mofetil [MMF], tacrolimus [TAC]+AZA, and TAC+MMF) on long-term survival, a multivariate Cox regression analysis was conducted on 19246 primary cadaveric kidney transplants during 1995 to 1998.. Compared with CYA+AZA, the combination of CYA+MMF was associated with a 10% reduced risk of graft loss (relative risk [RR] 0.90, 95% confidence limit [CL] 0.84-0.96, P<0.001), whereas TAC+AZA was associated with an 18% reduced risk (RR 0.82, 95% CL 0.67-1.005, P=0.06) and TAC+MMF with a 20% reduced risk of graft loss (RR 0.80, 95% CL 0.71-0.89, P<0.001). All three regimens benefited patients regardless of delayed graft function (DGF) or early acute rejection status. In addition, in the absence of DGF, the combinations of CYA+MMF, TAC+AZA, and TAC+MMF were associated with a reduced risk of mortality compared with CYA+AZA.. The major finding of this study was improved graft and patient survival associated with TAC+MMF and CYA+MMF in patients with or without DGF or early acute rejection.

Topics: Adolescent; Azathioprine; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Tacrolimus; Treatment Outcome

Living-unrelated donors may become an additional organ source for patients on the kidney waiting list. We studied the impact of a combination of calcineurin inhibitors and mycophenolate-mofetil together with steroids on the outcomes of living-related (LRD), unrelated (LUR), and cadaver transplantation.. Between September 1997 and January 2000, 129 patients underwent LRD (n = 80) or LUR (n = 49) kidney transplantation, and another 173 patients received a cadaveric kidney. Immunosuppressive protocols consisted of mycophenolate-mofetil with cyclosporine-Neoral (41%) or tacrolimus (59%) plus steroids. We compared the patient and graft survival data, rejection rate, and graft functional parameters.. LRD recipients were younger (33.6 years) than LUR (47.8 years) and cadaver (43.7 years) donor recipients (P <0.001). HLA matching was higher in LRD patients (P <0.001). Acute rejection developed in 28.6% of LUR versus 27.5% of LRD transplants and 29.7% of cadaver kidney recipients (P = not significant). The creatinine level at 1, 2, and 3 years after transplant was 1.63, 1.73, and 1.70 mg% for LRD patients; 1.48, 1.48, and 1.32 mg% for LUR patients; and 1.75, 1.68, and 1.67 mg% for cadaver kidney recipients (P = not significant), respectively. No difference in patient survival rates was found among the groups. The 1, 2, and 3-year graft survival rates were significantly better in recipients of LRD (91.3%, 90.0%, and 87.5%, respectively) and LUR transplants (89.8%, 87.8%, and 87.8%, respectively) than in cadaver kidney recipients (81.5%, 78.6%, 76.3%, respectively; P <0.01).. Despite HLA disparity, the rejection and survival rates of LUR transplants under current immunosuppressive protocols are comparable to those of LRD and better than those of cadaveric transplants.

Topics: Adult; Antilymphocyte Serum; Cadaver; Calcineurin Inhibitors; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Randomized, placebo-controlled studies have determined that administration of basiliximab (chimeric IL-2 receptor antagonist) decreases the acute rejection rate in kidney transplantation when used in combination with cyclosporine, azathioprine, and steroids. We report our experience using basiliximab with mycophenolate mofetil, a calcineurin inhibitor, and steroids in kidney transplantation.. We retrospectively analyzed 127 patients who received their first kidney transplant between September 1, 1998, and December 30, 2000, including 59 who received basiliximab (22 living and 37 cadaveric donor recipients) and the 68 that did not receive this antibody (31 living and 37 cadaveric donor recipients). The groups were demographically comparable for risk factors such as race, peak of panel-reactive antibody, delayed graft function, donor age, and cold ischemia time. The analysis assessed serum creatinine levels, acute rejection, cytomegalovirus infection, and posttransplant lymphoproliferative disease incidence as well as patient and graft survival at 6 months.. Serum creatinine levels were 3 +/- 3.1 and 2.6 +/- 2.5 mg/dL (P =.346) at discharge, 1.5 +/- 0.6 and 1.7 +/- 1.1 mg/dL (P =.098) at 1 month, and 1.5 +/- 0.7 and 1.6 +/- 0.7 mg/dL (P =.454) at 6 months posttransplantation for patients treated with versus without basiliximab, respectively. Only one episode of acute rejection was seen among patients treated with basiliximab within 1 month posttransplantation versus three episodes among patients treated without basiliximab (P =.382). Three patients (5.1%) treated with basiliximab and two patients (2.9%) treated without basiliximab developed acute rejection within 6 months posttransplantation (P =.536). Patient and graft survivals at 6 months posttransplantation were not significantly different between patients treated with versus without basiliximab (100% and 100% versus 100% and 98.3%, respectively). There was no increased incidence of cytomegalovirus infection with the use of basiliximab (5.1% vs 5.9%, P =.844). There was only one case of posttransplant lymphoproliferative disease within 6 months posttransplantation in a patient treated without basiliximab.. These data suggest that the routine addition of basiliximab to a mycophenolate mofetil-based regimens does not appear to be warranted. A larger prospective randomized study with longer follow-up is needed to confirm these results.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Cadaver; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Length of Stay; Living Donors; Male; Medical Records; Mycophenolic Acid; Racial Groups; Recombinant Fusion Proteins; Retrospective Studies; Time Factors; Tissue Donors

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Black People; Cadaver; Cause of Death; Daclizumab; Florida; Follow-Up Studies; Graft Rejection; Hispanic or Latino; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Middle Aged; Minority Groups; Mycophenolic Acid; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; Treatment Failure; Treatment Outcome; White People

Topics: Cadaver; Calcineurin; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; New York; Racial Groups; Risk Assessment; Sirolimus; Time Factors; Tissue Donors

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cadaver; Child; Drug Administration Schedule; Drug Monitoring; Female; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Adolescent; Antilymphocyte Serum; Azathioprine; Body Weight; Cadaver; California; Child; Cyclosporine; Drug Therapy, Combination; Female; Humans; Kidney Transplantation; Living Donors; Male; Medical Records; Mycophenolic Acid; Racial Groups; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Acute Disease; Adult; Black People; Cadaver; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Pennsylvania; Racial Groups; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

Topics: Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Replacement Therapy; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors; Treatment Failure

Topics: Adult; Cadaver; Drug Therapy, Combination; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Reoperation; Retrospective Studies; Risk Factors; Time Factors; Tissue Donors; Treatment Failure

Renal transplant recipients with positive flow cytometric crossmatches (FCXM) face greater risk of early rejection and graft failure. It is clear that the pharmacologic needs of this high risk group have not been identified. We retrospectively compared the impact of two drug regimens upon early rejection and 5 yr actuarial survival among 324 primary cadaveric transplant recipients with positive and negative FCXM. Patients received either Regimen I (OKT3 induction, cyclosporine and steroids) or Regimen II (mycophenolate mofetil with cyclosporine or Prograf). Recipient gender, age, disease etiology, ethnic distribution and cytotoxic panel reactive antibody (PRA) were equivalent between regimens (p=ns). With Regimen I, the incidence of rejection was greater for FCXM positive vs. FCXM negative patients (51 vs. 21%, p=0.001). In contrast, with Regimen II the incidence of rejection for FCXM positive and FCXM negative patients was equivalent (18 vs. 12%, p=ns) and lower than patients treated with Regimen I (p < 0.01). Ethnic variation was only observed with Regimen I in which African Americans with positive FCXM had more rejections than Caucasians (60 vs. 45%, p < 0.05). Five-year actuarial survival was lower for FCXM positive vs. FCXM negative patients treated with Regimen I (40 vs. 75%, p=0.0006) or Regimen 2 (60 vs. 90%, p=0.001). Allograft survival was equivalent (p=ns) among FCXM positive individuals receiving Regimen I or II. However, allograft survival among FCXM negative individuals improved with Regimen II (p < 0.05). Ethnic variation in survival was not observed with either regimen (p=ns).

Topics: Adult; Cadaver; Cyclosporine; Drug Therapy, Combination; Female; Flow Cytometry; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Prognosis; Retrospective Studies; Risk; Tacrolimus

Pancreatitis following kidney transplantation was first described by Starzl in 1964 [19]. The incidence rate of the disease involving severe complications ranges from 1.2 to 6.8%. The number of risk factors, besides those of the normal population, is increased by a number of other factors, i.e. uremia, disorder of lipid metabolism, polycystic kidney, immunosuppressive drugs, cytomegalovirus infection, etc. The mortality of acute pancreatitis in a kidney transplant patient is, in spite of treatment with the most up-to-date methods, is much higher (53-60%) than that for a non-transplant patient. In the period between 27 June 1991 and 31 December 2000 the number of cadaver kidney transplants performed in the Transplantation Division of the 1st Department of Surgery of the Medical and Health-Science Centre of the University of Debrecen was 349. During this period 9 incidences of acute pancreatitis were found in 8 patients. The frequency of incidence was 2.56%. In the present communication we analyse the prognosis of 9 kidney transplant patients, with special respect to immunosuppression.. One patient was administered Cyclosporin alone, four were given Cyclosporin and Steroids, a further one Cyclosporin, Steroids and Azathioprine, the remaining three were treated with Cyclosporin, steroids and Mycophenolate Mophetil. In six cases out of nine multiorgan insufficiency (kidney, lung, liver) was encountered on presentation, three cases were accompanied by peritonitis. In spite of early jejunal nutrition, intensive therapy, antibiotic treatment, CT monitoring, if needed, necrectomy and oncotomy, three of our patients died from multiorgan insufficiency induced by septico-toxic state (mortality 33.3%). Other six patients recovered.. The mortality rate of acute pancreatitis is much higher in immunosuppressed patients. The role of the etiological factors is not unequivocal in the development of pancreatitis. Nevertheless, all possible risk factors have to be taken into consideration when starting the immunosuppressive treatment of transplant patients and during their follow-up. By optimally adjusting the immunosuppressants we can decrease the risk of pancreatitis, however, the prognosis of the diseases, in agreement with the data in the literature, cannot be considerably improved even with the most up-to-date methods.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Azathioprine; Cadaver; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multiple Organ Failure; Mycophenolic Acid; Pancreatitis; Peritonitis; Retrospective Studies; Risk Factors

In the paper the authors tried to identify factors influencing prevalence and clinical course of cytomegalovirus (CMV) infection in kidney transplant patients. The study was performed in the group of 100 patients after cadaveric kidney transplant followed up in the Chair and Department of Nephrology, Collegium Medicum, Jagiellonian University in Krakow. CMV infection was demonstrated to occur more frequently and significantly earlier in the patients administered prednisone, cyclosporin A and mycophenolate mofetil, compared to the group treated with standard triple-drug-therapy (prednisone, cyclosporin A, azathioprine) or double-drug-therapy (prednisone, cyclosporin A). Higher serum levels of cyclosporin A did not increase prevalence of the infection but urged its onset. Risk for CMV infection was however higher in the group of patients treated for acute rejection episodes, especially with antilymphocyte preparations. No differences were shown in the immunological matching within HLA-A, -B and -DR antigens between the patients without features of CMV Infection and those treated for its active form. The infection occurred significantly more frequently in the recipients with HLA-A1 antigen than in those with HLA-A9 and -DR7. In patients with delayed transplanted kidney functioning, time of the infection onset and a number of its episodes were similar to the remaining population, however severity of the clinical course positively correlated with the duration of acute tubular necrosis (ATN). CMV infection occurred slightly more frequently in patients requiring transfusions compared to those not administered blood preparations. Among patients with AB blood type, active CMV infection occurred statistically less frequently, whereas in those with other blood types percentage of patients with/without CMV infection were comparable.

Topics: Adolescent; Adult; Aged; Azathioprine; Cadaver; Cyclosporine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prevalence; Risk Factors; Time Factors; Transplantation, Homologous

Mycophenolate-mofetil (MMF) is a nonnephrotoxic immunosuppressant most often used in combination with cyclosporine A (CsA) and prednisone (Pred). This study reports the outcome of 17 adult renal recipients whose immunosuppressive regimen was changed from CsA-Pred to MMF-Pred because of CsA nephrotoxicity.. CsA nephrotoxicity was diagnosed in all patients based on suggestive histopathological lesions on a renal biopsy. Sixteen patients had deteriorating graft function and 1 had isolated persistent proteinuria. Immunosuppressive therapy was changed 57+/-32 months posttransplant.. After replacement of CsA by MMF, a reduction in serum creatinine was observed in all patients (mean 26+/-17%). This reduction was maintained 20+/-8 months after the change in therapy without any episodes of acute rejection. Serum lipids and blood pressure also decreased significantly.. This study demonstrates that MMF-Pred can be an effective long-term immunosuppressive treatment alternative for renal transplant patients experiencing CsA nephrotoxicity. Such treatment may result in improved graft function, and better control of hypertension and hyperlipidemia.

Topics: Adult; Cadaver; Creatinine; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Time Factors

Recent multicenter reports have demonstrated improved outcome in recipients of cadaveric renal transplants treated with mycophenolate mofetil (MMF) versus azathioprine (AZA) in combination with cyclosporine A (CSA) and prednisone. We compared the outcome at our center in patients treated with MMF versus AZA, CSA, and prednisone.. We retrospectively reviewed 242 adult cadaveric renal transplant recipients treated between 11/91 and 5/97. We compared 25 donor variables and 27 recipient variables and outcome parameters between patients treated with MMF versus AZA. There were 117 patients treated with CSA+AZA, 84 with CSA+MMF, and 42 who received other immunosuppressive strategies.. There were no significant differences in any clinically important donor variables. Patients treated with MMF versus AZA and CSA had significantly fewer rejections and readmissions. There was no significant difference in 1- or 2-year patient survival. Recipients treated with MMF had a 5% higher graft survival at 2 years, although the difference did not reach statistical significance.. Outcome is improved in adult recipients of cadaveric renal transplants treated with MMF versus AZA in combination with CSA and prednisone.

Topics: Adult; Azathioprine; Cadaver; Cyclosporine; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Treatment Outcome

Topics: Azathioprine; Cadaver; Costs and Cost Analysis; Graft Rejection; Hospitals, University; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Ohio; Postoperative Complications; Tissue Donors

40 recipients of first cadaver kidney transplants were given perioperative donor vertebral bone marrow infusions (DBMC), compared with 100 controls who did not receive donor bone marrow. The immunosuppressive regimen included OKT3, Tacrolimus, and steroid maintenance therapy, and, in some patients, newly introduced mycophenolate mofetil. This report describes the 24-mo actuarial follow-up and several immunological monitoring studies including sequential measurements of donor bone marrow lineage subset chimerism by the recently reported PCR-flow assay. This is a sensitive in situ PCR detection system for donor versus recipient histocompatibility genes as well as cell surface CD epitope markers using flow cytometry. The results indicate (a) the stabilization of the donor CD3+ and CD34+ cells in recipient peripheral blood at levels below 1% between 6 mo and 1 yr postoperatively, with a 10-fold higher level of donor cell chimerism of these lineages in recipient iliac crest marrow; (b) significantly lower levels of chimerism in peripheral blood up to 6 mo postoperatively in patients who had early acute (reversible) rejection episodes compared with those who did not; (c) a higher degree of chimerism seen in patients who were class II MHC HLA DR identical with their donors; (d) the identification of a high proportion of the donor bone marrow derived CD3 dimly staining subset of T cells (to which regulatory functions have been ascribed) in recipient peripheral blood and especially in recipient bone marrow; and (e) an unexpectedly increased susceptibility to clinically significant infections (primarily viral), and even death in the DBMC-infused group, compared with controls, but no graft losses because of rejection in the DBMC-infused group. Mixed lymphocyte culture assays showed a trend toward a greater number of nonspecifically low reactors in the DBMC group, as well as a greater number of nonspecifically high reactors in the controls (P = 0.058). The autologous mixed lymphocyte reaction also indicated a trend towards nonspecific immune activation in the DBMC group. Finally, anti-cytomegaloviral IgG antibody reactivity was significantly inhibited in the DBMC group 4-6 mo postoperatively (P = < 0.05). In the controls, there were no donor cell lineages detected by PCR-flow in the peripheral blood. These rather unexpected findings, indicating a more depressed cellular and humoral immune capacity in the DBMC cadaver kidney transplant recipients in this relatively ea

Topics: Adolescent; Adult; Aged; Antigens, CD34; Bone Marrow Transplantation; Cadaver; CD3 Complex; Child; Cytomegalovirus Infections; Flow Cytometry; Follow-Up Studies; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; HLA-DR Antigens; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Polymerase Chain Reaction; T-Lymphocyte Subsets; Tacrolimus; Transplantation Chimera

The impact of obesity on graft survival after renal transplantation continues to be controversial. We have reviewed our experiences with living donor and cadaver transplantation in the current decade, focusing specifically on the impact of obesity on transplant outcome. Preoperative body mass index (BMI, kg/m2) was calculated for all adult renal transplant recipients between January 1990 and December 1995 and was used to classify patients as non-obese, moderately obese or morbidly obese. The effect of the degree of obesity on early and late outcomes after renal transplantation was examined. Three hundred and thirty-three recipients had pre-transplant BMI < 30 (normal or mild obesity), 68 BMI 30-40 (moderate obesity), and 7 BMI over 40 (morbid obesity). There was no correlation between obesity and other demographic factors. Wound infections and delayed graft function occurred more commonly in moderately and morbidly obese than in other cadaver donor recipients. Obese patients gained more weight after surgery and were given lower doses per kilogram of cyclosporine. There was, however, no significant correlation between obesity and graft survival for either cadaver or living donor transplants. Although obese patients have an increased risk of delayed graft function with cadaver donor transplantation, obesity has no discernible impact on either immunologic or overall graft survival with cadaver or living donor transplantation. The impact of moderate obesity on transplant outcome is modest and should not prevent these patients from receiving a transplant.

Topics: Adult; Azathioprine; Body Mass Index; Cadaver; Cyclosporine; Diabetes Mellitus; Female; Glucocorticoids; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Mycophenolic Acid; Obesity; Obesity, Morbid; Prednisone; Surgical Wound Infection; Survival Rate; Transplantation, Homologous; Treatment Outcome; Weight Gain

Renal transplantation is a treatment option that should be considered for the elderly (> or = 60 years old) with end-stage renal disease. Little is known regarding the use of tacrolimus (as induction and maintenance immunosuppression) in this age group. We report the outcome of kidney transplantation in 21 patients aged 60 years or more with tacrolimus. During the past few years in kidney transplant maintenance immunosuppressive regimens, we have revised our standard general protocol from cyclosporine to tacrolimus-based therapy for maintenance immunosuppression and for rescue therapy. We also introduced mycophenolate (RS-61443) while we have continued to use ATGAM/OKT3 as induction regimen in the immediate postoperative period. We treated these renal recipients with tacrolimus and steroids in combination with azathioprine or mycophenolate mofetil without antibody induction. This was well tolerated and not associated with a higher rate of rejection (20%) whereas the potential toxicity of antilymphocyte preparations was avoided.

Topics: Administration, Oral; Age Factors; Aged; Azathioprine; Cadaver; Cyclosporine; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus; Treatment Outcome

Topics: Azathioprine; Black or African American; Black People; Cadaver; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Mycophenolic Acid; Philadelphia; Retrospective Studies; Tacrolimus; Tissue Donors; White People

Progressive deterioration of renal function in kidney transplant recipients is the leading cause of graft failure. Both nonimmunologic and immunologic mechanisms contribute to this deterioration.. Twenty-eight cyclosporine (CsA)-treated renal transplant recipients (21 cadaveric, 5 living, 2 simultaneous kidney-pancreas) with progressive deterioration of renal function were prospectively enrolled in a clinical trial and had their immunosuppressive regimen changed 24.3+/-7.7 months after transplant. All patients had their CsA dose reduced by 50%, azathioprine was discontinued, and mycophenolate mofetil was added to the medical regimen. The mean creatinine of the patients at the initiation of the change in immunosuppression was 3.5+/-1.2 mg/dl (range 1.9 to 6.2 mg/dl).. Before the change in immunosuppression, the mean loss in renal function as indicated by the least-squares slope of the reciprocal of creatinine versus time was -0.006+/-0.002 (mg/dl)-1 per month. The change in immunosuppression significantly decreased the rate of loss in renal function for most patients when compared with their pretreatment values with a mean slope of 0.007+/-0.003 (mg/dl)-1 per month (P=0.003). Renal function improved in 21 of 28 patients. Only one patient had continued deterioration of renal function. In a multivariate analysis adjusting for CsA dose, mean arterial blood pressure, and baseline creatinine, the change in immunosuppression was significantly associated with improved renal function (P=0.02). There were no acute rejections after the immunosuppression change.. We conclude that adding mycophenolate mofetil and reducing CsA in patients with chronic deterioration of graft function is well tolerated and results in a short-term improvement in renal function.

Topics: Adult; Cadaver; Chronic Disease; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies

The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system.. The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared.. The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results.. Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.

Topics: Adult; Ambulatory Care; Azathioprine; Cadaver; Costs and Cost Analysis; Graft Rejection; Hospitalization; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Placebos; Postoperative Complications; Time Factors