sirolimus and Cadaver

Everolimus (Evl) plus tacrolimus (Tac) in de novo renal transplantation is effective and safe. Whether the concentration of Evl affects efficacy and safety in a Tac-based regimen has not been previously reported.. To evaluate whether the concentration of Evl affects biopsy-proven acute rejection (BPAR), renal function, adverse events (AEs); and to assess for pharmacokinetic (PK) interactions.. Data were from a prospective, multicenter, open-label, randomized, exploratory 6-month study of 92 renal transplant patients treated de novo with concentration-controlled Evl (target trough levels > or =3 ng/mL) plus low-dose Tac or Evl plus standard-dose Tac; both groups received basiliximab and corticosteroids. Data were pooled across study arms to examine BPAR rates in patients with Evl trough levels less than 3 (n=26), 3 to 8 (n=62), or more than 8 ng/mL (n=4). Groups were stratified by both Evl and Tac trough levels to evaluate glomerular filtration rate and AEs. Evl and Tac PK interactions were evaluated in a subset of 14 patients.. Evl trough level of more than or equal to 3 ng/mL was associated with significantly lower rates of BPAR as compared with a trough level of less than 3 ng/mL. Glomerular filtration rate was similar at 6 months for both the low and standard Tac groups. No apparent PK interactions were observed between Evl and Tac. AEs were infrequent and did not seem to be associated with the Evl or Tac level.. Evl trough levels > or =3 ng/mL plus Tac are associated with low rates of BPAR without adversely affecting renal function. No evident PK interaction exists between Evl and Tac.

Topics: Adult; Biopsy; Cadaver; Drug Therapy, Combination; Everolimus; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Sirolimus; Tacrolimus; Tissue Donors

Once-daily everolimus administration is a further option to improve compliance to immunosuppressive therapy. We randomized 23 stable kidney transplant recipients already on everolimus therapy to receive a single daily morning dose or to continue the twice-daily regimen. The everolimus levels evaluated after 2 weeks showed a slight reduction from 5.13 +/- 1.61 ng/mL at baseline to 4.76 +/- 1.61 ng/mL, which was not statistically significant. After 2 weeks we also evaluated cyclosporine (CsA) levels together with renal function parameters, neither of which showed episodes, any difference between the converted versus twice-daily groups. We did not record any adverse event, such as an infection, an acute rejection episode, or graft loss, over the 6-month study period. Single dosing of everolimus is possible and safe and may achieve better patient compliance to multiple-drug immunosuppressive therapy.

Topics: Adult; Aged; Cadaver; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Graft Rejection; Histocompatibility Testing; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Patient Compliance; Sirolimus; Tissue Donors

The safety and efficacy of concentration-controlled use of sirolimus (SRL) and cyclosporine (CsA) followed by CsA minimization (CsAm) or elimination (CsAe) beginning at week 13 was compared in a phase 4, open-label, randomized (1:1) trial of renal transplant recipients enrolled between March 2004 and November 2005. The primary endpoint was renal function, measured at 12 months using the Nankivell formula, in patients remaining on therapy. Though a total enrollment of 140 patients in each group was planned to provide an 80% power to detect a difference in means, only 207 subjects were enrolled in this study. Demographic characteristics were similar between groups, with 98.1% recipients of first grafts, 69.1% from living donors, and 7.2% diabetics. At 12 months, there were no differences in renal function (61.08 vs 65.24 mL/min, P = .132); incidence of biopsy-confirmed acute rejection (14.3% vs 22.5%, P = .152); and patient (89.5% vs 92.2%, P = .632), graft (87.6% vs 88.2%, P = .999), and death-censored graft (98.1% vs 94.1%, P = .166) survivals between CsAm and CsAe groups, respectively. There were no differences in the overall rate of study-drug discontinuation (32.4% vs 36.3%, P = .562) but more patients discontinued because of lack of efficacy/graft loss in the CsAe group (4.8% vs 14.7%, P = .018). This study was underpowered to demonstrate the superiority of one regimen over the other. In summary, SRL immunotherapy combined with CsA minimization or elimination showed comparative safety and efficacy. Both regimens offer potential treatment options for de novo renal allograft recipients.

Topics: Adult; Cadaver; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ethnicity; Female; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Patient Selection; Sirolimus; Tissue Donors; Transplantation, Homologous; Treatment Failure; 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

This study presents the first prospective multicenter study assessing sirolimus-based immunosuppression with early (4-day) corticosteroid withdrawal (CSWD) in renal transplantation. Immunosuppression included: anti-IL-2 receptor antibody and tacrolimus/sirolimus. Inclusion criteria included adult primary recipients. Exclusion criteria included: (i) African Americans, (ii) current PRA >50%, (iii) multiple organ transplants, (iv) WBC < 3000 cells/microL and (v) fasting hypercholesterolemia/hypertriglyceridemia. The primary endpoints were acute rejection and the proportion of patients off corticosteroids. Seventy-seven patients were enrolled: mean age of 49.7 +/- 12 years. Transplants included: cadaveric (26%) and living donor (74%). Patient and graft survival were 100%. Biopsy proven acute rejection occurred in 13%; presumptive rejection in 10.5%. Banff grades included: IA (seven patients), IB (one patient), IIA (one patient) and IIB (one patient). Renal function at 1 year: serum creatinine (1.18 +/- 0.06 mg/dL). Mean weight gain was minimal at 1 year: 3 +/- 2 kg/patient. Mild increases in total, LDL and HDL cholesterol were observed and new antilipid agent use occurred in 26 patients. In conclusion, early CSWD under tacrolimus/sirolimus-based immunosuppression in selected, low-risk renal transplant recipients provides: (i) excellent patient and graft survival, (ii) good renal function, (iii) reduced hyperlipidemia and antilipid agent use and (iv) low acute rejection rates.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Biopsy; Blood Pressure; Body Weight; Cadaver; Cardiovascular System; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Living Donors; Male; Middle Aged; Pilot Projects; Recombinant Fusion Proteins; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Basiliximab (BX) induction, tacrolimus (TAC), and steroids have sharply reduced acute cellular rejection at our institution. However, late graft loss has continued, for which sirolimus (SL) was introduced into the protocol.. From July 1, 2001 to December 31, 2003, 152 live donor (LD) renal transplant recipients received TAC (level 15 to 20 ng/mL) and steroids, with BX induction. One hundred twenty-two patients (Group 1) received SL (3 mg/d African-americans; 2 mg/d for others) starting on days 2 and 3. The SL level was adjusted to 8 to 10 ng/d, usually by weeks 3 to 4 posttransplant. The TAC doses were then progressively reduced. Records were reviewed for demographics, immunosuppressive drug levels, serum cholesterol and blood pressure, and complications. Graft and patient survival rates were calculated. Comparison was made to 53 LD recipients transplanted from July 1, 1998, to June 30, 2001 (Group 2) receiving BX, steroids and TAC, without SL. Recipients of deceased donor kidneys were excluded because of variability in kidney quality, ischemic time, and patient management.. Demographics were similar between groups: African Americans, 25% to 35%; mean age 36 years; mean HLA mismatch 3.7. Wound problems and infection were minimal in both groups. Mean serum creatinine and cholesterol and systolic and diastolic blood pressure measured periodically up to 1 year were similar, as was the incidence of rejection. In 25% of patients, SL was discontinued.. Gradual introduction of SL appears to be associated with minimal wound problems. With more aggressive reduction in TAC, better renal function, and better long-term graft survival may be attainable. We currently lower TAC levels to 5 ng/mL by 3 months.

Topics: Adult; Blood Pressure; Cadaver; Creatinine; Drug Therapy, Combination; Female; Histocompatibility Testing; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Safety; Sirolimus; Tacrolimus; Tissue Donors

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

Balancing the risk of acute rejection (AR) with drug-induced toxicities complicates the selection of the optimal immunosuppressive regimen, especially in the high-risk renal transplant recipient. This study was designed to determine the optimal dosage combinations of tacrolimus and sirolimus in a high-risk cadaveric renal transplant population.. Primary cadaveric renal transplant recipients were randomly assigned to receive either standard tacrolimus (trough levels of 10-15 ng/mL) plus reduced sirolimus (trough levels of 5-10 ng,mL) (Group I) or to receive reduced tacrolimus (trough levels of 5-10 ng,mL) plus standard sirolimus (trough levels of 10-15 ng/mL) (Group II). All patients received Thymoglobulin induction and steroids.. Thirty-nine (16 in Group I and 23 in Group II) high-risk renal transplant recipients (100% cadaveric donors, 79% African-American recipients, and 59% delayed graft function) are the subjects of this report. At 6 months, the patient survival rate was 94 and 100% and the graft survival rate was 94 and 83% in Groups I and II, respectively. The incidence of biopsy-proven AR was 6 and 5% in Groups I and II, respectively. Eight patients (50%) in Group I required discontinuation of tacrolimus, seven because of biopsy-proven tacrolimus nephrotoxicity and one secondarily to interstitial pneumonitis. Wound complications were the most frequent adverse event reported in both groups.. The combination of tacrolimus and sirolimus was associated with a low risk of AR in this cohort of high-risk renal transplant recipients. However, 50% of patients who received standard tacrolimus and reduced sirolimus combination had to be discontinued from the regimen because of biopsy-proven nephrotoxicity. These preliminary results provide evidence that sirolimus should not be added to tacrolimus without dosage adjustments. We have discontinued recruitment of patients to the standard tacrolimus and reduced sirolimus combination and we have tightened our criteria for selection of marginal donor kidneys with our high-risk renal transplant recipients.

Topics: Cadaver; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Risk; Sirolimus; Survival Rate; Tacrolimus

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

We show the key results of our 4-year experience with sirolimus in kidney transplant patients and in nontransplanted patients undergoing coronary angioplasty.. Recipients of one-haplotype living-related kidney allografts were randomized to receive sirolimus (2 mg/d, n = 35) or azathioprine (2 mg/kg per day, n = 35). Recipients of fully mismatched living kidney allografts (n = 55) received sirolimus (2 mg/day). High-risk recipients of black ethnicity (n = 68) were randomized to target whole-blood trough sirolimus concentrations between 8 and 12 ng/mL or 15 to 20 ng/mL. All kidney transplant patients received cyclosporine and prednisone. Sirolimus/cyclosporine pharmacokinetic studies were performed in 40 patients receiving 2 mg (n = 20) or 5 mg (n = 20) of sirolimus 7 days after transplantation. In the coronary intervention study, 12 patients at high risk for in-stent restenosis received sirolimus for 28 days after angioplasty.. The incidence of biopsy-confirmed acute rejection was 11.4% in recipients of one-haplotype living-related kidney allografts, 16.4% in recipients of fully mismatched living kidney allografts, and 15% (8 to 12 ng/mL) and 4% (15 to 20 ng/mL) in high-risk recipients of black ethnicity. Cyclosporine exposure was higher after morning administration compared to evening administration. There were poor correlations between sirolimus and cyclosporine exposures. The 4-month follow-up angiography revealed no restenosis (stenosis diameter > 50%), a late loss of 0.56 +/- 0.40 mm, and a loss index of 0.33 +/- 0.30. The follow-up 3D-intravascular ultrasound restudy showed an in-stent relative volumetric obstruction of 9.9 +/- 5.5%. Sirolimus in highly effective in preventing kidney allograft acute rejection and in-stent coronary restenosis.

Topics: Adult; Angioplasty, Balloon, Coronary; Azathioprine; Black People; Cadaver; Coronary Disease; Cyclosporine; Family; Female; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Risk Assessment; Safety; Sirolimus; Tissue Donors; Transplantation, Homologous

Despite the various immunosuppressive regimens presently in use, acute rejection in the early postoperative period continues to occur in 20 to 40% of renal transplant patients. In a double-blind, multicentred study, we investigated the ability of two different doses of sirolimus (rapamycin, RAPAMUNE), a new class of immunosuppressant that blocks cell cycle progression, to prevent acute rejection in recipients of primary mismatched renal allografts when added to a regimen of cyclosporine (cyclosporin A, CsA) and corticosteroids.. Between October 1996 and September 1997, 576 recipients of primary mismatched cadaveric or living donor renal allografts were randomly assigned in a 2:2:1 ratio (before the transplant operation) to receive an initial loading dose of either 6 or 15 mg of orally administered sirolimus, followed by a daily dose of either 2 or 5 mg/day, or to receive a matched placebo. All groups received cyclosporine (microemulsion formula, CsA) and corticosteroids. The primary endpoint was a composite of first occurrence of biopsy-confirmed acute rejection, graft loss, or death during the first 6 months after transplantation. Safety data were monitored by an independent drug safety monitoring board.. Based on an intention-to-treat analysis of 576 patients, there were no significant differences in patient demographic or baseline characteristics among treatment groups. The overall rate of the primary composite endpoint for the 6-month period after transplantation was 30.0% (68/227) in the 2 mg/day sirolimus group and 25.6% (56/219) in the 5 mg/day sirolimus group, significantly lower than the 47.7% (62/130) in the placebo group (P=0.002, P<0.001, respectively). During this period, the incidence of biopsy-confirmed acute rejection was 24.7% (56/227) in the 2 mg/day sirolimus group and 19.2% (42/219) in the 5 mg/day sirolimus group, compared with 41.5% (54/130) in the placebo group (P=0.003, P<0.001, respectively), representing a significant reduction in acute rejection of 40.5 and 53.7%, respectively. The need for antibody therapy to treat the first episode of biopsy-confirmed acute rejection was significantly reduced in the 5 mg/ day sirolimus group (3.2%) compared to the placebo group (8.5%; P=0.044). The results 1 year after transplantation were similar for the efficacy parameters studied. Adverse events and infections occurred in all groups.. The addition of either 2 mg/day sirolimus or 5 mg/day sirolimus to CsA/corticosteroid therapy significantly reduces the incidence of acute rejection episodes in primary mismatched renal allograft recipients, without an increase in immunosuppressant-related side effects, including infections and malignancy, at 6 months and at 1 year after transplantation.

Topics: Acute Disease; Adolescent; Adult; Cadaver; Cyclosporine; Double-Blind Method; Female; Graft Rejection; Histocompatibility Testing; Humans; Kidney Transplantation; Male; Middle Aged; Sirolimus

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cadaver; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Graft Survival; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Opportunistic Infections; Placebos; Postoperative Complications; Risk Factors; Sirolimus; Survival Rate; Thrombocytopenia; Time Factors; Tissue Donors; Transplantation, Homologous; Triglycerides

Our study assessed the factors that predispose renal transplant recipients to the occurrence of thrombocytopenia and leukopenia, as well as the severity and the time- and concentration-dependence of these side-effects, after administration of sirolimus (SRL) in combination with a cyclosporine (CsA) and prednisone (Pred) regimen.. The clinical courses of two cohorts of renal transplant recipients were compared over 1 year: 119 patients received SRL in addition to CsA and Pred, and 65 demographically similar, concurrent patients received only CsA and Pred. Using an analysis of variance, pretransplant laboratory values and SRL trough concentrations (C0) were correlated with the occurrence, severity, and persistence of drug-induced thrombocytopenia (platelet count <150x10(3) cell/mm3) and/or leukopenia (white blood cell count <5,000/mm3).. Neither the ethnic background nor the pretransplant cytomegalovirus serological status was associated with the occurrence of hematological complications. Thrombocytopenia was usually observed during the first 4 weeks of treatment (P=0.004). The occurrence, but not the severity or the persistence, of both thrombocytopenia and leukopenia correlated significantly with SRL trough concentrations > or =16 ng/ml (P=0.001 and 0.0001, respectively). A significant correlation is evident between the occurrence of the two adverse effects (P=0.001). In 89% of patients, the first episode of either type of cytopenia resolved spontaneously. Among the remaining 11%, 7% responded to SRL dose reduction, and 4% to temporary suspension. No patient required permanent cessation of SRL therapy. Most patients experienced repeated, but self-limited, episodes of toxicity.. Thrombocytopenia and leukopenia are not infrequent occurrences with SRL treatment, and they generally resolve spontaneously.

Topics: Adolescent; Adult; Aged; Cadaver; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Living Donors; Male; Middle Aged; Postoperative Complications; Prednisone; Sirolimus; Thrombocytopenia; Tissue Donors

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

We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin.. LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells.. Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vβ/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells.. High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

Topics: Adult; Antilymphocyte Serum; Cadaver; CD8-Positive T-Lymphocytes; Cytomegalovirus; Graft Rejection; Herpesvirus 4, Human; Humans; Immunologic Memory; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-7; Isoantibodies; Liver Transplantation; Lymphocyte Depletion; Sirolimus

Ischemia-reperfusion (IR) kidney damage is an important factor for allograft survival in kidney transplantation. Recently it has been shown that immune factors from donor-derived cells are important in IR injury. The aim of this article was to evaluate the impact of short-term immunosuppressive treatment of the donor over a time frame relevant to cadaveric transplantation on IR damage to the rat kidney.. Male Sprague-Dawley rats served as donors and recipients. Three experimental groups were evaluated according to the donor treatment (n = 6); control (no treatment); sirolimus (1 mg/kg orally) or FTY720 (1 mg/kg intravenously) at 6 or 1 hours prior to left nephrectomy. Kidneys were flushed with cold Euro-Collins solution and after 2 hours transplanted using microsurgical techniques concomittant with a left nephrectomy. After 48 hours (day 0), we removed the right kidney. Serum creatinine (SCr) was determined daily thereafter as well as differential leukocyte counts prior to donor nephrectomy and sirolimus plasma levels thereafter.. No difference was observed in SCr on day 1: control (3.97 ± 0.73 mg/dL), sirolimus (4.02 ± 1.44 mg/dL) and FTY 720 (3.27 ± 1.79 mg/dL; P = NS), or thereafter. Mortality was 50% in each group. Animals receiving FTY 720 showed a significant reduction in lymphocyte count (8.0 ± 3.1 to 1.1 ± 0.3 (P < .01). Sirolimus levels were 9.3 ± 1.5 ng/mL.. We concluded that immunosuppressive treament of the donor within a time frame relevant to cadaveric kidney transplantation did not offer a benefit in terms of preventing IR injury.

Topics: Animals; Cadaver; Creatinine; Fingolimod Hydrochloride; Graft Survival; Hypertonic Solutions; Immunosuppressive Agents; Kidney Transplantation; Male; Propylene Glycols; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sirolimus; Sphingosine; Tissue Donors

The clinical and pathological experience with sirolimus is limited at this time. In this study, we report severe isometric vacuolization of the proximal tubules after sirolimus therapy in two kidney transplant patients. Patient 1 is a hepatitis C virus-positive, 30-year-old African American man who had end-stage renal disease (ESRD) of unknown etiology. Patient 2 is a 62-year-old white woman with ESRD due to unknown etiology. Both patients were initially placed on tacrolimus, mycophenolic acid, and prednisone immunosuppressive therapy. These patients were switched to sirolimus at 1 and 5 month posttransplant, respectively, due to the development of new-onset hyperglycemia and an elevated serum creatinine. Both patients presented with acute renal failure and high sirolimus levels at 5 years (patient 1) and 10 months posttransplant (patient 2). Biopsies of their kidney transplants showed widespread isometric tubular cytoplasmic vacuolization and severe arterial hyalinosis. Acute renal insufficiency improved after sirolimus dose reduction. In this case report, we introduce a new morphological appearance after sirolimus therapy of isometric cytoplasmic vacuolization of the renal tubules and severe arterial hyalinosis, similar to that seen in calcineurin inhibitor induced tubular toxicity.

Topics: Adult; Cadaver; Creatinine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Sirolimus; Time Factors; Tissue Donors

Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center.. Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months.. PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication.. Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Topics: Adolescent; Cadaver; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Living Donors; Lymphoproliferative Disorders; Male; Postoperative Complications; Retrospective Studies; Sirolimus; Tacrolimus; Tissue Donors

The new class of immunosuppressants--inhibitors of the mammalian target of rapamycin--has no nephrotoxicity and the capacity to inhibit vascular smooth cell proliferation. These characteristics may afford considerable clinical advantages in the transplantation of kidneys from expanded criteria donors (ECD). Six clinical experiences of the use of sirolimus (SRL) in ECD kidneys recipients have been reported in the literature. Although the results varied somewhat, probably due to differences in the types of deceased donor and in the immunosuppressive regimens used, it seems that a calcineurin inhibitor free, SRL-based protocol can assure a good immunosuppressive effect with less nephrotoxicity and a low incidence of cytomegalovirus infection. For recipients of ECD kidneys at low immunological risk, we would recommend a regimen based on antithymocyte globulin induction and SRL, mycophenolate mofetil, and steroids for maintenance. For strongly responding recipients, we recommend SRL combined with a reduced, 76% to 87% dose of calcineurin inhibitor.

Topics: Aged; Cadaver; Clinical Trials as Topic; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Kidney Transplantation; Medical History Taking; Patient Selection; Postoperative Complications; Sirolimus; Tissue Donors

Sirolimus (SRL) is a non-nephrotoxic immunosuppressive drug blocking T-cell proliferation through mTOR inhibition. SRL can be used as (1) an early drug in a calcineurin inhibitor-free protocol in the first 3 months after transplantation, (2) in the early and late conversion protocols as suggested by the multicenter randomized CONVERT trial, and (3) in recipients from marginal donors, because calcineurin inhibitors can increase the preexisting renal damage induced by age, hypertension, and diabetes that are frequent in elderly cadaveric donors. In any case, SRL should be used in patients with a cutoff of proteinuria (

Topics: Cadaver; Cell Division; Creatinine; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Activation; Multicenter Studies as Topic; Patient Selection; Proteinuria; Randomized Controlled Trials as Topic; Sirolimus; T-Lymphocytes; Tissue Donors

The Symphony study compared four immunosuppressant regimens, defined by protocol-specified target drug concentrations. This subanalysis examines actual drug levels and the implications on the interpretation of results.. De novo renal transplant patients (n=1645) were randomized to receive mycophenolate mofetil (2 g/day) and corticosteroids in combination with standard-dose cyclosporine A (CsA; 150-300 ng/mL for 3 months then 100-200 ng/mL), or daclizumab induction and low-dose CsA (50-100 ng/mL), low-dose tacrolimus (Tac; 3-7 ng/mL), or low-dose sirolimus (SRL; 4-8 ng/mL).. Low-dose Tac was significantly superior for renal function, acute rejection, and graft survival at 12 months. Median trough levels of CsA, Tac, or SRL were toward the high end of target ranges in all groups, and 50% to 60% were within target. During weeks 1 to 8, only 6.5% to 11.0% of patients were consistently within target. At week 8, the range of concentrations encompassing 75% of patients on standard-dose CsA was 141 to 321 ng/mL; for low-dose CsA, 62 to 159 ng/mL; for low-dose Tac, 4.3 to 10.0 ng/mL, and for low-dose SRL, 4.4 to 11.2 ng/mL. The protocol-defined target levels were approximately, but not fully achieved.. To replicate the Symphony study results in clinical practice, the protocol-defined drug concentration targets should be aimed for, but the concentrations actually achieved may be regarded as acceptable. Future clinical studies should include measures of how well target drug levels were achieved to better guide further attempts to develop new regimens designed to reduce or eliminate calcineurin inhibitors.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cadaver; Clinical Trials as Topic; Cyclosporine; Daclizumab; Dose-Response Relationship, Drug; Drug Therapy; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Research Design; Sirolimus; 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

We studied early sirolimus (SRL) therapy in renal transplant recipients at high risk after administration of antithymocyte globulin or interleukin-2 receptor blockade induction.. In 45 patients, SRL therapy was started within 1 month after transplantation. The primary indications for conversion of treatment from calcineurin inhibitors (CNIs)-mycophenolate mofetil (MMF)-steroid to SRL-MMF-steroid were biopsy-proved rejection (after treatment), CNI toxicity, CNI elimination, and acute tubular necrosis. Pediatric, geriatric, and other patients with medical comorbidities were not excluded.. Post-SRL rejection episodes were reported in 22.2% of recipients including 15.6% who were resistant to steroid therapy. Mean (SD) follow-up after SRL therapy was 59.9 (8.1) months. Proteinuria greater than 2 g/d (P = .001), leukopenia (P < .001), hyperlipidemia (P < .001), and transaminases values (P = .02) increased significantly after SRL therapy. Graft survival was 88.8%, and patient survival was 93.3%. There was significant improvement in serum creatinine concentration and estimated creatinine clearance by the end of the study (P < .001). A high incidence of adverse effects and infections was noted post-SRL therapy, and the drug was discontinued in 31% of patients because of multiple adverse effects. At multivariate analysis, age, hypertension, nutritional status, bone marrow suppression, hyperlipidemia, and graft dysfunction were identified as risk factors for worse graft and patient outcome.. Early treatment with combined SRL-MMF-steroid may be effective as a CNI-free immunosuppression regimen in patients at high risk; however, there is a high rate of adverse effects during long-term follow-up.

Topics: Adult; Biopsy; Cadaver; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Patient Selection; Proteinuria; Risk Factors; Sirolimus; Tissue Donors; Treatment Failure; Treatment Outcome

Chronic allograft nephropathy (CAN) is a major cause of progressive renal failure in kidney transplant recipients. Its etiology is multifactorial and can be due to immunologic or nonimmunologic conditions including calcineurin inhibitor (CNI) toxicity.. To evaluate the effect of conversion from CNIs to everolimus in kidney transplant recipients with CAN.. In this 12-month pilot study in renal transplant recipients with biopsy-proved CAN, therapy was changed to an everolimus-based immunosuppression regimen. Cyclosporine or tacrolimus dosage was reduced by 80% (group 1, n = 10) or discontinued (group 2, n = 10). Mycophenolate mofetil or azathioprine were withdrawn in group 1, whereas both agents were maintained in group 2. All patients received prednisone.. Twenty renal allograft recipients switched to an everolimus-based regimen, and patients were followed up for a mean (SD) of 12 (0.1) months. Baseline and end-of-study data were as follows: serum creatinine concentration, 1.27 (0.35) mg/dL vs 1.24 (0.4) mg/dL in group 1, and 1.27 mg/dL (0.36) vs 1.25 (0.3) mg/dL in group 2 (difference not significant); and estimated glomerular filtration rate, 72.4 (19.86) mL/min vs 76.26 (22.69) mL/min in group 1 (not significant), and 66.2 (12.95) mL/min vs 66.2 (13.73) mL/min in group 2 (not significant). One patient in group 1 experienced an acute rejection episode (Banff grade Ib), and 2 patients in group 1 and 1 patient in group 2 demonstrated borderline changes, all associated with everolimus blood concentration less than 3 ng/mL.. Reduction or withdrawal of CNI and introduction of everolimus may be useful to slow the rate of loss of renal function in patients with CAN.

Topics: Adult; Albuminuria; Cadaver; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Administration Schedule; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Prospective Studies; Random Allocation; Sirolimus; Time Factors; Tissue Donors

Calcineurin inhibitors (CNI) have brought dramatic improvements in early renal allograft survival. However, CNI are associated with posttransplant hypertension (PTHTN), a risk factor for mortality from cardiovascular disease and graft failure. Sirolimus (SRL) is emerging as an alternative to CNI. SRL effects on blood pressure (BP) in humans are unclear. We compared the prevalence of PTHTN among patients receiving SRL as maintenance immunosuppression with a group receiving CNI by using 24-hour ambulatory BP (AMBP). AMBP has been shown to predict cardiovascular events and progression of kidney disease better than casual office BP measurements in chronic kidney disease (CKD) patients.. Renal transplant recipients with office hypertension (defined as BP > 130/80 or on antihypertensive medications), receiving stable immunosuppression and displaying consistent serum creatinine values for > or =6 months were eligible. We enrolled the first 40 patients to consent. Office BP was measured twice using a BP-Tru machine. AMBP was then analyzed for systolic BP (SBP), diastolic BP (DBP), and nocturnal blood pressure fall (NF; "dipping"). Patients were placed in the SRL group (n = 18) and the CNI group (n = 20) based on their maintenance immunosuppressive protocol. Two patients were excluded because of incomplete data. All patients received mycophenolate mofetil, and 14/38, maintenance steroids. We collected, demographics as well as type and date of renal allograft, medications, comorbidities, CKD stage, proteinuria, and plasma creatinine at the time of study enrollment.. Patients in the SRL group displayed lower 24-hour SBP than the CNI group (128.0 +/- 10.8 vs 137.7 +/- 14; P = .029). Nightime MAP, nightime SBP, and nighttime DBP were all lower in the SRL group. NF did not reach significance between the SRL and CNI groups (44% vs 15%; P = .074). Patient demographics and number of antihypertensive medications did not differ.. The lower 24-hour SBP seen in the SRL group by AMBP may lead to improved cardiovascular and renal outcomes over time. Long-term patient follow-up will be needed to clarify the effect of the lower 24-hour SBP.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Body Mass Index; Cadaver; Calcineurin; Cardiovascular Diseases; Diabetic Nephropathies; Female; Humans; Hypertension; Immunosuppression Therapy; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Monitoring, Ambulatory; Postoperative Complications; Postoperative Period; Sirolimus; Tissue Donors

Late spontaneous kidney graft decapsulation with fluid collection is a rare condition with only a few cases reported in the literature. Common causes of renal allograft rupture include acute rejection, acute tubular necrosis, renal vein thrombosis, and trauma. Sirolimus related late spontaneous decapsulation has not been reported in the past. Interestingly, sirolimus may promote lymphocele formation in renal transplant recipients, including those presenting with chronic hepatitis B or C. Herein, we report a case of late spontaneous decapsulation with subcapsular hematoma formation developing 12 years after receipt of a cadaveric allograft. The patient was infected with both hepatitis B and C viruses. Cyclosporine was replaced by sirolimus for maintenance therapy because of chronic rejection and acute deterioration of renal function. He presented to the hospital at 9 months after sirolimus inception because of a sudden onset of pain and swelling over the kidney graft. Magnetic resonance imaging found the capsule to be stripped from the kidney by a collection of liquefied hematomas. A laparoscopic fenestration was performed by creation of a peritoneal window adjacent to the renal allograft. When patients have chronic hepatitis, tacrolimus might be a better choice than sirolimus.

Topics: Bowman Capsule; Cadaver; Creatinine; Glomerulonephritis; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Magnetic Resonance Imaging; Male; Renal Artery; Sirolimus; Tissue Donors; Ultrasonography

Chronic allograft nephropathy is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to calcineurin inhibitors. In the present study, effects of a conversion protocol were investigated in pediatric chronic allograft nephropathy with declining glomerular filtration rate (GFR), defined by a Schwartz formula clearance below 60 mL/1.73 m(2)/min, steadily increasing serum creatinine and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kg bodyweight (BW), followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. Calcineurin inhibitors were reduced to 50% at the start of sirolimus and discontinued at median 7 days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m(2)/month, p = 0.025). Individual GFR increased in five out of eight patients (p = 0.026), and only one child exhibited unaltered progression of graft failure. In the responders, mean serum creatinine improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, or on time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, and serum lipids increased transiently. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from calcineurin inhibitors to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy-proven chronic allograft nephropathy.

Topics: Adolescent; Biopsy; Cadaver; Calcineurin Inhibitors; Child; Child, Preschool; Chronic Disease; Creatinine; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Living Donors; Male; Sirolimus; Transplantation, Homologous; Treatment Outcome

The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue.. HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days.. HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65- and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups.. Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.

Topics: Animals; Cadaver; Cell Division; Diabetes Mellitus, Type 1; Humans; Insulin; Insulin Secretion; Islets of Langerhans; Islets of Langerhans Transplantation; Mice; Pancreatic Ducts; Protein Kinases; Sirolimus; Swine; TOR Serine-Threonine Kinases

Cancer has been reported to be more common among kidney transplant recipients than waiting-list patients or the general population. Use of anticalcineurin agents and azathioprine are relevant risk factors. Nine renal allograft recipients (seven men and two women) of mean age 67.6 (55-77) years and mean time after transplantation of 30.7 (58-216) months were switched to everolimus-based immunosuppression because of the presence of biopsy-proven malignancies (eight patients) or neurological tacrolimus toxicity (one patient). One patient with posttransplant lymphoproliferative disease also received chemotherapy with a good evolution at 6 months. He showed an initial increase in the protein to creatinine ratio (peak 3.3 mg/mg at 3 months) that was controlled by increasing the enalapril dose. One patient with skin cancer and severe atheromatosis (baseline SCr 2.5 mg/dL, creatinine clearance 17 mL/min, and protein to creatinine ratio 3.2 mg/mg), had cyclosporine and everolimus overlapped for 25 days, showing a continued poor evolution requiring dialysis initiation at 3 months after switch. The other six patients with recurrent skin cancers had good cancer evolution, with no new skin tumors and regression of skin lesions in three, including not biopsied actinic keratosis. Sudden switching from calcineurin inhibitors to everolimus is safe and may be used in long-term transplant recipients with malignancies. In patients with advanced chronic nephropathy this approach appeared to be less beneficial.

Topics: Aged; Antineoplastic Agents; Cadaver; Calcineurin Inhibitors; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Neoplasms; Recurrence; Sirolimus; Skin Neoplasms; Tissue Donors; Treatment Outcome

Sirolimus (SRL) is a new, potent immunosuppressive agent. More recently, proteinuria has been reported as a consequence of sirolimus therapy, although the mechanism has remained unclear. We retrospectively examined the records of 25 renal transplant patients, who developed or displayed increased proteinuria after SRL conversion. The patient cohort (14 men, 11 women) was treated with SRL as conversion therapy, due to chronic allograft nephropathy (CAN) (n = 15) neoplasia (n = 8); Kaposi's sarcoma, Four skin cancers, One intestinal tumors, One renal cell carsinom) or BK virus nephropathy (n = 2). SRL was started at a mean of 78 +/- 42 (15 to 163) months after transplantation. Mean follow-up on SRL therapy was 20 +/- 12 (6 to 43) months. Proteinuria increased from 0.445 (0 to 1.5) g/d before conversion to 3.2 g/dL (0.2 to 12) after conversion (P = 0.001). Before conversion 8 (32%) patients had no proteinuria, whereas afterwards all patients had proteinuria. In 28% of patients proteinuria remained unchanged, whereas it increased in 68% of patients. In 40% it increased by more than 100%. Twenty-eight percent of patients showed increased proteinuria to the nephrotic range. Biopsies performed in five patients revealed new pathological changes: One membranoproliferative glomerulopathy and interstitial nephritis. These patients showed persistently good graft function. Serum creatinine values did not change significantly: 1.98 +/- 0.8 mg/dL before SRL therapy and 2.53 +/- 1.9 mg/dL at last follow-up (P = .14). Five grafts were lost and the patients returned to dialysis. Five patients displayed CAN and Kaposi's sarcoma. Mean urinary protein of patients who returned to dialysis was 1.26 (0.5 to 3.5) g/d before and 4.7 (3 to 12) g/d after conversion (P = .01). Mean serum creatinine level before conversion was 2.21 mg/dL and thereafter, 4.93 mg/dL (P = .02). Heavy proteinuria was common after the use of SRL as rescue therapy for renal transplantation. Therefore, conversion should be considered for patients who have not developed advanced CAN and proteinuria. The possibility of de novo glomerular pathology under SRL treatment requires further investigation by renal biopsy.

Topics: Adult; Cadaver; Creatinine; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Neoplasms; Postoperative Complications; Proteinuria; Retrospective Studies; Sirolimus; Tissue Donors

An 18-yr-old Hispanic female with end-stage renal disease secondary to chronic glomerulonephritis of unknown etiology underwent cadaveric renal transplantation. She was placed on a steroid-free protocol with tacrolimus and mycophenolate mofetil (MMF) for maintenance immunosuppression. Approximately 8 months post-transplantation, MMF was replaced by sirolimus (SRL) because of persistent leukopenia. Four months after the initiation of SRL, the patient began to experience chronic, constant periumbilical abdominal pain in the absence of vomiting, diarrhea or melena. Esophagogastroduodenoscopy and CT scans revealed significant diffuse mucosal thickening of the antrum, duodenum, and jejunum; leukocytoclastic vasculitis was identified on antral biopsy. A repeat biopsy after reduction of sirolimus dose by 50% over 6 months showed mild chronic inflammation of stomach and duodenum with some improvement in abdominal pain. Discontinuation of SRL and replacement with low dose MMF resulted in complete resolution of pain and normalization of gastrointestinal anatomy by imaging studies within 2 months. In light of this report, drug-induced leukocytoclastic vasculitis caused by SRL should be considered in the differential diagnosis of chronic abdominal pain in a patient with organ transplantation.

Topics: Abdominal Pain; Adult; Biopsy; Cadaver; Diagnosis, Differential; Female; Gastrointestinal Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Vasculitis, Leukocytoclastic, Cutaneous

The aim of this study was to evaluate the impact of sirolimus and cyclosporine (CsA) combined therapy on the incidence and duration of delayed graft function (DGF), and the impact of the latter on 1-year graft function. The study entailed 23 cadaveric renal recipients treated with sirolimus-CsA-prednisone regimen (sirolimus group). The reference group entailed 23 patients treated with CsA-azathioprine-prednisone. In the sirolimus group the frequency of DGF was 39% and was essentially the same as in reference group (34.8%). The duration of DGF was significantly longer in SRL group and lasted 21.2 +/- 12.2 days versus 6.8 +/- 2.5 in reference group (P = .004). Serum creatinine level decreased below 3.0 mg/dL after 36 +/- 22 days in sirolimus group versus 16.8 +/- 6 days in reference group (P < .04). Cold ischemia was slightly longer and donors were older in DGF patients in both groups. Sirolimus dose during first month was higher in DGF patients (3.5 versus 2.6 mg), whereas level of CsA was lower (230 versus 310 ng/mL). Biopsy-proven acute rejection (AR) occurred in most of DGF patients and during the DGF period. Serum creatinine level at the 12th month posttransplant was higher in DGF versus non-DGF patients (2.0 +/- 0.5 versus 1.5 +/- 0.4 mg/dL). One-year patient and graft survival was 100% in sirolimus group and 100% and 95% in reference group. In conclusion, sirolimus significantly retards the recovery from posttransplant renal failure; however, it does not increase the incidence of DGF. Patients who suffered from posttransplant acute renal failure had worse renal function at 1 year after transplantation, independent of the treatment protocol.

Topics: Adult; Cadaver; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prednisone; Sirolimus; Tissue Donors; Treatment Failure; Wound Healing

Kaposi's sarcoma (KS) is a rare complication of renal transplantation in Poland (in our center 2 of 1000 patients). Neovascularization (typical for KS) is promoted by KS-related vascular endothelial growth factor (t-r-VEGF). Sirolimus may reduce t-r-VEGF synthesis and inhibit PI3K-p70S6 kinase of endothelial cells. Two men, 58 and 51 years old, were transplanted in 2002. Initial immunosuppression consisted of cyclosporine, azathioprine, and prednisone. In the second patient, at the week 8 the immunosuppression was switched to tacrolimus and mycophenolate mophetil. KS symptoms appeared on hard palate and skin in month 7 in both patients. In the first patient, the X-ray showed enlargement of mediastinal lymph nodes and diffuse interstitial infiltrates with nodular changes in both lungs. Serum creatinine of the first patient was increased from 1.6 to 1.9 mg/dL, while in the second it remained stable (approximately 2.0 mg/dL). Since confirmation of KS immunosuppression has been minimized in both patients; all drugs except prednisone were withdrawn, and sirolimus was introduced (1-2 mg/24 hours blood level 5-8 ng/mL). Within a month the progression of lung and skin disease ceased, and patients' conditions began to improve with lung opacities regressing, the biggest skin lesions diminishing and smaller ones disappearing. Within 1 year renal function improved. Our observation suggests that sirolimus-based immunosuppression proffers the possibility of KS regression with concomitant renal function preservation among renal graft recipients. It is difficult to ascertain whether KS regression may be attributed to sirolimus treatment or to the reduced overall immunosuppression.

Topics: Antibiotics, Antineoplastic; Cadaver; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Tissue Donors; Treatment Outcome

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

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

Acute rejection is the major cause of graft loss in renal transplantation. Sirolimus (rapamycin) inhibits the effects of cytokines on T and B cells; therefore, it provides prophylaxis against acute renal rejection. This open-label trial assessed the incidence of biopsy-confirmed acute rejection episodes, variation in renal function, as well as graft and patient survival rates up to 12 months posttransplantation when using sirolimus in combination with cyclosporine and prednisolone as immunosuppressants.. Ten kidney transplant recipients received sirolimus 2 mg daily after a 6-mg loading dose. Doses were then adjusted to keep the whole-blood trough level between 5 and 20 mg/mL. All patients received sirolimus in combination with cyclosporine and prednisolone.. At 12 months after renal transplantation, the graft and patient survival rates were 90% and 90%, respectively. One patient died at 2 months due to sepsis with a functioning graft. The mean serum creatinine levels at 1, 3, and 6 months were 1.59 mg/dL, 1.71 mg/dL, and 1.65 ml/dL, respectively. There was no biopsy-confirmed acute rejection episode within 12 months.. Sirolimus in combination with cyclosporine and prednisolone significantly protected kidney transplant recipients from acute rejection for up to 1 year of follow-up.

Topics: Acute Disease; Adult; Cadaver; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Middle Aged; Sirolimus; Taiwan; Tissue Donors; Treatment Outcome

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

Sirolimus, lacking known nephrotoxicity, appeared to be an ideal immunosuppressive agent in the setting of delayed graft function (DGF) after renal transplantation. Coincident with our use of sirolimus however, we noticed prolongation of DGF. To investigate possible causes of prolonged DGF, extensive donor, recipient, transplant, and post-transplant data were collected on 132 consecutive cases of DGF at the University of California, San Francisco between 1/1/97 and 6/30/01. Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that prolong DGF. Sirolimus had a large and highly significant effect on time to graft function (hazard ratio 0.48, p = 0.0007). The hazard ratio indicates that a recipient on sirolimus is half as likely to resolve DGF or twice as likely to remain on dialysis as a recipient without sirolimus. Two other factors had less potent but still significant association with DGF duration: recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per 1.0 increase; p = 0.034). Sirolimus retained its profound negative association with time to graft function in all multivariate models. Because sirolimus appears to prolong DGF, it may not be the optimal immunosuppressive choice in the DGF setting.

Topics: Adult; Cadaver; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Sirolimus

Sirolimus (Rapammune, rapamycin, RAPA) is a strong immunosuppressive agent that reduces kidney transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment and often leads to vascular disease. We have studied the repeatability, reversibility, and dose dependence of the plasma lipid and apoprotein changing effects of sirolimus and attempted to determine the mechanism by which sirolimus induces hypertriglyceridemia in some kidney transplant recipients.. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short-term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/d sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apoprotein, and sirolimus levels.. During sirolimus administration, mean total plasma cholesterol increased from 214 to 322 mg/dL (+50%); low density lipoprotein-cholesterol levels changed in a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dL (+95%). ApoB-100 concentration rose from 124 to 160 mg/dL (+28%). ApoC-III level increased from 28.9 to 55.5 mg/dL (+92%). These lipid and apoprotein changes were found to be repeatable, reversible, and dose dependent. [(13)C(4)]-palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [(13)C(4)]-palmitate into triglycerides of very low density lipoprotien, intermediate density lipoprotein, low density lipoproteins was decreased 38.3%, 42.1%, and 38.4%, respectively, by sirolimus treatment of these patients.. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity, decrease lipoprotein lipase activity, or both, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.

Topics: Adult; Cadaver; Cholesterol; Cyclosporine; Female; Humans; Hyperlipidemias; Immunosuppressive Agents; Kidney Transplantation; Lipids; Lipoproteins; Living Donors; Male; Middle Aged; Prednisone; Sirolimus; Tissue Donors; Transplantation, Homologous; Triglycerides

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

Avoidance of calcineurin antagonists for a prolonged period de novo after cadaver donor renal transplantation may facilitate recovery from delayed graft function. The present study examined the benefit of prolonging the calcineurin antagonist-free interval by administering sirolimus (SRL) in combination with chimeric (c-) anti-interleukin-2 receptor (IL-2R) monoclonal antibodies (mAb).. Three contemporaneous but nonrandomized cohorts were compared for acute rejection episodes, patient and graft survival rates, renal function, and adverse reaction profiles for 12 months. Patients with delayed graft function were treated with either SRL/c-IL-2R mAb/prednisone (Pred) with inception of cyclosporine (CsA) once the serum creatinine value was < or =2.5 mg/dl (n=43; group 1) or anti-lymphocyte preparations/Pred/delayed CsA for 7 to 14 days (n=18; group 3). A third cohort displayed immediate function and was treated de novo with CsA/c-IL-2R mAb/Pred (n=21; group 2).. The incidence of acute rejection episodes was significantly lower among group 1 (16%) compared with groups 2 (52%, P=0.004) or 3 (39%, P=0.05). Among the seven rejection episodes in group 1, six of seven occurred among African-American or retransplant recipients, and a separate cluster of six of seven occurred among patients who displayed SRL trough concentrations < or =9 ng/ml. Furthermore, additional antilymphocyte antibody treatment was required to reverse either steroid-resistant or Banff grades II or III acute rejection episodes among 14%, 55% (P=0.08), and 71% (P=0.03) of patients in each group, respectively. Patient and graft survival rates, as well as mean serum creatinine values, were similar at 12 months among the three groups. However, group 1 patients displayed higher serum cholesterol and triglyceride values, as well as lower hemoglobin, platelet, and leukocyte values compared with the other two groups.. This pilot study suggests that a SRL/c-IL-2R mAb/Pred induction regimen provides excellent acute rejection prophylaxis.

Topics: Antibodies, Monoclonal; Cadaver; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Pilot Projects; Receptors, Interleukin-2; Recombinant Fusion Proteins; Risk Factors; Sirolimus