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1.
Transpl Int ; 29(2): 184-95, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26369526

ABSTRACT

An increased basiliximab dose may saturate T-cell CD25 receptors in kidney transplant patients receiving calcineurin inhibitor (CNI)-free immunosuppression. In a 12-week study, 16 de novo kidney transplant patients were randomized to (i) 40 mg basiliximab with cyclosporine [n = 3] (controls), (ii) 80 mg basiliximab with cyclosporine [n = 6], or (iii) 80 mg basiliximab with everolimus (CNI-free) [n = 7], all with mycophenolic acid and steroids. Recruitment was stopped prematurely due to increased biopsy-proven acute rejection (BPAR) in the basiliximab 80 mg CNI-free group. BPAR occurred in 1/3, 1/6, and 4/7 patients in the three treatment groups, respectively. The primary endpoint, area under the effect curve of CD25 saturation to week 12, was 8.4(1.6) % × weeks in the control group, 11.1(1.1) % × weeks with basiliximab 80 mg + cyclosporine, and 9.7(0.7) % × weeks in the basiliximab 80 mg CNI-free group (P = 0.020 for basiliximab 80 mg + cyclosporine versus controls; P = 0.119 for basiliximab 80 mg CNI-free versus controls). Although small patient numbers prohibit robust conclusions, these results suggest that doubling the cumulative basiliximab dose to 80 mg does not provide adequate immunosuppression during the first 3 months after kidney transplantation in the absence of CNI therapy (ClinicalTrials.gov number: NCT01596062).


Subject(s)
Antibodies, Blocking/administration & dosage , Antibodies, Monoclonal/administration & dosage , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Interleukin-2 Receptor alpha Subunit/immunology , Kidney Transplantation , Recombinant Fusion Proteins/administration & dosage , Adult , Aged , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Basiliximab , Calcineurin Inhibitors/therapeutic use , Female , Graft Rejection , Humans , Male , Middle Aged , Prospective Studies , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacokinetics
2.
Clin Res Hepatol Gastroenterol ; 38(3): 292-9, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24685602

ABSTRACT

BACKGROUND AND AIMS: Recurrent hepatitis C after liver transplantation (LT) is associated with rapid fibrosis progression. The aim of this study was to evaluate the cumulative risk for severe fibrosis and the factors influencing it. PATIENTS AND METHODS: Two hundred and fifty LT patients were included 1 to 15years after LT. Recurrence of chronic hepatitis C on liver graft was classified according to Metavir score. RESULTS: Kaplan-Meyer estimates for actuarial progression to severe fibrosis (Metavir>F3) showed a probability of 15.2% and 44.5% at 5 and 10years, respectively. Predictive factors for progression to severe fibrosis were: use of tacrolimus as main CNI, recipient age at time of biopsy<55, donor age ≥45, graft HCV re-infection<3months, biologically suspected graft re-infection and lack of response to antiviral treatment after LT. Multivariate analysis disclosed that only donor age ≥45 (hazard ratio 2.243, 95%CI 1.264-3.983, P=0.0058) and lack of response to antiviral treatment (hazard ratio 2.816, 95%CI 1.227-6.464, P=0.0146) were associated to severe fibrosis. CONCLUSIONS: Our study confirms that donor age ≥45 and lack of response to antiviral treatment after LT are major predictive factors of progression of HCV recurrence on liver graft.


Subject(s)
Hepatitis C, Chronic/epidemiology , Liver Cirrhosis/epidemiology , Liver Transplantation , Adult , Age Factors , Aged , Antiviral Agents/adverse effects , Cross-Sectional Studies , Disease Progression , Drug Resistance , Female , France/epidemiology , Hepatitis C, Chronic/drug therapy , Humans , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Recurrence , Severity of Illness Index , Tissue Donors
3.
Ann Transplant ; 17(1): 58-67, 2012.
Article in English | MEDLINE | ID: mdl-22466910

ABSTRACT

BACKGROUND: Data in kidney transplant recipients regarding elimination of calcineurin inhibitor (CNI) therapy from a de novo regimen based on low CNI exposure and an mTOR inhibitor are sparse, and restricted to CNI elimination within the first six months post-transplant. MATERIAL/METHODS: In a 12-month, randomized, multicenter, open-label study, kidney transplant patients who had received everolimus, low-exposure cyclosporine and corticosteroids from transplantation to month 12 (with proteinuria <1 g/24 h at month 12) were randomized to convert from cyclosporine to mycophenolate sodium 720 mg/day with increased everolimus exposure (6-10 ng/mL [CNI-free group], n=15) or continue unchanged (everolimus 3-8 ng/mL [CNI group], n=15). RESULTS: Median (range) baseline mGFR was 54 (21-87) mL/min and 37 (range 18-69) mL/min (p=0.053) in the CNI-free and CNI groups, respectively, compared to 56 (18-126) mL/min and 32 (12-63) mL/min at month 12 (p=0.007). The between-group difference in change in mGFR from baseline to month 12 post-conversion (the primary endpoint) was -14.4 mL/min (95% CI -29.3 to 0.6 mL/min, p=0.059 [least squares mean]). Changes in serum creatinine and estimated GFR to month 12 were significantly in favor of CNI-free patients. One CNI patient experienced biopsy-proven acute rejection. Study drug was discontinued due to adverse events in one CNI-free patient (7%) and three CNI-treated patients (20.0%). CONCLUSIONS: Elimination of CNI from a de novo regimen of everolimus with low-exposure CNI at one year post-transplant maintained efficacy and led to a non-significant but clinically relevant improvement in renal function, although patients numbers were low (n=30). Findings from this small study require confirmation in a larger controlled trial.


Subject(s)
Cyclosporine/administration & dosage , Kidney Transplantation , Mycophenolic Acid/analogs & derivatives , Sirolimus/analogs & derivatives , Adult , Aged , Calcineurin Inhibitors , Creatinine/blood , Drug Therapy, Combination , Everolimus , Female , France , Glomerular Filtration Rate , Humans , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/physiology , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Prospective Studies , Sirolimus/administration & dosage , TOR Serine-Threonine Kinases/antagonists & inhibitors , Time Factors
4.
Clin Nephrol ; 77(2): 126-36, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22257543

ABSTRACT

Mycophenolic acid (MPA) dose is frequently reduced in tacrolimus-treated kidney transplant patients, but alternatively the recommended MPA dose can be maintained with reduced tacrolimus exposure. In a 6-month, multicenter, randomized, openlabel study, maintenance kidney transplant patients receiving MPA (mycophenolate mofetil 1g/d or enteric-coated mycophenolate sodium (EC-MPS) 720 mg/d) and tacrolimus were randomized to convert to EC-MPS 1,440 mg/d with reduced tacrolimus (n = 46), or receive EC-MPS 720 mg/d with unchanged tacrolimus (n = 48). Mean estimated GFR (eGFR, aMDRD) at Month 6 was 49.1 ± 11.1 and 44.7 ± 11.5 ml/min/1.73 m2 in the EC-MPS 1,440 mg and 720 mg groups, respectively (p = 0.07). The primary endpoint, change in eGFR from Day 0 to Month 6, was 2.48 ± 0.95 ml/min/1.73 m2 with EC-MPS 1,440 mg and -0.48 ± 0.93 ml/min/1.73 m2 with EC-MPS 720 mg (difference 2.96 ml/min/1.73 m2; 95% CI 0.32 - 5.60; p = 0.028). There were no deaths, graft losses or acute rejections. Adverse events were more frequent with EC-MPS 1,440 mg than 720 mg (66.7% vs. 44.7%, p = 0.034). Adverse events with suspected relation to EC-MPS occurred in 26.7% and 21.3% of patients, respectively (p = 0.59). Conversion of kidney transplant patients to increased MPA dosing using EC-MPS 1,440 mg/d, with reduced tacrolimus exposure, appears an effective immunosuppression strategy and may improve renal function. Adverse events overall, but not those with a suspected relation to EC-MPS, were higher with ECMPS 1,440 mg/d.


Subject(s)
Immunosuppressive Agents/administration & dosage , Kidney Transplantation , Mycophenolic Acid/administration & dosage , Tacrolimus/administration & dosage , Adolescent , Adult , Aged , Creatinine/blood , Female , Glomerular Filtration Rate , Humans , Male , Middle Aged , Mycophenolic Acid/adverse effects , Prospective Studies , Tablets, Enteric-Coated , Tacrolimus/adverse effects
5.
Transpl Int ; 23(11): 1084-93, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20500493

ABSTRACT

Immediate or early use of proliferation signal inhibitor (PSI)/mammalian target of rapamycin (mTOR) inhibitor therapy can avoid high exposure to calcineurin inhibitors but concerns exist relating to the risk of delayed graft function (DGF) and impaired wound healing with the mTOR sirolimus. CALLISTO was a 12-month, prospective, multicenter, open-label study. Deceased-donor kidney transplant patients at protocol-specified risk of DGF were randomized to start everolimus on day 1 (immediate everolimus, IE; n = 65) or week 5 (delayed everolimus, DE; n = 74). Incidence of the primary endpoint (biopsy-proven acute rejection, BPAR; graft loss, death, DGF, wound healing complications related to transplant surgery or loss to follow-up) was 64.6% and 66.2% in the IE and DE groups, respectively, at month 12 (P = 0.860). The overall incidence of BPAR was 20.1%. Median estimated glomerular filtration rate was 48 ml/min/1.73 m(2) and 49 ml/min/1.73 m(2) in the IE and DE groups, respectively, at month 12. DGF and wound healing complications were similar between groups. Adverse events led to study drug discontinuation in 17 IE patients (26.2%) and 28 DE patients (37.8%) (NS). In conclusion, introduction of everolimus immediately or early posttransplant in DGF-risk patients is associated with good efficacy, renal function and safety profile. There seems no benefit in delaying initiation of everolimus.


Subject(s)
Cyclosporine/therapeutic use , Sirolimus/analogs & derivatives , Adult , Aged , Everolimus , Female , Glomerular Filtration Rate , Graft Survival , Humans , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/methods , Male , Middle Aged , Prospective Studies , Risk , Sirolimus/therapeutic use , Treatment Outcome , Wound Healing
6.
Transplantation ; 88(1): 69-76, 2009 Jul 15.
Article in English | MEDLINE | ID: mdl-19584683

ABSTRACT

BACKGROUND: Concerns about delayed graft function (DGF) and wound healing complications with sirolimus has led to suggestions that everolimus introduction could be delayed after transplantation. METHODS: In a prospective, multicenter, open-label study, deceased-donor kidney transplant recipients at protocol-specified risk of DGF (defined as > or =1 dialysis session during the first week posttransplant excluding day 1) were randomized to start everolimus therapy on day 1 posttransplant (immediate everolimus [IE]), or from week 5 (delayed everolimus [DE]) with mycophenolic acid until everolimus was initiated. All patients received anti-interleukin-2 receptor antibodies, cyclosporine A, and corticosteroids. A planned 3-month analysis from this 12-month study is presented here. RESULTS: One hundred and thirty-nine patients were randomized (IE 65, DE 74). The primary composite endpoint: biopsy-proven acute rejection, graft loss, death, DGF, wound healing events, or lost to follow-up at month 3, occurred in 36 IE patients (55.4%) and 47 DE patients (63.5%, P=0.387). The incidence of DGF was similar between groups (IE 24.6%, DE 24.3%; n.s.). Wound healing events of any type occurred in 40.0% and 41.9% of IE and DE patients (n.s.); events relating to initial transplant surgery occurred in 36.9% IE patients and 37.8% DE patients (n.s.), most of which were fluid collections. Study drug was discontinued due to adverse events or graft loss in 13 IE (20.0%) and 17 DE patients (23.0%). CONCLUSIONS: Findings from this randomized, multicenter trial indicate that kidney function recovery, wound healing, efficacy, and tolerance are similar at 3 months posttransplant with immediate or DE in patients at protocol-specified risk of DGF.


Subject(s)
Delayed Graft Function/prevention & control , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/adverse effects , Sirolimus/analogs & derivatives , Wound Healing/drug effects , Aged , Delayed Graft Function/etiology , Delayed Graft Function/mortality , Drug Administration Schedule , Drug Therapy, Combination , Everolimus , Female , France/epidemiology , Graft Rejection/etiology , Graft Rejection/prevention & control , Graft Survival/drug effects , Humans , Immunosuppressive Agents/adverse effects , Incidence , Kidney Function Tests , Kidney Transplantation/mortality , Male , Middle Aged , Prospective Studies , Sirolimus/administration & dosage , Sirolimus/adverse effects , Time Factors , Transplantation Tolerance/drug effects , Treatment Outcome
7.
Nephrol Dial Transplant ; 22(7): 1986-93, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17400559

ABSTRACT

BACKGROUND: New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality. METHODS: This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines. RESULTS: The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0). CONCLUSIONS: NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.


Subject(s)
Diabetes Mellitus/etiology , Kidney Transplantation/adverse effects , Adult , Blood Glucose/metabolism , Body Mass Index , Calcineurin Inhibitors , Cyclosporine/administration & dosage , Cyclosporine/therapeutic use , Diabetes Mellitus/epidemiology , Diabetes Mellitus/therapy , Emulsions , Fasting/blood , Female , France/epidemiology , Hepatitis C/complications , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Incidence , Kidney Diseases/complications , Kidney Diseases/surgery , Male , Middle Aged , Retrospective Studies , Risk Factors , Tacrolimus/adverse effects , Tacrolimus/therapeutic use , Time Factors
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