title: Belatacept for kidney transplant recipients.
abstract: BACKGROUND
  Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.
  
  
  OBJECTIVE
  1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).
  
  
  METHODS
  We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
  
  
  METHODS
  Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.
  
  
  METHODS
  Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI).  Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.
  
  
  RESULTS
  We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise.
  
  
  CONCLUSIONS
  There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.
authors.affiliation: Sydney School of Public Health, The University of Sydney, Sydney, Australia.
authors.forename: Philip
authors.initials: P
authors.lastname: Masson
authors.forename: Lorna
authors.initials: L
authors.lastname: Henderson
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Chapman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Craig
authors.forename: Angela C
authors.initials: AC
authors.lastname: Webster
mesh_terms: D000069594:Abatacept; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D000077552:Basiliximab; D065095:Calcineurin Inhibitors / Q000627:therapeutic use*; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000401:mortality / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D018796:Immunoconjugates / Q000009:adverse effects / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000401:mortality; D008232:Lymphoproliferative Disorders / Q000209:etiology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011241:Prednisone / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000961:Antilymphocyte Serum; D065095:Calcineurin Inhibitors; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000074323:Alemtuzumab; D000069594:Abatacept; D016572:Cyclosporine; D000077552:Basiliximab; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus; D016559:Tacrolimus