Impact of the reduction of calcineurin inhibitors on renal function in heart transplant patients: a systematic review and meta‐analysis

Abstract

AIMSCalcineurin inhibitors (CNIs) taken after heart transplantation lead to excellent short-term outcomes, but long-term use may cause chronic nephrotoxicity. Our aim was to identify, appraise, select and analyse all high-quality research evidence relevant to the question of the clinical impact of CNI-sparing strategies in heart transplant patients. METHODSWe carried out a systematic review and meta-analysis of randomized controlled trials on CNI reduction in heart transplant recipients. Primary outcomes were kidney function and acute rejection after 1 year. Secondary outcomes included graft loss, all-cause mortality and adverse events. RESULTSEight open-label studies were included, with 723 patients (four tested de novo CNI reduction and four maintenance CNI reduction). Calcineurin inhibitor reduction did not improve creatinine clearance at 12 months 5.46 [−1.17, 12.03] P = 0.32 I 2 = 65.4%. Acute rejection at 12 months (55/360 vs. 52/332), mortality (18/301 vs. 15/270) and adverse event rates (55/294 vs. 52/281) did not differ between the low-CNI and standard-CNI groups. There was significant benefit on creatinine clearance in patients with impaired renal function at 6 months [+12.23 (+5.26, +18.82) ml min −1 , P = 0.0003] and at 12 months 4.63 [−4.55, 13.82] P = 0.32 I 2 = 75%. CONCLUSIONSThis meta-analysis did not demonstrate a favourable effect of CNI reduction on kidney function, but there was no increase in acute rejection. To provide a better analysis of the influence of CNI reduction patterns and associated treatments, a meta-analysis of individual patient data should be performed.

Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study

“…The target MMF dose was 2000-3000 mg/day. All patients received corticosteroids (minimum 0.1 mg/kg during months 1-3 and 0.05-0.1 mg/kg during months [4][5][6][7][8][9][10][11][12].…”

“…Posttransplant renal deterioration is multifactorial in etiology, with pretransplant renal dysfunction (2,4), older age (2) and comorbidities such as diabetes (2,4) known to contribute, but long-term calcineurin inhibitor (CNI) therapy also plays an important role (3,5). A recent meta-analysis of randomized controlled trials in de novo and maintenance heart transplant patients found that reducing CNI exposure significantly improved posttransplant renal function (6).…”

Renal protection strategies after heart transplantation

“…These controversial results for CNI reduction were also confirmed in the meta‐analysis of eight open‐label studies (n = 723). Overall, CNI reduction did not have any favorable effect on the renal function at 12 months follow‐up …”

Impact of tacrolimus versus cyclosporin A on renal function during the first year after heart transplant

“…Therefore, renal protection strategies are warranted to further improve patients' outcomes after HTx. 5,6 Renal dysfunction after HTx is derived from preoperative, intraoperative, and post-operative factors. Among the post-operative factors, the use of calcineurin inhibitors (CNIs) has a marked effect on renal function.…”

“…Renal dysfunction is frequently observed prior to HTx and typically followed by a progressive decline over time after HTx, 2–4 which contributes late mortality in HTx recipients. Therefore, renal protection strategies are warranted to further improve patients' outcomes after HTx 5,6 …”