Background:

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine A (CsA) are effective immunosuppressive agents for renal transplantation, but they must be managed carefully to avoid toxicity. Routine therapeutic monitoring guides dosing, but uncertainty surrounds different monitoring methods and timepoints. Additionally, the effectiveness of strategies to reduce CNI exposure with lower therapeutic levels and other immunosuppressants is unclear. This systematic review evaluates the evidence for three Key Questions. Key Question 1 compares immunoassay analysis with liquid chromatographic or mass spectrometric analytical techniques for therapeutic monitoring of CNIs. Key Question 2 examines CsA monitoring timepoints. Key Question 3 evaluates alternatives to full-dose CNI regimens.

Methods:

We searched four bibliographic databases as well as gray literature sources, covering literature published from 1994 through December 2015 (for Key Questions 1 and 2) and May 2015 (for Key Question 3). English-language studies of adult renal transplants were included. All donor types and retransplants were eligible, but multiorgan recipients were excluded. We meta-analyzed data when appropriate, assessed studies for risk of bias, and evaluated the strength of evidence.

Results:

We included 105 studies; 11 addressed Key Question 1, six addressed Key Question 2, and 88 addressed Key Question 3. We included 91 randomized controlled trials and 14 nonrandomized controlled studies. Most studies examined CsA, although tacrolimus is used more widely. For Key Question 1, one study compared clinical utility outcomes associated with chromatographic techniques versus immunoassays. Evidence was insufficient to determine whether outcomes differed by technique. Eleven studies assessed analytical performance measures. Findings suggested that chromatographic techniques are more accurate and precise than immunoassays, but the clinical relevance of these differences is unclear. For Key Question 2, low-strength evidence suggested no difference in risk of acute rejection when monitoring CsA at trough versus 2-hour timepoints.

Eighty-eight studies examined regimens that limited or avoided CNI exposure. High-strength evidence suggests that early minimization with low-dose CNIs is associated with improved clinical outcomes. Moderate-strength evidence suggests that conversion from CNIs to alternative immunosuppressants results in improved renal function. High-strength evidence suggests that withdrawal of CNIs is associated with increased risk of acute rejection and graft loss. Finally, nine studies evaluated regimens that avoided CNIs and used sirolimus or belatacept immediately following transplantation. These studies were heterogeneous and were not combined for meta-analysis. Moderate-strength evidence suggests that renal function is better in patients receiving sirolimus or belatacept instead of CNIs.

Study limitations include small sample sizes, incomplete reporting of clinical outcomes, short followup periods, and multiple sources of heterogeneity (including adjunctive and induction therapies, and variation in therapeutic targets). Additionally, although tacrolimus is used more widely than CsA in current practice, most of the studies examined CsA.

Conclusions:

Most studies of CNI monitoring do not directly compare strategies or assess clinical validity or utility, and are insufficient to evaluate clinical outcomes. Few studies compare 2-hour with trough monitoring of CsA, and current evidence is insufficient to suggest a superior approach. Many studies suggest that early initiation of low-dose CNIs results in improved renal function and reduced risk of harm. Strategies that employ conversion from CNIs to mTOR (mammalian target of rapamycin) inhibitors are associated with improved renal function. Regimens that withdraw CNIs are not associated with improved renal function and may increase the risk of acute rejection. Avoidance strategies based on de novo use of alternative immunosuppressive drugs are not widely studied.