Higher calcineurin inhibitor levels predict better kidney graft survival in patients with de novo donor-specific anti-HLA antibodies: a cohort study

Abstract

The development of de novo anti-HLA donor-specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. Despite this, antibody screening post-transplant is not widespread, largely because the optimal management of patients with dnDSA remains undetermined. We hypothesized that in this population, calcineurin inhibitor blood levels would be an independent predictor of graft loss. We analyzed a cohort of unsensitized patients for whom anti-HLA antibody screening was performed prospectively post-transplant. During the screening period between January 2005 and April 2016, 42 patients developed dnDSA. There was no difference in the clinical characteristics or the histological scores of patients biopsied for clinical indication versus those biopsied solely due to detection of dnDSA. Cox modeling revealed a strong relationship between mean tacrolimus levels following dnDSA detection and graft loss, with a hazard ratio of 0.49 (95% CI, 0.33-0.75), which persisted following adjustment for established independent predictors (HR, 0.52, 95% CI, 0.30-0.89). Kaplan-Meier analysis by tertiles of tacrolimus levels and receiver operating curve analysis concurred to show that a threshold of 5.3 ng/ml could be predictive of graft loss. These data suggest that anti-HLA antibody monitoring post-transplant could guide maintenance immunosuppression and improve graft outcomes.

A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection

“…In an earlier study, Lederer et al 40 showed that alloantibody levels were reduced by implementation of MMF treatment. Moreover, reduced levels of immunosuppression were found to pose a risk of graft loss, 41,42 and recent studies have associated medication nonadherence with DSA formation, ABMR occurrence, and graft loss. 1,43 We are aware of the limitations of using eGFR decline as a surrogate of graft survival, but a study design to detect meaningful differences in survival rates would have necessitated a long-term multicenter trial including hundreds of patients.…”

Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients

“…Beland et al found that higher tacrolimus levels in patients with dnDSA were associated with better kidney graft survival. In 42 unsensitized patients who later developed dnDSA during their screening period, a positive association was found between higher mean tacrolimus concentrations and lower risk of graft loss (HR, 0.49; 95% CI, 0.33-0.75; p = 0.001) [73]. This effect persisted after adjusting for known predictors of graft loss such as delayed graft function, non-adherence, transplant glomerulopathy, interstitial fibrosis, tubular atrophy, and arteriolar hyaline thickening scores.…”

“…It is also unknown whether a higher tacrolimus therapeutic range might be able to attenuate ongoing immunological damage in patients who already have formed dnDSA. Beland et al found that higher tacrolimus levels in patients with dnDSA resulted in improved kidney graft survival [73]. Furthermore, Sablik et al showed that while a high tacrolimus IPV was not associated with the incidence of chronic active ABMR, it was associated to inferior graft survival in patients with chronic active ABMR [34].…”

Renal transplant patients with preformed anti-HLA antibodies: early biopsy findings and clinical outcomes

“…Another risk for poor outcome is the development of de novo DSA. However, its monitoring after transplantation is not well established 17 . The onset of new anti-HLA antibodies or the increase in the fluorescence intensity of existing antibodies could be related to the development of subclinical antibody-mediated rejections, and may lead to subtle histological changes in the absence of graft dysfunction or proteinuria.…”