*Purpose: The development of de novo anti-HLA donor specific antibodies (dnDSA) is associated with poorer outcomes in kidney transplant recipients. We and other previously reported that calcineurin inhibitor blood levels following dnDSA is an independent predictor of graft loss in small cohorts of patients. Whether or not this observation applies to both HLA classes of dnDSA (I and II) is undetermined.

*Methods: We analyzed a cohort of 966 unsensitized patients transplanted between February 2001 and September 2017, for whom anti-HLA antibody screening was performed at 0, 1, 3, 6, 12 months and then annually post-transplant as part of their routine surveillance protocol. dnDSA were detected by flow PRA and identified by Luminex. The endpoint used was a composite of doubling of serum creatinine or graft loss. Analysis was conducted using univariable and multivariable proportional hazards models. Mean tacrolimus post transplant was used as a linear predictor and as a categorical predictor (tertiles).

*Results: During the screening period, 58/966 (6.0 %) patients developed dnDSA; 18 (31%) to HLA class I only, 31 (53%) to HLA class II only, and 9 (16%) to both HLA classes. Among these, 25 patients experienced the composite outcome. The event occurred at a median of 15 months (25th-75th percentiles 5-29 months) post DSA detection. Cox modeling revealed that the risk of the composite endpoint decreased with higher mean tacrolimus levels following dnDSA detection (HR 0.83, 95% CI 0.71-0.97, p=0.02). The association remained significant following adjustment for age, sex, time post transplant and serum creatinine level (adjusted HR 0.64, 95% CI 0.50-0.83, p<0.01). The relationship was also consistent when restricted to patients with class I anti-HLA dnDSA (adjusted HR 0.57, p<0.01; n=27) or with class II dnDSA (adjusted HR 0.63, p<0.01; n=40). Analysis of tacrolimus levels by tertiles generated cut-offs at 5.6 and 6.8 ng/ml. Modelling using these tertiles suggested that, compared to mean levels of 6.8 ng/ml, levels <5.6 ng/ml was a strong predictor of the composite endpoint (HR 4.3; 95% CI 1.2-16.3, p=0.03; adjusted HR 19.4 95% CI 2.7-134.9, p<0.01). This effect was consistent for each anti-HLA class (class I adjusted HR 28.9, p=0.02; class II adjusted HR 35.7, p<0.01).

*Conclusions: These data validate previous observation about a relationship between tacrolimus levels and graft outcome post dnDSA detection. It further suggests that tacrolimus levels below 5.6 ng/ml are associated with worse outcome in kidney recipients with dnDSA of both HLA class I and class II.

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