Factors at de novo donor-specific antibody initial detection associated with allograft loss: a multicenter study

Abstract

We aimed to evaluate patient factors including nonadherence and viral infection and de novo donor-specific antibody (dnDSA) characteristics [total immunoglobulin G (IgG), C1q, IgG3, and IgG4] as predictors of renal allograft failure in a multicenter cohort with dnDSA. We performed a retrospective observational study of 113 kidney transplant recipients with dnDSA and stored sera for analysis. Predictors of death-censored allograft loss were assessed by Cox proportional modeling. Death-censored allograft survival was 77.0% (87/113) during a median follow-up of 2.2 (IQR 1.2-3.7) years after dnDSA detection. Predictors of allograft failure included medication nonadherence [HR 6.5 (95% CI 2.6-15.9)], prior viral infection requiring immunosuppression reduction [HR 5.3 (95% CI 2.1-13.5)], IgG3 positivity [HR 3.8 (95% CI 1.5, 9.3)], and time post-transplant (years) until donor-specific antibody (DSA) detection [HR 1.2 (95% CI 1.0, 1.3)]. In the 67 patients who were biopsied at dnDSA detection, chronic antibody-mediated rejection [HR 11.4 (95% CI 2.3, 56.0)] and mixed rejection [HR 7.4 (95% CI 2.2, 24.8)] were associated with allograft failure. We conclude that patient factors, including a history of viral infection requiring immunosuppression reduction or medication nonadherence, combined with DSA and histologic parameters must be considered to understand the risk of allograft failure in patients with dnDSA.

Keywords: HLA-antibody post-transplantation; histocompatibility and immunogenetics; infection; kidney clinical; other; rejection.

Figure 1.. IgG 3, IgG 4, and C1q positivity associated with high MFI of Dominant De novo DSA

Patients with de novo DSA positive for IgG 3, IgG 4, and C1q were more likely to have an dominant de novo DSA with a high MFI. IgG 3, IgG 4, and C1q positivity was based on MFI of 1000.

Figure 2. Overall and Death-censored Allograft Survival after De novo DSA Detection was Similar Among Centers.

The incidence of death-censored allograft failure by one year post dnDSA was 8.0% (9/113); and by 3 year post-de novo DSA 32.2% (20/62) of the patients lost their graft. Overall allograft survival was 75.2% (85/113) (A) and death-censored allograft survival was 77.0% (87/113) (B) during a median follow-up of 2.2 (IQR 1.2–3.7) years following dnDSA detection.

Figure 3.. Death-censored allograft survival was decreased if there was prior history patient induced medication nonadherence or viral infection leading to immunosuppressive reduction.

Death-censored allograft survival following dnDSA was 70.0% (21/30) in the medication nonadherence group, 67.4% (23/34) in the prior viral infection group, and higher at 87.8%(43/49) in the group with neither medication nonadherence nor prior viral infection during a mean follow-up of 2.2 (IQR 1.2–3.7) years post-dnDSA detection, p=0.009.

Figure 4.. Allograft Histology at the time of De novo DSA Detection.

Importantly, the biopsy findings at the time of de novo DSA detection were similar among centers (p=0.76) and no difference in death-censored graft loss was observed among those patients with or without biopsies performed at this time point [17.9% (12/67) allograft loss in patients with a biopsy versus 30.4% (14/46) allograft loss in patients without a biopsy, p=0.12].

Figure 5.. Allograft similar in IgG 3+ and IgG – patients who were negative for chronic ABMR at De novo DSA detection.