*Purpose: There is emerging evidence suggesting non-HLA autoantibodies triggered after the graft injury. Here, we report 3 cases where non-HLA autoantibodies were positive after 3 different kinds of insults to the renal allograft.

*Methods: Case1: A 31-year-old Hispanic female with history of End stage kidney disease (ESKD) due to reflux nephropathy, with pre-existing weak class I and class II DSAs, received a cross match negative Deceased Donor Kidney transplant (DDKT). Her 2 Allograft biopsies after 3 and 6 months were suggestive of borderline T cell mediated rejection & acute and chronic antibody mediated rejection (AMR) respectively. During this time her creatinine kept fluctuating higher than the baseline with down trending DSAs, but significantly high titers of various MICA autoantibodies. Even after extensive AMR therapy, serum creatinine remained above the baseline. Case2: A 27-year-old Hispanic male with ESKD due to presumed hypertensive nephrosclerosis, received a crossmatch negative DDKT and developed Acute allograft Kidney Injury (AKI) within 8-9 hours post-transplant. The allograft Kidney exhibited acute AMR and Acute tubular Necrosis (ATN) while the autoantibodies to Endothelial Cell 1 and AT1R were positive in the blood. Case3: A 46-year-old African American male with ESKD due to obstructive uropathy, who received ABO incompatible Living donor kidney transplant with Thymoglobulin induction along with a single dose of eculizumab developed AMR after 10 days. He was treated with pulse dose steroid, plasmapheresis, Intravenous immunoglobulin and Bortezomib, but renal functions never came down to the previous baseline. Repeat biopsy after 2 months for new AKI exhibited features of recovering AMR with ATN. Repeatedly negative DSA but significantly high AT1R Ab found at this time.

*Results: In the first case, the primary insult was the DSA associated AMR, which might have triggered the MICA Ab production. The ischemia reperfusion injury might have triggered the AT1R and EC1 autoantibodies, leading to the immediate post-transplant AMR in the second case. The third patient who developed AMR in the setting of possible ABO incompatibility associated humoral rejection severe enough to trigger the significantly high titer of AT1R Ab.

*Conclusions: The initial event in all three patients likely triggered the non-HLA autoantibodies production, explaining the poor recovery after extensive therapy for the rejection. The partial recovery post treatment should prompt to check non-HLA Ab to understand the role of this hidden culprit.

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