Background: Understanding the specific causes of TG and its long-term consequences at population scale is lacking.
Methods: This study includes all kidney allograft biopsies performed between January 2004 and January 2014 in three French referral centers and one Canadian center showing TG (Banff cg score≥1 by light microscopy).  All TG cases were extensively phenotyped and systematically assessed using light microscopy, immunohistochemistry (IH), immunofluorescence (IF), together with circulating anti-HLA-DSA at the time of biopsy.
Results: Among the 8,207 post-transplant allograft biopsies performed during the inclusion period, 552 (6.7%) presented with double contours and corresponded to 385 patients. Three predominant overlapping etiologies accounted for 466 (84.4%) cases. 417 biopsies showed antibody-mediated injury (75.5%), 90 biopsies showed TMA (16.3%), 65 showed MPGN (11.8%), while 86 (15.6%) remained equivocal with no specific cause identified (Figure 1). The median time of TG diagnosis post-transplant was 33.18 months (IQR: 12.12 – 78.72 months). Kidney allograft survival after TG diagnosis was 69.4% at 3 years, 57.1% at 5 years, 43.3% at 7 years and 25.5% at 10 years (Figure2). After adjusting for donor, recipient and transplant characteristics, immunological and histological parameters, we identified the following independent factors associated with long-term allograft survival in patients with TG: eGFR (HR: 0.96; CI 95% (0.95-0.98); p<0.001) and proteinuria level (squared transformation) (HR: 2.16; CI 95% (1.76-2.65); p<0.0001) at the time of biopsy, deceased donor (HR: 1.62; CI 95% (1.11-2.40); p=0.016), delay between transplantation and TG diagnosis (log transformation) (HR:1.31; CI 95% (1.16-1.49); p<0.001), vasculitis Banff score (HR: 1.66; IC 95% (1.04-2.65); p=0.032) and TG biopsy with ongoing disease process (HR: 1.55; IC 95% (1.01-2.391); p=0.047).
Conclusion: Using a large cohort of kidney recipients with a diagnosis of TG and a systematic phenotyping, we identify three overlapping pathways in TG: ABMR, TMA and MPGN. The identification of the main independent determinants of TG prognosis may help improving risk stratification and define specific causes and disease process in patients with TG.