Advanced Tertiary Lymphoid Tissues in Protocol Biopsies are Associated with Progressive Graft Dysfunction in Kidney Transplant Recipients

Background: Tertiary lymphoid tissues (TLTs) are ectopic lymphoid tissues found in chronically inflamed organs. Although studies have documented TLT formation in transplanted kidneys, the clinical relevance of these TLTs remains controversial. We examined the impacts of TLTs on future graft function using our histological TLT maturity stages and the association between TLTs and Banff pathologic scores. We also analyzed the risk factors for the development of TLTs Methods: Serial protocol biopsy samples (0-hour, 1-, 6-, and 12-months) without rejection were retrospectively analyzed from 214 patients who underwent living donor kidney transplantation. TLTs were defined as lymphocyte aggregates with signs of proliferation and their stages were determined by the absence (stage I) or presence (stage II) of follicular dendritic cells. Results: Only 4% of patients exhibited TLTs at the 0-hour biopsy. Prevalence increased to almost 50% at the 1-month biopsy and then slightly further for 12 months. The proportion of advanced stage II TLTs increased gradually, reaching 19% at the 12-month biopsy. Presence of stage II TLTs was associated with higher risk of renal function decline after transplantation compared to patients with no TLT or stage I TLTs. Stage II TLTs were associated with more severe tubulitis and interstitial fibrosis/tubular atrophy at 12 months and predicted poorer graft function independently from the degree of interstitial inflammation. Pre-transplantation rituximab treatment dramatically attenuated the development of stage II TLTs. Conclusions: TLTs are commonly found in clinically stable transplanted kidneys. Advanced stage II TLTs are associated with progressive graft dysfunction, independent of interstitial inflammation.