Microvascular inflammation in renal transplant recipients without antibody mediated rejection
Raad Chowdhury1, Johnny Bu Saba1, Sundaram Hariharan1, Aravind Cherukuri1.
1Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States
Purpose: Microvascular inflammation (MVI) defined by glomerulitis (g) and peritubular capillaritis (ptc) is a hallmark of ABMR in renal transplantation. The prevalence and significance of MVI in patients without ABMR is less understood.
Methods: Here, we analyzed MVI in the 1st post-transplant year, its relationship to DSA, and its clinical significance in a large cohort of patients without ABMR. Along with any for-cause biopsy (fcBx), patients underwent 2 protocol biopsies (pBx, 3 & 12mos). Bx were categorized as early (0-4mos) or late (5-12mos). Serum was screened for DSA at 0, 1, 3, 6, 9 & 12mos post-transplant.
Results: MVI Prevalence: 956/1187 patients transplanted between 2013-18 underwent 1950 Bx (67% protocol, 33% for-cause). Of these Bx, 64 had either ABMR or GN and were excluded. MVI was noted in 23% (g+ptc score 1-1.5 in 13% & ≥2 in 10%) of the remaining 1887 Bx with greater prevalence in fcBx (fcBx 14% vs. pBx 7%) and late Bx (late Bx 29% vs. early Bx 17%). Of note, the MVI prevalence and its severity increased with increasing grades of tubulointerstitial inflammation (TII) (Fig 1A). Of note, 65% of patients with allograft infections (pyelonephritis & BKVN) had MVI.
MVI & DSA: DSA was detected concurrently in 12% of all the 1887 Bx without ABMR. Although, MVI was associated with concurrent DSA detection in these Bx (OR 1.8, 95% CI 1.3-2.5, p<0.,001), ~60% of the biopsies never had DSA (concurrent/historic or future). Furthermore, in biopsies stratified by the grade of TCMR, there was no significant difference in concurrent DSA detection between patients with and without MVI (Fig.1B).
Outcomes: MVI in patients without ABMR was associated with decreased 7yr-graft survival (Fig 1C, p<0.001). Importantly, the combination of MVI and TII was associated with worse graft survival when compared to either no inflammation or TII alone (Fig1C, p<0.001). Further, in a select sub-group of patients with allograft infection, MVI was associated with a trend towards decreased graft survival compared to no MVI (76% vs. 88%). Finally, MVI was associated with poor graft survival independent of potential confounders including DSA (HR 2.5, 95% CI 1.6-3.4, p<0.001).
Conclusion: MVI is common even in the absence of ABMR or DSA and is a marker for the severity of allograft inflammation and subsequent poor clinical outcomes.
