Antibody-Mediated Microcirculation Injury Is the Major Cause of Late Kidney Transplant Failure

Abstract

We studied the phenotype of late kidney graft failure in a prospective study of unselected kidney transplant biopsies taken for clinical indications. We analyzed histopathology, HLA antibodies and death-censored graft survival in 234 consecutive biopsies from 173 patients, taken 6 days to 31 years posttransplant. Patients with late biopsies (>1 year) frequently displayed donor-specific HLA antibody (particularly class II) and microcirculation changes, including glomerulitis, glomerulopathy, capillaritis, capillary multilayering and C4d staining. Grafts biopsied early rarely failed (1/68), whereas grafts biopsied late often progressed to failure (27/105) within 3 years. T-cell-mediated rejection and its lesions were not associated with an increased risk of failure after biopsy. In multivariable analysis, graft failure correlated with microcirculation inflammation and scarring, but C4d staining was not significant. When microcirculation changes and HLA antibody were used to define antibody-mediated rejection, 17/27 (63%) of late kidney failures after biopsy were attributable to antibody-mediated rejection, but many were C4d negative and missed by current diagnostic criteria. Glomerulonephritis accounted for 6/27 late losses, whereas T-cell-mediated rejection, drug toxicity and unexplained scarring were uncommon. The major cause of late kidney transplant failure is antibody-mediated microcirculation injury, but detection of this phenotype requires new diagnostic criteria.

Comparing Molecular Assessment of Implantation Biopsies With Histologic and Demographic Risk Assessment

“…The histologic lesions that characterize old donor kidneys-atrophy, scarring, glomerulosclerosis, arterial fibrous intimal thickening, arteriolar The PPV and NPV of traditional indices correspond to the best discriminative cut point of present study. 3 Recipient variables in Irish score are PRA, duration of dialysis and recipient BMI (no recipient age) (14). hyalinosis-were associated with donor age as expected but their associations with early dysfunction were not as strong as donor age itself.…”

“…DGF is associated with reduced long-term outcomes in registry studies, but much of this is probably due to recipient comorbidities, which can contribute both to early dysfunction and late intercurrent illnesses and patient death. A common belief that DGF "causes" progressive late deterioration is not supported by phenotype data: recent biopsy studies of troubled transplants show that most late graft losses are attributable to definable entities such as antibody-mediated rejection (ABMR), nonadherence and recurrent disease (3,4), and no phenotype of late unexplained deterioration associated with early DGF has been identified.…”

“…arterial fibrous (1) Donor age more than or equal to 60 years or (2) Donor age 50-59 years, with at least two of the three following criteria: serum creatinine more than 1.5 mg/dL. 3 Excluded pre-emptive kidney transplantation, n = 2. 4 Donors who have underlying hypertension, dyslipidemia or diabetes and died from hemorrhagic or ischemic stroke.…”

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

“…The first 403 were interpreted centrally by Drs B. Sis and M. Mengel (9,10). During these studies, we discovered the importance of C4d-negative ABMR, and biopsies were interpreted accordingly (5). For the next 300 biopsies, the lesions were assessed locally and the diagnoses were updated centrally to ensure the classification reflected the Banff 2013 guidelines (11,12).…”

Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

“…This chronic endothelial damage is thought to be due to alloantibody fixation. 8,[12][13][14] Whereas the primary insult in TxG seems to be directed against GECs, other features of TxG, such as proteinuria 8 and focal and segmental glomerulosclerosis 15 are typical indicators of podocyte damage. Proteinuria suggests podocyte damage, because podocytes are considered to be the most important component of the glomerular filter.…”