Dataset Information

Glomerular C4d Immunoperoxidase in Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy.

ABSTRACT:

Introduction

The diagnosis of late antibody-mediated rejection (AMR) is compromised by frequent absence of C4d in peritubular capillaries (C4d_ptc), termed "C4d-negative" AMR. We hypothesized that glomerular capillary C4d (C4d_glom) reflected endothelial interaction with antibody and could improve immunologic classification of transplant glomerulopathy (TG).

Methods

We evaluated C4d using immunoperoxidase in 3524 consecutive, kidney transplant biopsies from a single center.

Results

C4d_glom was detected in 16.5% and C4d_ptc in 9.9% of biopsies. C4d_glom occurred in 60.3% of TG (n = 174) and was absent in normal glomeruli. Epidemiologic risk factors for C4d_glom were younger, female, living-donor recipients with early AMR, prior treated rejection, and late presentation using multivariable analysis. Semiquantitative C4d_glom score correlated with donor specific antibody (DSA) level, C4d_ptc, microvascular inflammation (MVI), Banff cg scores, renal dysfunction, and proteinuria. Principal component analysis colocalized C4d_glom with histologic AMR. Multivariable analysis of TG found DSA, C4d_ptc, and post-transplant time associated with C4d_glom. Addition of C4d_glom into Banff chronic AMR schema improved its diagnostic sensitivity for TG (verified by electron microscopy [EM]) from 22.2% to 82.4% and accuracy from 59.6% to 93.9%, compared with Banff 2019 using only C4d_ptc. Tissue C4d_glom and chronic AMR diagnosis incorporating C4d_glom were associated with death-censored allograft failure in TG (P < 0.001), independent of the severity of glomerulopathy and chronic interstitial fibrosis.

Conclusion

C4d_glom is a promising diagnostic biomarker of endothelial interaction with antibody which substantially improved test performance of the Banff schema to correctly classify TG by pathophysiology and prognosticate graft loss. We recommend routine C4d immunoperoxidase to minimize underdiagnosis of late AMR in TG.

SUBMITTER: Nankivell BJ

PROVIDER: S-EPMC9263257 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This study investigated the mechanisms involved in development of donor-specific antibody (DSA) and/or C4d-negative transplant glomerulopathy (TGP) by allograft gene expression profiles using microarrays.This cohort study was conducted in kidney transplant recipients. Patients were eligible for inclusion if they required a clinically indicated biopsy at any time point after their transplant. They were then classified according to their histopathology findings and DSA and C4d results. Eighteen chronic antibody-mediated rejection (CAMR), 14 DSA+/C4d- TGP, 25 DSA-/C4d- TGP, and 47 nonspecific interstitial fibrosis/tubular atrophy (IFTA) biopsy specimens were identified. In a subset of patients from the study population, biopsy specimens in each group and normal transplant kidney specimens were analyzed with Affymetrix Human Gene 1.0 ST Arrays.The mean sum score of glomerulitis and peritubular capillaritis increased from 0.28±0.78 in IFTA specimens to 0.75±0.85 in DSA-/C4d- TGP specimens, 1.71±1.49 in DSA+/C4d-/TGP specimens, and 2.11±1.74 in CAMR specimens (P<0.001). During a median follow-up time of 2 (interquartile range, 1.4-2.8) years after biopsy, graft loss was highest in CAMR specimens (27.8%) compared to IFTA specimens (8.5%), DSA+/C4d- TGP specimens (14.3%), and DSA-/C4d- TGP specimens (16%) (P=0.01). With use of microarrays, comparison of the gene expression profiles of DSA-/C4d- TGP specimens with glomerulitis + peritubular capillaritis scores > 0 to normal and IFTA biopsy specimens revealed higher expression of quantitative cytotoxic T cell-associated transcripts (QCAT). However, both CAMR and DSA+/C4d- TGP specimens had higher expression of not only QCAT but also IFN-? and rejection-induced, constitutive macrophage-associated, natural killer cell-associated, and DSA-selective transcripts. Endothelial cell-associated transcript expression was upregulated only in CAMR biopsy specimens.These results suggested that DSA+/C4d- TGP biopsy specimens may be classified as CAMR. In contrast, DSA-/C4d- TGP specimens showed increased cytotoxic T cell-associated transcripts, suggesting T cell activation as a mechanism of injury.