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Updated: Jun 18, 2025
Investigating the Immunological Mechanisms Underlying Organ Transplant Rejection
Published on: August 20, 2007
The relationship of microvascular inflammation with antibody-mediated rejection in kidney transplantation
Brian J Nankivell1, Anne Taverniti2, Seethalakshmi Viswanathan3
1Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
Abstract:
Microvascular inflammation (MVI) is a key diagnostic feature of antibody-mediated rejection (AMR); however, recipients without donor-specific antibodies (DSA) defy etiologic classification using C4d staining of peritubular capillaries (C4dptc) and conventional DSA assignment. We evaluated MVI ≥ 2 (Banff g + ptc ≥ 2) using Banff 2019 AMR (independent of MVI ≥ 2 but including C4dptc) with unconventional endothelial C4d staining of glomerular capillaries (C4dglom) and - arterial endothelium and/or intima (C4dart) using tissue immunoperoxidase, shared-eplet and subthreshold DSA (median fluorescence intensity, [MFI] 100-499), and capillary ultrastructure from 3398 kidney transplant samples for evidence of AMR. MVI ≥ 2 (n = 202 biopsies) from 149 kidneys (12.4% prevalence) correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, proteinuria, and graft failure compared with 202 propensity score matched normal controls. The laboratory reported DSA- MVI ≥ 2 (MFI ≥500) occurred in 34.7%; however, subthreshold (28.6%), eplet-directed (51.4%), and/or misclassified anti-Human leukocyte antigen (HLA) DSA (12.9%) were identified in 67.1% by forensic reanalysis, with vascular C4d+ staining in 67.1%, and endothelial abnormalities in 57.1%, totaling 87.1%. Etiologic analysis attributed 62.9% to AMR (77.8% for MVI with negative reported DSA [DSA- MVI ≥2] with glomerulitis) and pure T cellular rejection in 37.1%. C4dptc-DSA- MVI ≥ 2 was unrecognized AMR in 48.0%. Functional outcomes and graft survival were comparable to normal controls. We concluded that DSA- MVI ≥ 2 frequently signified a mild "borderline" phenotype of AMR which was recognizable using novel serologic and pathological techniques.
Insights
Microvascular inflammation (MVI) in kidney transplants, even without donor-specific antibodies (DSA), often indicates antibody-mediated rejection (AMR). Advanced diagnostics reveal underlying DSA or C4d staining, enabling better classification and treatment.
Area of Science:
- Transplant immunology
- Nephrology
- Pathology
Background:
- Microvascular inflammation (MVI) is a key marker for antibody-mediated rejection (AMR) in kidney transplants.
- Classifying AMR is challenging in patients lacking donor-specific antibodies (DSA) and exhibiting peritubular capillary C4d staining (C4dptc).
Purpose of the Study:
- To evaluate microvascular inflammation (MVI ≥ 2) using Banff 2019 criteria, incorporating unconventional C4d staining and subthreshold/eplet-directed DSA.
- To determine the etiology of MVI in kidney transplant recipients, particularly those negative for donor-specific antibodies (DSA).
Main Methods:
- Analysis of 3398 kidney transplant biopsies using Banff 2019 criteria, including MVI (g + ptc ≥ 2).
- Unconventional C4d staining (glomerular and arterial), forensic reanalysis of DSA (including subthreshold and eplet-directed), and capillary ultrastructure assessment.
- Comparison of MVI ≥ 2 cases with propensity score-matched normal controls.
Main Results:
- MVI ≥ 2 was observed in 12.4% of biopsies and correlated with AMR markers, graft dysfunction, and failure.
- Forensic reanalysis identified DSA in 67.1% of cases initially reported as DSA-negative MVI ≥ 2, with vascular C4d+ and endothelial abnormalities present in a significant proportion.
- Antibody-mediated rejection (AMR) was attributed to 62.9% of DSA-negative MVI ≥ 2 cases, with 48.0% being previously unrecognized AMR.
Conclusions:
- Microvascular inflammation (MVI ≥ 2) in DSA-negative kidney transplant recipients frequently represents a mild phenotype of antibody-mediated rejection (AMR).
- Novel serologic and pathological techniques, including advanced DSA and C4d assessment, are crucial for accurate AMR diagnosis in these cases.
- Timely diagnosis and management of this 'borderline' AMR can potentially improve graft survival outcomes.
