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Enhanced Diagnosis of Chronic Antibody-mediated Rejection Using Peritubular Capillary Multilayering
Brian J Nankivell1, Meena Shingde2, Chow Heok P'Ng2
1Department of Renal Medicine, Tissue Pathology and Diagnostic Oncology and Electron Microscopy Units, NSW Health Pathology, Sydney, NSW, Australia.
Insights
Peritubular capillary multilayering (PTCML) is a key marker for chronic antibody-mediated rejection (AMR). New criteria using circumferential scoring of PTCML show high sensitivity for detecting early chronic AMR, improving upon existing diagnostic methods.
Area of Science:
- Nephrology
- Transplant Immunology
- Histopathology
Background:
- Peritubular capillary multilayering (PTCML) is an ultrastructural feature of chronic antibody-mediated rejection (AMR).
- Current diagnostic thresholds for PTCML in chronic AMR are uncertain.
- Understanding PTCML is crucial for accurate diagnosis and patient management.
Purpose of the Study:
- To evaluate the relationship between PTCML and chronic AMR in kidney transplant recipients.
- To establish diagnostic thresholds for PTCML indicative of chronic AMR.
- To assess the diagnostic performance of novel PTCML criteria compared to existing Banff criteria.
Main Methods:
- A single-center, prospective cohort study involving 2541 kidney samples from 1195 recipients.
- Epidemiological modeling to identify clinical risk factors for abnormal PTCML scores.
- Histological analysis using Banff criteria and novel PTCML scoring methods, including circumferential assessment.
Main Results:
- Clinical risk factors for abnormal PTCML (≥3) included younger recipients, living donation, early AMR, and higher donor-specific antibody strength.
- PTCML layers correlated with transplant time, AMR histology, DSA, renal dysfunction, proteinuria, and graft failure.
- Modified PTCML criteria (≥7 or 2×PTCML ≥5) improved sensitivity for diagnosing chronic AMR compared to Banff 2013 criteria.
Conclusions:
- Circumferential PTCML (≥3) in multiple capillaries is a sensitive histological marker for mild chronic AMR and tissue injury.
- The proposed ultrastructural criteria offer a superior method for detecting early chronic AMR phenotypes.
- Multicenter validation of these novel diagnostic criteria is recommended.
Background:
Peritubular capillary multilayering (PTCML) of basement membranes is an ultrastructural feature of chronic antibody-mediated rejection (AMR) with uncertain diagnostic thresholds.
Methods:
This single-center, prospective cohort study evaluated the relationships of PTCML with chronic AMR in 2541 kidney samples from 1195 recipients.
Results:
Epidemiological modeling found that younger recipients, living donation, early AMR, pulse corticosteroid rejection treatment, later presentation, and higher donor-specific antibody strength were clinical risk factors for an abnormal PTCML score of ≥3. The total number of PTC layers was correlated with posttransplant time, AMR histology, donor-specific antibody positivity, renal dysfunction, proteinuria, and graft failure. Histological Banff cg, ptc, C4d ptc , and C4d glom independently predicted PTCML ≥3. Mild PTCML of 3-4 layers with circumferential remodeling in multiple PTC showed 82.9% sensitivity and 72.7% specificity against the Banff cg≥1a reference test, verified using Banff 2022 AMR criteria, and considered "suspicious" for chronic AMR. PTCML ≥5 correlated with late graft failure. Normal PTC (n = 322) in early protocol samples showed 1 basement membrane layer, except for 12.5% with mild segmental reduplication involving 13.7 ± 10.2% capillary circumference. Circumferential scoring efficiently separated mild segmental PTCML from normal variability against pathological AMR multilayering. The poor 30.0% sensitivity and 91.1% specificity (n = 374 late indication biopsies, 2029 PTCs) of the Banff 2013 AMR criteria improved to 55.0% and 89.7% using modified PTCML ≥7 or 2×PTCML ≥5 criteria, which allowed for a diagnostic disease "rule-in."
Conclusions:
Circumferential multilayering from PTCML ≥3 replicated across multiple capillaries optimally recognized mild chronic AMR as a superior histological marker of chronic tissue injury with high sensitivity. These ultrastructural diagnostic criteria for the detection of early chronic AMR phenotypes require multicenter validation.
