Transplantation reviews (Orlando, Fla.) · 2026
DSA-negative, C4d-negative microvascular inflammation after kidney transplantation as an endothelial injury syndrome: A narrative review.
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El Hennawy Hany M, Safar Omar, Aboalsamh Ghaleb, Banemah Turki, Almarzouk Saad, Neyas Afnan, El Hennawy Menna, Khedr Abdullah, Sharab Ahmed M, Jaber Tariq, Abudawood Rawabi, Balah Rahma, Tawahri Ibrahim
Аннотация
BACKGROUND: Microvascular inflammation (MVI), defined by glomerulitis and peritubular capillaritis, is a major predictor of kidney allograft failure. A clinically important subset develops MVI despite persistently negative donor-specific antibody (DSA) testing and the absence of C4d staining. Although recognized in the Banff 2022 classification, its mechanisms, prognosis, and management remain incompletely defined.
OBJECTIVE: To synthesize the evidence on DSA-negative, C4d-negative MVI in kidney transplantation, focusing on prognosis, biological heterogeneity, early post-transplant C4d-negative antibody-mediated rejection (AMR), biomarkers, and treatment, and to propose the Endothelial Injury Continuum Model as a hypothesis-generating framework.
METHODS: A narrative review with a structured, transparent literature search across five databases (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library) from January 2000 to June 2026. Studies were synthesized qualitatively; no quantitative pooling was performed.
RESULTS: The largest multicenter cohort (>16,000 biopsies from ∼6900 recipients across >30 centers) reported a graft-loss risk of DSA-negative MVI approaching that of AMR (hazard ratio [HR] 2.1, 95% CI 1.5-3.1 vs 2.7, 95% CI 2.2-3.3). Graft-failure rates ranged from 18% to 48%. Molecular DSA-negative AMR presented earlier than DSA-positive disease (2.4 vs 3.9 years). In a single-center Japanese cohort, lower tacrolimus (OR 0.169, p = 0.002) and everolimus exposure (OR 0.386, p = 0.022) were associated with MVI; these effect estimates are hypothesis-generating and require multicenter replication. Missing-self allorecognition (≥1 type) was associated with MVI risk (OR 1.40, 95% CI 1.08-1.80; p = 0.011); the association between ≥2 missing-self types and graft loss was not statistically significant (HR 1.97, 95% CI 0.89-4.37; p = 0.097). Pre-transplant AT1R antibodies predicted rejection (HR 2.09). Early MVI was DSA-associated in only 27% of cases, versus 79% of late biopsies.
CONCLUSIONS: DSA-negative, C4d-negative MVI is a biologically heterogeneous, high-risk phenotype rather than a single disease mechanism. The Endothelial Injury Continuum Model and accompanying pathway framework provide hypothesis-generating tools for organizing diverse mechanisms that converge on endothelial injury. We propose "endothelial injury syndrome" as a conceptual descriptor of this shared downstream phenotype while acknowledging biological heterogeneity; it is not intended to replace existing Banff diagnostic categories. Prospective multicenter validation is required before the proposed pathways can support etiologic classification or mechanism-directed treatment.
OBJECTIVE: To synthesize the evidence on DSA-negative, C4d-negative MVI in kidney transplantation, focusing on prognosis, biological heterogeneity, early post-transplant C4d-negative antibody-mediated rejection (AMR), biomarkers, and treatment, and to propose the Endothelial Injury Continuum Model as a hypothesis-generating framework.
METHODS: A narrative review with a structured, transparent literature search across five databases (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library) from January 2000 to June 2026. Studies were synthesized qualitatively; no quantitative pooling was performed.
RESULTS: The largest multicenter cohort (>16,000 biopsies from ∼6900 recipients across >30 centers) reported a graft-loss risk of DSA-negative MVI approaching that of AMR (hazard ratio [HR] 2.1, 95% CI 1.5-3.1 vs 2.7, 95% CI 2.2-3.3). Graft-failure rates ranged from 18% to 48%. Molecular DSA-negative AMR presented earlier than DSA-positive disease (2.4 vs 3.9 years). In a single-center Japanese cohort, lower tacrolimus (OR 0.169, p = 0.002) and everolimus exposure (OR 0.386, p = 0.022) were associated with MVI; these effect estimates are hypothesis-generating and require multicenter replication. Missing-self allorecognition (≥1 type) was associated with MVI risk (OR 1.40, 95% CI 1.08-1.80; p = 0.011); the association between ≥2 missing-self types and graft loss was not statistically significant (HR 1.97, 95% CI 0.89-4.37; p = 0.097). Pre-transplant AT1R antibodies predicted rejection (HR 2.09). Early MVI was DSA-associated in only 27% of cases, versus 79% of late biopsies.
CONCLUSIONS: DSA-negative, C4d-negative MVI is a biologically heterogeneous, high-risk phenotype rather than a single disease mechanism. The Endothelial Injury Continuum Model and accompanying pathway framework provide hypothesis-generating tools for organizing diverse mechanisms that converge on endothelial injury. We propose "endothelial injury syndrome" as a conceptual descriptor of this shared downstream phenotype while acknowledging biological heterogeneity; it is not intended to replace existing Banff diagnostic categories. Prospective multicenter validation is required before the proposed pathways can support etiologic classification or mechanism-directed treatment.