Clinical Relevance of Allograft Microvascular Inflammation

By Victoria Socha - Last Updated: December 26, 2024

Challenges associated with the management of patients with end-stage kidney disease include high morbidity, mortality, and costs. Kidney transplantation is the gold standard of treatment for end-stage kidney disease. Allograft rejection leading to long-term allograft loss is a major contributor to those challenges. 

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The failure of kidney allografts is attributed to antibody-mediated alloimmune responses. Allograft microvascular inflammation is the hallmark histologic lesion of antibody-mediated graft injury. The heterogeneous clinical presentation of graft microvascular inflammation may result in adverse outcomes in recipients of kidney transplantation. The mechanisms underlying graft microvascular inflammation are unclear, as is the effect of microvascular inflammation on allograft outcomes. 

Two new diagnostic categories were added to the 2022 Banff Classification of Renal Allograft Pathology: (1) probable antibody-mediated rejection (microvascular inflammation or injury [MVI], donor-specific antibody-negative [DSA-negative], and C4d-negative) and (2) microvascular inflammation without evidence of an antibody-mediated response (probable antibody-mediated rejection). 

A team of researchers led by Marta Sablik, MD, and Aurélie Sannier, MD, PhD, conducted a large, population-based, multicenter cohort study to examine the clinical relevance of allograft microvascular inflammation. The researchers also sought to assess the implications of the newly recognized phenotypes as related to precision diagnostics for kidney allografts, risk stratification, allograft outcomes, and potential therapeutic strategies. Results of their study were reported online in The New England Journal of Medicine. 

The study population included recipients of kidney transplants from more than 30 transplantation centers in Europe and North America. Eligible participants had undergone allograft biopsy between 2004 and 2023.  

The primary outcome of interest was the association between the newly recognized microvascular inflammation phenotypes and allograft survival, defined as return to dialysis or preemptive kidney retransplantation. Secondary outcomes included new or recurrent antibody-mediated rejection and transplant glomerulopathy—a chronic and progressive form of allograft injury—in patients with a first microvascular inflammation-related diagnosis. 

The primary analysis comprised 6,798 patients who had undergone at least one kidney-allograft biopsy following transplantation. Mean age was 44.6 years, 38.6% (n=2,590/6,708) were female, and 78.6% (n=5,270/6,705) had received a deceased-donor transplant. Of these patients, 12.7% (n=851/6,691) had undergone retransplantation, 1.6% (n=108/6,736) had an ABO-incompatible kidney transplant, and 25.1% (n=1,305/5,204) had circulating donor-specific antibodies. 

The analysis included 16,293 kidney-transplant biopsy specimens. The median time from transplantation to biopsy was 8.1 months. The newly recognized microvascular inflammation phenotypes were identified in 4.8% of the specimens (n=788). Of them, 3.1% (n=503) had a phenotype of MVI, DSA-negative, and C4d-negative, and 1.7% (n=285) had a phenotype of probable antibody-mediated rejection. 

Of the 788 specimens with the newly recognized inflammation phenotypes, 63.3% (n=641) were from patients with a nonrejection-related 2019 Banff classification (391 reclassified as MVI, DSA-negative, and C4d-negative and 250 reclassified as probable antibody-mediated rejection according to the 2022 Banff classification). According to the 2019 Banff classification, 781 specimens had a diagnosis of T-cell-mediated rejection. Of them, 9.7% (n=76) were reclassified according to the 2022 Banff classification as MVI, DSA-negative, and C4d-negative (n=48) or probable antibody-mediated rejection (n=28). 

Graft survival was worse among patients with a nonrejection-related diagnosis according to the 2019 Banff classification who were subsequently reclassified as MVI, DSA-negative, and C4d-negative according to the 2022 Banff classification compared to those with a nonrejection-related diagnosis according to both Banff classifications (hazard ratio [HR] for graft loss, 2.1; 95% CI, 1.5-3.1).  

Beyond year five following biopsy, patients with a nonrejection-related diagnosis with the 2019 Banff classification and a 2022 Banff diagnosis of probable antibody-mediated rejection had worse graft survival compared to patients with a nonrejection-related diagnosis according to both classifications (HR for graft loss, 1.7; 95% CI, 0.8-3.5). The difference was not seen through year five after biopsy (HR for graft loss, 1.3; 95% CI, 0.8-2.1). 

Graft survival was worse among patients with a diagnosis of antibody-mediated rejection according to both Banff classifications compared to patients with a nonrejection-related diagnosis according to both classifications (HR for graft loss, 2.7; 95% CI 2.2-3.3). Results were similar in a sensitivity analysis of the cumulative incidence of allograft loss according to the reclassified diagnosis where death was treated as a competing risk. 

The researchers also assessed the risk of new or recurrent antibody-mediated rejection during follow-up among 5,235 patients with a first microvascular inflammation-related diagnosis and no previous episodes of kidney-allograft rejection. Of them, 8.1% (n=423) had new or recurrent antibody-mediated rejection. Those with a diagnosis of MVI, DSA-negative, and C4d-negative or probable antibody-mediated rejection had an intermediate cumulative incidence of antibody-mediated rejection during follow-up compared to patients without a diagnosis of microvascular inflammation and those with active antibody-mediated rejection. Patients with MVI, DSA-negative, and C4d-negative and those with probable antibody-mediated rejection had similar risk of antibody-mediated rejection during follow-up. 

The risk of progression of transplant glomerulopathy during follow-up was higher among the patients with a diagnosis of either of the newly recognized microvascular inflammation phenotypes compared to patients without microvascular inflammation. Patients in the MVI, DSA-negative, and C4d-negative group and those in the probable antibody-mediated rejection group had similar risks of progression. 

The researchers cited some limitations to the study findings, including an inability to assess the association between graft outcomes and treatment, as well as an inability to fully assess the natural evolution of the microvascular inflammation phenotypes.  

In summary, the authors said, “Our study, which included a highly characterized multicenter cohort of more than 6,000 kidney transplant recipients, provides a detailed analysis of the clinical characteristics and prognostic importance of specific microvascular inflammation phenotypes that were introduced in the 2022 Banff classification for pathological assessment of renal allografts.” 

Source: The New England Journal of Medicine. 

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