Kidney Transplant Trouble Spelled Out for Newer Rejection Episode Categories

SAN DIEGO — Kidney transplant patients who shifted into newly recognized microvascular inflammation categories under revised definitions had an intermediate risk of poor allograft outcomes, a large study showed.

Researchers examined outcomes among more than 6,700 kidney transplant recipients, looking at two categories added in 2022 to the benchmark diagnostic framework for allograft rejection in kidney transplantation, the Banff Classification of Renal Allograft Pathology.

With the first category — microvascular inflammation or injury without evidence of a donor-specific antibody-mediated response — graft loss was 2.1-fold more likely (95% CI 1.5-3.1) than among patients with no evidence of rejection on biopsy.

That represented an “intermediate prognosis” compared with graft loss that was 2.7-fold more likely (95% CI 2.2-3.3) among patients with antibody-mediated rejection, as Aurelie Sannier, MD, PhD, of the Paris Institute for Transplantation and Organ Regeneration, reported at the American Society of Nephrology Kidney Week meeting.

The second category — probable antibody-mediated rejection with donor-specific antibodies but a mild form of microvascular inflammation in the absence of C4d as a marker of antibody-mediated allograft damage — had a higher risk of long-term graft failure. The hazard ratio was 1.7 (95% CI 0.8-3.5) beyond year 5 after biopsy compared with patients without rejection and 1.3 (95% CI 0.8-2.1) before that point.

Both of these newer microvascular inflammation phenotype groups had a higher risk of progression of transplant glomerulopathy than seen without microvascular inflammation.

“We think that the recognition of these phenotypes will improve the risk stratification and support more personalized management for kidney transplant patients, and that the difference that we observe in allograft outcomes implies that alternative mechanisms may contribute to the etiology of isolated microvascular inflammation, with potential important therapeutic implications,” Sannier said.

The findings were simultaneously published in the New England Journal of Medicine.

Antibodies against the donor tissue is a key factor in the failure of kidney allografts, and allograft microvascular inflammation is the “hallmark histologic lesion” in these cases. The 2019 Banff classification had focused on microvascular inflammation solely in the context of antibody-mediated rejection.

However, graft microvascular inflammation without such circulating donor-specific anti-HLA antibodies is common. “This heterogeneous presentation poses a major clinical challenge because current treatment strategies are often ineffective, which hinders improvements in allograft outcomes and patient care,” Sannier’s group wrote.

The study included 16,293 kidney-transplant biopsy specimens from 6,798 patients cared for at more than 30 transplantation centers in Europe and North America from 2004 to 2023. Median follow-up was 5.0 years after kidney transplant biopsy. Graft loss occurred in 490 patients (11.2%).

Of the 788 patients found by the researchers to have one of the two newly described microvascular inflammation classifications (3.1% antibody-negative and 1.7% probable antibody-mediated rejection), 641 of them had been previously categorized as having no evidence of rejection.

“As these diagnostic modifications are integrated into routine practice worldwide, they will probably have major implications for therapeutic decision making and patient care,” they wrote.

The difference in allograft outcomes between the groups “implies that alternative mechanisms may play a causal role in isolated microvascular inflammation,” perhaps an innate immune response driven by natural killer cells and T cells, the researchers suggested.

“Thus, although the use of antibody-targeted therapies might be considered for isolated microvascular inflammation, the treatment response may be limited, which suggests a need for therapies potentially directed toward innate immune mechanisms and T-cell-mediated responses,” they wrote.

Moreover, there could be implication for solid organ transplantation more broadly, as microvascular inflammation is also a key diagnostic feature of antibody-mediated rejection for those allografts but clinical phenotypes remain inadequately recognized in the diagnostic criteria, Sannier’s group noted.

“From a prognostic perspective, the identification of these phenotypes may improve the stratification of recipients of heart, lung, or liver transplants who are at risk for alloimmune-related disease progression and poor graft outcome, which would parallel observations in kidney-allograft recipients in the current study and have substantial implications for therapeutic decision making and patient care,” they added.

Of the biopsies they studied that fell into the newer categories defined in kidney transplantation rejection, most (57-63%) had been obtained because of a clinical indication for biopsy, with a median time from transplantation to biopsy of around 11 months.

Recipient, donor, and transplant characteristics were generally similar among patients with a first diagnosis of antibody-mediated rejection, probable antibody-mediated rejection, or no evidence of rejection. Fewer patients had circulating donor-specific antibodies at the time of transplantation in the no rejection group than in the antibody-mediated rejection group and the probable antibody-mediated rejection group (13.9%, 60.8%, and 74.8%, respectively).

Limitations of the study included lack of standardized immunosuppressive regimens and no consistently recorded data on what regimens were used, precluding assessment of the association between graft outcomes and treatment.

“Moreover, because surveillance biopsies were not systematically performed 1 year after transplantation, we were unable to fully assess the natural evolution of the microvascular inflammation phenotypes,” the researchers acknowledged. “However, our analysis integrated biopsies performed because of a clinical indication, which has provided valuable insights regarding disease progression.”