Donor-Specific Antibodies Accelerate Arteriosclerosis in Kidney Transplant Recipients

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Preformed donor-specific antibodies contribute to transplant patients’ development of arteriosclerosis of the kidneys and may play a key role in organ rejection, according to research reported in the May Journal of the American Society of Nephrology.

The findings may change the way physicians think about the kidney rejection process and could even impact care related to cardiovascular diseases in general.

Attack of the antibodies

The detection and treatment of donor organ rejection has historically focused on T-cell-mediated processes, but recent research by a number of institutions has revealed that antibody-mediated rejection—which can occur when a transplant recipient mounts

Preformed donor-specific antibodies contribute to transplant patients’ development of arteriosclerosis of the kidneys and may play a key role in organ rejection, according to research reported in the May Journal of the American Society of Nephrology.

The findings may change the way physicians think about the kidney rejection process and could even impact care related to cardiovascular diseases in general.

Attack of the antibodies

The detection and treatment of donor organ rejection has historically focused on T-cell-mediated processes, but recent research by a number of institutions has revealed that antibody-mediated rejection—which can occur when a transplant recipient mounts antibodies against their new organ—is a major contributor to the declining function and ultimate loss of transplanted kidneys (Terasaki P, Mizutani K. Antibody Mediated Rejection: Update 2006. Clin J Am Soc Nephrol 2006; 1:400–403).

To study the effects of antibody-mediated rejection, Gary Hill, MD, of the Hôpital Européen Georges Pompidou, APHP, in Paris and his colleagues examined kidney biopsies from transplant patients who mounted antibodies directed against their transplanted kidney and patients who did not. From January 2002 to March 2007, 40 consecutive kidney transplant recipients from the investigators’ transplant program of patients with preformed donor-specific anti-HLA antibodies were compared with a control group of 59 patients without preformed donor-specific antibodies.

Arteriosclerosis, in terms of Banff score, significantly progressed between three and 12 months after transplant in the antibody-positive patients. (Banff is a standardized international classification of kidney allograft biopsies.) Taken as a group, the antibody-positive group progressed from Banff cv grade 0.65 + 0.11 at three months to grade 1.12 + 0.10 at one year after transplant.

The antibody-negative group showed an increase from 0.65 + 0.11 to 0.81 + 0.10, but this difference was not significant at three months. Arteriosclerosis in antibody-negative patients progressed to approximately one third the degree of that in antibody-positive patients. In addition, conversion to de novo antibody-positivity in four initially antibody-negative patients speeded the rate of acceleration of arteriosclerosis to more near the rates seen in patients who were antibody-positive from the outset. In both antibody-positive and antibody-negative groups, the rate of progression of arteriosclerosis was unaffected by the age of the donor or recipient.

In the antibody-positive patients, “we found that the degree of arteriosclerosis in the transplanted kidney is much worse than would have been expected on the basis of the donor’s age, an increase calculated to be on the order of 28 years of ‘aging’ in the first year posttransplant,” said Hill.

All patients who showed acceleration of arteriosclerosis, either at one year or on late (24 to 84 months) biopsies, had subclinical antibody-mediated rejection at three months, 12 months, or both.

The findings should lend greater importance to arteriosclerosis, which may be conspicuous in organ recipients, among transplant researchers.

“Acceleration of arteriosclerosis was a totally unexpected finding, an important one since it broadens our thinking about what constitutes transplant rejection,” said Hill. “Accelerated arteriosclerosis can now be seen to form part of the rejection process, even in the absence of more overt vasculitic lesions, and it will probably be found to contribute to the ultimate decline of function in the transplanted kidney.”

Mechanisms involved

Various mechanisms could be responsible for the link between donor-specific antibodies and arteriosclerosis. For example, the binding of anti-class I antibodies to class I molecules on the vascular endothelium and smooth muscle cells is known to induce the release of a variety of cytokines and to stimulate proliferation of myofibroblasts. Similar reactions occur with anti-class II antibodies. Antibodies other than standard class I and class II antibodies, such as MHC class I–related chain A antibodies, might play a lesser role in the progression of arteriosclerosis, which by narrowing of the arteries supplying the kidney leads to reduced blood flow and oxygen supply to renal tissues, the investigators said.

Previous studies have shown that the development of lesions referred to as chronic transplant arteriopathy may be a manifestation of antibody responses against transplanted kidneys and other solid organs, said Mark Haas, MD, PhD, who was not involved with the research and is a renal pathologist in the department of pathology and laboratory medicine at Cedars-Sinai Medical Center in Los Angeles. These antibody responses may contribute to intimal arteritis, which is characterized by infiltration of immune cells beneath the endothelium, Haas said.

“A key implication of the findings of Hill and workers is that the spectrum of vascular lesions associated with donor-specific antibodies may be even wider,” he said. He added that important questions remain, such as whether removing donor-specific antibodies can halt or reverse these arterial effects.

“This study details a range of histologic lesions in arteries that are likely due to donor-specific antibodies and represent a form of chronic humoral rejection. Moreover, these antibody-mediated arterial lesions are progressive,” said Lynn Cornell, MD, an assistant professor of laboratory medicine and pathology at the Mayo Clinic in Rochester, Minn. “This is an interesting and important study that contributes to our overall knowledge of antibody-mediated damage to the allograft.”

Others pointed to potential changes that might be implemented in the clinic as a result of these findings.

“This study supports the utility of both performing protocol surveillance biopsies in clinically stable high risk kidney transplant recipients (those known to have anti-HLA Donor Specific Antibody at the time of surgery) as well as prospectively monitoring anti-HLA antibody status at fixed times posttransplantation and after sensitizing events such as infections, transfusions, surgery, and pregnancy,” said Erik Kraus, MD, a transplant nephrologist at Johns Hopkins Medical Center in Baltimore. “Although current interventions remain extremely limited to suppress ongoing antibody injury, pathologic staging of vascular injury combined with measurement of strength of circulating anti-HLA antibody will be useful metrics to assess the efficacy of trials of therapies in the future.”

The concept of immune-mediated arteriosclerosis fits well with recent animal data related to cardiovascular diseases, which revealed that B cell depletion reduces the development of atherosclerosis in mice. (Ait-Oufella H, et al. B Cell Depletion Reduces the Development of Atherosclerosis in Mice. J Exp Med 2010; 207:1579–1587).

“Our studies thus open a large area of investigation in the domain of immune-mediated arteriosclerosis beyond that of transplanted organs in the area of cardiovascular diseases in general,” Hill said. He noted that the study was limited by the short, roughly three-year, follow-up, and that to fully demonstrate the effects of accelerated arteriosclerosis will require a study extending out to 10 to 15 years.

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