Donor Gene Variant Associated with Higher Graft Failure Risk

Weaver, Janelle

doi: 10.1097/01.NEP.0000424000.24390.e5

Shedding light on an under-studied issue and highlighting an area for further work, new research has revealed a relationship between the genotype of the donor organ and long-term outcomes in the transplant recipient. In the study, which was published in the Journal of the American Society of Nephrology (2012;23:1891–1899), a donor ABCB1 variant was linked to an increased risk for kidney allograft failure.

“Maybe knowing the genetics of the donor can help with appropriate matching of donors to recipients,” said senior study author Richard J. Borrows, MB, Consultant Nephrologist at Queen Elizabeth Hospital Birmingham in the United Kingdom.

Calcineurin inhibitors (CNIs) are used as immunosuppressants for kidney transplantation, but they frequently cause toxicity and can ultimately lead to renal failure. The variability in patients' responses to CNIs could depend on differences in their levels of drug-metabolizing enzymes and drug transporters, such as P-glycoprotein, which is encoded by the ABCB1 gene.

While some past investigations have suggested that the recipient genotype for ABCB1 is associated with delayed graft function and acute rejection, relatively little is known about the influence of donor genotypes on the clinical outcomes of kidney transplantation. Two small published studies provide some evidence for an association between single nucleotide polymorphisms (SNPs, or DNA sequence variations) in donor ABCB1 and acute cyclosporine nephrotoxicity and allograft failure (Hauser IA et al: J Am Soc Nephrol 2005;16:1501-1511; Woillard JB et al: Clin Pharmacol Ther 2010;88:95-100).

“This is one of the first times where somebody has looked at genotype of the donor organ and found that it has a major effect on graft survival,” said Jonathan S. Bromberg, MD, PhD, Professor of Surgery and of Microbiology and Immunology at the University of Maryland School of Medicine, who was not involved in the study.

“It really zeroes in on one of the major causes of allograft loss or allograft damage, and it enables us to think about how to treat these patients better.”

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Genotype Matters

In the new study, Dr. Borrows and his team examined a comprehensive panel of 52 SNPs in five genes previously implicated in CNI metabolism and transport: ABCB1, CYP3A4, CYP3A5, PPIA, and NR1I2.

The relationship of donor and recipient gene variants with clinical outcomes were studied in 4,471 CNI-treated kidney transplant recipients in three separate cohorts followed for up to 20 years.

“This is the largest pharmacogenetic study, with longest follow-up to date, to assess the association of donor and recipient genotypes and important clinical endpoints in kidney transplantation,” the authors noted in the paper.

The discovery cohort consisted of 811 patients who underwent kidney transplant procedures at the Queen Elizabeth Hospital Birmingham between 1996 and 2006.

In these patients, whose clinical and demographic data were retrieved from a prospectively maintained institutional database, the researchers found that the kidney donor CC genotype at C3435T (rs1045642) within ABCB1 was associated with an increased risk for long-term graft failure. No other donor or recipient SNPs were associated with graft survival or mortality. This relationship was validated in 675 donors from Belfast in Northern Ireland and in a subgroup of 452 Collaborative Transplant Study patients who were treated with the CNI tacrolimus.

There was no association between donor genotype at ABCB1 C3435T and graft survival in the overall Collaborative Transplant Study cohort of 2,985 patients, who underwent transplantations between 1988 and 2010, or in the subgroup of 2,533 patients who were treated with cyclosporine. One reason for this finding could be the heterogeneity of this population, which consisted of patients from multiple countries and transplant centers that used different treatment approaches, unlike the single-center cohorts in the study.

The gene variant described could be useful for risk stratification in renal transplantation and in organ allocation policy, the study authors noted.

“Further dissecting the mechanisms of this might provide a novel strategy for preventing transplant decline,” Dr. Borrows said in a phone interview. “I think it may act as biomarker for predicting the risk to individual transplant recipients. And thirdly, it may contribute to helping define the perceived quality of the kidney transplant.”

However, Dr. Borrows and his team acknowledged that a panel of genetic biomarkers may be more useful.

“It is highly unlikely that one gene variant in its own right will tell the whole story,” Dr. Borrows said. “We hope that over time we may be able to develop a panel of genetic biomarkers and possibly even epigenetic biomarkers that can provide additional predictive utility over the standard ways that we use in transplantation.”

In addition to identifying other potential genetic biomarkers for risk stratification, future studies should focus on probing the mechanisms underlying the association between donor genotype and graft survival. Past studies in animals have shown that P-glycoprotein is associated with increased susceptibility to kidney injury.

Although the potential mechanisms are speculative at this point, “changes in the activity of this transporter could translate into changes in tubular integrity—the ability of the tubule to withstand toxic insults and regenerate,” explained Bruce Kaplan, MD, Professor of Medicine, Surgery, and Pharmacology at the University of Arizona, who was not involved in the study.

Dr. Bromberg also commented on possible explanations for the results.

“Maybe the transporter interacts with these drugs to determine whether or not people have calcineurin inhibitor-induced nephric toxicity,” he said. “If it turns out it's CNI toxicity, then I think we could maybe have a better understanding of what causes CNI toxicity and how to prevent it or treat it.”

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Modest Effect

One major strength of the study was its analysis of three cohorts of patients.

“This is very important when you're looking at these genome-wide associations,” Dr. Kaplan said. “The fact that they have a validation cohort makes the association potentially more robust.”

But given that all of the donors and most of the recipients analyzed in the study were white, it's not clear whether the findings can be generalized to other patient populations, he added. As a result, future studies should also attempt to replicate the findings in different ethnic groups.

Another potential limitation was the strength of the association between donor genotype and graft survival, Dr. Kaplan said.

“We wouldn't expect that one SNP would have an overwhelming effect on graft survival,” especially because P-glycoprotein transports a wide variety of substances—not just CNIs—across cell membranes.

It's not clear how the findings will impact clinical decision making.

“The field has been rife with SNP associations that have never panned out,” Dr. Kaplan said in a phone interview. “In the clinical population, there are so many heterogeneous insults, so many SNPs, and so many multifactorial processes that can go on, so it's very hard for one to have a large effect on something like graft survival.”

Taking an association that was picked up in a large study population and applying it at the bedside in an individual patient is not a straightforward undertaking.

“Many variables are important for graft survival on the donor side and on the recipient side,” Dr. Bromberg said. “You can see the effect in a large group of patients—several hundred or several thousand patients. It doesn't help me as a clinician when I have a patient and a kidney and I'm deciding whether or not to put that kidney into that patient and how best to treat that patient,” he said in a phone interview.

“In clinical medicine, we like black-and-white answers for things and stuff that works either 100 percent of the time or zero percent of the time. Unfortunately, in most of clinical medicine, there are very small differences that we can make in patients and outcomes, whether it's transplantation or almost anything else. You have to add up many, many modest effects to really make a huge difference.”

© 2012 Lippincott Williams & Wilkins, Inc.