A genetic mismatch could explain why many kidney transplants fail, despite donors and recipients being well-matched by HLA testing
A genetic mismatch could explain why many kidney transplants fail, even when donors and recipients are thought to be well-matched, according to a new study  published in the New England Journal of Medicine. This genomic collision is a genetic incompatibility between kidney donor and recipient, causing the recipient to mount an immune attack against the donor protein.
The findings could lead to more precise matching between donors and patients, and reduce kidney transplant failures.
Genetic compatibility testing between donor and recipient is done by matching the donor and recipient’s human leukocyte antigens (HLAs), cell surface proteins that help the immune system determine which cells are foreign. But HLA mismatches can only explain only about two-thirds of transplants that fail for immunological reasons. “The rest of those failures are probably due to less common antigens, or so-called minor histocompatibility antigens. However, the identity of most of these antigens and how they lead to rejection is largely not known,” said co-senior author Krzysztof Kiryluk, MD, the Herbert Irving Assistant Professor of Medicine at Columbia University Vagelos College of Physicians of Surgeons.
LIMS1 mismatches would be expected to occur in approximately 12 to 15 percent of transplants from unrelated donors among persons of European and African ancestry, but it would be very rare among persons of East Asian ancestry because the deletion is very rare in these populations
The researchers hypothesized that a person whose genome carries a kidney gene with a deleted section might be especially sensitive to organs from a donor whose genome carries the full-sized gene. “The recipient would then be exposed to a protein their immune system would sense as foreign,” said Kiryluk.
To test their hypothesis, they screened 705 kidney recipients transplanted at Columbia University Irving Medical Center for deletions in 50 kidney genes that were present as full-sized versions in the donor. The deletions associated with rejection were then confirmed in an additional 2,004 donor-recipient pairs from three international transplant groups.
The study found that kidney recipients with two copies of a deletion near a gene called LIMS1 had a significantly higher risk of rejection when the donor kidney had at least one full-sized version of the same gene. The risk of rejection was 63 percent higher among the donor-recipient pairs with this genomic collision, compared to those without this mismatch. “To put this into perspective, the risk of rejection from LIMS1 mismatch is roughly three times as high as the risk due to a single allele mismatch in the HLA,” Dr. Kiryluk said.
LIMS1 mismatches would be expected to occur in approximately 12 to 15 percent of transplants from unrelated donors among persons of European and African ancestry, but it would be very rare among persons of East Asian ancestry because the deletion is very rare in these populations.
“LIMS1 mismatches could be avoided by pre-transplant genetic screening,” Kiryluk said. “But first we need to validate our findings in larger studies.”
The findings may apply to other types of organ transplants since LIMS1 is also expressed in the lung, heart, and liver.
