A genomic incompatibility could explain why many kidney transplants fail, even when donors and recipients are thought to be well-matched, a new study from researchers at Columbia University Vagelos College of Physicians and Surgeons suggests. The 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. The same genomic collision may also potentially occur in heart, liver, and lung transplants.
The researchers identified a specific antibody response against LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1), a kidney-expressed protein. The response mostly involves IgG2 and IgG3 antibody types.
A successful organ transplant depends in large part on assuring genetic compatibility between donor and recipient. This 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 – as closely as possible.
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,”
says co-senior author Krzysztof Kiryluk, MD, the Herbert Irving Assistant Professor of Medicine at Columbia University Vagelos College of Physicians of Surgeons.
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,”
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 cohorts.
The study found that kidney recipients with two copies of a deletion near the LIMS1 gene 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 says.
Kidney transplant recipients with two copies of the deletion who developed rejection had detectable levels of anti-LIMS1 antibodies in their blood, further evidence that this genomic collision contributes to rejection.
“The exact mechanism by which this deletion exerts its effects is unknown. It’s likely that it reduces the amount of LIMS1 protein produced, since we find that individuals with two copies of the deletion have lower levels of LIMS1 gene transcript in their kidneys. When these individuals are exposed to a high level of LIMS1 protein in a newly transplanted organ, their immune system is more likely to recognize the LIMS1 antigen as foreign, resulting in rejection,”
1 In 7 Transplants
Transplanted organs commonly experience a significant period of low oxygenation, which appears to compound the genomic collision. In cells that produce LIMS1, the researchers found that low oxygen levels increase LIMS1 production on the cell surface, which may increase the risk of an immune attack.
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 says. “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. Similarly, other genetic incompatibilities may also be contributing to rejection of these organs.
The LIMS1 gene has gone previously undetected in earlier searches, partly due to the limited sample size of previous studies, Kiryluk says.
“We estimate that a traditional genome-wide association study would need to analyze a minimum of 13,000 kidney recipients to find this gene,” he adds. “The genomic collision approach provides a new method to find additional mismatches in a smaller number of donor-recipient pairs. And coupled with new methods of antibody detection, is likely to propel future discoveries in this area.”
The research was supported by the Columbia University Transplant Center, a New York Presbyterian Hospital Translational Pilot Grant funded by the New York State Empire Clinical Research Investigator Program, a Columbia University Precision Medicine Pilot Award funded by the Dean of the College of Physicians & Surgeons, and the Columbia Clinical and Translational Science Award Precision Medicine Pilot Program funded by a grant from the NIH National Center for Advancing Translational Sciences, and by grants from the National Institute of Diabetes and Digestive and Kidney Diseases.
Nicholas J. Steers, Ph.D., Yifu Li, M.D., Ph.D., Zahida Drace, Ph.D., Justin A. D’Addario, M.D., Clara Fischman, B.A., Lili Liu, Ph.D., Katherine Xu, Ph.D., Young-Ji Na, Ph.D., Y. Dana Neugut, M.S., Jun Y. Zhang, Roel Sterken, Ph.D., Olivia Balderes, B.A., Drew Bradbury, B.A., Nilgun Ozturk, M.D., Fatih Ozay, M.D., Sanya Goswami, B.S., Karla Mehl, M.D., Jaclyn Wold, B.S., Fatima Z. Jelloul, M.D., Mersedeh Rohanizadegan, M.D., M.P.H., Christopher E. Gillies, Ph.D., Elena-Rodica M. Vasilescu, M.D., George Vlad, Ph.D., Yi-An Ko, Ph.D., Sumit Mohan, M.D., M.P.H., Jai Radhakrishnan, M.D., David J. Cohen, M.D., Lloyd E. Ratner, M.D., M.P.H., Francesco Scolari, M.D., Katalin Susztak, M.D., Ph.D., Matthew G. Sampson, M.D., M.S.C.E., Silvia Deaglio, M.D., Ph.D., Yasar Caliskan, M.D., Jonathan Barasch, M.D., Ph.D., Aisling E. Courtney, M.D., Alexander P. Maxwell, M.D., Ph.D., Amy J. McKnight, Ph.D., Iuliana Ionita-Laza, Ph.D., Stephan J.L. Bakker, M.D., Ph.D., Harold Snieder, Ph.D., Martin H. de Borst, M.D., Ph.D., Vivette D’Agati, M.D., Antonio Amoroso, M.D., Ali G. Gharavi, M.D., and Krzysztof Kiryluk, M.D.
Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection
N Engl J Med 2019; 380:1918-1928 DOI: 10.1056/NEJMoa1803731
Image: David Gregory and Debbie Marshall