Last year, separate teams from NYU Langone Health and the University of Alabama at Birmingham demonstrated the feasibility of transplanting gene-modified pig kidneys into brain-dead human recipients without acute rejection. Now both teams are reporting remarkable progress.
The NYU Langone Health team newly reports that a pig kidney xenotransplant has been performing optimally after 32 days in a brain-dead man, producing urine with no signs of acute rejection. The team will continue to monitor the pig xenotransplant for another month. Both of the man’s native kidneys had been previously removed.
“This work demonstrates a pig kidney—with only one genetic modification and without experimental medications or devices—can replace the function of a human kidney for at least 32 days without being rejected,” Robert Montgomery, MD, DPhil, director of the NYU Langone Transplant Institute in New York, New York, stated in a news release from the center.
Continue Reading
In this case, the investigators knocked out only a single pig gene that encodes alpha-gal, which has been linked to rapid antibody-mediated rejection of pig organs by humans. The pig’s thymus gland also was implanted to stave off novel, delayed immune responses. The individual received standard transplant immunosuppression. For safety, the investigators performed enhanced screening of porcine cytomegalovirus (pCMV) in the donor pig and monitored the man for pCMV, porcine endogenous retrovirus (PERV), and 6 other viruses.
During the 32 days, no viruses were detected and serum creatinine remained within target range, Dr Montgomery and his colleagues reported.
In a research letter published in JAMA Surgery, the team from the University of Alabama at Birmingham, led by Jayme E. Locke, MD, MPH, newly report that their modified pig xenotransplant also lowers serum creatinine.
The case was a brain-dead man in his 50s who had hypertension, stage 2 chronic kidney disease, as well as acute kidney injury. His native kidneys were sustained on dialysis prior to bilateral nephrectomy. After crossmatching, surgeons transplanted the pig xenotransplants with attached vasculature en bloc.
Urine concentrated over the 7-day study period. Serum creatinine decreased from 3.9 mg/dL before xenotransplantation to 1.9 mg/dL within the first 24 hours, normalized to 1.1 mg/dL at 48 hours, and was 0.9 mg/dL on day 7, Dr Locke and colleagues reported. Creatinine clearance also improved from 0 mL/min on the day of surgery to 200 mL/min on day 7.
For immunosuppression, the decedent received the complement inhibitor eculizumab 24 hours before transplant surgery followed by standard induction therapy, including a solumedrol taper, antithymocyte globulin (6 mg/kg total), and rituximab. Maintenance immunosuppression included tacrolimus, mycophenolate mofetil, and prednisone. Tacrolimus reached the target of 8-10 ng/dL by postoperative day 2.
Serially biopsies of the xenografts showed normal histology without evidence of thrombotic microangiopathy, the investigators reported.
“This study showcases xenotransplant as a viable potential solution to an organ shortage crisis responsible for thousands of preventable deaths annually,” Dr Locke’s team stated.
Whether xenografts can provide long-term kidney function and possibly serve as a bridge or human kidney replacement for patients with kidney failure needs to be studied further.
Disclosure: This research was supported by United Therapeutics and its subsidiaries Lung Biotechnology PBC and Revivicor. Please see the original references for a full list of disclosures.
References
Pig kidney xenotransplantation performing optimally after 32 days in human body. News release. NYU Langone Health; August 16, 2023.
Locke JE, Kumar V, Anderson D, Porrett PM. Normal graft function after pig-to-human kidney xenotransplant. JAMA Surgery. Published online August 16, 2023. doi:10.1001/jamasurg.2023.2774
