Xeno-transplanted kidney

eGenesis, a biotech company based out of Cambridge, MA along with a group of surgeon/physician scientists at Massachusetts General Hospital (MGH) performed a xenotransplantation- transplanted a gene edited porcine kidney into a patient with kidney failure and on dialysis. The patient did well and had good kidney function but died unexpectedly likely from cardiac cause on day 52. 

The report has been published in the latest rendition of New England Journal of Medicine

https://lnkd.in/gEuKSaZ5

Few takeaways from this very interesting development:

- a genetically engineered pig was used with 69 gene edits but more importantly with 3 major glycan antigens eliminated (3KO)

- inactivation of porcine endogenous retroviruses and insertion of seven human transgenes 

-kidney from the gene edited pig transplanted into a 62 year old man on dialysis and significant vasculopathy 

Xeno-kidney made urine within 5 minutes of implantation. Patient received a single dose of rabbit thymoglobulin (rATC) and a lower trough level of tacrolimus was aimed for in the first week (<4ng/ml). There was one episode of T-cell mediated acute cellular rejection (proven by kidney biopsy, day 8) which was treated with IV steroids and IL-6 receptor antagonist (tocilizumab).

Another kidney biopsy was performed on day 34 because of increased serum Cr- no antibody mediated rejection was seen, no microthrombi was noted either. Sr Cr settled around 1.5 to 2 mg/dl. 

Authors presume that patient passed away from cardiac cause - likely cardiac arrythmia triggered by frequent fluctuations in intravascular volume, possibly caused by a dysfunctional RAAS in the pig kidney-patient was known to have severe ischemic heart disease.

Based on this study, the group propose a small, pilot clinical trial for well-informed dialysis patients who face a high risk of dying while awaiting a human transplant. 

Few thoughts- 

does the xenograft lead to a heightened inflammatory state? 

will the kidney size mismatch between pig and human result in higher serum creatinine at baseline - will this be a new normal in xenotransplanted patients 

should there be a separate group of dialysis and/or waitlisted patients who should be recruited for the pilot trials- avoiding patients with heavy atherosclerotic burden

Design and testing of a humanized porcine donor for xenotransplantation

https://www.nature.com/articles/s41586-023-06594-4