Renin‐Angiotensin‐Aldosterone System (RAAS) in Pig‐to‐Baboon Kidney Xenotransplantation—Relevance to Clinical Pig Kidney Xenotransplantation

BACKGROUND: Pig-to-human kidney xenotransplantation offers a potential solution to the organ shortage. However, the ability of the transplanted pig kidney to regulate blood pressure and fluid balance remains uncertain. The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in these functions, but species differences may impair its effectiveness in xenotransplantation. METHODS: Gene-edited pig kidneys were transplanted into six immunosuppressed baboons. Group A (n = 2) underwent bilateral native nephrectomy, while Group B (n = 4) had unilateral nephrectomy with one native kidney remaining in situ (with its ureter ligated) to avoid it contributing to salt and volume regulation. Plasma creatinine, potassium, renin, angiotensinogen, angiotensin I, and aldosterone levels were measured. RESULTS: Group A, but not Group B, exhibited increases in plasma creatinine and potassium levels, indicating hypovolemia that could be corrected by frequent fluid administration. Pig-specific renin was undetectable at all post-transplant time points in both groups. Baboon renin concentration and activity were measurable only in Group B, indicating that the native kidney contributed to renin production. Aldosterone levels remained unchanged in both groups. CONCLUSIONS: The absence of detectable pig renin highlights a potential physiological challenge in xenotransplantation. However, the retention of a native kidney may help maintain RAAS function and mitigate fluid and electrolyte imbalances. In clinical pig-to-human kidney transplantation, both native kidneys are usually retained, thus minimizing the development of hypovolemia.