RAAS in Pig-to-Baboon Kidney Xenotransplantation: Relevance to Clinical Use

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Background: Pig kidney transplant(KTx) offers a potential solution to organ shortage. However, ability of pig kidney grafts to regulate fluid balance remains uncertain. After pig-to-baboon KTx with bilateral nephrectomy (BN), hypovolemia occurs, requiring fluid infusions. Renin-angiotensin-aldosterone system(RAAS) is a key component of fluid balance, but pig renin does not effectively cleave primate angiotensinogen (AGT) in vitro studies. We aimed to detect pig renin and function after pig KTx in baboons. Additionally, we compared baboons with BN to baboons with one native kidney retained(but with ureter ligation) to mimic patients with end-stage kidney disease who typically retain their native kidneys at KTx. Methods: Gene-edited pig kidneys were transplanted into 6 baboons. Group A(n=2) underwent BN, while Group B(n=4) had unilateral nephrectomy with one native kidney in situ with ureter ligation so that it could not contribute to salt and water excretion. Plasma renin(pig and baboon), AGT, angiotensin-I (Ang I), and aldosterone(ALD) levels were measured by ELISAs. Specificities of the pig renin and baboon renin ELISAs were validated using naive pig and baboon plasmas. Results: Group A, but not Group B, exhibited increases in plasma creatinine and potassium, indicating hypovolemia as reported previously. Naive pigs showed positive pig renin, but pig renin was undetectable at all post-Tx time-points in both groups(Figure 1A). Baboon renin concentration was measurable only in Group B(Figure 1B), indicating that the remaining kidney contributed to renin production. There were no differences in AGT or ALD between groups, but Ang I was barely detectable in Group A. Conclusion: The absence of detectable pig renin highlights a potential physiological challenge in xeno KTx. However, retention of a native kidney may help maintain RAAS and mitigate fluid imbalance. In clinical pig-to-human KTx, both native kidneys are usually retained, thus minimizing the development of hypovolemia. Funding: Other NIH Support - NIH NIAID U19 grant AI090959

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