Purpose: The capacity of pig kidneys to fulfill diverse physiological roles after transplantation (Tx) into baboons, including endocrine function, remains uncertain. Previous reports in baboons in which bilateral native nephrectomy at the time of pig kidney Tx had been carried out have highlighted persistent dehydration requiring frequent infusions of normal saline to prevent a rise in serum creatinine. A persistent electrolyte imbalance (high calcium, low phosphate) has also been documented. These observations deviate from those in clinical kidney alloTx in which both native kidneys are usually retained. We investigated this topic by retaining one native kidney (after ligating the ureter) at the time of pig kidney Tx.
Methods: Baboons (n=6) were recipients of kidneys from gene-edited pigs (n=4, triple-knockout [TKO] with growth hormone receptor-knockout and expression of 6 human protective proteins [hCD46, hCD55, hTBM, hEPCR, hHO1, hCD47]). Two baboons underwent bilateral nephrectomy, while 4 retained one native kidney with ureter ligation (enabling assessment of life-supporting pig kidney function). Induction therapy comprised anti-thymocyte globulin, anti-CD20mAb, and C1-esterase inhibitor. Maintenance therapy comprised anti-CD154mAb (TNX-1500), rapamycin, methylprednisolone, and IL-6R blockade with tocilizumab. Monitoring included blood counts, serum and urine parameters, ultrasound, and renal biopsies.
Results: The immunosuppressive regimen has to date shown consistent efficacy, achieving graft survival of >8 months in 2 baboons with bilateral native nephrectomy, and >4 months in 1 and >3 months in 3 with retained one native kidney. In baboons with bilateral native nephrectomy (n=2), weekly, bi-, or tri-weekly normal saline administration was required to maintain the serum creatinine within normal levels. This was consistent with numerous previous results reported by our group. All of the baboons in which one native kidney had been retained (n=4) have maintained normal serum creatinine levels without the need for saline infusions. The reduction in serum phosphate and increase in serum calcium seen in dehydrated baboons has been prevented or minimized when one native kidney was retained.
Conclusions: 
(1) Retention of one native kidney compensates for the deficiencies in the renin-angiotensin-aldosterone system documented previously after TKO pig kidney Tx in baboons.
(2) Prevention of dehydration mitigates the low serum phosphate and high serum calcium levels documented previously.
(3) This study suggests that, in clinical pig kidney xenoTx, retention of the native human kidneys will compensate for any endocrine deficiencies of the pig kidney graft.