Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation [scRNA-Seq]

Progress in clinical translation of gene edited porcine kidney xenotransplantation is accelerating. However, kidney function entails more than removal of metabolic waste products and it is unknown if all endocrine functions will be faithfully reproduced by porcine kidneys in primate recipients. Seventeen cynomolgus macaques with survival >60days after life sustaining kidney xenotransplantation (LSKX) from gene edited Yucatan minipigs underwent measurement of xenograft growth and two kidney dependent endocrine pathways: renin-angiotensin-aldosterone-system (RAAS) and calcium-vitamin D-parathyroid-hormone. Clinical chemistries, plasma-renin-activity, Beta-C-terminal-telopeptide (CTx) assay, RNA-seq, single-cell RNA-seq, and serial ultrasonography were conducted and generalized linear models assessed statistical relationships. Xenografts transplanted from minipigs demonstrated only modest growth (estimated ~8.0% per year) and didn’t significantly contribute to recipient RAAS pathway. However, PTH-independent hypercalcemia and hypophosphatemia were observed and might be xenograft intrinsic suggesting close monitoring and timely intervention during the first month post-transplant. Further study of these phenotypes is warranted in designing prospective clinical trials. Comparative gene expression analysis of biopsy tissue from xenotransplanted as compared to contralateral, untransplanted kidneys.