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Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation

ABSTRACT: Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation

PROVIDER: PRJNA891740 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21954039_1.fastq.gz	Fastqsanger.gz
	SRR21954039_2.fastq.gz	Fastqsanger.gz
	SRR21954040_1.fastq.gz	Fastqsanger.gz
	SRR21954040_2.fastq.gz	Fastqsanger.gz
	SRR21954041_1.fastq.gz	Fastqsanger.gz

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

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

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

Project description: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.

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Project description:Porcine kidney xenotransplantation is accelerating towards clinical translation. However, despite the demonstrated ability of porcine kidneys to remove metabolic waste products, questions remain about their ability to faithfully recapitulate renal endocrine functions after transplantation. Here we analyze xenograft growth and function of two kidney dependent endocrine pathways in seventeen cynomolgus macaques after kidney xenotransplantation from gene edited Yucatan minipigs. Xenograft growth, the renin-angiotensinogen aldosterone-system, and the calcium-vitamin D-parathyroid hormone axis are assessed using clinical chemistries data, renin activity and beta-C-terminal-telopeptide assays, kidney graft RNA-sequencing and serial ultrasonography. We demonstrate that xenografts transplanted from minipigs show only modest growth and do not substantially contribute to recipient RAAS pathway activity. However, parathyroid hormone-independent hypercalcemia and hypophosphatemia are observed, suggesting a need for close monitoring and timely intervention during human testing. Further study of these phenotypes is warranted in designing prospective clinical trials.

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