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

ABSTRACT: 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.

ORGANISM(S): Sus scrofa

PROVIDER: GSE216029 | GEO | 2023/04/25

REPOSITORIES: GEO

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Project description:Description Primary membranous nephropathy (MN) is an autoimmune kidney disease histomorphologically defined by subepithelial deposition of immune complexes in the glomeruli, and exhibits a high risk for end-stage kidney disease. Circulating antibodies against phospholipase A2 receptor 1 (PLA2R1) are detected in 70-80% of MN patients and correlate with treatment response and prognosis. Experimental proof that human PLA2R1-antibodies induce MN is still missing. Methods: In passive transfer experiments, minipigs received plasma or purified IgG from patients with PLA2R1-associated MN or from healthy controls. PLA2R1-antibodies and proteinuria were monitored using Western blot, ELISA and Coomassie staining. Kidney tissues were analyzed using immunohistochemistry, immunofluorescence, electron microscopy and proteomic analyses. Results: We show that minipigs, like humans, express PLA2R1 on podocytes. Human PLA2R1-antibodies bound to minipig PLA2R1 in-vitro and in-vivo. Passive transfer of human PLA2R1-antibodies, derived from patients with PLA2R1- associated MN, led to the development of histomorphologic characteristics of human early-stage MN in minipigs, activation of components of the complement cascade and induction of low levels of proteinuria. In the later phases of disease, development of an autologous phase of disease was observed. Conclusions: Applying a translational approach from humans to minipigs we show that human PLA2R1-antibodies are pathogenic, although in the heterologous phase of disease only low level proteinuria developed. Proteomic samples: Porcine glomeruli were isolated following previously published protocols known for human glomeruli, with slight modifications (Stahl et al., Kidney Int. 1984;26(1):30–34.). A total of six samples of sieved glomeruli from porcine kidney were used. 1. untreated_negative_control Experiment 1 (passive transfer of human PLA2R1 antibody from PLA2R1-antibody positive patient into minipigs) 2. exp_1_passive_antibody_rep1 Same experimental procedure in two animals (replicate 1) (treated with patient antibody) 3. exp_1_passive_antibody_rep2 Same experimental procedure in two animals (replicate 2) (treated with patient antibody) 4. exp_1_passive_antibody_control control animal for Pig A and B (treated with healthy antibody) Experiment 2 (passive transfer of human plasma from PLA2R1-antibody positive patient into minipigs) 5. exp_2_passive_plasma treated animal (treated with patient plasma) 6. exp_2_passive_plasma_control control animal (treated with healthy plasma)

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

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