Transplantation of decellularized porcine kidney grafts repopulated with primary human cells demonstrates filtration function in pigs

Abstract

BackgroundEnd-stage renal disease is a growing global health issue, disproportionately impacting low- and middle-income countries. While kidney transplantation remains the best treatment for end-stage renal disease, access to this treatment modality is limited by chronic donor organ shortages. To address this critical need, we are developing transplantable bioengineered kidney grafts.MethodsPodocyte differentiation was achieved in adherent monoculture through Wnt and TGF-β inhibition with IWR-1 and SB431542, respectively. Podocytes along with endothelial cells were then used to recapitulate glomeruli within decellularized porcine kidney scaffolds to generate bioengineered kidneys grafts. These bioengineered kidney grafts were functionally assessed via normothermic perfusion which compared kidney grafts recellularized with only endothelial cells as a control to bi-culture kidney grafts comprised of endothelial cells and podocytes. Heterotopic implantation further tested bi-culture kidney graft function over 3 successive implant sessions with 1–2 grafts per session.ResultsWe demonstrate the ability to source primary human podocytes at scale. Decellularized porcine kidney grafts repopulated with podocytes and endothelial cells exhibit native glomerular structure and display blood filtration capabilities during normothermic perfusion testing. Extending these findings to a clinically relevant model, bioengineered kidneys produce urine with indices of filtration when heterotopically implanted in pigs.ConclusionsOur results showcase a human-scale, transplantable bioengineered kidney capable of performing requisite filtration function. This study reinforces the possibility for the bioengineering of transplantable human kidneys, which could someday provide increased and more equitable access to kidney grafts for the treatment of end-stage renal disease.