Xenogeneic Fetal Kidney Transplantation Across Three Species

 

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https://storage.unitedwebnetwork.com/files/1099/8396c6961a9ca3cffee41dab68eb333f.pdf
Xenogeneic Fetal Kidney Transplantation Across Three Species

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Keita
Morimoto
Keita Morimoto keita-m@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan *
Shuichiro Yamanaka shu.yamanaka@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Shutaro Yamamoto shutaro-yamamoto.urology@jikei.ac.jp The Jikei University School of Medicine Department of Urology Tokyo Japan -
Nagisa Koda nkohda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Takafumi Kuroda h25ms-kuroda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Takumi Ikeda h25ms-ikeda@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Hinari Ohashi hinari0421@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Toyoshi Seito sentkn@jikei.ne.jp The University of Tokyo Department of Urology Tokyo Japan -
Kei Matsumoto kmatsumoto@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
Katsusuke Ozawa ozawa-kt@ncchd.go.jp National Center for Child Health and Development Center for Maternal-Fetal, Neonatal and Reproductive Medicine Tokyo Japan -
Seiji Wada wada-s@ncchd.go.jp National Center for Child Health and Development Center for Maternal-Fetal, Neonatal and Reproductive Medicine Tokyo Japan -
Eiji Kobayashi qqhr7ct9k@river.ocn.ne.jp The Jikei University School of Medicine Department of Kidney Regenerative Medicine Tokyo Japan -
Takashi Yokoo tyokoo@jikei.ac.jp The Jikei University School of Medicine Division of Nephrology and Hypertension, Department of Internal Medicine Tokyo Japan -
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Bilateral renal agenesis, the underlying cause of Potter sequence, leads to severe oligohydramnios and pulmonary hypoplasia, often resulting in fatal outcomes shortly after birth. Although renal replacement therapy is essential, initiating dialysis immediately after birth is often not feasible due to extreme prematurity and gastrointestinal underdevelopment.

We propose an innovative in utero regenerative strategy—xenogeneic fetal kidney transplantation—to establish a functional urinary excretory system before birth. This approach aims to serve as a bridge until postnatal dialysis becomes feasible. Here, we assess the feasibility, developmental potential, and immunological outcomes of fetal kidney grafts across three species: rodents, pigs (microminipigs), and non-human primates (common marmosets).

Rodent model: GFP-positive fetal kidneys from Sprague–Dawley rats (E14–16) and C57BL/6 mice (E13) were transplanted into fetal rats (E18) via transuterine injection. Tacrolimus was administered in the mouse-to-rat xenogeneic model. Postnatal assessment included histology and repeated bladder aspiration.

Porcine model: To develop a clinically applicable transplantation method, fetal kidneys (E30–34) were transplanted under ultrasound guidance into the retroperitoneal space of recipient fetuses (E83–95). Gold markers were attached to grafts for postnatal localization. Tacrolimus monotherapy was used for immunosuppression.

Primate model: To examine immune compatibility in a system closer to clinical application, fetal pig kidneys (E30–34) were transplanted into fetal common marmosets (E130–132). Under immunosuppression, we assessed term delivery and postnatal growth, and evaluated whether the transplanted pig kidneys could grow and mature within the marmoset recipients.

Rodent experiments resulted in spontaneous delivery and sustained graft function. Transplanted kidneys exhibited glomerular and tubular structures, with urine production confirmed for over 150 days. No rejection was observed in allogeneic grafts without immunosuppression. In xenogeneic grafts under tacrolimus monotherapy, mild rejection was observed at day 18.

In the pig-to-pig model, we achieved safe in utero transplantation and successful term delivery. Urine production continued for 97 days postnatally. Histological analysis confirmed nephron formation and only mild immune rejection.

In the marmoset model, term offspring were delivered two weeks post-transplant. Although the offspring showed favorable postnatal growth, the transplanted pig kidneys were rejected under tacrolimus treatment, and proper graft development could not be confirmed. Future studies will consider using genetically modified fetal pig kidneys to improve graft acceptance and development.

This study presents the first successful in utero fetal kidney transplantation across rodents, pigs, and non-human primates. We demonstrated that fetal kidney grafts can engraft, vascularize, and produce urine before and after birth—without requiring vascular anastomosis. This approach offers a promising prenatal regenerative therapy for congenital renal diseases and may enable survival in cases previously deemed untreatable. Ongoing studies in non-human primates will further inform clinical translation.

Kewords