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      Renal Bioengineering with Scaffolds Generated from Human Kidneys

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          Abstract

          Background: In 2012, about 16,487 people received kidney transplants in the USA whereas 95,022 candidates were on the waiting list at the end of the year. Moreover, more than 2,600 kidneys procured annually for transplantation are discarded for a variety of reasons. We hypothesize that this pool of discarded kidneys could in part meet the growing, urgent need for transplantable kidneys using current methods for organ bioengineering and regeneration and surgical transplantation. The recellularization of extracellular matrix (ECM) scaffolds has the potential to meet the uniquely ambitious engineering challenges posed by complex solid organs such as the kidney. Summary: Attempts to manufacture and implant simpler, hollow structures such as bladders, vessels, urethras, and segments of the upper airways have been successful in the short and mid terms. However, the bioengineering of complex solid organs such as the kidney is a more challenging task that requires a different approach. In previous studies, we showed that decellularized porcine kidneys yield renal ECM scaffolds that preserve their basic architecture and structural components, support cell growth in vivo and in vitro, and maintain a patent vasculature capable of sustaining physiological blood pressure. In a subsequent report, using the same methods, we found that detergent-based decellularization of discarded human renal kidneys preserved their innate ECM framework, biochemical properties, and angiogenic capacity and - importantly - a patent vascular network. Furthermore, the process resulted in the clearance of immunogenic antigens, which has monumental implications for clinical outcomes in the long term in terms of graft rejection. Consequently, these kidneys show promise in bioengineering and transplantation. We refer to this avenue of research and development as ‘cell-scaffold technology'. Key Messages: In 2011, more than 4,700 patients died while on the waiting list for a kidney transplant. In this context, we believe that cell-scaffold technology has the potential to form a bridge between regenerative medicine and transplantation surgery. These methods, in theory, could provide a potentially inexhaustible source of transplantable organs. Unfortunately, current investigations are still in their very early stages and clinical translation is not immediately available in the short term. Thus, identifying the most important obstacles confronting cell-scaffold technology and focusing research efforts in this direction will be important for advancing the state of the art and meeting the clinical needs. We believe that cell-scaffold technology research and development would benefit greatly from a deeper understanding of the physiological mechanisms underlying the natural organogenesis, regeneration, and repair that characterize embryonic humans and simpler organisms. Furthermore, the importance of vascularization - the fundamental caveat of modern surgery - cannot be overstated, especially when discussing the implantation of de novo organs.

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          Most cited references18

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          Whole-organ tissue engineering: decellularization and recellularization of three-dimensional matrix scaffolds.

          The definitive treatment for end-stage organ failure is orthotopic transplantation. However, the demand for transplantation far exceeds the number of available donor organs. A promising tissue-engineering/regenerative-medicine approach for functional organ replacement has emerged in recent years. Decellularization of donor organs such as heart, liver, and lung can provide an acellular, naturally occurring three-dimensional biologic scaffold material that can then be seeded with selected cell populations. Preliminary studies in animal models have provided encouraging results for the proof of concept. However, significant challenges for three-dimensional organ engineering approach remain. This manuscript describes the fundamental concepts of whole-organ engineering, including characterization of the extracellular matrix as a scaffold, methods for decellularization of vascular organs, potential cells to reseed such a scaffold, techniques for the recellularization process and important aspects regarding bioreactor design to support this approach. Critical challenges and future directions are also discussed.
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            Regeneration and Experimental Orthotopic Transplantation of a Bioengineered Kidney

            Over 100,000 individuals in the United States currently await kidney transplantation, while 400,000 individuals live with end-stage kidney disease requiring hemodialysis. The creation of a transplantable graft to permanently replace kidney function would address donor organ shortage and the morbidity associated with immunosuppression. Such a bioengineered graft must have the kidney’s architecture and function, and permit perfusion, filtration, secretion, absorption, and drainage of urine. We decellularized rat, porcine, and human kidneys by detergent perfusion, yielding acellular scaffolds with vascular, cortical and medullary architecture, collecting system and ureters. To regenerate functional tissue, we seeded rat kidney scaffolds with epithelial and endothelial cells, then perfused these cell-seeded constructs in a whole organ bioreactor. The resulting grafts produced rudimentary urine in vitro when perfused via their intrinsic vascular bed. When transplanted in orthotopic position in rat, the grafts were perfused by the recipient’s circulation, and produced urine via the ureteral conduit in vivo.
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              Kidney transplantation as primary therapy for end-stage renal disease: a National Kidney Foundation/Kidney Disease Outcomes Quality Initiative (NKF/KDOQITM) conference.

              Kidney transplantation is the most desired and cost-effective modality of renal replacement therapy for patients with irreversible chronic kidney failure (end-stage renal disease, stage 5 chronic kidney disease). Despite emerging evidence that the best outcomes accrue to patients who receive a transplant early in the course of renal replacement therapy, only 2.5% of incident patients with end-stage renal disease undergo transplantation as their initial modality of treatment, a figure largely unchanged for at least a decade. The National Kidney Foundation convened a Kidney Disease Outcomes Quality Initiative (KDOQI) conference in Washington, DC, March 19 through 20, 2007, to examine the issue. Fifty-two participants representing transplant centers, dialysis providers, and payers were divided into three work groups to address the impact of early transplantation on the chronic kidney disease paradigm, educational needs of patients and professionals, and finances of renal replacement therapy. Participants explored the benefits of early transplantation on costs and outcomes, identified current barriers (at multiple levels) that impede access to early transplantation, and recommended specific interventions to overcome those barriers. With implementation of early education, referral to a transplant center coincident with creation of vascular access, timely transplant evaluation, and identification of potential living donors, early transplantation can be an option for substantially more patients with chronic kidney disease.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-318-02677-1
                978-3-318-02678-8
                1660-2129
                2014
                May 2014
                19 May 2014
                : 126
                : 2
                : 119-124
                Affiliations
                aWake Forest School of Medicine, Winston-Salem, N.C., USA; bGeneral Surgery, Fondazione IRCCS Policlinico San Matteo Pavia and University of Pavia, Pavia, Italy
                Author notes
                *Giuseppe Orlando, MD, PhD, Wake Forest School of Medicine, Winston-Salem, NC 27157 (USA), E-Mail gorlando@wakehealth.edu
                Article
                360684 Nephron Exp Nephrol 2014;126:119-124
                10.1159/000360684
                24854653
                75c21af1-b205-42e6-9505-0b543d2fb33b
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 2, Pages: 6
                Categories
                Further Section

                Cardiovascular Medicine,Nephrology
                Scaffolds,Kidney,Renal bioengineering
                Cardiovascular Medicine, Nephrology
                Scaffolds, Kidney, Renal bioengineering

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