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      Renal Cell Therapy Is Associated with Dynamic and Individualized Responses in Patients with Acute Renal Failure

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          Abstract

          Background: Renal cell therapy in conjunction with continuous hemofiltration techniques may provide important cellular metabolic activities to patients with acute renal failure (ARF) and may thereby change the natural history of this disorder. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10<sup>9</sup> human renal proximal tubule cells provides an opportunity to evaluate this form of therapy in patients with ARF in the intensive care unit. Methods: Nine patients with ARF and multi-organ systems failure (MOSF) have been treated so far with a tissue-engineered kidney in an FDA-approved Phase I/II clinical study currently underway. Acute physiologic parameters and serum cytokine levels were assessed before, during and after treatment with a bioartificial kidney. Results: Use of the RAD in this clinical setting demonstrates maintenance of cell viability and functionality. Cardiovascular stability appears to be maintained during RAD treatment. Human tubule cells in the RAD demonstrated differentiated metabolic and endocrinologic activity. Acute physiologic and plasma cytokine data demonstrate that renal cell therapy is associated with rapid and variable responses in patients with ARF and MOSF. Conclusion: The initial clinical experience with the bioartificial kidney and the RAD suggests that renal tubule cell therapy may provide a dynamic and individualized treatment program as assessed by acute physiologic and biochemical indices.

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          Most cited references 5

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          Tissue engineering of a bioartificial renal tubule assist device: in vitro transport and metabolic characteristics.

          Current renal substitution therapy for acute or chronic renal failure with hemodialysis or hemofiltration is life sustaining, but continues to have unacceptably high morbidity and mortality rates. This therapy is not complete renal replacement therapy because it does not provide active transport nor metabolic and endocrinologic functions of the kidney, which are located predominantly in the tubular elements of the kidney. To optimize renal substitution therapy, a bioartificial renal tubule assist device (RAD) was developed and tested in vitro for a variety of differentiated tubular functions. High-flux hollow-fiber hemofiltration cartridges with membrane surface areas of 97 cm2 or 0. 4 m2 were used as tubular scaffolds. Porcine renal proximal tubule cells were seeded into the intraluminal spaces of the hollow fibers, which were pretreated with a synthetic extracellular matrix protein. Attached cells were expanded in the cartridge as a bioreactor system to produce confluent monolayers containing up to 1.5 x 109 cells (3. 5 x 105 cells/cm2). Near confluency was achieved along the entire membrane surface, with recovery rates for perfused inulin exceeding 97 and 95% in the smaller and larger units, respectively, compared with less than 60% recovery in noncell units. A single-pass perfusion system was used to assess transport characteristics of the RADs. Vectorial fluid transport from intraluminal space to antiluminal space was demonstrated and was significantly increased with the addition of albumin to the antiluminal side and inhibited by the addition of ouabain, a specific inhibitor of Na+,K+-ATPase. Other transport activities were also observed in these devices and included active bicarbonate transport, which was decreased with acetazolamide, a carbonic anhydrase inhibitor, active glucose transport, which was suppressed with phlorizin, a specific inhibitor of the sodium-dependent glucose transporters, and para-aminohippurate (PAH) secretion, which was diminished with the anion transport inhibitor probenecid. A variety of differentiated metabolic functions was also demonstrated in the RAD. Intraluminal glutathione breakdown and its constituent amino acid uptake were suppressed with the irreversible inhibitor of gamma-glutamyl transpeptidase acivicin; ammonia production was present and incremented with declines in perfusion pH. Finally, endocrinological activity with conversion of 25-hydroxy(OH)-vitamin D3 to 1,25-(OH)2 vitD3 was demonstrated in the RAD. This conversion activity was up-regulated with parathyroid hormone and down-regulated with increasing inorganic phosphate levels, which are well-defined physiological regulators of this process in vivo. These results clearly demonstrate the successful tissue engineering of a bioartificial RAD that possesses critical differentiated transport, and improves metabolic and endocrinological functions of the kidney. This device, when placed in series with conventional hemofiltration therapy, may provide incremental renal replacement support and potentially may decrease the high morbidity and mortality rates observed in patients with renal failure.
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            Replacement of renal function in uremic animals with a tissue-engineered kidney.

            Current renal substitution therapy with hemodialysis or hemofiltration has been the only successful long-term ex vivo organ substitution therapy to date. Although this approach is life sustaining, it is still unacceptably suboptimal with poor clinical outcomes of patients with either chronic end-stage renal disease or acute renal failure. This current therapy utilizes synthetic membranes to substitute for the small solute clearance function of the renal glomerulus but does not replace the transport, metabolic, and endocrinologic functions of the tubular cells. The addition of tubule cell replacement therapy in a tissue-engineered bioartificial kidney comprising both biologic and synthetic components will likely optimize renal replacement to improve clinical outcomes. This report demonstrates that the combination of a synthetic hemofiltration device and a renal tubule cell therapy device containing porcine renal tubule cells in an extracorporeal perfusion circuit successfully replaces filtration, transport, metabolic, and endocrinologic functions of the kidney in acutely uremic dogs.
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              Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells.

              Current renal substitution therapy with hemodialysis or hemofiltration has been an important life-sustaining technology, but it still has suboptimal clinical outcomes in patients with end-stage renal disease or acute renal failure. This therapy replaces the small solute clearance function of the glomerulus but does not replace the metabolic and endocrinologic functions of the tubular cells. This article shows that the combination of a synthetic hemofiltration cartridge and a renal tubule cell assist device (RAD) containing human cells in an extracorporeal circuit replaces filtration, metabolic, and endocrinologic functions in acutely uremic dogs. The RAD maintained excellent performance and durability characteristics for 24 hours of continuous use in the uremic animals. The RAD increased ammonia excretion, glutathione metabolism, and 1,25-dihydroxyvitamin D3 production. Cardiovascular stability in the animals was documented in these studies during this extracorporeal treatment. With these results, clinical evaluation of this device in the treatment of severely ill patients with acute renal failure in an intensive care unit has been initiated. Copyright 2002 by the National Kidney Foundation, Inc.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                978-3-8055-7535-5
                978-3-318-00939-2
                0253-5068
                1421-9735
                2003
                2003
                22 January 2003
                : 21
                : 1
                : 64-71
                Affiliations
                Departments of Medicine and Surgery, University of Michigan Medical Center and Departments of Nephrology and Hypertension, Cleveland Clinic Foundation, Ann Arbor, Mich., USA
                Article
                67864 Blood Purif 2003;21:64–71
                10.1159/000067864
                12566664
                © 2003 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.

                Page count
                Figures: 3, Tables: 1, References: 28, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/67864
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                Paper

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