[Frontiers in Bioscience, Elite, 7, 248-262, January 1, 2015]

Current strategies and challenges in engineering a bioartificial kidney

Steven Kim 1 2 , William H. Fissell 3 , H. David Humes 4 , Shuvo Roy1

1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158 2Division of Nephrology, Department of Medicine, University of California, San Francisco, San Francisco, CA 94158 3Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN 37232 4Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Growing a kidney in-situ: de novo organogenesis
4. Supplementing a failing kidney: cell transplantation
5. Growing a kidney in-vitro
    5.1. Kidney factory: stem cells
    5.2. Cloning a kidney: nuclear transplantation
6. Reseeding a kidney: decellularized scaffolds
7. Bioengineering a kidney
    7.1. Renal assist device (RAD)
    7.2. Bioartificial renal epithelial cell system (BRECS)
    7.3. Implantable renal assist device (iRAD)
8. Discussion
9. Conclusion
10. Acknowledgements
11. References

1. ABSTRACT

Renal replacement therapy was an early pioneer in both extra-corporeal organ replacement and whole organ transplantation. Today, the success of this pioneering work is directly demonstrated in the millions of patients worldwide successfully treated with dialysis and kidney transplantation. However, there remain significant shortcomings to current treatment modalities that limit clinical outcomes and quality of life. To address these problems, researchers have turned to using cell-based therapies for the development of a bioartificial kidney. These approaches aim to recapitulate the numerous functions of the healthy kidney including solute clearance, fluid homeostasis and metabolic and endocrine functions. This review will examine the state-of-the-art in kidney bioengineering by evaluating the various techniques currently being utilized to create a bioartificial kidney. These promising new technologies, however, still need to address key issues that may limit the widespread adoption of cell therapy including cell sourcing, organ scaffolding, and immune response. Additionally, while these new methods have shown success in animal models, it remains to be seen whether these techniques can be successfully adapted for clinical treatment in humans.

11. REFERENCES

1. ESRD Patients in 2011 A Global Perspective, (2011)

2. USRDS Annual Data Report 2013, (2013)

3. R. Saran, J. L. Bragg-Gresham, N. W. Levin, Z. J. Twardowski, V. Wizemann, A. Saito, N. Kimata, B. W. Gillespie, C. Combe, J. Bommer, T. Akiba, D. L. Mapes, E. W. Young and F. K. Port: Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS, Kidney Int 69, 1222-1228 (2006).
DOI: 10.1038/sj.ki.5000186

4. U. Buoncristiani, Fifteen years of clinical experience with daily haemodialysis, Nephrol Dial Transplant 13 Suppl 6, 148-151 (1998)
DOI: 10.1093/ndt/13.suppl_6.148

5. G. M. Chertow, N. W. Levin, G. J. Beck, T. A. Depner, P. W. Eggers, J. J. Gassman, I. Gorodetskaya, T. Greene, S. James, B. Larive, R. M. Lindsay, R. L. Mehta, B. Miller, D. B. Ornt, S. Rajagopalan, A. Rastogi, M. V. Rocco, B. Schiller, O. Sergeyeva, G. Schulman, G. O. Ting, M. L. Unruh, R. A. Star, A. S. Kliger and FHN Trial Grp: In-Center Hemodialysis Six Times per Week versus Three Times per Week, N Engl J Med 363, 2287-2300 (2010).
DOI: 10.1056/NEJMoa1001593

6. B. F. Culleton, M. Walsh, S. W. Klarenbach, G. Mortis, N. Scott-Douglas, R. R. Quinn, M. Tonelli, S. Donnelly, M. G. Friedrich, A. Kumar, H. Mahallati, B. R. Hemmelgarn and B. J. Manns: Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial, JAMA 298, 1291-1299 (2007).
DOI: 10.1001/jama.298.11.1291

7. Global Observatory on Donation and Transplantation (GODT), World Health Organization, Organ Donation and Transplantation Activities 2011, (2013)

8. US Department of Health and Human Services, OPTN: Data Organ Procurement and Transplantation Network, (2013)

9. M. Horster, G. Braun and S. Huber: Embryonic renal epithelia: Induction, nephrogenesis, and cell differentiation, Physiol Rev 79, 1157-1191 (1999)

10. M. R. Hammerman, Transplantation of renal primordia: renal organogenesis, Pediatr Nephrol 22, 1991-1998 (2007).
DOI: 10.1007/s00467-007-0554-7

11. S. Rogers and M. Hammerman: Transplantation of metanephroi after preservation in vitro, American Journal of Physiology-Regulatory Integrative and Comparative Physiology 281, R661-R665 (2001)

12. M. Hammerman, Tissue engineering the kidney, Kidney Int 63, 1195-1204 (2003).
DOI: 10.1046/j.1523-1755.2003.00890.x

13. S. Rogers, J. Lowell, N. Hammerman and M. Hammerman: Transplantation of developing metanephroi into adult rats, Kidney Int 54, 27-37 (1998).
DOI: 10.1046/j.1523-1755.1998.00971.x

14. D. Marshall, M. Clancy, M. Bottomley, K. Symonds, P. Brenchley and C. Bravery: Transplantation of metanephroi to sites within the abdominal cavity, Transplant Proc 37, 194-197 (2005).
DOI: 10.1.016/j.transproceed.2004.1.2.2.83

15. S. A. Rogers and M. R. Hammerman: Prolongation of life in anephric rats following de novo renal organogenesis, Organogenesis 1, 22-25 (2004)
DOI: 10.4161/org.1.1.1009

16. D. Marshall, M. R. Dilworth, M. Clancy, C. A. Bravery and N. Ashton: Increasing renal mass improves survival in anephric rats following metanephros transplantation, Exp Physiol 92, 263-271 (2007).
DOI: 10.1113/expphysiol.2006.036319

17. S. Kim, H. J. Park, J. Han, S. Gwak, M. H. Park, K. W. Song, Y. H. Rhee, H. M. Chung and B. Kim: Improvement of kidney failure with fetal kidney precursor cell transplantation, Transplantation 83, 1249-1258 (2007).
DOI: 10.1097/01.tp.0000261712.93299.a6

18. S. Kim, S. Gwak, J. Han, H. J. Park, M. H. Park, K. W. Song, S. W. Cho, Y. H. Rhee, H. M. Chung and B. Kim: Kidney tissue reconstruction by fetal kidney cell transplantation: Effect of gestation stage of fetal kidney cells, Stem Cells 25, 1393-1401 (2007).
DOI: 10.1634/stemcells.2006-0183

19. T. Yokoo, T. Ohashi, J. Shen, K. Sakurai, Y. Miyazaki, Y. Utsunomiya, M. Takahashi, Y. Terada, Y. Eto, T. Kawamura, N. Osumi and T. Hosoya: Human mesenchymal stem cells in rodent whole-embryo culture are reprogrammed to contribute to kidney tissues, Proc Natl Acad Sci U S A 102, 3296-3300 (2005).
DOI: 10.1073/pnas.0406878102

20. T. Yokoo, A. Fukui, T. Ohashi, Y. Miyazaki, Y. Utsunomiya, T. Kawamura, T. Hosoya, M. Okabe and E. Kobayashi: Xenobiotic kidney organogenesis from human mesenchymal stem cells using a growing rodent embryo, J Am Soc Nephrol 17, 1026-1034 (2006).
DOI: 10.1681/ASN.2005101043

21. T. Yokoo, A. Fukui, K. Matsumoto, T. Ohashi, Y. Sado, H. Suzuki, T. Kawamura, M. Okabe, T. Hosoya and E. Kobayashi: Generation of a transplantable erythropoietin-producer derived from human mesenchymal stem cells, Transplantation 85, 1654-1658 (2008).
DOI: 10.1097/TP.0b013e318173a35d

22. R. Lanza, H. Chung, J. Yoo, P. Wettstein, C. Blackwell, N. Borson, E. Hofmeister, G. Schuch, S. Soker, C. Moraes, M. West and A. Atala: Generation of histocompatible tissues using nuclear transplantation, Nat Biotechnol 20, 689-696 (2002).
DOI: 10.1038/nbt703

23. E. A. Ross, M. J. Williams, T. Hamazaki, N. Terada, W. L. Clapp, C. Adin, G. W. Ellison, M. Jorgensen and C. D. Batich: Embryonic Stem Cells Proliferate and Differentiate when Seeded into Kidney Scaffolds, J Am Soc Nephrol 20, 2338-2347 (2009).
DOI: 10.1681/ASN.2008111196

24. K. H. Nakayama, C. A. Batchelder, C. I. Lee and A. F. Tarantal: Decellularized Rhesus Monkey Kidney as a Three-Dimensional Scaffold for Renal Tissue Engineering, Tissue Eng Part A 16, 2207-2216 (2010).
DOI: 10.1089/ten.tea.2009.0602

25. J. J. Song, J. P. Guyette, S. E. Gilpin, G. Gonzalez, J. P. Vacanti and H. C. Ott: Regeneration and experimental orthotopic transplantation of a bioengineered kidney, Nat Med 19, 646-651 (2013).
DOI: 10.1038/nm.3154

26. H. C. Ott, T. S. Matthiesen, S. Goh, L. D. Black, S. M. Kren, T. I. Netoff and D. A. Taylor: Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart, Nat Med 14, 213-221 (2008).
DOI: 10.1038/nm1684

27. H. C. Ott, B. Clippinger, C. Conrad, C. Schuetz, I. Pomerantseva, L. Ikonomou, D. Kotton and J. P. Vacanti: Regeneration and orthotopic transplantation of a bioartificial lung, Nat Med 16, 927-U131 (2010).
DOI: 10.1038/nm.2193

28. H. Humes, D. Buffington, S. MacKay, A. Funke and W. Weitzel: Replacement of renal function in uremic animals with a tissue-engineered kidney, Nat Biotechnol 17, 451-455 (1999).
DOI: 10.1038/8626

29. J. Tumlin, R. Wali, W. Williams, P. Murray, A. J. Tolwani, A. K. Vinnikova, H. M. Szerlip, J. Ye, E. P. Paganini, L. Dworkin, K. W. Finkel, M. A. Kraus and H. D. Humes: Efficacy and safety of renal tubule cell therapy for acute renal failure, J Am Soc Nephrol 19, 1034-1040 (2008).
DOI: 10.1681/ASN.2007080895

30. C. J. Pino, A. S. Yevzlin, J. Tumlin and H. D. Humes: Cell-Based Strategies for the Treatment of Kidney Dysfunction: A Review, Blood Purif 34, 117-123 (2012).
DOI: 10.1159/000341649

31. D. Buffington, C. Pino, L. Chen, A. Westover, G. Hageman and H. D. Humes: Bioartificial Renal Epithelial Cell System (BRECS): A Compact, Cryopreservable Extracorporeal Renal Replacement Device, Cell Medicine 4, 33-43 (2012)
DOI: 10.3727/215517912X653328

32. W. H. Fissell, A. Dubnisheva, A. N. Eldridge, A. J. Fleischman, A. L. Zydney and S. Roy: High-Performance Silicon Nanopore Hemofiltration Membranes, J Memb Sci 326, 58-63 (2009).
DOI: 10.1016/j.memsci.2008.09.039

33. W. H. Fissell and S. Roy: The implantable artificial kidney, Semin Dial 22, 665-670 (2009).
DOI: 10.1111/j.1525-139X.2009.00662.x

34. S. Roy, A. Dubnisheva, A. Eldridge, A. J. Fleischman, K. G. Goldman, H. D. Humes, A. L. Zydney and W. H. Fissell: Silicon nanopore membrane technology for an implantable artificial kidney, Proceedings of the 15th International Conference on Solid-State Sensors, Actuators, and Microsystems - Transducers 2009 (2009)

35. S. Roy, K. Goldman, R. Marchant, A. Zydney, D. Brown, A. Fleischman, A. Conlisk, T. Desai, S. Duffy, H. Humes and W. Fissell: Implanted renal replacement for end-stage renal disease, Panminerva Med 53, 155-166 (2011)

36. A. T. Conlisk, S. Datta, W. H. Fissell and S. Roy: Biomolecular transport through hemofiltration membranes, Ann Biomed Eng 37, 722-736 (2009).
DOI: 10.1007/s10439-009-9642-0

37. W. H. Fissell, A. J. Fleischman, H. D. Humes and S. Roy: Development of continuous implantable renal replacement: past and future, Transl Res 150, 327-336 (2007).
DOI: 10.1016/j.trsl.2007.06.001

38. D. M. Kanani, W. H. Fissell, S. Roy, A. Dubnisheva, A. Fleischman and A. L. Zydney: Permeability - Selectivity Analysis for Ultrafiltration: Effect of Pore Geometry, J Memb Sci 349, 405 (2010).
DOI: 10.1016/j.memsci.2009.12.003

39. W. Fissell, N. Ferrell, J. Groszek, A. Conlisk, D. Kanani and A. Zydney: Enhanced B2-microglobulin Clearance by Silicone Nanopore Membranes, ASN 46th Renal Week, F-PO1078 (2010)

40. W. H. Fissell, S. Manley, A. Westover, H.D. Humes, A. J. Fleischman and S.Roy: Differentiated growth of human renal tubule cells on thin-film and nanostructured materials, ASAIO J 52, 221-227 (2006).
DOI:10.1097/01.mat.0000205228.30516.9c

41. A. J. Westover, D. A. Buffington and H. D. Humes: Enhanced propagation of adult human renal epithelial progenitor cells to improve cell sourcing for tissue-engineered therapeutic devices for renal diseases, Journal of Tissue Engineering and Regenerative Medicine 6, 589-597 (2012).
DOI: 10.1002/term.471

42. J. J. Song and H. C. Ott: Organ engineering based on decellularized matrix scaffolds, Trends Mol Med 17, 424-432 (2011).
DOI: 10.1016/j.molmed.2011.03.005

43. M. R. Hammerman, Transplantation of developing kidneys, Transplant Rev 16, 62-71 (2002).
DOI: 10.1053/trre.2002.29160

44. S. Yokote and T. Yokoo: Stem Cells in Kidney Regeneration, Curr Med Chem 19, 6009-6017 (2012)
DOI: 10.2174/092986712804485890

Key words: Kidney bioengineering, Organ development, Cell therapy, Bioartificial , Review

Send correspondence to: Steven H. Kim, University of California, San Francisco, Department of Medicine, Division of Nephrology, 521 Parnassus Ave, C443, Box 0532, San Francisco, CA 94143, Tel: 415-476-5714, Fax: 415-514-9656, E-mail: Steven.Kim@ucsf.edu