Goligorsky: Regenerative Nephrology

Somewhere along the tortuous evolutionary path “from fish to philosopher”, the ability to regenerate vital organs such as the kidney has been lost, or repressed. This book represents the first attempt to summarize more than a decade of kidney regeneration research. Regenerative nephrology is a subdomain of a broader emerging field of science, regenerative medicine. It is variously defined as “an interdisciplinary field of research and clinical applications focused on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function” [1]; or “regenerative medicine replaces or regenerates human cells, tissue or organs, to restore or establish normal function” [2]; or “the use of cells for the treatment of disease and encompasses both organ repair and the de novo regeneration of an entire organ” [3]. Considering the youth of the field and multitude of remaining hurdles, while providing up-to-date reviews of respective subjects, all contributors to the current book kept an open mind and anticipatory stance, alas, for the lack of a more solid ground. Indeed, the immaturity of this field of knowledge could make one wonder whether the time is ripe for a book on the subject: “Are we there yet?” To me, this situation is reminiscent of Ray Bradbury’s finale of “The Martian Chronicles” [4], when a child asks his father of Martians’ whereabouts, and the father shows him their own reflection in the water: “’I’ve always wanted to see a Martian,’ said Michael. ’Where are they, Dad? You promised.’ ’There they are,’ said Dad . and pointed straight down. The Martians stared back up at them for a long, long silent time from the rippling water .”. Yes, I believe the field is here to stay, and the chapters collected in this volume are the reflection of it.
During my professional lifetime, a paradigm shift on chronic kidney diseases has occurred. Initially, the prevailing dogma stated that inevitable progression of chronic kidney diseases accelerates as the glomerular filtration rate (GFR) drops below 60 ml/min and becomes inexorably fast when it drops below 25 30 ml/min, with dialysis-free time usually limited to 2 years, even when a low-protein diet was instituted. The process was imagined as an example of classical mechanics when a body is rolling down a sloping, non-resistive surface and gravitational forces are the only driver of the falling object. It has been quite rewarding to witness the collapse of this dogma. The dismantling process started earlier when angiotensinconverting enzyme (ACE) inhibitors, and to a lesser degree statins, phosphate binders and erythropoietin, were introduced into daily clinical practice [5]. Therapy with ACE inhibitors had an impressive success in nephrotic patients in the Ramipril Efficacy in Nephropathy (REIN) extension study and in diabetics (reviewed in Ref. 6). This tide was further enhanced by the observation that, after a prolonged period of normoglycemia in diabetic patients who received a pancreas transplantation, kidney function and glomerular lesions showed improvement [7]. These achievements are masterfully summarized in several reviews [6,8 10]. With infallibility of the dogma being questioned, the ideas of reversibility based on regenerative process began creeping in.
The scientific basis for the newscience of regeneration is provided by the plethora of investigations into wound repair. Mythology abounds with the ideas of regeneration. It was the Phoenix that was able to reconstitute itself after it had been consumed by fire; and the deliverer of fire, Prometheus, who was capable of bringing his liver back to the normal size only to provide the persistent eagle with the fresh tissue to sup on the next day. As much as the ancients were sensitive to the delicate ideas of recuperation and restitution, the modern era supplied some mechanistic insights into these processes. An acute, postinjury phase is characterized by the release of soluble mediators increasing vascular permeability, neutrophil ingress and platelet aggregation, while the regenerative phase is marked by the in growth of new blood vessels, accumulation of chronic inflammatory cells and fibroblasts in the wound bed (reviewed in Ref. 11). Two outcomes of wound healing are either a complete restoration of structure and function or fibrosis, with the combination of both bridging these two extremes. The simplest distinguishing feature between the two is the chronicity of the injurious agent; however, other stigmata determining full regeneration vis-a`-vis fibrosis do exist and are the subject of intense research. Planarians, fish and amphibians, exhibit the ability for the massive regeneration and restitution of lost body parts. This is accomplished by proliferation of stem cells, their migration to the site of injury and formation of a conglomerate of undifferentiated cells, blastema, which, receiving guidance cues from Wnt and BMP signals, proliferate, differentiate and restore the body plan. In higher organisms, the regenerative potential is much more modest, where the goal is accomplished via compensatory hypertrophy (liver and pancreas), stem cells (liver, pancreas, epithelial, bone, muscle, etc.) and cellular dedifferentiation (in fish: retina, spinal cord, fins; in reptiles: tails) (reviewed in Ref. 12). The end result of wound healing in mammals beyond embryonic age is matrix deposition and scar formation, which in parenchymal organs results in fibrosis. Injury to the kidney is more complex: true kidney regeneration would require formation of new nephrons, but this does not occur in postnatal mammals. Learning how to recapitulate the embryonic conditions, when healing does not result in scarring, and gaining insights into how to achieve restitution of structure functional organization of the lost or damaged tissue, thus preventing scarring and fibrosis, is the goal of regenerative sciences.
Fibrosis is the major process accompanying, and is at least partially responsible for, the functional demise of the kidney, or any other organ in chronic diseases. In the kidney, fibrotic processes may originate from the glomerulus [13], tubulointerstitium [14] and vasculature [15,16], forging the disease progression. In some cases, as in systemic sclerosis, a prototypic example of fibrotic processes with multiorgan involvement, there is clear evidence of vasculopathy preceding fibrosis [17,18]; in others, the sequence of events is more subtle, but the association of fibrosis and vascular dropout is unquestionable [15]. Only in rare cases, employing genetically engineered animals, is the sequence of events reversed. Such are, for instance, transgenic mice overexpressing transforming growth factor-b (TGF-b) receptor type II in fibroblasts [19], caveolin-1-deficient mice [20] and relaxin knockout mice [21], to name a few. Paradoxically, developing hypoxia and induction of proangiogenic factors not only fail to stimulate angiogenesis, but are associated with continuing vascular rarefaction. This phenomenon has been linked to the reduction of endothelial progenitor cells, or their incompetence [22,23]. By all accounts, induction of TGF-b signaling represents a final common pathway for development of fibrosis, while interferon-g, with or without interleukin-10, serves as a break in this system [24], as recently summarized by Varga and Abraham [18].
One of the intriguing questions is: Why are proregenerative processes not triggered by the encroaching disease? There should exist an element of molecular deception, when a pathological process evades the repair and/or regenerative mechanisms. It is reminiscent of an episode when Odysseus identifies himself to Polyphemus as “Nobody” and, when blinded Polyphemus calls for help and is asked whether he is affected by someone, he responds that “Nobody” attacks him.
This stealth mechanism or its opposite, an exaggerated repair response, is counteracted by SOS signaling devices, some of them employing purinergic metabolites [25], others high-mobility group protein-1 (HMGP-1), cytokines and chemokines, to name a few. The molecular mechanisms responsible for either masking the pathological process or inducing exaggerated response to injury, as well as the panoply of SOS signals, remain to be determined. It would be fair to state, therefore, that the imbalance between profibrotic and proregenerative processes, when the former prevails, is a driving force for progression of chronic kidney disease.
It is said that one should avoid cross-disciplinary extrapolation of principles from a particular field of studies to other fields. Do ideas and principles of classical Newtonian mechanics fall into this category and are not to be extrapolated? I believe that the principles of action and counteraction have broader application, and the entire field of regenerative medicine with the discovery of intrinsic mechanisms of repair or counteraction to destructive disease processes is an ample example of this.
Quoting Claude Bernard, “The science of life is a superb and dazzling lighted hall which may be reached only by passing through a long and ghastly kitchen.” This collection of chapters should take the reader through this path with the hope that it will be of help for the future entrance to the “lighted hall”. Indeed, written by the most prominent scientists, this book should illuminate such a passage. Commencing with the phylogenetic and ontogenetic overviews of kidney regeneration, it proceeds to account for several humoral and immune cell-dependent mediators of regeneration, subjects of intense research which is disclosing novel functions of macrophages and T cells, thus changing our perception of their functional role in inflammation and recovery. The contribution of stem cells to renal repair and trafficking of stem cells from their niches to the sites of repair are discussed in detail in the following two sections of the book. How stem cell repair is modified by disease and in aging and what strategies may improve their regenerative potential is the subject of the following section. The last portion of the book examines the rules for current and future clinical trials, safety of stem cell therapy, tissue engineering, as well as ethical issues related to stem cell therapy and storage of stem cells. Certainly, within the framework of the book it was impossible to embrace all of the exciting developments in the field, but the subjects discussed herein represent the core issues of the main theme of kidney regeneration. If omissions occurred, they are my responsibility. The only excuse I can invoke is the youth of the subject and the lack of precedents attempting to combine the entirety of the fledgling field of knowledge into a concise and thought provoking narrative.
In preparing this book, I was tremendously helped by Megan Wickline and Mara Conner from Elsevier, and Patricia Meravy, from New York Medical College, whose assistance, linguistic skills and remarkable insights have been invaluable. I am also indebted to several colleagues, especially Drs M. Little and C. Westenfelder, who provided me with their criticisms of the earlier structural versions of the book. It is now up to the reader to contribute to this process, with my humble assurance that suggestions and critique will be gratefully acknowledged.
Michael S. Goligorsky

[1] H. Greenwood, H. Thorsteinsdottir, G. Perry, J. Renihan, P. Singer, A. Daar, Regenerative medicine: new opportunities for developing countries, Int. J. Biotechnol. 8 (2006) 60e77.
[2] C. Mason, P. Dunnill, A brief definition of regenerative medicine, Regen. Med. 3 (2008) 1e5.
[3] M. Little, Regrow or repair: potential regenerative therapies for the kidney, J. Am. Soc. Nephrol. 17 (2006) 2390e2401.
[4] R. Bradbury, The Martian Chronicles, Doubleday, New York, 1958, p. 222.
[5] B.M. Brenner, Retarding the progression of renal disease, Kidney Int. 64 (2003) 370e378.
[6] G. Remuzzi, A. Benigni, A. Remuzzi, Mechanisms of progres sion and regression of renal lesions of chronic nephropathies and diabetes, J. Clin. Invest. 116 (2006) 288e296.
[7] P. Fioretto, M. Steffes, D. Suthrland, F. Goetz, M. Mauer, Reversal of lesions of diabetic nephropathy after pancreas transplantation, N. Engl. J. Med. 339 (1998) 69e75.
[8] A. Khwaja, M. Kossi, J. Floege, M. El Nahas, The management of CKD: a look into the future, Kidney Int. 72 (2007) 1316e1323.
[9] B.M. Brenner, Remission of renal disease: recounting the chal lenge, acquiring the goal, J. Clin. Invest. 110 (2002) 1753e1758.
[10] N. Perico, A. Benigni, G. Remuzzi, Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection, Nat. Rev. Drug. Discov. 7 (2008) 936e953.
[11] T. Stappenbeck, H. Miyoshi, The role of stromal stem cells in tissue regeneration and wound repair, Science 324 (2009) 1666e1669.
[12] D. Stocum, G. Zupanc, Stretching the limits: stem cells in regeneration science, Dev. Dynam. 237 (2008) 3648e3671.
[13] W. Kriz, M. LeHir, Pathways to nephron loss starting from glomerular diseases: insights from animal models, Kidney Int. 67 (2005) 404e419.
[14] R. Risdon, J. Sloper, H. DeWardener, Relationship between renal function and histological changes found in renal biopsy speci mens from patients with persistent glomerular nephritis, Lancet ii (1968) 363e366.
[15] K. Eardley, C. Kubal, D. Zehnder, et al., The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease, Kidney Int. 74 (2008) 495e504.
[16] B. Hohenstein, A. Braun, K.U. Amann, R.J. Johnson, C.P. Hugo, A murine model of site specific renal microvascular endothelial injury and thrombotic microangiopathy, Nephrol. Dial. Trans plant. 23 (2008) 1144e1156.
[17] M. Kahaleh, G. Sherer, E. LeRoy, Endothelial injury in scleroderma, J. Exp. Med. 149 (1979) 1326e1335.
[18] J. Varga, D. Abraham, Systemic sclerosis: a prototypic multi system fibrotic disorder, J. Clin. Invest. 117 (2007) 557e567.
[19] C. Denton, G.E. Lindahl, K. Khan, et al., Activation of key profibrotic mechanisms in transgenic fibroblasts expressing kinase deficient type II TGF beta receptor, J. Biol. Chem. 280 (2005) 16053e16065.
[20] B. Razani, T.P. Combs, X.B.Wang, et al., Caveolin 1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities, J. Biol. Chem. 276 (2001) 38121e38138.
[21] C. Samuel, C. Zhao, Q. Yang, et al., The relaxin gene knockout mouse: a model of progressive scleroderma, J. Invest. Dermatol. 125 (2005) 692e699.
[22] M. Kuwana, Y. Okazaki, H. Yasuoka, Y. Kawakami, Y. Ikeda, Defective vasculogenesis in systemic sclerosis, Lancet 364 (2004) 603e610.
[23] N. Del Papa, N. Quirici, D. Soligo, et al., Bone marrow endo thelial progenitors are defective in systemic sclerosis, Arthritis. Rheum. 54 (2006) 2605e2615.
[24] A. Ghosh, W. Yuan, Y. Mori, S.J. Chen, J. Varga, Antagonistic regulation of type I collagen gene expression by interferon gamma and transforming growth factor beta, J. Biol. Chem. 276 (2001) 11041e11048.
[25] M.S. Goligorsky, D. Patschan, M. C. Kuo, WeibelePalade bodies e sentinels of acute ischemia, Nat. Rev. Nephrology. 5
(2009) 423e426.


1. Glomerulogenesis and de novo nephrogenesis in medaka fish - evolutionary approach
2. Renal Organogenesis: Growing a replacement kidney in situ from transplanted renal primordia
3. Use of Genetic Mouse Models to study Kidney Regeneration

4. Endogenous Anti-Inflammatory and Pro-Resolving Lipid Mediators in Renal Disease
5. Tissue protection and regeneration aided by erythropoietin and erythropoietin-derived peptides
6. Mast cells in kidney regeneration
7. Role of macrophages in renal injury, repair and regeneration
8. T-cells contribution to regenerative processes

9. MSC and reparative processes
10. Stem cells in regenerative processes: Endothelial progenitor cells and the kidney
11. The potential of the side population in regenerative nephrology
12. Very small embryonic like stem cells (VSELs) and their potential relevance for kidney homeostasis
13. Stem Cells in Regenerative Processes; Induced Pluripotent Stem Cells
14. Methods of Isolation and Culture of Adult Stem cells

15. Stem Cell Niche in the Kidney
16. Creation of artificial niches
17. Imaging of transplanted and native stem cells

18. Stem cell injury and premature senescence
19. Regeneration and Aging: Regulation by Sirtuins and the NAD+ Salvage Pathway
20. Bone Marrow Mesenchymal Stem Cells in Organ Repair and Strategies to Optimize their Efficacy

21. Treatment of Acute Kidney Injury with allogeneic Mesenchymal Stem Cells: Preclinical and initial Clinical Data
22. Clinical trials in Renal Regenerative Medicine
23. Potential risks of stem cell therapies
24. Tissue engineering in urology
25. Ethical issues in SC therapy
26. Stem Cell Banking


Book Details

  • Hardcover: 442 pages
  • Publisher: Academic Press; 1 edition (2011)
  • Language: English 
  • ISBN-10: 0123809282
  • ISBN-13: 978-0123809285
  • Product Dimensions: 10.9 x 8.7 x 1.1 inches
List Price: $129.95 

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