RENAL FAILURE: Improve Renal Function in Preclinical Acute Kidney Injury Study

PRESS RELEASE
Oct. 5, 2010, 8:50 a.m. EDT •
Adipose-Derived Stem & Regenerative Cells Reduce Mortality, Improve Renal Function in Preclinical Acute Kidney Injury Study Data Published Today

SAN DIEGO, Oct 05, 2010 (BUSINESS WIRE) — Preclinical data was published today on research performed by Cytori Therapeutics /quotes/comstock/15*!cytx/quotes/nls/cytx (CYTX 4.98, +0.28, +5.96%) showing adipose (fat)-derived stem and regenerative cells (ADRCs), either fresh or banked, demonstrated statistically significant improvements in animal survival and kidney function in an acute kidney injury animal model. Complete results appear in the latest issue of Nephrology Dialysis Transplantation, available for download at http://ndt.oxfordjournals.org.
Two separate controlled studies were performed. One compared a mixed population of uncultured rodent ADRCs, delivered immediately after extraction (fresh cells), to a control group (n=29; 15 treated: 14 control). The other compared ADRCs, which were cryopreserved and subsequently thawed (banked cells), to a control group (n=19; 10 treated:9 control). ADRCs are comprised of several cell types, including adipose stem cells, endothelial progenitor cells, smooth muscle cells and smooth muscle progenitor cells.
Acute kidney injury was induced by occluding blood flow into and out of both kidneys for 38 minutes. Twenty minutes after reperfusion of the kidneys, 5 x 10(6)ADRCs or saline only were injected intra-arterially. All rodents were assessed daily for seven days for markers of kidney function (serum creatinine and blood urea nitrogen) and survival.
In the fresh ADRC arm, 100% of the treated group survived after seven days, compared to only 57% of the control group (p = 0.005). In the banked ADRC arm, 90% of the treated group survived after seven days, compared to 33% in the control group (p = 0.019).
The ADRC-treated subjects showed statistically significant improvements in kidney function, as measured by serum creatinine (p In addition, substantial improvement in the histologic structure within the kidney was observed as measured by a reduction in tubular cell death and epithelial shedding (p<0.0001).
Cautionary Statement Regarding Forward-Looking Statements
This communication includes forward-looking statements regarding events, trends and business prospects, which may affect our future operating results and financial position. Such statements, including, but not limited to, those regarding the ability of ADRC’s to improve the survival, function and physiology in an acute kidney injury model in a rodent, are subject to risks and uncertainties that could cause our actual results and financial position to differ. Some of these risks and uncertainties include the challenges inherent in transitioning animal research model to the human therapies, as well as our history of operating losses, regulatory uncertainties, dependence on third party performance, maintaining sufficient capital resources, and other risks and uncertainties described under the “Risk Factors” in Cytori’s Securities and Exchange Filings, including its annual report on Form 10-K for the year ended December 31, 2009 and subsequent quarterly reports on Form 10-Q. Cytori assumes no responsibility to update or revise any forward-looking statements contained in this press release to reflect events, trends or circumstances after the date of this press release.
SOURCE: Cytori Therapeutics

Cytori Therapeutics
Tom Baker, 858-875-5258 858-875-5258
tbaker@cytori.com

ARTICLES
Am J Physiol Renal Physiol. 2011 Jan;300(1):F207-18. Epub 2010 Oct 13.
VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury.
Yuan L, Wu MJ, Sun HY, Xiong J, Zhang Y, Liu CY, Fu LL, Liu DM, Liu HQ, Mei CL.
Affiliated Hospital of Nantong University, Nantong, Jiangsu, China.
Abstract
The implantation of mesenchymal stem cells (MSC) has been reported as a new technique to restore renal tubular structure and improve renal function in acute kidney injury (AKI). Vascular endothelial growth factor (VEGF) plays an important role in the renoprotective function of MSC. Whether upregulation of VEGF by a combination of MSC and VEGF gene transfer could enhance the protective effect of MSC in AKI is not clear. We investigated the effects of VEGF-modified human embryonic MSC (VEGF-hMSC) in healing cisplatin-injured renal tubular epithelial cells (TCMK-1) with a coculture system. We found that TCMK-1 viability declined 3 days after cisplatin pretreatment and that coculture with VEGF-hMSC enhanced cell protection via mitogenic and antiapoptotic actions. In addition, administration of VEGF-hMSC in a nude mouse model of cisplatin-induced kidney injury offered better protective effects on renal function, tubular structure, and survival as represented by increased cell proliferation, decreased cellular apoptosis, and improved peritubular capillary density. These data suggest that VEGF-modified hMSC implantation could provide advanced benefits in the protection against AKI by increasing antiapoptosis effects and improving microcirculation and cell proliferation.
PMID: 20943766 [PubMed – indexed for MEDLINE]

Ren Fail. 2010;32(10):1237-44.
Role of stem cells in kidney repair.
Petrovic V, Jovanovic I, Pesic I, Stefanovic V.
Faculty of Medicine, University of Nis, Nis, Serbia.
Abstract
End-stage renal disease and acute renal failure are the most important issues of practical and clinical nephrology, bearing in mind their high mortality rate, solely symptomatic treatment, and overall economic impact on society. The advances in stem cell biology opened the door for the new era in treatment of many disorders, including renal, offering new therapeutical solutions. Findings suggesting that the adult kidney contains stem cells and that stem cells from bone marrow have potential to differentiate into renal cells focused research on the possible application of these cells in therapy of kidney disorders. The other promising candidates for stem cell therapy for the kidney are embryonic stem cells and amniotic fluid-derived stem cells. This article focuses on the characteristics and possible application of these types of stem cells.
PMID: 20954989 [PubMed – in process]

Urol Int. 2010 Sep 28. [Epub ahead of print] Mesenchymal Stem Cells Ameliorate Ischemia-Reperfusion-Induced Renal Dysfunction by Improving the Antioxidant/Oxidant Balance in the Ischemic Kidney.
Zhuo W, Liao L, Xu T, Wu W, Yang S, Tan J.
Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, PR China.
Abstract
Background: Renal ischemia followed by reperfusion leads to acute renal failure in both native kidneys and renal allograft. This study aimed at investigating the effects ofmesenchymal stem cells (MSC) on ischemia/reperfusion (I/R) injury and the underlying mechanisms in a rat model. Methods: Renal ischemia was produced by clamping the right renal vessels for 60 min after the left kidney was removed. Immediately after visual confirmation of reflow, 1 × 10(6) MSC were administered by intravenous injection, followed by reperfusion for 24 h. The kidney functions, tissue malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels were evaluated. Histopathological examinations were also performed. Results: MSC infusion significantly improved kidney function as indicated by lower urea and creatinine levels in the MSC compared to the vehicle group (p < 0.05). I/R-induced reduction in renal tissue SOD enzyme activity and GSH-Px was significantly improved by MSC (p < 0.05). Treatment with MSC also resulted in significant reduction in renal tissue MDA levels that were increased by renal I/R injury (p < 0.05). At histological examination, the kidneys of MSC-treated rats showed a fairly normal morphology. Conclusions: MSC protects the kidneys against I/R injury at least via their antioxidant effects.
Copyright © 2010 S. Karger AG, Basel.
PMID: 20881358 [PubMed – as supplied by publisher]

Transl Res. 2010 Sep;156(3):161-8. Epub 2010 Jul 30.
Stem cell technology for the treatment of acute and chronic renal failure.
Pino CJ, Humes HD.
Innovative BioTherapies, Inc, Ann Arbor, MI 48108, USA.
Abstract
Acute and chronic renal failure are disorders with high rates of morbidity and mortality. Current treatment is based upon conventional dialysis to provide volume regulation and small solute clearance. There is growing recognition that renal failure is a complex disease state requiring a multifactorial therapy to address the short-comings of the conventional monofactorial approach. Kidney transplantation remains the most effective treatment, however, organ availability lags far behind demand. Many key kidney functions including gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation are provided by renal tubule cells. Therefore, cell-based therapies are promising multifactorial treatment approaches. In this review, current stem cell technologies including adult stem cells, embryonic stem cells and induced pluripotent stem cells will be discussed as cell sources for the treatment of acute and chronic renal failure.
Copyright 2010 Mosby, Inc. All rights reserved.
PMID: 20801413 [PubMed – indexed for MEDLINE]

Stem Cells. 2010 Sep;28(9):1649-60.
Concise review: Kidney stem/progenitor cells: differentiate, sort out, or reprogram?
Pleniceanu O, Harari-Steinberg O, Dekel B.
Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Israel.
Abstract
End-stage renal disease (ESRD) is defined as the inability of the kidneys to remove waste products and excess fluid from the blood. ESRD progresses from earlier stages of chronic kidney disease (CKD) and occurs when the glomerular filtration rate (GFR) is below 15 ml/minute/1.73 m(2). CKD and ESRD are dramatically rising due to increasing aging population, population demographics, and the growing rate of diabetes and hypertension. Identification of multipotential stem/progenitor populations in mammalian tissues is important for therapeutic applications and for understanding developmental processes and tissue homeostasis. Progenitor populations are ideal targets for gene therapy, cell transplantation, and tissue engineering. The demand for kidney progenitors is increasing due to severe shortage of donor organs. Because dialysis and transplantation are currently the only successful therapies for ESRD, cell therapy offers an alternative approach for kidney diseases. However, this approach may be relevant only in earlier stages of CKD, when kidney function and histology are still preserved, allowing for the integration of cells and/or for their paracrine effects, but not when small and fibrotic end-stage kidneys develop. Although blood- and bone marrow-derived stem cells hold a therapeutic promise, they are devoid of nephrogenic potential, emphasizing the need to seek kidney stem cells beyond known extrarenal sources. Moreover, controversies regarding the existence of a true adult kidney stem cell highlight the importance of studying cell-based therapies using pluripotent cells, progenitor cells from fetal kidney, or dedifferentiated/reprogrammed adult kidney cells.
PMID: 20652959 [PubMed – indexed for MEDLINE]

Expert Opin Biol Ther. 2010 Aug;10(8):1217-26.
Mesenchymal stem cell therapy for chronic renal failure.
Choi SJ, Kim JK, Hwang SD.
Soonchunhyang University Bucheon Hospital, Internal Medicine, Wonmi-gu, Bucheon-si, Republic of Korea.
Abstract
IMPORTANCE OF THE FIELD: Chronic kidney disease (CKD) has become a worldwide public health problem. Renal transplantation is the treatment of choice for end-stage renal disease, but is limited by a small number of organ donors and the immune barrier. To overcome these problems, new therapeutic strategies for tissue repair have recently emerged.
AREAS COVERED IN THIS REVIEW: We discuss the therapeutic potential of mesenchymal stem cells (MSCs) in kidney injury and examine the latest reports providing evidence supporting MSC efficacy in the treatment of chronic renal failure (CRF).
WHAT THE READER WILL GAIN: MSCs improve histological and functional outcomes in various CRF model systems. Paracrine effects rather than transdifferentiation might result in the prevention of progressive renal failure. In addition, MSCs can reprogram kidney cell differentiation, and modulate neo-kidney transplantation in CRF.
TAKE HOME MESSAGE: Although many practical problems remain to be addressed, treatment with MSCs will enter the mainstream of CRF treatment.
PMID: 20560782 [PubMed – indexed for MEDLINE]

Am J Physiol Renal Physiol. 2010 Aug;299(2):F325-35. Epub 2010 May 19.
Bone marrow-derived endothelial progenitor cells confer renal protection in a murine chronic renal failure model.
Sangidorj O, Yang SH, Jang HR, Lee JP, Cha RH, Kim SM, Lim CS, Kim YS.
1Department of Internal Medicine, Seoul National University College of Medicine, Jongro-gu, Korea.
Abstract
Endothelial cell damage and impaired angiogenesis substantially contribute to the progression of chronic renal failure (CRF). The effect of endothelial progenitor cell (EPC) treatment on the progression of CRF is yet to be determined. We performed 5/6 nephrectomy to induce CRF in C57BL/6 mice. EPCs were isolated from bone marrow, grown in conditioned medium, and characterized with surface marker analysis. The serial changes in kidney function and histological features were scrutinized in CRF mice and EPC-treated CRF (EPC-CRF) mice. Adoptively transferred EPCs were present at the glomeruli and the tubulointerstitial area until week 8 after transfer. In CRF mice, renal function deteriorated steadily over time, whereas the EPC-CRF group showed less deterioration of renal function as well as reduced proteinuria along with a relatively preserved kidney structure. Renal expression of proinflammatory cytokines and adhesion molecules was already decreased in the EPC-CRF group at the early stage of disease, at which point the renal function and histology of CRF and EPC-CRF mice were not different. Angiogenic molecules including VEGF, KDR, and thrombospondin-1, which were decreased in the CRF group, were restored by EPC treatment. In conclusion, EPCs trafficked into the injured kidney protected the kidney from the inflammatory condition and consequently resulted in functional and structural renal preservation. Our study suggests EPCs as a potential candidate for a novel therapeutic approach in CRF.
PMID: 20484299 [PubMed – indexed for MEDLINE]

J Surg Res. 2010 Jul 8. [Epub ahead of print] Arterially Delivered Mesenchymal Stem Cells Prevent Obstruction-Induced Renal Fibrosis.
Asanuma H, Vanderbrink BA, Campbell MT, Hile KL, Zhang H, Meldrum DR, Meldrum KK.
Department of Urology, Indiana University School of Medicine, Indianapolis, Indianapolis, Indiana.
Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated.
MATERIALS AND METHODS: Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E-cadherin/α-smooth muscle actin (α-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson’s trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR).
RESULTS: Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced α-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E-cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor-α (TNF-α) levels, but did not alter transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression.
CONCLUSIONS: Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-α production may be involved.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 20850784 [PubMed – as supplied by publisher]

J Surg Res. 2010 Jul 8. [Epub ahead of print] Arterially Delivered Mesenchymal Stem Cells Prevent Obstruction-Induced Renal Fibrosis.
Asanuma H, Vanderbrink BA, Campbell MT, Hile KL, Zhang H, Meldrum DR, Meldrum KK.
Department of Urology, Indiana University School of Medicine, Indianapolis, Indianapolis, Indiana.
Abstract
BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated.
MATERIALS AND METHODS: Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E-cadherin/α-smooth muscle actin (α-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson’s trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR).
RESULTS: Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced α-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E-cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor-α (TNF-α) levels, but did not alter transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression.
CONCLUSIONS: Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-α production may be involved.
Copyright © 2010 Elsevier Inc. All rights reserved.
PMID: 20850784 [PubMed – as supplied by publisher]

Nephron Exp Nephrol. 2010;114(3):e107-16. Epub 2009 Dec 2.
Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury.
Burst VR, Gillis M, Pütsch F, Herzog R, Fischer JH, Heid P, Müller-Ehmsen J, Schenk K, Fries JW, Baldamus CA, Benzing T.
Renal Division, Department of Medicine, University of Cologne, Cologne, Germany. volker.burst@uk-koeln.de
Abstract
BACKGROUND: Although renal tubular epithelium has a great capacity for repair it has been suggested that the administration of mesenchymal stem cells may accelerate the recovery following severe ischemic injury.
METHODS: Here we analyzed the survival rate and organ distribution of transplanted mesenchymal stem cells as well as their contribution to kidney regeneration after ischemic renal injury using functional tests, histological examination as well as quantitative real-time PCR.
RESULTS: Intravenously injected stem cells were mainly trapped in lungs and liver. One hour after injection, less than 1% of the injected stem cells could be detected in the injured kidneys. These cells disappeared within the first few days and did not replace renal epithelial cells precluding substantial transdifferentiation. To clarify whether reinforced stem cell delivery might promote sustained survival or conversion to tubular epithelia, stem cells were directly injected into the injured kidneys. Although these grafted cells also did not show sustained survival or contribute to structural renal repair, stem cell injection was associated with a significant but transient initial decrease in serum creatinine.
CONCLUSION: These data suggest that mesenchymal stem cells do not significantly contribute to epithelial renewal after ischemic injury, promoting the idea that the major impact of cell-based therapy for acute kidney injury may result from paracrine or endocrine effects unrelated to stem cell transdifferentiation.
PMID: 19955830 [PubMed – indexed for MEDLINE]

Nat Rev Nephrol. 2010 Mar;6(3):179-83.
Mesenchymal stem cells: a new therapeutic tool for AKI.
Tögel FE, Westenfelder C.
Department of Medicine, Weill Cornell College of Medicine and New York Presbyterian Hospital, New York, NY 10021, USA.
Abstract
Acute kidney injury (AKI) is a common clinical complication, associated with poor outcomes and the development of chronic kidney disease. Despite major advances in the understanding of its pathophysiology, available therapies for AKI are only supportive; therefore, adequate functional recovery from AKI must predominantly rely on the kidney’s own reparative ability. An extensive body of preclinical data from our own and from other laboratories has shown that administration of adult multipotent marrow stromal cells (commonly referred to as mesenchymal stem cells [MSCs]), effectively ameliorates experimental AKI by exerting paracrine renoprotective effects and by stimulating tissue repair. Based on these findings, a clinical trial has been conducted to investigate the safety and efficacy of MSCs administered to open-heart surgery patients who are at high risk of postoperative AKI. In this Perspectives article, we discuss some of the early data from this trial and describe potential applications for stem cell therapies in other fields of nephrology.
PMID: 20186233 [PubMed – indexed for MEDLINE]

Nephrol Dial Transplant. 2010 Jan;25(1):17-24. Epub 2009 Oct 26.
Multipotent mesenchymal stromal cell therapy in renal disease and kidney transplantation.
Reinders ME, Fibbe WE, Rabelink TJ.
Abstract
Cell therapies aim at differentiation of stem cells into the specific cell type required to repair damaged or destroyed cells or tissues. Over recent years, cell therapy has been introduced in a variety of application areas, including cardiovascular repair, diabetes, musculoskeletal disorders and renal repair. Multipotent mesenchymal stromal cells (MSCs), often referred to as mesenchymal stem cells, are of particular interest as a cell therapy model, as this is one of the few cell types that are on the brink of entering the clinical arena in different areas of application. MSCs can be differentiated in vitro and in vivo into various cell types of mesenchymal origin such as bone, fat and cartilage. They have important effects on the innate and adaptive immune system and possess striking anti-inflammatory properties that make them attractive for potential use in diseases characterized by autoimmunity and inflammation. In addition, MSCs have been shown to migrate to sites of tissue injury and to enhance repair by secreting anti-fibrotic and pro-angiogenic factors. In this review, evidence for the renoprotective mechanisms of MSCs as well as their therapeutic possibilities and potential hazards in acute and chronic renal disease and allograft rejection is summarized.
PMID: 19861311 [PubMed – indexed for MEDLINE] Biol Blood Marrow Transplant. 2009 Nov;15(11):1354-65.
Endovenous administration of bone-marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice.
Ezquer F, Ezquer M, Simon V, Pardo F, Yañez A, Carpio D, Conget P.
Instituto de Ciencias, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Abstract
Twenty-five to 40% of diabetic patients develop diabetic nephropathy, a clinical syndrome that comprises renal failure and increased risk of cardiovascular disease. It represents the major cause of chronic kidney disease and is associated with premature morbimortality of diabetic patients. Multipotent mesenchymal stromal cells (MSC) contribute to the regeneration of several organs, including acutely injured kidney. We sought to evaluate if MSC protect kidney function and structure when endovenously administered to mice with severe diabetes. A month after nonimmunologic diabetes induction by streptozotocin injection, C57BL/6 mice presented hyperglycemia, glycosuria, hypoinsulinemia, massive beta-pancreatic islet destruction, low albuminuria, but not renal histopathologic changes (DM mice). At this stage, one group of animals received the vehicle (untreated) and other group received 2 doses of 0.5 x 10(6) MSC/each (MSC-treated). Untreated DM mice gradually increased urinary albumin excretion and 4 months after diabetes onset, they reached values 15 times higher than normal animals. In contrast, MSC-treated DM mice maintained basal levels of albuminuria. Untreated DM mice had marked glomerular and tubular histopathologic changes (sclerosis, mesangial expansion, tubular dilatation, proteins cylinders, podocytes lost). However, MSC-treated mice showed only slight tubular dilatation. Observed renoprotection was not associated with an improvement in endocrine pancreas function in this animal model, because MSC-treated DM mice remained hyperglycemic and hypoinsulinemic, and maintained few remnant beta-pancreatic islets throughout the study period. To study MSC biodistribution, cells were isolated from isogenic mice that constitutively express GFP (MSC(GFP)) and endovenously administered to DM mice. Although at very low levels, donor cells were found in kidney of DM mice 3 month after transplantation. Presented preclinical results support MSC administration as a cell therapy strategy to prevent chronic renal diseases secondary to diabetes.
PMID: 19822294 [PubMed – indexed for MEDLINE]

Minerva Urol Nefrol. 2009 Dec;61(4):373-84.
Contribution of bone marrow-derived cells in renal repair after acute kidney injury.
Masereeuw R.
Department of Pharmacology and Toxicology Radboud University Nijmegen Medical Centre Nijmegen Centre for Molecular Life Sciences Nijmegen, The Netherlands. R.Masereeuw@ncmls.ru.nl
Abstract
Acute kidney injury (AKI) is a frequent clinical problem with a high mortality rate, generally caused by ischemic insults. Nevertheless, the kidney has a remarkably high capacity to regenerate after ischemic injury. Tubular cells can restore renal function by proliferation and dedifferentiation into a mesenchymal cell-type, but also stem cells residing in bone marrow (BM) have been suggested to contribute. Considerable progress has been made in the development of different techniques to study the role of BM-derived stem cells in renal regeneration after AKI. Trans-differentiation of BM cells to functional tubular epithelium has been demonstrated previously, however, beneficial effects of BM transplantations may have been accelerated by irradiation of mice prior to transplantation and kidney injury. Recent studies support a paracrine or endocrine role of BM-derived cells, in which an improvement of renal function is observed without direct involvement in tubular epithelial engraftment. On the other hand, BM cells have also shown not to improve renal function despite their tubular engraftment. This review gives an overview of the recent progress in studying the role of BM-derived cells as therapeutic strategy in renal tubular repair after acute injury.
PMID: 19816390 [PubMed – indexed for MEDLINE]

Stem Cells. 2009 Dec;27(12):3063-73.
Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model.
Semedo P, Correa-Costa M, Antonio Cenedeze M, Maria Avancini Costa Malheiros D, Antonia dos Reis M, Shimizu MH, Seguro AC, Pacheco-Silva A, Saraiva Camara NO.
Nephrology Division, Medicine Department, Federal University of São Paulo, 05508-900 São Paulo, SP, Brazil.
Abstract
Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2|x|10(5) MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73(+)CD90(+) cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson’s trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor beta, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and alpha smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor alpha mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney.
PMID: 19750536 [PubMed – indexed for MEDLINE] Biol Blood Marrow Transplant. 2009 Nov;15(11):1354-65.
Endovenous administration of bone-marrow-derived multipotent mesenchymal stromal cells prevents renal failure in diabetic mice.
Ezquer F, Ezquer M, Simon V, Pardo F, Yañez A, Carpio D, Conget P.
Instituto de Ciencias, Facultad de Medicina Clínica Alemana Universidad del Desarrollo, Santiago, Chile.
Abstract
Twenty-five to 40% of diabetic patients develop diabetic nephropathy, a clinical syndrome that comprises renal failure and increased risk of cardiovascular disease. It represents the major cause of chronic kidney disease and is associated with premature morbimortality of diabetic patients. Multipotent mesenchymal stromal cells (MSC) contribute to the regeneration of several organs, including acutely injured kidney. We sought to evaluate if MSC protect kidney function and structure when endovenously administered to mice with severe diabetes. A month after nonimmunologic diabetes induction by streptozotocin injection, C57BL/6 mice presented hyperglycemia, glycosuria, hypoinsulinemia, massive beta-pancreatic islet destruction, low albuminuria, but not renal histopathologic changes (DM mice). At this stage, one group of animals received the vehicle (untreated) and other group received 2 doses of 0.5 x 10(6) MSC/each (MSC-treated). Untreated DM mice gradually increased urinary albumin excretion and 4 months after diabetes onset, they reached values 15 times higher than normal animals. In contrast, MSC-treated DM mice maintained basal levels of albuminuria. Untreated DM mice had marked glomerular and tubular histopathologic changes (sclerosis, mesangial expansion, tubular dilatation, proteins cylinders, podocytes lost). However, MSC-treated mice showed only slight tubular dilatation. Observed renoprotection was not associated with an improvement in endocrine pancreas function in this animal model, because MSC-treated DM mice remained hyperglycemic and hypoinsulinemic, and maintained few remnant beta-pancreatic islets throughout the study period. To study MSC biodistribution, cells were isolated from isogenic mice that constitutively express GFP (MSC(GFP)) and endovenously administered to DM mice. Although at very low levels, donor cells were found in kidney of DM mice 3 month after transplantation. Presented preclinical results support MSC administration as a cell therapy strategy to prevent chronic renal diseases secondary to diabetes.
PMID: 19822294 [PubMed – indexed for MEDLINE]

Nephrology (Carlton). 2009 Sep;14(6):544-53.
Review article: Potential cellular therapies for renal disease: can we translate results from animal studies to the human condition?
Little MH, Rae FK.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia. m.little@imb.uq.edu.au
Abstract
The incidence of chronic kidney disease is increasing worldwide, prompting considerable research into potential regenerative therapies. These have included studies to determine whether an endogenous renal stem cell exists in the postnatal kidney and whether non-renal adult stem cells, such as mesenchymal stem cell, can ameliorate renal damage. Such stem cells will either need to be recruited to the damaged kidney to repair the damage in situ or be differentiated into the desired cell type and delivered into the damaged kidney to subsequently elicit repair without maldifferentiation. To date, these studies have largely been performed using experimental and genetic models of renal damage in rodents. The translation of such research into a therapy applicable to human disease faces many challenges. In this review, we examine which animal models have been used to evaluate potential cellular therapies and how valid these are to human chronic kidney disease.
PMID: 19712255 [PubMed – indexed for MEDLINE]

Biol Blood Marrow Transplant. 2009 Jul;15(7):812-6.
Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma.
Parikh GC, Amjad AI, Saliba RM, Kazmi SM, Khan ZU, Lahoti A, Hosing C, Mendoza F, Qureshi SR, Weber DM, Wang M, Popat U, Alousi AM, Champlin RE, Giralt SA, Qazilbash MH.
Department of Stem Cell Transplantation and Cellular Therapy, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract
Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).
PMID: 19539212 [PubMed – indexed for MEDLINE]

Bull Exp Biol Med. 2009 Jan;147(1):113-9.
Morphological changes in the kidneys of rats with postischemic acute renal failure after intrarenal administration of fetal mesenchymal stem cells from human bone marrow.
[Article in English, Russian] Kudryavtsev YV, Kirpatovskii VI, Plotnikov EY, Kazachenko AV, Marei MV, Khryapenkova TG, Zorov DB, Sukhikh GT.
Research Institute of Urology, Russian Medical Technologies, Russia.
Abstract
Chronic experiments on outbred albino rats were performed to compare the dynamics of histological signs for postischemic renal injury (90-min thermal ischemia) after intraparenchymal injection of cultured fetal MSC from human bone marrow. Functional indexes of the ischemic kidney were predetermined. In the early period after ischemia (day 4), administration of human bone marrow MSC was followed by the increase in blood flow in the microcirculatory bed and decrease in the degree of alteration in renal tubules. An increase in the area of zones with histological signs for normal function of tubules was accompanied by the improvement of biochemical indexes for renal function. In the delayed period, a protective effect of cell therapy was manifested in the prevention of death of renal tubules. Mild calcification of the necrotic tubular epithelium served as a marker of this process. Human bone marrow MSC were labeled with the fluorescent probe Calcein. These cells migrated from the site of injection, spread in the interstitium, and retained viability for 7 days. During this period, some cells were incorporated into the lumen of renal tubules.
PMID: 19526146 [PubMed – indexed for MEDLINE] Curr Stem Cell Res Ther. 2009 Jan;4(1):2-8.
Contribution of stem cells to kidney repair.
Bussolati B, Hauser PV, Carvalhosa R, Camussi G.
Cattedra di Nefrologia, Dipartimento di Medicina Interna, Ospedale Maggiore S. Giovanni Battista, Corso Dogliotti 14, Turin, Italy.
Abstract
A current explanation for development of chronic renal injury is the imbalance between injurious mechanism and regenerative repair. The possibility that stem cells contribute to the repair of glomerular and tubular damage is of great interest for basic and translational research. Endogenous bone marrow-derived stem cells have been implicated in the repair of renal tissue, although the lineage of stem cells recruited has not been determined. If endogenous bone marrow-derived stem cells repopulate injured nephrons directly or act indirectly over a paracrine/endocrine mechanism remains also controversial. Therapeutic administration of exogenous bone marrow derived stem cells in animal models of acute renal injury suggests that a stem cell-based therapy may improve the recovery of both glomerular and tubular compartments. Whereas the therapeutic benefit of sorted hematopoietic stem cells remains uncertain, several studies showed a beneficial effect of mesenchymal stem cell administration in models of acute tubular injury and of endothelial progenitors in acute glomerular injury. Recent studies demonstrate the presence of resident stem cells within the adult kidney. These cells are capable, when injected in animals with acute tubular injury, to localize to renal compartments and contribute to regeneration. This review summarizes the current literature on the physiological role of endogenous stem cells in renal regeneration and on the therapeutic potential of exogenous stem cell administration. Moreover, critical points that still need clarification, such as the homing mechanisms of stem cells to injured tissue, the secreted factors underlying the paracrine/endocrine mechanisms and the long-term behaviour of in vivo administered stem cells, are discussed.
PMID: 19149624 [PubMed – indexed for MEDLINE]

Internist (Berl). 2007 Aug;48(8):813-8.
[Regenerative therapy in nephrology. Repair or construction?].
[Article in German] Haller H.
Klinik für Nieren- und Hochdruckkrankheiten, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover. haller.hermann@mh-hannover.de
Abstract
Animal experiments and analyses of human renal tissues show that regeneration of degraded renal tubules is caused by adjacent surviving tubules. Differentiation, migration, proliferation and redifferentiation are regulated by local growth factors. Renal stem cells can also participate in this process. Mesenchymal stem cells play a pivotal role in renal regeneration and if these are still present in the adult kidney, they could be the source material for repair and regeneration following injury. The exact location and role of resident mesenchymal stem cells which have been demonstrated in the kidneys is still unclear. New surface markers and a better characterisation of the many cell populations possibly participating in the regeneration process are necessary in order to clarify their complex interaction. It is also unclear whether mesenchymal stem cells from bone marrow or other organs are also involved. In addition to structural regeneration, the stem cells also play a role in the functional recovery following acute renal failure. Artificial regeneration of human kidneys is difficult due to their functional and spatial complexity. By the additional use of cells in dialysis machines it may be possible to improve the quality of filtration and also replace other renal functions. Initial results using this new technique in clinical phase I/II studies on patients with acute renal failure are promising.
PMID: 17628761 [PubMed – indexed for MEDLINE]

Nephrol Dial Transplant. 2006 Dec;21(12):3349-53. Epub 2006 Oct 5.
Cell therapy for renal regeneration–time for some joined-up thinking?
Poulsom R, Prodromidi EI, Pusey CD, Cook HT.
No abstract
PMID: 17023491 [PubMed – indexed for MEDLINE]