The Promise of Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease
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Diabetes mellitus (DM) commonly leads to progressive chronic kidney disease despite current best medical practice. The pathogenesis of diabetic kidney disease (DKD) involves a complex network of primary and secondary mechanisms with both intra-renal and systemic components. Apart from inhibition of the renin angiotensin aldosterone system, targeting individual pathogenic mediators with drug therapy has not, thus far, been proven to have high clinical value. Stem or progenitor cell therapies offer an alternative strategy for modulating complex disease processes through suppressing multiple pathogenic pathways and promoting pro-regenerative mechanisms. Mesenchymal stem cells (MSCs) have shown particular promise based on their accessibility from adult tissues and their diverse mechanisms of action including secretion of paracrine anti-inflammatory and cyto-protective factors. In this review, the progress toward clinical translation of MSC therapy for DKD is critically evaluated. Results from animal models suggest distinct potential for systemic MSC infusion to favourably modulate DKD progression. However, only a few early phase clinical trials have been initiated and efficacy in humans remains to be proven. Key knowledge gaps and research opportunities exist in this field. These include the need to gain greater understanding of in vivo mechanism of action, to identify quantifiable biomarkers of response to therapy and to define the optimal source, dose and timing of MSC administration. Given the rising prevalence of DM and DKD worldwide, continued progress toward harnessing the inherent regenerative functions of MSCs and other progenitor cells for even a subset of those affected has potential for profound societal benefits.
KeywordsDiabetes mellitus Diabetic nephropathy Stem cells Mesenchymal stem cells Inflammation
The authors are supported by grants from the European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM (grant number 634086; TPG, WPM, NI, TO’B, MDG) and FP7 Collaborative Health Project VISICORT (grant number 602470; MDG)] and from Science Foundation Ireland [REMEDI Strategic Research Cluster (grant number 09/SRC-B1794; TO’B, MDG) and CÚRAM Research Centre (grant number 13/RC/2073; TO’B, MDG)] and by the European Regional Development Fund. TPG is supported by a Hardiman Scholarship from the College of Medicine, Nursing and Health Science of the National University of Ireland, Galway.
Compliance with Ethical Guidelines
Conflict of Interest
Tomás P. Griffin declares that he has no conflict of interest.
William Patrick Martin reports grant support from the European Commission.
Nahidul Islam reports grant support from the European Commission.
Timothy O’Brien reports grants from the European Commission, Science Foundation Ireland, and Medtronic. He reports other from the European Regional Development Fund, Orbsen Therapeutics and Onkimmune. He reports personal fees from Merck Sharp and Dohme, Sanofi Regeneron, Eli Lilly and Novo Nordisk.
Matthew D. Griffin reports grants from the European Commission, Science Foundation Ireland and Randox Teoranta; and other from the European Regional Development Fund,
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance
- 3.World Health Organization: Diabetes Fact Sheet, 2012. Available at: http://www.whoint/mediacentre/factsheets/fs312/en/indexhtml
- 7.USRDS: the United States Renal Data System. Am J Kidney Dis. 2003;42(6 Suppl 5):1–230.Google Scholar
- 9.Yokoyama H, Sone H, Oishi M, Kawai K, Fukumoto Y, Kobayashi M, et al. Prevalence of albuminuria and renal insufficiency and associated clinical factors in type 2 diabetes: the Japan Diabetes Clinical Data Management study (JDDM15). Nephrol Dial Transplant. 2009;24:1212–9.PubMedCrossRefGoogle Scholar
- 16.Orchard TJ, Secrest AM, Miller RG, Costacou T. In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2010;53:2312–9.PubMedPubMedCentralCrossRefGoogle Scholar
- 17.••Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24:302–8. This epidemiological study, based on the NHANES cohort from the USA, underscores the fact that the excess cardiovascular morbidity and mortality associated with type 2 DM is predominantly manifest among those with CKD.PubMedPubMedCentralCrossRefGoogle Scholar
- 18.•Tancredi M, Rosengren A, Svensson AM, Kosiborod M, Pivodic A, Gudbjörnsdottir S, et al. Excess mortality among persons with type 2 diabetes. New Engl J Med. 2015;373:1720–32. This epidemiological study from Sweden demonstrated that the excess risk of all-cause and cardiovascular death in type 2 DM increased with greater severity of renal complications as well as with younger age and worse glycaemic control.PubMedCrossRefGoogle Scholar
- 20.United States Renal Data System, 2014 Annual Data Report. Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease; 2014. [cited 2015 16 June]. Available from: http://www.usrds.org/adr.aspx.Google Scholar
- 21.••Sharma K, Karl B, Mathew AV, Gangoiti JA, Wassel CL, Saito R, et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013;24:1901–12. Using metabolomics screening of urine, the authors identified a 14-metabolite signature that was altered in DKD and that provided evidence for intra-renal mitochondrial dysfunction as an important pathophysiological abnormality.PubMedPubMedCentralCrossRefGoogle Scholar
- 31.•Sun L, Kanwar YS. Relevance of TNF-alpha in the context of other inflammatory cytokines in the progression of diabetic nephropathy. Kidney Int. 2015;88:662–5. This recent review focusses on clinical and experimental evidence for the role of TNF-α in the pathogenesis of DKD.PubMedPubMedCentralCrossRefGoogle Scholar
- 33.Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, Schena FP. High glucose concentration induces the overexpression of transforming growth factor-beta through the activation of a platelet-derived growth factor loop in human mesangial cells. Am J Pathol. 1996;149:2095–106.PubMedPubMedCentralGoogle Scholar
- 41.•Griffin MD, Elliman SJ, Cahill E, English K, Ceredig R, Ritter T. Concise review: adult mesenchymal stromal cell therapy for inflammatory diseases: how well are we joining the dots? Stem Cells. 2013;31:2033–41. This recent review provides a critical evaluation of current progress in understanding the anti-inflammatory properties of MSCs and in developing successful MSC therapies for human inflammatory diseases with emphasis on key challenges in the translational process.PubMedCrossRefGoogle Scholar
- 45.Xu L, Chen SY, Nie WH, Jiang XL, Yao YG. Evaluating the phylogenetic position of Chinese tree shrew (Tupaia belangeri chinensis) based on complete mitochondrial genome: implication for using tree shrew as an alternative experimental animal to primates in biomedical research. J Genet Genomics. 2012;39:131–7.PubMedCrossRefGoogle Scholar
- 50.•Zhang L, Li K, Liu X, Li D, Luo C, Fu B, et al. Repeated systemic administration of human adipose-derived stem cells attenuates overt diabetic nephropathy in rats. Stem Cell Dev. 2013;22:3074–86. In this pre-clinical study, repeated intravenous administration of human adipose-derived MSCs resulted in improvements to albuminuria and structural features of renal damage in an accelerated model of DKD in rat.CrossRefGoogle Scholar
- 52.Devarapu SK, Junhui X, Darisipudi M, Rocanin Arjo A, Anders HJ. CD362+ mesenchymal stem cell treatment of kidney disease in type 2 diabetic Lepr db/db mice. Nephrol Dial Transplant. 2015;30 suppl 3:iii223–4.Google Scholar
- 57.Kraynak AR, Storer RD, Jensen RD, Kloss MW, Soper KA, Clair JH, et al. Extent and persistence of streptozotocin-induced DNA damage and cell proliferation in rat kidney as determined by in vivo alkaline elution and BrdUrd labeling assays. Toxicol Appl Pharmacol. 1995;135:279–86.PubMedCrossRefGoogle Scholar
- 62.Fang Y, Tian X, Bai S, Fan J, Hou W, Tong H, et al. Autologous transplantation of adipose-derived mesenchymal stem cells ameliorates streptozotocin-induced diabetic nephropathy in rats by inhibiting oxidative stress, pro-inflammatory cytokines and the p38 MAPK signaling pathway. Int J Mol Med. 2012;30:85–92.PubMedGoogle Scholar
- 66.•Lv SS, Liu G, Wang JP, Wang WW, Cheng J, Sun AL, et al. Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. Int Immunopharmacol. 2013;17:275–82. In this study, administration of autologous bone marrow-derived MSCs to rats with streptozotocin-induced DM resulted in improvements in the severity of DKD with reduced intra-renal expression of MCP-1 and pro-inflammatory cytokines as well as reduced renal macrophage infiltration.PubMedCrossRefGoogle Scholar
- 69.•Li D, Wang N, Zhang L, Hanyu Z, Xueyuan B, Fu B, et al. Mesenchymal stem cells protect podocytes from apoptosis induced by high glucose via secretion of epithelial growth factor. Stem Cell Res Ther. 2013;4:103. This mechanistic study provided evidence that epithelial growth factor secreted by human adipose-derived MSCs protect podocytes from hyperglycaemia-induced apoptosis.PubMedPubMedCentralCrossRefGoogle Scholar
- 74.Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, Conget P. The anti-diabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells. 2012;30:1664–74.PubMedCrossRefGoogle Scholar
- 79.•Wu S, Li L, Wang G, Shen W, Xu Y, Liu Z, et al. Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats. Int J Nanomedicine. 2014;9:5639–51. The authors of this innovative study demonstrated that release of SDF-1 in the kidney by USTMD resulted in increased homing of intravenously administered MSCs and improved MSC efficacy in a rat model of DKD.PubMedPubMedCentralGoogle Scholar
- 82.Parving HH, Oxenboll B, Svendsen PA, Christiansen JS, Andersen AR. Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh). 1982;100:550–5.Google Scholar
- 87.Stevens PE, Levin A, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158:825–30.PubMedCrossRefGoogle Scholar
- 96.••Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, et al. Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol. 2012;23:507–15. This biomarker study provides strong evidence that elevated serum sTNFR 1 and 2 concentrations in subjects with type 2 diabetes mellitus predict progression to ESRD.PubMedPubMedCentralCrossRefGoogle Scholar
- 109.Costacou T, Zgibor JC, Evans RW, Otvos J, Lopes-Virella MF, Tracy RP, et al. The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia. 2005;48:41–8.Google Scholar
- 114.•Panduru NM, Saraheimo M, Forsblom C, Thorn LM, Gordin D, Waden J, et al. Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy. Diabetes Care. 2015;38:883–90. This recent study from the FinnDiane study group demonstrated that urinary adiponectin independently predicts progression from macro-albuminuria to ESRD in type 1 DM.PubMedCrossRefGoogle Scholar
- 127.Vaidya VS, Niewczas MA, Ficociello LH, Johnson AC, Collings FB, Warram JH, et al. Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-beta-D-glucosaminidase. Kidney Int. 2011;79:464–70.PubMedPubMedCentralCrossRefGoogle Scholar
- 130.••Looker HC, Colombo M, Hess S, Brosnan MJ, Farran B, Dalton RN, et al. Biomarkers of rapid chronic kidney disease progression in type 2 diabetes. Kidney Int. 2015;88(4):888–96. In this study the authors screened a large number of putative biomarkers for associations with DKD progression. A panel of 14 biomarkers including FGF-21, symmetric to asymmetric dimethylarginine ratio, β2-microglobulin, C16-acylcarnitine and KIM-1 was identified as improving the prediction of rapidly progressive decline in eGFR when added to clinical predictors.PubMedCrossRefGoogle Scholar
- 134.Santilli F, Spagnoli A, Mohn A, Tumini S, Verrotti A, Cipollone F, et al. Increased vascular endothelial growth factor serum concentrations may help to identify patients with onset of type 1 diabetes during childhood at risk for developing persistent microalbuminuria. J Clin Endocrinol Metab. 2001;86:3871–6.PubMedCrossRefGoogle Scholar
- 139.Petrica L, Vlad A, Gluhovschi G, Gadalean F, Dumitrascu V, Gluhovschi C, et al. Proximal tubule dysfunction is associated with podocyte damage biomarkers nephrin and vascular endothelial growth factor in type 2 diabetes mellitus patients: a cross-sectional study. PLoS One. 2014;9:e112538.PubMedPubMedCentralCrossRefGoogle Scholar
- 146.•Siwy J, Schanstra JP, Argiles A, Bakker SJL, Beige J, Boucek P, et al. Multicentre prospective validation of a urinary peptidome-based classifier for the diagnosis of type 2 diabetic nephropathy. Nephrol Dial Transplant. 2014;29:1563–70. This study provided the first validation of the CKD273 urinary proteome-based classifier of DKD in a multicentre prospective setting involving type 2 diabetic subjects.PubMedPubMedCentralCrossRefGoogle Scholar
- 150.••Packham DK, Fraser I, Kerr PG, Lichliter J, Itescu S, Skerrett D, et al. Mesenchymal stem cell therapy for diabetic nephropathy: a phase 2 randomized controlled trial. Diabetes. 2015;64(Suppl 1A):LB6. Although only reported in abstract form to date, the preliminary results for this completed Phase I/II trial provide key insights into the safety and potential efficacy of MSC therapy for established DKD.Google Scholar