title: Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis.
abstract: Cell-based therapy is a promising strategy for treating chronic kidney disease (CKD) and is currently the focus of preclinical studies. We performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in preclinical (animal) studies of CKD, and determined factors affecting cell-based therapy efficacy in order to guide future clinical trials. In total, 71 articles met the inclusion criteria. Standardised mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcome parameters including plasma urea, plasma creatinine, urinary protein, blood pressure, glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Sub-analysis for each outcome measure was performed for model-related factors (species, gender, model and timing of therapy) and cell-related factors (cell type, condition and origin, administration route and regime of therapy). Overall, meta-analysis showed that cell-based therapy reduced the development and progression of CKD. This was most prominent for urinary protein (SMD, 1.34; 95% CI, 1.00-1.68) and urea (1.09; 0.66-1.51), both P<0.001. Changes in plasma urea were associated with changes in both glomerulosclerosis and interstitial fibrosis. Sub-analysis showed that cell type (bone-marrow-derived progenitors and mesenchymal stromal cells being most effective) and administration route (intravenous or renal artery injection) were significant predictors of therapeutic efficacy. The timing of therapy in relation to clinical manifestation of disease, and cell origin and dose, were not associated with efficacy. Our meta-analysis confirms that cell-based therapies improve impaired renal function and morphology in preclinical models of CKD. Our analyses can be used to optimise experimental interventions and thus support both improved preclinical research and development of cell-based therapeutic interventions in a clinical setting.
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors: Diana A
authors: DA
authors: Papazova
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors: Nynke R
authors: NR
authors: Oosterhuis
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors: Hendrik
authors: H
authors: Gremmels
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors: Arianne
authors: A
authors: van Koppen
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
authors: Jaap A
authors: JA
authors: Joles
authors: Department of Nephrology and Hypertension, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands m.c.verhaar@umcutrecht.nl.
authors: Marianne C
authors: MC
authors: Verhaar
mesh_terms: D000818:Animals; D001794:Blood Pressure; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D017063:Outcome Assessment, Health Care; D011507:Proteinuria / Q000097:blood / Q000150:complications / Q000378:metabolism; D017594:Publication Bias; D012044:Regression Analysis; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D014508:Urea / Q000097:blood
chemical_list: D014508:Urea
keywords: Cell-based therapy; Chronic kidney disease; Meta-analysis
references: Biol Blood Marrow Transplant. 2013 Apr;19(4):538-46
references: 23295166
references: Kidney Int Suppl. 1996 May;54:S2-9
references: 8731185
references: J Am Soc Nephrol. 2006 Jul;17(7):1896-912
references: 16707564
references: Kidney Int. 2006 Jul;70(1):121-9
references: 16723981
references: J Am Soc Nephrol. 2007 Jun;18(6):1754-64
references: 17460140
references: Kidney Int. 2007 Dec;72(11):1316-23
references: 17700639
references: Transplant Proc. 2008 Apr;40(3):853-5
references: 18455035
references: Nephron Exp Nephrol. 2008;110(3):e91-8
references: 18957871
references: Am J Pathol. 2009 Feb;174(2):701-11
references: 19147816
references: Circulation. 2009 Feb 3;119(4):547-57
references: 19153272
references: Stem Cells Dev. 2009 Apr;18(3):475-85
references: 18564903
references: Stem Cells Dev. 2009 Apr;18(3):521-9
references: 18647091
references: Transplant Proc. 2009 Apr;41(3):947-51
references: 19376395
references: Stem Cells. 2009 Mar;27(3):682-92
references: 19096042
references: Stem Cells Dev. 2009 Jun;18(5):683-92
references: 19099374
references: Biol Blood Marrow Transplant. 2009 Nov;15(11):1354-65
references: 19822294
references: Chin Med J (Engl). 2009 Nov 5;122(21):2573-9
references: 19951572
references: Stem Cells. 2009 Dec;27(12):3063-73
references: 19750536
references: PLoS One. 2010;5(3):e9543
references: 20209052
references: Stem Cells. 2010 Jun;28(6):1039-47
references: 20506499
references: Am J Physiol Renal Physiol. 2010 Jul;299(1):F178-86
references: 20410213
references: PLoS One. 2013;8(3):e59693
references: 23555748
references: Arterioscler Thromb Vasc Biol. 2013 May;33(5):1006-13
references: 23430615
references: Cell Transplant. 2012;21(11):2425-39
references: 22525004
references: Clin Sci (Lond). 2013 Aug;125(4):199-210
references: 23480877
references: Cytotherapy. 2013 Jun;15(6):663-72
references: 23419679
references: Cytotherapy. 2013 Jun;15(6):703-11
references: 23499348
references: Biomed Res Int. 2013;2013:526367
references: 23762850
references: Int Immunopharmacol. 2013 Oct;17(2):275-82
references: 23791972
references: Cell Physiol Biochem. 2013;32(3):699-718
references: 24080824
references: PLoS One. 2013;8(11):e78464
references: 24223811
references: Stem Cells. 2013 Nov;31(11):2408-19
references: 23922321
references: Am J Med Sci. 2013 Dec;346(6):486-93
references: 23514668
references: Stem Cells Dev. 2013 Dec 1;22(23):3074-86
references: 23844841
references: J Neurosci Methods. 2014 Jan 15;221:92-102
references: 24099992
references: J Am Soc Nephrol. 2014 Feb;25(2):316-28
references: 24136918
references: Nephrol Dial Transplant. 2014 Feb;29(2):274-82
references: 24097799
references: Am J Nephrol. 2014;39(1):75-84
references: 24457259
references: Kidney Int. 2014 Mar;85(3):536-46
references: 24048382
references: Cytotherapy. 2014 Apr;16(4):471-84
references: 24119646
references: PLoS One. 2014;9(3):e92115
references: 24667162
references: Kidney Int. 2014 Apr;85(4):794-806
references: 24048378
references: Stem Cell Res Ther. 2013;4(3):59
references: 23734757
references: Mol Ther. 2014 Nov;22(11):1960-70
references: 25174586
references: Biometrics. 2000 Jun;56(2):455-63
references: 10877304
references: BMJ. 2003 Sep 6;327(7414):557-60
references: 12958120
references: Kidney Int. 2004 Jan;65(1):209-18
references: 14675052
references: J Cell Mol Med. 2012 Dec;16(12):2935-49
references: 22862802
references: Lab Anim. 2010 Jul;44(3):170-5
references: 20551243
references: Expert Opin Biol Ther. 2010 Aug;10(8):1217-26
references: 20560782
references: Ren Fail. 2010;32(7):840-8
references: 20662698
references: Am J Physiol Renal Physiol. 2010 Aug;299(2):F325-35
references: 20484299
references: Stem Cells Dev. 2010 Aug;19(8):1267-75
references: 19874085
references: Lupus. 2010 Nov;19(13):1502-14
references: 20647254
references: Cell Transplant. 2011;20(2):245-57
references: 20719085
references: Nephrol Dial Transplant. 2011 May;26(5):1474-83
references: 21324974
references: Saudi J Kidney Dis Transpl. 2011 May;22(3):501-10
references: 21566308
references: Exp Biol Med (Maywood). 2011 Jun 1;236(6):746-54
references: 21606119
references: Clin Sci (Lond). 2011 Dec;121(11):489-99
references: 21675962
references: Cardiovasc Res. 2011 Sep 1;91(4):649-58
references: 21498423
references: Arterioscler Thromb Vasc Biol. 2011 Sep;31(9):e45-54
references: 21680902
references: Nephrol Dial Transplant. 2012 Jan;27(1):218-25
references: 21622994
references: PLoS One. 2012;7(2):e32296
references: 22389693
references: Cell Biochem Funct. 2012 Mar;30(2):139-44
references: 22105543
references: JAMA. 2012 Mar 21;307(11):1169-77
references: 22436957
references: Atherosclerosis. 2012 Apr;221(2):350-8
references: 22341593
references: Stem Cells. 2012 May;30(5):1030-41
references: 22290832
references: Int J Mol Med. 2012 Jul;30(1):85-92
references: 22552764
references: Transplant Proc. 2012 May;44(4):1123-6
references: 22564642
references: Am J Physiol Renal Physiol. 2012 Jun 1;302(11):F1478-85
references: 22419692
references: PLoS One. 2012;7(6):e38746
references: 22723882
references: Nephrology (Carlton). 2012 Jul;17(5):493-500
references: 22369283
references: Diabetes. 2012 Aug;61(8):2114-25
references: 22596053
references: Mol Cell Biochem. 2012 Sep;368(1-2):137-45
references: 22661380
references: Ren Fail. 2012;34(10):1270-80
references: 23013219
references: Cell Transplant. 2012;21(8):1727-41
references: 22305061
references: Am J Physiol Renal Physiol. 2012 Nov 1;303(9):F1370-81
references: 22952284
references: PLoS One. 2012;7(10):e47559
references: 23133515
references: Kidney Int. 2012 Oct;82(7):748-58
references: 22695328
references: Stem Cells Dev. 2012 Nov 20;21(17):3125-35
references: 22494435
references: Am J Kidney Dis. 2012 Dec;60(6):1012-22
references: 23036928
references: Stem Cells Transl Med. 2012 May;1(5):373-83
references: 23197816
references: Diabetes Res Clin Pract. 2012 Dec;98(3):465-73
references: 23026513
references: Cell Transplant. 2012;21(10):2299-312
references: 23231961
references: Pharmacol Rep. 2012;64(5):1223-33
references: 23238478
references: J Am Soc Nephrol. 2013 Mar;24(4):587-603
references: 23471196
references: Stem Cells. 2013 Jan;31(1):117-25
references: 23097349
references: Am J Kidney Dis. 2013 Feb;61(2):300-9
references: 22938846
references: Cell Transplant. 2012;21(9):2009-19
references: 22525800
references: Mol Ther. 2013 Feb;21(2):433-44
references: 23089735
references: Stem Cells Transl Med. 2013 Feb;2(2):107-11
references: 23349326