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1/5nature reviews|nephrology volume 6 | marCH 2010 | 179

Introduction

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AKI: a therapeutic problem

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AKI: progression to CKD

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New biomarkers for AKI

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opInIon

Mcma tm c: a wtautic t f AKI

Florian E. Tgel and Christof Westenfelder

Abtact | Acute kidney injuy (AKI) is a common clinical complication, associated

with poo outcomes and the deelopment of chonic kidney disease. Despite majo

adances in the undestanding of its pathophysiology, aailable theapies fo AKI ae

only suppotie; theefoe, adequate functional ecoey fom AKI must pedominantly

ely on the kidneys own epaatie ability. An extensie body of peclinical data

fom ou own and fom othe laboatoies has shown that administation of adult

multipotent maow stomal cells (commonly efeed to as mesenchymal stem cells

[MSCs]), effectiely amelioates expeimental AKI by exeting paacine enopotectie

effects and by stimulating tissue epai. Based on these findings, a clinical tial has

been conducted to inestigate the safety and efficacy of MSCs administeed to open-

heat sugey patients who ae at high isk of postopeatie AKI. In this Pespecties

aticle, we discuss some of the ealy data fom this tial and descibe potential

applications fo stem cell theapies in othe fields of nephology.

Tgel, F. E. & Westenfelde, C. Nat. Rev. Nephrol.6, 179183 (2010); doi:10.1038/nneph.2009.229

Cmti itt

F. E. Tgel declaes no competing inteests.C. Westenfelde declaes an association with thefollowing company: Allocue. See the aticleonline fo full details of the elationship.

PErSPECTIvES

20 Macmillan Publishers Limited. All rights reserved10
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h aKi c.

MSC therapy: preclinical data

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msC fbb-k c gd

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a g bdy f dc d

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b c f h g c h b,1417 dg chc xp f hbd bfc ffc f h c. w k h msC c g pf gh fc d h kckd fc dh gh fc (veGF) iGF-i c dc h -pc p f msC.11,19 th d-y f gh fc h jd d ck b msC d jd d fy c pbbyxp h py f msC-dd

Injured tubular cellsInfammatory cell

EC

EC

MSC

MSC in glomeruli

MSC in peritubular capillary

Glomerular basement membrane

Paracrine actions

Crosstalk

Endocrine actions2

Filtration 1

3

4

3

Figure 1 | Intaenal actions of MSCs in acute kidney injuy. Infusion of MSCs esults in theihoming to sites of enal injuy and tempoa y adhesion to glomeula and postglomeulacapillaies. Gowth factos and cytokines ae seceted and delieed to the luminal aspects ofinjued poximal tubules by filtation acoss the glomeula basement membane (1). Thesefactos ae also eleased into postglomeula capillaies (2), theeby eaching poximal tubulacells fom thei basolateal side. Gowth-facto-ecepto expession is upegulated in iabletubula cells, and ecepto distibution in injued, poximal tubula cells is both luminal andbasolateal. Adheent MSCs act in a paacine fashion (3) in glomeuli and in the postglomeulaciculation, tageting glomeula, micoascula endothelial, and inflammatoy cells.(4) Cosstalk (blue aows) between MSCs and adjacent enal and inflammatoy cells causesbeneficial changes in the espectie gene expession pofiles. Abbeiations: EC, endothelialcell; MSC, mesenchymal stem cell.

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Phase I preliminary data

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g d d pgd pp), fb d f. th pyd p f h fy f gcmsC d d bydc f h cdc f d, d , gh f h-p y d d gd cp -chd h-c c c f h cc (i mdc C,

Acute kidney injury

Mesenchymal stem cells

Inammation Tubular cell damage Vascular damage

Figure 2 | Mesenchymal stem cells (MSCs) taget all pathophysiological components of acutekidney injuy (AKI). Majo axes of the pathophysiology of AKI include inflammation, ascula andtubula damage. Inflammation is tiggeed by ischemiaepefusion injuy, inflammatoycytokines, and immune cell attachment and migation. vascula damage is caused by ischemiaepefusion. Endothelial injuy and futhe micociculatoy impaiment aggaates tubula celldamage and inceases inflammation. Tubula cell injuy is caused by hypoxia and by the

geneation of eactie oxygen species duing epefusion. MSCs educe inflammation by diect(cellcell contact) and indiect (paacine) actions, by modulating immune esponses, bysuppession of T-cell, B-cell and natual-kille-cell polifeation, and by potecting endothelialcells, theeby educing ascula damage and impoing micociculation.12 Tubula andmicoascula damage ae educed by the secetion of gowth factos (fo example, EGF, HGF,vEGF and IGF-I), which collectiely decease apoptosis and enhance polifeation of citicallydamaged tubula and endothelial cells.

Table 1 | Cuently ecuiting tials of MSCs in nephology26

stud Dia tit Itvti pa Ciica tiaidtifi

Allogeneic multipotent stomal cell teatmentfo AKI following cadiac sugey

Kidney tubula necosis, AKI Administation of MSCs Phase I NCT00733876

MSC tansplantation in ecipients of liing kidneyallogafts

Tansplantation Administation of MSCs Phase I & II NCT00658073

MSCs unde basiliximab and/o low-dose ATGto induce enal tansplant toleance

Kidney tansplantation Administation of MSCs, basiliximab,methylpednisolone, ATG, ciclospoin,mycophenolate mofetil

Phase I & II NCT00752479

MSCs and subclinical ejection Ogan tansplantation Administation of MSCs Phase I & II NCT00734396

MSC tansplantation fo efactoy systemic lupuseythematosus

refactoy systemic lupuseythematosus

Administation of allogeneic MSCs Phase I & I I NCT00698191

Abbeiations: AKI, acute kidney injuy; MSC, mesenchymal stem cell; ATG, abbit antithymocyte globulin.

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my, ut, usa, d s. mk Hp,s lk Cy, ut, usa). th b dd h h pp ff gc msC c d f, d d bb h hpy bd (C. wfd, pb-hd k). i dd, h cpd cy chd hc c c,bh gh f hp y d d- dy p dcdby ~40%. Pp fc d dd d b d p qd hdy,h ~20% f c c dpdaKi (C. wfd, pbhd k).i dd, fc dy ph dyg CKD b f p 16 h f f-p, h cp-b pp p, fc- chd c c hd

pg d. ipy, ch b y d cc cp h bd pcck, b h cc d -d h c f h xp aKid d.11,12,1416

Other stem-cell-based trials

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p f cdc gy b, dcd b. H, msC f p phgbc f h b dypp, ggg hy y b d h dj g f pjc d chc p ph-phy.21,26 oh pg ppcf msC cd dch ph cd h ycp yh (tb 1). D fy h dy cy b. H, h d

gc x f h cgg ccf b p ph dcd, - g fgf--h d.26

Conclusions

th b f ph i c-c d h fby dfy f h pc dg. Pyc h d bc fy d fc- p dd msC pg. th py ffccy d cgg b cd ph ii(c, dzd, db-bd), hch h ffccy f h - pppy d, h x p. Pp f dqypd ph ii h pp h c d h ph i cy dy. w hp h h

y b f ph i dy,gh h h dp f y d dgc bk f aKi, gfc p h pg f p h aKi.

ad f hp bd h-pc c, msC-bd hp cy h dcd -c-bd hp f ccg. H, pcc d hdh pg c, dcd p-p c, d byc c dcd g, d pbby

gy xpd d fh p -c hp h y b d g dc.

Department of Medicine, Weill Cornell College

of Medicine and New York Presbyterian

Hospital, 1300 York Avenue, New York,

NY 10021, USA (F. E. Tgel). Division of

Nephrology, University of Utah and VA Medical

Centers, 500 Foothill Boulevard, Salt Lake City,

UT 84148, USA (C. Westenfelder).

Correspondence to: C. Westenfelder

[email protected]

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perspeCtIves

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Ackwdmt

The authos eseach discussed in this Pespectiesaticle was in pat suppoted by funds fom the Meitreiew pogam of the veteans Administation,Washington, DC, the NIH, the Ameican HeatAssociation, the National Kidney Foundation, theWesten Institute fo Biomedical reseach, andAllocue, Inc. The human MSCs that weeadministeed to study subjects in the phase I clinicaltial wee pepaed in the cGMP Cell Theapy Facility

of the Uniesity of Utah, UT, USA. The outstandingskills of the pincipal inestigatos (J. Doty,Intemountain Medical Cente, Muay, UT; D. Affleck,St. Maks Hospital, Salt Lake City, UT), co-pincipal

inestigatos (B. Hone and B. Muhlestein,Intemountain Medical Cente; S. Kawande andG. Scholemme, St. Maks Hospital), and studynuses (J. Floes, Intemountain Medical Cente;A. Cee, St. Maks Hospital) ae gatefullyacknowledged. The contibutions of the membes ofthe Data Safety and Monitoing Boad fo the phase Itial discussed in this aticle, C. Kablitz, G. r. reiss,and S. Beddhu, ae also geatly appeciated. Finally,the excellent bench wok of Z. Hu and P. Zhang fo the

conduct of the descibed peclinical studies isacknowledged, and the egulatoy contibutions ofA. Gooch wee inaluable fo the conduct of thedescibed clinical tial.

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