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Rationale of mesenchymal stem cell therapy in kidney injury.

1. January 2013

Rationale of Mesenchymal Stem Cell Therapy in Kidney Injury
Vincenzo Cantaluppi, MD, Luigi Biancone, MD, Alessandro Quercia, MD,
Maria Chiara Deregibus, MD, Giuseppe Segoloni, MD, and Giovanni Camussi, MD
Numerous preclinical and clinical studies suggest that mesenchymal stem cells, also known as multipotent
mesenchvmal stromal cells (MSCS),
improve pathologic conditions involving different organs.
beneticial ettects initial v were ascribed to the ditterentiation of MsCs into organ parenchumal cels. However
at least in the kidnev. this is a verv rare event and the kidnev-protective ettects of MSCs have been attributed
mainly to paracrine mechanisms. MSCs release a number of trophic, anti-inflammatory, and immune-
modulatory factors that may limit kidney inlury and tavor recoverv. In this article, we provide an overview or the
bIolOgIc activitles or Mous that mav be relevant tor the treatment or Kidney injury In the context or a case
vignette concerning a patient at hign immunologic risk who underwent a second kidney transplantation
followed by the development of ischemia-repertusion injury and acute allogramt rejection. ve alscuss ine
possible beneficial effect of MSC treatment in the light of preclinical and clinical data supporting the
regenerative and immunomodulatory potential of MSCs
Am J KIdnev Dis. 61 2):300-309. © 2013 bv the National Kidnev Foundation. Inc.
INDEX WORDS: Mesenchvmal stem cells: kidnev injurv: kidney transplantation: reiection.
Tissue damage with loss of parenchymal cells is
common final outcome of different pathologic condi-
tions. The process of repair tends to counteract the
loss of parenchymal cells and replace dead cells.
However, in the kidney, this process frequently is
hampered by evolution to fibrosis and long-term loss
of function.” Therapeutic strategies to optimize the
repair therefore should inhibit the mechanisms in-
volved in cellular loss and stimulate the proliferation
of parenchymal cells.’ In the context of kidney trans-
plantation, several immunologic and nonimmuno-
logic factors contribute to the loss of transplant func-
Among these factors, delayed graft function
(DGF)4.5 due to ischemia-reperfusion injury, T-cell-
mediated rejection, 6,7
and antibody-mediated rejec
tion&-10 are recognized to significantly affect long-
term allograft survival.
bone marrow-derived stem cells have been Dro
posed as an appealing therapeutic approach to avoid
or at least limit allograft injury.” In particular, mesen-
chymal stem cells, cautiously renamed multipotent
mesenchymal stromal cells (MSCs) by the Interna-
tional Society for Cellular Therapy, ‘2 have garnered
great interest for their regenerative and immunomodu-
latory properties, mainly due to the release of para-
crine factors. 13
From the Nephrologv, Dialysis and Renal Transplantation Unit,
Centre for Experimental Medical Research (CeRMS) and Depart
ment of Internal Medicine, University of Torino, Torino, Italy.
Received Januarv 30. 2012. Accented in revised torm Mav 23.
zUl2. Originally nulished online August 31. 2012.
Address correspondence to Giovanni Camussi, MD. Cattedra di
Netrologia. Dipartimento di Medicina Interna, Uspedale Mag
giore S. Giovanni Battista
“Molinette”, Corso Dogliotti 14, 10120,
Torino, Italv. E-mail:
© 2013 by the National Kidney Foundation, Inc.
. 40-Vear-Old man With dialVs1S-treated end-stage renal diseast
(1980-1900, peritoneal dialysiS: 1980- 198, hemodi
lalVs1s) second•
arv to vesicoureteral reflux received a first K1dney transplant from &
decensed donor in 1989 (Box 1). T-Cell-mediated rejection was
fOllowed by the development or chronic transplant glomerulopa-
thv, severe
interstitial fibrosis, and vascular damage.
and the
patient experienced a progressive deterioration in K1dney functior
and fluid overload. In 2007. he returned to hemodialvsis therapy. In
Julv 2011. he underwent a second kidney transplantation in the
presence of a heightened immunologic profile with different sub.
sets of anti-HLA antibodies (anti-HLA-A1. A2. A3. A9. Al0. All
A28. A36, A80; anti-HLA-B13, B27, B37, B40, B44. B47. B57:
and anti-HLA-DR3-DR13) and panel-reactive antibody level of
Y%%. He received immunosuppressive therapy with basiliximab
20 mg
, at days U and 4; tacrolimus, 0.2 mg/kg, daily
: mvcopheno-
late motetil.
g. twice dailv: and steroids. In the first davs atter
transplantation, a clinical picture of DGF characterized by
and increase in serum creatinine level was observed.
and dialvsis
was pertormed on davs I.
and J. K1dnev blosv showec
tubular necrosis due to ischemic damage. In the tollow
urine outout increased and serum creatinine level decreased
. How-
ever. at dav l 2 posttransplantation. urme outout
igain decreasec
and serum creatinine level increased. For this reason. he underv
second biopsy showing the presence of I-cell-mediated rejection
association with congestion of tubulomnterstitial and
and mild positivity for C4d staining. He v
with thvmoglobulin (100 mg dailv tor a total of l.l a. withdrawa
mvcophenolate moteti theranv.
and decreasing blood levels of
Kidney tunction improved and the patient
charged 36 days atter transplantation (serum creatinine, 2.4 mg,
dl, corresponding
glomerular filtration
mL/min/1.73 mz
determined bv the 4-variable Modification of

DGF, a form of acute kidney injury (AKI), usually
is defined as the need for dialysis in the first week
after transplantation.+,5.14 The incidence of DGF ranges
from 2%-50% in kidney transplants from deceased
donors, with the variation associated with the trans-
plantation center. In contrast. DGF has a lower inci-
dence in living donor transplants, likely due to less
ischemia-reperfusion injury (5%-15%).” Although
many factors may be responsible for DGF (urinary
obstructions, artery/vein thrombosis, early acute rejec-
tion, drug nephrotoxicity, viral infections,
depletion, etc), ischemia-reperfusion injury is known
to contribute to the delay of cellular regeneration and
functional recovery of grafted kidneys.t» The in-
crease in cold ischemia time is considered the major
determinant of DGES,15,16 In addition. DGF may
increase allograft immunogenicity, with a consequent
increased risk of acute rejection and early occurrence
of chronic allograft nephropathy,S. 17
Several stildies
reported an association between DGF and decreased
Am J Kidnev Dis. 2013:61(2):300-309
transplant survival.4 Others found a
DGF with decreased transplant survival only when
associated with acute rejection 4,18 These
ations are strengthened by changing clinical scenarios
in kidney transplantation over recent years. 17
patients increasingly are being considered for kidney
19 On this basis, several transplanta-
tion programs using non-heart-beating donors and in
particular suboptimal deceased donors have been de-
veloped. 19,20 Unfortunately. kidneys from such do-
nors are exposed to increased ischemic injury and
The cellular and molecular mechanisms involved in
tissue damage after kidney ischemia-reperfusion in-
jury have been studied extensivelv.I,l© Ischemia can
activate a comnlex sequence of events (release of
oxygen free radicals, increased expression of major
histocompatibility complex class I and II antigens.
endothelia activation with consequent evtokine re-
that sustain kidney injury and favor
DGF. 16,21 Tubular epithelial cells are the main target
of hypoxia within the kidney. I,I6 Ischemia leads to the
loss of tubular cell polarity and cytoskeleton
brush-border integrity, leading to mislocalization of
molecules usually expressed at the apical/basolateral
membrane or tight junctions. 1.23 These events are
responsible for the functional impairment of tubules
that are not alle to preserve distinct fud-illed com-
partments with precise electrolyte concentrations.22
In the presence of a sustained ischemic injury.
tubular cells not only show functional impairment, but
also undergo necrosis and apoptosis through activa-
tion of the death receptor (tumor necrosis factor
tumor necrosis factor receptor and Fas/Fas-ligand)
‘ In the meantime, trans-
plant metabolism shifts from an aerobic to anaerobic
state, with consequent accumulation of lactate and
oxygen free radicals that lead to the release of proin-
Hammatory cytokines and activation of innate immu-
The final stage of ischemic injury
occurs during the
reperfusion period, characterized by reoxygenation,
production of adenosine triphosphate, and generation
of high concentrations of radical oxidants that cause
hyperoxidation of cell membranes and synthesis of
different types of chemokines. 16,21-23 Moreover, dif-
ferent adhesion and antigenic molecules are upregu-
lated on tubular cells, favoring T-lymphocyte adhe-
sion.?1 Tubular cells are immunologically active and
in the presence of an inflammatory state may express
surface adhesion molecules, chemokines, and costimu-
latory molecules such as CD40, able to directly bind
to CD40-ligand present on activated T cells -3,24 These

events may lead to amplifcation of the immune re-
sponse and recruitment and activation of other inflam-
matory cells able to perpetuate tissue injury, 21,24 Apart
from its effects on tubular cells, ischemic injury also
is known to affect the function and survival of endo-
thelial cells within the kidney. 24 Microvascular injury
is one of the hallmarks of ischemia and is responsible
for the extension phase of AKI, which involves en-
hanced coagulation and adhesion of inflammatory
cells.34 Ischemia-reperfusion injury can be worsened
by the nephrotoxic effect of immunosuppressive drugs
such as calcineurin inhibitors, tacrolimus, and cyclo-
sporine.?5 The restoration of kidney function after
DGF is related to replacement of necrotic cells with
functional tubular epithelium.5,26,27 Surviving tubular
cells are able to dedifferentiate, expressing mesenchy-
mal (vimentin) and embryonic (Pax-2) markers; pro.
liferate; migrate to cover the denudated basal mem-
brane; and finally redifferentiate, restoring polarity
and epithelial integrity to the cell. 5,26-27 These mecha-
nisms are orchestrated by a series of growth factors
able to promote tubular cell proliferation. 23,26,27
Triggering of the immune response against the
allograft is based on antigen presentation to T lympho-
cvtes by different cell types. 28 Cells expressing class
II HLA antigen molecules on their surface, including
B cells, dendritic cells, and macrophages, may operate
as professional antigen-presenting cells able to acti-
vate naive or memory T cells.28,29 Of interest, the
existence of biologically active resident dendritic cells
has been demonstrated within the kidney, 28,29 Kidney
dendritic cells may initiate allograft rejection by di-
rect antigen presentation to infiltrating T cells., 28,29
Moreover, recent investigations have shown a key
role for innate immunity in the triggering of the
adaptive immune response.?8 The presence of an
inflammatory microenvironment created by different
causes may induce the maturation of kidney dendritic
cells, allowing antigen presentation to activated T
cells, 28,29 Moreover, further studies showed that an
influx of myeloid and plasmocytoid dendritic cells is a
hallmark of allograft rejection that correlates with the
development of tubular atrophy and interstitial fibro-
28-30 Tubular epithelial cells may deeply influence
the biological behavior of infiltrating T cells because
they may express class II HLA antigen and costimula-
tory molecules such as CD40, B7-H1, and inducible
costimulator ligand.3 Furthermore.
also can occur through indirect T-cell-antigen presen-
tation of HLA antigen molecules by antigen-present-
ing cells.28-30 Regulatory T cells originating from the
thymus or from T-cell conversion in the periphery
may counteract the effector T cells 31,32 Recent stud-
ies showed a critical function of CD4+CD25+
Cantaluppi et al
regulatory I cells in
the mechanisms
induction of transplant tolerance. 31,32
Recent studies have highlighted the role of humoral
rejection in the acute and chronic loss of function of
kidney transplants.3 Humoral rejection is mediated
by activation of different cell types, including B cells,
plasma cells, and plasmoblasts, that may produce
different classes of alloantibodies. 10.33 In particular,
immunoglobulin M (IgM) and IgG may activate the
classical pathway of the complement system. 10
body-mediated rejection is recognized at present as
the preeminent mechanism of loss of kidney trans-
plant and is defined as a syndrome characterized by
transplant dysfunction, microvascular damage (glo-
merulitis, capillaritis, and microthrombi formation) in
the presence of donor-specific anti-HLA antibodies in
the circulation and C4d deposition in peritubular
capillaries.34 In antibody-mediated reiection, after an-
tibody activation and triggering of the complement
cascade, endothelial cells upregulate the expression of
adhesion molecules, induce a procoagulant state, and
finally undergo apoptosis, or programmed cell death.34
Recent studies show the involvement of natural killer
cells in antibody-mediated rejection through the re-
lease of cytotoxic granules.J
New MSC-Based Therapeutic Perspectives
Could a patient with Dur and acute
benefit from treatment with MSCs? Numerous preclini-
cal and clinical studies provide evidence that MSCs
ameliorate different organ pathologic conditions by
modulating tissue regeneration and immunity. MSCs
belong to a rare population of cells of mesenchymal
origin first isolated from bone marrow and then from
several tissues and organs. Because MSCs do not
express specific cell markers, the Mesenchymal and
Tissue Stem Cell Committee of the International Soci-
ety for Cellular Therapy has suggested the following
minimal criteria to define human MSCs’2: adherence
to plastic; cell positivity for CD90, CD73, and CD105
and negativity for CD34, CD14, CD45, CD19, CD79a.
CD11b, and HLA-DR’2: and in vitro osteo-, chondro-,
and adipogenic differentiation capabilities. At molecu-
lar levels, it has been shown that MSCs express 113
RNA transcripts and 17 proteins not expressed by the
hematopoietic stem cells.»© Also, the microRNA
(miRNA) present may provide a cell signature.37
The rationale for the use of MSCs in regenerative
medicine is based on the following properties: (1)
their ability to migrate to the site of injury; (2) the
potential to differentiate in various mesenchymal tis-
sues and, at least in vitro, into different cell lineages;
(3) the ability to release factors that influence cell
survival and proliferation; and (4) the modulation of

Figure 1.
Schematic representation of multipotent mesenchy-
ma stroma cel (MSC) involvement in
tubular repair.
phases are represented. (1) Migration or Mous to the site o1
inurv atter Interaction between stroma derived factor 1 (SD–1)
ligand and CXCR chemokine receptor 43 (2) Recruitment of
Mous to endothellum following the very late antigen 4 (VLA-4)/
CD44-hyaluronic acid interaction.4
Tavoring the prollferation or dederentlated epltnellal cells surviv-
Ing the injury by the release or exosomes/ microvesicles that may
reprogram the injured, gells by delivering messenger ANAg
(mRNAs) and microRNAs that induce the dedifferentiation.
The paracrine action also involves the production by MSCs of
trophic factors, such as vascular endothelial growth factor (VEGF),
tor (HGF), transforming growth factor B (TGF-B), epidermal
growth factor (EGF), insulin-like growth factor (IGF), SDF-1,
andiopoietin1. macrophage inflammatorv orotein. keratinocvte
growth factor, and erythropoetin. 13,49,59 The cell cycle re-entry of
the tissue-iniured cells favors tissue repair.
immune response and inflammation. Are these proper-
ties applicable to kidney injury?
Migration of MSCs to the site of injury within the
kidneys has been studied extensively. Using iron
dextran-labeled MSCs that can be detected by mag-
netic resonance imaging, Lange et al38
accumulation in the cortex of the injured kidney.
Tögel et a( 39,40 showed early localization of MSCs in
AKI by 2-photon microscopy
luminescence in living animals prompt homing to the
injured kidney after intra-arterial administration of
The molecular mechanisms responsible for the re-
cruitment of MSCs are only partially known (Fig 1).
Although the chemokine receptor CXCR4 has
basal expression on the MSC surface.#’ it has been
suggested that its interaction with stromal derived
factor (SDF-1) may induce migration of MSCs to the
site of injury in the brain.
42 Tögel et alts
that SDF-1 favors homing of MSCs to the kidney after
Am J KIdnev DIS. 2013:61(2 :300-309
interaction with CXCR4, which is upregulated after
kidney injury. The other SDF-1 receptor that could be
involved in MSC migration is CXCR7.44 It has been
shown that CXCR4 and CXCR7 act independently to
regulate migration. 45 In particular, CXCR7 is required
to provide directional migration16. however, knock-
down of CXCR7 has a minimal effect on MSC migra-
tion. 14 The interaction between CD44 and hyaluronic
acid also may guide MSCs to the site of injury. The
relevance of this interaction for regulation of MSC
in Vivo.
an anti-CD44 blocking antibody or soluble hyaluronic
acid inhibited in vitro migration of MSCs and that in
Vivo MSCs from knockout mice failed to home to the
damaged kidney.48 The in vitto migration and in vivo
homing of CD44 knockout MSCs was recapitulated
after transfection with complementary DNA encoding
wild-type CD44, but not with complementary DNA
encoding a (D44 loss-of-tunction mutant that was
unable to bind hyaluronic acid.18
After being localized in the kidney, do MISCs con-
tribute to tissue repair by a direct substitution of dead
cells or a mechanism of protection? This point has
been debated extensively. In vitro, MSCs have the
potential, after appropriate stimulation, to transdiffer-
entiate into different cell lines, including epithelial
and endothelial cells. It is not clear if this also may
OCcur in VIVO
After Kidney injury, it has been shown that bone
marrow-derived stem cells and kidney resident stem
cells may participate in kidney repair. However, it is
widely accepted that the beneficial effect of bone
marrow-derived stem cells in AKI is
die to
generation of an environment that favors the prolifera-
tion of dedifferentiated epithelial cells surviving the
injury rather than to direct transdifferentiation of stem
cells into mature tissues.4
Preclinical studies have consistently shown that
administration of ex vivo-expanded MSCs acceler-
ates recoverv in AKI induced by
a toxic agent48,50-52
orischemia-reperfusion3o,39,25 and induces functional
improvement in chronic kidney disease.”
some tubular engraftment of MSCs was described in
AKI induced by cisplatin50,51
and glycero|48,52
systemic injection, this was not observed in the isch-
emia-reperfusion injury model of AKI.53 Moreover, at
least in the model of glycerol-induced AKI, after early
localization of exogenous MSCs to peritubular capil-
laries and glomeruli, 48
most of them disappeared from
the kidney after a few days.”S Similarly, no evidence
of permanent MSC engraftment in the kidney was
obtained in ischemia-reperfusion AKI.53 Thus. MSCs
in the kidney function not by replacing kidney tubular
cells, but by ameliorating injury by giving paracrine

support to the repair process (Fig 1). This was con-
firmed in living animals by bioluminescence imaging,
in which kidney localization of MSCs decreased after
24 hours.
By means of genetic fate-mapping techniques,
has been shown that kidney repair after ischemic
tubular injury depends on proliferation of tubular
epithelial cells.
So Tubular regeneration has been as-
cribed to a mechanism defined as “epithelial-mesen-
chymal-epithelial cycling.”57
The concept of a para-
crine/endocrine action of MSCs in kidney tissue repair
has been strengthened by the study of Bi et al58
showed that the conditioned medium of MSCs mim-
ics the beneficial effects of the cells of origin.
addition, MSC homing does not seem to be an abso-
lute requirement for therapy with MSCs because
intraperitoneal administration of an MSC-conditioned
medium to mice in which AKI has been induced by
cisplatin is enough to reduce tubular cell apoptosis,
increase tuhu ar cell survival. and diminish kidnev
These data suggest that the renoprotective
effect of MSCs arises from the factors they secrete.
MSCs are able to produce a number of trophic factors,
including vascular endothelial growth factor (VEGF),
basic fibroblast growth factor (FGF-2), interleukin 6
(IL-6), monocyte chemoattractant protein 1, hepato-
cyte growth factor, transforming growth factor B,
epidermal growth factor, insulin-like growth factor
(IGF-1), SDF-1, angiopoietin 1, keratinocyte growth
factor, and erythropoietin.
In particular, it has been
shown that the effects of MSCs on tubular repair
partially depend on the production of IGF-1.60
et al”‘ also reported that VEGF has a key role in the
recovery of ischemia-reperfusion AKI because VEGF
gene knockdown by short interfering RNA reduces
the effectiveness of MSC infusion. Furthermore, other
studies have indicated a possible role of MSCs in the
mechanisms of angiogenesis and vascular remodeling
through upregulation of prosurvival and proangio-
genic factors such as VEGF-a, angiopoietins, IGF-1,
and hepatocyte growth factor: 5° This may be relevant
in the setting of kidney regeneration after ischemia-
reperfusion injury because the damage of peritubular
endothelial cells has been involved in an “extension
of ischemic AKI that is characterized by sus-
tained tissue hypoxia and an inflammatory and proco-
agulant state triggered by endothelial cell injury. 02
MSCs have been shown to inhibit inflammatory
and immune response through modulation of cytokine
production, restraint of T-cell proliferation and den-
dritic cell maturation, modulation of B-cell function,
and suppression of natural killer cell proliferation and
cytotoxicity. The immune-modulatory action of MSCs
is still a matter of extensive studies, but it is evident
that hoth direct interactions of Ve(s With dendritic or
Cantaluppi et al
antigen-presenting cells and release of soluble factors
(Fig 2). Based on these properties,
MSCs have been investigated as a new therapy for
several immune-mediated diseases, such as graft-
versus-host disease,69,70 Crohn disease,
and rejec-
tion in organ transplantation.’
Recent studies also suggest that extracellular
vesicles may participate in the paracrine/endocrine
network involved in the MSC biologic action. Extra-
cellular vesicles released by MSCs after receptor-
ligand interaction are internalized in target cells, trans-
proteins, bioactive lipids,
and surtace
73 Extracellular vesicles released by MSCs
contain selected patterns of messenger RNA
(mRNA) and miRNA74.
•D and mav he instrumental in
the exchange of genetic information between cells. 76-78
We demonstrated a horizontal transfer of mRNA
through extracellular vesicles released from endothe-
lial progenitors. with consequent activation of ar
angiogenic program in quiescent endothelial cells.78
Extracellular vesicles derived from human MSCs
mimic the beneficial effects of cells because they
favor the recovery of AKI in severe combined immu-
nodeficiency mice by inhibiting apoptosis and promot-
ing kidney tubular epithelial cell proliferation74,79
(Fig 1). Administration of extracellular vesicles not
only abated the acute injury, but also prevented the
development of chronic kidney disease.”
The mecha-
nism was ascribed to the transfer of specific MSC-
derived miRNA and mRNA.’4.’» The cargo of
mRNAs and miRNAs shuttled by stem cell-derived
microvesicles potentially may trigger the regeneration
of injured tissues and modulation of the activities of
different cells of the immune system, finally allowing
transplant tolerance.
Clinical Trials and Potential Risks of MSC Therapy
MSCs have been used safely in several phase 1 and
clinical trials ammed to treat a broad range of
inflammatory and degenerative diseases (Table 1). In
the transplantation setting, a model of cotransplanting
MSCs with purified human pancreatic islets has been
developed with the aim to protect islets from inflam-
matory and immune-mediated damage and improve
transplant vascularization.
Perico et all
recently reported a
pilot studv of
safety and clinical feasibility of autologous MSC
infusion in kidney transplantation. In this study, 2
recipients of kidneys from living related donors under
rabbit antithymocyte globulin induction
MSCs on day 7 posttransplantation, demonstrating
the feasibility of this approach, enlargement of regula-
tory T cells in the peripheral blood, and control of
memory CD8+
-cell tunction. However in hofr
patients, MSC infusion after kidney transplantation

cells, and natural killer cells. In the field of kidney
diseases. MSCs also sparked great interest in the
prevention of AKI and progression toward the final
stages of chronic kidney disease. In a phase 1 clinical
trial, the prevention and treatment of AKI with infu-
sion of allogeneic MSCs have been evaluated.83 The
trial involved adult patients who underwent coronary
artery bypass graft and/or major cardiac valve sur-
gery; these patients then were infused through the
suprarenal aorta with allogeneic MSCs. In analyzing
outcomes in this group of patients, the investigators
determined that postoperative suprarenal administra-
tion of allogeneic MSCs is feasible and safe. More-
over, efficacy data appeared promising, showing that
MSC therapy prevented postoperative deterioration in
kidney function and decreased durations of intensive
care unit stay and hospitalization.
The ongoing clinical trials in the field of MSC-
based therapies in AKI and solid-organ transplanta-
tion will be the platform for newly evolving pluripo-
tent stem cell therapeutics in the near future. However,
some notes of caution must he taken into account.
The heterogeneity of the MSC population may gener-
ate some difficulties in the evaluation of their potency
different studies. Some potential complications
may arise from MSC administration into the hlood-
stream. such as nulmonarv emboli or intarctions.
possibility of tumorigenesis or maldifferentiation also
should be considered. Myocardial calcifications®
enhanced accumulation of fbroblasts and myollbro.
blasts in the lung have been reported86
in preclinical
studies. In the experimental model of mesangioprolif-
erative anti-Thy1.1 glomerulonephritis, after an early
beneficial effect, MSCs were shown in the long term
to maldifferentiate in adipocytes, favoring the devel-
opment of chronic kidney disease. 87
However, in
humans to date, no significant detrimental effects
have been reported and MJC-based therapies raise
significantly fewer concerns than embryonic stem
cells or genetically modified cells. Additional studies
are necessary to define the contexts in which MSCs
could be beneficial in kidney disease and transplanta-
MSCs represent the new frontier for cell-based
therapies of ditterent inflammatory and degenerative
diseases, and several phase 1 and 2 clinical trials
currently are underway. The rationale for the use of
MSCs is based on their ability to migrate to the sites
of injury, differentiate into multiple cell types,
release trophic mediators and factors that modulate
the immune and inflammatory response. In the field of
kidney diseases, preclinical studies have suggested a
beneficial effect of MSCs in various models of AKI
and chronic kidney injury. Clinical trials with MSCs
in AKI after cardiac surgery and kidney transplanta-
tion have been started. The mechanisms involved in
regeneration are related mainly to the release of fac-
tors including extracellular vesicles from MSCs that
promote tubular cell proliferation and survival.
The patient described in the case vignette experi-
enced DGF due to ischemia-reperfusion injury and
acute kidney transplant rejection. In light of preclini-

cal and clinical studies, one might predict a beneficial
effect of MSCs to prevent DGF or accelerate recovery
from DGF. In addition, the anti-inflammatory and
immunomodulatory properties of MSCs may interfere
with the pathogenic mechanisms involved in kidney
allograft rejection. In conclusion, MSCs may find
potential therapeutic application in different patho-
logic conditions occurring in kidney transplant recipi-
We thank Danilo Bozzetto for the artwork.
Support: None.
Financial Disclosure•
Deregibus and Camussi have re-
ceived funding
tor research trom Hresenius Medical Care. Drs
Cantaluppi, Deregibus,
and Camussi are named inventors in re
lated patents on microvesicles. Drs Biancone. Vuercia, and Segoloni
declare that thev have no relevant financial interests.
Bonventre JV. Yang L. Cellular pathophysiology of ischemic
acute kidney injury. J Chin Invest. 2011:121(11):4210-4221.

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