Basic Science for Clinicians Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative ...
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Basic Science for Clinicians
Progress toward the Clinical Application of
Mesenchymal Stromal Cells and Other
Disease-Modulating Regenerative Therapies: Examples
from the Field of Nephrology
LaTonya J. Hickson,1 Sandra M. Herrmann,2 Bairbre A. McNicholas,3,4,5 and Matthew D. Griffin 3,4
Abstract
Drawing from basic knowledge of stem-cell biology, embryonic development, wound healing, and aging, re-
generative medicine seeks to develop therapeutic strategies that complement or replace conventional treatments
by actively repairing diseased tissue or generating new organs and tissues. Among the various clinical-translational
strategies within the field of regenerative medicine, several can be broadly described as promoting disease
resolution indirectly through local or systemic interactions with a patient’s cells, without permanently integrating
or directly forming new primary tissue. In this review, we focus on such therapies, which we term disease-
modulating regenerative therapies (DMRT), and on the extent to which they have been translated into the clinical
arena in four distinct areas of nephrology: renovascular disease (RVD), sepsis-associated AKI (SA-AKI), diabetic
kidney disease (DKD), and kidney transplantation (KTx). As we describe, the DMRT that has most consistently
progressed to human clinical trials for these indications is mesenchymal stem/stromal cells (MSCs), which potently
modulate ischemic, inflammatory, profibrotic, and immune-mediated tissue injury through diverse paracrine
mechanisms. In KTx, several early-phase clinical trials have also tested the potential for ex vivo–expanded
regulatory immune cell therapies to promote donor-specific tolerance and prevent or resolve allograft injury.
Other promising DMRT, including adult stem/progenitor cells, stem cell–derived extracellular vesicles, and
implantable hydrogels/biomaterials remain at varying preclinical stages of translation for these renal conditions.
To date (2021), no DMRT has gained market approval for use in patients with RVD, SA-AKI, DKD, or KTx, and
clinical trials demonstrating definitive, cost-effective patient benefits are needed. Nonetheless, exciting progress in
understanding the disease-specific mechanisms of action of MSCs and other DMRT, coupled with increasing
knowledge of the pathophysiologic basis for renal-tissue injury and the experience gained from pioneering early-
phase clinical trials provide optimism that influential, regenerative treatments for diverse kidney diseases will
emerge in the years ahead.
KIDNEY360 2: 542–557, 2021. doi: https://doi.org/10.34067/KID.0005692020
Introduction manufacturing procedures to reverse disease more
Since it was first introduced into biomedical par- effectively than can currently be achieved by con-
lance by William Haseltine, the term regenerative ventional pharmacotherapy and interventional
medicine has become broadly recognizable to health- procedures (1,2).
care providers and the general public alike. After two For the nephrologist, the promise of regenerative
decades of intense interest and diverse research initia- medicine is compelling. Most acute and chronic kidney
tives, the original concept of “an approach to therapy diseases remain incurable, life limiting, and are typi-
that...employs human genes, proteins and cells to re- cally managed with drug combinations or procedures
grow, restore or provide mechanical replacements for that are costly and carry a high burden of adverse
tissues that have been injured by trauma, damaged effects. Added to this is the nephrologist’s natural
by disease or worn by time” still conveys a succinct affinity for the application of cellular and physio-
and valid definition of the field (1). Critically, one of logic science to patient management. In this article,
the central tenets of regenerative medicine has been we describe recent progress within a specific aspect
the merging of basic insights into organ/tissue devel- of regenerative medicine, which we term “disease-
opment, stem-cell science, and disease pathophysi- modulating regenerative therapies” (DMRT), in the field
ology with innovative translational concepts and of nephrology. In focusing on DMRT, we specifically
1
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida
2
Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
3
Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of
Ireland Galway, Ireland
4
Nephrology Services, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland
5
Critical Care Services, Galway University Hospitals, Saolta University Healthcare System, Galway, Ireland
Correspondence: Prof. Matthew D. Griffin, Biomedical Sciences, Regenerative Medicine Institute, National University of Ireland Galway,
Corrib Village, Dangan, Galway, H91 TK33, Ireland. Email: matthew.griffin@nuigalway.ie
542 Copyright © 2021 by the American Society of Nephrology www.kidney360.org Vol 2 March, 2021
KIDNEY360 2: 542–557, March, 2021 Disease-Modulating Regenerative Therapies in Nephrology, Hickson et al. 543
refer to therapeutic concepts based on systemic or localized DMRT have made varying degrees of progress along a sim-
administration of cells, subcellular components, biomateri- ilar translational path: (1) regulatory T cells (T-reg) and
als, or combinations of these that engage in a complex other immunologic cells, which suppress inflammation or
molecular crosstalk with resident cells and tissues of the harmful immune responses (8,9); (2) additional types of
host to modify or reprogram damaging biologic activity. We adult progenitor cells (including those derived from the
distinguish DMRT from other regenerative strategies that kidney) with prorepair paracrine effects (10,11); (3) stem/
are based on harnessing pluripotent/multipotent stem progenitor cell–derived extracellular vesicles (EVs), which
cells and advances in tissue engineering to directly repair may transfer proregenerative biomolecules to target cells
or replace damaged organs and tissue. This aspect of re- (12); and (4) injectable hydrogels and other biomaterials,
generative medicine, which might be termed “organ- and which may have inherent regenerative properties or serve to
tissue-replacing regenerative therapies,” will not be enhance the benefits of cell-based therapies (13). As sum-
addressed in this article but has been expertly reviewed marized in Figure 1 and described in detail in subsequent
by others (3–5). sections of the review, we focus on the progress toward
First and foremost among DMRT are mesenchymal stem/ clinical translation of MSCs and other DMRT that has oc-
stromal cells (MSCs), the subject of two decades of trans- curred to date in four important areas of clinical practice in
lational research, which have been administered safely to nephrology: renovascular disease (RVD), sepsis-associated
patients in numerous clinical trials (6,7). Critically, MSCs are AKI (SA-AKI), diabetic kidney disease (DKD), and kidney
now considered to mediate their therapeutic benefits pre- transplantation (KTx). For each of these exemplars, we
dominantly through inducible secretion of paracrine medi- highlight the extent to which early-phase clinical trial expe-
ators and reprogramming of myeloid and lymphoid im- riences with DMRT are being driven by increased under-
mune cells, and can be expanded in culture to large numbers standing of their potential mechanisms of action and are
from a range of autologous or allogeneic tissue sources (6). linked to advances in knowledge of the pathophysiologic
In addition to MSC-based cell therapies, other forms of basis of the targeted condition.
nslation
Clinical Tra
Progress to
Basic Mechanistic Pre-clinical Development of Case Series / Phase 2/3 Market Approval
Studies Disease Models Clinical Products Phase 1 Trials Clinical Trials for Clinical Use
RVD
Mesenchymal SA-AKI
Stromal Cells
DKD
KTx
RVD
Regulatory SA-AKI
Immune Cells
DKD
KTx
RVD
Other Adult SA-AKI
Progenitor Cells
DKD
KTx
RVD
Extracellular SA-AKI
Vesicles
DKD
KTx
RVD
Hydrogels and
SA-AKI
Other Biomaterials
DKD
KTx
Figure 1. | Variable progress has been made toward clinical translation of five categories of disease-modulating regenerative therapies
(DMRT) for four different areas of nephrology practice. The figure summarizes current translational status of mesenchymal stromal/stem cells,
regulatory immune cells, other adult progenitor cells, extracellular vesicles, and hydrogel/biomaterials as potential DMRT for renovascular
disease (RVD), sepsis-associated AKI (SA-AKI), diabetic kidney disease (DKD), and kidney transplantation (KTx). *Broken line indicates that
clinical trials of MSCs have been reported in sepsis, including some patients with SA-AKI, but not with kidney function as a primary outcome.
Figure created using Biorender.com.
544 KIDNEY360 Renovascular Disease derived EVs in renal diseases has been highlighted by Hypertension is a major risk factor for CKD, with hyper- showing decreased renal inflammation and injury through tensive kidney disease accounting for approximately 30% of intrarenal delivery of EVs in pigs with RVD and concom- all ESKD cases (14). Hypertensive kidney disease—charac- itant metabolic syndrome (27). Other studies have demon- terized by vascular damage, endothelial dysfunction, and strated their role as carriers of anti-inflammatory genes and loss of endogenous vasodilators—results in progressive proteins and their capacity to be engineered to deliver loss of the renal microvasculature (15). RVD is a common specific substances or to have enhanced uptake by target cause for secondary hypertension in individuals aged $65 cells (28–30). Therefore, MSC-derived EVs may serve as an years, and RVD attributed to atherosclerotic plaque devel- acellular therapeutic option to attenuate inflammation and opment with reduction in renal-artery dimension repre- fibrosis in RVD and other forms of renal disease. As illus- sents a unique intersection between hypertension and CKD/ trated in Figure 2 for the clinical target of RVD and asso- ESKD leading to progressive renal insufficiency (16). In ciated ischemic nephropathy, the paracrine, regenerative the setting of significant RVD, further reduction of renal activities of MSCs, including both secreted soluble media- blood flow (RBF) and hypoxia trigger inflammation, oxida- tors and released EVs, are now recognized to be “tunable.” tive stress, and profibrotic pathways, leading to scarring Thus, as described later in greater detail, disease-associated and further deterioration of renal function (ischemic ne- dysfunction of ex vivo–expanded, autologous MSCs may phropathy) (17). Importantly, recent clinical trials and ex- be reversed through hypoxic preconditioning and other perimental studies indicate that restoration of large-vessel manipulations (31,32). patency alone is not enough to regain kidney function in There is now promising evidence that observations of most patients with atherosclerotic RVD (18,19). The limited RVD modulation by MSCs in animal models can be trans- number of currently available strategies for effectively mod- lated into clinical benefits. In a phase 1 trial in patients with ulating RVD, and the realization that the natural history RVD, we (L.J.H. and S.M.H.) recently demonstrated that of this disease involves transition from a hemodynamic intra-arterial infusion of autologous adipose tissue– component to a proinflammatory and profibrotic disease, derived MSCs into poststenotic kidneys (without con- highlight the need for a paradigm shift in therapy (20). comitant renal-artery angioplasty) resulted in increased Importantly, RVD-associated ischemic nephropathy and cortical RBF and GFR compared with the baseline val- hypertensive kidney disease, in the absence of RVD, share ues. These improvements in hemodynamic and func- common pathophysiologic features that include activated tional indices were associated with attenuation of tissue renin-angiotensin-aldosterone system (RAAS), increased so- hypoxia, inflammatory cytokines, and angiogenic bio- dium retention, and—consequently—increased oxygen con- markers, along with a fall in BP between baseline and sumption (21). In evidence of this, studies in hypertensive 3 month follow-up. These changes were more prominent rats using oxygen microelectrodes found pronounced med- in the patients treated with a higher MSC dose (26,33). ullary and cortical hypoxia in spontaneously hypertensive Of further interest, we also observed RBF increases in the rats compared with normotensive controls (22). Further- (non-MSC-infused) contralateral kidneys (26,33). This more, the presence of ischemic, rather than hypertrophic, phenomenon likely occurred due to “crosstalk” signal- glomeruli in hypertensive kidney disease suggests that ing between kidneys and/or wider systemic effects of hypoxia and ischemia are the predominant mechanisms signaling and homing signals for MSCs. Moreover, ben- (23). Therefore, in subjects with prolonged hypertension eficial off-target effects, beyond the kidney, are also and relevant genetic-, environmental-, and lifestyle-related possible because infusion of MSCs or endothelial pro- risk factors, limited blood flow and oxygenation to areas of genitor cells into the renal artery has been associated renal parenchyma, where the oxygen tension is ,10 mm Hg, with attenuation of hypertensive cardiomyopathy in makes the kidney vulnerable to ischemic injury which experimental models of renovascular hypertension resembles that due to RVD. In this context, implementation (34). Despite the promising evidence base of preclinical of DMRT, in particular the use of MSCs, can be viewed as and clinical application of MSCs and MSC-derived EVs a novel therapeutic option for RVD and hypertensive kid- in RVD, there has been limited exploration to date of ney disease. alternative DMRT (such as regulatory immune cells, Importantly, MSCs have immunomodulatory, anti- other adult progenitor cells, and implantable hydrogels) inflammatory, and proangiogenic properties that have been in this area (Figure 1). Nonetheless, experimental evi- demonstrated in experimental studies in animals and dence in models of renal ischemia-reperfusion injury humans with RVD (24–26). Arterial delivery of MSCs in could provide a basis for the translation of such thera- the swine model of RVD was associated with protection of pies for chronic ischemic nephropathy in the future the stenotic kidney and improved RBF and function, with (13,35,36). reduction of oxidative stress and inflammation, contributing to tissue repair (24). The strong paracrine effect of MSCs, and not their differentiation capacity, seems to be the prin- Sepsis-Associated Acute Kidney Injury cipal mechanism of their therapeutic action. In clinically AKI has a prevalence ranging from 1% to 20% of patients relevant, large-animal models of RVD, MSCs have been who are hospitalized and 50% to 60% of patients in the shown to release a variety of soluble mediators that act intensive care unit. Mortality is proportional to the severity locally within the kidney to ameliorate ischemic nephrop- of AKI, and 30% of survivors die within the first year after athy through proangiogenic, anti-inflammatory, and anti- hospital discharge. Sepsis, which is the most frequent cause oxidative mechanisms (24). Also consistent with a paracrine of AKI in patients who are critically ill (37), is a life- model, the therapeutic potential of stem/progenitor cell– threatening syndrome resulting from a disordered immune
KIDNEY360 2: 542–557, March, 2021 Disease-Modulating Regenerative Therapies in Nephrology, Hickson et al. 545
Hypertension
Renovascular lschemic
Disease Nephropathy
Stromal Cell
Dysfunction
Disease Modulation
Limited MSC Paracrine
Regenerative Factors
Hypoxic Pre-conditioning
Inflammatory Stimuli
Enhanced MSC Paracrine
Regenerative Factors
Figure 2. | Hypoxic pre-conditioning is a potential strategy for enhancing MSC therapeutic potency in hypertensive kidney disease. As
illustrated, chronic hypertension, RVD, and ischemic nephropathy lead to stromal-cell dysfunction, which is associated with limited production
of paracrine regenerative factors (released extracellular vesicles and soluble mediators) by patient-derived, culture-expanded, mesenchymal
stem/stromal cells (MSCs). Culture under low oxygen tension (hypoxic preconditioning) may restore the production of extracellular vesicles and
soluble mediators, resulting in enhanced paracrine regenerative activity and increased potential for disease modulation after localized or
systemic delivery of autologous MSCs. Figure created using Biorender.com.
response to uncontrolled microbial infection (38). The and resident parenchymal cells (37). In SA-AKI, there is
pathophysiology of sepsis is dominated by dysregulated an abnormal repair process due to prolonged hypoxia,
inflammation and immune suppression, with endothelial cytokine expression, and defective adaptive immune cell
and epithelial injury, leukocyte aggregation, mitochondrial function. Patients who are critically ill with persistent
dysfunction, apoptosis, and impaired regeneration (37). SA- or recurrent AKI are at very high risk for secondary
AKI differs from ischemic and toxic AKI, being characterized infection and increased mortality, and represent a key
by global renal hyperemia with altered RBF distribution target for novel and more-effective therapies (39). In this
and inflammation incited by both infiltrating immune cells regard, MSCs have demonstrated benefits in multiple
546 KIDNEY360
sepsis models, including LPS administration, bacterial crosstalk with immune cells that result in modulatory effects
pneumonia, and polymicrobial abdominal sepsis (40–42). on cytokine expression, vascular permeability, removal of
In animal models of sepsis, MSC administration is report- apoptotic cells, and clearance of bacteria by neutrophils and
edly associated with improved survival; reduced organ macrophages (Figure 3) (46). In addition to release of soluble
injury; increased clearance of bacteria, cells, and fluid; and mediators and reprogramming of immune cells by viable
resolution of inflammation (43–45). Some animal-model MSCs, it has recently been shown that disease modula-
studies of SA-AKI have demonstrated improvement in tion may occur as a result of the induction of apoptosis
tubular-injury scores and kidney function (42,45), whereas of intravenously infused MSCs by cytotoxic lymphocytes
others have not (43,44)—an inconsistency that may reflect followed by their phagocytosis by resident myeloid cells
differences among the models used. (monocytes and macrophages). This process, referred to as
From a mechanistic perspective, it is now clear that MSCs efferocytosis, results in polarization of myeloid cells toward
administered intravenously in models of sepsis localize alternatively activated (M2-like) phenotypes with potent
predominantly in the lungs. From this location, they medi- anti-inflammatory effects (47,48). Furthermore, either di-
ate their systemic benefits through mechanisms involving rectly or through their effects on myeloid cells, MSCs also
Sepsis + AKI
Increased bacterial, cellular
and fluid clearance;
resolution of inflammation
MSC/Immune Cell
Cross-talk and
Efferocytosis
Neutralization of LPS;
Increased secretion of IL-10, PGE2, VEGF, KGF,
HGF; Enhanced macrophage phagocytosis;
Reduced pro-inflammatory cytokines;
Improved vascular permeability;
Enhanced clearance of apoptotic cells
Renal functional improvement
secondary to improved
cardiorespiratory function
AKI Resolution
Figure 3. | The systemic therapeutic effects of intravenousMSC therapy in SA-AKI are triggered by immune cell interactions in the lungs. As
illustrated, intravenous administration of MSCs in the setting of SA-AKI results in MSC trapping in the lungs, where complex interactions
(crosstalk and efferocytosis) with resident immune cells (mononuclear phagocytes [macrophages] and lymphocytes) result in beneficial lo-
calized effects within the alveolar spaces and systemic effects (LPS neutralization, secretion of anti-inflammatory factors, enhanced
phagocytosis) with potential to promote resolution of inflammation, disrupted vascular integrity, and increased cell death in the kidneys.
Improved cardiorespiratory function as a result of MSC local and systemic effects may provide further indirect effects to more effectively resolve
SA-AKI. Figure created using Biorender.com. HGF, hepatocyte growth factor; KGF, keratinocyte growth factor.KIDNEY360 2: 542–557, March, 2021 Disease-Modulating Regenerative Therapies in Nephrology, Hickson et al. 547 augment tissue-repair processes through promoting expan- SA-AKI. Indeed, trials of MSCs and other DMRT in sepsis sion of T-reg (49). may be better suited to detecting their effects on the de- A number of specific soluble factors have been identified velopment or severity of AKI. Because sepsis is a multiorgan as mediating the paracrine effects of MSCs and their disorder, favorable effects of systemically administered immune-cell partners in models of sepsis. These include MSCs on kidney function may derive from improved func- IL-10, keratinocyte growth factor, PGE2, vascular endothe- tion of other organ systems and from reprogramming of lial growth factor (VEGF), antibacterial peptides LL-37 and immune cells at distant sites. Indeed, preclinical studies hepcidin, and other proresolution factors (50). The role of IL- indicate that infusion of apoptotic versus viable MSCs 10 has been most convincingly demonstrated. In the mouse within the lung led to greater suppression of inflammation, cecal ligation and puncture model of polymicrobial sepsis, oxidative stress, cellular markers of immune reactivity, and Németh et al. (45) first reported that intravenously admin- a less marked kidney injury in a cecal ligation and perfo- istered MSCs stimulate IL-10 production by macrophages ration model of sepsis (59). Given the high prevalence of through PGE2/EP2-receptor interaction, resulting in the AKI among patients with sepsis and its implications for prevention of neutrophil extravasation into tissue. This morbidity and mortality, it will be important for future MSC-induced pulse of IL-10 production has since been clinical trials of DMRT in sepsis to include patients with replicated in several other studies (49). Transfer of specific —or at risk for developing—AKI, for equal numbers of microRNAs or mitochondria via nanotubes may also un- patients with similar stages of AKI to be randomized, derlie some of the effects of MSCs to enhance macrophage and for specific renal end points to be included in the trial phagocytic activity or endogenous stem-cell fitness in the design. septic environment (51). A further strategy to enhance the immunomodulatory features of MSCs in sepsis is through preconditioning (“licensing”) with proinflammatory cyto- Diabetic Kidney Disease kines, toll-like receptor ligands, carbon monoxide, and eico- Due to the growth of the aging population, the estimated sapentaenoic acid (52–54). In the case of carbon-monoxide number of individuals with diabetes mellitus (DM) world- licensing of MSCs, this was reported by Tsoyi et al. (52) to wide increased from 108 million in 1980 to 422 million in result in reduced organ damage (including kidney injury) 2014 (60). Moreover, the global epidemic of DM has con- and superior survival in mouse models of sepsis, while tributed approximately 50% of the increased health burden also allowing for later MSC administration. Mechanisms due to CKD (61). DKD is characterized by vascular damage, by which preconditioning has been reported to enhance resulting from cumulative effects of a wide range of pre- MSC activity include activation of the lipoxygenase pathway dominantly hyperglycemia-driven maladaptive processes, and enhanced exosome delivery of microRNA to macro- including chronic inflammation, increased oxidative stress, phages. As already described in the context of RVD, MSC- advanced accumulation of glycation end products, steatosis, derived EVs also have the potential to be developed as insulin resistance, renal hypoxia, apoptosis, cellular dedif- a subcellular DMRT for sepsis and SA-AKI through the ferentiation and senescence, and altered RAAS activation transfer of a wide range of bioactive molecules (49,55). (62–64). Intrinsic renal regenerative capacity is limited in Although the clinical application of MSCs in sepsis and DM, exacerbating chronic glomerulosclerosis, tubulointer- SA-AKI is at an early stage, they have shown promising stitial fibrosis, and chronic inflammation (62,64,65). Al- safety profiles in early-phase human trials (49). For example, though recent clinical trials of sodium-glucose cotransporter- in a phase 1, dose-escalation trial involving nine patients 2 inhibitors and other pharmacologic agents have shown with sepsis, treatment with MSCs was found to be safe and that the rate of renal functional loss can be slowed in DKD well tolerated, albeit with no overt effect on sepsis param- due to type 2 DM (66–68), successful targeting of multi- eters. An analysis of cytokine levels in treated patients ple injurious pathways—such as those mediating inflam- demonstrated no increase in known proinflammatory medi- mation, oxidative stress, renal hypoxia, and fibrosis—may ators or biomarkers of organ dysfunction after MSC treat- be necessary to truly halt DKD. ment (56,57). In a phase 2, multicenter, randomized, With this goal in mind, DMRT represent novel therapeu- placebo-controlled, clinical trial, Swaminathan et al. exam- tic options for the delivery or induction of a wide range of ined the effect of allogeneic MSC therapy delivered intra- mediators to simultaneously target maladaptive processes aortically in patients undergoing cardiac surgery who de- that contribute to DKD progression. As with other renal veloped postbypass AKI. More than half of these patients diseases, the most extensively studied DMRT in DKD is the had impaired renal function at baseline (58). Although this MSC (64). In many preclinical experimental models of DM trial was carried out in patients with a sterile form of AKI, and diabetic nephropathy (64,68), the paracrine-mediated the design and results have important implications for the actions and cell-cell interactions of exogenously adminis- future planning of clinical trials of DMRT in SA-AKI. Dis- tered MSCs have shown potential to modulate a range of appointingly, in this trial, MSC administration resulted in pathophysiologic processes that contribute, both locally and no difference in recovery of renal function, dialysis, or death systemically, to the progressive renal injury and functional compared with placebo (58). Although carried out in a rel- loss that characterize DKD (Figure 4). External to the kid- atively homogenous patient population, differences in renal neys, MSCs delivered intravenously or by other routes have reserve, complexity of cardiac surgical procedure, bypass been experimentally shown in models of DM to modulate time, and other postoperative complications may yet have adipose-tissue inflammation, preserve islet function, and hindered the ability to observe any modest clinical benefit of enhance insulin sensitivity, leading indirectly to beneficial MSCs. This negative study in sterile AKI does not neces- renal effects through reducing glycemia and the proinflam- sarily blunt interest in the clinical translation of MSCs for matory systemic environment (64,69,70). Concomitantly,
548 KIDNEY360
Preserved Modulation of:
Extra-renal Modulatory Effects Tubular atrophy
islet function
Interstitial inflammation
Oxidative stress
Reduced adipose Fibrogenesis
tissue inflammation Senescence
Modulation of:
Podocyte oxidative stress
and apoptosis
Mesangial expansion
Glomerular fibrosis
Key Mediators
Hepatocyte Growth Factor
Indoleamine 2,3 Dioxygenase
Enhanced insulin Prostaglandin E2
sensitivity Vascular Endothelial Growth Factor
Hemoxygenase 1
Interleukin 10
Extracellular Vesicles Modulation of:
Re-programmed Macrophages and T-cells Capillary rarefaction
Hypoxia
Improved glycemic control
Reduced systemic inflammation
and oxidative stress Intra-renal Modulatory Effects
Figure 4. | Multiple potential therapeutic effects have been identified for systemically administered MSCs in DKD. Extensive preclinical and
limited clinical trial data indicate that MSCs (center) may exert both extrarenal and intrarenal modulatory effects, through a range of key
mediators, after intravenous administration in diabetes and DKD. Upper left: Extrarenal effects which diminish adipose-tissue inflammation,
enhance insulin sensitivity, and preserve islet function can stabilize or reverse the course of DKD by improving glycemic control and reducing
systemic inflammation and oxidative stress. Lower right: Intrarenal effects by which key MSC-generated and -induced mediators have been
shown experimentally to modulate multiple aspects of DKD pathophysiology within the glomerulus, the tubulointerstitial compartment, and the
microvasculature. Figure created using Biorender.com.
MSCs themselves, their released mediators, and regulatory T-reg induced by interactions with, or uptake of, exoge-
immune cells induced as a result of MSC administration nously administered MSCs. One of the most important
may transfer to the kidneys to mediate beneficial effects growth factors, HGF, reduces kidney fibrosis by blocking
within distinct renal compartments, including the glomer- tubular epithelial cell dedifferentiation and inhibiting intra-
ulus, microvasculature, tubules, and interstitium. Reduc- renal expression of monocyte chemoattractant protein-1 and
tions in glomerular size, podocyte apoptosis, glomerular macrophage infiltration (70,71). Other key mediators asso-
matrix expansion/sclerosis, peritubular interstitial fibrosis, ciated with the direct and induced paracrine effects of MSCs
renal tubular epithelial cell death and dedifferentiation, in DKD include indoleamine 2,3-dioxygenase, a potent im-
tubulointerstitial fibrosis, and microvascular rarefaction munomodulatory enzyme; PGE2, a likely mediator of T-reg
have been observed in association with reduced albumin- differentiation; and IL-10, an anti-inflammatory cytokine
uria and stabilization of GFR (64,69,70). released by macrophages after phagocytosis of apoptotic
Preclinical, MSC-based, experimental studies have dem- MSCs (64,72,73). The many observations from experimental
onstrated benefits derived from a variety of therapeutically models of DM and DKD that key soluble and released
relevant mediators (Figure 4). These include soluble factors factors mediate the disease-modulatory effects of MSCs
with antifibrotic (hepatocyte growth factor [HGF]), proan- have also stimulated interest in the use of MSC-derived
giogenic (VEGF), antiapoptotic/homeostasis (HGF, VEGF, conditioned medium and EVs as alternative DMRT (74,75).
stromal cell–derived factor [SDF-1/CXCL-12]), and immu- Despite the focus on paracrine mechanisms in many
nomodulatory (indoleamine 2,3-dioxygenase, PGE2, and IL- preclinical studies, however, it remains unclear whether
10) activity. Such soluble factors may be secreted inherently soluble factors released by MSCs after systemic delivery
by MSCs, triggered in MSCs by signaling from proinflam- can explain all of the beneficial effects reported in experi-
matory cytokines and immune cells, or secondarily pro- mental DKD. Specifically, the transient survival of intrave-
duced by alternatively activated (M2) macrophages and nously administered MSCs, and reports in other diseaseKIDNEY360 2: 542–557, March, 2021 Disease-Modulating Regenerative Therapies in Nephrology, Hickson et al. 549 models of therapeutic effects mediated by apoptotic or administration (78). Although also promising, injection of heat-inactivated MSCs, suggest the existence of other DRMT-derived EVs is not yet underway in human DKD mechanisms (47,48,72,76). Although transmigration and studies. prolonged engraftment of a minority of administered cells to the kidneys remains theoretically possible, the phenom- ena of MSC apoptosis and efferocytosis by macrophages Kidney Transplantation (48) and MSC-induced expansion of T-reg (77) repre- Beyond the “holy grail” of donor-specific tolerance, steady sent more compelling mechanisms by which their anti- advances in understanding pathologic processes that un- inflammatory, prorepair effects within the kidneys could derlie the common causes of early and late renal allograft be augmented and prolonged beyond the initial release of failure have revealed other important new therapeutic tar- soluble mediators. gets that are not adequately addressed by conventional In addition to MSCs from various tissue sources, similar immunosuppressive drugs and clinical practices (82). These renal regenerative effects have been observed for a variety of include inflammatory and metabolic pathways that mediate other stem/progenitor-like cells and their secreted trophic donor-organ injury before and early after transplantation, factors or EVs (36,68). Primary cells derived from the kidney immunologic processes that drive the formation of donor- may also exert paracrine-mediated, disease-modulating specific antibodies and antidonor memory T cells, effector effects in a similar fashion to MSCs, and are being actively mechanisms responsible for subsequent acute or chronic pursued as potential DMRT. For example, selected renal immune-mediated rejection, and maladaptive cellular pro- cells (SRC), composed of isolated tubular and aquaporin cesses such as fibrosis and senescence. Against this back- 2–positive collecting duct cells, have advanced to the drop, the potential for DMRT, such as MSCs and regulatory clinical-translation phase (78). These primary cells induce immune cells, to address some or all of these major unmet tubular cell proliferation while attenuating TNF-a–induced needs for improved long-term KTx survival is being ro- NF-kB and TGF-b1–mediated plasminogen activator bustly pursued. In the following paragraphs and illustrated inhibitor-1 signaling pathways that contribute to inflamma- in Figure 5, we provide overviews of recent progress in the tion and fibrosis in experimental DKD (79). Given the tran- translation of these DMRT to the field of KTx, and how they sient period in which exogenously administered cells reside may address key mechanisms of graft injury. in the diseased microenvironment, use of biomaterials, such as hydrogels, to enrich cell delivery and duration of action Mesenchymal Stem/Stromal Cells have been pursued (13,80). As discussed below, this has Extensive preclinical evidence that MSCs modulate harm- since been translated to a locally delivered therapeutic ful antidonor immune responses and maladaptive inflam- strategy for DKD in which a gelatin-based hydrogel con- mation associated with allogeneic organ transplants and taining expanded autologous SRC is implanted into the may promote immune tolerance has accumulated over the kidneys (78). past 18 years (83). In 2012, Tan et al. (84) reported the results Despite numerous studies in experimental DKD, clinical of a phase 2 clinical trial in which 104 recipients of living- translation of DMRT has been limited. In 2016, Packham related-donor KTx received a novel induction regimen con- et al. reported the results of a randomized, placebo- sisting of two intravenous infusions of autologous bone controlled, dose-escalation study that tested the safety marrow–derived MSCs at the time of transplantation and and feasibility of intravenous infusion of allogeneic mesen- 2 weeks later, followed by maintenance therapy with con- chymal precursor cells (rexlemestrocel-L) in adults with ventional- or low-dose cyclosporine. For MSC-induced type 2 DM and CKD stages 3/4. The cell infusions were recipients, early recovery of renal function and frequency well tolerated, and trends in kidney function during a 12- of acute rejection and opportunistic infection during the first week follow-up period favored stabilization or improve- post-transplant year were comparable or superior to those ment in 20 patients treated with cell infusions compared of a control group induced with anti–IL-2 receptor antibody with ten patients treated with placebo (81). Other early- followed by conventional-dose cyclosporine (84). Although phase clinical trials are now investigating allogeneic bone the trial provided an encouraging demonstration of the marrow–derived MSCs (M.D.G.; Italy, Ireland, United safety and potential efficacy of peritransplant MSC infu- Kingdom; ClinicalTrials.gov, NCT02585622), autologous sions, the lack of mechanistic studies and of a measurable adipose-derived MSCs (L.J.H., S.M.H.; NCT03840343), and indicator of the in vivo activities of the infused cells pre- allogeneic umbilical cord–derived MSCs (Japan, NCT04125329; cluded any immediate progress toward wider clinical prac- China, NCT04216849) in DKD. As mentioned above, the tice. For this reason, several other centers have focused on therapeutic combination of primary kidney cells (SRC) evaluating both autologous and allogeneic MSC therapies in in hydrogels (named Neo-Kidney Augment) is also being smaller numbers of KTx recipients, along with longitudinal investigated as a DMRT for DKD in phase 1 and 2 clinical immunologic and, in some cases, histologic monitoring of trials (NCT02008851, NCT03270956, NCT02836574). Of the grafts. Details of the designs, major outcomes, and note, a report of the phase 1 trial involving laparoscopically documented immunologic consequences of MSC adminis- assisted intracortical implantation of SRC, in seven male tration to KTx recipients in such early-phase trials carried patients with type 2 DM and CKD stages 3/4, indicated an out to date have been summarized and expertly reviewed unacceptable number of postprocedural complications, by Podestà et al. (83). Results from one further phase 1 prompting changes in implantation methodology. None- trial have also been very recently reported (85). In addi- theless, renal function and urine albumin-creatinine ra- tion to determining safety profiles, these trials have begun tio remained relatively stable for 12 months, whereas to address whether autologous or allogeneic MSC infu- eGFR tended to decline from months 12 to 24 after SRC sions can: (1) promote T-reg and/or donor-specific T-cell
550 KIDNEY360
DMRT MSC T-reg M-reg Tol-DC
Site of Action Systemic Local
Naive Lymphocytes Activated Lymphocytes Myeloid Cells
Target
Cells Dendritic Cells Fibroblasts Epithelial Cells
Promote Donor-specific Immune Modulate Pre-existing Anti-donor
Tolerance Immune Responses
Promote Epithelial Repair and Suppress Pro-fibrotic
Regeneration Inflammation
Reduced burden of
Reduced ischemic injury/ Increased maximum Stabilization of declining
immunosuppressive
Delayed Graft Function glomerular filtration rate transplant function
medications
Figure 5. | Disease modulating regenerative therapies for kidney transplantation address diverse mechanisms and potential clinical benefits.
Upper panel: Diverse types of modulatory cellular therapies that have been the subject of early-phase clinical trials in KTx recipients along with
their potential sites of action and target cells. Middle panel: Four major mechanistic goals of DMRT applied to KTx with illustration of the most
relevant cellular therapies for each, along with their predicted sites of action and most significant cell targets for each (based on preclinical
studies and profiling/monitoring analyses of subjects from clinical trial). Lower panel: Significant clinical benefits that represent the most
immediate goals for the clinical translation of DMRT in KTx. Figure created using Biorender.com. M-reg, regulatory macrophages; Tol-DC,
tolerogenic dendritic cells; T-reg, regulatory T cell.
hypo-responsiveness (86–88), (2) reverse or stabilize subclinical Taken together, the trial reports to date support the
tubulointerstitial inflammation and fibrosis/tubular atro- conclusion that intravenous or intrarenal infusion of MSCs
phy (89), and (3) allow for early or delayed reduction (or in KTx recipients is safe and associated with comparable
even eventual withdrawal) of calcineurin inhibitor–based early-to-midterm patient/graft outcomes and potentially
immunosuppression (85,90,91). A further interesting ques- superior renal function compared with conventional thera-
tion, currently being addressed in preclinical studies (92–94) peutic regimens. Where examined, they also provide evi-
and an early-phase clinical trial (NCT04388761), is whether dence that pre- or early post-transplant MSC infusions may
ex vivo perfusion of kidneys procured for transplantation be associated with favorable immunologic effects, such as
with MSCs can modulate ischemic tissue injury and ame- increases in circulating T-reg or T-reg/effector T cell ratios.
liorate subsequent delayed graft function. Nonetheless, it should be acknowledged that overall patientKIDNEY360 2: 542–557, March, 2021 Disease-Modulating Regenerative Therapies in Nephrology, Hickson et al. 551
numbers remain small and the possibility of more subtle macrophage, or one tolerogenic dendritic cell therapeutic
adverse effects—such as localized proinflammatory re- product, in combination with a tapered conventional im-
sponse, reduced antiviral immunity, or (in the case of allo- munosuppressive drug regimen, were collated and com-
geneic MSCs) stimulation of anti-HLA antibodies—should pared with results for a group of 66 recipients that were
be carefully addressed by larger trials and longer follow-up managed by a standard-of-care regimen across eight sites in
(83). Development of clinically applicable assays of potency Europe and the United States. Although no conclusions
and in vivo effects in the context of KTx will also likely be about the protolerogenic efficacy for any single regulatory
required for optimal translation of MSCs and other DMRT cell therapy can be made from this report, the authors
into routine clinical practice. For example, for the clinical convincingly show a good safety profile for such therapies
target of acute graft versus host disease after allogeneic in KTx recipients. In addition, the combined cell-therapy
hematopoietic stem cell transplantation, Cheung et al. (95) cohort had no increase in graft rejection or reduction in graft
recently demonstrated that an increase in serum PGE2 1– survival, experienced a strikingly reduced rate of viral
4 days after MSC infusion distinguished patients with infections, and appeared to revert to a more favorable
clinical response to cell therapy from nonresponders; this peripheral blood immune cell profile compared with recip-
finding being consistent with in vitro cellular assays and ients who were treated conventionally (100). Subsequently,
mechanistic animal model studies carried out by the same Roemhild et al. (101) published a very detailed report of the
group (48). ONEnTreg13 Trial—a component of the ONE Study. In this
phase 1/2a trial, autologous, ex vivo–expanded, natural
T-reg (nTreg) were administered 7 days after transplanta-
Regulatory Immune Cells tion to 11 recipients of living-donor KTx at Charité – Berlin
Because the recognition that forkhead box P3 (FoxP3)– University of Medicine (Berlin, Germany) and the results
positive T-reg are essential for maintaining peripheral im- were compared with those of nine patients who were pre-
mune tolerance to autoantigens and nonthreatening foreign viously transplanted and managed with the standard-of-
antigens, the concept that treatment with ex vivo–expanded care regimen at the same center. These results demonstrated
regulatory immune cells could prevent allogeneic transplant excellent safety and 3-year graft outcomes for the KTx
rejection and foster donor-specific tolerance in organ allo- recipients treated with nTreg, along with successful tapering
graft recipients has been energetically pursued (96,97). In of immunosuppression to tacrolimus monotherapy in eight
addition to T cells, it has also become clear that other major of 11 subjects and evidence of oligoclonal (presumably
types of immune effector cells, including macrophages, alloantigen-driven) expansion of nTreg at 60 weeks post-
dendritic cells, and B cells, incorporate subpopulations or transplant (101). Finally, in another very recent, early-phase
alternative functional states that mediate counter-regula- trial report, Morath et al. (104) describe favorable safety
tory/suppressive effects and may be amenable to clinical and graft outcomes after pretransplant administration of
exploitation (97). In keeping with the concept of DMRT, the donor-derived modified immune cell (mitomycin C–treated
potential therapeutic actions of regulatory immune cell PBMC) infusions to ten recipients of living-donor KTx. Post-
therapies can be broadly viewed as modulating (as opposed transplant immunologic studies also provided evidence for
to blocking) the interactions between donor-derived (allo-) prolonged donor-specific T-cell hypo-responsiveness and in-
antigens or proinflammatory stimuli and recipient immune creased numbers of circulating IL-10–producing regulatory
effectors to prevent or reverse acute and chronic organ B cells (which have been associated with immune tolerance)
allograft injury. On the basis of evidence from almost two (104).
decades of basic and preclinical research, early-phase clin- Overall, recently reported and ongoing early-phase clin-
ical trials of ex vivo–expanded autologous T-reg have been ical trials of several cell-based DMRT in the area of KTx
recently completed in recipients of KTx and liver transplant provide important reassurances regarding the safety and
(8,96,98–101). Those carried out in KTx recipients have, to feasibility of such therapies, both before and at early or later
date, consistently demonstrated safety in combination with times after transplantation. The generally favorable short-
various conventional immunosuppressive regimens, pre- to-midterm patient and graft outcomes, and promising im-
liminary evidence for persistence of infused T-reg in the mune profiling and histologic studies, should be interpreted
blood for 1–3 months (99), and of an increase in total with caution in the absence of larger, randomized controlled
circulating T-reg numbers for at least 12 months after ad- trials. Nonetheless, cohesion among some of the observa-
ministration (98). Ongoing early-phase trials and planned tions made in patients participating in these trials and the
phase 2 trials are likely to further clarify whether polyclonal, growing scientific knowledge regarding immunologic tol-
autologous T-reg therapies robustly modulate post- erance and of the pathobiology of KTx complications should
transplant immune responses toward donor-specific toler- provide a strong impetus for further progress. As illustrated
ance (96). Other regulatory immune cell types—specifically in Figure 5, individual DMRT have the potential to target
regulatory macrophages and tolerogenic dendritic cells— specific clinical and immunologic challenges associated
have also been developed to the point of early-phase clinical with current limitations to the long-term health of KTx
trials in KTx recipients (102,103). Very recently, a report of recipients.
the post-transplant outcomes and immunologic profiling
results for recipients of living-donor KTx enrolled into a suite
of early-phase regulatory cell therapy trials has been pub- Autologous versus Allogeneic Cell Therapies: The
lished by the ONE Study consortium (100). In this unique Influence of Patient-Specific Factors
study, the observed results for 38 recipients of living-donor As we move toward clinical application of DMRT, optimi-
KTx receiving one of four different T-reg, one regulatory zation of cell product remains vital to successful translation552 KIDNEY360 of preclinical findings. Allogeneic cell–based products offer Conclusions and Future Directions a readily available “off-the-shelf” treatment option. Yet, As we have reviewed here, extensive preclinical research patient-derived (autologous) cells may be preferable for has greatly increased our understanding of the in vivo individualized therapy or for repeated dosing, given the distribution, longevity, and mechanisms of action of MSCs lower risk for allosensitization. In this regard, the influ- and other potential regenerative therapies in the setting of ence of patient- or disease-specific factors on the growth and kidney diseases. These insights have extended the rationale functionality of culture-expanded stromal and other pri- for regenerative therapies beyond the initial concept of mary cell therapies represents a key research area—partic- engraftment and differentiation into functional tissues to ularly in settings of high relevance to kidney disease, such as include modulatory effects of, typically, short-lived cells, older age, DM, vascular disease, and reduced renal function vesicles, or biomaterials that ameliorate disease processes (105). In DM and kidney disease, oxidative stress, autoph- through complex, paracrine interactions with host cells and agy, and cellular senescence induce dysfunction of autolo- tissues which promote inherent mechanisms of repair and gous cells (106). In metabolic syndrome and DM, stem-cell regeneration. Well-conducted small- and large-animal mobilization and therapeutic effect are diminished (65,74). model studies have been essential to determining the opti- In older individuals with atherosclerotic RVD, we identified mal parameters for clinical application of MSCs and other altered MSC functional capacity (migration, angiogenesis) DMRT to kidney diseases—including the route of delivery and increased cellular-senescence burden compared with and localization after administration; the key responder controls (32). Despite this, our clinical trial results, described compartments and cell responses within the kidney; and above in RVD, confirm that intrarenal administration of the source, timing of release, and activity of the most im- autologous MSC was associated with improved RBF and portant soluble mediators. In keeping with the literature preserved GFR (26,33). Similarly, in MSCs harvested from reviewed in this article, we believe that these critical param- adults with DKD and healthy controls, we have observed eters must be defined for each specific disease and therapy. transcriptome alterations and reduced in vitro MSC migra- Conversely, lack of concordance between animal-model re- tion but preserved or increased immunomodulatory and search and human clinical application of regenerative ther- renal reparative activities in vitro (L.J.H., under review). In apies continues to be a major challenge to the field. For the ESKD and KTx recipients, autologous MSCs have been four distinct renal-disease areas we have focused on, trans- shown to undergo comparable culture-expansion charac- lation of DMRT into clinical nephrology practice remains at teristics to those from individuals with normal kidney an early stage. Indeed, of the translational strategies we function, and to maintain the capacity to inhibit antidonor review here, only MSC therapy for RVD and T-reg therapy HLA immune response when compared with control MSCs in KTx could be said to have shown preliminary (early- (83,107). phase) clinical trial evidence of superior efficacy compared Despite these encouraging results, counteracting biologic with conventional pharmacotherapy and interventional processes that potentially limit the regenerative functions of procedures. Nonetheless, research in this area has gener- manufactured cell products may prove to be important for ated a wealth of novel scientific insight and a growing maximizing the benefits of autologous cell therapies. Re- number of informative clinical trial experiences with MSC- cent developments in the understanding of cellular senes- and regulatory immune cell–based investigational medici- cence may offer exciting opportunities for the application nal products. Reassuringly, the safety profiles for such of DMRT to kidney disease. Premature senescence reduces cell therapies in patients with kidney diseases and KTx MSC replicative capacity and limits cell expansion in enrolled into clinical trials has, thus far, proven to be very manufacturing protocols. The abundance of senescent cells good. For some of these clinical applications, preliminary also fuels proinflammatory pathways in the pathogenesis of signals of in vivo disease modulation have also emerged disease processes, such as DM and DKD (108,109). Further- (26,33,84,86,88,100,101,104), whereas others have lacked ev- more, the microenvironmental stressors of kidney diseases idence of efficacy (58). (uremia, hyperglycemia, kidney aging, RAAS alteration, In considering how future clinical effect could be maxi- oxidative stress, inflammation) contribute to senescent-cell mized for cell-based DMRT that have undergone early- accumulation, potentially diminishing endogenous and ex- phase clinical trials in patients with kidney disease, a num- ogenous MSC regenerative capacity (105,110). Emerging ber of critical missing elements should be highlighted: (1) therapeutic strategies offer the possibility of modulating development of disease-specific assays to quantify potency the microenvironments from which primary stromal cells of, and patient response to, DMRT to account for complex- are extracted through senescent-cell clearance in vivo. In ities, such as interindividual heterogeneity and changes in a pilot clinical trial, we recently observed that a 3-day oral cell functionality, that occur during ex vivo expansion; (2) senolytic regimen of dasatinib and quercetin can diminish definition of optimal dosing, distribution, and frequency of senescent-cell abundance in adipose and epithelial tissue administration of DMRT for specific clinical targets; (3) and improve MSC proliferation in subjects with DKD (111). consensus on the influence of cryopreservation, which We and others are also pursuing other preconditioning may negatively affect the consistency of DMRT therapeutic methods to optimize autologous MSC functionality. Inter- effects (6,7,113); (4) increased understanding of relative ventions such as exposure to hypoxia or melatonin during clinical efficacy of autologous and allogeneic cell therapies culture expansion may enhance the prorepair properties of for specific patient groups; (5) innovations in manufacturing MSCs (32,112). Taken together, these insights suggest that procedures that will eventually allow for cost-effective de- further integration of in vivo or ex vivo conditioning regi- livery of DMRT to large numbers of patients. As is clear mens could improve the success of autologous (and perhaps from Figure 1, other DMRT for which preclinical evidence also allogeneic) cell-based DMRT in kidney disease. bases and technological developments are building await
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Disclosures neonates as a novel source of kidney progenitor cells. J Am Soc
M. Griffin reports receiving honoraria from American Society of Nephrol 27: 2762–2770, 2016 https://doi.org/10.1681/
Nephrology, Hebei Medical University (China), and National ASN.2015060664
11. Leuning DG, Reinders ME, Li J, Peired AJ, Lievers E, de Boer HC,
Institutes of Health; being an associate editor for JASN, being on the Fibbe WE, Romagnani P, van Kooten C, Little MH, Engelse MA,
editorial boards for Frontiers in Antigen Presenting Cell Biology, Rabelink TJ: Clinical-grade isolated human kidney perivascular
Frontiers in Renal Pharmacology, Kidney International, and Trans- stromal cells as an organotypic cell source for kidney re-
plantation; being a section editor for Mayo Clinic Proceedings; and generative medicine. Stem Cells Transl Med 6: 405–418, 2017
https://doi.org/10.5966/sctm.2016-0053
receiving research funding from Randox Laboratories for research
12. Rani S, Ryan AE, Griffin MD, Ritter T: Mesenchymal stem cell-
not related to this article. S. Herrmann reports having patents and derived extracellular vesicles: Toward cell-free therapeutic
inventions with Pfizer, but these are not related to this research. All applications. Mol Ther 23: 812–823, 2015 https://doi.org/
remaining authors have nothing to disclose. 10.1038/mt.2015.44
13. McFetridge ML, Del Borgo MP, Aguilar MI, Ricardo SD: The use
of hydrogels for cell-based treatment of chronic kidney disease.
Funding
Clin Sci (Lond) 132: 1977–1994, 2018 https://doi.org/10.1042/
L. Hickson is supported by Regenerative Medicine Minnesota CS20180434
grant RMM 091718, National Institute of Diabetes and Digestive 14. US Renal Data System, US Renal Data System 2016 annual data
and Kidney Diseases (NIDDK) grants DK109134 and DK123492, report 2016. Available at: https://www.ajkd.org/article/S0272-
and NIDDK Diabetic Complications Consortium grants DK076169 6386(16)30703-X/fulltext. Accessed February 12, 2020
15. Long DA, Norman JT, Fine LG: Restoring the renal microvas-
and DK115255 (RRID:SCR_001415, www.diacomp.org). S. Herr- culature to treat chronic kidney disease. Nat Rev Nephrol 8:
mann is supported by NIDDK grant DK118120, and by a Mary 244–250, 2012 https://doi.org/10.1038/nrneph.2011.
Kathryn and Michael B. Panitch Career Development Award. M. 219
Griffin is supported by European Commission grants 634086 16. Herrmann SM, Textor SC: Renovascular hypertension. Endo-
crinol Metab Clin North Am 48: 765–778, 2019 https://doi.org/
(Horizon 2020 Collaborative Health Project NEPHSTROM) and 10.1016/j.ecl.2019.08.007
602470 (FP7 Collaborative Health Project VISICORT), Science 17. Eirin A, Textor SC, Lerman LO: Emerging paradigms in chronic
Foundation Ireland grants 09/SRC-B1794 (REMEDI Strategic Re- kidney ischemia. Hypertension 72: 1023–1030, 2018 https://
search Cluster) and 13/RC/2073 (CÚRAM Research Centre), and doi.org/10.1161/HYPERTENSIONAHA.118.11082
18. Cooper CJ, Murphy TP, Cutlip DE, Jamerson K, Henrich W, Reid
the European Regional Development Fund. DM, Cohen DJ, Matsumoto AH, Steffes M, Jaff MR, Prince MR,
Lewis EF, Tuttle KR, Shapiro JI, Rundback JH, Massaro JM,
D’Agostino RB Sr, Dworkin LD; CORAL Investigators: Stenting
Author Contributions and medical therapy for atherosclerotic renal-artery stenosis.
M. Griffin was responsible for funding acquisition; and M. Griffin, N Engl J Med 370: 13–22, 2014 https://doi.org/10.1056/
S. Herrmann, L. Hickson, and B. McNicholas conceptualized the NEJMoa1310753
19. Saad A, Herrmann SM, Crane J, Glockner JF, McKusick MA,
article, wrote the original draft, and reviewed and edited the
Misra S, Eirin A, Ebrahimi B, Lerman LO, Textor SC: Stent re-
manuscript. vascularization restores cortical blood flow and reverses tissue
hypoxia in atherosclerotic renal artery stenosis but fails to re-
verse inflammatory pathways or glomerular filtration rate. Circ
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