Mesenchymal stem cells form a population of self-renewing, multipotent cells that can be isolated from several tissues. Multiple preclinical studies have demonstrated that the administration of exogenous MSC could prevent renal injury and could promote renal recovery through a series of complex mechanisms, in particular via immunomodulation of the immune system and release of paracrine factors and microvesicles. Due to their therapeutic potentials, MSC are being evaluated as a possible player in treatment of human kidney disease, and an increasing number of clinical trials to assess the safety, feasibility, and efficacy of MSC-based therapy in various kidney diseases have been proposed. In the present review, we will summarize the current knowledge on MSC infusion to treat acute kidney injury, chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis, systemic lupus erythematosus, and kidney transplantation. The data obtained from these clinical trials will provide further insight into safety, feasibility, and efficacy of MSC-based therapy in renal pathologies and allow the design of consensus protocol for clinical purpose.
The mesenchymal stem cells (MSC), also called mesenchymal stromal cells, are adherent, fibroblast-like cells capable of self-renewal and multilineage differentiation. They were identified nearly half a century ago from cell cultures of murine bone marrow by Friedstein, who defined them as colony-forming unit fibroblasts [
Interestingly, the MSC currently used for patient therapy are nonclonal MSC, a more heterogeneous population of cells. In effect, clonal cultures would be more homogeneous and therefore preferable but cannot be expanded into a sufficient number of daughter cells. Therefore, the percentage of stem cells contained in every nonclonal population can vary and must be evaluated independently before clinical use through, for example, colony-forming unit (CFU) assays and the evaluation of the multipotential capacity of CFU [
MSC form a heterogeneous cell population likely to have a pericytic origin [
Current clinical trials conducted worldwide using MSC to treat kidney diseases, from the US National Institute of Health database (
NCT number/references | Title | Trial centers | Phase | Conditions | Primary end point | Secondary endpoint | Follow-up period | Enrollment (planned) | Type of MSC | Cell regimen | Therapy (control/placebo) | Start and completion date/status |
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Mesenchymal stem cells in cisplatin-induced acute renal failure in patients with solid organ cancers | Bergamo, Italy | I | Cisplatin-induced AKI | Rate of renal function loss (sCr) | NGAL, NAG | 1 month | 9 | Allogeneic bmMSC | Single i.v. infusion |
Single group assignment | Nov 2010–Mar 2016; recruiting |
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A study to evaluate the safety and efficacy of AC607 for the treatment of kidney injury in cardiac surgery subjects | AlloCure Inc., Burlington, Massachusetts, USA | II | Postcardiac surgery AKI | Time to kidney recovery (sCr) | All-cause mortality or dialysis | 36 months | 156 | Allogeneic AC607 bmMSC | Single i.v. infusion |
Randomized, parallel assignment, double-blind, placebo-controlled | Jun 2012–Aug 2014; completed |
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Allogeneic multipotent stromal cell treatment for acute kidney injury following cardiac surgery | AlloCure Inc., Burlington, Massachusetts, USA | I | Postoperative AKI (patients who require on-pump cardiac surgery) | Absence of MSC-specific adverse or serious adverse events | 36 months | 15 | Allogeneic bmMSC | Experimental: dose-escalating intra-aortic infusion | Nonrandomized, single group assignment | Aug 2008–Oct 2013; completed | |
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Mesenchymal stem cells transplantation in patients with chronic renal failure due to polycystic kidney disease | Tehran, Islamic Republic of Iran | I | Chronic renal failure due to autosomal dominant polycystic kidney disease (ADPKD) | Probability of mass formation in patients with PKD | Renal function (GFR) | 18 months | 6 | Autologous bmMSC | Experimental: single i.v. infusion |
Single group assignment | Mar 2014–Jan 2016; completed |
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Hypoxia and inflammatory injury in human renovascular hypertension | Birmingham, Alabama; Rochester, Minnesota; Jackson, Mississippi, United States | I | Renal artery stenosis, ischemic nephropathy, renovascular disease, chronic kidney disease in human renovascular hypertension | Renal function, safety of MSC infusion | Decrease in kidney inflammation | 36 months | 42 | Autologous adMSC | Active comparator 1: single i.a. infusion |
Nonrandomized, parallel assignment | Oct 2014–Mar 2019; recruiting |
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MSC for occlusive disease of the kidney | Rochester, Minnesota, United States | I | Atherosclerotic renal artery stenosis, ischemic nephropathy, renovascular hypertension | Renal blood flow (CT), renal function (GFR) | Blood pressure levels (oscillometric measurement) | 24 months | 6 | Autologous adMSC | Experimental: single i.a. infusion | Single group assignment | Apr 2013–Apr 2017; ongoing |
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Autologous bone marrow derived mesenchymal stromal cells (bmMSC) in patients with chronic kidney disease (CKD) | Tehran, Islamic Republic of Iran | I | Chronic kidney disease | Mass formation, renal function (sCr) | GFR | 18 months | 7 | Autologous bmMSC | Experimental: single i.v. infusion |
Single group assignment | Apr 2014–Jan 2016; completed |
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Allogenic adMSC transplantation in idiopathic nephrotic syndrome (focal segmental glomerulosclerosis) | Tehran, Islamic Republic of Iran | I | Focal segmental glomerulosclerosis | Renal function (sCr, proteinuria) | Renal function (sCr, urea, GFR), increase in anti-inflammatory factors (sIL-2, I-10), increase in Treg | 12 months | 5 | Allogeneic adMSC | Experimental: single i.v. injection | Single group assignment | May 2015–Oct 2017; recruiting |
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Novel stromal cell therapy for diabetic kidney disease (NEPHSTROM) | Galway, Ireland; Bergamo, Italy; Belfast, United Kingdom; Birmingham, United Kingdom | I/II | Diabetic kidney disease | Number of adverse events | GFR, UAE | 24 months | 48 | Allogeneic bmMSC | Experimental: MSC i.v. infusion 3 doses 80, 160, |
Randomized, parallel assignment, double-blind, placebo-controlled | May 2016–Apr 2019; not yet recruiting |
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Mesenchymal stem cells transplantation for refractory systemic lupus erythematosus | Nanjing, Jiangsu, China | I/II | Refractory systemic lupus erythematosus | Systemic lupus erythematosus disease activity index (SLEDAI), lupus serology (ANA, dsDNA, C3, C4), renal function (GFR, BUN, urinalysis) | Percentage of systemic T regulatory population | 24 months | 20 | Allogeneic bmMSC | Experimental: pretreatment with cyclophosphamide then transplantation i.v. with 106 cells/kg MSC | Nonrandomized, single group assignment | Mar 2007–Dec 2012; unknown, not verified recently |
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Phase 2 study of human umbilical cord derived mesenchymal stem cell for the treatment of lupus nephritis | Kunming, Yunnan, China | II | Lupus nephritis | Efficacy and safety (renal function, urinary RBC, proteinuria) | 6 months | 25 | Allogeneic ucMSC | Experimental: MSC i.v. infusion |
Randomized, double-blind, parallel group, placebo controlled | Feb 2012–May 2013; unknown, not verified recently | |
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A controlled trial of allogeneic mesenchymal stem cells for the treatment of refractory lupus | Los Angeles, California; Atlanta, Georgia; Chicago, Illinois; Rochester, New York; Chapel Hill, North Carolina; Charleston, South Carolina, United States | II | Systemic lupus erythematosus | Clinical response defined by the SLE responder index | Change in SLEDAI score, renal and nonrenal organ system flares | 12 months | 81 | Allogeneic ucMSC | Experimental 1: single MSC i.v. infusion |
Randomized, double-blind, placebo controlled | Jul 2016–Jun 2021; not yet recruiting |
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Umbilical cord derived mesenchymal stem cells transplantation for active and refractory systemic lupus erythematosus | Nanjing, Jiangsu, China | I/II | Systemic lupus erythematosus | BILAG score | Lupus serology (Alb, ANA, dsDNA, C3, C4), renal function (GFR, BUN, urinalysis) | 12 months | 40 | Allogeneic ucMSC | Experimental: MSC transplantation | Single group assignment | Jan 2012–Dec 2013; unknown, not verified recently |
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Effect of mesenchymal stem cell transplantation for lupus nephritis | Fuzhou, Fujian, China | I/II | Lupus nephritis | Number of achieved and maintained remissions | Patient survival, sCr and proteinuria, SLE disease activity index, serology (ANA, dsDNA), complement (C3 and C4) | 12 months | 20 | Autologous MSC | Experimental 1: prednisone administration |
Single group assignment | May 2008–May 2010; unknown, not verified recently |
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Mesenchymal stem cell transplantation in the treatment of chronic allograft nephropathy | Fuzhou, Fujian, China | I/II | Kidney transplant, chronic allograft nephropathy | Renal function (sCr and Cr clearance rate) | Patient and graft survival, the proportion of renal biopsy, the incidence of infectious complications Incidence of adverse events associated with MSC and immunosuppression | 12 months | 20 | Allogeneic MSC | Experimental 1: MSC infusion and full immunosuppressive therapy |
Randomized, placebo-controlled | May 2008–May 2010; unknown, not verified recently |
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To elucidate the effect of mesenchymal stem cells on the T-cell repertoire of the kidney transplant patients | Chandigarh, India | I | Renal transplant rejection | T-cell expansion, renal function (sCr) | T-cells proliferation changes, regulatory T-cells changes, memory T-cells changes, B-cells changes, cytokine profile change | 24 months | 30 | Allogeneic/ |
Experimental: two doses of autologous MSC infusion, one day before transplant and 30 days after transplant |
Randomized, parallel assignment | Sep 2013–Dec 2016; recruiting |
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Effect of bmMSC in DCD kidney transplantation | Guangdong, China | I/II | Kidney transplantation, acute kidney tubular necrosis | Renal function (estimated GFR) | Incidence of slow graft function, incidence of delayed graft function, proportion of normal renal function recovery, time to renal function recovery, patient survival, renal graft survival, incidence of acute rejection, severe adverse events | 12 months | 120 | Allogeneic bmMSC | Experimental: four doses of MSC |
Randomized, parallel assignment, single-blind, placebo-controlled | Oct 2015–Oct 2017; completed |
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Mesenchymal stem cells after renal or liver transplantation | Liège, Belgium | I/II | Kidney failure | Safety (MSC infusion toxicity), incidence of infections and cancers | Patient and graft survivals, feasibility and safety, effects of MSC on graft function, rejection rates, recipient's immune function, development of anti-MSC donor HLA antibodies | 24 months | 40 | Allogeneic bmMSC | Experimental: single MSC infusion 1, 5–3, |
Nonrandomized, parallel assignment | Feb 2012–Feb 2017; recruiting |
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Induction therapy with autologous mesenchymal stem cells for kidney allografts | Fuzhou, Fujian, China | Renal transplant rejection | Incidence of acute rejection and early renal function recovery | Patient and graft survival and prevalence of adverse events | 12 months | 165 | Autologous bmMSC | Active comparator 1: two infusions of MSC, one at releasing renal artery clamp and one two weeks after transplantation and regular immunosuppressive agents |
Randomized, parallel assignment | Mar 2008–Oct 2010; completed | |
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Effect of bmMSC on early graft function recovery after DCD kidney transplant | Guangzhou, Guangdong, China | I/II | Kidney transplantation, acute kidney tubular necrosis | Renal function (estimated GFR) | Proportion of normal renal function recovery, time to renal function recovery, acute rejection rate, patient and graft survival rate, incidence of severe adverse events | 12 months | 120 | Allogeneic bmMSC | Experimental: four i.v. administration doses of MSC |
Randomized, parallel assignment, single-blind | Nov 2015–Dec 2017; not yet recruiting |
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A perspective multicenter controlled study on application of mesenchymal stem cell (MSC) to prevent rejection after renal transplantation by donation after cardiac death | Guangzhou, Guangdong, China | I | Disorder related to renal transplantation, renal transplant rejection | Safety (Incident rates of BPAR and DGF) | 12 months | 260 | bmMSC | Experimental 1: routine treatment protocol plus MSC i.v. |
Randomized, parallel assignment, single-blind | Jan 2016–Dec 2018; enrolling | |
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Mesenchymal stem cells under Basiliximab/low dose RATG to induce renal transplant tolerance | Bergamo, Italy | Kidney transplant | Inhibition of memory T-cell response and/or naive T-cell response, Induction of donor-reactive T-cell anergy and the appearance in the peripheral blood of regulatory T-cells | Safety of MSC infusion, graft function, graft rejection | 12 months | 4 | Syngeneic bmMSC | Experimental: MSC infusion |
Randomized, parallel assignment | May 2008–Dec 2013; completed | |
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Effect of bmMSC on chronic AMR after kidney transplantation | Guangzhou, Guangdong, China | I/II | Kidney transplant | Renal function (estimated GFR) | Patient survival rate, graft survival rate, DSA level, pathological manifestation (Banff 2013 criteria), severe adverse events | 12 months | 60 | Allogeneic bmMSC | Experimental: four i.v. MSC infusions |
Nonrandomized, parallel assignment, single-blind | Nov 2015–Nov 2017; not yet recruiting |
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Effect of SVF derived MSC in DCD renal transplantation | Fuzhou, Fujian, China | I/II | Kidney transplant | Safety (incidence of DGF: 3-month reduction of CNI) | Renal function (eGFR, proteinuria), incidence of acute rejection, allograft survival, SAE, nonhematologic toxicities | 12 months | 120 | Autologous adMSC | Experimental: four i.v. MSC infusions during kidney transplant operation and at days 7, 14, 21 |
Randomized, parallel assignment | Dec 2014–Nov 2016; recruiting |
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Mesenchymal stem cells and subclinical rejection | Leiden, Netherlands | I/II | Kidney transplant | Rate of (serious) adverse events, feasibility (number of expanded MSC in relation to the amount of BM collected) | Acute rejection, renal cortical matrix accumulation, immunologic response evaluation | 24 months | 15 | Autologous bmMSC | Experimental: two i.v. MSC infusions 1- |
Nonrandomized, single group assignment | Feb 2009–Dec 2012; completed |
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Induction with SVF derived MSC in living-related kidney transplantation | Fuzhou, Fujian, China | I/II | Living-relative kidney transplantation | Effects on dosage of immunosuppressant | Renal function (eGFR, proteinuria), incidence of acute rejection, allograft survival, infection adverse event, nonhematologic toxicities, hematologic toxicities, incidence of delayed graft function | 12 months | 120 | Autologous adMSC | Experimental: four i.v. MSC infusions during kidney transplant operation and at days 7, 14, 21 |
Randomized, parallel assignment | Dec 2014–Dec 2017; recruiting |
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Allogeneic mesenchymal stromal cell therapy in renal transplant recipients | Leiden, Netherlands | I | Rejection, graft loss | Biopsy proven acute rejection/graft loss | Comparison of fibrosis by quantitative Sirius Red scoring, serious adverse events, renal function measured by eGFR (MDRD formula) and iohexol clearance, CMV, BK infection (viremia, disease, and syndrome; and subtypes of BK viremia) and other opportunistic infections, development of |
12 months | 10 | Allogeneic bmMSC | Experimental: two i.v. MSC infusions 1- |
Single group assignment | Mar 2015–Mar 2017; recruiting |
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Mesenchymal stromal cells in kidney transplant recipients | Bergamo, Italy | I | Kidney transplant rejection | Naive and memory T-cell count (CD45RA/CD45RO), T-cell function (ELISPOT assay), number of adverse events, regulatory T-cell count, urinary FOXP3 mRNA expression (RT qPCR) | 12 months | 6 | Autologous bmMSC | Experimental: single i.v. MSC infusion |
Single group assignment | Dec 2013–Mar 2018; recruiting | |
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MSC and kidney transplant tolerance | Bergamo, Italy | I | Kidney transplant | Number of adverse events, T-cell function, urinary FOXP3 mRNA expression (RT qPCR), naive and memory T-cell count (CD45RA/CD45RO), regulatory T-cell count | 12 months | 22 | Allogeneic bmMSC | Experimental: single i.v. MSC infusion 1- |
Randomized, parallel assignment | Sep 2015–Dec 2021; recruiting | |
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Mesenchymal stromal cell therapy in renal recipients | Leiden, Netherlands | II | Renal transplant rejection, fibrosis | Histology (fibrosis evaluation by Sirius Red) | Renal function and proteinuria, number of participants with CMV and BK infection and other opportunistic infections between groups, number of participants with adverse events, composite, end point efficacy failure, presence of donor specific antibodies and immunologic monitoring | 6 months | 70 | Autologous bmMSC | Experimental: three i.v. MSC infusions 1- |
Randomized, parallel assignment | Mar 2014–Mar 2017; recruiting |
ADPKD: autosomal dominant polycystic kidney disease; ALB: albumin; ANA: antinuclear antibodies; BILAG: British Isles Lupus Assessment Group; BPAR: biopsy-proven acute rejection; BUN: blood urea nitrogen; CMV: cytomegalovirus; CNI: calcineurin inhibitor; DGF: delayed graft function; DSA: donor-specific antibody; ELISPOT: enzyme-linked immunospot; GFR: glomerular filtration rate; HLA: human leukocyte antigen; i.a.: intra-arterial; i.v.: intravenous; MDRD: modification of diet in renal disease; NAG: N-acetyl-p-D glucosaminidase enzyme; NGAL: neutrophil gelatinase-associated lipocalin; RBC: red blood cells; SAE: severe adverse effects; sCr: serum creatinine; SLE: systemic lupus erythematosus; SLEDAI: systemic lupus erythematosus disease activity index; UAE: urinary albumin excretion.
Sources of MSC used in experimental models of renal injury. Preclinical studies have shown that MSC used to treat renal diseases can be isolated from the following tissues: (A) tooth pulp, (B) kidney, (C) adipose tissue, (D) umbilical cord, (E) amniotic fluid, and (F) bone marrow.
Properties of MSC in kidney diseases. MSC, soluble factors, or microvesicles can be delivered to the kidney via the intraperitoneal, intra-arterial, intravenous, intraparenchymal, or intraosseous route. They exert a series of renoprotective and regenerative actions on the injured tissues through various paracrine mechanisms: antifibrotic and antiapoptotic, proangiogenic, proliferative and differentiative, antioxidative stress, and immunosuppression and immunomodulation of the immune system. ROS: reactive oxygen species. Arrow: enhancement; T-bar: reduction.
MSC possess the ability to migrate into damaged tissues in response to combinational signals [
While initial findings on the therapeutic properties of MSC indicated an important role for homing, engrafting, and differentiation of the cells at the site of injury, numerous additional studies demonstrate a very limited replacement of damaged tissues by transdifferentiation ability and replacement potential [
From the first published article in 2000 by Liechty et al., numerous studies have demonstrated the ability of MSC to modulate the immune system [
Recent evidence emphasizes the importance of the interactions between the MSC and their environment, as other immunomodulatory properties come into effect in a paracrine/endocrine manner. MSC are able to release dozens of active biological factors that act on local cell dynamics, by decreasing apoptosis, reducing inflammation and fibrosis formation, promoting angiogenesis and recruiting resident progenitor cells, and stimulating mitosis and/or differentiation process [
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Additionally, recent studies showed positive effect on the kidney structure through fibrosis reduction mediated by MSC. This effect occurs independently of the source of MSC (adMSC, ucMSC, and bmMSC) and injury model (ischemia-reperfusion, IgA nephropathy, and unilateral ureteral obstruction) [
An additional important property of the MSC is to decrease the severity of organ injury through the reduction of the oxidative stress [
The promising results obtained from numerous
They span a wide range of renal pathologies: acute kidney injury (3 trials), chronic kidney injury (4 trials), focal segmental glomerulosclerosis (1 trial), diabetic kidney disease (1 trial), autoimmune disease (5 trials), and kidney transplantation (16 trials).
AKI—previously called acute renal failure—is characterized by the rapid loss of kidney excretory function. Its causes are numerous and can be divided into three categories: prerenal disease such as renal ischemia (from low blood pressure, crush injury, etc.), intrinsic renal disease such as exposure to nephrotoxic substances (antibiotics or contrast agents, e.g.), and systemic disease, or postrenal-like obstruction of the urinary tract. It is typically diagnosed on the basis of characteristic laboratory findings, that is, elevated blood urea nitrogen and creatinine, or decreased urine output, or both [
Interesting preclinical results obtained in various mouse models paved the way for the development of novel therapies involving the use of MSC in AKI patients. In fact, no drug is presently available to treat this condition, and the treatment is essentially supportive, including renal replacement therapy whenever necessary. Around 50% of critically ill patients die from AKI, and while most surviving patients completely recover their renal function within weeks, some develop chronic kidney disease (CKD) requiring kidney transplant [
The number of individuals affected with chronic kidney disease (CKD) is rising worldwide, mainly due to a remarkable increase in atherosclerosis and type 2 diabetes. An estimated 8–16% of the general population has CKD, and its prevalence increases with age to about 30% in people aged over 70 years [
CKD is characterized by reduced renal regenerative capacity. Several
Diabetic kidney disease (DKD)—also called diabetic nephropathy—is a clinical syndrome associated with kidney damage, which can progress to chronic kidney disease. It is the leading cause of ESRD in the industrialized world, accounting for about 40% of new cases in the US and EU. The five-year mortality rate is 39%—a rate comparable to many cancers. The economic cost of DKD and its progression to ESRD represents an astounding 13% of the US healthcare budget. In spite of this enormous social and economic cost, there have been no specific therapies successfully developed for DKD in the past 25 years. The current treatment paradigm relies on early detection, glycemic control, and tight blood pressure management with preferential use of renin-angiotensin system blockade [
Focal segmental glomerulosclerosis (FSGS) is a rare but major cause of ESRD. The rate of recurrence is higher in children compared with adults and in patients submitted to a subsequent kidney transplant. Furthermore, after kidney transplantation, approximately 30–40% of patients with FSGS develop recurrent FSGS. Its incidence is increasing worldwide [
In FSGS, glomerular lesions caused by various insults directed to or inherent within the podocyte lead to foot process effacement. The resulting loss of integrity of the glomerular filtration barrier, which regulates permselectivity, causes in turn proteinuria. Traditional pharmacological approaches, consisting of corticosteroids and calcineurin inhibitors, fail to achieve a sustained remission in most patients. Therefore, there is a pressing need to develop alternative therapies for this glomerulopathy [
SLE is a chronic autoimmune disease characterized by a wide range of clinical manifestations that can affect many organs in the body, with significant morbidity and mortality. Nephritis remains the most significant manifestation of SLE and standard treatments include high doses of corticosteroids, cyclophosphamides, and other immunosuppressive and biological agents. Most patient outcome improves greatly following therapy, but strong side effects including infection, ovarian failure, and secondary malignancy can worsen the prognosis and lead to patient death [
Kidney transplant in ESRD patients offers the best chance of survival and improves health-related quality of life compared to remaining on dialysis. Better and more potent immunosuppressive drugs have improved significantly the short-term outcome of the surgery in the last two decades. However, the long-term graft survival rate beyond the first year showed only a small increase [
It is noteworthy that one registered clinical trial aims to compare the use of autologous and allogenic bmMSC treatment in kidney transplantation patients and will help to elucidate the effect of the bmMSC on the T-cell repertoire of the recipients (
Over the past several years, the discrepancy between the number of wait-listed patients and the number of kidneys from brain-dead donors has been increasing steadily, leading to a shortage of organs and resulting in an extension of the criteria for kidney donors, including non-heart-beating donors (NHBD) [
MSC form a population of well-characterized, easily obtainable cells with therapeutic properties effective in numerous experimental models of kidney diseases. The underlying mechanisms of action of the MSC have been extensively described and consist essentially in immunomodulatory and paracrine effects. However, the translation of preclinical studies into robust, effective, and safe patient therapies remains limited. The many clinical trials that have been conducted and completed will undoubtedly provide further insight into safety, feasibility, and efficacy of MSC-based therapy in renal pathologies. The preliminary results available still lack long-term follow-up data and the absence of consensus between therapeutic protocols, in particular in terms of MSC preparation, donor characteristics, and concomitant immunosuppressive treatment in kidney transplant recipients, is noteworthy. As a broad range of approaches have been developed, a careful selection of the best one will have to be made in the future in an effort to reach a certain harmonization in clinical practices [
The authors declare that there are no competing interests regarding the publication of this paper.
Paola Romagnani has received funding from the European Community under the European Community’s Seventh Framework Programme (FP7/2012–2016), Grant no. 305436, STELLAR Project.