Nephroprotective Effect of Mesenchymal Stem Cell-Based ...The Cochrane Library, Embase, ISI Web of...

Research ArticleNephroprotective Effect of Mesenchymal Stem Cell-BasedTherapy of Kidney Disease Induced by Toxicants

Shujun Lin, Wenshan Lin, Chunling Liao, and Tianbiao Zhou

Department of Nephrology, The Second Affiliated Hospital, Shantou University Medical College, 515041 Shantou, China

Correspondence should be addressed to Tianbiao Zhou; [email protected]

Received 27 August 2020; Revised 28 October 2020; Accepted 10 December 2020; Published 23 December 2020

Academic Editor: Erika B. Rangel

Copyright © 2020 Shujun Lin et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Renal damage caused by drug toxicity is becoming increasingly common in the clinic. Preventing and treating kidneydamage caused by drug toxicity are essential to maintain patient health and reduce the social and economic burden. In this study,we performed a meta-analysis to assess the nephroprotective effect of mesenchymal stem cells (MSCs) in the treatment of kidneydisease induced by toxicants. Methods. The Cochrane Library, Embase, ISI Web of Science, and PubMed databases were searchedup to December 31, 2019, to identify studies and extract data to assess the efficacy of MSCs treatment of kidney disease induced bytoxicants using Cochrane Review Manager Version 5.3. A total of 27 studies were eligible and selected for this meta-analysis.Results. The results showed that a difference in serum creatinine levels between the MSC treatment group and control group wasobserved for 2, 4, 5, 6-8, 10-15, 28-30, and ≥42 days (2 days: WMD= −0:88, 95% CI: -1.34, -0.42, P = 0:0002; 4 days: WMD= −0:74, 95% CI: -0.95, -0.54, P < 0:00001; 5 days: WMD= −0:46, 95% CI: -0.67, -0.25, P < 0:0001; 6-8 days: WMD= −0:55, 95%CI: -0.84, -0.26, P = 0:0002; 10-15 days: WMD= −0:37, 95% CI: -0.53, -0.20, P < 0:0001; 28-30 days: WMD= −0:53, 95% CI:-1.04, -0.02, P = 0:04; ≥42 days: WMD= −0:22, 95% CI: -0.39, -0.06, P = 0:007). Furthermore, a difference in blood ureanitrogen levels between the MSC treatment group and control group was observed for 2-3, 4-5, 6-8, and ≥28 days. The resultsalso indicate that MSC treatment alleviated inflammatory cells, necrotic tubules, regenerative tubules, and renal interstitialfibrosis in kidney disease induced by toxicants. Conclusion. MSCs may be a promising therapeutic agent for kidney diseaseinduced by toxicants.

1. Introduction

Kidney injury occurs during acute kidney injury (AKI) andchronic kidney disease (CKD), and it is a common conditionassociated with the morbidity and mortality of patients. Atotal of 80% of patients who survive an AKI episodecompletely recover kidney function, and recovered AKIpatients present an almost 9-fold increase in risk for CKDdevelopment [1]. Toxicant-induced kidney injury is one ofthe most common causes of kidney disease, causing substan-tial morbidity and hampering drug development [2]. Atpresent, renal damage caused by drug toxicity is becomingincreasingly common in the clinic. Preventing and treatingkidney damage caused by drug toxicity is essential to main-tain patient health and reduce the social and economicburden.

Mesenchymal stem cells (MSCs), which are multipotentmesenchymal cells present in various tissues, have multiline-age differentiation ability under appropriate conditions andare easy to obtain. They are a promising therapeutic optionfor some diseases because of their unique property of releas-ing some important bioactive factors [3–5]. Drug toxicity caninduce renal tubular epithelial cell damage or death and canlead to renal interstitial inflammation, which eventuallydevelops into renal interstitial fibrosis and renal loss. Previ-ous studies have shown that MSCs can play a protective roleagainst injury of renal tubular epithelial cells and preventrenal interstitial fibrosis [6–10]. Before clinical application,animal experiments in vivo are generally required to confirmthe effectiveness of MSCs. Furthermore, there are few clinicaltrials of MSCs on kidney disease induced by toxicants. There-fore, in this study, we performed a meta-analysis to assess the

HindawiStem Cells InternationalVolume 2020, Article ID 8819757, 12 pageshttps://doi.org/10.1155/2020/8819757

https://orcid.org/0000-0001-8065-1644

https://creativecommons.org/licenses/by/4.0/

https://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1155/2020/8819757

nephroprotective effect of MSCs in the treatment of kidneydisease induced by toxicants in animals.

2. Materials and Methods

2.1. Search Strategy. We searched databases (CochraneLibrary, Embase, ISI Web of Science, and PubMed) up toDec 31, 2019, using the following search terms: (mesenchy-mal stem cells OR MSC OR MSCs OR multipotent stromalcells OR mesenchymal stromal cells OR mesenchymal pro-genitor cells OR stem cells) AND (gentamicin OR aristo-lochic acid OR cisplatin OR adriamycin OR cadmiumchloride OR methotrexate OR rifampicin OR glycerol ORstreptozocin) AND (kidney injury OR renal failure OR kid-ney disease). The search was confined to English-languageliterature. An additional search was conducted among theeligible manual references of the cited articles.

2.2. Inclusion and Exclusion Criteria. Our meta-analysisincluded studies analyzing the efficacy of MSC treatment inmice or rats with kidney disease. The following studies wereexcluded from the analysis: (1) letters, case reports, reviews,clinical studies, editorials, meta-analysis, and systematicreviews; (2) studies lacking the targeted indicators or numberof case or control groups and were conducted in humans; (3)studies of kidney disease that was not induced by toxicants;and (4) studies with therapeutic regimen for kidney diseasethat included other agents with undefined effects.

2.3. Outcome Measures. We filtered the following outcomesassociated with the efficacy of MSC treatment from therecruited studies: serum creatinine (Scr), blood urea nitrogen(BUN), urinary albumin excretion (UAE), malondialdehyde(MDA), L-glutathione (GSH), superoxide dismutase (SOD),and renal pathology. In addition, we conducted a mutualconsensus when met with disagreements.

2.4. Quality Assessment. Two investigators independentlyevaluated the methodological quality using the CochraneHandbook for Interventions. We assessed the following sec-tions of every investigation: selection bias, attrition bias, per-formance bias, detection bias, reporting bias, and other bias.Each item was classified as unclear, high risk, or low risk.

2.5. Statistical Analysis. Review Manager Version 5.3 wasapplied to explore whether MSC treatment achieved a goodefficacy in kidney disease induced by toxicants, and STATA12.0 was used to test the publication bias. Heterogeneity ofvariation among individual studies was quantified anddescribed using I2. The fixed effects model was used if the Pvalue of the heterogeneity test was ≥ 0.1. Otherwise, the ran-dom effects model was applied to pool the outcomes. In addi-tion, to compute continuous variables, we analyzed weightedmean differences (WMDs) for the mean values. We also cal-culated 95% confidence intervals (95% CI) for the includedstudies using the Mantel-Haenszel (M-H) method. Addition-ally, we evaluated the publication bias using Begg’s rank

Potentially relevant studies retrieved formore detailed evaluation: 34

7 studies excluded:(i) Did not provide the detailed

data for case or control group: 3(ii) Therapeutic regimen for kidney

disease including other agents: 4

Studies included in the meta-analysis: 27

751 articles were excluded:(i) Letters/case

reports/reviews/clinicalstudies/editorials/meta-analysis/systematic reviews: 237

(ii) Preliminary results not on MSCor kidney disease: 341Kidney disease not induced bytoxicant: 173

Articles retrieved for review fromPubMed, Embase, ISI Web of Science,and Cochrane Library: 785

(iii)

Figure 1: Flow diagram of the selection process.

2 Stem Cells International

Table1:Characteristics

ofthestud

iesinclud

edin

thismeta-analysis.

Autho

r,year

nTypeof

anim

alTypeof

injury

MSC

type

Num

berof

MSC

Rou

teof

delivery

End

pointsforthismeta-analysis

Herrera

2004

24Mice

Glycerol-indu

ced

BM-M

SCs

1×10

6Intravenou

sinjection

Scr

Bi2

007

12Mice

Cisplatin-ind

uced

BM-M

SCs

2×10

5Intravenou

sinjectionor

intraperiton

eal

injection

Scr,BUN

Sun2008

40Rat

Glycerol-indu

ced

BM-M

SCs

2×10

6Abd

ominalaortainjection

Scr,BUN

Qian2008

6Rat

Glycerol-indu

ced

BM-M

SCs

1×10

4Intravenou

sinjection

Scr

Magnasco2008

22Rat

Adriamycin-ind

uced

BM-M

SCs

3×10

6Intravenou

sinjection

Scr,BUN,U

AE,renaldamagescore

Bruno

2009

16Mice

Glycerol-indu

ced

BM-M

SCs

—Intravenou

sinjection

Scr,BUN,M

DA,G

SH,SOD,renal

damagescore

Elio

poulos

2010

10Mice

Cisplatin-ind

uced

BM-M

SCs

5×10

6Intraperiton

ealinjection

Scr,BUN

Kim

2012

17Rat

Cisplatin-ind

uced

AD-M

SCs

5×10

5Intravenou

sinjection

Scr,BUN

Zickri2

012

30Rat

Adriamycin-ind

uced

hUC-M

SCs

5×10

5Intravenou

sinjection

Scr

Sarhan

2014

19Rat

Adriamycin-ind

uced

BM-M

SCs

4×10

6Intravenou

sinjection

Scr,BUN,U

AE,renalpathology,MDA,

GSH

Mou

stafa2016

80Rat

Cisplatin-ind

uced

BM-M

SCs

5×10

6Intravenou

s,intraarterialo

rkidn

eysubcapsularinjection

Scr,MDA,G

SH,SOD

Elhusseini2

016

40Rat

Cisplatin-ind

uced

AD-M

SCs

5×10

6Intravenou

sinjection

Scr,BUN,C

cr,renalpathology,MDA,

GSH

,SOD

Anan2016

13Rat

Adriamycin-ind

uced

BM-M

SCs

1×10

6Intravenou

sinjection

Scr,BUN,SOD

Gad

2017

24Rat

Metho

trexate-indu

ced

BM-M

SCs

2×10

6Intraperiton

ealinjection

Scr,BUN,M

DA,G

SH

Rashed2018

20Rat

Streptozotocin

-ind

uced

BM-M

SCs

1×10

6Intravenou

sinjection

Scr,BUN,U

AE,C

cr

Elbaghd

ady2018

20Rat

Cadmium

chloride-

indu

ced

BM-M

SCs

2×10

6Intravenou

sinjection

Scr

Danjuma2018

16Rat

Rifampicin-indu

ced

BM-M

SCs

2:5×10

5Intravenou

sinjection

Scr,BUN

Putra

2019

10Rat

Gentamicin

indu

ced

hUC-M

SCs

1×10

6Intraperiton

ealinjection

Scr,BUN,renalpathology

Cetinkaya

2019

17Rat

Aristolochicacid

indu

ced

hAMSC

6×10

5Intravenou

sinjection

Scr,BUN

Selim

2019

70Rat

Cisplatin-ind

uced

AD-M

SCs;BM-

MSC

s4×

106

Intravenou

sinjection

Scr,BUN

Mata-Miranda

2019

10Mice

Cisplatin-ind

uced

mESC

s1×

106

Intraperiton

ealinjection

Scr

Vazqu

ez-Zapien

2019

19Mice

Cisplatin-ind

uced

mESC

s1×

106

Intraperiton

ealinjection

Scr

Minocha

2019

3Rat

Cisplatin-ind

uced

AFSC

2×10

6Intravenou

sinjection

Scr,BUN

3Stem Cells International

Table1:Con

tinu

ed.

Autho

r,year

nTypeof

anim

alTypeof

injury

MSC

type

Num

berof

MSC

Rou

teof

delivery

End

pointsforthismeta-analysis

SunB2019

10Rat

Cisplatin-ind

uced

USC

s2×

106

Intravenou

sinjection

Scr

Sun2019

6Rat

Cisplatin-ind

uced

BM-M

SCs

—Renalparenchymainjection

Scr,BUN

Zhang

2020

9Rat

Cisplatin-ind

uced

USC

s5×

106

Subcutaneous

injection

Scr,Ccr,renalpathology

Foroutan

2020

6Rat

Cisplatin-ind

uced

BM-M

SCs

—Intraperiton

ealinjection

Scr,BUN

Note:BM-M

SCs:bone

marrowmesenchym

alstem

cells;hAMSC

s:hu

man

amnion

-derived

mesenchym

alstem

cells;hUC-M

SCs:hu

man

umbilicalcord-m

esenchym

alstem

cells;A

D-M

SCs:adiposetissue-derived

mesenchym

alstem

cells;m

ESC

s:mou

seem

bryonicstem

cells;A

FSCs:am

nioticfluidstem

cells;U

SCs:urine-derivedstem

cells;Scr:serum

creatinine;B

UN:blood

urea

nitrogen;U

AE:urinary

albu

min

excretion;

Ccr:creatinineclearancerate;M

DA:m

alon

dialdehyde;G

SH:L

-glutathione;SOD:sup

eroxidedism

utase.


Anan 2016Bi 2007

Bruno 2009Cetinkaya 2019Danjuma 2018

Elbaghdady 2018Elhusseini 2016Eliopoulos 2010

Foroutan 2020Gad 2017

Herrera 2004Kim 2012

Magnasco 2008Mata-Miranda 2019

Minocha 2019Moustafa 2016

Putra 2019Qian 2008

Rashed 2018Sarhan 2014

Selim 2019Sun 2008Sun 2019

Sun B 2019Vazquez-Zapien 2019

Zhang 2020Zickri 2012

Rand

om se

quen

ce g

ener

atio

n (s

elect

ion

bias

)

Allo

catio

n co

ncea

lmen

t (se

lect

ion

bias

)

Blin

ding

of p

artic

ipan

ts an

d pe

rson

nel (

perfo

rman

ce b

ias)

Blin

ding

of o

utco

me a

sses

smen

t (de

tect

ion

bias

)

Oth

er b

ias

Sele

ctiv

e rep

ortin

g (r

epor

ting

bias

)

Inco

mpl

ete o

utco

me d

ata (

attr

ition

bia

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?

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(a)

Figure 2: Continued.


correlation test as well as Egger’s linear regression methodamong the studies. A P value < 0.05 was considered ofstatistical significance.

3. Results

3.1. Search Results. The databases mentioned above weresearched, and only studies in mice or rats that evaluated thetherapeutic efficacy of MSC treatment on kidney diseaseinduced by toxicants were selected. Twenty-seven studies[11–37] were eligible and selected for this meta-analysis,and a flowchart of inclusion of studies is presented inFigure 1. Study characteristics are shown in Table 1.

3.2. Quality Assessment of Included Studies. The methodolog-ical quality of the selected studies was considered acceptablebecause most study domains were ranked as unclear risk orlow risk of bias. Unclear risk of bias was mostly detected inperformance and selection bias. Low risk of bias mostlyoccurred in detection, reporting, and attrition bias. Figure 2shows a summary of the risk of biases of the selected studies.

3.3. Scr. A total of 27 studies [11–37] were selected to assessthe effect of MSCs on Scr, and the results show that a differ-ence between the MSC treatment and control groups wasobserved for 2, 4, 5, 6-8, 10-15, 28-30 days, and ≥42 days (2days:WMD= −0:88, 95% CI: -1.34, -0.42, P = 0:0002; 4 days:WMD= −0:74, 95% CI: -0.95, -0.54, P < 0:00001; 5 days:WMD= −0:46, 95% CI: -0.67, -0.25, P < 0:0001; 6-8 days:WMD= −0:55, 95% CI: -0.84, -0.26, P = 0:0002; 10-15 days:WMD= −0:37, 95% CI: -0.53, -0.20, P < 0:0001; 28-30 days:WMD= −0:53, 95% CI: -1.04, -0.02, P = 0:04; ≥42 days:WMD= −0:22, 95% CI: -0.39, -0.06, P = 0:007; Figure 3and Table 2). However, no difference was observed betweenthe MSC treatment and control groups for 3 days (3 days:

WMD= −0:09, 95% CI: -0.25, -0.06, P = 0:24; Figure 3 andTable 2).

3.4. BUN. A total of 18 studies [11–15, 17–19, 21, 22, 24, 26–29, 32–34, 36, 37] were selected to assess the effect of MSCson BUN, and the results indicate that the difference betweenthe MSC treatment and control groups was observed for 2-3,4-5, 6-8, and ≥28 days (2-3 days: WMD= −25:08, 95% CI:-37.49, -12.67, P < 0:0001; 4-5 days: WMD= −45:71, 95%CI: -59.36, -32.05, P < 0:00001; 6-8 days: WMD= −57:55,95% CI: -99.19, -15.91, P = 0:007; ≥28 days: WMD= −23:39, 95% CI: -36.39, -10.40, P = 0:0004; Figure 4 and Table 2).However, no difference was observed between the MSC treat-ment and control groups for 13-15 days (WMD= −13:40,95% CI: -32.34, 5.54, P = 0:17; Figure 4 and Table 2).

3.5. Urinary Albumin Excretion. Three studies [22, 26, 27]were selected in the meta-analysis for the assessment ofMSCs on UAE. The results show that the MSC group had alower UAE than the control group (WMD= −22:66, 95%CI: -26.41, -18.90, P < 0:00001; Table 2).

3.6. Oxidative Stress. Four studies [17, 19, 23, 27] wereselected for the assessment of MDA, four [17, 19, 23, 27]for GSH, and three [11, 17, 23] for SOD. The results indicatethat a difference between the MSC treatment and controlgroups was observed for MDA, GSH, and SOD (MDA:WMD= −17:21, 95% CI: -20.38, -14.04, P < 0:00001; GSH:WMD= 4:62, 95% CI: 2.74, 6.50, P < 0:00001; SOD: WMD= 5:42, 95% CI: 2.92, 7.93, P < 0:0001; Table 2).

3.7. Assessment of Renal Pathology. Four studies [17, 24, 27,35] for inflammatory cells, two studies [17, 27] for necrotictubules, two studies [17, 27] for regenerative tubules, andthree studies [17, 27, 35] for renal interstitial fibrosis wereincluded in this meta-analysis. The results indicate that thedifference in inflammatory cells, necrotic tubules,

Random sequence generation (selection bias)

Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)

Blinding of outcome assessment (detection bias)

Other bias

Selective reporting (reporting bias)

Incomplete outcome data (attrition bias)

100%75%50%25%0%

Low risk of bias

Unclear risk of bias

High risk of bias

(b)

Figure 2: (a) Aggregate Risk of bias graph for each experimental animal studies; “?”: Unclear risk; “+”: Low risk. (b) Risk of bias summary.


MSC ControlMean SD Total Mean SD Total WeightStudy or subgroup

Mean differenceIV, random, 95% CI


1.1.1 2-dayKim 2012Sun 2008Sun 2019Subtotal (95% CI)

1.2 0.25 10 2.2 0.19 7 2.2% –1.00 [–1.21, –0.79]–1.35 [–1.99, –0.71]–0.47 [–0.71, –0.23]–0.88 [–1.34, –0.42]

–0.20 [–1.20, –0.19]–0.00 [–0.10, –0.10]–0.01 [–0.30, –0.28]–0.14 [–0.61, –0.33]–0.09 [–0.25, –0.06]

–0.90 [–1.00, –0.80]–0.30 [–0.55, –0.05]–0.47 [–1.00, –0.06]–0.92 [–1.48, –0.36]–0.78 [–1.04, –0.52]–0.95 [–1.09, –0.81]–0.74 [–0.95, –0.54]

–0.21[–0.29, –0.13]–0.30 [–0.42, –0.18]–0.75 [–0.99, –0.51]–0.14 [–0.55, –0.27]–0.83 [–1.58, –0.08]–0.83 [–1.14, –0.52]–0.46 [–0.67, –0.25]

–0.04 [–0.08, 0.00]–0.28 [–0.36, –0.20]–0.76 [–0.87, –0.65]–0.89 [–1.04, –0.74]

–0.62 [–0.80, –0.44]–0.91 [–1.42, –0.40]–0.55 [–0.84, –0.26]

–0.27 [–0.41, –0.13]–0.20 [–0.33, –0.07]–0.65 [–0.89, –0.41]–0.31 [–0.62, –0.00]–0.42 [–2.04, –0.80]–1.05 [–1.24, –0.86]

–0.12 [–0.19, –0.05]

–0.37 [–0.53, –0.20]

–0.20 [–0.27, –0.13]–0.23 [–0.49, –0.03]–1.38 [–1.44, –1.31]–0.09 [–0.17, –0.01]–0.88 [–1.34, –0.42]–0.53 [–1.04, –0.02]

–0.35 [–0.62, –0.08]

–2.13 [–2.77, –1.49]

–0.13 [–0.56, –0.30]–0.20 [–0.27, –0.13]–0.22 [–0.39, –0.06]

–2 –1 1 20

–0.47 [–0.56, –0.38]

–0.03 [–0.09, 0.03]

0.01 [–0.04, 0.06]

–0.26 [–0.46, –0.06]–0.70 [–0.97, –0.43]

–0.14 [–0.61, 0.33]

–0.22 [–0.56, 0.13]

–0.26 [–0.36, –0.16]0.00 [–0.05, 0.05]

–0.47 [–0.99, 0.05]

2.39 0.43 56

3.742.19 0.25

0.59 56

18

1.1%2.1%5.3%

1.1.2 3-day

1.1.3 4-day

Bi 2007Bruno 2009Herrera 2004Vazquez-Zapien 2019Subtotal (95% CI)

1.72 0.1721

0.110.11 0.110.01 0.016

10121947

610121947

0.310.7

1.031.76

0.35 0.370.730.74

0.71.021.62

2.5%2.4%2.0%1.5%8.3%

Elhusseini 2016Foroutan 2020Mata-Miranda 2019Moustafa 2016Sun 2008Sun B 2019Subtotal (95% CI)

1.1.4 5-dayBruno 2009Eliopoulos 2010Herrera 2004Minocha 2019Putra 2019Qian 2008Subtotal (95% CI)

1.1.5 6-8 dayBi 2007Bruno 2009Elhusseini 2016

Elhusseini 2016

Elhusseini 2016

Anan 2016Cetinkaya 2019

Cetinkaya 2019Danjuma 2018Gad 2017Magnasco 2008Sarhan 2014

Selim 2019

Herrera 2004Mata-Miranda 2019Minocha 2019Moustafa 2016Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

Subtotal (95% CI)

1.1.6 10-15 days

1.1.7 28-30 days

1.1.8 >= 42 days

Bruno 2009Elbaghdady 2018

Herrera 2004Minocha 2019Moustafa 2016

Moustafa 2016

Putra 2019Rashed 2018Vazquez-Zapien 2019Zhang 2020

Zhang 2020

Zhang 2020

Zickri 2012

Zickri 2012

1.02

0.33

0.09 0.01 0.130.451.611.081.621.421.73 0.52

0.110.830.260.06

0.05 2.4%2.4%2.4%2.3%

2.2%1.3%

1.4%14.5%

0.1685

1210

35

49

685

1210

35

49

0.050.11

0.110.110.25

0.06

0.170.850.191.15

0.821.8

0.2 0.2 0.04 2.4%2.4%2.3%2.3%2.1%1.9%1.1%

1.5%

1.8%2.4%

22.4%

2.2%

0.130.140.210.120.290.670.290.73

0.10.31

610

512

355

95

10

89

19

610

512

355

95

10

89

19

1

0.7

0.8 0.22 5 1.5 0.220.170.040.24

0.110.49

0.107

0.790.760.79

0.712.115

1.642

555

9

6

942

379 375 100.0%

40

8

11

46

8

85

9

4

4

5

10

44

5 2.0%

2.0%

2.2%2.4%

2.4%

2.4%

2.4%

2.4%11.9%

2.0%

1.1%

1.6%

1.5%15.0%

2.4%

655

95

10

45

0.160.070.17

0.050.18

0.023

0.530.560.560.74

0.76

0.440.741.020.320.820.62

0.29 0.79 0.170.060.850.02

0.10.55

0.773.15.0.310.950.82

0.020.370.050.330.03

0.62

0.80.2

0.10.6

0.660.040.09 0.92

0.970.351.650.982.221.651.760.691.03

0.090.18

0.24

0.740.050.24

0.080.15

0.67

1.620.57

0.814

0.07 0.541.06

1.83

1.03

0.09 2.4%2.4%2.1%1.6%0.9%1.9%

11.3%

0.41

0.720.23

0.2

0.22.552.39

0.110.08

0.30.470.15

0.760.282.411.56

1

81512

46

3

35

81512

46

3

35

1.251.860.980.960.61

0.110.130.53

0.250.08

0.29

56

10 10

10

55

4110

55

41

1.921.552.33

1.91.741.56

0.040.280.680.570.170.21

56

2.4%2.1%1.3%1.3%2.0%2.3%

11.3%

Favours MSC Favours control

Figure 3: Effect of MSC on Scr.


regenerative tubules, and renal interstitial fibrosis betweenthe MSC treatment and control groups was significant(inflammatory cells: WMD= −2:66, 95% CI: -3.83, -1.49, P< 0:00001; necrotic tubules: WMD= −2:58, 95% CI: -4.75,-0.40, P = 0:02; regenerative tubules: WMD= 6:00, 95% CI:3.45, 8.55, P < 0:00001; renal interstitial fibrosis: WMD= −5:82, 95% CI: -7.41, -4.23, P < 0:00001; Table 2).

3.8. Publication Bias. Publication bias was tested in this meta-analysis, and a funnel plot generated using STATA 12.0 forthe primary outcome. Begg’s test and Egger’s test results sug-gest that publication bias was present (P ≤ 0:01 and P ≤ 0:01,respectively; Figure 5).

4. Discussion

We reviewed all the selected studies and evaluated the Scr,BUN, UAE, oxidative stress, and renal pathology results toassess the nephroprotective effect of MSCs in the treatmentof kidney disease induced by toxicants. We found that MSCtreatment reduced Scr levels at 2, 4, 5, 6-8, 10-15, 28-30,and ≥42 days and reduced BUN levels at 2-3, 4-5, 6-8, and≥28 days. We also found that the MSC group had a lowerUAE than the control group. It has been previously shownthat MSC treatment reduces the levels of Scr, BUN, and pro-teinuria in lupus nephritis in mice [38]. Chen et al. [39]

found that MSC ameliorates ischemia/reperfusion injury-induced acute kidney injury in rats and reduces Scr levels.Xiu et al. [40] found that MSC transplantation significantlyreduces the concentration of BUN and Scr, prevents tissueinjury, and reduces mortality after lipopolysaccharide-induced acute kidney injury. Clinical trials also supportedthat MSC injection decreases rejection after transplantation.Tan et al. [41] found that the therapy with MSCs achieve bet-ter renal function and lower incidence of acute rejection at 1year compared with the anti-IL-2 receptor antibody induc-tion. Vanikar et al. [42] demonstrated that infusion of MSCsas well as hematopoietic stem cells eases immunosuppressionin living donor renal transplantation. Our previous meta-analysis also found that MSCs reduce Scr levels, BUN levels,and proteinuria, as well as alleviate renal damage in animalmodels of AKI [43]. Lower proteinuria was also found inpatients with SLE after MSC therapy [44].

The MSC treatment group had a higher level of GSH,SOD, and a lower level of MDA when compared with thecontrol group. El-Metwaly et al. [45] found that MSCsincrease GSH levels and reduce MDA levels in lung tissueof rats subjected to acute lung injury. Li et al. [46] reportedthat MSCs can restore the levels of GSH and MDA in ratswith chronic alcoholism, and its effects on repairing sciaticnerve were obvious. Liu et al. [47] reported that MSCssignificantly increase the activity of glutathione (GSH) and

Table 2: Meta-analysis of the efficacy of MSC in therapy of renal injury induced by toxicant.

Indicators Time pointStudies Q test Model OR/WMD Pnumber P value selected (95% CI)

Scr

2 days 3 0.001 Random -0.88 (-1.34, -0.42) 0.0002

3 days 4 0.0004 Random -0.09 (-0.25, 0.06) 0.24

4 days 6 0.0002 Random -0.74 (-0.95, -0.54) <0.000015 days 6 <0.00001 Random -0.46 (-0.67, -0.25) <0.00016-8 days 7 <0.00001 Random -0.55 (-0.84, -0.26) 0.0002

10-15 days 11 <0.00001 Random -0.37 (-0.53, -0.20) <0.000128-30 days 7 <0.00001 Random -0.53 (-1.04, -0.02) 0.04

≥42 days 6 <0.00001 Random -0.22 (-0.39, -0.06) 0.007

BUN

2-3 days 6 <0.00001 Random -25.08 (-37.49, -12.67) <0.00014-5 days 8 <0.00001 Random -45.71 (-59.36, -32.05) <0.000016-8 days 5 <0.00001 Random -57.55 (-99.19, -15.91) 0.007

13-15 days 4 <0.00001 Random -13.40 (-32.34, 5.54) 0.17

≥28 days 8 <0.00001 Random -23.39 (-36.39, -10.40) 0.0004

UAE — 3 0.72 Fixed -22.66 (-26.41, -18.90) <0.00001MDA — 4 0.41 Fixed -17.21 (-20.38, -14.04) <0.00001GSH — 4 <0.00001 Random 4.62 (2.74, 6.50) <0.00001SOD — 3 <0.00001 Random 5.42 (2.92, 7.93) <0.0001Renal pathology

Inflammatory cells — 4 <0.00001 Random -2.66 (-3.83, -1.49) <0.00001Necrotic tubule — 2 <0.00001 Random -2.58 (-4.75, -0.40) 0.02

Regenerative tubules — 2 — Fixed 6.00 (3.45, 8.55) <0.00001Renal interstitial fibrosis — 3 <0.00001 Random -5.82 (-7.41, -4.23) <0.00001

Note: Scr: serum creatinine; BUN: blood urea nitrogen; UAE: urinary albumin excretion; Ccr: creatinine clearance rate; MDA: malondialdehyde; GSH: L-glutathione; SOD: superoxide dismutase.


reduce the levels of MDA in rats induced by unilateralureteral obstruction.

The mechanism by which MSCs repair injured kidneysmay be complex. After kidney injury, VCAM-1, GFP, SDF-1/CXCR4, and CD44 are upregulated in the injured tissue,which may play important roles in the migration of MSCs

to the damaged area. These substances may be partly secretedby the MSCs themselves [20, 48, 49]. The presence of MSCsmay limit the injury and repair the ischemic tubular damageto maintain the glomerular filtration rate and downregulateBUN [50]. In addition, MSCs lower the expression of severalproinflammatory cytokines such as TNF-α, IL-1β, and IFN-γ

MSC ControlMean SD Total Mean SD Total WeightStudy or subgroup



2.1.1 2-3 day

2.1.2 4-5 day

Kim 2012Sun 2008Sun 2019

Sun 2008Sun 2019

Subtotal (95% CI)

Subtotal (95% CI)

2.5

Heterogeneity: Tau2 = 214.65; Chi2 = 80.05, df = 5 (P < 0.00001); I2 = 94%Test for overall effect: Z = 3.96 (P < 0.0001)



Heterogeneity: Tau2 = 358.68; Chi2 = 414.98, df = 3 (P < 0.00001); I2 = 99%Test for overall effect: Z = 1.39 (P = 0.17)

Bi 2007Bruno 2009

Bruno 2009

Bruno 2009

Bruno 2009

Vazquez-Zapien 2019

6

6

6

6 6

1010

1013

19 1947

Elhusseini 2016

Foroutan 2020

Subtotal (95% CI)

Subtotal (95% CI)

Heterogeneity: Tau2 = 238.23; Chi2 = 2384.21, df = 30 (P < 0.00001); I2 = 99%

Test for subgroup differences: Chi2 = 11.26, df = 4 (P = 0.02); I2 = 64.5%Test for overall effect: Z = 11.01 (P < 0.00001)


Subtotal (95% CI)

Total (95% CI)

Eliopoulos 2010

Minocha 2019

Elhusseini 2016Eliopoulos 2010

Eliopoulos 2010

Minocha 2019

Putra 2019

Putra 2019

40149.32

75149.32 14.32

18.2814.32

12.19

13264 16.79421 36

16

56 53

44

40.8 502.16

5 57

3.4%

3.4%

3.7%

3.7%

3.7%3.6%

3.2%

3.2%

3.2%3.8%

3.8%

2.9%

2.9%

26.8%

2.3%

–15.00 [–19.96, –10.04]–31.00 [–36.77, –25.23]

–25.08 [–37.49, –12.67]–9.20 [–14.77, –3.63]

–35.00 [–45.59, –24.41]0.00 [–12.55, 12.55]

–68.00 [–85.08, –50.92]

20.5%

–45.71[–59.36, –32.05]

–92.20 [–109.12, –75.28]–168.90 [–179.07,–158.73]

–55.50 [–67.92, –43.08]–10.00 [–14.40, –5.60]

–6.68 [–30.83, 17.47]–19.74 [–21.21, –18.28]

–7.00 [–10.16,–3.84]–10.80 [–11.96, –9.64]

–31.25 [–38.46, –24.04]

–57.55[–99.19, –15.91]–53.33 [–72.80, –33.86]

0.06 [–4.71, 4.83]–152.30 [–168.52, –136.08]

–53.17 [–68.50, –37.84]

–13.40[–32.34, 5.54]

–20.45 [–34.43, –6.47]8.43 [5.90, 10.96]

–20.77 [–22.03, –19.50]–21.83 [–28.19, –15.47]

–23.39[–36.39, –10.40]

–33.05[–38.93, –27.17]

–23.92 [–26.46, –21.38]–100.28 [–195.09, –5.47]

6.00 [–14.46, 26.46]–34.18 [–45.97, –22.39]–43.12 [–53.98, –32.26]

–2.18 [–3.62, –0.74]–28.44 [–46.44, –10.44]

–27.00 [–46.68, –7.32]

2.1.3 6-8 days

2.1.4 13-15 days

2.1.5 >=28 days

Bi 2007 52.540.976.4

28.8678.66

5

512.27

4.38.88

1437

15

68

3

83.7594.07228.7

131.9928.8

7.518.41

18

104.05

685

253

47

3.6%

3.7%2.7%

15.9%

3.0%2.9%

Rashed 2018

32.7231.08

1062.23

6.142.23

1.23.9

615

51036

53.17 16.3622.65

30.76984.06

5.770.8

9.49

625

51046

3.1%3.8%3.8%3.6%

14.3%

52.897.882.5

23.33

266.7

133.32 13.3314.102

1010

20

8

14 1457.6718.6

18.8

8.7

3.89 3.8916.67

1.32 1.03

1.3833.33

33.8463

0.5

85

55

57

15 16

171.8

63

10

85

55

57

1563140

2

Anan 2016Cetinkaya 2019Danjuma 2018Elhusseini 2016Gad 2017Magnasco 2008Sarhan 2014Selim 2019

Favours MSC Favours control

–100 –50 100500

100.0%254238

3336.14

28.468.3422.93

48160.954.16

15.8819.95

1.16

1.08

4.62.88

1684.08

55

54

84

111052

6064.5830.58

57.11111.46

42261.18

78.08

15.885.32

0.911.5

16.7715

116.523.96

5645858

1051

2.7%2.8%3.8%3.4%3.3%2.6%0.3%3.8%

22.6%

Figure 4: Effect of MSC on BUN.


as well as increase anti-inflammatory cytokines such as IL-1,IL-10, Bcl-2, TNF-α, bFGF, and prostaglandin E2 [49, 51].Another possibility is that MSCs may restore damaged cellsand prevent apoptosis by secreting microvesicles, which con-tain microRNAs, mRNAs, or proteins [49]. To conclude,MSCs can migrate to the damaged tissue, promote the recov-ery of renal function, enhance proliferation, and reducefibrosis and inflammation.

Furthermore, our study indicates that MSC treatmentcan alleviate inflammatory cells, necrotic tubules, regenera-tive tubules, and renal interstitial fibrosis in kidney diseaseinduced by toxicants. Some previous studies indicated thatMSC treatment can alleviate renal pathological changes inunilateral ureteral obstruction rat or mice [9, 10, 52].

However, this meta-analysis also has some limitations.First, a small sample size was found for the recruited studies.The administered dose and the type of MSCs were not exactlythe same. Publication bias was found in this meta-analysis,and the results should be reassessed in the future. Further-more, the studies frequently had different animal models(mouse or rat), toxin doses, and administration routes forrenal injury. These limitations may affect the robustness ofour results.

5. Conclusions

TheMSC treatment reduced Scr levels after 2, 4, 5, 6-8, 10-15,28-30, and ≥42 days and reduced BUN levels after 2-3, 4-5, 6-8, and ≥28 days. The results also indicate that MSC treatmentalleviated the inflammatory cells, necrotic tubules, regenera-tive tubules, and renal interstitial fibrosis in kidney diseaseinduced by toxicants.

Abbreviations

MSCs: Mesenchymal stem cellsScr: Serum creatinineBUN: Blood urea nitrogen

UAE: Urinary albumin excretionMDA: MalondialdehydeGSH: L-glutathioneSOD: Superoxide dismutaseWMDs: Weighted mean differencesCI: Confidence intervalsM-H: Mantel-Haenszel.

Data Availability

The data supporting this meta-analysis are from previouslyreported studies and datasets, which have been cited. Theprocessed data are available from the corresponding authorupon request.

Consent

There are no human subjects in this article and informedconsent is not applicable.

Conflicts of Interest

The authors declare that they have no competing interests.

Authors’ Contributions

TBZ contributed to the conception and design of the study.TBZ and SJL were responsible for collection of data and per-forming the statistical analysis and manuscript preparation.WSL and CLL were responsible for checking the data. Allauthors were responsible for drafting the manuscript, read,and approved the final version.

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