Nephroprotective Effect of Mesenchymal Stem Cells in Therapy of Kidney Disease Induced by Toxicant

Background: Renal damage caused by drug toxicity is becoming more and more common in clinic. How to avoid and treat kidney damage caused by drug toxicity is essential to maintain patient health and reduce social economic burden. In this study, we performed a meta-analysis to assess the nephroprotective effect of mesenchymal stem cells (MSCs) in therapy of kidney disease induced by toxicant. Methods: Cochrane Library, Embase, ISI Web of Science and PubMed databases were searched up to Dec 31, 2019 to identify the studies and extract the data to assess the ecacy of MSCs for kidney disease induced by toxicant using Cochrane Review Manager Version 5.3. 27 studies were eligible and recruited for this meta-analysis. Results: The results showed that the difference of Scr between MSCs treatment group and control group was notable for 2 days, 4 days, 5 days, 6-8 days, 10-15 days, ≥ 42 days (2 days: WMD =-0.88, 95%CI: -1.34, -0.42, P=0.0002; 4 days: WMD=-0.69, 95%CI: -0.99, -0.39, P<0.00001; 5 days: WMD=-0.46, 95%CI: -0.67, -0.25, P<0.0001; 6-8 days: WMD=-0.51, 95%CI: -0.79, -0.22, P=0.0005; 10-15 days: WMD =-0.38, 95%CI: -0.56, -0.20, P<0.0001; ≥ 42 days: WMD =-0.22, 95%CI: -0.39, -0.06, P=0.007). Furthermore, the difference of BUN between MSCs treatment group and control group was notable for 2-3 days, 4-5 days, 6-8 days, ≥ 28 days. The results also indicated that MSCs treatment can alleviate the inammatory cells, necrotic tubule, regenerative tubules, renal interstitial brosis in kidney disease induced by toxicant. Conclusion: MSCs might be a promising therapeutic agent for kidney disease induced by


Introduction
Kidney injury includes acute kidney injury and chronic kidney disease and it is a common condition to be associated with the morbidity and mortality of patients. When the acute kidney injury is not alleviated in time, it will develop into chronic kidney disease. Toxicant-induced kidney injury is one of the most common causes for kidney disease, and it also causes substantial morbidity and retards drug development 1 . At present, renal damage caused by drug toxicity is becoming more and more common in clinic. How to avoid and treat kidney damage caused by drug toxicity is essential to maintain patient health and reduce social economic burden.
Mesenchymal stem cells (MSCs), being pluripotent mesenchymal cells present in various tissues with self-regeneration, have multilineage differentiation ability under an appropriate environment, and are easy to obtain; therefore, they are a promising therapeutic option for some diseases due to their unique properties of releasing some important bioactive factors [2][3][4] . Drug toxicity results in renal tubular epithelial cell damage or death, and can lead to renal interstitial in ammation which develops into renal interstitial brosis and renal loss. In previous, some studies found that MSCs can play a protective role against the injury of renal tubular epithelial cell and prevent the renal interstitial brosis [5][6][7][8][9] . In this study, we performed a meta-analysis to assess the nephroprotective effect of MSCs in therapy of kidney

Inclusion And Exclusion Criteria
Inclusion criteria: Our meta-analysis includes studies analyzing the e cacy of MSCs treatment on the mice or rat with kidney disease.

Exclusion criteria
(1) letters, case reports, reviews, clinical studies, editorials, meta-analysis and systematic reviews; (2) studies lacked the targeted indicators or number of case group or control group, and were conducted in humans; (3) the kidney disease was not induced by toxicant, and (4) the therapeutic regimen for kidney disease including other agents with unde ned effects.

Outcome Measures
We lter the following outcomes associated with the e cacy of MSCs treatment from the recruited studies: serum creatinine (Scr), blood urea nitrogen (BUN), urinary albumin excretion (UAE), malondialdehyde (MDA), L-Glutathione (GSH), CAT, superoxide dismutase (SOD), and renal pathology. Also, we conducted a mutual consensus when met with disagreements.

Quality Assessment
Two investigators evaluate the methodological quality with The Cochrane Handbook for Interventions independently. We assessed the following sections of every investigation: selection bias, attrition bias, performance bias, detection bias, reporting bias, and other bias. Each item was classi ed as unclear, high risk or low risk.

Statistical analysis
Review Manager Version 5.3 was applied to explore whether MSCs treatment can acquire a good e cacy on kidney disease induced by toxicant and STATA 12.0 were used to test the publication bias.
Heterogeneity of variation among individual studies was quanti ed and described with the I 2 . The xed effect model was used if the p-value of the the heterogeneity test was ≥ 0.1. Otherwise, the random effects model will be applied to pool the outcomes. Besides, to compute the continuous variables, we analyze weighted mean differences (WMDs) for the mean values. We also calculated 95% con dence intervals (95% CI) for the included studies using the Mantel-Haenszel (M-H) method. Additionally, we evaluate the publication bias with Begg's rank correlation test as well as Egger's linear regression method among the studies. A p-value < 0.05 was considered as statistical signi cance.

Search results
The databases mentioned above were searched for this meta-analysis, and we only recruited these studies in mice or rat for evaluation of therapeutic e ciency of MSCs treatment on kidney disease induced by toxicant. Twenty studies  were eligible and recruited for this meta-analysis, and the owchart of inclusion of studies is presented in Fig. 1. The included study characteristics are shown in Table 1. In the recruited studies, the methodological quality was considered as acceptable, for the result that most of the domains of the recruited investigations were ranked as unclear risk of bias or low risk of bias. Unclear risk of bias mostly detected in performance bias and selection bias. Low risk of bias was mostly occurred in detection bias, reporting bias, and attrition bias. Figure 2 showed the summary of the risk of biases of the recruited investigations.  Table 2).
However, the difference between MSCs treatment group and control group was not notable for 3 days and  Table 2).  Fig. 4 and Table 2). However, the difference between MSCs treatment group and control group was not notable for 13-15 days (WMD=-13.40, 95%CI: -32.34, 5.54, P = 0.17; Fig. 4 and Table 2).

Urinary Albumin Excretion
Three studies 21,25,26 were recruited into the meta-analysis for the assessment of MSCs on UAE. The results showed that the MSCs group had lower UAE than the control group (WMD=-22.66, 95%CI: -26.41, -18.90, P < 0.00001; Table 2).

Oxidative Stress
In this meta-analysis, four studies 16,18,22,26 were included for the assessment of MDA, four 16 Table 2).

Assessment Of Renal Pathology
Four studies 16,23,26,34 for in ammatory cells, two studies 16,26 for necrotic tubule, two studies 16, 26 for regenerative tubules and three studies 16,26,34 for renal interstitial brosis were included into this metaanalysis. The results indicated that the difference of in ammatory cells, necrotic tubule, regenerative tubules, renal interstitial brosis between MSCs treatment and control group was signi cant  Table 2).

Publication bias
The publication bias was tested in this meta-analysis, and a funnel plot generated used STATA 12.0 for the primary outcome, and Begg'stest and Egger's test suggested that publication bias was found (Egger's: P = 0.000, Begg's: P = 0.000; Fig. 5).

Discussion
We reviewed all the included studies and included the various of Scr, BUN, urinary albumin excretion, oxidative stress, renal pathology to assess the nephroprotective effect of MSCs in therapy of kidney disease induced by toxicant. We found that MSCs treatment can reduce the Scr levels at 2 days, 4 days, 5 days, 6-8 days, 10-15 days, ≥ 42 days in animal models of kidney disease induced by toxicant. Furthermore, MSCs treatment also can reduce the levels of BUN at 2-3 days, 4-5 days, 6-8 days, ≥ 28 days. We also found that MSCs group had lower UAE than the control group. In previous, MSCs treatment can reduce the levels of Scr, BUN, proteinuria in lupus nephritis in mice 37  Furthermore, our study indicated that the MSCs treatment can alleviate the in ammatory cells, necrotic tubule, regenerative tubules, renal interstitial brosis in kidney disease induced by toxicant. In previous, there were some studies indicated that MSCs treatment can alleviate the renal pathological changes in unilateral ureteral obstruction rat or mice 8,9,43 .
However, some limitations were also found in this meta-analysis. First, the small sample size was found for the recruited studies. The dose of MSCs administered and the type of MSCs were not exactly same. Publication bias was found in this meta-analysis, and the results should be re-assessed in the future.
Furthermore, there were different animal types (mouse and rat). These limitations mentioned above may affect the robust of our results.

Conclusions
The

Declarations Ethical Approval
Ethical Approval is not applicable to this study.

Statement of Human and Animal Rights
This article does not contain any studies with human or animal subjects.

Statement of Informed Consent
There are no human subjects in this article and informed consent is not applicable.

Funding
This study was supported by Guangdong Medical Science and Technology Research Fund Project (no. A2018336).

Availability of data and materials
Not applicable.
Authors' contributions TBZ contributed to the conception and design of the study. TBZ and SJL were responsible for collection of data and performing the statistical analysis and manuscript preparation. WSL and CLL were responsible for checking the data. All authors were responsible for drafting the manuscript, read and approved the nal version.
Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.
43. Wang Z, Li S, Wang Y, Zhang X, Chen L, Sun D. GDNF enhances the anti-in ammatory effect of human adipose-derived mesenchymal stem cell-based therapy in renal interstitial brosis. Stem cell research. 2019;41:101605. Figure 1 Flow diagram of the selection process.    Publication bias.