Efficacy of Vitamin D3 in Patients With Diabetic Nephropathy: An Updated Meta-Analysis

AUTHORS

Min Zhang 1 , Tiejun Liu 1 , Wenge Li 2 , Weijun Gong 1 , Xusheng Yang 1 , Jianing Xi 1 , *

1 Department of Nephrology, Beijing Rehabilitation Hospital of Capital Medical University, Beijing, P.R. China

2 Department of Nephrology, China-Japan Friendship Hospital, Beijing, P.R. China

How to Cite: Zhang M, Liu T, Li W, Gong W, Yang X, et al. Efficacy of Vitamin D3 in Patients With Diabetic Nephropathy: An Updated Meta-Analysis, Iran Red Crescent Med J. 2017 ; 19(12):e64275. doi: 10.5812/ircmj.64275.

ARTICLE INFORMATION

Iranian Red Crescent Medical Journal: 19 (12); e64275
Published Online: December 2, 2017
Article Type: Review Article
Received: December 14, 2016
Revised: February 16, 2017
Accepted: July 8, 2017
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Abstract

Context: Diabetic nephropathy is a common complication of diabetes mellitus with a higher incidence. Renin-angiotensin system blockers, as the main treatment for patients with diabetic kidney disease, can not only reduce albuminuria, but also lead to hyperkalaemia and creatinine. Therefore, additional protective therapeutic interventions are needed.

Evidence Acquisition: An electronic literature search was conducted in international and domestic databases including PubMed, Embase, CNKI, Scopus, Index Copernicus, DOAJ, and Wanfang database for trials up to January 2017. The search terms used were as follow: "Diabetic Nephropathies", "vitamin D3", "Cholecalciferol", "Calcitriol", "Alfacalcidol", "Paricalcitol", and "Randomized Controlled Trial". Quality assessments were evaluated with the Newcastle-Ottawa Quality Assessment Scale. Data were extracted by 2 independent reviewers (TJL and WGL). For all analysis, the standard mean difference (SMD) or odds ratio (OR) with 95% confidence intervals (CIs) were calculated, and heterogeneity of the studies was analyzed using I2 statistics.

Results: Twenty-four studies were (1,978 patients) identified in the literature retrieve process. The assessment scores indicated that all the admitted studies were reliable with scores ranging from 6 to 9. The pooled results indicated that vitamin D3 had a significant effect in reducing albuminuria (MD = -0.23, 95% CI: -0.30, -0.15) and that the vitamin D3 group had a low ratio of urinary microalbumin to creatinine than the control group (SMD = -0.49, 95% CI: -0.90, -0.08). The results also revealed that vitamin D3 group had a lower hs-CRP than the control group (MD = -0.80, 95% CI: -1.26, -0.34).

Conclusions: Based on the evidence of this study, vitamin D3 could be suggested as a recommended drug for patients with diabetic nephropathy in clinical practice.

Keywords

Vitamin D3 Meta-Analysis Urinary Albumin/Creatinine Ratio

Copyright © 2017, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

1. Context

Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM), usually accounting for chronic renal failure in many countries (1). The prevalence of diabetic kidney disease is 30% among patients with type I DM, and about 20% to 50% of type II DM patients would probably be accompanied with renal lesions (2). Although it has been suggested that abnormalities of renal hemodynamics, hyperglycemia-induced metabolic disorders, and the imbalance of vasoactive substances may be involved in the development of diabetic kidney disease, the mechanism responsible for diabetic nephropathy remains incomplete, and thus the corresponding optimal therapy is undecided (3).

Multiple agents have been used to delay the progression of diabetic nephropathy including beta-blockers, calcium channel blockers, diuretics, angiotensin converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARB). In accordance with several large-scale randomized controlled trials (RCTs), ACEI and ARB have been proposed as the first line agents for treating diabetic nephropathy because of their role in reducing proteinuria (4). However, these agents also contribute to elevated levels of hyperkalaemia and creatinine, finally limiting their actions to improve kidney function (5). Therefore, additional interventions that are against diabetic nephropathy are needed.

Vitamin D3 belongs to fat-soluble secosteroids, and its major activating mode is shown as 1,25(OH)2D3, whose activity is mediated by vitamin D receptor (VDR). Moreover, 1,25(OH)2D3-VDR has manifold physiological and pathological functions including regulation of mineral metabolism, renal function, and cardiovascular function (6). Importantly, Mattila et al. found that high vitamin D level could significantly lower the risk of DM, and Gursoy et al. also reported that vitamin D deficiency was related to development of DN (7, 8). Therefore, the above contents provide solid evidence that vitamin D might serve as a novel breakout for preventing and treating DN.

Nonetheless, the results of interventional experiments exploring the efficacy of vitamin D on DN are controversial and the renoprotective effects of vitamin D have not yet been clinically demonstrated. Therefore, this study aimed at prospectively evaluating the efficacy and safety of vitamin D and their analogues including calcitriol, alfacalcidol, and paricalcitol for DN patients.

2. Evidence Acquisition

2.1. Search Strategy

Electronic databases (PubMed, Embase, Scopus, Index Copernicus, DOAJ, CNKI, and Wanfang) were searched, and randomized clinical trials that investigated vitamin D3 for DN patients and published before January 2017 were included in this study. The search terms used were as follow: "Diabetic Nephropathies", "vitamin D3", "Cholecalciferol", "Calcitriol", "Alfacalcidol", "Paricalcitol", and "Randomized Controlled Trial". Additional related studies were added manually after checking the reference lists of all qualified publications including relevant meta-analyses and systematic reviews.

2.2. Inclusion and Exclusion Criteria

Trials had to meet the following criteria: (i) the DN patients had to be 18 years or older; being diagnosed with DN within a minimum of 4 weeks; (ii) the interventions in the studies had to include vitamin D3 or its analogs; (iii) estimated glomerular filtration rate (eGFR) had to be > 20 mL/min per 1.73 m2 or serum creatinine as < 3 mg/dL; and (iv) microalbuminuria, or macroalbuminuria (urinary albumin/creatinine ratio (UACR) > 3 mg/mmol, or UAER > 0.2 mg/min) had to be confirmed. Major exclusion criteria were as follow: (i) animal experiments and cell-line studies; (ii) editorial, commentaries, review articles and case reports; (iii) studies without relevant or sufficient data.

2.3. Outcomes and Data Extraction

The primary clinical outcomes included 24-hour proteinuria and urinary albumin-creatinine ratio (UACR), while the secondary measures were related to high sensitivity C reactive protein (hs-CRP), glycosylated hemoglobin (HbA1c), serum calcium, and serum creatinine. Safety outcomes were presented as adverse events. Two reviewers extracted the data from eligible studies independently. If some discrepancies were present, then, the third reviewer resolved the disagreements. The extracted information mainly included baseline characteristics (including age, type of diabetes, and concomitant drug), type of interventions (including type and dose of vitamin D3 and therapy duration), and outcome measures.

2.4. Quality Assessment

Quality assessment was independently performed by 2 reviewers using Newcastle-Ottawa quality assessment scale, which consists of 9 questions in 3 sections (selection, comparability, and exposure section). The quality of the studies was evaluated by examining 9 questions and each question had to be answered with “yes”, “no”, or “unclear”. An answer of “yes” got the score of 1, indicating a low risk of bias, whereas an answer of “no” or “unclear” gained a score of “0”, suggesting a high risk of bias may exist.

2.5. Statistical Analysis

This meta-analysis was conducted to perform direct comparisons between the intervention and placebo. Interstudy heterogeneity was evaluated by the I2 test when I2 > 50% random effect model was used, otherwise, fixed-effects model was adopted. The dichotomous variables were evaluated by mean difference (MD) or standard mean difference (SMD), with 95% confidential interval (CI). Continuous variables were assessed by odds ratio (OR), with 95% confidential interval. Subgroup analysis by intervention (whether ACEI/ARB was used or not) was performed. Sensitivity analysis was performed to find the source of heterogeneity and evaluate whether the results could be significantly affected. All the analyses were conducted by R 3.2.3 software.

3. Results

The retrieved literature included 158 citations, 83 of which were excluded after reviewing their titles and abstracts. A total of 75 articles were available for the process of full text screening and 24 studies were finally identified for this meta-analysis after considering the inclusion and exclusion criteria (Figure 1) (9-31). These eligible studies were published during 2010 and 2017 and focused on the efficacy of vitamin D3 or its analogues including alfacalcidol, calcitriol, cholecalciferol, and paricalcitol for DN patients.

Table 1. The Main Characteristics of Included Studies
AuthorYearCountryDiseaseType of DiabeticConcomitant DrugPatientsAgePeriodNOS Score
Momeni2017IranDiabetic nephropathy + D deficient2Conventional therapy57NR8 weeks8
Shi2016ChinaDiabetic nephropathyNRConventional therapy12459.328 weeks9
Tiryaki2016TurkeyDiabetic nephropathy2Conventional therapy985124 weeks8
Munisamy2016MalaysiaDiabetic nephropathy2Conventional therapy6056.856 months7
Thethi2015USADiabetic nephropathy2Conventional therapy6062.53 months7
Joergensen2015DenmarkDiabetic nephropathy1RAAS-blocking treatment and diuretics455712 weeks8
Mustafar-a2014MalaysiaDiabetic nephropathy + D deficient2Conventional therapy3153.512 weeks7
Mustafar-b2014MalaysiaDiabetic nephropathy + D deficient2Conventional therapy3153.56 weeks7
Zhan2013ChinaDiabetic nephropathyNRConventional therapy6852.756 months7
Pang2013ChinaDiabetic nephropathyNRConventional therapy8052.052 months9
Ni2013ChinaDiabetic nephropathy2Oral hypoglycemic drugs/insulin6059.214 weeks7
Zhou2013ChinaDiabetic nephropathyNROral hypoglycemic drugs/insulin7245.626 months8
Zhou-a2013ChinaDiabetic nephropathy2Oral hypoglycemic drugs4252.133 months7
Zhou-b2013ChinaDiabetic nephropathy2Oral hypoglycemic drugs4252.133 months7
Ahmadi2013IranDiabetic nephropathy + D deficient2ACEI/ARB6057.712 weeks9
Guan2012ChinaDiabetic nephropathyNROral hypoglycemic drugs/insulin6553.96 months6
Zhu2012ChinaDiabetic nephropathy2Oral hypoglycemic drugs138573 months8
Shui2012ChinaDiabetic nephropathy2Oral hypoglycemic drugs + insulin3059.213 months7
Zhou2012ChinaDiabetic nephropathy2NR4050.1212 weeks7
Krairittichai2012ThailandDiabetic nephropathy + D deficient2Standard treatment9160.7516 weeks8
Huang2012ChinaDiabetic nephropathy2Conventional therapy4656.736 months7
Xu2011ChinaDiabetic nephropathy2Novolin 30R7050.812 weeks8
Ding2011ChinaDiabetic nephropathyNROral hypoglycemic drugs/insulin4652.046 months6
Lu2011ChinaDiabetic nephropathy2Insulin8250.512 weeks8
Xu2010ChinaDiabetic nephropathy2Insulin8050.6312 weeks7
de Zeeuw-a2010MultinationalDiabetic nephropathy2Conventional therapy18064.3324 weeks9
de Zeeuw-b2010MultinationalDiabetic nephropathy2Conventional therapy18064.3324 weeks9

Abbreviations: NR, none reported; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker

Table 2. The Intervention and Endpoint Information of Included Studies
Study IDTreatmentControlEndpoints
Momeni 2017CholecalciferolPlacebo24-hour proteinuria; HbA1c
Shi 2016CalcitriolPlaceboHbA1c
Tiryaki 2016CalcitriolPlaceboUACR
Munisamy 2016AlfacalcidolPlacebohs-CRP; serum calcium
Thethi 2015ParicalcitolPlacebo24-hour proteinuria; serum creatinine
Joergensen 2015ParicalcitolPlacebo24-hour proteinuria; adverse events
Mustafar-a 2014CalcitriolPlaceboUrine PCI; serum calcium; serum creatinine
Mustafar-b 2014CalcitriolPlaceboUrine PCI; serum calcium; serum creatinine
Zhan 2013CalcitriolPlacebo24-hour proteinuria; hs-CRP; serum calcium; HbA1c
Pang 2013Calcitriol + TelmisartanTelmisartan24-hour proteinuria; serum calcium; HbA1c; Serum creatinine; adverse events
Ni 2013Calcitriol + FosinoprilFosinopril24-hour proteinuria; adverse events
Zhou 2013Calcitriol + IrbesartanIrbesartan24-hour proteinuria; serum calcium; HbA1c; adverse events
Zhou-a 2013CalcitriolPlacebohs-CRP; HbA1c
Zhou-b 2013Calcitriol + IrbesartanIrbesartanhs-CRP; HbA1c
Ahmadi 2013CholecalciferolPlaceboUACR; serum calcium; HbA1c; serum creatinine; adverse events
Guan 2012Calcitriol + TelmisartanTelmisartan24-hour proteinuria; serum calcium; HbA1c; serum creatinine; adverse events
Zhu 2012CalcitriolPlacebo24-hour proteinuria; hs-CRP; adverse events
Shui 2012Calcitriol + ValsartanValsartan24-hour proteinuria; adverse events
Zhou 2012Calcitriol + TelmisartanTelmisartanUAER; serum calcium; HbA1c; serum creatinine
Krairittichai 2012CalcitriolPlaceboUPCR; adverse events
Huang 2012CholecalciferolPlaceboSerum calcium; HbA1c
Xu 2011AlfacalcidolPlacebohs-CRP; serum creatinine; adverse events
Ding 2011CalcitriolPlacebo24-hour proteinuria; hs-CRP; serum calcium; HbA1c; serum creatinine; adverse events
Lu 2011Calcitriol + FosinoprilFosinopril24-hour proteinuria; adverse events
Xu 2010Alfacalcidol + BenazeprilBenazepril24-hour proteinuria; serum calcium; serum creatinine; adverse events
de Zeeuw-a 2010ParicalcitolPlacebo24-hour proteinuria; UACR; adverse events
de Zeeuw-b 2010ParicalcitolPlacebo24-hour proteinuria; UACR; adverse events

Abbreviations: UACR, urinary albumin-creatinine ratio; hs-CRP, high sensitivity C reactive protein; Urine PCI, urine protein creatinine index; HbA1c, glycosylated hemoglobin; UPCR, urine protein-creatinine index

As 3 studies had a multiple-group design, at last, 26 trials were collected; 15 trials were designed to compare vitamin D3 or its analogs with placebo, while the rest trials compared vitamin D3 or its analogues with ACEI/ARB and ACEI/ARB. Among the aggregate 1978 patients, 1478 (74.72%) were diagnosed with Type 2 diabetes with nephropathy, 45 (2.27%) were diagnosed with Type 1 diabetes, and the rest of 455 patients (23.00%) were not classified within DN. Besides, most patients continued conventional therapy after the intervention including insulin, ACEI/ARB, and oral hypoglycemic drugs. The design features of each trial, patients’ characteristics, and outcomes are summarized in Tables 1 and 2.

A total of 14 studies recorded the change of 24-hour proteinuria, and their results indicated that vitamin D3 has a significant effect on reducing albuminuria (MD = -0.23, 95% CI: -0.30, -0.15) (Figure 2). The subgroup analysis confirmed the efficacy of vitamin D3 when it was compared with placebo (MD = -0.15, 95% CI: -0.23, -0.06) or ACEI/ARB (MD = -0.49, 95% CI: -0.72, -0.26). Furthermore, the vitamin D3 group had a low ratio of urinary microalbumin to creatinine (ie, UACR) than the control group (SMD = -0.49, 95% CI: -0.90, -0.08) (Figure 3). Compared with ACEI/ARB, vitamin D3 had a better performance in lowering UACR (SMD = -1.86, 95% CI: -2.61, -1.10), while vitamin D3 tended to reduce UACR compared to placebo (SMD = -0.33, 95% CI: -0.70, 0.03). Of the trials, 7 had been involved in hs-CRP, showing that vitamin D3 group had a notably lower hs-CRP than the control group (MD = -0.80, 95% CI: -1.26, -0.34) (Figure 4). When compared with placebo, the subtotal results had a similar implication of vitamin D3’s effect (MD = -0.91, 95% CI: -1.15, -0.67), yet no significant difference was found in the comparison between vitamin D3 and ACEI/ARB.

In the 12 trials that studied serum calcium, vitamin D3 elevated serum calcium level in either the total results or the subtotal results compared with placebo (MD = 0.04, 95% CI: 0.01, 0.06; MD = 0.07, 95% CI: 0.01, 0.12). No difference was obtained between the serum calcium level in vitamin D3 group and ACEI/ARB group. Figure 6 demonstrates that there was no difference in the occurrence of adverse events between vitamin D3 group and ACEI/ARB group (OR = 1.06, 95% CI: 0.68, 1.64). Also, no significant difference was found in HbA1c and serum creatinine (supplementary file Appendix 1 and supplementary file Appendix 2).

Potential publication bias of the included studies was assessed by the funnel plot, revealing no statistical significance in the 6 outcomes (all p-values > 0.05) (Figure 7). Sensitive analysis indicated that the results would not be significantly affected after omitting each individual study (supplementary file Appendix 3).

Figure 2. Forest Plot of 24-Hour Proteinuria Change in Patients With Diabetic Nephropathy
Forest Plot of 24-Hour Proteinuria Change in Patients With Diabetic Nephropathy

The mean difference from each study is represented by square, and the confidence interval is indicated by error bars. The subtotal and overall odds ratio is signified by rhombus.

Figure 3. Forest Plot of Urinary Albumin-Creatinine Ratio Change in Patients With Diabetic Nephropathy
Forest Plot of Urinary Albumin-Creatinine Ratio Change in Patients With Diabetic Nephropathy

The standard mean difference from each study is represented by square, and the confidence interval is indicated by error bars. The subtotal and overall odds ratio is signified by rhombus.

Figure 4. Forest Plot of High Sensitivity Creactive Protein Change in Patients With Diabetic Nephropathy
Forest Plot of High Sensitivity Creactive Protein Change in Patients With Diabetic Nephropathy

The mean difference from each study is represented by square, and the confidence interval is indicated by error bars. The subtotal and overall odds ratio is signified by rhombus.

Figure 5. Forest Plot of Serum Calcium Change in Patients With Diabetic Nephropathy
Forest Plot of Serum Calcium Change in Patients With Diabetic Nephropathy

The mean difference from each study is represented by square, and the confidence interval is indicated by error bars. The subtotal and overall odds ratio is signified by rhombus.

Figure 6. Forest Plot of Adverse Events in Patients With Diabetic Nephropathy
Forest Plot of Adverse Events in Patients With Diabetic Nephropathy

The odds ratio from each study is represented by square, and the confidence interval is indicated by error bars. The subtotal and overall odds ratio is signified by rhombus.

Funnel Plot of Included Studies in Each Outcomes
Figure 7. Funnel Plot of Included Studies in Each Outcomes

4. Discussion

It has been widely accepted that vitamin D3 functions in multiple approaches to protect kidneys of DN patients including antagonism of inflammatory responses, restraint of renin-angiotensin system (RAS), and mesangial cell proliferation, reduction of proteinuria, prevention of glomerular hypertrophy, as well as improvement of tubulointerstitial fibrosis (8). Our study indicated that vitamin D3 has a remarkable renoprotective effect by reducing 24-hour proteinuria and lowering the ratio of urinary albumin to creatinine, and alleviating hs-CRP.

In fact, elevated AGT expressions in the state of high glucose would lead to increased synthesis of Ang II, whose contractile effects on afferent arteriole of glomerulus was smaller than those on revehent artery. Thus, hemodynamic changes featured by high pressure, hyper-transfusion, and high filtration at the early stage of DM appeared, which became the vital parameter inducing DN development. Vitamin D3 could serve to reduce composition of Ang II through reduction of the activity of renin gene promoter, upgradation of blood calcium levels to reverse hyperparathyroidism, and blocking of NF-kB signal transduction. Besides, after examining male Sprague-Dawley rats that received total resection of kidney with 3 ng/100g vitamin D3, deregulated desmin, proliferating cell nuclear antigen (PCNA), and p27 expressions were observed, and augmented glomerular size was found to recover with alleviated proteinuria, suggesting that vitamin D3 could relieve progression of chronic renal failure and restrain renal growth through targeting sertoli cell and mesangial cell (32). Furthermore, active vitamin D3 was also demonstrated to be correlated with downregulated expressions of inflammatory factors including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α (33). Due to the far-ranging mechanisms of vitamin D3, it displayed its protective role for kidney from initial treatments of diet, decreasing sugar, and reducing proteinuria. For instance, during the process of drug therapy, one randomized and double-blind study documented that vitamin D3 could clinically cut down urinary protein levels of DN patients, and this action was not dependent on such drugs as ACEI (34). Moreover, by examining DN veterans, who did not undergo dialysis, it was found that they can elongate their life expectancy and simultaneously lower the incidence of complications by using vitamin D3 (35). In the course of replacement therapy, an investigation comparing 61 children, who were undergoing dialysis and taking vitamin D3, with 40 age-matched children indicated that vitamin D3 might protect patients’ vasculature system by regulation of calcic/phosphor and anti-inflammatory action (36).

As for the combined therapy of ACEI and ARB, they appeared to repress the production of Ang II, which could contribute to vessel contraction. To be specific, ACEI could hold up the conversion of Ang I to Ang II by suppressing the activity of angiotensin converting enzyme (37). Simultaneously, ACEI might enable activity of bradykinin to last long and alter renal hemodynamics, delaying fall of glomerular filtration rate (GFR) (37). Moreover, the interdiction of RAS by ACEI was suggested to restrain production and activity of TGF-β1 within nephridial tissues, which caused sclerosis and fibrosis of glomerular (38-40). Clinical studies also confirmed the meaningful role of ACEI (eg, benazepril and captopril) in doubling blood creatinine levels and improving prognosis of DN patients (41). Nonetheless, as production of Ang II was featured by multiple sources and channels, ACEI could merely restrain the channel of Ang II conversion enzyme. In addition, long-term use of ACEI would lift the responsiveness of renin activity and make Ang II to recur.

Considering the limitations of ACEI, ARB was also used as the combined therapy because it blocked the adverse effects of Ang II within renal through specifically uniting with AT1 receptor of Ang II, which reduced the prevalence of side effects for not affecting the kinin system (eg, edema). Besides, ARB indirectly facilitated combination of Ang II with AT2, by vasodilation (blood vessels) and lowering blood pressure (42). Moreover, ARB (losartan) can boost the excretion of uric acid by kidney, preventing damages imposed by hyperuricemia on kidney (43). The combined treatment efficacy of AECI and ARB has been clinically explored and found to be more superior to AECI or ARB alone, yet certain scholars did not support the idea (44, 45).

After comprehensively exploring the mechanisms of action among vitamin D3, AECI, and ARB, it was not hard to discover that vitamin D3 acted in more channels than AECI and ARB to fight against DN. Moreover, vitamin D3 is a natural ingredient found within organisms, which could account for less side effects of vitamin D3 than AECI and ARB. This meta-analysis was an updated pooled analysis, which included the latest articles published in 2016 and 2017. Furthermore, this meta-analysis contained 7 outcomes to present the renoprotective effect of vitamin D, which was more comprehensive than the existed meta-analysis. Lastly, in this analysis, we not only compared the difference between vitamin D and placebo, but also took AECI and ARB into consideration. In clinical practice, we cannot neglect the mutual function of treatments of patients with diabetic nephropathy. However, there were some limitations in this study. Firstly, all the 24 studies took active substance or analogs of vitamin D3 as intervention; secondly, patients with Type 1 diabetes had only been enrolled in Joergensen’s study, and 5 studies had not reported the type of their diabetic patients, and 4 trials had been grouped based on the different dose of drugs; and thirdly, the concomitant drugs varied in the 24 studies.

5. Conclusions

In summary, vitamin D3 is a promising therapy for diabetes patients with proteinuria. Based on the evidence of this study, vitamin D3 is suggested as a recommended drug for diabetic nephropathy in clinical practice. Nonetheless, large and more randomized clinical trials should be conducted to confirm and elucidate the efficacy and mechanism of vitamin D3.

Acknowledgements

Footnote

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