Therefore, the present MR study highlights EPA as the predominant active component of omega-3 fatty acids in relation to decreased risk of IBD, potentially via its interaction with linoleic acid and histidine metabolites. Additionally, the FADS2 gene likely mediates the effects of omega-3 PUFAs on IBD risk.Epidemiological evidence regarding the effect of omega-3 polyunsaturated fatty acid (PUFA) supplementation on inflammatory bowel disease (IBD) is conflicting. Additionally, little evidence exists regarding the effects of specific omega-3 components on IBD risk. We applied two-sample Mendelian randomization (MR) to disentangle the effects of omega-3 PUFAs , or docosahexaenoic acid (DHA)) on the risk of IBD, Crohn’s disease (CD) and ulcerative colitis (UC). Our findings indicated that genetically predicted increased EPA concentrations were associated with decreased risk of IBD (odds ratio 0.78 (95% CI 0.63–0.98)). This effect was found to be mediated through lower levels of linoleic acid and histidine metabolites. However, we found limited evidence to support the effects of total omega-3, α-linolenic acid, and DHA on the risks of IBD. In the  The t process .In randomized controlled trials (RCTs), EPA and DHA have often been combined as the active components of omega-3 fatty acids and consumed together, despite their distinct molecular functions and clinical impacts . Daily sFADS2 gene were eliminated, which may have important influences on the reliability of the findings. Meanwhile, there remains a knowledge gap in evaluating the separate biological effects of α-linolenic acid, EPA, and DHA, with their metabolic mechanisms being unexplored.Mendelian randomization (MR) is an approach that could estimate causal effect of an exposure on an outcome and overcome issues related to residual confounding or reverse causality . MoreoveFADS2 gene in omega-3 PUFAs’ metabolism, further analyses in this specific region were essential through genetic colocalization. This approach allowed us to assess whether there were shared causal variants within the FADS2 gene region that could influence both omega-3 PUFAs and IBD risk [In this study, we aimed to explore the effects of omega-3 PUFAs  on the risk of IBD and its subtypes, and the potential metabolic pathways linking omega-3 PUFAs with IBD. Given the central role of the IBD risk .FADS2 gene region to test for pleiotropic effect and investigate the underlying mechanisms. A bidirectional MR analysis was applied to estimate the effect of genetic liability to IBD on omega-3 PUFAs. Mediation MR analysis estimated the effect of potential metabolites linking omega-3 PUFAs with the IBD. All datasets were publicly available, and ethical approval was acquired for all original studies.A schematic overview of the study design was detailed in Single-nucleotide polymorphisms (SNPs) associated with total omega-3 fatty acid were derived from UK Biobank, which collected deep genetic and phenotypic data from approximately 500,000 individuals aged between 40 and 69 . Geneticp value < 5 × 10−8) and showed independence (with linkage disequilibrium (LD) r2 < 0.01 in European ancestry) were selected as candidate instruments. Given the limited sample size of the α-linolenic acid, EPA, and DHA GWASs, a slightly more relaxing threshold (p < 5 × 10−6) was used to select instruments for these exposures. After harmonization with outcome data and removing palindromic or mismatching alleles, 42 independent SNPs for total omega-3 fatty acid, 12 independent SNPs for α-linolenic acid, 23 independent SNPs for EPA, and 6 independent SNPs for DHA were selected as instruments , which represents the same signal in this region).In this study, the genetic variants that showed robust association with total omega-3 fatty acid  , which cThe full GWAS summary statistics of the 974 circulating metabolites were derived from the IEU OpenGWAS database with GWAS identifier met-a, met-b, met-c, and met-d.The inverse weighted variance (IVW) method was used as a primary analysis to estimate the causal effects of omega-3 PUFAs on IBD and its subtypes, which were calculated by a weighted linear regression of the instrument–outcome association estimates on the instrument–exposure association estimates assuming that all genetic variants were valid instruments .MR analysis had several assumptions. The genetic instruments need to (1) be robustly associated with the exposure (“relevance”), (2) be independent of potential confounders of the instrument–outcome association (“exchangeability”), and (3) only affect the outcome through the exposure being tested and not through alternative pathways .The relevance MR assumption was assessed from the mean F statistics within univariable MR, which was greater than ten for every instrument–exposure association, demonstrating the small possibility of weak instrumental variable bias .FADS2 gene encoded key fatty acid desaturase enzymes, which are pivotal for omega-3 PUFA biosynthesis. Therefore, we performed colocalization analyses in this gene region. A generated colocalization posterior probability greater than 0.70 indicated the same variant causal for both traits and indirectly denied the possibility of “exchangeability”. We attempted using colocalization to test exchangeability MR assumption whether SNPs associated with two traits are possibly in LD, or a single shared signal  . The FADTo check for violation of the “exclusion restriction” assumption of MR and assess pleiotropy, we made different assumptions regarding MR instrument validity using several sensitivity analyses, that included the weighted median method which permitted up to 50% of the information in the MR analysis to come from invalid instruments , and thep < 5 × 10−8) as exposures to assess their effect on total omega-3 fatty acid, α-linolenic acid, EPA, and DHA, respectively.We also sought to evaluate whether there was a reverse causal effect where liability to IBD consequently altered the levels of omega-3 PUFAs by performing a bidirectional MR analysis . TherefoWe further estimated the mediation effects of circulating metabolites linking EPA with IBD risk. We used a novel analytical pipeline that integrated mediation MR with metabolite set enrichment analyses. First, we used a two-step MR approach to: (1) assess the causal effect of EPA on 974 potential metabolites (step 1) that have publicly available GWAS datasets in the IEU OpenGWAS database, which selected 237 metabolites with FDR < 0.05; and (2) estimate the effect of 237 metabolites on IBD (step 2), which further selected 211 metabolites associated with both EPA and IBD as candidate mediation metabolites. Second, we performed the metabolite set enrichment analysis on the 211 selected candidate metabolites, which aimed to select key metabolites enriched in certain metabolic pathways . For thep ≤ 0.05. Metabolites associated with omega-3 PUFAs or IBD were considered significant with an FDR < 0.05. Enrichment analysis was performed using the online MetaboAnalyst software  [Univariable, bidirectional, and multivariable MR analyses were considered significant with a 2-sided er 2022) . All anaWe selected 42, 12, 23, and 6 SNPs as instruments to proxy life-long effect of total omega-3 fatty acid, α-linolenic acid, EPA, and DHA, respectively. In bidirectional MR, there were 117, 89, and 62 independent instruments incorporated for IBD, CD, and UC, respectively. Mean F statistics of the exposures ranged from 29.82 to 262.21 indicating that the MR estimates were not likely to be influenced by weak instrument bias .hP= 0.10), pleiotropy (MR-Egger intercept interceptP= 0.97), or any outliers . Estimated effect was consistent using the weighted median approach . However, there was little evidence to support the effect of DHA on IBD .The results of the primary MR analyses of CD and UC are presented in FADS2 gene region   were 0.85 (0.79–0.92), 0.59 (0.43–0.80), and 0.53 (0.37–0.75), respectively. On the contrary, α-linolenic acid showed a strong effect on the increasing risk of IBD . As shown in the leave-one-out analyses, the MR estimates of omega-3 PUFAs on IBD, CD, and UC were mainly driven by SNP effects in the for DHA) . As showFADS2 gene showed a stronger effect on lowering the risk of CD (ORs (95% CI) were 0.78 (0.71–0.86) for total omega-3, 0.38 (0.25–0.57) for EPA, and 0.35 (0.23–0.55) for DHA) but was absent for UC. Meanwhile, a FADS2 single-SNP in α-linolenic acid had a positive effect on increasing CD risk , but with less effect on UC risk.As for IBD subtypes, the FADS2 region, we observed compelling evidence of colocalization for α-linolenic acid with CD , but with little evidence for UC  is shown in FADS2 gene region. Therefore, desaturation steps during omega-3 PUFAs’ biosynthesis might play a critical role in the relationship between omega-3 PUFAs and IBD. Meanwhile, higher genetic liability to UC might be associated with lower levels of DHA, potentially indicating a weaker absorption or abnormal metabolism of omega-3 PUFAs in UC. Collectively, our results suggest that supplementation with EPA (rather than α-linolenic acid or DHA) might be a more effective strategy to prevent the onset of IBD, especially CD, rather than UC with high probability of weak absorption or abnormal metabolism on omega-3 PUFAs. These findings shed light on the potential differential impacts of specific omega-3 PUFAs on IBD risk and highlight the importance of considering individual PUFA components in designing prevention strategies for this complex disease.The present study employed a comprehensive analysis using MR to strengthen the inferences regarding the effects of different omega-3 PUFAs  on IBD risk. We provided evidence supporting that increased levels of EPA are causally associated with a lower risk of IBD and CD, but the effect on UC is relatively weaker. The mediation MR analysis further suggested that EPA may influence IBD via α-linolenic acid, linoleic acid and methylhistidine metabolism pathways. Linoleic acid and histidine were estimated to mediate the effect of EPA on IBD. However, we found limited evidence to support the effects of total omega-3, α-linolenic acid, and DHA on the risk of IBD. Furthermore, leave-one-out, single-locus, and colocalization analyses indicated that the effects of omega-3 PUFAs on IBD were massively driven by SNP effects in the Previous systematic reviews and meta-analysis of RCTs have not yielded firm recommendations regarding the usefulness of omega-3 PUFAs in treating IBD ,30. In aα-linolenic acid serves as a substrate for other essential omega-3 PUFAs in the body. In our study, genetically predicted α-linolenic acid levels showed a trend toward an increased risk of IBD, although the statistical power of the analysis was relatively low. Observational studies have also provided inconclusive evidence regarding the relationship between α-linolenic acid and IBD. For instance, a case-control study has reported higher dietary α-linolenic acid intakes in newly diagnosed UC patients compared with healthy controls . HoweverEPA and DHA are the main components of long-chain omega-3 fatty acids, which are derived from α-linolenic acid through a series of elongation and desaturation steps and β-oxidation. The beneficial effects of EPA and DHA have been investigated as a combination or as part of omega-3 supplementation in observational studies and experimental trials. However, the distinct effects of EPA and DHA on the risk of IBD have been relatively unexplored. In our study, we conducted separate evaluations and found evidence suggesting that increased levels of EPA were associated with a lower risk of IBD and CD. Interestingly, our findings indicate that EPA might play a more important role than DHA in relation to IBD risk. Although direct comparative studies on the effects of EPA and DHA on IBD risk are limited, other research has provided insights that align with our results . In twenWe further demonstrated that the protective effect of EPA on risk of IBD was mainly influenced by α-linolenic acid, linoleic acid, and methylhistidine metabolism pathways. These findings are consistent with a previous study that has indicated that krill oil, rich in omega-3 PUFAs, exerts an inhibitory effect on histidine metabolism, leading to attenuated intestinal inflammation . MoreoveFADS2 gene will lead to changes in both upstream α-linolenic acid and downstream EPA concentrations [FADS2 gene is crucial and merits further investigation.Collectively, the increased risk of IBD is primarily associated with higher levels of α-linolenic acid or lower levels of EPA, as the differences in desaturation steps driven by the trations . Thus, tFADS2 variants on IBD and CD, but not on UC. Furthermore, we found robust colocalization evidence between omega-3 PUFAs and CD in the FADS2 gene region, but little colocalization evidence for UC. These findings suggest that the key link between omega-3 PUFAs and IBD is driven by effects in the FADS2 gene cluster. Several lines of evidence support our observations and indicate that the FADS2 gene is associated with inflammation [FADS2 gene regulated immune functions and showed colocalization evidence on PUFAs and CD (posterior probability = 0.94) [FADS2 against chronic inflammation among CD patients [FADS2 is a crucial gene linking omega-3 PUFAs and IBD risk, particularly in the case of CD. Our study also revealed a massive influence of ammation  and CD rammation ,46. For  = 0.94) . In addipatients . TherefoFADS2 region. As mentioned above, the FADS gene cluster plays a central role on PUFAs’ metabolism, where genetic effects in the FADS2 region massively influenced the MR estimates of omega-3 PUFAs on IBD and its subtypes. The effects of total omega-3 fatty acid were found to potentially increase IBD risks after removing the FADS2 instrument (Despite the protective role on CD, our study provided little evidence to support the effect of omega-3 PUFAs on UC risk. Previous epidemiological studies also indicated that an increasing dietary intake of EPA or DHA had no association with a decreased risk or maintenance of remission in UC ,48. It istrument . In summFADS2 gene region, thus validating the underlying mechanism linking omega-3 PUFAs with CD. There were several strengths of the present study. First, our study comprehensively explored the causal effects of the different components of omega-3 PUFAs on IBD risk by using a robust MR setting, which reduced bias from residual confounding and excluded reverse causality. Current data contributed to produce informed recommendations based on the relative importance of EPA in preventing IBD. Second, our investigation of the metabolic pathways involving linoleic acid and histidine metabolites provided valuable insights into the mechanisms underlying the effect of EPA on IBD risk, which may have implications for future clinical practice. Third, our findings suggest that supplementation policies should consider the different subtypes of IBD, as EPA demonstrated a significant effect on reducing the risk of CD but not UC, and genetic liability to UC was associated with lower concentrations of DHA. Additionally, we used colocalization methods to thoroughly explore the possibility of a single shared effect signal in the However, there were some limitations that should be considered when interpreting our findings. First, we used different data sources for the exposure variables. The genetic instruments for total omega-3 were obtained from the UK Biobank study, while instruments for α-linolenic acid, EPA, and DHA were derived from the CHARGE Consortium. Although both datasets involved participants with European ancestry, there could still be potential biases introduced by using different sources. Second, we assumed that the relationships between omega-3 fatty acids and IBD risk were linear. Non-linear relationships were not taken into consideration and further investigation is needed to explore potential non-linear effects. Finally, although we used univariable MR analyses to estimate the effect of each fatty acid, we were unable to directly estimate the effect of EPA-to-DHA ratio. The EPA-to-DHA ratio is considered important in the clinical application of fish oil, and its potential impact on IBD risk merits further exploration. In conclusion, our comprehensive MR analyses identified that EPA was the key component among the omega-3 PUFAs that may exhibit a protective effect on IBD and CD, but not on UC. There was little evidence to support the effect of total omega-3, α-linolenic acid, or DHA on IBD risks. We also provided novel insights into the underlying mechanisms of EPA, which may influence IBD via α-linolenic acid, linoleic acid and methylhistidine metabolic pathways. Furthermore, the FADS2 gene is likely to be a core gene that mediates the effects of omega-3 PUFAs on IBD risk. Based on these findings, our study recommended the supplementation or dietary intake of EPA, rather than α-linolenic acid or DHA, might be beneficial for preventing the onset of IBD. The proposed mediators have provided novel insights into the underlying mechanisms of EPA. More well powered epidemiological studies and clinical trials are needed to explore the potential benefits of high EPA concentration or EPA/DHA in IBD and its subtypes. Moreover, further research is needed to investigate the role of histidine metabolites in the context of IBD.


Toxoplasma gondii. OT is the leading cause of posterior uveitis globally; it is a recurrent disease that may result in visual impairment and blindness. This systematic review and meta-analysis aim to summarize and evaluate the risk factors for recurrences, visual impairment, and blindness described in the literature worldwide.Ocular toxoplasmosis (OT) is caused by the parasite We performed a systematic literature search in PubMed, Embase, VHL, Cochrane Library, Scopus, and DANS EASY Archive. All studies reporting patients with clinically and serologically confirmed OT presenting any clinical or paraclinical factor influencing recurrences, visual impairment, and blindness were included. Studies presenting secondary data, case reports, and case series were excluded. An initial selection was made by title and abstract, and then the studies were reviewed by full text where the eligible studies were selected. Then, the risk of bias was assessed through validated tools. Data were extracted using a validated extraction format. Qualitative synthesis and quantitative analysis were done. This study was registered on PROSPERO (CRD42022327836).Seventy two studies met the inclusion criteria. Fifty-three were summarized in the qualitative synthesis in three sections: clinical and environmental factors, parasite and host factors, and treatment-related factors. Of the 72 articles, 39 were included in the meta-analysis, of which 14 were conducted in South America, 13 in Europe, four in Asia, three multinational, two in North America and Central America, respectively, and only one in Africa. A total of 4,200 patients with OT were analyzed, mean age ranged from 7.3 to 65.1 year of age, with similar distribution by sex. The frequency of recurrences in patients with OT was 49% (95% CI 40%–58%), being more frequent in the South American population than in Europeans. Additionally, visual impairment was presented in 35% (95% CI 25%–48%) and blindness in 20% (95% CI 13%–30%) of eyes, with a similar predominance in South Americans than in Europeans. On the other hand, having lesions near the macula or adjacent to the optic nerve had an OR of 4.83  for blindness, similar to having more than one recurrence that had an OR of 3.18 . Finally, the prophylactic therapy with Trimethoprim/Sulfamethoxazole versus the placebo showed a protective factor of 83% during the first year and 87% in the second year after treatment.Our Systematic Review showed that clinical factors such as being older than 40 years, patients with de novo OT lesions or with less than one year after the first episode, macular area involvement, lesions greater than 1 disc diameter, congenital toxoplasmosis, and bilateral compromise had more risk of recurrences. Also, environmental and parasite factors such as precipitations, geographical region where the infection is acquired, and more virulent strains confer greater risk of recurrences. Therefore, patients with the above mentioned clinical, environmental, and parasite factors could benefit from using prophylactic therapy. Toxoplasma gondii (Tg), considered a neglected tropical disease  (3 Table) , 83, 85.Multiple articles described clinical factors that influence the recurrence rate. One of them was time since the disease onset. Most authors found a higher risk of reactivation in the first years after primary acquired infection, which tends to decrease over time. This risk can reduce by 72% in the first decade, and the decrease is continuous over time , 76, 78.On the other hand, environmental factors, such as living in regions with high precipitation rates, were also associated with higher recurrence rates. An Argentinian study found that for every mm of precipitation, the frequency of consultations due to OT recurrences increased by 2% in an ophthalmological center  . Other fRegarding recurrences in previous and no previous involved eye, they usually occur in the affected eye , 85. FinConcerning visual impairment, studies have found that patients > 45 years of age who debut with active lesions have a ten times higher risk of developing visual impairment , 32, 79.The development of blindness, as reactivations and visual impairment, was affected by the location of the lesion. It was estimated that central lesions raise 8.95 to 68.6 times the risk of blindness compared to a lesion located outside the macula , 37, 64.Factors related to the parasite can influence OT recurrences, L Shobab et al. found that patients infected with serotypes non-reactive (NR) to GRA6 and GRA7 allelic peptide motifs derived from distinct parasite types were more likely to have recurrences  compared to OT patients infected with a type I/III, type II, or atypical parasites. Moreover, they described that patients with NR serotype had 2.42 times more recurrences than those infected with type II strains .On the other hand, there are protective and risk factors related to the human host. The AT heterozygosis polymorphisms in the IFN-γ gene at position +874 increases the risk of recurrence by 49%  . AdditioFinally, a study involving intraocular fluids have found that elevated levels of IL-5 and VEGF positively correlated with recurrences . Also, SSeveral treatment regimens used in active OT seem to influence the risk of recurrences, such as trimethoprim-sulfamethoxazole (TMP/SMX), spiramycin (Sp), and pyrimethamine sulfadiazine (P+Sdz), in combination with or without systemic and topical steroids. However, studies have not shown that treatment in the disease’s active phase can significantly reduce the recurrence rate. Prospective studies are needed to analyze this outcome in more detail , 61, 71.S2 Table).On the other hand, studies have shown that the regimen of azithromycin alone or with a steroid has less effectiveness than other schemes , 71, achThe use of pyrimethamine/sulfadoxine (Sdx) as secondary antifolate prophylaxis can lead to 3,5-year recurrence-free survival in 90.9% of cases  . AnotherRegarding VA, a significant effect of antibiotic therapy is observed in general, but more studies of better quality are needed to make any affirmation , 87, 89.P < 0.01). Given the demonstrated high level of heterogeneity, an analysis by continental subgroups was performed, where the p-value lost statistical significance (P = 0.63). The highest prevalence was reported in South America at 56%  P = 0.01)), followed by Europe 27% ) [.Four hundred seventy one eyes were analyzed to estimate the prevalence of visual impairment secondary to OT . This wa= 0.06)) , 88. FunP <0.01)). Subgroup analysis showed the frequency of blindness was slightly lower in Europe 19% ) than in South America 22% ). In addition, in visual impairment even performing a subgroup analysis the statistically significant difference between studies remains [S1 Fig, the Fail-Safe N analysis , Rank correlation test , Asymetry .Regarding the prevalence of blindness in OT , 969 eye remains , 72, 88.P = 0.49)) [P = 0.41)) [P = 0.95)) [P = 0.90)) [None of the factors evaluated was significantly associated with recurrences. However, some tendencies were found. = 0.49)) , 28, 40.= 0.41)) , 82. Fig= 0.95)) , 30. FigP <0.00001)) [P = 0.001)) [We evaluated the factors related to blindness in OT patients. .00001)) , 35. Als 0.001)) .P = 0.83)) [P = 0.47)) [P = 0.89) [We sought to determine if any treatment further reduced recurrences, none of them were significantly associated with a reduction on recurrences. = 0.83)) , 56), Fi= 0.47)) , 67. Fig = 0.89) , 43. In P = 0.03)). P = 0.03)). In this case, a statistical significant result was evidenced, also, a tendency of reduction in the risk of recurrence was incremental over time.This analysis sought to determine the effect of prophylactic treatments reducing recurrences , 53. FigOur systematic review and meta-analysis evaluated the effect of multiple clinical, environmental, geographic, parasite, genetic, and management factors on the recurrences, visual impairment, and blindness in OT.One of the most critical factors related to recurrences was the first year after the first lesion because the risk tends to decrease in the subsequent years , 14. AddAdditionally, we meta-analyzed the prevalence of recurrences, visual impairment, and blindness worldwide. We found that recurrences are most common in South American and Central American patients, corroborating that these latitudes have more severe cases of OT, possibly due to more virulent strains , 93. HowRegarding visual acuity and blindness prevalence in OT eyes, we found that in South America there is a greater prevalence of visual impairment and blindness than in Europe but not in the rest of the world. However, some studies’ incorrect reports of this outcome can limit our results. Additionally, it should be noted that the sub-analysis by subgroups appropriately controlled the heterogeneity of the metanalysis.In the analysis of risk factors associated with blindness, we found that recurrences and the macular localization of the lesion are the most important factors related to blindness. This has been supported by previous studies, which evidenced that macular lesions have up to 8.95 to 68.6 times increased risk of blindness , 37, 64.In addition to the previously mentioned factors (macular location of the lesions and recurrences) , 64, 65,Table 4 [Prophylaxis in patients with OT is a protective factor that increases over time, reaching a reduction of almost 87% compared to placebo. This metanalysis does not have a high risk of publication bias. Also, it is essential to consider there were evaluated few studies; we suggest conducting more studies in this field to expand the evidence and assess the superiority of the different schemes. Our results are supported by the marked reduction trend in recurrences that has been reported with the use of antibiotic prophylaxis with TMP/SMX in any scheme, more detailed information on schemes, doses and times see Table 4 , 53. NevTable 4 . We propTable 4 , 11, 53.In conclusion, considering the results of our meta-analysis and the evidence previously presented, we suggest that patients older than 40 years, patients with de novo OT lesions or with less than one year after the first episode, macular area involvement, lesions greater than 1DD, congenital toxoplasmosis, and bilateral compromise could benefit from using prophylactic therapy, especially if they live in South America or in a high precipitation area. However, due to the number of studies and their characteristics, it is not possible to determine which prophylactic strategy is superior , 11, 53.S1 Checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 FigP <0.001), Rank correlation test , Asymmetry . Fail-Safe N analysis , Rank correlation test , Asymmetry .Fail-Safe N analysis , Rank correlation test , Asymmetry . Fail-Safe N analysis Click here for additional data file.


The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory.Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran’s Q-statistic test and Begg’s test were employed to identify heterogeneity among studies and publication bias, respectively.2, 95% confidence interval [95% CI] = 0.12 to 0.29 kg/m2, p < 0.001), waist circumference  and blood glucose  than the TT homozygotes. Regarding the rs8192678 polymorphism, no significant associations with the indexes of obesity, glucometabolic disorder and dyslipidemia were detected. However, significant correlations between the rs8192678 polymorphism and multiple glucometabolic indexes were observed in subgroup analyses stratified by sex, age, ethnicity and health status.Fifty studies  and 51 studies  were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/mThe meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease.https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543. The genes and their polymorphisms from the melanocortin system and peroxisome proliferator activated receptor signaling pathway have been extensively investigated with regard to their relations with obesity, metabolic abnormalities and CVD (Cardiovascular disease (CVD) remains the number one killer among the world’s population, and the mortality and severe disability rates are still on the increase in some countries such as China –3. Metab and CVD –12.Melanocortin 4 receptor (MC4R), a member of the G protein-coupled receptor family and with alpha-melanocyte-stimulating hormone (a-MSH) as its ligand, is mainly distributed in the ventromedial hypothalamus and is a crucial modulator of food intake and energy homeostasis . Human MHowever, there are many inconsistencies and contradictions in the published data on these two polymorphic sites and metabolic abnormalities. Some researchers reported that C allele of the rs17782313 polymorphism is correlated with a higher level of body mass index (BMI) –43, waisThe systematic review and meta-analysis was conducted to clarify the relationships between the rs17782313 and rs8192678 variants and the indexes of obesity, glucometabolic disorder and dyslipidemia. The obtained findings can help clarify the interrelationships among the rs17782313 and rs8192678 variants, metabolic abnormalities and CVD.This meta-analysis has been registered and supported by PROSPERO International Prospective Register of Systematic Reviews (identifier CRD42022373543), following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. Electronic databases such as Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were thoroughly retrieved from 1980 to February 2023. The literature search keywords were as follows: (“melanocortin 4 receptor” or “MC4R”) and  and (“rs17782313” or “rs8192678” or “variant” or “polymorphism” or “variance” or “mutation”) and (“body mass index” or “BMI” or “waist circumference” or “WC” or “waist-to-hip ratio” or “WHR”) and (“glucose” or “GLU” or “insulin” or “INS” or “homeostasis model assessment of insulin resistance” or “HOMA-IR”) and . The parameters assessed in the meta-analysis include three obesity indexes , three glucometabolic disorder indexes , and four dyslipidemia indexes . Any studies that explored the relations of the rs17782313 and rs8192678 variants with the ten indexes were screened and reviewed.Inclusion criteria: 1) The genotype distribution and sample size were presented clearly and accurately; 2) One or more of the ten variables  were reported; 3) Data format of the variables were shown as mean/standard deviation or mean/standard error. Exclusion criteria: 1) Repeatedly published data of the variables; 2) Low quality data; 3) Case reports or conference abstracts.2 (BMI), cm (WC), μmol/μL (INS) and mg/dL , and units were converted if other units were used.Data were carefully checked and verified after extraction from the enrolled articles. The data extracted from each article were as follows: title, year of publication, author’s names, age, gender, ethnicity, health status, sample size, and means as well as standard deviations/standard errors by genotypes. Standard deviation was calculated if standard error was given. Units used for the variables included kg/mp ≤ 0.05 was considered as statistically significant.The STATA software package  was employed in this systematic review and meta-analysis. Most of the included studies presented their research results in a dominant way, therefore the present meta-analysis also adopted the dominant model . Subgroup analyses were conducted according to gender, age, ethnicity and health condition. Each subgroup was defined as a comparison in the meta-analysis, and subgroup analyses were performed with three or more comparisons to ensure statistical power. Standardized mean difference (SMD) was employed to express the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. The random effects model usually provides a more reliable analysis result, so this study selected the random effects model for analysis. Cochran’s Q-statistic test was used to assess heterogeneity among the studies, and Galbraith plot was drawn to discover the potential sources of heterogeneity. Subgroup analyses were performed, and the subgroups were classified by gender , age (adults and children/adolescents), ethnicity , and health condition . Begg’s test was conducted to evaluate publication bias, and the trim and fill method was used to assess the potential influence of the missing studies on the pooled result if there was a publication bias. All analyses were two-tailed, and Flow diagram of the literature search is displayed in Characteristics of the studies included for the rs8192678 variant are shown in 2, 95% confidence interval [95% CI] = 0.12 to 0.29 kg/m2, p < 0.001) (p < 0.001) (p = 0.01)  or GLU  in adults, but not in children/adolescents. The C allele of the rs17782313 polymorphism is associated with a higher level of BMI in European Caucasians  and East Asians , but not in South Americans and West Asians. Similarly, the C allele of the rs17782313 polymorphism is associated with higher levels of WC  and GLU  in European Caucasians, but not in any other ethnicities. The C allele of the rs17782313 polymorphism is associated with a higher level of WHR  in West Asians, but not in the whole population or any other ethnicities. The C allele of the rs17782313 polymorphism is associated with a higher level of BMI in T2DM patients , hypertensive patients  and general/control subjects , but not in overweight/obesity patients. Notably, the C allele of the rs17782313 variant is correlated with a higher level of WC  or GLU  in general/control subjects, but not in any of the patient populations.The interactions of the rs17782313 polymorphism with age, ethnicity and health condition on the indexes of obesity and glucometabolic disorder were observed . The A-allele carriers of the rs8192678 polymorphism had a higher level of GLU in East Asians  and T2DM patients , a higher level of INS in South Americans  and overweight/obesity patients , and a higher level of HOMA-IR in children/adolescents , overweight/obesity patients  as well as T2DM patents  than the GG homozygotes. Somehow, the A-allele carriers of the rs8192678 polymorphism had a lower level of INS than the GG homozygotes in females  and European Caucasians . Notably, the A-allele carriers of the rs8192678 polymorphism were found to have a higher level of LDL-C  than the GG homozygotes in East Asians.As indicated in -PHeterogeneity = 0.24, PSMD < 0.001).Significant heterogeneity was found in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms in the overall population . Interestingly, another polymorphic site near the MC4R gene, rs12970134, was also found to be strongly associated with obesity risk, with 24 studies out of 25 studies reporting a significant impact of the rs12970134 polymorphism on obesity risk (data not shown).p = 1.7 × 10-4) and an increased mRNA expression level of MC4R (p = 1.9 × 10-3). We used GTEx Analysis Release V8 (dbGaP Accession phs000424.v8.p2) to assess the impact of the rs17782313 polymorphism on the mRNA expression pattern of MC4R, and the results displayed that the MC4R mRNA level increases orderly with the TT, TC and CC genotypes in brain nucleus accumbens and putamen, but decreases orderly in cerebellum . However, Lauria et al. (The mechanisms underlying the correlations of the rs17782313 polymorphism with obesity as well as hyperglycemia may be that this variant leads to abnormal expression of MC4R as it is located downstream of the MC4R gene without any amino acid alteration in MC4R receptor. Indeed, Tang and colleagues  conductea et al.  did not a et al. –95. TherThe PGC1α rs8192678 polymorphism has also been shown to affect the expression and function of PGC-1α. Taghvaei et al.  demonstrSignificant heterogeneity was existed in the pooled meta-analyses of the rs17782313 polymorphism with BMI, WC and GLU. The outlier studies were figured out by observing Galbraith plots. No significant alterations in SMDs as well as 95% CIs were observed after removing the outlier studies, which indicates that the associations between the rs17782313 variant and these indexes are very robust. WHR, an indicator of abdominal obesity, was shown to be significantly associated with the rs17782313 polymorphism after exclusion of the outlier studies. It suggests that the significant correlation between the rs17782313 polymorphism and WHR has been masked by the extensive heterogeneity among studies. Significant heterogeneity was also detected in the association analyses between the rs8192678 polymorphism and the indexes of obesity, glucometabolic disorder and dyslipidemia. The outlier studies were identified and excluded, but there were still no significant correlations between the rs8192678 polymorphism and all of these indexes in the whole population, which indicates that the associations of the rs8192678 polymorphism with obesity, diabetes and dyslipidemia are weak, although PGC1α works as an activator of PPARγ, an important modulator of glucose and lipid metabolism (There are several limitations to current study. Firstly, this meta-analysis only included the studies that published in Chinese or English as it is difficult to obtain the full articles written in various languages. Secondly, the interactions of the rs17782313 and rs8192678 polymorphisms with other genetic variants or non-genetic factors other than age, gender, ethnicity and health condition on metabolic abnormalities were not investigated in this meta-analysis due to lack of original data from the enrolled studies. A large number of genes, diets, physical activities and environmental factors are implicated in the pathogenesis of metabolic disorders such as dyslipidemia, diabetes and obesity. More precise results could be obtained if gene-gene interactions were explored, or stratification analyses according to diets, physical activities and environmental factors were conducted.In conclusion, the C allele of the rs17782313 polymorphism near MC4R confers a higher risk of obesity and hyperglycemia, and the A allele of the rs8192678 polymorphism is associated with glucometabolic disorder in some specific populations. These findings can provide a direct link between the rs17782313 and rs8192678 polymorphisms and T2DM as well as CVD.The original contributions presented in the study are included in the article/YS, YZ and SL conceived of the systematic review and meta-analysis, participated in the design, analyzed the data, and drafted the manuscript. HN, XW, XL, JW and ML carried out the literature search, collected the data, and revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.


In the pathogenesis of inflammatory bowel disease (IBD), the advanced glycation end product receptor (RAGE) has been involved. IBD is classified into Chron’s disease (CD) and ulcerative colitis (UC). The promoter gene of the RAGE gene was discovered to have had unique polymorphisms that increased its transcriptional activity. This study, therefore, used a systematic review and meta-analysis to examine the relationship between the RAGE gene polymorphism and the risk of IBD.  Databases such as PubMed, Scopus, and Cochrane library were searched to identify the relationship between RAGE gene polymorphisms and IBD susceptibility. We identified three Single Nucleotide Polymorphism (SNPs) . The data were analyzed by RevMan 5.4. Four studies (932 cases/1366 controls) were included. The findings showed no relationship between RAGE –429T/C and –G82S polymorphisms and the risk of IBD in all genetic models significantly. TT genotype of RAGE –374T/A polymorphisms was related to increased CD risk , while TA genotype was determined to be a protective factor . In UC, A allele of RAGE -374T/A was related to increase risk , while T allele was determined to decrease risk .Our findings demonstrated that TT genotype and A allele of RAGE -374T/A polymorphisms were related to CD and UC risks, respectively, while the TA genotype and T allele possibly had a protective effect. RAGE –429T/C and RAGE –G82S polymorphisms were not related to increased IBD risk. IBDs are the condition of chronic inflammation of the gastrointestinal system, including Chron's disease (CD) and ulcerative colitis (UC). There were around 6 to 8 million IBD cases worldwide in 2017 . Some CDThe capacity of the RAGE receptor to attach to advanced glycation end-products, whose particular polymorphisms of the promoter gene were identified to boost its transcriptional activity, is one of its main functions . RAGE ge5 The putative binding location of the receptor experiences an amino acid exchange as a result of the G82S RAGE polymorphism. The -374T/A RAGE promoter polymorphism increases transcriptional activity via decreasing the attachment of a nuclear factor to a regulatory region of the RAGE gene promoter. However, data on the -429T/C promoter polymorphism are scarcer. Recently, studies have found that RAGE polymorphisms were associated with IBD, but the results are inconclusive. Research carried out by Wang et al. showed that the RAGE G28S variant genotype was associated with UC susceptibility (The regulatory components of the RAGE gene contain a number of single nucleotide polymorphisms (SNPs), such as G82S, -374T/A, -492T/C, and others.tibility . Study btibility . RAGE poStrategy of search: To find pertinent studies from the time of publication to July 1, 2022, systematic literature searches of electronic databases comprising PubMed, Scopus, and the Cochrane library were carried out, utilizing the following terms: “Inflammatory Bowel Disease,” “IBD” “Chron disease,” “Ulcerative Colitis,” “advanced glycation end products receptor,” “RAGE,” “Genetic polymorphisms,” “SNP”. The language was restricted in English. The study was expanded to incorporate the bibliographies of every study that was qualified. A manual search of reviews of lifespan research was also conducted to find any more studies that could be pertinent. Then, authors were contacted personally if needed for any more information needed.Selection of study: Inclusion and exclusion criteria: The articles for the meta-analysis were chosen based on the inclusion criteria listed below: (i) case-control; (ii) cohort; (iii) comparative study; (iv) case group was a group of patients diagnosed with either CD or UC according to clinical, radiological, endoscopic, and pathology criteria; (v) control group was a group of healthy individual having neither a personal nor family history of IBD, nor a history of malignancy; (vi) the primary outcome was the relationship between the RAGE G82S, -374T/A, and -429T/C gene polymorphism and the risk of IBD; (vii) supplied enough genotype information to compute the odds ratio (OR) and 95% confidence range (CI). Meanwhile, here is the list of exclusion criteria: if any of the following conditions apply: i) there was no control group; ii) the distribution genotypes in the placebo group did not match with Hardy-Weinberg equilibrium (WHE); iii) the study populations overlapped; iv) there were small numbers more than 100 cases; v) the articles were not available in English; vi) the findings were only reported in conference proceeding book.Extraction of data: We were adhered to The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. The online supplement contains the comprehensive strategies of search. Two authors (B.R. and I.S.P.) independently assessed the titles and abstracts of publications after receiving preliminary database search results to weed out studies that did not answer the main study issue. Each included study's reference list was thoroughly investigated to find other pertinent researches. The remaining publications' entire texts were then separately evaluated by the same two authors (B.R. and I.S.P.) to determine if they offered pertinent and comprehensive material using the predetermined inclusion and exclusion criteria, as described below. Additionally, the bibliographies of the chosen publications and review articles on the subject were looked into to find any undiscovered research. Then, the reviewers' discussion helped to settle any disagreements amongst the authors about the inclusion of studies . In addition, we used information from the most recent thorough report, where duplicate studies from the same cohort were found. Author/s, year of publication, ethnicity, number of sample (cases and controls), and genotype/allele frequencies were all retrieved. If not expressly supplied, information on HWE was also manually estimated or retrieved.Assessment of study quality: Included studies were assessed using the Newcastle-Ottawa Scale (NOS), which assigns a point from 0 (the lowest) to 9 (maximum). There are eight elements on this scale, divided into three groups . Studies were rated as high quality if they had a total score of six or above, moderate quality if they had a score of four to six, and low quality if they scored lower or equal to four  5.4 was used to analyze the data. The relationship between the gene polymorphisms and longevity were estimated using allelic ratios and 95% confidence intervals. The inverse variance approach was applied to a random or fixed-effects model. We used Z test to assess the significance of the pooled OR. Study heterogeneity was characterized as low (25%), medium (50%) or high (75%), and the I2 statistic was used to determine the amount of variance across the results owing to study heterogeneity rather than sampling error. No significant heterogeneity was stated by an I2 score of less than 50% and/or a p-value of 0.05. Forest plots were prepared for each study. After sequentially removing each included study, sensitivity analyses were carried out to determine how each one affected the aggregate OR. Visual examination of funnel plots was used to assess potential publication bias.Critical appraisal: A critical review was carried out using the Oxford Center for Evidence-Based Medicine (CEBM) which included the validity, importance, and applicability of the articles that had been selected  are one of the ligands with high binding affinity for the trans-membrane receptor known as RAGE -18. RAGEin vitro study showed that RAGE gene polymorphism in -429T/C increased its expression, around twofold. The expression of RAGE is not only affected by the polymorphism. Concomitant factors such as environment and comorbid could alter the RAGE expression and increase RAGE level in IBD patient. The promotor's genetic polymorphism may be overpowered by this.The RAGE gene, which may be found on chromosome 6p21.3, encodes for RAGE expression. It has been demonstrated that the promotor region's SNPs -374A/T and -429T/C enhance protein synthesis by around thrice and twice, respectively. On the other side, the SNP at the G82S occur in exon 3 of RAGE . The rel In contrast, we found that some alleles and genotypes were associated with IBD susceptibility.


Following the “hygiene hypothesis”, the role of sibship composition in asthma and wheezing has been extensively studied, but the findings are inconsistent. For the first time, this systematic review and meta-analysis synthesized evidences from studies investigating the association of sibship size and birth order with risk of asthma and wheezing.Fifteen databases were searched to identify eligible studies. Study selection and data extraction were performed independently by pairs of reviewers. Meta-analysis with robust variance estimation (RVE) was used to produce pooled risk ratio (RR) effect estimates from comparable numerical data.From 17,466 identified records, 158 reports of 134 studies (> 3 million subjects) were included. Any wheezing in the last ≤ 1.5 years occurred more frequently in infants with ≥ 1 sibling  and ≥ 1 older sibling . The pooled effect sizes for asthma were overall statistically nonsignificant, although having ≥ 1 older sibling was marginally protective for subjects aged ≥ 6 years . The effect estimates weakened in studies published after 2000 compared with earlier studies.Being second-born or later and having at least one sibling is associated with a slightly increased risk of temporary wheezing in infancy. In contrast, being second-born or later is associated with marginal protection against asthma. These associations appear to have weakened since the turn of the millennium, possibly due to lifestyle changes and socioeconomic development.Video AbstractThe online version contains supplementary material available at 10.1007/s12519-023-00706-w. Asthma is a heterogeneous chronic inflammatory pulmonary disease –3 characAsthma and other atopic diseases commonly coexist  and demoThis study was conducted according to an a priori published protocol , which wAMED, CABI, CINAHL, Embase, Google Scholar, OAIster, Open Access Theses and Dissertations, Open Grey, ProQuest Dissertations & Theses Global, PsycINFO, PubMed, SciELO, Scopus, Web of Science, and WHO Global Index Medicus were searched from inception through the search date (30 September 2020). An updated search was performed on 20 October 2021. From Google Scholar, the first 300 results were retrieved . ArticleObservational studies  of any publication status  were eligible. Reviews, case series/studies, and expert opinions were excluded. There was no restriction on subject characteristics or sample size. Studies with defined sibship composition as an independent variable and asthma—either self-reported, including symptom-based definitions, e.g., wheezing , or baseDeduplication was performed by DL in EndNote X9  using a method proposed by Bramer et al. . DL and Assessment of quality in the included studies was performed using the Effective Public Health Practice Project (EPHPP)  tool, morobu function from the robumeta [forest function from the forestploter [RR ≈RR ≈Descriptive tables summarizing key characteristics of the included studies were generated. Findings were narratively synthesized. Comparable (regarding independent/dependent variables and participant characteristics) numerical data from ≥ 2 separate studies  were anarobumeta  R packagrobumeta . In the robumeta , and thestploter  R packagstploter –48, withstploter :RR ≈\docIncidence risk ratio (IRR), prevalence ratio (PR), and relative risk ratio (RRR) estimates were used without conversion, as these are mathematically identical to RR . Effect sensitivity function from the robumeta [I2) statistic was calculated to quantify the proportion of variance across study estimates not due to random sampling error [τ2) was calculated to assess the between-study variance [df) < 4 were considered unreliable [Sensitivity analysis was conducted by excluding studies with a “weak” overall rating and studies where the outcome was not clinically confirmed . Furthermore, sensitivity analysis on the basis of the rho value in the meta-analyses was performed using the robumeta  R packagng error , 57. Tauvariance . Meta-anreliable .funnel function); (b) statistically, with Begg and Mazumdar rank correlation test [ranktest function) and Egger’s regression test [regtest function), regarding P < 0.05 as significant. The trim-and-fill method [trimfill function. Publication bias assessment was performed with the metafor [https://osf.io/kmfe2).Publication bias was assessed: (a) visually for indications of asymmetry with funnel plots  or cross-sectional (n = 71) designs, while 13 were case‒control studies and four were nested case‒control studies. Fifty-six reports had “high”, 78 had “moderate”, and 24 had “weak” overall ratings  and birth order .Any wheezing was assessed with meta-analysis in 27 reports for birth order and 15 reports for sibship  and sibship size ≥ 2 vs. 1 .Recurrent wheezing was assessed with meta-analysis in five reports for birth order and three reports for sibship size . There were insufficient studies to perform subgroup analysis, and the pooled effect sizes were nonsignificant. Heterogeneity was moderate for both birth order ≥ 2 vs. 1 . A dose-dependent increase could be discerned in the subgroup analysis for birth order, but none of the cardinalities had a significant pooled effect size. The association did not vary notably by overall quality. For sibship size ≥ 2 vs. 1, the only significant finding was for studies published before 2000 .Current asthma was assessed with meta-analysis in 23 reports for birth order and 13 reports for sibship size  compared to later studies . Studies of strong overall quality indicated a slightly stronger association than studies of moderate overall quality. Heterogeneity was moderate for both birth order  and sibship size .Ever asthma was assessed with meta-analysis in 19 reports for birth order and 7 reports for sibship size , and the corresponding funnel plot appeared asymmetric; however, the outlying estimates were mostly derived from one study [The funnel plots  did not indicate substantial publication bias. For birth order on current asthma, Egger’s regression test was significant  compared to the pooled effect size of all studies , while the association of sibship size with any wheezing remained significant. For asthma outcomes, the overall pooled effect sizes remained similar across sensitivity analyses, while there were too few studies on recurrent wheezing to draw any conclusions (Supplementary Table S7). Different values of rho only marginally shifted the pooled effect sizes (Supplementary Table S8).We found a slight but significantly increased risk of wheezing in infants with siblings and second-born or later infants. This association was not significant for recurrent wheezing and did not remain beyond infancy; however, the risk of current asthma was marginally lower for individuals aged ≥ 6 years with at least one older sibling. The investigated associations weakened in studies published after 2000 compared to earlier studies. This trend was also seen in studies of moderate or strong overall rating from before vs. after the turn of the millennium. The findings were comparable between continents for most outcomes; however, for the association of birth order with any wheezing, a statistically significant increased risk was indicated in Europe, in contrast to Asia and North America.To our knowledge, this systematic review is the first to assess the association between sibship composition and the risk of asthma. We searched 15 databases and identified a substantial body of relevant research, allowing for precise meta-analysis and detailed analyses of trends and associations at the subgroup level. However, most studies were from high-income countries, which limited subgroup analysis by income. Similarly, as most studies were conducted in geographically limited areas, we had insufficient data to discern any clear and consistent trend or difference in the association by continent. Furthermore, the included studies were heterogeneous in methodology, participants, and definition of asthma, restricting generalizability of the results. This also limited the number of studies eligible for meta-analysis, particularly due to substantial differences in the cardinalities  and reference groups used, as well as heterogeneous outcome definitions, e.g., with variations in healthcare use, concomitant symptoms such as wheezing, presence of atopy, etc. Observational studies—constituting the basis for our analyses—are prone to risk of confounding ; thus, tTo the best of our knowledge, this is the first systematic review on the role of sibship composition in asthma. Furthermore, we performed the first quantitative synthesis including dependent data for this association, enabling precise pooled effect size estimates.Between birth order and sibship size in relation to the risk of asthma, the impact of birth order appears stronger than that of sibship size, which may be because being second-born presupposes having at least one sibling, while having at least one sibling does not presuppose having at least one older sibling. Furthermore, the proposed “hygiene hypothesis” is likely driven by older siblings, who may be old enough to attend school or have outdoor activities from which contracted infections can be transmitted to younger siblings , 69, 70.The association between sibship composition and transient wheezing appears to stem from respiratory infections, commonly caused by cross-infection between siblings during infancy , 77, andIn conclusion, our findings indicate that having siblings and being second-born or later, respectively, may constitute a slightly increased risk of transient wheezing in infancy. This association does not extend beyond infancy. In contrast, being second-born or later appears to be associated with marginal protection against asthma. These associations have seemingly weakened since the turn of the millennium, possibly due to lifestyle changes and socioeconomic development.Supplementary file1 (DOCX 3823 KB)Below is the link to the electronic supplementary material.


The incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application.This study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs.We searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted.In total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age , preexisting chronic kidney disease (CKD) , ipilimumab , combination of ICIs , extrarenal immune-related adverse events (irAEs) , and proton pump inhibitor (PPI) , nonsteroidal anti-inflammatory drug (NSAID) , fluindione , diuretic  and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs)  use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study.The occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs.https://www.crd.york.ac.uk/prospero/, identifier CRD42023391939. OncologAlong with the wide application of ICIs in cancer treatment, multisystem autoimmune phenomena termed immune-related adverse events (irAEs) have markedly emerged into our vision for their nonselective role on immune checkpoints. The overall incidences of irAEs in patients treated with ICIs range from 15% to 90%, of which the most frequently observed are dermal, gastrointestinal tract, endocrine system and liver , 7. Alth22.1The study protocol has already been registered in PROSPERO (CRD42023391939) and in accordance with the Cochrane handbook and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) .2.2Electronic databases of English language publications, PubMed/Medline, Web of Science, Cochrane and Embase were searched to collect studies dated to 1 February 2023 in terms of the incidence and risk factors of AKI in patients treated with ICIs. We retrieved relevant articles through the combination of Medical Subject Headings (MeSH) terms comprising “immune checkpoint inhibitors”, “acute kidney injury”, “risk factor” or “incidence” and all the corresponding free words. Complete and detailed search strategies of each database are provided in 2.3The inclusion criteria were as follows: (a) the study sample consisted of patients with malignancy and treated with ICIs aged 18 years or above; (b) the study reported the incidence or risk factors of AKI in patients receiving ICIs. AKI is defined as an increase in serum creatinine to≥1.5 times the baseline level, which is known or presumed to have occurred within the prior 7 days; or an increase in serum creatinine by ≥26.5 µmol/L within 48 hours; or oliguria  sufficient data were provided on the event number or effect size, the odds ratios (OR) or hazard ratio (HR), and 95% confidence intervals (95% CI) with full texts.Studies were excluded for the following reasons: (a) they were reviews, meta-analyses, case reports, conference abstracts and guidelines; and (b) the study was conducted based on animals.2.4After excluding duplicates, two researchers independently screened the titles and abstracts of all identified records to remove irrelevant documents. Then, a full-text review was conducted to determine the eligibility for inclusion. Any disagreement on study selection was resolved by discussion with the third researcher . The study selection process is shown in 2.5The following data were extracted from the included studies: (a) the basic information, including first author, publication year, region, data source, data, study design, study type, and enrollment period; (b) characteristics of the participants, including sample size, number of AKI cases, sex ratio , and median age; and (c) the incidence, median time and interquartile ranges and effect size (OR or HR) and 95% CI of potential risk factors in each study, encompassing sex, older age, comorbidities, baseline eGFR, ICIs, extrarenal irAEs, and concomitant agents. We prioritized the extraction of multivariate analysis data from the adjustment model. According to the Newcastle−Ottawa Scale (NOS) designed for cohort studies and case−control studies and the Cochrane Handbook designed for randomized clinical trial, two researchers (LC and ZY) independently assessed the risk of bias. For 23 observational studies, selection (0-4 scores), comparability (0-2 scores) and outcome or exposure (0-3 scores) are the three evaluation domains containing an eight-item checklist ranging from 0 to 9 scores. The scores of the included articles ranged from 6 to 9 and were classified as high quality. Among the three domains, the outcome of the included records performed the worst due to scant time for the occurrence of potential ICI-AKI. For 4 randomized clinical trials, 2 studies that did not adopt blinding methods for participants and outcome were evaluated as ‘‘High risk.” A study failing to elaborate specific method of allocation concealment was classified as ‘‘Unclear”. Other evaluation items were mostly ‘‘Low risk.” Generally, the included studies had low methodological bias. Detailed information is illustrated in 2.6I2 statistics for between-study heterogeneity . Meta-regression was conducted to explore the contributor of substantial heterogeneity. OR and 95% CI were employed as pooled effects, and P<0.05 was considered to be statistically significant. We regarded HR as a good estimate of OR only if HR was represented in original studies. IBM SPSS Statistics 20 was used to calculate ORs and 95% CIs if neither ORs nor HRs were provided in the primary texts. All statistical analyses were performed using Stata Statistical Software, version 16.0. Moreover, sensitivity analyses by sequentially omitting studies and publication bias analyses by funnel plots, Begg’s and Egger’s statistical tests were shown to evaluate the robustness of the results.In this meta-analysis, the incidence, median time from ICIs initiation and risk factors of AKI encompassing sex, older age, comorbidities, baseline eGFR, ICIs, extrarenal irAEs, and concomitant agents in cancer patients receiving ICIs were pooled and compared between patients with AKI and without AKI using random effects and 33.1A total of 401 documents were initially searched for incidence and risk factors. After removing 92 duplicates, we screened the title and abstract of each study and found that 128 citations were apparently irrelevant. In the remaining records, 3 studies based on animals, 15 meta-analyses, 80 reviews, 19 identified as case reports and guidelines were deleted. Besides, 19 conference abstracts and 18 without full articles were also excluded. Then, 27 full texts were scrutinized, and 6 studies were excluded for insufficient data on risk factors. In addition, 6 studies were added by searching from reference lists of 21 identified articles. Finally, 27 literatures were carried out in this systematic review and meta-analysis, with 22 for incidence, 17 for risk factors and 12 shared , 15–36.3.2A total of 24048 participants receiving different types of ICIs due to malignancies from 27 studies were investigated in our systematic review and meta-analysis. The sample size varied between 89 and 3109, and the median age of recorded patients ranged from a minimum of 57 years to a maximum of 69 years. The majority were native to America and Asia. These articles were all published between 2017 and 2022, and studies were performed from 2010 to 2021. Despite 4 randomized clinical trials and a case-control study, the remaining 22 were cohort studies Table 1.3.3P< 0.001, I2 = 97.3%)       or who received combined treatment with two or more kinds of ICIs      .3.4.3P< 0.001, I2 = 0.0%, n= 8 studies), NSAID , fluindione , diuretics  and ACEI/ARB   are at greater risk of AKI . PPIs an4.2This systematic review and meta-analysis filled the gap of insufficient and not comprehensive data on AKI following ICIs with regard to incidence and risk factors, as well as latency period of ICI-AKI. Several limitations should be noted when interpreting the results of this study. First, publications enrolled in this meta-analysis were mostly retrospective cohort studies. Potential bias is unavoidable due to the nature of source studies. Second, the definition of ICI-AKI varied across studies. A universal diagnostic criterium of ICI-AKI is needed. Third, the number of studies included in the analysis of certain risk factors was limited, which might hamper the robustness of the study findings, especially for preexisting CKD, ipilimumab and fluindione investigated by only 2 studies. In addition, as only a small fraction of the primary studies reported tumor-type specific data of AKI following ICI use, we were unable to perform subgroup analysis stratified by type of tumor.4.3Some potential risk factors were not included in this meta-analysis due to the limited number of primary studies. For example, Asian participants were found by Abdelrahim et al. to have a stronger tendency to contract AKI secondary to ICIs . In term5This systematic review and meta-analysis demonstrated a substantial incidence (5.7%) of AKI in cancer patients receiving ICIs with a median latency period of 108.07 days. Older age, preexisting CKD, ipilimumab, joint use of more than one ICI, extrarenal irAEs, and use of PPI, NSAID, fluindione, diuretics and ACEI/ARB were all identified as risk factors for ICI-AKI. These findings may provide insights into the optimization of the management of patients who receive ICI treatment.The original contributions presented in the study are included in the article/Conceptualization: YZ, LZ and PF. Data Curation: YZ, CL, WW, LY, and CY. Formal analysis: YZ, CL, WW, YP, TY, and FN. Funding Acquisition: YZ. Supervision: YZ and PF. Writing-original draft: CL and YZ. Writing review/editing: all co-authors.


Malnutrition in childhood has lasting consequences; its effects not only last a lifetime but are also passed down from generation to generation such as short stature, school-aged children are the most vulnerable section of the population and require special attention, including nutrition.We searched Medline through PubMed, Scopus, and Web of Science to identify all observational studies published before Jun 2022. Observational studies with a pediatric population aged 5–18 years that evaluated risk estimate with 95% confidence intervals the relationship between dietary diversity and undernutrition  were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) were followed.This is a first systematic review and meta-analysis with a total of 20 studies were eligible (n = 18 388). Fourteen data evaluated stunting resulting in a pooled effect size estimated odds ratio of 1.43 . Ten data evaluated Thinness resulting in a pooled effect size estimated odds ratio of 1.10 . Two studies were revealed wasting with a odds ratio of 2.18 .According to the conclusions of this meta-analysis of cross-sectional studies, inadequate dietary diversity increases the risk of undernutrition in growth linear but not in thinness in school-aged children. The findings of this analysis suggest that initiatives that support improvements to the diversity of children’s diets to reduce the risk of undernutrition may be warranted in LMICs.The online version contains supplementary material available at 10.1186/s12887-023-04032-y. Malnutrition is a term that refers to energy or nutritional deficiency, as well as excess or imbalanced nutrition intake. There are three distinct forms of malnutrition: 1) malnutrition due to micronutrient deficiency, (2) malnutrition due to micronutrient deficiency and obesity, (3) undernutrition classified as wasting (low weight-to-height ratio), stunting (low height-to-age ratio), and underweight (low weight-for-age) /log (OR). The natural logarithms of the ORs, as well as their SEs and 95% CIs, were calculated.2 Index, Cochran’s Q statistic, and the associated P-value for heterogeneity were utilized. To detect publication bias, visual inspection of funnel plots and Egger’s tests for funnel plot asymmetry were performed. We were able to investigate consistency in the pooled data by removing one trial at a time and re-estimating the pooled OR. All statistical analyses were performed using STATA 11.0 software (STATA Corp.). Statistical significance was defined as P values less than 0.05 [To examine homogeneity, the Ihan 0.05 .The flow diagram depicts the search strategy and results Fig. . During The review examined the following data released between 2011 and 2022: 2011 (n = 1), 2013 (n = 1), 2015 (n = 1), 2017 (n = 1), 2018 (n = 2), 2019 (n = 4), 2020 (n = 5), 2021 (n = 3), 2022 (n = 1). The features of the included studies are shown in Table Fourteen effect sizes reported stunting, ten effect sizes reported thinness, and only two studies revealed wasting.According to our findings, all the included studies received a high-quality score Table . As prevQ−test <0.001), subgroup analysis was conducted based on different parameters (Table Q−test =0.086), and studies were conducted in both groups of sex (Q−test =0.063).Fourteen effect sizes were included in the final analysis with 8539 individuals. Participants with inadequate dietary diversity had a 43% higher  estimated odds of stunting compared to those with adequate diet diversity Fig. . Due to entclass1pt{minimaWe visually inspected the funnel plot for asymmetry for stunting and dietary diversity. The funnel plot Figure  appearedQ−test <0.001). Due to considerable between-study heterogeneity, Subgroup analysis was conducted based on different parameters    by removing data from the meta-analytic model. There was no sensitivity among all studies Figure , S4.GRADE was performed for evaluated the certainty of studies. The result of GRADE showed that the certainty of both outcome stunting and thinness is very low while wasting is moderate Table .Concerning survey data, our meta-analysis and systematic evaluation of cross-sectional research comprised 18,388 participants from 20 studies. According to the findings of this study, school-aged children with a limited diet are more likely to have a higher estimated pooled risk of stunted growth and wasting. However, there is no association between a limited diet and thinness.Dietary Diversity (DD) is the variety of foods or food categories ingested throughout a certain time period . DiverseSchool-aged is a period of great change . DependiA lack of variety in one’s diet has been linked to an increased risk of short height in adolescents. This might be due to a cereal-based monotonous diet with inadequate quality, amount, and frequency of feeding that does not meet micronutrient needs for child development, such as iron, vitamin B12, folate, and other necessities . In addiDue to our analysis, dietary diversity has not been linked to thinness which is different from another study that discovered low dietary diversity, three times more likely to become thin . This miDue to rapid development and increasing nutritional needs throughout adolescence, a low frequency of meals will cause them to become underweight or thin . School-However, our stratified analysis failed to show a significant association between sex and stunting and thinness, other studies indicated that stunting is significantly higher in female adolescents , 48, 49.As this duration is a phase of fast growth, proper nutrition is essential to reach full growth potential, and failure to acquire appropriate food may result in delayed and stunted linear growth and poor organ remodeling . The durOur stratified analysis showed a significant relationship between stunting and studied conducted in Asia. This might be because more low- and middle-income countries (LMICs) are from the Asian continent, and various research from LMICs have shown a lack of nutritional variety and inadequacy , 54. SinThe current studies have many strengths. To the best of our knowledge, this is the first systematic review and meta-analysis to evaluate the risk estimations for the relationship between dietary variety and undernutrition in school-aged children, and both groups of sex were included. The meta-analysis had a reasonable sample size, indicating that it improved the power of the meta-analysis to detect meaningful conclusions and precise estimates. Finally, all studies included in this review were deemed high-quality based on the assessment tool.However, limitations should be considered when evaluating the findings of this meta-analysis. We used dietary diversity as a proxy for the overall nutritional quality of the child’s diet. Since this study did not account for the number of foods consumed, it is impossible to determine with certainty if the foods consumed corresponded to the recommended dietary intake. Considerable heterogeneity was found in the primary analysis. However, a subgroup-stratified analysis was performed to evaluate potential causes for heterogeneity. Most studies used a 24-hour dietary recall assessment, which is subject to erroneous categorization and reporting bias and may not capture all relevant dietary data. Finally, all studies were cross-sectional, meaning causality cannot be established, and there remains a limited understanding of the longitudinal relationship between dietary diversity and undernutrition.According to the conclusions of this meta-analysis of cross-sectional studies, inadequate dietary diversity increases the risk of undernutrition in growth linear and wasting but not in thinness in school-aged children. The findings of this analysis suggest that initiatives that support improvements to the diversity of children’s diets to reduce the risk of undernutrition may be warranted in LMICs. However, future research, specifically longitudinal cohorts, and clinical trials, with age-classification are needed to confirm these findings and determine the mechanisms responsible for the association between dietary diversity and undernutrition.Below is the link to the electronic supplementary material.Supplementary Material 1


Hypertension is a risk factor for cardiovascular diseases which also causes progressive kidney damage leading to chronic kidney disease (CKD), so the rate of progression of CKD can be controlled by reducing blood pressure (BP). Many anti-hypertensive drugs are available. Cilnidipine is a new-generation calcium channel blocker (CCB). This meta-analysis is aimed to generate pooled evidence about the effectiveness of cilnidipine as an anti-hypertensive and to explore its reno-protective actions. Pubmed, Scopus, Cochrane Library, and Google Scholar were searched from January 2000 to December 2022 to include the studies. The pooled mean difference, along with 95% CI, was computed using Revman 5.4.1 software . The Cochrane risk-of-bias assessment tool was used for bias assessment. This meta-analysis was registered in PROSPERO with Reg. no. CRD42023395224. This meta-analysis included seven studies with 289 participants in the intervention group and 269 in the comparator group, and were selected from Japan, India, and Korea. Systolic blood pressure (SBP) was significantly reduced in cilnidipine treated group among hypertensives with CKD subjects weighted mean difference (WMD) was 4.33, and the 95% confidence interval (CI) was 1.26 to 7.31 as compared to the other group. Cilnidipine also shows a significant reduction in proteinuria with WMD 0.61 and 95% CI 0.42 to 0.80. Both groups were similar in adverse drug reactions (ADR). Cilnidipine is a more effective anti-hypertensive as compared to Amlodipine or other CCBs, mainly in reducing SBP. Besides this, cilnidipine also shows better reno-protective action because it also significantly reduces proteinuria in such patients. Hypertension (HTN) is a worldwide problem and is also increasing day by day. It is a risk factor for not only cardiovascular diseases but also chronic kidney diseases (CKD). Initially, CKD classification was based only on glomerular filtration rate (GFR), but now proteinuria or the amount of albuminuria has also been incorporated in its definition. Kidney size of less than 10-15 cm in renal ultrasonography (USG) is suggestive of chronicity. Hypertension and CKD go hand in hand in the long run in life. Both are interrelated to each other. One of the major risk factors for developing CKD is HTN. So control of HTN is very important to slow the progression of CKD. Controlling blood pressure (BP) not only reduces CKD progression but also reduces cardiovascular risk -3. The rate of progression of CKD can be controlled by reducing BP, so along with antihypertensive drug treatment, regular BP monitoring is also essential. Evidence shows that there are more chances of nocturnal HTN in hypertensive patients with CKD as compared to HTN without CKD. So nocturnal BP measurement is also important, which is only possible through ambulatory BP monitoring .Different pharmacological treatments for HTN are available. Among various groups of antihypertensive drugs, diuretics, angiotensin-converting enzyme (ACE)-inhibitors, angiotensin receptor antagonists, calcium channel blockers (CCBs), vaso dilators, centrally acting alpha agonists, and β-blockers are commonly used in our community . The renCCBs are another class of drugs for HTN. They block voltage-gated calcium channels (CC). Chemically, amlodipine is a dihydropyridine (DHP), which blocks L-type voltage-gated CC. Blockade of these channels causes vasodilatation. They show more affinity for plasma proteins, so they are mainly metabolized in the liver. Their dose modification is not required in kidney dysfunction patients.Another type of CC is N-type channels which are present in the brain and nerves. Cilnidipine blocks both N as well as L-type calcium channels. By blocking these channels, cilnidipine suppresses the hyperactivity of the sympathetic nervous system (SNS) and RAAS. Thereby it might show some reno-protective actions . NowadayMethodologyStudy Selection ProcessThe guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) have been followed for preparing this meta-analysis. Two independent reviewers searched Pubmed, Scopus, Cochrane Library, and Google Scholar to search for the required studies from Jan. 2000 to Dec. 2022. These studies were searched using the keywords hypertension or cilnidipine OR reno-protective action.Research QuestionThe study included a population of hypertensive adult patients suffering from CKD for more than three months. The intervention group received treatment with cilnidipine, while the comparative group was treated with any other CCB except cilnidipine. The outcomes were mean systolic and diastolic BP reduction, decrease in serum creatinine or urinary protein/creatinine ratio, and estimated GFR along with any adverse outcome. Eligibility criteria have been shown in Table Data ExtractionTwo independent reviewers extracted the data from the included studies. Data was cross-checked for consistency, and any difference in data was corrected by rechecking and discussion. Data was collected in the form of the year of publication, author name, sample size, study population, any comorbidity, mean age of study participants, drugs used in the intervention and comparator group, and the outcome parameters. Any adverse drug reaction (ADR) data was also reported.Statistical AnalysisContinuous data was computed in the form of weighted mean difference (WMD) with 95% confidence interval (CI). In case of significant heterogeneity (chi²>50%), the random effect model was used, while a fixed effect model was used for homogeneous data. All the continuous variable was presented along with standard deviation (SD). In case of heterogeneity, STATA software  was used to explore the cause of heterogeneity. Dichotomous data was also collected with 95% CI. All the data was entered in Revman 5.4.1 , and pooled analysis was done.Bias Assessment ToolBias assessment of all the included randomized controlled trials (RCTs) was done using the Cochrane risk-of-bias assessment tool. Six domains of this tool were assessed by two different reviewers independently. For assessing selection bias, random sequence generation and allocation concealment were checked. Performance bias was assessed by checking the blinding procedure used for participants and other personnel. Detection bias was assessed by observing the blinding status of the outcome assessor. The above domains were categorized into low-risk and high-risk. Reporting bias was assessed based on the completeness of outcome data. If all the given parameters were reported as mentioned in the methodology section, then it was low-risk; otherwise, it was considered as high-risk bias. Lastly, attrition bias was assessed based on the number of losses to follow-up participants. If less than 10% loss to follow-up, it was low-risk, and if more than 10%, then it was high-risk. Bias assessment was done using Revman software 5.4.1.This study has been registered in PROSPERO with registration number CRD42023395224.ResultsStudy Selection ProcessBy using different databases and registers, a total of 852 studies were identified. Before screening, 675 studies were excluded due to irrelevant studies. One hundred forty-nine were again excluded after screening as they did not match our objectives. A further three studies could not be retrieved so among 25 eligible studies, 18 were again excluded due to not meeting inclusion criteria, no proper data outcome, and the absence of any comparable group. Finally, seven eligible studies  were useCharacteristics of Included StudiesDetails of the selected studies are shown in Table Primary Outcome2=6.46, I2=23%, p=0.26).The primary outcome of this meta-analysis was a reduction in the mean SBP and DBP among study participants. We got reductions in both SBP and DBP in the cilnidipine-treated arm as compared to the comparator arm, but SBP reduction was significant with a weighted mean difference (WMD) of 4.33 and 95% confidence interval of 1.26 to 7.39 as shown in Figure DBP reduction was not significant by cilnidipine with WMD 1.74 and 95% CI -0.15 to 3.62. No heterogeneity was seen.Secondary OutcomeChanges in different renal parameters were our secondary outcome. Insignificant change in serum creatinine was seen in cilnidipine treated group as compared to the comparator group, with WMD -0.02 and 95% CI -0.11 to 0.08, which indicates that serum creatinine level increases by cilnidipine. Similarly, insignificant change was found in the GFR level also, where WMD was 0.75 with 95% CI -1.66 to 3.16, as shown in Table 2=8.90 and p<0.00001. Seven studies were included, as shown in Figure We found a significant decrease in proteinuria with WMD 0.61 and 95% CI 0.42 to 0.80. Thirty-three percent heterogeneity was seen with ChiTwo studies reported ADR Figure , which dRisk-of-Bias AssessmentFive studies showed low risk in random sequence generation, while one study showed high risk. In only one study, allocation concealment was followed. All the included studies showed high risk of performance bias because all were open-label studies. Only one study showed low risk in detection bias; three showed unclear risk, while two showed high risk Figure . In two Surprisingly, all the studies showed a low risk of reporting bias. The risk-of-bias assessment graph is shown in Figure , which sDiscussionIn this meta-analysis, seven studies from different countries  were included, with 289 participants in the cilnidipine-treated group and 269 in the comparator group. The study participants were those hypertensive patients who were also suffering from CKD for more than three months. Our pooled analysis showed that cilnidipine decreased mean SBP significantly with an insignificant lowering of mean DBP value. Our finding is different from the previous meta-analysis conducted among hypertensive Chinese patients, which showed that there was no difference in cilnidipine and amlodipine among mild to moderate essential hypertensive patients . This diCilnidipine and amlodipine are both CCBs belonging to the DHP group. Both block L-type voltage-gated CC, but cilnidipine additionally blocks N-type CC also . Due to Our pooled analysis also shows that cilnidipine does not significantly change serum creatinine levels as well as GFR. But this study provides evidence that cilnidipine has renal protective actions as it significantly decreases proteinuria in CKD patients, which supports the previous meta-analysis in which renal function was assessed among hypertensive patients receiving cilnidipine and L-type CCBs and cilnidipine showed better improvement in urinary protein excretion with similar effect on serum creatinine. It can Renoprotective action of cilnidipine has been shown in hypertensive rats also, in which HTN was induced by oral administration of one of the L-arginine analogs in distilled water for four weeks. InteresBlocking of N-type CC provides additional organ protective activity to cilnidipine, like cardio-protection and reno-protection . One stuNoveltyThis is the first time the anti-hypertensive action of cilnidipine among hypertensive patients with CKD in Jharkhand has been assessed. In addition to this, its renal protective action was also assessed for the first time among CKD patients, and a meta-analysis was done, which will provide better evidence for choosing the better drug for treating physicians, especially for CKD patients.Our pooled analysis shows that cilnidipine is more effective than amlodipine in reducing SBP among patients with CKD. Cilnidipine is a more lipophilic drug than amlodipine, so its bioavailability increases. Cilnidipine has an inhibitory action on SNS, which increases its BP-reducing potential. Its alpha-blocking action also helps in BP reduction; thereby, it can be a better choice than amlodipine as an antihypertensive drug.Further, cilnidipine also significantly decreases proteinuria in CKD patients, so it shows its renal protective actions. It also inhibits RAAS, which adds to its renal protective action. So cilnidipine can be preferred over amlodipine or other L-type CCBs, especially in CKD patients, because it can better control BP as well as proteinuria. It has the potential to prevent the progression of CKD, which is very important. It is also advantageous because it also lowers the triglyceride level, which is again helpful in reducing mortality among hypertensive subjects.