Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis.
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SUBMITTER: Tziastoudi M
PROVIDER: S-EPMC9736240 | biostudies-literature | 2022 Dec
REPOSITORIES: biostudies-literature
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Key Genetic Components of Fibrosis in Diabetic Nephropathy: An Updated Systematic Review and Meta-Analysis.
Tziastoudi Maria M Theoharides Theoharis C TC Nikolaou Evdokia E Efthymiadi Maria M Eleftheriadis Theodoros T Stefanidis Ioannis I
International journal of molecular sciences 20221205 23
Renal fibrosis (RF) constitutes the common end-point of all kinds of chronic kidney disease (CKD), regardless of the initial cause of disease. The aim of the present study was to identify the key players of fibrosis in the context of diabetic nephropathy (DN). A systematic review and meta-analysis of all available genetic association studies regarding the genes that are included in signaling pathways related to RF were performed. The evaluated studies were published in English and they were incl ...[more]
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Project description:Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger's test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.
| S-EPMC7577775 | biostudies-literature
Project description:Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Many trials have shown that Abelmoschus manihot could further improve proteinuria and protect kidney function in patients with DN when added to a renin-angiotensin system (RAS) blocker. A systematic assessment of the efficacy and safety of A. manihot in DN is essential. Eight electronic databases were searched to identify eligible trials published from inception to December 2017. The Cochrane Risk of Bias Tool was used to evaluate the methodological quality of eligible studies. Seventy-two studies with 5,895 participants were identified. The methodological quality of included studies was generally low. The results indicated that, compared to a RAS blocker, combined treatment of A. manihot with a RAS blocker was more effective for 24h urinary protein (24h UP) (mean difference [MD], -0.39 [95% confidence interval [CI], -0.46 to -0.33] g/d; P<0.00001), urinary albumin excretion rate (UAER)(MD, -19.90 [95% CI, -22.62 to -17.18] μg/min; P<0.00001), 24h UP reduction rate (risk ratio [RR], 1.43; 95% CI, 1.26-1.63; P<0.00001), normalization of UAER (RR, 1.48; 95% CI, 1.29-1.70; P<0.00001), and serum creatinine (SCr) (MD, -7.35 [95% CI, -9.95 to -4.76] umol/L; P<0.00001). None of these trials reported the ESRD rate. No statistically significant difference occurred between A. manihot combined with a RAS blocker and a RAS blocker alone in estimated glomerular filtration rate (eGFR) (MD, 4.43 [95% CI, -1.68 to 10.54] mL/min; P=0.16). A. manihot did not increase the rates of adverse drug events. A. manihot in addition to a RAS blocker was effective and safe to further improve proteinuria and protect kidney function in patients with DN. However, due to the generally low methodological quality, significant heterogeneity, and publication bias, high-quality randomized controlled trials are required to confirm these findings before the routine use of A. manihot can be recommended.
| S-EPMC6500631 | biostudies-literature
Project description:IntroductionDiabetic nephropathy (DN) is a long-term kidney disease among diabetic patients. It is the leading cause of end-stage renal failure. In Ethiopia, DN affects the majority of diabetic populations, but there were inconsistent findings about the determinant factors across the studies.MethodsWe have accessed studies using PubMed, Embase, EBSCO, Web of Science, OVID, and search engines including Google and Google Scholar published up to June 2023. The study populations were diabetic patients with nephropathy. The quality of each included article was assessed using the Newcastle-Ottawa quality assessment scale. The odds ratios of risk factors were pooled using a random-effect meta-analysis model. Heterogeneity was assessed using the Cochrane Q statistics and I-Square (I2). The publication bias was detected using the funnel plot and/or Egger's test (p< 0.05). Trim and fill analysis was carried out to treat the publication bias. The protocol has been registered with the reference number CRD42023434547.ResultsA total of sixteen articles were used for this reviewed study. Of which, eleven articles were used for advanced age, ten articles for duration of diabetic illness, ten articles for poor glycemic control, and eleven articles for having co-morbid hypertension. Diabetic patients with advanced age (AOR = 1.11, 95% CI: 1.03-120, I2 = 0.0%, p = 0.488), longer duration of diabetic illness (AOR = 1.23, 95% CI = 1.05-1.45, I2 = 0.0%, p = 0.567), poor glycemic control (AOR = 2.57, 95% CI: 1.07-6.14; I2 = 0.0%, p = 0.996), and having co-morbid hypertension (AOR = 4.03, 95% CI: 2.00-8.12, I2 = 0.0%, p = 0.964) were found to be factors associated with DN.ConclusionsThe findings of the study revealed that diabetic patients with advanced age, longer duration of diabetic illness, poor glycemic control status, and co-morbid hypertension were the determinant factors of DN. Therefore, treatment of co-morbid hypertension and high blood glucose and regular screening of renal function should be implemented to detect, treat, and reduce the progression of DN. Furthermore, healthcare workers should give due attention to diabetes with advanced age and a longer duration of diabetes illness to prevent the occurrence of DN.
| S-EPMC10836702 | biostudies-literature
Project description:A large amount of researches have demonstrated that vitamin D receptor (VDR) gene polymorphisms are associated with diabetic nephropathy (DN) risk in diabetes mellitus (DM) patients. Nevertheless, the results are inconclusive and inconsistent.We screened PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Wanfang databases for those relevant studies updated in May 2016.7 studies involving 2564 subjects were recruited. We evaluated the genotypic and allelic differences between DN patients and DM controls. Overall analysis showed that no significant association was found among the ApaI, BsmI, FokI,TaqI gene polymorphisms and DN susceptibility in diabetic patients (all P values > 0.05). In the stratified analysis, TT genotype was related to DN susceptibility in Asians (TT vs Tt + tt: OR =2.21, 95% CI: 1.05-4.67, p = 0.04). The sensitivity analysis showed that the results in overall populations, Caucasians and Asians were dependable.No significant association was found among the ApaI, BsmI, FokI, TaqI polymorphisms and DN risk in overall populations, the TaqI variants might related to DN susceptibility in Asians. Further researches are required to testify our meta-analysis.
| S-EPMC5575903 | biostudies-other
Project description:Aims/hypothesisThis meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.MethodsPubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.ResultsThe literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).Conclusions/interpretationThis meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.
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Project description:AimsChanges of serum galectin-3 (Gal-3) is associated with the pathogenesis of diabetic nephropathy (DN). However, current literature indicates that the given results remain debatable and inconsistent. Hence, the aim of this present meta-analysis was to focus on the predictive role of serum Gal-3 in patients with DN.MethodsThe PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched for studies that reported the relationship between Gal-3 levels and DN risk, from the inception of each database to March, 2023. The literature we selected for inclusion based on inclusion and exclusion criteria. The standard mean difference (SMD) with corresponding 95% confidence intervals (95% CI) were used to investigate the association. When I2 value exceeding 50%, we will consider it has the presence of a higher level of heterogeneity. A sensitivity analysis and subgroup analysis were performed to seek the potential sources of heterogeneity. The quality assessment was performed using according to the Newcastle-Ottawa Quality Assessment Scale (NOS). The data analysis was conducted using STATA version 13.0 software.ResultsWe ultimately enrolled 9 studies enrolling a total of 3137 patients in the final analysis. The SMD of serum Gal-3 was higher in patients with DN group (SMD 1.10 ng/mL [0.63, 1.57]; I2: 96.1%). Upon removal of a study in sensitivity analysis, patients with DN had higher serum Gal-3 levels compared to control patients (SMD 1.03 ng/mL [0.52, 1.54], I2: 94.4%). Further subgroup analysis was performed based on the region. No matter in Asia, Europe or Africa, the serum Gal-3 level of DN patients is significantly higher than that of the control population (SMD: 0.73; 95% CI: 0.58 to 0.87 for Asian; SMD: 0.79; 95% CI: 0.48 to 1.10 for Europe; SMD: 3.15; 95% CI: 2.73 to 3.56 for Africa).ConclusionIn conclusion, these results suggested that higher serum Gal-3 may increase the risk of DN. More fundamental studies are necessary to clarify the exact physiopathological basis mechanisms of Gal-3 effects. In addition, further research, especially emphasis on the cut-off value should be given, and is best to predict their actual importance as well as the diagnostic accuracy.
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Project description:Diabetic nephropathy (DN) is a major microvascular complication of both type 1 and type 2 diabetes mellitus and is the most frequent cause of end-stage renal disease with an increasing prevalence. Presently there is no non-invasive method for differential diagnosis, and an efficient target therapy is lacking. Extracellular vesicles (EV), including exosomes, microvesicles, and apoptotic bodies, are present in various body fluids such as blood, cerebrospinal fluid, and urine. Proteins in EV are speculated to be involved in various processes of disease and reflect the original cells' physiological states and pathological conditions. This systematic review is based on urinary extracellular vesicles studies, which enrolled patients with DN and investigated the proteins in urinary EV. We systematically reviewed articles from the PubMed, Embase, Web of Science databases, and China National Knowledge Infrastructure (CNKI) database until January 4, 2022. The article quality was appraised according to the Newcastle-Ottawa Quality Assessment Scale (NOS). The methodology of samples, isolation and purification techniques of urinary EV, and characterization methods are summarized. Molecular functions, biological processes, and pathways were enriched in all retrievable urinary EV proteins. Protein-protein interaction analysis (PPI) revealed pathways of potential biomarkers. A total of 539 articles were retrieved, and 13 eligible records were enrolled in this systematic review and meta-analysis. And two studies performed mass spectrometry to obtain the proteome profile. Two of them enrolled only T1DM patients, two studies enrolled both patients with T1DM and T2DM, and other the nine studies focused on T2DM patients. In total 988 participants were enrolled, and DN was diagnosed according to UACR, UAER, or decreased GFR. Totally 579 urinary EV proteins were detected and 28 of them showed a potential value to be biomarkers. The results of bioinformatics analysis revealed that urinary EV may participate in DN through various pathways such as angiogenesis, biogenesis of EV, renin-angiotensin system, fluid shear stress and atherosclerosis, collagen degradation, and immune system. Besides that, it is necessary to report results compliant with the guideline of ISEV, in orderto assure repeatability and help for further studies. This systematic review concordance with previous studies and the results of meta-analysis may help to value the methodology details when urinary EV proteins were reported, and also help to deepen the understanding of urinary EV proteins in DN.
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Project description:A dietary protein intake (DPI) of between 0.6 and 0.8 g protein per kilogram body weight per day (g/kg/day) is frequently recommended for adults with moderate-to-advanced chronic kidney disease (CKD). However, evidence on whether patients with diabetic kidney disease (DKD) actually benefit from a DPI of ≤ 0.8 g/kg/day and from a low-protein diet (LPD) at CKD stages 1-3 has not been consistent. We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, as well as the bibliographies of articles identified in the search, for eligible randomized controlled trials that had investigated the effects of LPD (prescribed DPI < 0.8 g/kg/day) versus control diet on the progression of DKD. Nine trials that included 506 participants and follow-up periods varying from 4.5 to 60 months were included in the subsequent systematic review and meta-analysis. The data showed that patients with DKD who consumed < 0.8 g protein/kg/day had a significantly reduced decline in glomerular filtration rate (GFR) (mean difference [MD] 22.31 mL/min/1.73 m2, 95% confidence interval [CI] 17.19, 27.42; P < 0.01) and a significant decrease in proteinuria (standard mean difference [SMD] - 2.26 units, 95% CI - 2.99, - 1.52; P < 0.001) versus those on the control diet. The benefits of LPD to patients with DKD at CKD stages 1-3 were a markedly decreased proteinuria (SMD - 0.96 units, 95% CI - 1.81, - 0.11; P = 0.03) and slight but significant decreases in glycated hemoglobin (- 0.42%) and cholesterol levels (- 0.22 mmol/L). Our meta-analysis indicated that a DPI of < 0.8 g/kg/day was strongly associated with a slow decline in GFR and decreased proteinuria in the patients with DKD. Patients with CKD stages CKD 1-3 benefited from LPD in terms of a marked decrease of proteinuria and slight but significant improvements in lipid and glucose control.
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Project description:Diabetic nephropathy causes cardiovascular complications among individuals with diabetes which results in decreased kidney function and overall physical decline. The objective of this systematic review was to determine effects of exercise on various renal function parameters amond individuals with type 2 diabetes and nephropathy. It was registered with PROSPERO (CRD42020198754). Total 6 databases (PubMed/Medline, Scopus, Web of Science, CINAHL, ProQuest, and Cochrane) were searched. Among 1734 records, only four randomized controlled trials were included. The review included a total of 203 participants (103 in the intervention group and 100 in the control/standard group) with type 2 diabetic nephropathy or stage 2,3, or 4 of chronic kidney disease. The meta-analysis showed no effects of exercise on serum creatinine, serum cystatin c and varied eGFR equations. However, exercise decreased urinary albumin to creatinine ratio, urinary protein to creatinine ratio, serum urea nitrogen, creatinine clearance, and urinary protein excretion while increasing urea clearance. Limited evidence on the reno-protective role of exercise demands future research in this direction.
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Project description:Diabetic nephropathy (DN) is a common microvascular complication of diabetes and the main cause of end-stage nephropathy (ESRD). Inflammation and fibrosis play key roles in the development and progression of diabetic nephropathy. By using in vivo and in vitro DN models, our laboratory has identified the protective role of carnosine (CAR) on renal tubules. Our results showed that carnosine restored the onset and clinical symptoms as well as renal tubular injury in DN. Furthermore, carnosine decreased kidney inflammation and fibrosis in DN mice. These results were consistent with high glucose (HG)-treated mice tubular epithelial cells (MTECs). Using web-prediction algorithms, cellular thermal shift assay (CETSA) and molecular docking, we identified glycine N-methyltransferase (GNMT) as a carnosine target. Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice. Moreover, using cultured TECs, we confirmed that the increased GNMT expression by transient transfection mimicked the protective role of carnosine in reducing inflammation and fibrosis. Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN.
| S-EPMC7726623 | biostudies-literature