High triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, is associated with an increased risk of albuminuria in adults. However, the relationship between high TyG index associated with renal hyperfiltration (RHF) and albuminuria among young adults is unclear. Methods: A total of 5420 participants aged 19–39 years were enrolled from the Korean National Health and Nutrition Examination Survey (2011–2014 and 2019) and their TyG index levels were analyzed. RHF was defined as eGFR with residuals > 90th percentile after adjusting for age, sex, weight, and height. Albuminuria was defined as urinary albumin-to-creatinine ratio ≥ 30 mg/g Cr. Logistic regression analyses were used to evaluate the association between TyG index, RHF, and albuminuria. Results: The mean age was 30.7 ± 6.0 years and 46.4% were male. The prevalence of albuminuria and RHF was higher in the higher tertiles of TyG index. In our multivariable model, high TyG index showed higher risk of albuminuria (odds ratio (OR) per 1.0 increase in TyG index, 1.56; 95% confidence interval (CI), 1.24–1.95 and OR in the highest tertile, 1.65; 95% CI, 1.08–2.52). High TyG index was associated with higher risk of RHF (OR per 1.0 increase in TyG index, 1.56; 95% CI, 1.32–1.84 and OR in the highest tertile, 1.73; 95% CI, 1.31–2.30). When participants were divided into with or without RHF, high-TyG index-associated high risk of albuminuria was only observed in those with RHF. Participants with concurrent high TyG index and RHF showed the highest risk of albuminuria. Mediation analysis showed that 54.2% of the relation between TyG index and albuminuria was mediated by RHF (95% CI of indirect effect, 0.27–0.76). Finally, incorporating TyG index into our basic model improved the predictive value for albuminuria only in participants with RHF. Conclusion: High TyG index associated with RHF was the strongest risk factor for albuminuria in this study. Early identification of high TyG index with RHF may prevent future development of CKD in relatively healthy and young adults.
BackgroundHigh pulse pressure (PP) is associated with increased risk of decline of kidney function. However, little is known about the association between PP and RHF in young adults. This study aimed to evaluate the association between PP and RHF in healthy young adults.MethodsData were retrieved from the Korea National Health and Nutrition Examination Survey from 2010 to 2019. A total of 10,365 participants aged 19–39 years with no hypertension and normal kidney function were analyzed. RHF was defined as logarithm transformed estimated glomerular filtration rate (eGFR) with residuals >90th percentile after adjustment for sex, logarithm transformed age, weight, and height. Participants were divided into tertile based on PP levels.ResultsThe prevalence of RHF was higher in higher PP tertile group (6.6, 10.5, and 12.7% in T1, T2, and T3; P for trend < 0.001). In multivariable logistic regression analyses, the risk for RHF was increased in higher PP tertiles compared to the lowest tertile [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.19–1.69 in T2; OR, 1.44; 95% CI, 1.20–1.73 in T3]. When PP levels were treated as continuous variable, the risk of RHF was increased 2.36 per 1.0 increase of PP (P < 0.001). In subgroup analyses stratified sex, histories of diabetes or dyslipidemia, and isolated systolic hypertension or isolated diastolic hypertension, there were no significant interactions with PP for the risk for RHF, suggesting that high PP was associated with increased risk of RHF regardless of subgroups. However, the subgroup with BMI showed significant interaction with PP for the risk of RHF, indicating that participants with BMI ≥ 25 kg/m2 were at higher risk of RHF with increasing PP levels than those with BMI < 25 kg/m2 (OR, 1.89; 95% CI, 1.25–2.87 in BMI < 25 kg/m2; OR, 3.16; 95% CI, 1.74–5.73 in BMI ≥ 25 kg/m2; P for interaction = 0.01).ConclusionHigh PP is associated with an increased risk of RHF in healthy young adults and this association is prominent in obese young adults. The assessment of PP and associated RHF may give benefit to early detect the potential risk of CKD development in young adults.
BACKGROUND AND AIMS Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are primarily cholesterol-lowering drugs that have become standard of care in the primary and secondary prevention of cardiovascular diseases. Apart from lipid-lowering, statins may act beneficially through anti-fibrotic mechanisms to protect the diseased kidney. This study evaluated anti-fibrotic effects of rosuvastatin (RSV) in a chronic kidney fibrosis model and against the TGF-ß1 stimulated Madin-Darby canine kidney (MDCK) cells in vitro. METHOD Mice subjected to unilateral ischemic reperfusion injury with contralateral nephrectomy (uIRIx) were treated with vehicle or RSV (10 mg/kg, by oral gavage) daily for 4 weeks and kidneys were analyzed for markers of fibrosis, bone morphogenetic protein-7 (BMP-7), uterine sensitization-associated gene-1 (USAG-1), and SMAD signaling. Control and homeobox protein Hox-A13 (HOXA13) knocked down MDCK cells were stimulated with TGF- ß1 (5 ng/ml) and then treated with RSV. RESULTS Kidneys from uIRIx mice showed increased expression of α-SMA, Collagen 1 and decrease in BMP-7 (20.35 ± 2.37 versus 1.00 ± 0.27, P < 0.05; 8.43 ± 1.55 versus 1.00 ± 0.35, P < 0.05; 0.75 ± 0.06 versus 1.00 ± 0.15, P < 0.05, respectively). In contrast, expression of USAG-1, a BMP-7 antagonist, was markedly increased in fibrotic kidney (6.60 ± 1.11 versus 1.00 ± 0.02, P < 0.05). Interestingly, RSV treatment not only attenuated expression of USAG-1 (0.72 ± 0.08 versus 1.36 ± 0.14, P < 0.05) but also showed a tendency to activate expression of HOXA13 (0.36 ± 0.14 versus 0.51 ± 0.15, P > 0.05) and improved other markers of fibrosis. Moreover, RSV treatment significantly reduced phosphorylated Smad3 (3.94 ± 0.81 versus 7.17 ± 1.50, P < 0.05) and increased phosphorylation levels of Smad 1/5/9 (0.67 ± 0.10 versus 0.30 ± 0.09, P < 0.05) that is associated with BMP-7 signaling in the fibrotic kidney. MDCK cells stimulated with TGF-β1 in vitro showed increased expression of α-SMA, fibronectin, vimentin, collagen 1, USAG-1, and phosphorylation of Smad3 as well as decreased expression of phosphorylated Smad 1/5/9. RSV treatment significantly reversed these changes as well as increased level of transcriptional factor HOXA13 (0.89 ± 0.12 versus 0.33 ± 0.08, P < 0.05), which negatively regulates USAG-1, without changes in BMP-7 expression. In addition, effect of RSV treatment on USAG-1 expression was significantly decreased in HOXA13 gene knocked down MDCK cells (1.01 ± 0.19 versus 2.04 ± 0.38, P < 0.05; 1.66 ± 0.13 versus 2.04 ± 0.38, P > 0.05; TGF- ß1 + RSV versus TGF- ß1 and TGF- ß1 + RSV + siRNA vs TGF- ß1, respectively). These in vitro data suggest that RSV enhanced anti-fibrotic pathway by downregulating a dominant BMP-7 antagonist USAG-1 via HOXA13 upregulation and not by enhancing BMP-7 production. CONCLUSION The present results demonstrate that RSV inhibits the progression of kidney fibrosis in part by upregulating BMP-7-mediated signaling via HOXA13 expression and down regulation of USAG-1.
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