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The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association of UAGT with renal outcomes in patients with non-dialysis CKD irrespective of the primary cause, a total of 1688 subjects from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into the quintile by UAGT to urine creatinine ratio (UAGT/Cr) level. The primary outcomes of interest were composite renal event, which included decline in kidney function and onset of end-stage renal disease during follow-up periods. The median follow-up duration was 6.257 years. Cox regression model analysis unveiled that the risk of composite renal event was significantly higher in the fifth quintile (adjusted hazard ratio 1.528, 95% confidence interval 1.156 to 2.021) compared to that of the first quartile. The association between high UAGT/Cr level and adverse renal outcome remained consistent in sensitivity analyses, including the analysis of the cause-specific hazard model. Subgroup analyses revealed that the association of UAGT level with renal outcomes is modified by certain clinical contexts, such as BMI and albuminuria. In conclusion, high UAGT level is associated with adverse renal outcomes in patients with non-dialysis CKD. Further studies are warranted to elaborate and expand the predictive role of UAGT as a biomarker for renal outcomes in CKD. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency is a growing health problem in both the general population and in patients with chronic kidney disease (CKD). However, the relationship between serum 25-hydroxyvitamin D levels and health-related quality of life in CKD is not well established. This study examined the association between vitamin D deficiency and quality of life in pre-dialysis CKD patients. Serum 25-hydroxyvitamin D levels and the Korean version of the Kidney Disease Quality of Life short form were obtained for 1844 pre-dialysis CKD patients in the prospective KoreaN cohort Study for Outcomes in patients With Chronic Kidney Disease (KNOW-CKD). The baseline estimated glomerular filtration rate was 50.26 ± 0.71 mL/min/1.73 m2. We identified 1294 (70.2%) patients with vitamin D deficiency, defined as a 25-hydroxyvitamin D level < 20 ng/ml. The scores of the kidney disease component summary, physical component summary, and mental component summary in the vitamin D deficiency group were significantly lower compared to the scores of those without vitamin D deficiency. The serum 25-hydroxyvitamin D level was independently associated with the kidney disease component summary and mental component summary scores (β = 0.147, p = 0.003 and β = 0.151, p = 0.047). In conclusion, there was a significant association between serum 25-hydroxyvitamin D levels and kidney disease component summary and mental component summary scores in pre-dialysis CKD patients. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is common after gastric surgery for gastric cancer and associated with adverse outcomes. However, the impact of transient or persistent AKI on clinical outcomes after gastric surgery for gastric cancer has not been described. We performed a retrospective study of 4,886 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2012. AKI patients were classified as transient and persistent AKI based on the return of serum creatinine to the level indicating no AKI within 7 days. Our outcomes included occurrence of new-onset chronic kidney disease (CKD) and mortality 1 year after gastric surgery. AKI occurred in 638 (13.1%) after gastric surgery. Transient AKI was documented in 574 (90%). Use of diuretics and contrast agents was a common risk factor for persistent and transient AKI. Length of intensive care unit (ICU) and hospital stay, and ICU admission rate were higher in patients with transient AKI than in those without AKI. Although patients with persistent AKI had a higher new-onset CKD 1 year after gastric surgery after adjusting for multiple covariates, transient AKI was not associated with new-onset CKD. The 1-year mortality rates were significantly higher in patients with transient and persistent AKI. Not only persistent AKI but transient AKI is associated with increased risk of hospital complications and a significantly higher risk of long-term mortality than patients without AKI after gastric surgery. Moreover, persistent AKI, but not transient AKI, is associated with CKD progression at 1 year. [ABSTRACT FROM AUTHOR]

Renal fibrosis is a common final pathway of end-stage kidney disease which is induced by aberrant accumulation of myofibroblasts. This process is triggered by reactive oxygen species (ROS) and proinflammatory cytokines generated by various source of injured kidney cells. Peroxiredoxin 5 (Prdx5) is a thiol-dependent peroxidase that reduces oxidative stress by catalyzing intramolecular disulfide bonds. Along with its antioxidant effects, expression level of Prdx5 also was involved in inflammatory regulation by immune stimuli. However, the physiological effects and the underlying mechanisms of Prdx5 in renal fibrosis have not been fully characterized. Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) for 1 or 7 days. For the in vitro model, NRK49F cells, a rat kidney interstitial fibroblast cell lines, were treated with transforming growth factor β (TGF-β) for 0, 1, 3, or 5 days. To access the involvement of its peroxidase activity in TGF-β induced renal fibrosis, wild type Prdx5 (WT) and double mutant Prdx5 (DM), converted two active site cysteines at Cys 48 and Cys 152 residue to serine, were transiently expressed in NRK49F cells. The protein expression of Prdx5 was reduced in UUO kidneys. Upregulation of fibrotic markers, such as fibronectin and alpha-smooth muscle actin (α-SMA), declined at 5 days in time point of higher Prdx5 expression in TGF-β treated NRK49F cells. The overexpression of wild type Prdx5 by transient transfection in NRK49F cells attenuated the TGF-β induced upregulation of fibronectin and α-SMA. On the other hand, the transient transfection of double mutant Prdx5 did not prevent the activation of fibrotic markers. Overexpression of Prdx5 also suppressed the TGF-β induced upregulation of Stat3 phosphorylation, while phosphorylation of Smad 2/3 was unchanged. In conclusion, Prdx5 protects TGF-β induced fibrosis in NRK49F cells by modulating Stat3 activation in a peroxidase activity dependent manner. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a major complication of chronic kidney disease. The coronary artery calcium (CAC) score is a surrogate marker for the risk of coronary artery disease. The purpose of this study is to predict outcomes for non-dialysis chronic kidney disease patients under the age of 60 with high CAC scores using machine learning techniques. We developed the predictive models with a chronic kidney disease representative cohort, the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD). We divided the cohort into a training dataset (70%) and a validation dataset (30%). The test dataset incorporated an external dataset of patients that were not included in the KNOW-CKD cohort. Support vector machine, random forest, XGboost, logistic regression, and multi-perceptron neural network models were used in the predictive models. We evaluated the model's performance using the area under the receiver operating characteristic (AUROC) curve. Shapley additive explanation values were applied to select the important features. The random forest model showed the best predictive performance (AUROC 0.87) and there was a statistically significant difference between the traditional logistic regression model and the test dataset. This study will help identify patients at high risk of cardiovascular complications in young chronic kidney disease and establish individualized treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: The present study was aimed to determine whether there is an altered role of local nitric oxide (NO) and atrial natriuretic peptide (ANP) systems in the kidney in association with the angiotensin (Ang) II-induced hypertension. Male Sprague–Dawley rats were used. Ang II (100ng·min−1·kg−1) was infused through entire time course. Thirteenth day after beginning the regimen, kidneys were taken. The protein expression of NO synthase (NOS) and nitrotyrosine was determined by semiquantitative immunoblotting. The mRNA expression of components of ANP system was determined by real-time polymerase chain reaction. The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and ANP, respectively. There developed hypertension and decreased creatinine clearance in the experimental group. The protein expression of eNOS, nNOS and nitrotyrosine was increased in the cortex, while that of iNOS remained unaltered. The urinary excretion of NO increased in Ang II-induced hypertensive rats. The catalytic activity of soluble guanylyl cyclase was blunted in the glomerulus in Ang II-induced hypertensive rats. The mRNA expression of ANP was increased in Ang II-induced hypertensive rats. Neither the expression of NPR-A nor that of NPR-C was changed. The protein expression of neutral endopeptidase was decreased and the activity of particulate guanylyl cyclase was blunted in the glomerulus and papilla in Ang II-induced hypertensive rats. In conclusion, the synthesis of NO and ANP was increased in the kidney of Ang II-induced hypertension, while stimulated cGMP response was blunted. These results suggest desensitization of guanylyl cyclase in the kidney of Ang II-induced hypertensive rats, which may contribute to the associated renal vasoconstriction and hypertension. [Copyright &y& Elsevier]

1. The effects of volume depletion and NaHCO3 loading on the expression of Na+/H+ exchanger isoform 3 (NHE3), Na+ : cotransporter type 1 (NBC1) and neuronal (n) and inducible (i) isoforms of nitric oxide synthase (NOS) were determined in rat kidney. 2. Adult male Sprague-Dawley rats were used. Rats were divided into four groups: (i) euvolaemic (EC); (ii) hypovolaemic (HC); (iii) euvolaemia with NaHCO3 loading (EB); and (iv) hypovolaemia with NaHCO3 loading (HB). The expression of NHE3, NBC1, nNOS and iNOS proteins was determined in the cortex of the kidney by immunoblotting and immunohistochemistry. Tissue content of nitric oxide (NO) metabolites (NOx) were also determined in the cortex using a colourimetric assay. 3. Compared with the EC group, the expression of NHE3 and NBC1 was increased in the HC group and decreased in the EB group. Comparing the EB and HB groups, the expression of NHE3 and NBC1 was higher in the latter group. The expression of NHE3 was decreased and that of NBC1 was increased in the HB group compared with the HC group. The NOx content and nNOS expression were decreased in the hypovolaemic (HC) and NaHCO3-loaded (EB and HB) rats. Moreover, the expression of iNOS was decreased in the HB group compared with the other groups. 4. An altered volume status and NaHCO3 loading may affect the regulation of NHE3 and NBC1 in the kidney and the endogenous NO system may play a role in the observed effects. [ABSTRACT FROM AUTHOR]

Aims: A neural mechanism regulating aquaporin (AQP) water channels in the kidney was investigated. Methods: Male Sprague-Dawley rats were used. Renal denervation was induced by painting the renal vessels with 10% phenol. The expression of AQP1–4 proteins was determined in the denervated and contralateral kidneys. The expression was also examined in rats which were renally denervated and subjected to water restriction or deoxycorticosterone acetate (DOCA)-salt treatment. Results: Following the unilateral denervation, tissue contents of norepinephrine were significantly decreased in the denervated kidney, while increased in the contralateral kidney. Accordingly, the expression of AQP1–4 proteins was decreased by 15–40% in the denervated kidney, and increased by 30–50% in the contralateral kidney. Immunohistochemistry of AQP2 confirmed its decreases in the denervated kidney and increases in the contralateral kidney. In bilaterally denervated rats, the urine flow increased along with decreased osmolarity. The water restriction increased the expression of AQP channels, however, the magnitude of which was lower in the denervated than in the contralateral kidney. Renal denervation decreased the degree of DOCA-salt hypertension, along with lower expression of AQP channels. Conclusion: It is suggested that the sympathetic nerve should play a specific excitatory role in the regulation of AQP channels in the kidney. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

PAI-1 and CTGF are overexpressed in kidney diseases and cause fibrosis of the lungs, liver, and kidneys. We used a rat model of unilateral ureteral obstruction (UUO) to investigate whether 6-BIO, a glycogen synthase kinase-3β inhibitor, attenuated fibrosis by inhibiting PAI-1 and CTGF in vivo. Additionally, TGFβ-induced cellular fibrosis was observed in vitro using the human kidney proximal tubular epithelial cells (HK-2), and rat interstitial fibroblasts (NRK49F). Expression of fibrosis-related proteins and signaling molecules such as PAI-1, CTGF, TGFβ, αSMA, SMAD, and MAPK were determined in HK-2 and NRK49F cells using immunoblotting. To identify the transcription factors that regulate the expression of PAI-1 and CTGF the promoter activities of AP-1 and SP-1 were analyzed using luciferase assays. Confocal microscopy was used to observe the co-localization of AP-1 and SP-1 to PAI-1 and CTGF. Expression of PAI-1, CTGF, TGFβ, and α-SMA increased in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Furthermore, UUO and TGFβ treatment induced the activation of P-SMAD2/3, SMAD4, P-ERK 1/2, P-P38, and P-JNK MAPK signaling pathways. PAI-1, CTGF, AP-1 and SP-1 promoter activity increased in response to TGFβ treatment. However, treatment with 6-BIO decreased the expression of proteins and signaling pathways associated with fibrosis in UUO model as well as in TGFβ-treated HK-2 and NRK49F cells. Moreover, 6-BIO treatment attenuated the expression of PAI-1 and CTGF as well as the promoter activities of AP-1 and SP-1, thereby regulating the SMAD and MAPK signaling pathways, and subsequently exerting anti-fibrotic effects on kidney cells. [Display omitted] • 6-BIO inhibits UUO- and TGFβ induced kidney fibrosis. • 6-Bio reduces PAI-1 and CTGF expression associated with kidney fibrosis. • 6-BIO regulates AP-1 and SP-1 transcription activity in kidney cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] MSP/RON system is activated in rat kidney damaged by gentamicin. [•] MSP inhibits GM-induced cellular apoptosis and inflammation in HK-2 cells. [•] MSP attenuates GM-induced activation of MAPKs and NF-κB pathways in HK-2 cells. [ABSTRACT FROM AUTHOR]