Protective effect of Cyclo(His-Pro) on peritoneal fibrosis through regulation of HDAC3 expression.

Peritoneal dialysis is a common treatment for end-stage renal disease, but complications often force its discontinuation. Preventive treatments for peritoneal inflammation and fibrosis are currently lacking. Cyclo(His-Pro) (CHP), a naturally occurring cyclic dipeptide, has demonstrated protective effects in various fibrotic diseases, yet its potential role in peritoneal fibrosis (PF) remains uncertain. In a mouse model of induced PF, CHP was administered, and quantitative proteomic analysis using liquid chromatography-tandem mass spectrometry was employed to identify PF-related protein signaling pathways. The results were further validated using human primary cultured mesothelial cells. This analysis revealed the involvement of histone deacetylase 3 (HDAC3) in the PF signaling pathway. CHP administration effectively mitigated PF in both peritoneal tissue and human primary cultured mesothelial cells, concurrently regulating fibrosis-related markers and HDAC3 expression. Moreover, CHP enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) while suppressing forkhead box protein M1 (FOXM1), known to inhibit Nrf2 transcription through its interaction with HDAC3. CHP also displayed an impact on spleen myeloid-derived suppressor cells, suggesting an immunomodulatory effect. Notably, CHP improved mitochondrial function in peritoneal tissue, resulting in increased mitochondrial membrane potential and adenosine triphosphate production. This study suggests that CHP can significantly prevent PF in peritoneal dialysis patients by modulating HDAC3 expression and associated signaling pathways, reducing fibrosis and inflammation markers, and improving mitochondrial function.

Inflammatory chemokine (C-C motif) ligand 8 inhibition ameliorates peritoneal fibrosis.

Peritoneal fibrosis (PF) is an irreversible complication of peritoneal dialysis (PD) that leads to loss of peritoneal membrane function. We investigated PD effluent and serum levels and the tissue expression of chemokine (C-C motif) ligand 8 (CCL8) in patients with PD. Additionally, we investigated their association with PF in a mouse model. Eighty-two end-stage renal disease (ESRD) patients with PD were examined. CCL8 levels were measured via enzyme-linked immunosorbent assays in PD effluents and serum and analyzed with peritoneal transport parameters. Human peritoneal mesothelial cells (hPMCs) were obtained from the PD effluents of 20 patients. Primary cultured hPMCs were treated with recombinant (r) transforming growth factor (TGF)-ß, and CCL8 expression was assessed via western blotting. As the duration of PD increased, the concentration of CCL8 in PD effluents significantly increased. Correlations between peritoneal transport parameters and dialysate CCL8 levels were observed. Western blotting analysis showed that CCL8 was upregulated via rTGF-ß treatment, accompanied by increases in markers of inflammation, fibrosis, senescence, and apoptosis in hPMCs after induction of fibrosis with rTGF-ß. Anti-CCL8 monoclonal antibody (mAb) treatment suppressed the rTGF-ß-induced increase in all analyzed markers. Immunohistochemical analysis revealed that CCL8 along with fibrosis- and inflammation-related markers were significantly increased in the PF mouse model. Functional blockade of CCL8 using a CCR8 inhibitor (R243) abrogated peritoneal inflammation and fibrosis in vivo. In conclusion, high CCL8 levels in PD effluents may be associated with an increased risk of PD failure, and the CCL8 pathway is associated with PF. CCL8 blockade can ameliorate peritoneal inflammation and fibrosis.

Oral phosphate binders and incident osteoporotic fracture in patients on dialysis.

BACKGROUND AND HYPOTHESIS: End-stage kidney disease (ESKD) has an elevated risk of osteoporotic fractures in relation to mineral and bone disorder (MBD) as well as conventional risks of osteoporosis. We investigated the association between oral phosphate binders, the mainstay of MBD treatment, and osteoporotic fracture in dialysis patients. METHODS: We obtained data from the National Health Insurance database for incident dialysis patients without a history of osteoporotic fractures. Participants were categorized into four groups based on their initial 1-year prescription profiles: calcium-based phosphate binder (CBPB), non-calcium-based phosphate binder (NCBPB), both calcium and non-calcium-based binders (Mixed), and non-phosphate binder (non-user) groups. The primary outcome was the occurrence of new-onset osteoporotic fractures after 1 year of dialysis. Secondary outcomes included cardiovascular events and mortality. RESULTS: Out of 69 368 incident dialysis patients, 22 326, 5020, 2853, and 39 169 were included in the CBPB, NCBPB, mixed, and non-user groups, respectively. The overall risk of osteoporotic fractures was lower in patients taking any phosphate binders compared to non-users. Specifically, only the CBPB group showed a reduced risk of vertebral (adjusted hazard ratio (aHR) 0.83 [0.76-0.92]), hip (aHR 0.81 [0.74-0.89]), and distal radius (aHR 0.88 [0.78-0.99]) fractures compared to non-users. This relationship was represented by a time-dependent manner with fracture risk reduction in patients taking CBPB for 3-6 months (aHR 0.9 [0.83-0.99]) and ≥ 6 months (aHR 0.83 [0.78-0.89]), compared to those using CBPB for less than 3 months. Additionally, only the CBPB group had a lower risk of MACE, cardiac arrest, and ventricular arrhythmia than non-users. All phosphorus binder groups showed a reduced mortality risk compared to non-users. CONCLUSIONS: Our findings indicate that the using phosphate binders in ESKD patients is lowers the risk of osteoporotic fractures. Notably, those taking CBPB had a reduced risk without increasing cardiovascular events or mortality compared to non-users.

Menopausal hormone therapy and risk for dementia in women with CKD: A nationwide observational cohort study.

AIM: The risk for dementia is increased in postmenopausal women. The incidences of premature menopause and dementia have increased in patients with chronic kidney disease (CKD). The potential benefits of hormone replacement therapy (HRT) on cognitive function may be a more critical issue for patients with CKD. METHODS: Women aged >40 years with or without HRT were identified using the 2009 National Health Screening Questionnaire. Women who were newly diagnosed with CKD between 2009 and 2013 were enrolled. HRT was used as an exposure variable, and participants were followed from the day CKD was diagnosed to December 2019. The hazard ratio (HR) for dementia was evaluated using Cox proportional hazards regression analysis. RESULTS: We included 755 426 postmenopausal women with CKD. The median follow-up period was 7.3 (IQR, 5.8-8.7) years. All-cause dementia, Alzheimer's disease, and vascular dementia occurred in 107 848 (14.3%), 87 833 (11.6%), and 10 245 (1.4%) women, respectively. HRT was significantly associated with a lower risk for dementia in the adjusted Cox regression model (all-cause dementia: HR 0.80; 95% confidence interval [CI] 0.78-0.82; p < 0.001; Alzheimer's disease: HR 0.80; 95% CI 0.77-0.82; p < 0.001; vascular dementia: HR 0.80; 95% CI 0.74-0.87; p < 0.001). CONCLUSIONS: HRT was significantly associated with a lower risk for CKD-related cognitive dysfunction in postmenopausal women. Prospective studies are needed to determine whether HRT lowers the risk for dementia in menopausal women with CKD.

Novel Genetic Variants Associated with Chronic Kidney Disease Progression.

SIGNIFICANCE STATEMENT: eGFR slope has been used as a surrogate outcome for progression of CKD. However, genetic markers associated with eGFR slope among patients with CKD were unknown. We aimed to identify genetic susceptibility loci associated with eGFR slope. A two-phase genome-wide association study identified single nucleotide polymorphisms (SNPs) in TPPP and FAT1-LINC02374 , and 22 of them were used to derive polygenic risk scores that mark the decline of eGFR by disrupting binding of nearby transcription factors. This work is the first to identify the impact of TPPP and FAT1-LINC02374 on CKD progression, providing predictive markers for the decline of eGFR in patients with CKD. BACKGROUND: The incidence of CKD is associated with genetic factors. However, genetic markers associated with the progression of CKD have not been fully elucidated. METHODS: We conducted a genome-wide association study among 1738 patients with CKD, mainly from the KoreaN cohort study for Outcomes in patients With CKD. The outcome was eGFR slope. We performed a replication study for discovered single nucleotide polymorphisms (SNPs) with P <10 -6 in 2498 patients with CKD from the Chronic Renal Insufficiency Cohort study. Several expression quantitative trait loci (eQTL) studies, pathway enrichment analyses, exploration of epigenetic architecture, and predicting disruption of transcription factor (TF) binding sites explored potential biological implications of the loci. We developed and evaluated the effect of polygenic risk scores (PRS) on incident CKD outcomes. RESULTS: SNPs in two novel loci, TPPP and FAT1-LINC02374 , were replicated (rs59402340 in TPPP , Pdiscovery =7.11×10 -7 , PCRIC =8.13×10 -4 , Pmeta =7.23×10 -8 ; rs28629773 in FAT1-LINC02374 , Pdiscovery =6.08×10 -7 , PCRIC =4.33×10 -2 , Pmeta =1.87×10 -7 ). The eQTL studies revealed that the replicated SNPs regulated the expression level of nearby genes associated with kidney function. Furthermore, these SNPs were near gene enhancer regions and predicted to disrupt the binding of TFs. PRS based on the independently significant top 22 SNPs were significantly associated with CKD outcomes. CONCLUSIONS: This study demonstrates that SNP markers in the TPPP and FAT1-LINC02374 loci could be predictive markers for the decline of eGFR in patients with CKD.

Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1.

BACKGROUND: Overexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines. METHODS: Using three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions. RESULTS: In this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin. CONCLUSION: Based on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.

Economic Impact of Donating a Kidney on Living Donors: A Korean Cohort Study.

RATIONALE & OBJECTIVE: Although existing studies have reported adverse health outcomes after kidney donation, its socioeconomic impact on living donors requires further study. STUDY DESIGN: A retrospective observational cohort study including a matched comparison group. SETTING & PARTICIPANTS: 1,285 living kidney donors from 7 tertiary hospitals between 2003 and 2016, and a matched comparison group consisting of the same number of health screening examinees with similar baseline clinical characteristics and socioeconomic status. All participants were receiving Korean national health insurance. EXPOSURE: Kidney donation as reflected in the Korean National Health Insurance System (NHIS) database. OUTCOME: Changes in household economic status estimated by Korean national health insurance fees and changes in employment status reflected in the NHIS database. ANALYTICAL APPROACH: The outcomes of the donor group and matched control group were compared annually using multivariable logistic regression analyses adjusted for clinical and demographic characteristics. RESULTS: The median ages of the donors and matched controls were 45 and 46 years, respectively; 44.6% of both groups were male. Compared to the comparison group, living donors were at higher risk of being unemployed or losing employment during the first 2 years after donation (eg, first-year loss of employment: odds ratio (OR), 2.27 [95% CI, 1.55-3.33]); however, this association did not persist. Donors also had a significantly lower odds of improvement in economic status (OR, 0.57 [95% CI, 0.47-0.71]) and a higher odds of deterioration in financial status (OR, 1.54 [95% CI, 1.23-1.93]) in the first year after transplantation and subsequently. LIMITATIONS: Unmeasured differences between donors and matched controls creating residual selection bias and confounding. CONCLUSIONS: Living kidney donors may suffer loss of employment and poor economic status after their voluntary donation. The socioeconomic impact on these donors should be considered in conjunction with the potential long-term adverse health outcomes after donation.

Soluble α-klotho anchors TRPV5 to the distal tubular cell membrane independent of FGFR1 by binding TRPV5 and galectin-1 simultaneously.

Hypercalciuria is one of the early manifestations of diabetic nephropathy (DN). This is partially due to a decrease in the expression of renal transient receptor potential vanilloid type 5 (TRPV5), which is responsible for renal Ca2+ reabsorption. Soluble klotho has been previously determined to increase TRPV5 by cleaving sialic acid, causing TRPV5 to bind to membrane protein galectin-1. However, a recent study showed that soluble klotho binds to α2-3-sialyllactose, where sialic acid is located, on TRPV5, rather than cleave it. Here, we report that soluble klotho tethers TRPV5 on the membrane by binding both TRPV5 and galectin-1, thereby protecting membrane TRPV5 from diabetes-induced endocytosis. In the present study, we injected recombinant soluble α-klotho protein (rKL) into db/db and db/m mice for 8 wk and collected urine and kidneys. We administered rKL, AZD4547 [fibroblast growth factor (FGF) receptor type 1 inhibitor], and OTX008 (galectin-1 inhibitor) to cultured mouse distal tubular cells with or without 30 mM high-glucose (HG) exposure. db/db mice showed increased renal Ca2+ excretion and decreased renal TRPV5 expression. rKL treatment reversed this change. In vitro, TRPV5 expression in distal tubular cells decreased under HG conditions, and rKL successfully upregulated TRPV5 with or without FGF23. Also, immunofluorescence showed colocalization of klotho, TRPV5, and galectin-1 in distal tubule cells, suggesting that klotho binds to both TRPV5 and galectin-1. Moreover, when both FGF receptor type 1 and galectin-1 were inhibited, rKL failed to increase TRPV5 under HG conditions. Our results indicate that soluble klotho prevents TRPV5 from degradation and subsequent diabetes-induced endocytosis by anchoring TRPV5 through binding with both TRPV5 and galectin-1.NEW & NOTEWORTHY Soluble α-klotho anchors transient receptor potential vanilloid type 5 (TRPV5) on the apical membrane of the distal tubule by binding both TRPV5 and a membrane-abundant protein, galectin-1. This newly discovered mechanism works even when fibroblast growth factor (FGF)23 signaling is inhibited by treatment with FGF receptor type 1 inhibitor. Therefore, we identified how soluble α-klotho increases TRPV5 without FGF23. We confirmed this mechanism by observing that soluble α-klotho fails to enhance TRPV5 when both FGF receptor type 1 and galectin-1 are inhibited.

Measured sodium excretion is associated with CKD progression: results from the KNOW-CKD study.

BACKGROUND: Diet is a modifiable factor of chronic kidney disease (CKD) progression. However, the effect of dietary salt intake on CKD progression remains unclear. Therefore, we analyzed the effect of dietary salt intake on renal outcome in Korean patients with CKD. METHODS: We measured 24-h urinary sodium (Na) excretion as a marker of dietary salt intake in the prospective, multi-center, longitudinal KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). Data were analyzed from CKD patients at Stages G3a to G5 (n = 1254). We investigated the association between dietary salt intake and CKD progression. Patients were divided into four quartiles of dietary salt intake, which was assessed using measured 24-h urinary Na excretion. The study endpoint was composite renal outcome, which was defined as either halving the estimated glomerular filtration rate or developing end-stage renal disease. RESULTS: During a median (interquartile range) follow-up of 4.3 (2.8-5.8) years, 480 (38.7%) patients developed the composite renal event. Compared with the reference group (Q2, urinary Na excretion: 104.2 ≤ Na excretion < 145.1 mEq/day), the highest quartile of measured 24-h urinary Na excretion was associated with risk of composite renal outcome [Q4, urinary Na excretion ≥192.9 mEq/day, hazard ratio 1.8 (95% confidence interval 1.12-2.88); P = 0.015] in a multivariable hazards model. Subgroup analyses showed that high-salt intake was particularly associated with a higher risk of composite renal outcome in women, in patients <60 years of age, in those with uncontrolled hypertension and in those with obesity. CONCLUSIONS: High salt intake was associated with increased risk of progression in CKD.

Impact of a nationwide prospective drug utilization review program to improve prescribing safety of potentially inappropriate medications in older adults: An interrupted time series with segmented regression analysis.

PURPOSE: A nationwide prospective drug utilization review (DUR) for potentially inappropriate medications (PIMs) in older adults was implemented in October 2015 in South Korea. We aimed to evaluate the effects of the DUR on reducing PIMs, in comparison with the PIMs defined using the Beers criteria that were not included in the DUR. METHODS: We divided the study period into a pre- and post-DUR period. The monthly percentage of patients or prescriptions with at least one PIM in the DUR or defined by the Beers criteria was calculated using national health insurance data. We evaluated the effect of the DUR on the prevalence of PIM use in older adults using an interrupted time series with segmented regression analysis. RESULTS: The prevalence of older adults prescribed PIMs in the DUR decreased by 0.49% (95% confidence interval (CI) [-0.60, -0.37]) based on patient-based measures and, by 0.41% (95% CI [-0.58, -0.23]) based on prescription-based measure, immediately after DUR implementation. However, there were no statistically significant changes in trend. Further, the prevalence of PIMs based on the Beers criteria had no statistically significant changes in terms of either level or trend. After 12 months of DUR, there was a reduction of 11.5% (95% CI [2.6 20.4]) relative to the PIMs in Beers. CONCLUSIONS: The implementation of a nationwide prospective DUR lowered the prescription of PIMs for older adults. On the other hand, PIMs that were not included were unchanged. Thus, it is worth considering expanding the DUR list to improve prescribing safety.

Serum uric acid is associated with coronary artery calcification in early chronic kidney disease: a cross-sectional study.

BACKGROUND: Although uric acid (UA) is regarded as a risk factor for cardiovascular disease, whether UA is an independent risk factor contributing to coronary artery calcification in chronic kidney disease (CKD) is not well known. We evaluated whether UA level is associated with coronary artery calcium (CAC) score in a predialysis CKD cohort. METHODS: A total of 1,350 subjects who underwent coronary computed tomography as part of the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease were analysed. We conducted a logistic regression analysis to evaluate the association between UA and the presence of CAC. RESULTS: CAC was detected in 705 (52.2 %) patients, and the level of UA was significantly higher in CAC > 0 patients. UA showed a positive relationship with CAC > 0 in age- and sex-adjusted logistic regression analysis (Odds ratio (OR) 1.11, 95 % confidence interval (CI) 1.04-1.19, P = 0.003). However, UA showed no association with CAC > 0 in multivariate analysis. Further analysis showed that UA showed a positive association with CAC > 0 only in estimated glomerual filtration rate (eGFR) > 60 ml/min/1.73 m2 (OR 1.23, 95 % CI 1.02-1.49, P = 0.036) but not in eGFR 30-59 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.78-1.08, P = 0.309) or < 30 ml/min/1.73 m2 (OR 0.92, 95 % CI 0.79-1.08, P = 0.426). CONCLUSIONS: UA level was significantly associated with CAC in early CKD, but not in advanced CKD.

Rapid Weight Change Over Time Is a Risk Factor for Adverse Outcomes in Patients With Predialysis Chronic Kidney Disease: A Prospective Cohort Study.

OBJECTIVE: Both obesity and being underweight are risk factors for adverse outcomes in chronic kidney disease (CKD) patients. However, the effects of longitudinal weight changes on patients with predialysis CKD have not yet been studied. In this study, we analyzed the effects of weight change over time on the adverse outcomes in predialysis CKD population. METHODS: Longitudinal data from a multicenter prospective cohort study (KNOW-CKD) were analyzed. In a total of 2,022 patients, the percent weight change per year were calculated using regression analysis and the study subjects were classified into five categories: group 1, ≤ -5%/year; group 2, -5< to ≤ -2.5%/year; group 3, -2.5< to <2.5%/year; group 4, 2.5≤ < 5%/year; and group 5, ≥5%/year. The incidences of end-stage renal disease (ESRD) and the composite outcome of cardiovascular disease (CVD) and death were calculated in each group and compared to group 3 as reference. RESULTS: During a median 4.4 years of follow-up, 414 ESRD, and 188 composite of CVD and mortality events occurred. Both weight gain and loss were independent risk factors for adverse outcomes. There was a U-shaped correlation between the degree of longitudinal weight change and ESRD (hazard ratio 3.61, 2.15, 1.86 and 3.66, for group 1, 2, 4 and 5, respectively) and composite of CVD and death (hazard ratio 2.92, 2.15, 1.73 and 2.54, respectively), when compared to the reference group 3. The U-shape correlation was most prominent in the subgroup of estimated glomerular filtration rate <45 mL/min/1.73 m2. CONCLUSION: Both rapid weight gain and weight loss are associated with high risk of adverse outcomes, particularly in the advanced CKD.

The Post-Translational Regulation of Epithelial-Mesenchymal Transition-Inducing Transcription Factors in Cancer Metastasis.

Epithelial-mesenchymal transition (EMT) is generally observed in normal embryogenesis and wound healing. However, this process can occur in cancer cells and lead to metastasis. The contribution of EMT in both development and pathology has been studied widely. This transition requires the up- and down-regulation of specific proteins, both of which are regulated by EMT-inducing transcription factors (EMT-TFs), mainly represented by the families of Snail, Twist, and ZEB proteins. This review highlights the roles of key EMT-TFs and their post-translational regulation in cancer metastasis.

Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.

Comparing South Korean and US self-rated health using anchoring vignettes.

PURPOSE: This study compares the self-rated health (SRH) of South Korean and US respondents, using anchoring vignettes to adjust for reporting heterogeneity, i.e., cross-national differences in use of response categories. METHODS: Study participants, ages 20 to 59, were recruited from online survey panels retained by Embrain in Korea (N = 1170) and the US (N = 1033). In the analyses, we first examined the two key measurement assumptions of the anchoring vignette method. Response consistency was examined by regressing SRH on vignette ratings and EQ-5D, and was satisfied when the relationship between SRH and vignette ratings was significant and positive. Vignette equivalence was assessed by examining whether respondents correctly rank-ordered vignettes by health status severity. We then compared estimates of the between-country difference in SRH from two models: a standard ordered probit regression, and a hierarchical ordered probit (Hopit) regression, which adjusted for cross-country differences in use of response categories. RESULTS: The anchoring vignettes satisfied both measurement assumptions. Results from the ordered probit regression indicated that Korean SRH was worse than that in the US. However, results from the Hopit regression revealed that Korean SRH was actually better than that in the US, after adjusting for Korean respondents' significantly higher intercategory thresholds (demarcating between "very bad" and "bad," "bad" and "fair," etc.). CONCLUSION: The apparently lower SRH of Korean vis-à-vis US respondents is an artifact of Koreans' higher standards for health-related response categories. After adjusting for these different standards, Korean SRH is revealed to be higher than US SRH.

Discrepant glomerular filtration rate trends from creatinine and cystatin C in patients with chronic kidney disease: results from the KNOW-CKD cohort.

BACKGROUND: Serum creatinine (Cr) and cystatin C (CysC) can both be used to estimate glomerular filtration rate (eGFRCr and eGFRCysC). However, certain conditions may cause discrepancies between eGFR trends from Cr and CysC, and these remain undetermined in patients with chronic kidney disease (CKD). METHODS: A total of 1069 patients from the Korean CKD cohort (KNOW-CKD), which enrolls pre-dialytic CKD patients, whose Cr and CysC had been followed for more than 4 years were included in the sample. We performed trajectory analysis using latent class mixed modeling and identified members of the discrepancy group when patient trends between eGFRCr and eGFRCysC differed. Multivariate logistic analyses with Firth's penalized likelihood regression models were performed to identify conditions related to the discrepancy. RESULTS: Trajectory patterns of eGFRCr were classified into three groups: two groups with stable eGFRCr (stable with high eGFRCr and stable with low eGFRCr) and one group with decreasing eGFRCr. Trajectory analysis of eGFRCysC also showed similar patterns, comprising two groups with stable eGFRCysC and one group with decreasing eGFRCysC. Patients in the discrepancy group (decreasing eGFRCr but stable & low eGFRCysC; n = 55) were younger and had greater proteinuria values than the agreement group (stable & low eGFRCr and eGFRCysC; n = 706), differences that remained consistent irrespective of the measurement period (4 or 5 years). CONCLUSIONS: In the present study, we identify conditions related to discrepant trends of eGFRCr and eGFRCysC. Clinicians should remain aware of such potential discrepancies when tracing both Cr and CysC.

Biobanking for glomerular diseases: a study design and protocol for KOrea Renal biobank NEtwoRk System TOward NExt-generation analysis (KORNERSTONE).

BACKGROUNDS: Glomerular diseases, a set of debilitating and complex disease entities, are related to mortality and morbidity. To gain insight into pathophysiology and novel treatment targets of glomerular disease, various types of biospecimens linked to deep clinical phenotyping including clinical information, digital pathology, and well-defined outcomes are required. We provide the rationale and design of the KOrea Renal biobank NEtwoRk System TOward Next-generation analysis (KORNERSTONE). METHODS: The KORNERSTONE, which has been initiated by Korea Centres for Disease Control and Prevention, is designed as a multi-centre, prospective cohort study and biobank for glomerular diseases. Clinical data, questionnaires will be collected at the time of kidney biopsy and subsequently every 1 year after kidney biopsy. All of the clinical data will be extracted from the electrical health record and automatically uploaded to the web-based database. High-quality digital pathologies are obtained and connected in the database. Various types of biospecimens are collected at baseline and during follow-up: serum, urine, buffy coat, stool, glomerular complementary DNA (cDNA), tubulointerstitial cDNA. All data and biospecimens are processed and stored in a standardised manner. The primary outcomes are mortality and end-stage renal disease. The secondary outcomes will be deterioration renal function, remission of proteinuria, cardiovascular events and quality of life. DISCUSSION: Ethical approval has been obtained from the institutional review board of each participating centre and ethics oversight committee. The KORNERSTONE is designed to deliver pioneer insights into glomerular diseases. The study design allows comprehensive, integrated and high-quality data collection on baseline laboratory findings, clinical outcomes including administrative data and digital pathologic images. This may provide various biospecimens and information to many researchers, establish the rationale for future more individualised treatment strategies for glomerular diseases. TRIAL REGISTRATION: NCT03929887 .

Acute Kidney Injury in Pediatric Cancer Patients.

OBJECTIVE: To analyze the incidence of acute kidney injury (AKI) in the first year after cancer diagnosis in children and to evaluate the short-term and long-term effects on renal function and proteinuria. STUDY DESIGN: Retrospective review of medical records was done on children who were diagnosed and treated for cancer at Seoul National University Hospital between 2004 and 2013. AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. Impaired renal function of estimated glomerular filtration rate less than 90 mL/minute/1.73 m2 and development of proteinuria of cancer survivors were also assessed. RESULTS: This study included 1868 patients who were diagnosed with cancer at a median age of 7.9 years. During the course of treatment, 983 patients (52.6%) developed 1864 episodes of AKI, and the cumulative incidence at 2 weeks, 3 months, and 1 year after diagnosis was 28.9%, 39.6%, and 53.6%, respectively. The 1-year cumulative incidence was the highest in patients with acute myeloid leukemias (88.4%). In all, 6.1% of patients had more than 4 episodes of AKI and 11.8% of patients had stage 3 AKI. Among the 1096 childhood cancer survivors, 22.6% were found to have impaired renal function. A greater number of AKI episodes (≥4 times) and nephrectomy were independent risk factors of impaired renal function. Also, 8.2% of the survivors developed proteinuria among 742 childhood cancer survivors. CONCLUSIONS: A large percentage of children with cancer experience AKI during the course of treatment, and AKI is associated with impaired long-term renal function.

Genetic risk score raises the risk of incidence of chronic kidney disease in Korean general population-based cohort.

BACKGROUND: Chronic kidney disease (CKD) is a common disease, affecting about 10% of the general population. The genetic component about CKD incidence in Asian population is not well known. The aim of the study is to find the genetic loci associated with incident CKD and to figure out the effect of genetic variation on the development of CKD. METHODS: We conducted a genome-wide association (GWA) study regarding the development of CKD based on two population-based cohorts of Korean Genome Epidemiology Study. 3617 Koreans from two different cohorts, aged 40-49 years without CKD at initial visit, were included in our analysis. We used 2510 individuals in Ansan as the discovery set and another 1107 individuals from Ansung as the replication set. At baseline, members of both cohorts provided information on creatinine, and DNA samples were collected for genotyping. Single nucleotide polymorphisms that surpassed a significance threshold of P < 5 × 10-3 were selected. RESULTS: A total of 281 among 3617 developed CKD during the follow-up period. Incident CKD group was older (P < 0.001), included more female (P < 0.001), and had more hypertension and diabetes (P < 0.001). We identified 12 SNPs that are associated with incident CKD in the GWA study and made genetic risk score using these SNPs. In multiple Cox regression analysis, genetic risk score was still a significant associated factor (HR 1.311, CI 1.201, 1.431, P < 0.001). CONCLUSIONS: We identified several loci highly associated with incident CKD. The findings suggest the need for further investigations on the genetic propensity for incident CKD.

Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway.

Protein phosphorylation affects conformational change, interaction, catalytic activity, and subcellular localization of proteins. Because the post-modification of proteins regulates diverse cellular signaling pathways, the precise control of phosphorylation states is essential for maintaining cellular homeostasis. Kinases function as phosphorylating enzymes, and phosphatases dephosphorylate their target substrates, typically in a much shorter time. The c-Jun N-terminal kinase (JNK) signaling pathway, a mitogen-activated protein kinase pathway, is regulated by a cascade of kinases and in turn regulates other physiological processes, such as cell differentiation, apoptosis, neuronal functions, and embryonic development. However, the activation of the JNK pathway is also implicated in human pathologies such as cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, the proper balance between activation and inactivation of the JNK pathway needs to be tightly regulated. Dual specificity phosphatases (DUSPs) regulate the magnitude and duration of signal transduction of the JNK pathway by dephosphorylating their substrates. In this review, we will discuss the dynamics of phosphorylation/dephosphorylation, the mechanism of JNK pathway regulation by DUSPs, and the new possibilities of targeting DUSPs in JNK-related diseases elucidated in recent studies.