Silent gallbladder stone in kidney transplantation recipients: should it be treated? a retrospective cohort study.

BACKGROUND: Treatment and follow-up strategies for silent gallbladder stones in patients before kidney transplantation (KT) remain unknown. Therefore, we aimed to elucidate the role of pre-KT cholecystectomy in preventing biliary and surgical complications. MATERIALS AND METHODS: This study retrospectively analyzed 2,295 KT recipients and 3,443 patients waiting for KT at a single tertiary center from January 2005 to July 2022. The primary outcomes were the incidences of biliary and post-cholecystectomy complications in KT recipients. Firth's logistic regression model was used to assess the risk factors for biliary complications. RESULTS: Overall, 543 patients awaiting KT and 230 KT recipients were found to have biliary stones. Among the KT recipients, 16 (7%) underwent cholecystectomy before KT, while others chose to observe their biliary stones. Pre-KT cholecystectomy patients did not experience any biliary complications, and 20 (9.3%) patients who chose to observe their stones experienced complications. Those who underwent cholecystectomy before KT developed fewer post-cholecystectomy complications (6.3%) compared with those who underwent cholecystectomy after KT (38.8%, P=0.042), including reduced occurrences of fatal postoperative complications based on the Clavien-Dindo classification. Multiple stones (odds ratio [OR], 3.09; 95% confidence interval [CI], 1.07-8.90; P=0.036), thickening of the gallbladder wall (OR, 5.39; 95% CI, 1.65-17.63; P=0.005), and gallstones>1 cm in size (OR 5.12, 95% CI: 1.92-13.69, P=0.001) were independent risk factors for biliary complications. Among patients awaiting KT, 23 (4.2%) underwent cholecystectomy during the follow-up, resulting in one post-cholecystectomy complication. CONCLUSION: Gallstone-related biliary complications following KT and subsequent cholecystectomy was associated with more serious complications and worse treatment outcomes. Therefore, when KT candidates had risk factor for biliary complications, preemptive cholecystectomy for asymptomatic cholecystolithiasis could be considered to reduce further surgical risk.

Non-indicated initiation of proton pump inhibitor and risk of adverse outcomes in patients with underlying chronic kidney disease: a nationwide, retrospective, cohort study.

OBJECTIVE: Evidence related to the risk of kidney damage by proton pump inhibitor (PPI) initiation in patients with 'underlying' chronic kidney disease (CKD) remains scarce, although PPI use is generally associated with acute interstitial nephritis or incident CKD. We aimed to investigate the association between PPI initiation and the risk of adverse outcomes in patients with CKD in the absence of any deterministic indications for PPI usage. DESIGN: Retrospective observational study. SETTING: Korea National Health Insurance Service database from 2009 to 2017. PARTICIPANTS: A retrospective cohort of new PPI and histamine H2-receptor antagonists (H2RA) users among people with CKD. Patients with a history of gastrointestinal bleeding or those who had an endoscopic or image-based upper gastrointestinal tract evaluation were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The study subjects were followed to ascertain clinical outcomes including mortality, end-stage kidney disease (ESKD), myocardial infarction and stroke. The HRs of outcomes were measured using a Cox regression model after adjusting for multiple variables. We applied an inverse probability of treatment weighting (IPTW) model to control for residual confounders. RESULTS: We included a total of 1038 PPI and 3090 H2RA users without deterministic indications for treatment. IPTW-weighted Cox regression analysis showed that PPI initiation was more significantly associated with a higher ESKD risk compared with that of H2RA initiation (adjusted HR 1.72 (95% CI 1.19 to 2.48)), whereas the risks of mortality or cardiovascular outcomes were similar between the two groups. In the subgroup analysis, multivariable Cox regression analysis showed that the association between PPI use and the progression to ESKD remained significant in non-diabetic and low estimated glomerular filtration rate (<60 mL/min/1.73 m2) groups (adjusted HR 1.72 (95% CI 1.19 to 2.48) and 1.63 (95% CI 1.09 to 2.43), respectively). CONCLUSIONS: Initiation of PPI administration may not be recommended in patients with CKD without deterministic indication, as their usage was associated with a higher risk of ESKD.

Associations of metabolic variabilities and cardiovascular outcomes according to estimated glomerular filtration rate in chronic kidney disease: a nationwide observational cohort study.

Background: The impact of baseline estimated glomerular filtration rate (eGFR) on the risk of adverse outcomes according to metabolic parameter variabilities in chronic kidney disease has rarely been investigated. Methods: We conducted a retrospective nationwide cohort study using the National Health Insurance System data in Korea from 2007 to 2013 to identify individuals with three or more health screenings. The metabolic components variability was defined as intraindividual variability between measurements using the variability independent of the mean. The metabolic variability score was defined as the total number of high-variability metabolic components. Multivariable-adjusted Cox regression analysis was conducted to evaluate the risks of all-cause mortality, myocardial infarction, and ischemic stroke. Results: During a mean follow-up of 6.0 ± 0.7 years, 223,531 deaths, 107,140 myocardial infarctions, and 116,182 ischemic strokes were identified in 9,971,562 patients. Low eGFR categories and higher metabolic variability scores were associated with a higher risk of adverse outcomes. The degree of association between metabolic variability and adverse outcomes was significantly larger in those with low eGFR categories than in those with preserved eGFR (p for interaction < 0.001). Representatively, those with high metabolic variability in the eGFR of <15 mL/min/1.73 m2 group showed a prominently higher risk for all-cause mortality (adjusted hazard ratio [aHR], 5.28; 95% confidence interval [CI], 4.02-6.94) when the degree was compared to the findings in those with preserved (eGFR of ≥60 mL/min/1.73 m2) kidney function (aHR, 2.55; 95% CI, 2.41-2.69). Conclusion: The degree of adverse association between metabolic variability and poor prognosis is accentuated in patients with impaired kidney function.

The association of time-updated ambulatory blood pressure and renal progression in hypertensive patients with chronic kidney disease: post hoc analysis of ACCURATE study.

OBJECTIVES: : This study aimed to evaluate the effect of time-updated ambulatory blood pressure on chronic kidney disease (CKD) progression in patients with hypertension. METHODS: : Among patients with hypertension and CKD stages 3 and 4, enrolled in a clinical trial in which hypertension was treated based on office or ambulatory blood pressure (BP), participants assigned to the ambulatory BP were included in this study. Ambulatory BP was measured at the start of the study and 3, 6, and 18 months. Renal events were defined as a decrease in the estimated glomerular filtration rate (eGFR) by at least 30%, dialysis, or transplantation. RESULTS: : A total of 21 cases of renal events were observed. For baseline BP, a multivariate Cox model revealed that neither office SBP nor any component of ambulatory SBP, including mean, day-time, night-time BPs was associated with the risk of renal events. For time-updated BP, a marginal structural model revealed that the office SBP was not associated with renal events [hazard ratio 1.03, 95% confidence interval (CI) 0.99-1.07, P  = 0.117], but higher ambulatory SBPs, including day-time (hazard ratio 1.05, 95% CI 1.01-1.10, P  = 0.014), night-time (hazard ratio 1.05, 95% CI 1.02-1.08, P  = 0.001), and mean (hazard ratio 1.06, 95% CI 1.02-1.10, P  = 0.002) ambulatory SBPs, were significantly associated with an increased risk of renal events. CONCLUSION: : A higher time-updated ambulatory BP was associated with an increased risk of renal events in patients with hypertension and CKD, whereas baseline office and ambulatory BP, and time-updated office BP were not.

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.

Cardiovascular and Mortality Risks in Young Health Screening Examinees With Marginal Estimated GFR.

Introduction: Additional evidence is necessary to interpret kidney function parameters in young adults, particularly in those with marginal estimated glomerular filtration rate (eGFR) values. Therefore, we aimed to investigate the association between eGFR and adverse outcomes in general young adults. Methods: We performed a nationwide retrospective cohort study using the health-screening database of South Korea. We included young adults aged 20-39 years without a history of major adverse cardiovascular events (MACE) or kidney failure, who underwent nationwide health screening in 2012. The study exposure was eGFR categorized into 15 ml/min per 1.73 m2 intervals. The risks of all-cause mortality and MACE were calculated using Cox regression analysis, adjusted for various clinicodemographic characteristics. Results: In total, 3,132,409 young adults were included in this study. During a median follow-up of 7.3 years, marginal eGFR (60-75 ml/min per 1.73 m2) was not significantly associated with a higher risk of all-cause mortality (adjusted hazard ratio [aHR], 0.80 [0.74-0.87]). The results were similar for MACE outcomes (aHR, 0.94 [0.87-1.01]). Although the presence of dipstick albuminuria had a significant interaction with the association between eGFR categories and all-cause mortality (interaction term P = 0.028), the risks of all-cause mortality were not significantly higher (aHR, 0.98 [0.62, 1.55]) in those with albuminuria and eGFR 60-75 ml/min per 1.73 m2. Conclusion: Marginal eGFR was not associated with higher risks of all-cause mortality and MACE in general young adults. Additional clinical investigations for incidentally found marginal eGFR values may be discouraged in general young adults.

Impact of albuminuria on early-onset type 2 diabetes mellitus: a nationwide population-based study.

Background: Early-onset diabetes mellitus has a significant lifetime burden and is associated with higher morbidity and mortality. Since insulin resistance is one of the mechanisms of podocyte injury, we aimed to evaluate the effect of albuminuria on newly developed early-onset type 2 diabetes mellitus (T2DM). Methods: We screened 6,891,399 subjects aged ≥20 and <40 years without a history of prediabetes or diabetes from the Korean National Health Insurance Service database between 2009 and 2012. A multivariate Cox proportional hazard model was used to identify the impact of albuminuria on early-onset T2DM. Results: Among a total of 5,383,779 subjects, 62,148 subjects (1.2%) developed early-onset diabetes over 7.3 ± 1.2 years. Albuminuria was significantly associated with early-onset T2DM (adjusted hazard ratio [aHR], 1.62; 95% confidence interval [CI], 1.55-1.70) after adjustment for age, sex, anthropometric data, physical exercise status, serum glucose, and total cholesterol. The risk of early-onset T2DM increased more in subjects with more components of metabolic syndrome (MetS). Among each component of MetS, hypertriglyceridemia was prominently associated with early-onset T2DM (aHR, 2.02; 95% CI, 1.81-2.25) in subjects with albuminuria. Conclusion: Dipstick albuminuria was significantly associated with early-onset T2DM in young adult populations. Close monitoring of albuminuria is warranted for disease risk modification, especially in subjects with MetS.

Regulation of anti-inflammatory and antioxidant responses by methanol extract of Mikania cordata (Burm. f.) B. L. Rob. leaves via the inactivation of NF-κB and MAPK signaling pathways and activation of Nrf2 in LPS-induced RAW 264.7 macrophages.

Mikania cordata (Burm. f.) B.L. Rob. has been traditionally used in tropical countries throughout Asia and Africa to treat gastric ulcers, dyspepsia, and dysentery. However, the mechanisms responsible for its anti-inflammatory and antioxidant activities are not fully understood. Therefore, this study sought to investigate the anti-inflammatory and antioxidant effects of methanol extracts of M. cordata (MMC) on inflammation and oxidative stress in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 macrophages and elucidate its underlying regulatory mechanism. MMC significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-stimulated RAW 264.7 macrophages by downregulating the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) at both the mRNA and protein levels. Moreover, MMC effectively reduced the mRNA expression levels and production of pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α (TNF-α). These suppressive effects of MMC on pro-inflammatory mediators and cytokines were mediated through the inhibition of transforming growth factor beta-activated kinase 1 (TAK1), which subsequently blocked the activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). MMC also upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2) by inducing the degradation of Kelch-like ECH-related protein 1 (Keap1), an Nrf2-specific E3 ligase. Accordingly, MMC enhanced Nrf2 target gene expression of anti-oxidative regulators such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). However, it had minimal effect on the DPPH radical scavenging capacity in vitro. Collectively, these findings demonstrate that MMC holds promise as a potential therapeutic agent for alleviating inflammation-related diseases and oxidative stress.

Measured sodium excretion is associated with cardiovascular outcomes in non-dialysis CKD patients: results from the KNOW-CKD study.

Background: There are insufficient studies on the effect of dietary salt intake on cardiovascular (CV) outcomes in chronic kidney disease (CKD) patients, and there is no consensus on the sodium (Na) intake level that increases the risk of CV disease in CKD patients. Therefore, we investigated the association between dietary salt intake and CV outcomes in CKD patients. Methods: In the Korean cohort study for Outcome in patients with CKD (KNOW-CKD), 1,937 patients were eligible for the study, and their dietary Na intake was estimated using measured 24h urinary Na excretion. The primary outcome was a composite of CV events and/or all-cause death. The secondary outcome was a major adverse cardiac event (MACE). Results: Among 1,937 subjects, there were 205 (10.5%) events for the composite outcome and 110 (5.6%) events for MACE. Compared to the reference group (urinary Na excretion< 2.0g/day), the group with the highest measured 24h urinary Na excretion (urinary Na excretion ≥ 8.0g/day) was associated with increased risk of both the composite outcome (hazard ratio 3.29 [95% confidence interval 1.00-10.81]; P = 0.049) and MACE (hazard ratio 6.28 [95% confidence interval 1.45-27.20]; P = 0.013) in a cause-specific hazard model. Subgroup analysis also showed a pronounced association between dietary salt intake and the composite outcome in subgroups of patients with abdominal obesity, female, lower estimated glomerular filtration rate (< 60 ml/min per 1.73m2), no overt proteinuria, or a lower urinary potassium-to-creatinine ratio (< 46 mmol/g). Conclusion: A high-salt diet is associated with CV outcomes in non-dialysis CKD patients.

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.

Anti-migration and anti-invasion effects of LY-290181 on breast cancer cell lines through the inhibition of Twist1.

Breast cancer has become the most common cancer among women worldwide. Among breast cancers, metastatic breast cancer is associated with the highest mortality rate. Twist1, one of the epithelial-mesenchymal transition-regulating transcription factors, is known to promote the intravasation of breast cancer cells into metastatic sites. Therefore, targeting Twist1 to develop anti-cancer drugs might be a valuable strategy. In this study, LY-290181 dose-dependently inhibited migration, invasion, and multicellular tumor spheroid invasion in breast cancer cell lines. These anti-cancer effects of LY-290181 were mediated through the down-regulation of Twist1 protein levels. LY-290181 inhibited extracellular signal-regulated kinase and c-Jun N-terminal kinase signaling pathways. Therefore, our findings suggest that LY-290181 may serve as a basis for future research and development of an anti-cancer agent targeting metastatic cancers. [BMB Reports 2023; 56(7): 410-415].

Epigenome-wide association study of diabetic chronic kidney disease progression in the Korean population: the KNOW-CKD study.

Since the etiology of diabetic chronic kidney disease (CKD) is multifactorial, studies on DNA methylation for kidney function deterioration have rarely been performed despite the need for an epigenetic approach. Therefore, this study aimed to identify epigenetic markers associated with CKD progression based on the decline in the estimated glomerular filtration rate in diabetic CKD in Korea. An epigenome-wide association study was performed using whole blood samples from 180 CKD recruited from the KNOW-CKD cohort. Pyrosequencing was also performed on 133 CKD participants as an external replication analysis. Functional analyses, including the analysis of disease-gene networks, reactome pathways, and protein-protein interaction networks, were conducted to identify the biological mechanisms of CpG sites. A phenome-wide association study was performed to determine the associations between CpG sites and other phenotypes. Two epigenetic markers, cg10297223 on AGTR1 and cg02990553 on KRT28 indicated a potential association with diabetic CKD progression. Based on the functional analyses, other phenotypes (blood pressure and cardiac arrhythmia for AGTR1) and biological pathways (keratinization and cornified envelope for KRT28) related to CKD were also identified. This study suggests a potential association between the cg10297223 and cg02990553 and the progression of diabetic CKD in Koreans. Nevertheless, further validation is needed through additional studies.

Comparison of cardiovascular event predictability between the 2009 and 2021 Chronic Kidney Disease Epidemiology Collaboration equations in a Korean chronic kidney disease cohort: the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease.

BACKGROUND: The 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine-based estimated glomerular filtration rate (eGFRcr) equation contains a race component that is not based on biology and may cause a bias in results. Therefore, the 2021 eGFRcr and creatinine-cystatin C-based eGFR (eGFRcr-cysC) equations were developed with no consideration of race. This study compared the cardiovascular event (CVE) and all-cause mortality and CVE combined predictability among the three eGFR equations in Korean chronic kidney disease (CKD) patients. METHODS: This study included 2,207 patients from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) index were used to compare the predictability of the study outcomes according to the 2009 eGFRcr, 2021 eGFRcr, and 2021 eGFRcr-cysC equations. RESULTS: The overall prevalence of CVE and all-cause mortality were 9% and 7%, respectively. There was no difference in area under the curve of ROC for CVE and mortality and CVE combined among all three equations. Compared to the 2009 eGFRcr, both the 2021 eGFRcr (NRI, 0.013; 95% confidence interval [CI], - 0.002 to 0.028) and the eGFRcr-cysC (NRI, -0.001; 95% CI, -0.031 to 0.029) equations did not show improved CVE predictability. Similar findings were observed for mortality and CVE combined predictability with both the 2021 eGFRcr (NRI, -0.019; 95% CI, -0.039-0.000) and the eGFRcr-cysC (NRI, -0.002; 95% CI, -0.023 to 0.018). CONCLUSION: The 2009 eGFRcr equation was not inferior to either the 2021 eGFRcr or eGFRcr-cysC equation in predicting CVE and the composite of mortality and CVE in Korean CKD patients.

Association of Chronic Kidney Disease With Atrial Fibrillation in the General Adult Population: A Nationwide Population-Based Study.

Background The incidences of atrial fibrillation (AF) and chronic kidney disease (CKD) are increasing, and AF is prevalent in patients with CKD. However, few studies have investigated the incidence or association of AF in a large CKD population from a longitudinal study. Methods and Results From a nationwide cohort, a total of 4 827 987 Korean individuals without prior AF, who received biennial health checkups provided by the National Health Insurance Service between 2009 and 2012 in Korea, were analyzed. Incidence of AF was ascertained through the end of 2018. During a median follow-up of 8.1 years, the annual incidence rate of AF was 1.17 per 1000 person-years among subjects without CKD, 1.55 for stage 1 CKD, 1.86 for stage 2 CKD, 2.1 for stage 3 CKD, and 4.33 for stage 4 CKD. In Fine-Gray regression models, CKD was associated with an increased risk of AF; the adjusted hazard ratios and 95% CIs of AF occurrence were 1.77 (1.69-1.85), 1.85 (1.80-1.91), 1.99 (1.95-2.04), and 4.04 (3.07-5.33) in individuals with CKD stages 1, 2, 3, and 4, respectively, compared with non-CKD. The association between CKD and incident AF remained statistically significant after adjustment for multiple confounding factors and was consistent across subgroups stratified by sex and age. Conclusions CKD is associated with an increased incidence of AF. Even mild CKD is associated with incident AF, and there was a stepwise increase in the risk of incident AF with a decrease in renal function.

Comparison of outcomes of chronic kidney disease based on etiology: a prospective cohort study from KNOW-CKD.

The causes of chronic kidney disease (CKD) affects its outcomes. However, the relative risks for adverse outcomes according to specific causes of CKD is not well established. In a prospective cohort study from KNOW-CKD, a cohort was analyzed using overlap propensity score weighting methods. Patients were grouped into four categories according to the cause of CKD: glomerulonephritis (GN), diabetic nephropathy (DN), hypertensive nephropathy (HTN), or polycystic kidney disease (PKD). From a total of 2070 patients, the hazard ratio of kidney failure, the composite of cardiovascular disease (CVD) and mortality, and the slope of the estimated glomerular filtration rate (eGFR) decline according to the cause of CKD were compared between causative groups in a pairwise manner. There were 565 cases of kidney failure and 259 cases of composite CVD and death over 6.0 years of follow-up. Patients with PKD had a significantly increased risk for kidney failure compared to those with GN [Hazard ratio (HR) 1.82], HTN (HR 2.23), and DN (HR 1.73). For the composite outcome of CVD and death, the DN group had increased risks compared to the GN (HR 2.07), and HTN (HR 1.73) groups but not to the PKD group. The adjusted annual eGFR change for the DN and PKD groups were - 3.07 and - 3.37 mL/min/1.73 m2 per year, respectively, and all of these values were significantly different than those of the GN and HTN groups (- 2.16 and - 1.42 mL/min/1.73 m2 per year, respectively). In summary, the risk of kidney disease progression was relatively higher in patients with PKD compared to other causes of CKD. However, the composite of CVD and death was relatively higher in patients with DN-related CKD than in those with GN- and HTN-related CKD.

Metabolomic profiling of overnight peritoneal dialysis effluents predicts the peritoneal equilibration test type.

This study primarily aimed to evaluate whether peritoneal equilibration test (PET) results can be predicted through the metabolomic analysis of overnight peritoneal dialysis (PD) effluents. From a total of 125 patients, overnight PD effluents on the day of the first PET after PD initiation were analyzed. A modified 4.25% dextrose PET was performed, and the PET type was categorized according to the dialysate-to-plasma creatinine ratio at the 4-h dwell time during the PET as follows: high, high average, low average, or low transporter. Nuclear magnetic resonance (NMR)-based metabolomics was used to analyze the effluents and identify the metabolites. The predictive performances derived from the orthogonal projection to latent structure discriminant analysis (OPLS-DA) modeling of the NMR spectrum were estimated by calculating the area under the curve (AUC) using receiver operating characteristic curve analysis. The OPLS-DA score plot indicated significant metabolite differences between high and low PET types. The relative concentrations of alanine and creatinine were greater in the high transporter type than in the low transporter type. The relative concentrations of glucose and lactate were greater in the low transporter type than in the high transporter type. The AUC of a composite of four metabolites was 0.975 in distinguish between high and low PET types. Measured PET results correlated well with the total NMR metabolic profile of overnight PD effluents.

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.

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.

Clinical outcomes of posttransplantation diabetes mellitus in kidney transplantation recipients: a nationwide population-based cohort study in Korea.

Posttransplantation diabetes mellitus (PTDM) is an important metabolic complication after KT that causes graft failure and cardiovascular complications in kidney transplantation (KT) recipients. Using the national claim data of South Korea, 7612 KT recipients between 2009 and 2017 were analyzed. PTDM was defined as a consecutive 30-day prescription history of antidiabetic medication after KT. Among these patients, 24.7% were diagnosed with PTDM, and 51.9% were diagnosed within 6 months after KT. Compared to patients without PTDM, those with PTDM were older, more likely to be men, more likely to be diagnosed with hypertension and cardio-cerebrovascular disease, and experienced more rejection episodes requiring high-dose steroid treatment after KT. During the follow-up, 607 DCGFs, 230 DWGFs, 244 MACEs, and 260 all-cause mortality events occurred. Patients with PTDM showed a higher risk of DCGF (adjusted hazard ratio [aHR] 1.49; 95% confidence interval [CI] 1.22-1.82; P < 0.001) and MACEs (aHR 1.76; 95% CI 1.33-2.31; P < 0.001) than patients without PTDM. The risks for all clinical outcomes were higher in the insulin group than in the non-use insulin group. PTDM in KT recipients resulted in both worse allograft and patient outcomes represented by DCGF and MACE, especially in patients needing insulin treatment.