Multifaceted association of overweight and metabolically unhealthy with the risk of Barrett's esophagus in the UK Biobank cohort.

The association of overweight/obesity and metabolically unhealthy (MU) with the risk of developing Barrett's esophagus (BE) remains uncertain. We evaluated whether MU and overweight/obesity are associated with increased BE incidence and whether they have a synergistic impact on BE development. We analyzed the body mass index (BMI) and metabolic indicators at baseline of 402,510 individuals from the UK Biobank with no history of BE. Overweight/obesity and MU were defined as BMI ≥ 25.0 kg/m2 and presence of ≥ 1 MU indicators, respectively. Accordingly, the participants were categorized into four groups: (1) metabolically healthy non-overweight/obesity (MHNO), (2) metabolically unhealthy non-overweight/obesity (MUNO), (3) metabolically healthy overweight/obesity (MHO), and (4) metabolically unhealthy overweight/obesity (MUO). During a median follow-up of 13.5 years, 6195 (1.5%) individuals were newly diagnosed with BE. Among them, 39,281 (9.8%), 92,000 (22.9%), 25,297 (6.3%), and 245,932 (61.1%) individuals were classified as MHNO, MUNO, MHO, and MUO, respectively. In Cox regression analyses, both MU and overweight/obesity were independently associated with BE incidence. Moreover, BE incidence was significantly higher in the MUNO, MHO, and MUO groups, compared to the MHNO group. MU and overweight/obesity are independent risk factors for BE and have a synergistic effect on BE development.

Impact of Serum Creatinine- and Cystatin C-Based Sarcopenia Index on Renal Outcomes in Non-Dialysis-Dependent Chronic Kidney Disease Patients: Results From the KNOW-CKD Study.

OBJECTIVE: To evaluate the impact of the serum creatinine- and cystatin C-based new sarcopenia index (SI) on renal outcomes in non-dialysis-dependent patients with chronic kidney disease (CKD). METHODS: In this observational Korean Cohort Study for Outcome in Patients With CKD (KNOW-CKD), 1957 patients with CKD stage 1 to stage 4 were analyzed from 2011 to 2019. Men and women were separately assigned to quartile groups according to their SI. The primary outcome was a composite renal outcome consisting of 50% reduction in estimated glomerular filtration rate or end-stage kidney disease. With use of Fine and Gray subdistribution hazard models, the association between the SI and the primary outcome was analyzed. RESULTS: During a median follow-up of 6.0 (4.2 to 7.7) years, the primary composite renal outcome occurred in 528 (28.6%) patients within a median of 3.0 (1.8 to 5.0) years. In unadjusted and adjusted models, lower SI groups had a poor primary outcome compared with the highest group (quartile 4). The hazard ratios for quartiles 1, 2, and 3 compared with quartile 4 in the fully adjusted model were 4.47 (95% CI, 3.05 to 6.56; P<.001), 3.08 (95% CI, 2.13 to 4.48; P<.001), and 2.09 (95% CI, 1.45 to 3.01; P<.001), respectively. Restricted cubic spline regression analyses found a relatively inverse linear relationship between the SI and the composite renal outcome. CONCLUSION: The new SI is an independent predictor of renal outcomes. A low SI is associated with poor renal outcome.

The role of PCSK9 in glomerular lipid accumulation and renal injury in diabetic kidney disease.

AIMS/HYPOTHESIS: Glomerular lipid accumulation is a defining feature of diabetic kidney disease (DKD); however, the precise underlying mechanism requires further elucidation. Recent evidence suggests a role for proprotein convertase subtilisin/kexin type 9 (PCSK9) in intracellular lipid homeostasis. Although PCSK9 is present in kidneys, its role within kidney cells and relevance to renal diseases remain largely unexplored. Therefore, we investigated the role of intracellular PCSK9 in regulating lipid accumulation and homeostasis in the glomeruli and podocytes under diabetic conditions. Furthermore, we aimed to identify the pathophysiological mechanisms responsible for the podocyte injury that is associated with intracellular PCSK9-induced lipid accumulation in DKD. METHODS: In this study, glomeruli were isolated from human kidney biopsy tissues, and glomerular gene-expression analysis was performed. Also, db/db and db/m mice were used to perform glomerular gene-expression profiling. We generated DKD models using a high-fat diet and low-dose intraperitoneal streptozocin injection in C57BL/6 and Pcsk9 knockout (KO) mice. We analysed cholesterol and triacylglycerol levels within the kidney cortex. Lipid droplets were evaluated using BODIPY staining. We induced upregulation and downregulation of PCSK9 expression in conditionally immortalised mouse podocytes using lentivirus and siRNA transfection techniques, respectively, under diabetic conditions. RESULTS: A significant reduction in transcription level of PCSK9 was observed in glomeruli of individuals with DKD. PCSK9 expression was also reduced in podocytes of animals under diabetic conditions. We observed significantly higher lipid accumulation in kidney tissues of Pcsk9 KO DKD mice compared with wild-type (WT) DKD mice. Additionally, Pcsk9 KO mouse models of DKD exhibited a significant reduction in mitochondria number vs WT models, coupled with a significant increase in mitochondrial size. Moreover, albuminuria and podocyte foot process effacement were observed in WT and Pcsk9 KO DKD mice, with KO DKD mice displaying more pronounced manifestations. Immortalised mouse podocytes exposed to diabetic stimuli exhibited heightened intracellular lipid accumulation, mitochondrial injury and apoptosis, which were ameliorated by Pcsk9 overexpression and aggravated by Pcsk9 knockdown in mouse podocytes. CONCLUSIONS/INTERPRETATION: The downregulation of PCSK9 in podocytes is associated with lipid accumulation, which leads to mitochondrial dysfunction, cell apoptosis and renal injury. This study sheds new light on the potential involvement of PCSK9 in the pathophysiology of glomerular lipid accumulation and podocyte injury in DKD.

Difference Between Estimated GFR Based on Cystatin C Versus Creatinine and Incident Atrial Fibrillation: A Cohort Study of the UK Biobank.

RATIONALE & OBJECTIVE: The difference between cystatin C-based and creatinine-based estimated glomerular filtration rate (eGFRdiff) has been suggested to reflect factors distinct from kidney function that are associated with cardiovascular risk. However, the association between eGFRdiff and atrial fibrillation (AF) risk has not been extensively evaluated. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Using data from the UK Biobank, this study included 363,494 participants with measured serum creatinine and cystatin C levels and without a prior diagnosis of AF or a history of related procedures. EXPOSURE: Estimated GFRdiff, calculated as cystatin C-based eGFR minus creatinine-based eGFR. Estimated GFRdiff was also categorized as negative (<-15mL/min/1.73m2), midrange (-15 to 15mL/min/1.73m2), or positive (≥15mL/min/1.73m2). OUTCOME: Incident AF. ANALYTICAL APPROACH: Subdistribution hazard models were fit, treating death that occurred before development of AF as a competing event. RESULTS: During the median follow-up period of 11.7 years, incident AF occurred in 18,994 (5.2%) participants. In the multivariable-adjusted model, participants with a negative eGFRdiff had a higher risk of incident AF (subdistribution HR [SHR], 1.25 [95% CI, 1.20-1.30]), whereas participants with a positive eGFRdiff had a lower risk of AF (SHR, 0.81 [95% CI, 0.77-0.87]) compared with those with a midrange eGFRdiff. When eGFRdiff was treated as a continuous variable in the adjusted model, every 10mL/min/1.73m2 higher eGFRdiff was associated with a 0.90-fold decrease in the risk of incident AF. LIMITATIONS: A single measurement of baseline serum creatinine and cystatin C levels. CONCLUSIONS: The difference between cystatin C- and creatinine-based eGFRs was associated with the risk of AF development. A higher eGFRdiff was associated with a lower risk of AF. These findings may have implications for the management of patients at risk of incident AF. PLAIN-LANGUAGE SUMMARY: The difference between cystatin C-based estimated glomerular filtration rate (eGFR) and creatinine-based eGFR has recently gained attention as a potential indicator of cardiovascular outcomes influenced by factors other than kidney function. This study investigated the association between the differences in 2 eGFRs (cystatin C-based eGFR minus creatinine-based eGFR) and incident atrial fibrillation (AF) among>340,000 participants from the UK Biobank Study. Compared with those with a near zero eGFR difference, participants with a negative eGFR difference had a higher risk of AF, while those with a positive eGFR difference had a lower risk. These findings suggest that measuring eGFR differences may help identify individuals at a higher risk of developing AF.

Presence of periodontal disease and the incidence of inflammatory arthritides in the general population: data from the UK Biobank.

OBJECTIVES: To investigate the association between periodontal disease and the development of inflammatory arthritides in the general population. METHODS: In total, 489 125 participants from the UK Biobank without a previous history of RA, AS and PsA were enrolled. The primary outcome was the incidence of inflammatory arthritides, which was a composite of RA, AS and PsA according to the presence of periodontal disease based on self-reported oral health indicators. Multivariate Cox proportional hazard regression analyses using four different models were performed to assess the association between periodontal disease and inflammatory arthritides development. RESULTS: In all, 86 905 and 402 220 individuals were categorized as with and without periodontal disease, respectively. Cox hazard analysis indicated that the presence of periodontal disease was an independent predictor of the occurrence of composite outcomes of inflammatory arthritides, which was also consistent for RA and AS. Significant associations were found to be consistent in the four Cox models and were replicated even when different criteria were used to define periodontal disease. Subgroup analyses indicated that periodontal disease was associated with an increased RA risk in those aged <60 years, and this risk was persistent for both male and female patients and for patients with seropositive/seronegative RA. CONCLUSION: Self-reported periodontal disease is associated with inflammatory arthritides incidence in participants included in the UK Biobank, particularly for RA and AS. Higher clinical attention and optimal dental care in patients with signs of periodontal disease may be recommended for early disease detection and for reducing this risk.

Association of Plant Protein Intake With Risk of Incident CKD: A UK Biobank Study.

RATIONALE & OBJECTIVE: Data suggest that various dietary interventions slow kidney disease progression and improve clinical outcomes for those with chronic kidney disease (CKD). However, the association between plant protein intake and incident CKD has been uncertain. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 117,809 participants who completed at least 1 dietary questionnaire and had an estimated glomerular filtration rate (eGFR) ≥ 60mL/min/1.73m2, a urinary albumin-creatinine ratio (UACR)<30mg/g, and no history of CKD. EXPOSURE: Daily plant protein intake in g/kg/day. OUTCOME: Incident CKD based on the International Classification of Diseases, 10th Revision (ICD-10) or the Office of Population Censuses and Surveys Classification of Interventions and Procedures, version 4 (OPCS-4) codes. ANALYTICAL APPROACH: A cause-specific proportional hazards analysis incorporating competing risks that treated death occurring before incident CKD as a competing event. RESULTS: During a median follow-up period of 9.9 years, incident CKD occurred in 3,745 participants (3.2%; incidence rate, 3.2 per 1,000 person-years). In a multivariable model, the adjusted hazard ratio (AHR) for the second, third, and highest quartiles of plant protein intake was 0.90 (95% CI, 0.82-0.99), 0.83 (95% CI, 0.75-0.92), and 0.82 (95% CI, 0.73-0.93), respectively, compared with the lowest quartile. Modeled as a continuous variable, the AHR per 0.1g/kg/day plant protein intake increase was 0.96 (95% CI, 0.93-0.99). This beneficial association was also consistent in secondary analyses for which CKD was defined based on codes or 2 consecutive measures of eGFR<60mL/min/1.73m2 or UACR>30mg/g. Various sensitivity analyses demonstrated consistent findings. LIMITATIONS: Potential incomplete dietary assessments; limited generalizability due to the characteristics of participants in the UK Biobank Study. CONCLUSIONS: In this large, prospective cohort study, greater dietary plant protein intake was associated with a lower risk of incident CKD. Further interventional studies demonstrating the kidney-protective benefits of plant protein intake are warranted. PLAIN-LANGUAGE SUMMARY: Plant-based diets confer various health benefits, including lowering the risk of cardiovascular disease and certain cancers. However, the relationship between plant protein intake and the risk of chronic kidney disease (CKD) remains unclear. Our study investigated the association between plant protein intake and the development of CKD. Using the UK Biobank Study data, we found that participants with a higher plant protein intake had a lower risk of developing CKD. Our finding suggests that a higher dietary intake of plant-based protein may be beneficial for kidney health and provides insight into dietary interventions to prevent CKD in primary care settings.

Predictive performance of the new race-free Chronic Kidney Disease Epidemiology Collaboration equations for kidney outcome in Korean patients with chronic kidney disease.

BACKGROUND: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without a race coefficient have gained recognition across the United States. We aimed to test whether these new equations performed well in Korean patients with chronic kidney disease (CKD). METHODS: This study included 2,149 patients with CKD G1-G5 without kidney replacement therapy from the Korean Cohort Study for Outcome in Patients with CKD (KNOW-CKD). The estimated glomerular filtration rate (eGFR) was calculated using the new CKD-EPI equations with serum creatinine and cystatin C. The primary outcome was 5-year risk of kidney failure with replacement therapy (KFRT). RESULTS: When we adopted the new creatinine equation [eGFRcr (NEW)], 81 patients (23.1%) with CKD G3a based on the current creatinine equation (eGFRcr) were reclassified as CKD G2. Accordingly, the number of patients with eGFR of <60 mL/min/1.73 m2 decreased from 1,393 (64.8%) to 1,312 (61.1%). The time-dependent area under the receiver operating characteristic curve for 5-year KFRT risk was comparable between the eGFRcr (NEW) (0.941; 95% confidence interval [CI], 0.922-0.960) and eGFRcr (0.941; 95% CI, 0.922-0.961). The eGFRcr (NEW) showed slightly better discrimination and reclassification than the eGFRcr. However, the new creatinine and cystatin C equation [eGFRcr-cys (NEW)] performed similarly to the current creatinine and cystatin C equation. Furthermore, eGFRcr-cys (NEW) did not show better performance for KFRT risk than eGFRcr (NEW). CONCLUSION: Both the current and the new CKD-EPI equations showed excellent predictive performance for 5-year KFRT risk in Korean patients with CKD. These new equations need to be further tested for other clinical outcomes in Koreans.

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 Between Proton Pump Inhibitor Exposure and Acute Kidney Injury After Cardiac Surgery.

OBJECTIVE: To evaluate the association of preoperative proton pump inhibitor (PPI) exposure with incident acute kidney injury (AKI) after cardiac surgery. PATIENTS AND METHODS: The Severance cardiac surgery cohort included 9860 cardiac surgery patients aged 18 years or older. The National Health Insurance Service-senior cohort included 2933 patients aged 60 years or older who underwent cardiac surgery. Preoperative PPI exposure was defined as a PPI prescription within 3 weeks prior to cardiac surgery. Primary outcomes were postoperative AKI and AKI requiring dialysis (AKI-dialysis). RESULTS: In the Severance cardiac surgery cohort after propensity score matching for PPI exposure, incident AKI (44.0% [472 of 1073] vs 40.5% [1304 of 3219]) and AKI-dialysis (5.8% [62 of 1073] vs 3.7% [119 of 3219]) were more common in patients exposed to PPI than in those who were not. Hospital and intensive care unit stay durations were longer among PPI-exposed than PPI-nonexposed patients. Multivariable conditional logistic analyses revealed that PPI exposure was significantly associated with incident AKI (adjusted odds ratio [AOR], 1.21; 95% CI, 1.03 to 1.42; P=.02) and AKI-dialysis (AOR, 1.74; 95% CI, 1.15 to 2.63; P=.009). The National Health Insurance Service-Senior cohort had similar results, revealing a significant association between PPI exposure and incident AKI-dialysis (AOR, 1.87; 95% CI, 1.25 to 2.81; P=.003). Discontinuation of PPI prior to operation was associated with a lower odds of AKI development in both cohorts. CONCLUSION: Preoperative PPI exposure may be a modifiable risk factor for AKI among patients undergoing cardiac surgery.

Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis.

Statin use in end-stage kidney disease (ESKD) patients are not encouraged due to low cardioprotective effects. Although the risk of hepatocellular carcinoma (HCC), a frequently occurring cancer in East Asia, is elevated in ESKD patients, the relationship between statins and HCC is not known despite its possible chemopreventive effect. The relationship between statin use and HCC development in ESKD patients with chronic hepatitis was evaluated. In total, 6165 dialysis patients with chronic hepatitis B or C were selected from a national health insurance database. Patients prescribed with ≥ 28 cumulative defined daily doses of statins during the first 3 months after dialysis commencement were defined as statin users, while those not prescribed with statins were considered as non-users. Primary outcome was the first diagnosis of HCC. Sub-distribution hazard model with inverse probability of treatment weighting was used to estimate HCC risk considering death as competing risk. During a median follow-up of 2.8 years, HCC occurred in 114 (3.2%) statin non-users and 33 (1.2%) statin users. The HCC risk was 41% lower in statin users than in non-users (sub-distribution hazard ratio, 0.59; 95% confidence interval [CI], 0.42-0.81). The weighted incidence rate of HCC was lower in statin users than in statin non-users (incidence rate difference, - 3.7; 95% CI - 5.7 to - 1.7; P < 0.001). Incidence rate ratio (IRR) was also consistent with other analyses (IRR, 0.56; 95% CI, 0.41 to 0.78; P < 0.001). Statin use was associated with a lower risk of incident HCC in dialysis patients with chronic hepatitis B or C infection.

External validation of the international prediction tool in Korean patients with immunoglobulin A nephropathy.

BACKGROUND: The International IgA Nephropathy Prediction Tool has been recently developed to estimate the progression risk of immunoglobulin A nephropathy (IgAN). This study aimed to evaluate the clinical performance of this prediction tool in a large IgAN cohort in Korea. METHODS: The study cohort was comprised of 2,064 patients with biopsy-proven IgAN from four medical centers between March 2012 and September 2021. We calculated the predicted risk for each patient. The primary outcome was occurrence of a 50% decline in estimated glomerular filtration rate (eGFR) from the time of biopsy or end-stage kidney disease. The model performance was evaluated for discrimination, calibration, and reclassification. We also constructed and tested an additional model with a new coefficient for the Korean race. RESULTS: During a median follow-up period of 3.8 years (interquartile range, 1.8-6.6 years), 363 patients developed the primary outcome. The two prediction models exhibited good discrimination power, with a C-statistic of 0.81. The two models generally underestimated the risk of the primary outcome, with lesser underestimation for the model with race. The model with race showed better performance in reclassification compared to the model without race (net reclassification index, 0.13). The updated model with the Korean coefficient showed good agreement between predicted risk and observed outcome. CONCLUSION: In Korean IgAN patients, International IgA Nephropathy Prediction Tool had good discrimination power but underestimated the risk of progression. The updated model with the Korean coefficient showed acceptable calibration and warrants external validation.

Creatinine-cystatin C ratio and mortality in cancer patients: a retrospective cohort study.

BACKGROUND: Muscle wasting is prevalent in cancer patients, and early recognition of this phenomenon is important for risk stratification. Recent studies have suggested that the creatinine-cystatin C ratio may correlate with muscle mass in several patient populations. The association between creatinine-cystatin C ratio and survival was assessed in cancer patients. METHODS: A total of 3060 patients who were evaluated for serum creatinine and cystatin C levels at the time of cancer diagnosis were included. The primary outcome was 6-month mortality. The 1-year mortality, and length of intensive care unit (ICU) and hospital stay were also evaluated. RESULTS: The mean age was 61.6 ± 13.5 years, and 1409 patients (46.0%) were female. The median creatinine and cystatin C levels were 0.9 (interquartile range [IQR], 0.6-1.3) mg/dL and 1.0 (IQR, 0.8-1.5) mg/L, respectively, with a creatinine-cystatin C ratio range of 0.12-12.54. In the Cox proportional hazards analysis, an increase in the creatinine-cystatin C ratio was associated with a significant decrease in the 6-month mortality (per 1 creatinine-cystatin C ratio, hazard ratio [HR] 0.35; 95% confidence interval [CI], 0.28-0.44). When stratified into quartiles, the risk of 6-month mortality was significantly lower in the highest quartile (HR 0.30; 95% CI, 0.24-0.37) than in the lowest quartile. Analysis of 1-year mortality outcomes revealed similar findings. These associations were independent of confounding factors. The highest quartile was also associated with shorter lengths of ICU and hospital stay (both P < 0.001). CONCLUSIONS: The creatinine-cystatin C ratio at the time of cancer diagnosis significantly associates with survival and hospitalization in cancer patients.

Preoperative Ionized Magnesium Levels and Risk of Acute Kidney Injury After Cardiac Surgery.

RATIONALE & OBJECTIVE: Although postoperative acute kidney injury (AKI) is a serious complication after cardiac surgery, preventive measures are limited. Despite the known association of preoperative low magnesium levels with cardiac surgery-related atrial fibrillation, the association between preoperative magnesium concentration and postoperative AKI has not been fully elucidated. This study evaluated the association between preoperative serum magnesium level and the development of AKI after cardiac surgery. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: Patients aged≥18 years who underwent cardiac surgery at 2 South Korean tertiary hospitals between 2006 and 2020 were identified from medical records. Patients with missing information, an estimated glomerular filtration rate<15mL/min/1.73m2, receiving maintenance dialysis, or a history of AKI treated by dialysis within 1 year before surgery were excluded. EXPOSURE: Preoperative serum magnesium levels. OUTCOME: Postoperative AKI within 48 hours after surgery, defined using the Acute Kidney Injury Network (AKIN) criteria, and dialysis-treated AKI within 30 days after surgery. ANALYTICAL APPROACH: Multivariable logistic regression analysis. RESULTS: Among the 9,766 patients (median age, 64.0 years; 60.1% male), postoperative AKI and dialysis-treated AKI were observed in 40.1% and 4.3% patients, respectively. Postoperative AKI was more prevalent in patients with lower serum magnesium levels (44.9%, 41.4%, 39.4%, and 34.8% in quartiles 1-4, respectively). Multivariable logistic regression analysis revealed that the odds ratios (ORs) for postoperative AKI were progressively larger across progressively lower quartiles of serum magnesium concentration (adjusted ORs of 1.53 [95% CI, 1.33-1.76], 1.29 [95% CI, 1.12-1.48], 1.15 [95% CI, 1.01-1.31] for quartiles 1-3, respectively, relative to quartile 4, P for trend<0.001). Preoperative hypomagnesemia (serum magnesium level<1.09mg/dL) was also significantly associated with AKI (adjusted OR, 1.39 [95% CI, 1.10-1.77]) and dialysis-treated AKI (adjusted OR, 1.67 [95% CI, 1.02-2.72]). LIMITATIONS: Causality could not be evaluated in this observational study. CONCLUSIONS: Lower serum magnesium levels were associated with a higher incidence of AKI in patients undergoing cardiac surgery.

PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis.

The NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-ß1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-ß1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-ß1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.

Canagliflozin protects against cisplatin-induced acute kidney injury by AMPK-mediated autophagy in renal proximal tubular cells.

Sodium-glucose cotransporter 2 inhibitors, which are recently introduced as glucose-lowering agents, improve cardiovascular and renal outcomes in patients with diabetes mellitus. These drugs also have beneficial effects in various kidney disease models. However, the effect of SGLT2 inhibitors on cisplatin-induced acute kidney injury (AKI) and their mechanism of action need to be elucidated. In this study, we investigated whether canagliflozin protects against cisplatin-induced AKI, depending on adenosine monophosphate-activated protein kinase (AMPK) activation and following induction of autophagy. In the experiments using the HK-2 cell line, cell viability assay and molecular analysis revealed that canagliflozin protected renal proximal tubular cells from cisplatin, whereas addition of chloroquine or compound C abolished the protective effect of canagliflozin. In the mouse model of cisplatin-induced AKI, canagliflozin protected mice from cisplatin-induced AKI. However, treatment with chloroquine or compound C in addition to administration of cisplatin and canagliflozin eliminated the protective effect of canagliflozin. Collectively, these findings indicate that canagliflozin protects against cisplatin-induced AKI by activating AMPK and autophagy in renal proximal tubular cells.

Therapeutic application of extracellular vesicles for various kidney diseases: a brief review.

Extracellular vesicles (EVs) released from different types of kidney cells under physiologic conditions contribute to homeostasis maintenance, immune-modulation, and cell-to-cell communications. EVs can also negatively affect the progression of renal diseases through their pro-inflammatory, pro-fibrotic, and tumorigenic potential. Inhibiting EVs by blocking their production, release, and uptake has been suggested as a potential therapeutic mechanism based on the significant implication of exosomes in various renal diseases. On the other hand, stem cell-derived EVs can ameliorate tissue injury and mediate tissue repair by ameliorating apoptosis, inflammation, and fibrosis while promoting angiogenesis and tubular cell proliferation. Recent advancement in biomedical engineering technique has made it feasible to modulate the composition of exosomes with diverse biologic functions, making EV one of the most popular drug delivery tools. The objective of this review was to provide updates of recent clinical and experimental findings on the therapeutic potential of EVs in renal diseases and discuss the clinical applicability of EVs in various renal diseases. [BMB Reports 2022; 55(1): 3-10].

Ideal cardiovascular health duration and risk of chronic kidney disease and cardiovascular disease.

OBJECTIVE: Increasing number of clinical guidelines are adopting comprehensive cardiovascular risk assessment tools for treatment decision and disease management. Yet, little is known regarding cardiovascular risks associated with the length of favourable cardiometabolic profile. In this context, we examined whether the duration of strictly ideal cardiovascular health (CVH), based on body mass index, blood pressure, fasting glucose, total cholesterol, cigarette smoking, alcohol drinking and physical activity, in middle age is associated with risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD) in mid-to-late life. METHODS: From the Korean Genome and Epidemiology Study Ansung-Ansan cohort, we included 8020 participants (median age 50.0 years, 47.9% male), of whom, 7854 without CKD and 7796 without CVD at baseline. Cox proportional hazards models were employed to assess CKD and CVD risks, adjusting for age, sex, education level, examination sites and renal markers. RESULTS: Over a median follow-up of 15.0 years, 1401 cases of CKD and 493 cases of CVD were newly developed. Compared with participants with <5 years of ideal CVH duration, HR (95% CI) of those who maintained for 5-<10 years or ≥10 years had negatively graded risks for CKD (5-<10 years, 0.63 (0.39 to 0.93); ≥10 years, 0.33 (0.15 to 0.74)) and CVD (5-<10 years, 0.83 (0.54 to 1.27); ≥10 years, 0.22 (0.08 to 0.60)). In parallel, participants with delayed decline to suboptimal level had lower disease risks compared with counterparts with consistently suboptimal CVH. CONCLUSION: Our findings confer that maintaining favourable health behaviours and clinical risk factor levels in midlife will improve later-life cardiovascular outcomes.

The difference between cystatin C- and creatinine-based eGFR is associated with adverse cardiovascular outcome in patients with chronic kidney disease.

BACKGROUND AND AIMS: Decreased kidney function is an important risk factor for cardiovascular disease (CVD). However, assessing risk of CVD may be difficult when there is a gap between creatinine- and cystatin C-based estimated glomerular filtration rate (eGFR). We studied the association of the difference in eGFRs with major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD). METHODS: This prospective cohort study was conducted in 2076 patients with CKD stages based on the KDIGO guideline (eGFR categories of G1: ≥90; G 2: 60-89; G3: 30-59; G4: 15-29; G5: <15 mL/min/1.73 m2 without kidney replacement therapy). The difference in eGFR (eGFRdiff) was calculated by subtracting the cystatin C-based eGFR (eGFRcys) from the creatinine-based eGFR (eGFRcreat). The primary outcome was MACE, defined as non-fatal acute myocardial infarction and unstable angina, stroke, congestive heart failure, symptomatic arrhythmia, and cardiac death. RESULTS: During a median follow-up of 4.1 years, MACE occurred in 147 patients (incidence rate, 15.0 per 1000 patient-years). When patients were categorized into baseline eGFRdiff tertiles, the highest tertile was associated with a significantly higher risk of MACE (hazard ratio, 2.12; 95% confidence interval [CI], 1.28-3.51) than the lowest tertile when adjusted for eGFRcreat, eGFRcys, or eGFR based on both creatinine and cystatin C. Patients in the highest tertile had more baseline coronary artery calcification (CAC) than those in the lowest tertile (odds ratio [OR], 1.38; 95% CI, 1.03-1.86). In addition, 978 patients had data for both baseline and follow-up CAC at year 4. In this subgroup, baseline eGFRdiff was significantly associated with accelerated CAC progression (≥50/year) (OR, 1.03; 95% CI, 1.01-1.05). CONCLUSIONS: A large positive difference between eGFRcreat and eGFRcys was associated with a higher risk of MACE and faster CAC progression in patients with CKD. Therefore, careful monitoring of CVD is needed for patients with a higher eGFRdiff.

Erythropoiesis stimulating agent recommendation model using recurrent neural networks for patient with kidney failure with replacement therapy.

In patients with kidney failure with replacement therapy (KFRT), optimizing anemia management in these patients is a challenging problem because of the complexities of the underlying diseases and heterogeneous responses to erythropoiesis-stimulating agents (ESAs). Therefore, we propose a ESA dose recommendation model based on sequential awareness neural networks. Data from 466 KFRT patients (12,907 dialysis sessions) in seven tertiary-care general hospitals were included in the experiment. First, a Hb prediction model was developed to simulate longitudinal heterogeneous ESA and Hb interactions. Based on the prediction model as a prospective study simulator, we built an ESA dose recommendation model to predict the required amount of ESA dose to reach a target hemoglobin level after 30 days. Each model's performance was evaluated in the mean absolute error (MAE). The MAEs presenting the best results of the prediction and recommendation model were 0.59 (95% confidence interval: 0.56-0.62) g/dL and 43.2 µg (ESAs dose), respectively. Compared to the results in the real-world clinical data, the recommendation model achieved a reduction of ESA dose (Algorithm: 140 vs. Human: 150 µg/month, P < 0.001), a more stable monthly Hb difference (Algorithm: 0.6 vs. Human: 0.8 g/dL, P < 0.001), and an improved target Hb success rate (Algorithm: 79.5% vs. Human: 62.9% for previous month's Hb < 10.0 g/dL; Algorithm: 95.7% vs. Human:73.0% for previous month's Hb 10.0-12.0 g/dL). We developed an ESA dose recommendation model for optimizing anemia management in patients with KFRT and showed its potential effectiveness in a simulated prospective study.

Synergic association of diabetes mellitus and chronic kidney disease with muscle loss and cachexia: results of a 16-year longitudinal follow-up of a community-based prospective cohort study.

Muscle loss is a serious complication in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). However, studies on a long-term change in muscle mass presence or absence of DM and CKD are scarce. We included 6247 middle-aged adults from the Korean Genome and Epidemiology Study (KoGES) between 2001 and 2016. Bioimpedance analysis (BIA) was performed biennially. Patients were classified into four groups according to the presence or absence of DM and CKD. The primary outcome was muscle depletion, which was defined as a decline in fat-free mass index (FFMI) below the 10th percentile of all subjects. The secondary outcomes included the occurrence of cachexia, all-cause mortality, and the slopes of changes in fat-free mass and weight. During 73,059 person-years of follow-up, muscle depletion and cachexia occurred in 460 (7.4%) and 210 (3.4%), respectively. In the multivariable cause-specific hazards model, the risk of muscle depletion was significantly higher in subjects with DM alone than in those without DM and CKD (HR, 1.37; 95% CI, 1.04-1.80) and was strongly pronounced in subjects with both conditions (HR, 3.38; 95% CI, 1.30-8.75). The secondary outcome analysis showed consistent results. The annual decline rates in FFMI, fat mass, and body mass index (BMI) were the steepest in subjects with DM and CKD among the four groups. DM and CKD are synergically associated with muscle loss over time. In addition, the mortality risk is higher in individuals with muscle loss.