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Background/aims: Obesity has known to be a modifiable risk factor associated with worse outcomes in chronic kidney disease (CKD), but few studies have examined the impact of obesity on CKD incidence in the general population. The purpose of this study was to investigate the role of body mass index (BMI) and waist-to-hip ratio (WHR) as predictors of incident CKD and to evaluate the impact of weight reduction on CKD prevention., Methods: A total of 2,711 participants from a community-based cohort with normal renal function were prospectively analyzed. Among participants with obesity, we analyzed the change in WHR to evaluate the association of obesity reduction with CKD development., Results: During a mean follow-up of 11.03 ± 4.22 years, incident CKD occurred in 190 (7.0%) participants. In the fully adjusted multivariable Cox proportional hazard models, the risk of incident CKD increased with higher BMI (hazard ratio, 1.06; 95% confidence interval, 1.00-1.11; p = 0.033) and higher WHR (hazard ratio, 1.33; 95% confidence interval, 1.07-1.66; p = 0.009). In the Kaplan-Meier analysis, cumulative adverse renal events were significantly more common in the maintained obesity group than in the reduced obesity group (p = 0.001)., Conclusions: Both higher BMI and WHR were associated with development of CKD, but the magnitude of the effect of WHR was higher than that of BMI. Moreover, reducing obesity would be beneficial for renal prognosis.

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., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Sepsis-associated acute kidney injury (SA-AKI) is a prominent sepsis complication, often resulting in adverse clinical outcomes. Hyperbaric oxygen therapy (HBOT), known for its anti-inflammatory characteristics, antioxidant effects, and ability to deliver high oxygen tension to hypo-perfused tissues, offers potential benefits for SA-AKI. This study investigated whether HBOT improved renal injury in sepsis and elucidated its underlying mechanisms., Methods: A lipopolysaccharide (LPS)-induced endotoxemia model was established using 8-week-old C57BL/6 mice. Thirty minutes post-LPS administration, a group of mice underwent HBOT at a 2.5 atmospheric pressure absolute with 100% oxygen for 60 minutes. After 24 hours, all mice were euthanized for measurements., Results: Our results demonstrated that HBOT effectively mitigated renal tubular cell apoptosis. Additionally, HBOT significantly reduced phosphorylated p53 proteins and cytochrome C levels, suggesting that HBOT may attenuate renal apoptosis by impeding p53 activation and cytochrome C release. Notably, HBOT preserved manganese-dependent levels of superoxide dismutase, an antioxidant enzyme, compared to the LPS group. Furthermore, transforming growth factor beta (TGF-β)/Smad4 and alpha smooth muscle actin expressions were significantly reduced in the LPS + HBOT group., Conclusion: An early single session of HBOT exhibited renoprotective effects in LPS-induced endotoxemia mice models by suppressing p53 activation and cytochrome C levels to mitigate apoptosis. The observed TGF-β decrease, downstream Smad expression reduction, and antioxidant capacity preservation following HBOT may contribute to these effects.

Background: Fabry disease (FD) is an X-linked lysosomal disorder caused by α-galactosidase A enzyme activity deficiency. Although glycosphingolipid analogs have been identified in the plasma or urine of patients with FD, there is a limited understanding of altered metabolomics profiles beyond the globotriaosylceramide accumulation in FD., Methods: Metabolomics study was performed for monitoring of biomarker and altered metabolism related with disease progression in serum and urine from male α-galactosidase A knockout mice and age-matched wild-type mice at 20 and 40 weeks. Profiling analysis for metabolites, including organic acids, amino acids, fatty acids, kynurenine pathway metabolites, and nucleosides in the serum and urine was performed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry combined with star symbol patterns and partial least squares discriminant analysis (PLS-DA)., Results: A total of 27 and 23 metabolites from the serum and urine of Fabry mice were distinguished from those of wild-type mice, respectively, based on p-value (<0.05) and variable importance in projection scores (>1.0) of PLS-DA. In the serum, metabolites of the glutathione, glutathione disulfide, citrulline, and kynurenine pathways that are related to oxidative stress, nitric oxide biosynthesis, and inflammation were increased, whereas those involved in pyruvate and tyrosine metabolism and the tricarboxylic acid cycle were altered in the 20- and 40-week-old urine of FD model mice., Conclusion: Altered metabolic signatures associated with disease progression by oxidative stress, inflammation, nitric oxide biosynthesis, and immune regulation in the early and late stages of FD.

Although renal infarction (RI) is not a rare disease, its outcomes have not been well-documented. Furthermore, transient resolution and recurrence of RI have not been captured through imaging. We report a case of idiopathic RI that recurred within a short period following transient resolution, as demonstrated by serial computed tomography (CT). A 53-year-old man diagnosed with RI was transferred to the emergency room. An abdominal CT scan at the local hospital revealed a segmental wedge-shaped perfusion defect in the left kidney and a focal thrombotic filling defect in the anterior segmental branch of the left renal artery. Since his left flank pain improved, another CT scan was performed again 6 hours after the initial CT scan. A repeat CT scan showed that the thrombus in the renal artery remained, but the perfusion defect had spontaneously resolved. We initiated anticoagulant therapy using unfractionated heparin. On the sixth day of hospitalization, the left flank pain recurred, prompting another CT scan. The follow-up CT scan confirmed that RI had recurred in the same area as before. We continued anticoagulant therapy and switched to warfarin. After treatment, his symptoms improved, and he was discharged. RI can recur at any time, even after it has spontaneously resolved, as evidenced by our case. Therefore, it is crucial to closely monitor patients who experience resolution of RI for any recurrence of symptoms, and repeat radiological evaluation should be performed even within a short period., Competing Interests: Disclosure: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 Korean Society for Electrolyte and Blood Pressure Research.)

Background: Transferrin saturation (TSAT) has been used as an indicator of iron deficiency. However, there is no consensus regarding its optimal range for patient with chronic kidney disease (CKD). We aimed to analyze the effect of TSAT on the prognosis of patients with non-dialysis CKD (NDCKD)., Methods: From 2011 to 2016, 2157 NDCKD patients with baseline TSAT measurements were followed for 10 years. Patients were divided into three groups based on baseline TSAT values: <25%, ≥25% and <45%, and ≥45%. All-cause mortality and 4-point major adverse cardiovascular events (MACE) were analyzed using multivariable Cox regression analysis. Other iron biomarkers and mortality were also analyzed., Results: During a mean follow-up of 7.1 ± 2.9 years, 182 of a total of 2,157 patients (8.4%) died. Compared with the TSAT ≥25% and <45% group, the TSAT <25% group showed significantly increased all-cause mortality (hazard ratio [HR], 1.44; 95% confidence interval (CI), 1.02-2.03; p = 0.04). The occurrence of 4-point MACE was significantly increased in univariable analysis in the TSAT <25% group (HR, 1.48; 95% CI, 1.02-2.15; p = 0.04), but it was not significant in the multivariable analysis (HR, 1.38; 95% CI, 0.89-2.15; p = 0.15). Tertile comparisons of the iron-to-log-ferritin ratio showed increased mortality in the first tertile group., Conclusion: TSAT <25% is an independent risk factor for all-cause mortality in patients with NDCKD and care should be taken to prevent TSAT values of <25%. Other indicators, such as serum iron and iron-to-log-ferritin ratio, may also be used to assess iron deficiency.

Background: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multipotent protein that plays essential roles in cellular responses to oxidative stress., Methods: To examine the role of APE1/Ref-1 in ischemia-reperfusion (I/R) injuries and hydrogen peroxide (H2O2)-induced renal tubular apoptosis, we studied male C57BL6 mice and human proximal tubular epithelial (HK-2) cells treated with H2O2 at different concentrations. The colocalization of APE1/Ref-1 in the proximal tubule, distal tubule, thick ascending limb, and collecting duct was observed with confocal microscopy. The overexpression of APE1/Ref-1 with knockdown cell lines using an APE1/Ref-1-specific DNA or small interfering RNA (siRNA) was used for the apoptosis assay. The promotor activity of nuclear factor kappa B (NF-κB) was assessed and electrophoretic mobility shift assay was conducted., Results: APE1/Ref-1 was predominantly localized to the renal tubule nucleus. In renal I/R injuries, the levels of APE1/Ref-1 protein were increased compared with those in kidneys subjected to sham operations. The overexpression of APE1/Ref-1 in HK-2 cells enhanced the Bax/Bcl-2 ratio as a marker of apoptosis. Conversely, the suppression of APE1/Ref-1 expression by siRNA in 1-mM H2O2-treated HK-2 cells decreased the Bax/Bcl-2 ratio, the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and NF-κB. In HK-2 cells, the promoter activity of NF-κB increased following H2O2 exposure, and this effect was further enhanced by APE1/Ref-1 transfection., Conclusion: The inhibition of APE1/Ref-1 with siRNA attenuated H2O2-induced apoptosis through the modulation of mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 and the nuclear activation of NF-κB and proapoptotic factors.

While the relationship between circulating osteoprotegerin (OPG) and cardiovascular events is well-established in the general population, its association with cardiovascular risks in chronic kidney disease (CKD) patients remains less robust. This study hypothesized that elevated circulating OPG levels might be associated with an increased risk of major adverse cardiac events (MACE) in CKD patients, a total of 2,109 patients with CKD stages 1 through pre-dialysis 5 from the KNOW-CKD cohort were categorized into quartiles based on serum OPG levels. The primary outcome of the study was 3-point MACE, defined as a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiac death. The median follow-up duration was 7.9 years. The cumulative incidence of 3-point MACE significantly varied across serum OPG levels in Kaplan-Meier curve analysis (P < 0.001, log-rank test), with the highest incidence observed in the 4th quartile. Cox regression analysis indicated that, relative to the 1st quartile, the risk of 3-point MACE was significantly higher in the 3rd (adjusted hazard ratio 2.901, 95% confidence interval 1.009 to 8.341) and the 4th quartiles (adjusted hazard ratio 4.347, 95% confidence interval 1.410 to 13.395). In conclusion, elevated circulating OPG levels are associated with adverse cardiovascular outcomes in pre-dialysis CKD patients., (© 2024. The Author(s).)

Background: Heart failure with preserved ejection fraction (HFpEF) is a major cause of mortality in patients with chronic kidney disease (CKD), and diagnosis is challenging. Moreover, no specific biomarker for HFpEF has been validated in patients with CKD. The present study aimed to investigate the association between serum osteoprotegerin (OPG) levels and the risk of left ventricular diastolic dysfunction (LVDD), a surrogate of HFpEF, in patients with pre-dialysis CKD., Methods: A total of 2039 patients with CKD at stage 1 to pre-dialysis 5 were categorized into quartiles (Q1 to Q4) by serum OPG levels, and were cross-sectionally analyzed. The study outcome was LVDD, which was operationally defined as the ratio of early transmitral blood flow velocity to early diastolic velocity of the mitral annulus (E/e') > 14., Results: In the analysis of baseline characteristics, higher serum OPG levels were clearly related to the risk factors of HFpEF. A scatter plot analysis revealed a moderate correlation between serum OPG levels and E/e' (R = 0.351, P < 0.001). Logistic regression analysis demonstrated that the risk of LVDD in Q3 (adjusted odds ratio 2.576, 95% confidence interval 1.279 to 5.188) and Q4 (adjusted odds ratio 3.536, 95% confidence interval 1.657 to 7.544) was significantly higher than that in Q1., Conclusions: Elevated serum OPG levels are associated with the risk of LVDD in patients with pre-dialysis CKD. The measurement of serum OPG levels may help the diagnosis of LVDD, which is an important echocardiographic feature of HFpEF., (© 2024. The Author(s).)

Introduction: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients., Methods: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur., Results: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group., Conclusion: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase (α-Gal A), affecting multiple organs including kidney. In this study, we aimed to determine the prevalence of FD in patients with chronic kidney disease (CKD) including those on renal replacement therapy in Korea., Methods: This is a national, multicenter, observational study performed between August 24, 2017 and February 28, 2020. Patients with the presence of proteinuria or treated on dialysis were screened by measuring the α-Gal A enzyme activity using either dried blood spot or whole blood, and plasma globotriaosylsphingosine (lyso-GL3) concentration. A GLA gene analysis was performed in patients with low α-Gal A enzyme activity or increased plasma lyso-GL3 concentration., Results: Of 897 screened patients, 405 (45.2%) were male and 279 (31.1%) were on dialysis. The α-Gal A enzyme activity was measured in 891 patients (99.3%), and plasma lyso-GL3 concentration was measured in all patients. Ten patients were eligible for a GLA gene analysis: eight with low α-Gal A enzyme activity and two with increased plasma lyso-GL3 concentration. The GLA mutations were analyzed in nine patients and one patient was found with a pathogenic mutation. Therefore, one patient was identified with FD, giving a prevalence of 0.1% (1 of 897) in this CKD population., Conclusion: Although the prevalence of FD in the CKD population was low (0.1%), screening tests are crucial to detect potential diseases in patients with relatives who can benefit from early treatment.

Background: Insulin resistance is prevalent in chronic kidney disease and may accelerate the progression of chronic kidney disease. This study aimed to investigate whether insulin resistance is associated with the development of incident chronic kidney disease in a population with normal renal function., Methods: A total of 3,331 participants from a community-based cohort with normal renal function were prospectively analyzed. We determined the relationship of insulin resistance indices with the incident chronic kidney disease using the Cox proportional hazard model and Kaplan-Meier survival analysis., Results: During a mean follow-up of 11.03 ± 4.22 years, incident chronic kidney disease occurred in 414 participants (12.4%). The high homeostasis model assessment-insulin resistance level group had an increased risk of incident chronic kidney disease (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.13-1.74; p = 0.002) compared to the normal group after adjustment for age, sex, history of hypertension, body mass index, total cholesterol, alcohol drinking status, smoking status, and baseline estimated glomerular filtration rate. The risk of incident chronic kidney disease also increased with the lower quantitative insulin sensitivity check index level (HR, 0.62; 95% CI, 0.41-0.92; p = 0.02) and higher leptin-adiponectin ratio level (HR, 1.23; 95% CI, 1.06-1.42; p = 0.006)., Conclusion: Higher insulin resistance indices are associated with the incidence of chronic kidney disease. Our data suggest that increased insulin resistance may be involved in the development of incident chronic kidney disease in a population with normal renal function.

Background: The medium cutoff (MCO) dialyzer increases the removal of several middle molecules more effectively than high-flux hemodialysis (HD). However, comparative data addressing the efficacy and safety of MCO dialyzers vs. postdilution hemodiafiltration (HDF) in Korean patients are lacking., Methods: Nine patients with chronic HD were included in this pre-post study. Patients underwent HD with an MCO dialyzer for 4 weeks, followed by a 2-week washout period using a high-flux dialyzer to minimize carryover effects, and then turned over to postdilution HDF for 4 weeks. Reduction ratios and differences in the uremic toxins before and after dialysis were calculated from the MCO dialysis, postdilution HDF, and high-flux HD. In the in vitro study, EA.hy926 cells were incubated with dialyzed serum., Results: Compared to postdilution HDF, the MCO dialyzer achieved significantly higher reduction ratios for larger middle molecules (myoglobin, kappa free light chain [κFLC], and lambda FLC [λFLC]). Similarly, the differences in myoglobin, κFLC, and λFLC concentrations before and after the last dialysis session were significantly greater in MCO dialysis than in postdilution HDF. The expression of Bax and nuclear factor κB was decreased in the serum after dialysis with the MCO dialyzer than with HDF., Conclusion: Compared with high-volume postdilution HDF, MCO dialysis did not provide greater removal of molecules below 12,000 Da, whereas it was superior in the removal of larger uremic middle molecule toxins in patients with kidney failure. Moreover, these results may be expected to have an anti-apoptotic effect on the human endothelium.

Background: Underweight status increases the risk of cardiovascular disease and mortality in the general population. However, whether underweight status is associated with an increased risk of developing end-stage kidney disease is unknown., Methods: A total of 9 845 420 participants aged ≥20 years who underwent health checkups were identified from the Korean National Health Insurance Service database and analysed. Individuals with underweight (body mass index [BMI] < 18.5 kg/m 2 ) and obesity (BMI ≥ 25 kg/m 2 ) were categorized according to the World Health Organization recommendations for Asian populations., Results: During a mean follow-up period of 9.2 ± 1.1 years, 26 406 participants were diagnosed with end-stage kidney disease. After fully adjusting for other potential predictors, the moderate to severe underweight group (<17 kg/m 2 ) had a significantly higher risk of end-stage kidney disease than that of the reference (normal) weight group (adjusted hazard ratio, 1.563; 95% confidence interval, 1.337-1.828), and competing risk analysis to address the competing risk of death also showed the similar results (adjusted hazard ratio, 1.228; 95% confidence interval, 1.042-1.448). Compared with that of the reference BMI group (24-25 kg/m 2 ), the adjusted hazard ratios for end-stage kidney disease increased as the BMI decreased by 1 kg/m 2 . In the sensitivity analysis, sustained underweight status or progression to underweight status over two repeated health checkups, when compared with normal weight status, had a higher hazard ratio for end-stage kidney disease., Conclusions: Underweight status is associated with an increased risk of end-stage kidney disease, and this association gradually strengthens as BMI decreases., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd.)

Background/aims: The neutrophil-to-lymphocyte ratio (NLR) has a prognostic value in cardiovascular disease, infection, inflammatory disease, and several malignancies. Therefore, the NLR has a possible predictive value in patients with chronic kidney disease (CKD), but this predictive value has not been validated. Here, we aimed to investigate the possibility of NLR as a predictor of CKD progression., Methods: This retrospective observational study included 141 patients with non-dialysis CKD. The participants were divided into terciles (T1, T2, and T3) according to NLR. The primary outcome was defined as a composite kidney event, which included a decline in the estimated glomerular filtration rate (eGFR) of at least 50% or initiation of renal replacement therapy during the follow-up period., Results: The mean follow-up duration was 5.45 ± 2.11 years. The mean NLRs were 1.35 ± 0.05 in T1 (n = 47), 2.16 ± 0.04 in T2 (n = 47), and 4.29 ± 0.73 in T3 (n = 47). The group with the highest NLR (T3) had higher baseline CKD and serum creatinine and lower eGFR levels than the group with the lowest NLR (T1). The cumulative incidence rate of composite kidney events was significantly higher in T3 compared with T1 (p < 0.001, log-rank test). Cox regression analysis revealed that high NLR was associated with the risk of composite kidney events (adjusted hazard ratio, 3.33; 95% confidence interval, 1.43-7.76)., Conclusion: A higher NLR reflects the more advanced stage of CKD and suggests a role for NLR as a biomarker for predicting CKD progression.

Dyslipidemia is a potentially modifiable cardiovascular risk factor. Whereas the recommendations for the treatment target of dyslipidemia in the general population are being more and more rigorous, the 2013 Kidney Disease: Improving Global Outcomes clinical practice guideline for lipid management in chronic kidney disease (CKD) presented a relatively conservative approach with respect to the indication of lipid lowering therapy and therapeutic monitoring among the patients with CKD. This may be largely attributed to the lack of high-quality evidence derived from CKD population, among whom the overall feature of dyslipidemia is considerably distinctive to that of general population. In this review article, we cover the characteristic features of dyslipidemia and impact of dyslipidemia on cardiovascular outcomes in patients with CKD. We also review the current evidence on lipid lowering therapy to modify the risk of cardiovascular events in this population. We finally discuss the association between dyslipidemia and CKD progression and the potential strategy to delay the progression of CKD in relation to lipid lowering therapy.

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 1.73m 2 ), 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors EK and K-HO declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Kang, Kang, Ryu, Kim, Kim, Kang, Jeong, Kim, Kim, Kim, Kim and Oh.)

Objective: The aim of the work described here was to determine the feasibility of using a novel biopsy needle detection technique that achieves high sensitivity and specificity in a trade-off of resolution, detectability and depth of imaging., Methods: The proposed needle detection method consists of a model-based image analysis, temporal needle projection and needle library matching: (i) Image analysis was formulated under the signal decomposition framework; (ii) temporal projection converted the time-resolved needle dynamics into a single image of the desired needle; and (iii) the enhanced needle structure was spatially refined by matching a long, straight linear object in the needle library. The efficacy was examined with respect to different needle visibility., Results: Our method effectively eliminated confounding effects of the background tissue artifacts more robustly than conventional methods, thus improving needle visibility even with the low contrast between the needle and tissue. The improvement in needle structure further resulted in an improvement in estimation performance for the trajectory angle and tip position., Conclusion: Our three-step needle detection method can reliably detect needle position without the need for external devices, increasing the needle conspicuity and reducing motion sensitivity., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Backgroud: Hypertension is highly prevalent in patients with kidney transplantation caused by transplantation-related immunologic or non-immunologic risk factors. However, whether a strict definition of hypertension (≥130/80 mmHg) and subdivided blood pressure (BP) groups are associated with an increased risk of graft failure after kidney transplantation using a nationwide large cohort study are still unknown., Methods: Using Korean National Health Insurance Service data, we included 14,249 patients who underwent kidney transplantation from 2002 to 2016. Patients were categorized into five BP groups according to the 2021 Kidney Disease: Improving Global Outcomes practice guidelines for BP management: normal BP (<120/80 mmHg), elevated BP (120-129/ < 80 mmHg), incident hypertension (≥130/80 mmHg), and controlled or uncontrolled hypertension with anti-hypertensive medications., Results: The primary outcome was graft failure, which occurred in 1934 (13.6%) participants during the 6-year follow-up. After adjusting for covariates, hypertension was associated with a higher risk of graft failure [Adjusted hazard ratio (AHR), 1.70; 95% confidence interval (CI), 1.48-1.96)] than no-hypertension. The AHR for graft failure was the highest in patients with uncontrolled hypertension (AHR, 2.13; 95% CI, 1.80-2.52). The risk of graft failure had a linear relationship with systolic and diastolic BP, and pulse pressure., Conclusions: In this nationwide population-based study, hypertension ≥130/80 mmHg based on the 2021 KDIGO BP guidelines in kidney transplantion recipients, and elevated systolic and diastolic BP, and pulse pressure were associated with the risk of developing graft failure in kidney transplant recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kim, Oh, Suh, Choi, Bae, Ma, Jung, Kim, Han and Kim.)

Backgruound: The optimal level of glycosylated hemoglobin (HbA1c) to prevent adverse clinical outcomes is unknown in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM)., Methods: We analyzed 707 patients with CKD G1-G5 without kidney replacement therapy and T2DM from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD), a nationwide prospective cohort study. The main predictor was time-varying HbA1c level at each visit. The primary outcome was a composite of development of major adverse cardiovascular events (MACEs) or all-cause mortality. Secondary outcomes included the individual endpoint of MACEs, all-cause mortality, and CKD progression. CKD progression was defined as a ≥50% decline in the estimated glomerular filtration rate from baseline or the onset of end-stage kidney disease., Results: During a median follow-up of 4.8 years, the primary outcome occurred in 129 (18.2%) patients. In time-varying Cox model, the adjusted hazard ratios (aHRs) for the primary outcome were 1.59 (95% confidence interval [CI], 1.01 to 2.49) and 1.99 (95% CI, 1.24 to 3.19) for HbA1c levels of 7.0%-7.9% and ≥8.0%, respectively, compared with <7.0%. Additional analysis of baseline HbA1c levels yielded a similar graded association. In secondary outcome analyses, the aHRs for the corresponding HbA1c categories were 2.17 (95% CI, 1.20 to 3.95) and 2.26 (95% CI, 1.17 to 4.37) for MACE, and 1.36 (95% CI, 0.68 to 2.72) and 2.08 (95% CI, 1.06 to 4.05) for all-cause mortality. However, the risk of CKD progression did not differ between the three groups., Conclusion: This study showed that higher HbA1c levels were associated with an increased risk of MACE and mortality in patients with CKD and T2DM.

The relationship between 24-h urinary phosphorus excretion (24 h UPE) and cardiovascular disease in patients with pre-dialysis chronic kidney disease (CKD) has rarely been studied, despite the fact that the relationship between serum phosphorus level and the risk of a cardiovascular event is well established. A total of 1701 patients with pre-dialysis CKD were finally included for the analyses and were divided into tertiles by 24 h UPE (first tertile (T1, 349.557 (mean) ± 88.413 (standard deviation)), second tertile (T2, 557.530 ± 50.738), and third tertile (T3, 851.695 ± 171.593). The study outcome was a six-point major adverse cardiac event (MACE). The median follow-up duration was 7.992 years. Kaplan-Meier curve analysis visualized that the cumulative incidences of a six-point MACE ( p = 0.029) significantly differed from 24 h UPE levels, as the incidence rate of the study outcomes was highest in T1 and lowest in T3. Cox proportional hazard models unveiled that, compared to T1, the risk of a six-point MACE was significantly decreased in T3 (adjusted hazard ratio (HR) 0.376, 95% confidence interval (CI) 0.207 to 0.683). The restricted cubic spline curve analysis visualized an inverted S-shaped association between 24 h UPE level and the risk of a six-point MACE, indicating a significantly increased risk of a six-point MACE in patients with a low 24 h UPE level. In conclusion, low 24 h UPE is associated with adverse cardiovascular outcomes in patients with CKD. Our finding emphasizes that low 24 h UPE should not be a reliable marker for dietary restriction of phosphorus that essentially leads to better outcomes in patients with CKD.

Background: Determination of the release from isolation for coronavirus disease 2019 (COVID-19) in immunocompromised patients who need additional hospitalization for treatment of non-COVID-19 related disease is important to prevent nosocomial transmission. However, there is insufficient evidence for an extended isolation period., Materials and Methods: In September 2021, when the Delta variant was dominant, a nosocomial outbreak of COVID-19 occurred in the nephrology ward of a tertiary hospital in Gwangju, Korea. We conducted epidemiological investigations and whole-genome sequencing (WGS) of this virus., Results: A man who underwent kidney transplantation was admitted to our hospital for the treatment of acute kidney injury. He was diagnosed with asymptomatic COVID-19 infection during a pre-admission screening test on September 1, 2021 and underwent isolation. After 10 days of isolation in the COVID-19-designated ward, he was transferred to the general nephrology ward. He underwent steroid pulse therapy (September 17 to September 23, >60 mg/day prednisolone) due to acute T-cell rejection. On September 28, 2021, the first patient with COVID-19 was identified in the nephrology ward, and a rapid-response team was activated to identify additional patients with COVID-19 and prevent the spread of COVID-19. Epidemiological investigations revealed that 12 patients, two caregivers, and three healthcare workers from the nephrology ward were diagnosed with COVID-19. The WGS of specimens from 14 nosocomial outbreak samples and released an index patient exhibited the same Delta variant originating from the B.1.617.2 lineage. This hospital-acquired COVID-19 outbreak in the nephrology ward resulted in two (11.7%) deaths in patients who underwent kidney transplantation., Conclusion: We demonstrated that an immunocompromised patient can cause a nosocomial outbreak due to the prolonged shedding of infectious viruses. Prolonged isolation in patients under active immunosuppressive therapy may be necessary to prevent transmission, especially in the hospital setting., Competing Interests: SIJ is associate editor of Infect Chemother; however, she did not involve in the peer reviewer selection, evaluation, and decision process of this article. Otherwise, no potential conflicts of interest relevant to this article was reported., (Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.)

Background: Tolvaptan reduces height-adjusted total kidney volume (htTKV) and renal function decline in autosomal dominant polycystic kidney disease (ADPKD). This study was aimed at investigating the efficacy and safety of tolvaptan in Korean patients with ADPKD during the titration period., Methods: This study is a multicenter, single-arm, open-label phase 4 study. We enrolled 108 patients with ADPKD (age, 19-50 years) with an estimated glomerular filtration rate (eGFR) of &gt;30 mL/min/1.73 m2 and factors defined as indicative of rapid disease progression. After tolvaptan titration, we evaluated efficacy and side effects and assessed factors associated with the effects., Results: After titration for 4 weeks, eGFR and htTKV decreased by 6.4 ± 7.9 mL/min/1.73 m2 and 16 ± 45 mL/m, respectively. No serious adverse drug reactions were observed during the titration period. The greatest eGFR decline was observed in the first week, with a starting tolvaptan dose of 45 mg. Multivariate linear regression for htTKV decline showed that the greater the change in urine osmolality (Uosm), the greater the decrease in htTKV (β, 0.436; p = 0.009) in the 1D group stratified by the Mayo Clinic image classification. Higher baseline eGFR was related to a higher htTKV reduction rate in the 1E group (β, -0.642; p = 0.009)., Conclusion: We observed short-term effects and safety during the tolvaptan titration period. The decline of htTKV can be predicted as a short-term effect of tolvaptan by observing Uosm changes from baseline to end of titration in 1D and baseline eGFR in 1E groups.

Background: Urine chloride has recently been suggested as a biomarker of renal tubule function in patients with nondialysis chronic kidney disease (CKD), as low urinary chloride concentration is associated with an increased risk of CKD progression. We investigate the association between urinary chloride excretion and the progression of coronary artery calcification (CAC)., Methods: A total of 1,065 patients with nondialysis CKD were divided into tertiles by spot urine chloride-to-creatinine ratios. The 1st, 2nd, and 3rd tertiles were defined as low, moderate, and high urinary chloride excretion, respectively. The study outcome was CAC progression, which was defined as an increase in coronary artery calcium score of more than 200 Agatston units during the 4-year follow-up period., Results: Compared to moderate urinary chloride excretion, high urinary chloride excretion was associated with decreased risk of CAC progression (adjusted odds ratio, 0.379; 95% confidence interval, 0.190-0.757), whereas low urinary chloride excretion was not associated with risk of CAC progression. Restricted cubic spine depicted an inverted J-shaped curve, with a significant reduction in the risk of CAC progression in subjects with high spot urine chloride-to-creatinine ratios., Conclusion: High urinary chloride excretion is associated with decreased risk of CAC progression in patients with nondialysis CKD.

Background: Although multiple factors influence the risk of major adverse cardiovascular events (MACE), the effects of socioeconomic status on MACE in the presence and absence of renal dysfunction (RD) have not been comprehensively explored in Korea., Methods: We examined the effects of socioeconomic status on MACE in individuals with and without RD. The data of 44,473 Koreans from 2008 to 2017 were obtained from the Health Care Big Data Platform of the Ministry of Health and Welfare in Korea. Their socioeconomic status was assessed using a socioeconomic score (SES) based on marital status, education, household income, and occupation. The incidence of myocardial infarction (MI), stroke, and death was compared according to SES level (0-4). Multiple linear regression analysis was used to evaluate the hazard ratios and 95% confidence intervals for outcomes based on participant SES., Results: MI risk was only affected by education level. The participants' income, education, and SES affected their stroke risk, whereas death was associated with all four socioeconomic factors. The incidence of stroke and death increased as SES worsened (from 0 to 4). SES was positively related to risk of stroke and death in participants without RD. SES did not affect MI, stroke, or death in participants with RD., Conclusion: A low socioeconomic status is associated with risk of stroke and death, especially in individuals without RD.

Despite the clear association between low BMD and all-cause mortality in the general population, the association has not been validated in patients with nondialysis CKD. To investigate the association of low BMD with all-cause mortality in this population, a total of 2089 patients with nondialysis CKD at stages 1 to predialysis 5 were categorized into normal BMD (T-score ≥ -1.0), osteopenia (-2.5 < T-score < -1.0), and osteoporosis (T-score ≤ - 2.5) by the BMD at femoral neck. The study outcome was all-cause mortality. Kaplan-Meier curve depicted a significantly increased number of all-cause death events in the subjects with osteopenia or osteoporosis during the follow-up period compared with subjects with normal BMD. Cox regression models demonstrated that osteoporosis, but not osteopenia, was significantly associated with an increased risk of all-cause mortality (adjusted hazard ratio 2.963, 95% confidence interval 1.655 to 5.307). Smoothing curve fitting model visualized a clear inverse correlation between BMD T-score and the risk of all-cause mortality. Even after recategorizing the subjects by BMD T-scores at total hip or lumbar spine, the result was similar to the primary analyses. Subgroup analyses revealed that the association was not significantly modified by clinical contexts, such as age, gender, body mass index, estimated glomerular filtration rate, and albuminuria. In conclusion, low BMD is associated with an increased risk of all-cause mortality in patients with nondialysis CKD. This emphasizes that the routine measurement of BMD by DXA may confer an additional benefit beyond the prediction of fracture risk in this population.

Backgrounds: Some observational studies have suggested a possible association between vitamin D deficiency and CKD. However, in most studies, the causality between low levels of vitamin D and risk of renal events could not be explained. We investigated the relationship between vitamin D deficiency and risk of severe CKD stage and renal event in a large-scale prospective cohort study., Methods: We used data from a prospective cohort of 2,144 patients with available information on serum 25-hydroxyvitamin D (25(OH)D) levels at baseline from KNOW-CKD, 2011-2015 were included. Vitamin D deficiency was defined as serum 25(OH)D levels < 15 ng/mL. We performed a cross-sectional analysis to elucidate the relationship between 25(OH)D and CKD stage using baseline CKD patient data. We further examined a cohort analysis to clarify the association between 25(OH)D and risk of renal event. Renal event was a composite of the first occurrence of a 50% decline in eGFR from the baseline value or the onset of CKD stage 5 (initiation of dialysis or kidney transplantation) across the follow-up period. We also investigated the associations of vitamin D deficiency with risk of renal event according to diabetes and overweight status., Results: Vitamin D deficiency were significantly associated with an increased risk of severe CKD stage - 1.30-fold (95% CI: 1.10-1.69) for 25(OH)D. Deficiency of 25(OH)D with 1.64-fold (95% CI: 1.32-2.65) was related to renal event compared with the reference. Furthermore, vitamin D deficiency patients with presence of DM and overweight status also displayed higher risk than non-deficient patients for risk of renal event., Conclusion: Vitamin D deficiency is associated with significantly increased risk of severe CKD stage and renal event., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Bae, Kim, Chung, Kim, Oh, Kim, Oh and Park.)

Ferroptosis is a cell death mechanism characterized by intracellular iron accumulation and lipid peroxidation. Effects of uremic toxins on ferroptosis in the kidney are not well understood. We investigated whether protein-bound uremic toxins induce ferroptosis, resulting in cell death, using the bilateral ureteral obstruction (BUO) mouse model and kidney cells. In BUO mice, we observed elevated lipid peroxidation, increased iron concentration, and decreased glutathione peroxidase 4 (GPX4) expression. Levels of transferrin receptor 1 and system Xc-, which are involved in iron transport and storage, were also elevated, while those of ferritin heavy and light chains (FHC and FLC) were reduced. Treatment of HK-2 and NRK49F kidney cells with CMPF decreased GSH levels and the expression of GPX4, FHC, and FLC, and increased levels of ROS, lipid peroxidation, and intracellular iron concentration. CMPF-induced and erastin-induced decreases in GPX4 levels and increases in Bax and cytochrome C levels were counteracted by ferrostatin-1 pretreatment. However, GPX4 mRNA levels, protein abundance, or promoter activity were not restored by Z-VAD-FMK, a multi-caspase inhibitor. These results suggest that ferroptosis induced by CMPF treatment induces apoptosis, and inhibition of ferroptosis reduces apoptosis, suggesting that ferroptosis plays a role in triggering cell death by apoptosis., (© 2023. The Author(s).)

Introduction: Despite the risk of incident chronic kidney disease among the patients with rheumatoid arthritis (RA), the association of RA and the risk of end-stage renal disease (ESRD) has not been clearly elucidated. We aimed to investigate the association of RA and the risk of ESRD., Materials and Methods: A total of 929,982 subjects with ( n  = 154,997) or without ( n  = 774,985) RA from the National Health Insurance Service (NHIS) database in Koreas (corresponding to the period between 2009 and 2017) were retrospectively analyzed. RA was defined by the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), codes plus any dispensing of disease-modifying anti-rheumatic drugs. The primary outcome was incident ESRD, identified by a combination of the ICD-10-CM codes and a special code assigned to patients receiving maintenance dialysis for ≥ 3 months or those with a transplant kidney., Results: Compared to the subjects without RA, the subjects with RA resulted in an increased incidence of ESRD (incidence rates of 0.374 versus 0.810 cases per 1,000 person-years). Accordingly, compared to the subjects without RA, the risk of ESRD was significantly increased among the subjects with RA (adjusted hazard ratio 2.095, 95% confidence interval 1.902-2.308). Subgroup analyses revealed that the risk of ESRD imposed by RA is relatively higher in relatively young and healthy individuals., Conclusion: Rheumatoid arthritis (RA) increase the risk of ESRD. As the risk of ESRD imposed by RA is relatively higher in relatively young and healthy individuals, kidney-protective treatment, such as biologic agents, should be preferentially considered among these patients with RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Suh, Jung, Oh, Yang, Choi, Kim, Bae, Ma, Han and Kim.)

The prevalence of kidney diseases has been increasing worldwide due to the aging population and has results in an increased socioeconomic burden as well as increased morbidity and mortality. A deep understanding of the mechanisms underlying the physiological regulation of the kidney and the pathogenesis of related diseases can help identify potential therapeutic targets. The farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid receptor that transcriptionally regulates bile acid homeostasis as well as glucose and lipid metabolism in multiple tissues. The roles of FXR in tissues other than hepatic and intestinal tissues are poorly understood. In studies over the past decade, FXR has been demonstrated to have a protective effect against kidney diseases through its anti-inflammatory and antifibrotic effects; it also plays roles in glucose and lipid metabolism in the kidney. In this review, we discuss the physiological role of FXR in the kidney and its pathophysiological roles in various kidney diseases, including acute kidney injury and chronic kidney diseases, diabetic nephropathy, and kidney fibrosis. Therefore, the regulatory mechanisms involving nuclear receptors, such as FXR, in the physiology and pathophysiology of the kidney and the development of agonists and antagonists for modulating FXR expression and activation should be elucidated to identify therapeutic targets for the treatment of kidney diseases., (© 2023. The Author(s).)

This study aimed to evaluate changes in health-related quality of life (HRQOL) in patients with chronic kidney disease (CKD) according to decline in kidney function. HRQOL was assessed using the Short Form-36 questionnaire composed of a physical component summary (PCS) and mental component summary (MCS). Rapid decline in kidney function was defined as a decline in the estimated glomerular filtration rate (eGFR) of > 3 mL/min/1.73 m 2 /year. Rapid deterioration of HRQOL was defined a change in the HRQOL value greater than the median. Among 970 patients, 360 (37.1%) were in the rapid kidney function decline group. In 720 patients who were 1:1 propensity score-matched, the baseline eGFR was not significantly different between the non-rapid and rapid kidney function decline groups. Compared with the baseline PCS score, the 5-year PCS score decreased in the non-rapid and rapid kidney function decline groups. The 5-year MCS score significantly decreased in the rapid kidney function decline group alone. Rapid decline in kidney function was significantly associated with rapid deterioration of the PCS (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 1.07-2.05; P = 0.018) and MCS (OR: 1.89; 95% CI 1.36-2.62; P < 0.001) scores. Rapid decline in kidney function was associated with rapid deterioration of HRQOL in patients with CKD., (© 2023. The Author(s).)

Background: Several studies have reported that depression is prevalent in patients with diabetes or chronic kidney disease. However, the relationship between weight changes and the risk of depression has not been elucidated in patients with diabetic kidney disease (DKD)., Methods: From the Korean National Health Insurance Service database, we selected 67,866 patients with DKD and body weight data from two consecutive health examinations with a 2-year interval between 2009 and 2012. Weight change over 2 years was categorized into five groups: ≥-10%, &lt;-10% to ≥-5%, &lt;-5% to &lt;5%, ≥5% to &lt;10%, and ≥10%. The occurrence of depression was monitored via the codes of International Statistical Classification of Diseases, 10th revision through the end of 2018., Results: During the 5.24-year follow-up, 17,023 patients with DKD developed depression. Weight change and the risk of depression had a U-shaped relationship: patients with ≥-10% weight change (hazard ratio [HR], 1.12) and those with ≥10% weight change (HR, 1.11) showed higher HRs for depression than those with &lt;-5% to &lt;5% weight change, even after adjusting for several confounding factors. In the subgroup analyses, the risk of depression tended to increase as weight gain or weight loss increased in all subgroups., Conclusion: Both weight loss and weight gain increased the risk of depression in patients with DKD.

To investigate whether high serum triglycerides (TG) level is associated with adverse renal outcomes in patients with non-dialysis chronic kidney disease (CKD), a total of 2,158 subjects from a prospective cohort study (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were divided into the quartile by serum TG level. The primary outcomes were composite renal events, which is defined as a composite of decline of kidney function (the first occurrence of > 50% decline of estimated glomerular filtration rate or doubling of serum creatinine from the baseline) or onset of end-stage renal disease (initiation of dialysis or kidney transplantation). During the median follow-up of 6.940 years, the cumulative incidence of composite renal event was significantly differed by serum TG level in Kaplan-Meier curve analysis (P < 0.001, by Log-rank test). Cox regression analysis demonstrated that, compared to that of the 1st quartile, the risk of composite renal event was significantly higher in the 4th quartile (adjusted hazard ratio 1.433, 95% confidence interval 1.046 to 1.964). The association between high serum TG level and adverse renal outcome remained consistent in the cause-specific hazard model. Subgroup analyses revealed that the association is modified by age, estimated glomerular filtration rate, and spot urine albumin-to-creatinine ratio. In conclusion, high serum TG level is independently associated with adverse renal outcomes in patients with non-dialysis CKD. Interventional studies are warranted to determine whether lowering serum TG levels may alter the natural course of CKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Suh, Oh, Choi, Kim, Bae, Oh, Han, Ma and Kim.)

Context: There are relatively few data on noncardiovascular (non-CV) long-term clinical outcomes of dipeptidyl peptidase 4 inhibitor (DPP4i) treatment., Objective: We aimed to evaluate some non-CV effects of DPP4is in patients with diabetes., Methods: Based on data from the National Health Insurance Service database in Korea (2007-2018), we conducted 3 pairwise comparisons of metformin-combined antidiabetic therapies in adult patients with diabetes: DPP4is vs (1) all other oral antidiabetic agents, (2) sulfonylureas/glinides, and (3) thiazolidinediones (TZDs). Major outcomes were liver cirrhosis, end-stage renal disease (ESRD), and cancers in the liver, kidney, and pancreas. Adjusted hazard ratios (HRs) and 95% CIs for the outcomes were estimated using an adjusted Cox model., Results: Of the 747 124 patients included, 628 217 had received DPP4i therapy for a mean duration of 33.8 ± 25.0 months. Compared with TZD therapy, DPP4i therapy was associated with higher adjusted HRs [95% CIs] for liver cirrhosis (1.267 [1.108-1.449]), ESRD (1.596 [1.139-2.236]), liver cancer (1.117 [1.011-1.235]), and pancreatic cancer (1.158 [1.040-1.290]). Furthermore, apart from liver cirrhosis, a higher risk of each of these outcomes was associated with DPP4i use than with non-DPP4i use. The higher adjusted HRs associated with DPP4i use further increased when patients with long-term exposure to DPP4is were analyzed., Conclusion: DPP4i therapy in patients with diabetes was associated with a higher risk of liver cirrhosis and cancer, ESRD, and pancreatic cancer than TZD therapy and, except for liver cirrhosis, the risk of these outcomes was greater with DPP4i treatment than with non-DPP4i treatment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hollow-fiber membranes are widely used in various fields of membrane processes because of their numerous properties, e.g., large surface area, high packing density, mass production with uniform quality, obvious end-of-life indicators, and so on. However, it is difficult to control the pores and internal properties of hollow-fiber membranes due to their inherent structure: a hollow inside surrounded by a wall membrane. Herein, we aimed to control pores and the internal structure of hollow-fiber membranes by fabricating a dual layer using a dual nozzle. Two different pore formers, polyethylene glycol (PEG) and polyvinyl pyrrolidone (PVP), were separately prepared in the dope solutions and used for spinning the dual layer. Our results show that nanoscale pores could be formed on the lumen side (26.8-33.2 nm), and the open pores continuously increased in size toward the shell side. Due to robust pore structure, our fabricated membrane exhibited a remarkable water permeability of 296.2 ± 5.7 L/m 2 ·h·bar and an extremely low BSA loss rate of 0.06 ± 0.02%, i.e., a high BSA retention of 99.94%. In consideration of these properties, the studied membranes are well-suited for use in either water treatment or hemodialysis. Overall, our membranes could be considered for the latter application with a high urea clearance of 257.6 mL/min, which is comparable with commercial membranes.

As the relation between serum non-high-density lipoprotein cholesterol (nHDL) level and renal outcomes has never been investigated in patients with non-dialysis chronic kidney disease (CKD) yet, we here aimed to unveil the association of nHDL with CKD progression. A total of 2152 patients with non-dialysis CKD at stages 1 to 5 from the KNOW-CKD study were categorized into the tertile (i.e., 1st (T1), 2nd (T2), and 3rd (T3) tertiles) by nHDL, and were prospectively analyzed. The primary outcome was the composite renal event, defined as a composite of decline of kidney function or onset of end-stage renal disease. Kaplan-Meier survival curves analysis demonstrated that the cumulative incidence of the composite renal event was significantly increased in T1 and T3, compared to T2 ( p = 0.028, by Log-rank test). Cox regression analysis revealed that both T1 (adjusted hazard ratio 1.309, 95% confidence interval 1.074-1.595) and T3 (adjusted hazard ratio 1.272, 95% confidence interval 1.040-1.556) are associated with significantly increased risk of a composite renal event, compared to T2. The restricted cubic spline plot demonstrated a non-linear, U-shaped association between nHDL and the risk of a composite renal event. In conclusion, both low and high serum nHDL levels are associated with increased risk of CKD progression.

Flexible capacitive pressure sensors with a simple structure and low power consumption are attracting attention, owing to their wide range of applications in wearable electronic devices. However, it is difficult to manufacture pressure sensors with high sensitivity, wide detection range, and low detection limits. We developed a highly sensitive and flexible capacitive pressure sensor based on the porous Ecoflex, which has an aligned airgap structure and can be manufactured by simply using a mold and a micro-needle. The existence of precisely aligned airgap structures significantly improved the sensor sensitivity compared to other dielectric structures without airgaps. The proposed capacitive pressure sensor with an alignment airgap structure supports a wide range of working pressures (20-100 kPa), quick response time (≈100 ms), high operational stability, and low-pressure detection limit (20 Pa). Moreover, we also studied the application of pulse wave monitoring in wearable sensors, exhibiting excellent performance in wearable devices that detect pulse waves before and after exercise. The proposed pressure sensor is applicable in electronic skin and wearable medical assistive devices owing to its excellent functional features.

Proteinuria is typically quantified according to the spot urine protein-creatinine ratio (UPCR) and an association with cardiovascular events has not been thoroughly investigated in chronic kidney disease (CKD) patients. We investigated whether the severity of proteinuria assessed by spot UPCR is associated with an increased risk for cardiovascular outcomes in the CKD population, and whether the relationship is influenced by urine creatinine concentration. We analyzed 1746 patients enrolled as part of The KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable Cox proportional hazard analysis was performed to evaluate models with proteinuria as a predictor of renal events and extended major adverse cardiovascular events (eMACEs). Risk for renal events was significantly associated with proteinuria across all eGFR and UPCR categories. By contrast, risk for eMACEs increased significantly with UPCR in patients with eGFR ≥ 60 mL/min/1.73 m 2 (hazard ratio [HR] 2.109; 95% confidence interval [CI] 1.375-3.235; P = 0.001), but not in patients with eGFR < 60 mL/min/1.73 m 2 (HR 1.086; 95% CI 0.910-1.296; P = 0.358). However, in those with the lower eGFR, risk for eMACEs increased significantly with UPCR in participants with urine creatinine concentration ≥ 95 mg/dL (HR 1.503; 95% CI 1.047-2.159; P = 0.027). In non-dialysis CKD patients, the prognostic value of UPCR for eMACEs is weakened in patients with reduced eGFR levels, for whom it has prognostic significance only in patients with high urine creatinine concentration., (© 2022. The Author(s).)

As non-high-density lipoprotein cholesterol (non-HDL-C) levels account for all atherogenic lipoproteins, serum non-HDL-C level has been suggested to be a marker for cardiovascular (CV) risk stratification. Therefore, to unveil the association of serum non-HDL-C levels with CV outcomes in patients with non-dialysis chronic kidney disease (ND-CKD), the patients at stages 1 to 5 ( n = 2152) from the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into quintiles by serum non-HDL-C level. The primary outcome was a composite of all-cause death or non-fatal CV events. The median duration of follow-up was 6.940 years. The analysis using the Cox proportional hazard model unveiled that the composite CV event was significantly increased in the 5th quintile (adjusted hazard ratio 2.162, 95% confidence interval 1.174 to 3.981), compared to that of the 3rd quintile. A fully adjusted cubic spline model depicted a non-linear, J-shaped association between non-HDL-C and the risk of a composite CV event. The association remained robust in a series of sensitivity analyses, including the analysis of a cause-specific hazard model. Subgroup analyses reveled that the association is not significantly altered by clinical conditions, including age, gender, body mass index, estimated glomerular filtration rate, and albuminuria. In conclusion, high serum non-HDL-C level increased the risk of adverse CV outcomes among the patients with ND-CKD. Further studies are warranted to define the optimal target range of non-HDL-C levels in this population.

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

Background/aims: Renal recovery of a kidney donor after undergoing nephrectomy though challenging is essential. We aimed to examine the effect of estimated glomerular filtration rate (eGFR) percent change at 1-month post-donation on insufficient kidney function after kidney donation., Methods: A total of 3,952 living kidney donors who underwent donor nephrectomy from 1982 to 2019 from eight different tertiary hospitals in Korea were initially screened. Percent changes in the eGFR from baseline to 1-month post-donation were calculated. The degree of percent changes was categorized by quartile, and the 1st quartile was regarded as the group with the lowest decreased eGFR at 1-month after donation. The remaining eGFR less than 60 mL/min/1.73 m2 was the end-point. The Cox proportional hazard model was used for evaluating the impact of initial eGFR and eGFR percent change at 1-month post-donation on the condition with remaining eGFR &lt; 60 mL/ min/1.73 m2. In the multivariate analysis, we used variables with a p &lt; 0.1 in the univariate analysis., Results: A total of 1,585 donors were included in the analysis. During 62.2 ± 49.3 months, 13.7% of donors showed renal insufficiency. The 4th (adjusted hazard ratio [aHR], 10.41; 95% confidence interval [CI], 5.15 to 21.04) and the 3rd (aHR, 4.29; 95% CI, 2.15 to 8.56) quartiles of percent change in eGFR and the pre-donation eGFR (aHR, 0.90; 95% CI, 0.88 to 0.92) were associated with the development of renal insufficiency., Conclusion: The impact of worse initial renal recovery on renal insufficiency was pronounced in donors with lower pre-donation eGFRs. Additionally, worse initial renal recovery of remaining kidney affected the long-term development of renal insufficiency in kidney donors.

Background: Recent hypertension guidelines have recommended lower blood pressure (BP) targets in high-risk patients. However, there are no specific guidelines based on age or systolic and diastolic blood pressure (SBP and DBP, respectively). We aimed to assess the effects of age-related BP on development of end-stage renal disease (ESRD) in patients with diabetes., Methods: A total of 2 563 870 patients with diabetes aged >20 years were selected from the Korean National Health Screening Program from 2009 to 2012 and followed up until the end of 2019. Participants were categorized into age and BP groups, and the hazard ratios for ESRD were calculated., Results: During a median follow-up of 7.15 years, the incidence rates of ESRD increased with increasing SBP and DBP. The hazard ratio for ESRD was the highest in patients younger than 40 years of age with DBP≥100 mm Hg. The effect of SBP and DBP on ESRD development was attenuated with age (interaction P was <0.0001 for age and SBP, and 0.0022 for age and DBP). The subgroup analysis for sex, antihypertension medication, and history of chronic kidney disease showed higher hazard ratios for ESRD among males, younger than 40 years, not taking antihypertension medications and chronic kidney disease compared to those among females, older than 40 years, antihypertension medication, and nonchronic kidney disease groups., Conclusions: Higher SBP and DBP increase the risk of developing ESRD in patients with diabetes, and in particular, younger individuals face greater risk. Therefore, intensive BP management is warranted in younger patients to prevent ESRD.

The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Stanniocalcin‑1 (STC1), a multifunctional glycoprotein with antioxidant and anti‑inflammatory properties, serves an important role in kidney protection. STC1 is one of the few hormones targeted to the mitochondria to regulate mitochondrial quality control by suppressing oxidative stress and mitochondrial damage. However, the mechanisms underlying the effect of STC1 remain unclear. The present study aimed to investigate the protective role of recombinant STC1 (rSTC1) in renal fibrosis and to identify the mechanisms underlying cellular fibrosis in HK2 human renal proximal tubular cells. Semi‑quantitative PCR, western blot analysis and confocal microscopy were used to detect the mRNA levels, protein levels and mitochondrial membrane potential (MMP). Mitochondrial superoxide production was evaluated using MitoSox staining. rSTC1 attenuated TGF‑β‑induced downregulation of AMP‑activated protein kinase and uncoupling protein 2 (UCP2). Treatment of HK2 cells with TGF‑β reduced the MMP and increased the production of reactive oxygen species (ROS). In addition, TGF‑β treatment upregulated fibrotic markers, such as α‑SMA and fibronectin, in HK2 cells. Treatment with rSTC1 and TGF‑β suppressed mitochondrial ROS production by recovering the MMP and reversed the upregulation of fibrotic markers in HK2 cells. The effects of rSTC1 were reversed when UCP2 expression was silenced. The present study revealed a novel role of STC1 in preventing TGF‑β induced cellular fibrosis in HK2 cells.

Background: The increased risk of fracture has been associated with weight loss in patients with diabetes or chronic kidney disease. However, the relationship between weight changes over time and fracture risk in patients with diabetic kidney disease is still unknown., Methods: A total number of 78,922 patients with diabetic kidney disease, aged ≥ 40 years, were selected using the Korean National Health Insurance Service database, between 2009 and 2012. They were followed up until the end of 2018. Weight change was defined as the difference in body weight from the index year to 2 years later. Weight changes were then divided into five categories, ranging from weight loss of ≥10% to weight gain of ≥10%., Results: Fractures were identified in 9,847 patients with diabetic kidney disease, over a median follow-up of 5.2 years. The risk of composite fracture of the vertebral, hip, or other sites increased as the weight change increased. Specifically, patients with ≥10% weight loss (hazard ratio [HR], 1.286; 95% confidence interval [CI], 1.184-1.398) and ≥10% weight gain (HR, 1.198; 95% CI, 1.080-1.330) showed a higher HR compared to those with ≤ 5% weight change after adjusting for several confounding factors. Higher HR of vertebral and hip fractures was also seen with increased weight loss or gain. In particular, patients with ≥10% weight loss showed the highest HR for hip fractures (HR, 1.738; 95% CI, 1.489-2.028)., Conclusions: Both weight loss and weight gain increase the risk of fracture in patients with diabetic kidney disease. Therefore, patients with diabetic kidney disease who experience weight changes should be made aware of the risk of fracture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Choi, Bae, Ma, Kim, Han and Kim.)