Proteinuria, measured or estimated albuminuria for risk prediction in patients with chronic kidney disease?

BACKGROUND: Although albuminuria is the gold standard for defining chronic kidney disease (CKD), total proteinuria has also been widely used in real-world clinical practice. Moreover, the superiority of the prognostic performance of albuminuria over proteinuria in patients with CKD remains inconclusive. Therefore, we aimed to compare the predictive performances of albuminuria and proteinuria in these patients. METHODS: From the Korean Cohort Study for Outcome in Patients with CKD we included 2099 patients diagnosed with CKD grades 1-5 who did not require kidney replacement therapy. We measured the spot urine albumin:creatinine ratio (mACR) and protein:creatinine ratio (PCR) and estimated the ACR (eACR) using the PCR. Kidney failure risk equation (KFRE) scores were calculated using the mACR, PCR and eACR. The primary outcome was the 5-year risk of kidney failure with replacement therapy (KFRT). RESULTS: The eACR significantly underestimated mACR in patients with low albuminuria levels. The time-dependent area under the receiver operating characteristics curve showed excellent predictive performance for all KFRE scores from the mACR, PCR and eACR. However, eACR was inferior to mACR based on the continuous net reclassification index (cNRI) and integrated discrimination improvement index (IDI) in all CKD cause groups, except for the group with an unclassified aetiology. Moreover, the cNRI and IDI statistics indicated that both eACR and PCR were inferior to mACR in patients with low albuminuria (<30 mg/g). Conversely, the predictive performance of PCR was superior in severe albuminuria and nephrotic-range proteinuria, in which the IDI and cNRI of the PCR were greater than those of the mACR. CONCLUSIONS: The mACR, eACR and PCR showed excellent performance in predicting KFRT in patients with CKD. However, eACR was inferior to mACR in patients with low albuminuria, indicating that measuring rather than estimating albuminuria is preferred for these patients.

Relationship between urinary potassium excretion, serum potassium levels and cardiac injury in non-dialysis chronic kidney disease: KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD).

Although the cardiovascular benefits of an increased urinary potassium excretion have been suggested, little is known about the potential cardiac association of urinary potassium excretion in patients with chronic kidney disease. In addition, whether the cardiac association of urinary potassium excretion was mediated by serum potassium levels has not been studied yet. We reviewed the data of 1633 patients from a large-scale multicentre prospective Korean study (2011-2016). Spot urinary potassium to creatinine ratio was used as a surrogate for urinary potassium excretion. Cardiac injury was defined as a high-sensitivity troponin T ≥ 14 ng/l. OR and 95 % (CI for cardiac injury were calculated using logistic regression analyses. Of 1633 patients, the mean spot urinary potassium to creatinine ratio was 49·5 (sd 22·6) mmol/g Cr and the overall prevalence of cardiac injury was 33·9 %. Although serum potassium levels were not associated with cardiac injury, per 10 mmol/g Cr increase in the spot urinary potassium to creatinine ratio was associated with decreased odds of cardiac injury: OR 0·917 (95 % CI 0·841, 0·998), P = 0·047) in multivariate logistic regression analysis. In mediation analysis, approximately 6·4 % of the relationship between spot urinary potassium to creatinine ratio and cardiac injury was mediated by serum potassium levels, which was not statistically significant (P = 0·368). Higher urinary potassium excretion was associated with lower odds of cardiac injury, which was not mediated by serum potassium levels.

Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

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.

Bias reduction for semi-competing risks frailty model with rare events: application to a chronic kidney disease cohort study in South Korea.

In a semi-competing risks model in which a terminal event censors a non-terminal event but not vice versa, the conventional method can predict clinical outcomes by maximizing likelihood estimation. However, this method can produce unreliable or biased estimators when the number of events in the datasets is small. Specifically, parameter estimates may converge to infinity, or their standard errors can be very large. Moreover, terminal and non-terminal event times may be correlated, which can account for the frailty term. Here, we adapt the penalized likelihood with Firth's correction method for gamma frailty models with semi-competing risks data to reduce the bias caused by rare events. The proposed method is evaluated in terms of relative bias, mean squared error, standard error, and standard deviation compared to the conventional methods through simulation studies. The results of the proposed method are stable and robust even when data contain only a few events with the misspecification of the baseline hazard function. We also illustrate a real example with a multi-centre, patient-based cohort study to identify risk factors for chronic kidney disease progression or adverse clinical outcomes. This study will provide a better understanding of semi-competing risk data in which the number of specific diseases or events of interest is rare.

The 2021 KDIGO blood pressure target and the progression of chronic kidney disease: Findings from KNOW-CKD.

BACKGROUND: The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for the management of blood pressure (BP) in chronic kidney disease (CKD) recommends a target systolic BP of <120 mmHg as this target can provide cardiovascular benefits. However, it remains unclear whether implementing the new BP target could improve kidney outcomes. METHODS: The association between the 2021 KDIGO BP target and CKD progression was examined and compared with the 2012 KDIGO BP target among 1724 participants included in the KoreaN Cohort Study for Outcomes in Patients With CKD. The main exposure was the BP status categorized according to the 2012 or 2021 KDIGO guideline: (1) controlled within the 2021 target, (2) controlled within the 2012 target only, and (3) above both targets. The primary outcome was a composite kidney outcome of ≥50% decline in the estimated glomerular filtration rate from baseline or the initiation of kidney replacement therapy during the follow-up period. RESULTS: Composite kidney outcomes occurred in 650 (37.7%) participants during the 8078 person-years of follow-up (median, 4.9 years). The incidence rates of this outcome were 55, 66.5, and 116.4 per 1000 person-years in BP controlled within the 2021 and 2012 KDIGO targets, and BP above both targets, respectively. In the multivariable cause-specific hazard model, hazard ratios for the composite outcome were 0.76 (95% confidence interval (CI), 0.60-0.95) for BP controlled within the 2021 target and 1.36 (95% CI, 1.13-1.64) for BP above both targets, compared with BP controlled within 2012 target only. CONCLUSION: The newly lowered BP target by the 2021 KDIGO guideline was associated with improved kidney outcome compared with BP target by the 2012 KDIGO guideline.

Soluble ST2 and Galectin-3 as Predictors of Chronic Kidney Disease Progression and Outcomes.

BACKGROUND: Soluble suppression of tumorigenicity-2 (sST2) and galectin-3, novel biomarkers of heart failure and cardiovascular stress, predict cardiovascular events (CVEs) and mortality. However, their relationship with kidney function and adverse outcomes in CKD are uncertain. The purpose of this study was to determine the association between sST2 and galectin-3 with CKD progression and adverse clinical outcomes. METHODS: We measured baseline sST2 and galectin-3 levels in the CKD patient cohort at our institution between October 2013 and December 2014. The primary outcome was CKD progression (kidney failure with replacement therapy or ≥50% reduction in estimated glomerular filtration rate from the baseline). The secondary outcome was the composite of CVEs and death. We used a Cox proportional hazards model to evaluate the associations between sST2 and galectin-3 levels, with kidney and clinical outcomes. RESULTS: In total, 352 patients were enrolled in this study. At baseline, log sST2 and galectin-3 were directly associated with the serum creatinine (Cr) and urine protein-to-Cr ratio. Cox regression analysis showed that the baseline log sST2 level independently predicted CKD progression and composite outcome after adjustment for age, sex, smoking, diabetes mellitus, hypertension, cardiovascular disease, renin-angiotensin system blocker, calcium channel blocker, ß-blocker, diuretics, antiplatelet agents, anemia, and hypoalbuminemia. The baseline log galectin-3 level was independently associated with CKD progression, but not with the composite outcome after adjustment for confounding variables. CONCLUSIONS: Elevated levels of sST2 and galectin-3 are significantly associated with CKD progression, but only sST2 is associated with adverse clinical outcomes.

Reduction of Secreted Frizzled-Related Protein 5 Drives Vascular Calcification through Wnt3a-Mediated Rho/ROCK/JNK Signaling in Chronic Kidney Disease.

Vascular calcification (VC) is commonly associated with bone loss in patients with chronic kidney disease (CKD). The Wingless-related integration site (Wnt) regulates osteoblast activation through canonical signaling pathways, but the common pathophysiology of these pathways during VC and bone loss has not been identified. A rat model of adenine-induced CKD with VC was used in this study. The rats were fed 0.75% adenine (2.5% protein, 0.92% phosphate) with or without intraperitoneal injection of calcitriol (0.08 µg/kg/day) for 4 weeks. Angiotensin II (3 µM)-induced VC was achieved in high phosphate medium (3 mM) through its effect on vascular smooth muscle cells (VSMCs). In an mRNA profiler polymerase chain reaction assay of the Wnt signaling pathway, secreted frizzled-related protein 5 (sFRP5) levels were significantly decreased in the CKD rat model compared with the control group. The repression of sFRP5 on VSMC trans-differentiation was mediated through Rho/Rho-associated coiled coil containing protein kinase (ROCK) and c-Jun N-terminal kinase (JNK) pathways activated by Wnt3a. In a proof of concept study conducted with patients with CKD, serum sFRP5 concentrations were significantly lower in subjects with VC than in those without VC. Our findings suggest that repression of sFRP5 is associated with VC in the CKD environment via activation of the noncanonical Wnt pathway, and thus that sFRP5 might be a novel therapeutic target for VC in CKD.

Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice.

Lysophosphatidic acid (LPA) is known to regulate various biological responses by binding to LPA receptors. The serum level of LPA is elevated in diabetes, but the involvement of LPA in the development of diabetes and its complications remains unknown. Therefore, we studied LPA signaling in diabetic nephropathy and the molecular mechanisms involved. The expression of autotaxin, an LPA synthesis enzyme, and LPA receptor 1 was significantly increased in both mesangial cells (SV40 MES13) maintained in high-glucose media and the kidney cortex of diabetic db/db mice. Increased urinary albumin excretion, increased glomerular tuft area and volume, and mesangial matrix expansion were observed in db/db mice and reduced by treatment with ki16425, a LPA receptor 1/3 antagonist. Transforming growth factor (TGF)ß expression and Smad-2/3 phosphorylation were upregulated in SV40 MES13 cells by LPA stimulation or in the kidney cortex of db/db mice, and this was blocked by ki16425 treatment. LPA receptor 1 siRNA treatment inhibited LPA-induced TGFß expression, whereas cells overexpressing LPA receptor 1 showed enhanced LPA-induced TGFß expression. LPA treatment of SV40 MES13 cells increased phosphorylated glycogen synthase kinase (GSK)3ß at Ser9 and induced translocation of sterol regulatory element-binding protein (SREBP)1 into the nucleus. Blocking GSK3ß phosphorylation inhibited SREBP1 activation and consequently blocked LPA-induced TGFß expression in SV40 MES13 cells. Phosphorylated GSK3ß and nuclear SREBP1 accumulation were increased in the kidney cortex of db/db mice and ki16425 treatment blocked these pathways. Thus, LPA receptor 1 signaling increased TGFß expression via GSK3ß phosphorylation and SREBP1 activation, contributing to the development of diabetic nephropathy.

The association of kidney function with repetitive breath-hold diving activities of female divers from Korea, Haenyeo.

BACKGROUND: Voluntary apnea during breath-hold diving (BHD) induces cardiovascular changes including bradycardia, reduced cardiac output, and arterial hypertension. Although the impacts of repetitive BHD on cardiovascular health have been studied previously, the long-term risk for kidney dysfunction has never been investigated. METHODS: A cross-sectional propensity score-matched study was performed to evaluate the influence of repetitive long-lasting BHD on kidney function. Using matching propensity scores (PS), 715 breath-hold female divers (Haenyeo) and non-divers were selected for analysis from 1,938 female divers and 3,415 non-divers, respectively. The prevalence of chronic kidney disease (CKD) defined as an estimated glomerular filtration rate (eGFR) calculated to be less than 60 ml/min/1.73 m2 was investigated in both diver and non-diver groups. RESULTS: The prevalence of CKD was significantly higher in breath-hold divers compared with non-divers after PS matching (12.6% vs. 8.0%, P = 0.004). In multivariate analysis, BHD activity was significantly associated with the risk of CKD in an unmatched cohort (OR, 1.976; 95% CI, 1.465-2.664). In the PS-matched cohort, BHD remained the independent risk factor for CKD even after adjusting for multiple covariates (OR 1.967; 95% CI, 1.341-2.886). CONCLUSION: Shallow but repetitive intermittent apnea by BHD, sustained for a long period of time, may potentially cause a deterioration in kidney function, as a long-term consequence.

Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients.

Hemodialysis (HD) patients experience vascular calcification, ultimately leading to high mortality rates. Previously, we reported associations between soluble receptor for advanced glycation end products (sRAGEs) and extracellular newly identified RAGE-binding protein S100A12 (EN-RAGE) and vascular calcification. Here, we extended our observations, investigating whether these biomarkers may be useful for predicting cardiovascular morbidity and mortality in these subjects. Thus, we evaluated the relationship between sRAGE and S100A12 and mortality in long-term HD patients. This was a prospective observational cohort study in 199 HD patients from an extended analysis of our previous study. Plasma sRAGE, S100A12, comorbidities, and other traditional risk factors were investigated. The cumulative incidences for death using Cox proportional hazards regression were evaluated in multivariable analyses. The observation period was 44 months. During the observation period, 27 (13.6%) patients died. Univariate analysis demonstrated that S100A12 was correlated with diabetes (P = 0.040) and high-sensitivity C-reactive protein (hsCRP) (P = 0.006). In multivariable analyses, plasma sRAGE (hazard ratio [HR] = 1.155; 95% confidence interval [CI] = 0.612-2.183; P = 0.656) and S100A12 (HR = 0.960; 95% CI = 0.566-1.630; P = 0.881) were not associated with mortality in HD patients, although traditional predictors of mortality, including age, history of cardiovascular diseases (CVDs), and serum levels of albumin and hsCRP were related to mortality. Powerful predictors of mortality were age, CVD, and albumin levels. Plasma sRAGE and S100A12 may be weak surrogate markers for predicting all-cause mortality in patients undergoing HD, although S100A12 was partly related to diabetes and inflammation.

The Prevalence and Management of Anemia in Chronic Kidney Disease Patients: Result from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD).

Anemia is a common and significant complication of chronic kidney disease (CKD). However, its prevalence and current management status has not been studied thoroughly in Korea. We examined the prevalence of anemia, its association with clinical and laboratory factors, and utilization of iron agents and erythropoiesis stimulating agents using the baseline data from the large-scale CKD cohort in Korea. We defined anemia when hemoglobin level was lower than 13.0 g/dL in males and 12.0 g/dL in females, or received by erythropoiesis stimulating agents. Overall prevalence of anemia was 45.0% among 2,198 non-dialysis CKD patients from stage 1 to 5. Diabetic nephropathy (DN) as a cause, CKD stages, body mass index (BMI), smoking, leukocyte count, serum albumin, iron markers, calcium, and phosphorus concentration were identified as independent risk factors for anemia. Considering the current coverage of Korean National Health Insurance System, only 7.9% among applicable patients were managed by intravenous iron agents, and 42.7% were managed by erythropoiesis stimulating agents.

The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy.

TNF superfamily member 13 (TNFSF13) has been identified as a susceptibility gene for IgA nephropathy in recent genetic studies. However, the role of TNFSF13 in the progression of IgA nephropathy remains unresolved. We evaluated two genetic polymorphisms (rs11552708 and rs3803800) and plasma levels of TNFSF13 in 637 patients with IgA nephropathy, and determined the risk of ESRD according to theses variable. Neither of the examined genetic polymorphisms associated with a clinical outcome of IgA nephropathy. However, high plasma levels of TNFSF13 increased the risk of ESRD. To explore the causal relationship and underlying mechanism, we treated B cells from patients (n=21) with or without recombinant human TNFSF13 (rhTNFSF13) and measured the expression of IgA and galactose-deficient IgA (GdIgA) using ELISA and flow cytometry. Treatment with rhTNFSF13 significantly increased the total IgA level among B cells, and TNFSF13 receptor blockade abrogated this increase. Furthermore, the absolute levels of GdIgA increased with rhTNFSF13 treatment, but the total IgA-normalized levels did not change. Both RNA sequencing and quantitative PCR results showed that rhTNFSF13 did not alter the expression of glycosyltransferase enzymes. These results suggest that high plasma TNFSF13 levels associate with a worse prognosis of IgA nephropathy through the relative increase in GdIgA levels.

S-nitrosylation of fatty acid synthase regulates its activity through dimerization.

NO regulates a variety of physiological processes, including cell proliferation, differentiation, and inflammation. S-nitrosylation, a NO-mediated reversible protein modification, leads to changes in the activity and function of proteins. In particular, the role of S-nitrosylation during adipogenesis is largely unknown. We hypothesized that the normal physiological levels of NO, but not the excess levels generated under severe conditions, such as inflammation, may be critically involved in the proper regulation of adipogenesis. We found that endogenous S-nitrosylation of proteins was required for adipocyte differentiation. By performing a biotin-switch assay, we identified FAS, a key lipogenic enzyme in adipocytes, as a target of S-nitrosylation during adipogenesis. Interestingly, we also observed that the dimerization of FAS increased in parallel with the amount of S-nitrosylated FAS during adipogenesis. In addition, we found that exogenous NO enhanced the dimerization and the enzymatic activity of FAS. Moreover, site-directed mutagenesis of three predicted S-nitrosylation sites indicated that S-nitrosylation of FAS at Cys(1471)and Cys(2091), but not at Cys(1127), increased its enzymatic activity. Taken together, these results suggest that the S-nitrosylation of FAS at normal physiological levels of NO increases its activity through dimerization and may contribute to the proper regulation of adipogenesis.

Lipin-1 expression is critical for keratinocyte differentiation.

Lipin-1 is an Mg(2+)-dependent phosphatidate phosphatase that facilitates the dephosphorylation of phosphatidic acid to generate diacylglycerol. Little is known about the expression and function of lipin-1 in normal human epidermal keratinocytes (NHEKs). Here, we demonstrate that lipin-1 is present in basal and spinous layers of the normal human epidermis, and lipin-1 expression is gradually downregulated during NHEK differentiation. Interestingly, lipin-1 knockdown (KD) inhibited keratinocyte differentiation and caused G1 arrest by upregulating p21 expression. Cell cycle arrest by p21 is required for commitment of keratinocytes to differentiation, but must be downregulated for the progress of keratinocyte differentiation. Therefore, reduced keratinocyte differentiation results from sustained upregulation of p21 by lipin-1 KD. Lipin-1 KD also decreased the phosphorylation/activation of protein kinase C (PKC)α, whereas lipin-1 overexpression increased PKCα phosphorylation. Treatment with PKCα inhibitors, like lipin-1 KD, stimulated p21 expression, while lipin-1 overexpression reduced p21 expression, implicating PKCα in lipin-1-induced regulation of p21 expression. Taken together, these results suggest that lipin-1-mediated downregulation of p21 is critical for the progress of keratinocyte differentiation after the initial commitment of keratinocytes to differentiation induced by p21, and that PKCα is involved in p21 expression regulation by lipin-1.

Hypoxia leads to abnormal epidermal differentiation via HIF-independent pathways.

Atmospheric oxygen is important for the epidermis, as the skin epidermis is not greatly affected by blood circulation. Therefore, it is necessary to understand the effect of hypoxic signals on the epidermis as some environmental stimuli can induce skin hypoxia. Here, we investigated how hypoxia (1% O2) affected skin equivalents (SEs) and normal human epidermal keratinocytes. We found that hypoxia specifically decreased the protein levels of keratin 1 (K1)/keratin 10 (K10), a representative marker of the epidermal spinous layer in the epidermis. However, hypoxia-inducible factors, the major regulators of hypoxia, did not affect hypoxia-induced down-regulation of K1/K10. We also found that N-acetyl-l-cysteine (NAC), a reactive oxygen species scavenger, antagonized the hypoxia-induced reduction of K1/K10 in keratinocytes and SEs. In contrast to the findings for NAC, inhibitors that blocked reactive oxygen species generation did not cause recovery of K1/K10 protein levels under hypoxic conditions. Taken together, these results indicate that hypoxia leads to abnormal keratinocyte differentiation by down-regulating K1/K10 and that this phenomenon can be ameliorated by NAC.

Outcomes of hepatitis B surface antigenaemia in patients with incident end-stage renal disease.

AIM: Hepatitis B virus (HBV) infection is an important risk factor for morbidity and mortality in the general population. However, limited data are available on the progression of HBV infection in patients with end-stage renal disease (ESRD), and available data are controversial. Therefore, we investigated the association between hepatitis B surface antigen (HBsAg) seropositivity and mortality in patients with incident ESRD. METHODS: All adult patients (≥18 years of age) starting dialysis for ESRD from January 2000 to December 2011 were included. A total of 1090 patients with ESRD were analyzed. HBsAg-positive patients were paired 1:6 with HBsAg-negative patients using propensity score matching. RESULTS: Eighty one (7.4%) patients were HBsAg positive. No differences in the survival rates of the HBsAg-positive and HBsAg-negative patients with ESRD were detected in either the entire cohort or the propensity score matched cohort. No differences in survival were detected between the groups of HBsAg-positive patients based on the hepatitis B envelope antigen, hepatitis B envelope antibody, HBV DNA status, or use of antiviral agents. No difference in mortality was found between the haemodialysis (HD) and peritoneal dialysis (PD) subgroups among HBsAg-positive patients. CONCLUSION: Our results suggest that hepatitis B surface antigenaemia is not related to increased mortality in patients with incident ESRD. Survival of HBsAg-positive patients undergoing PD was comparable to that of patients undergoing HD.

Renin-Angiotensin-Aldosterone System Blockade in Critically Ill Patients Is Associated with Increased Risk for Acute Kidney Injury.

Acute kidney injury (AKI) is a major clinical problem and a predictor of outcomes in critically ill patients who frequently required treatments in the intensive care unit (ICU). Renin-angiotensin-aldosterone system (RAAS) blockers are commonly used for treating hypertension but demands caution because of accompanying illnesses including AKI. The aim of this study was to evaluate whether the use of RAAS blockers affected the incidence of AKI in ICU patients. From a total of 26,287 patients who were admitted to the ICU from January 2003 to December 2013 were included in the final analyses. The primary outcome was the incidence of AKI based on the prescription of RAAS blockers. The secondary outcomes were all-cause mortality. RAAS blocker users were more likely to develop AKI (P < 0.001) and remained an independent risk factor for AKI (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.37-1.79; P < 0.001) after adjusting confounding factors. There was no significant difference in the cumulative 90-day survival rate between the RAAS blocker users and non-users (P = 0.381). However, the adjusted mortality risk associated with AKI was 1.38 (95% CI, 1.22 to 1.56; P < 0.001) and increased as the severity of AKI stage increased from 1 to 3: 1.17 (1.02 to 1.36), 1.77 (1.45 to 2.16), and 1.93 (1.55 to 2.41; P < 0.01 for the trend). RAAS blockers may have a harmful influence to increase the incidence of AKI and temporary withholding of these medications may deserve careful consideration in ICU patients.

Human Dermal Stem/Progenitor Cell-Derived Conditioned Medium Improves Senescent Human Dermal Fibroblasts.

Adult skin stem cells are recognized as potential therapeutics to rejuvenate aged skin. We previously demonstrated that human dermal stem/progenitor cells (hDSPCs) with multipotent capacity could be enriched from human dermal fibroblasts using collagen type IV. However, the effects of hDSPCs on cellular senescence remain to be elucidated. In the present study, we investigated whether conditioned medium (CM) collected from hDSPC cultures (hDSPC-CM) exhibits beneficial effects on senescent fibroblasts. We found that hDSPC-CM promoted proliferation and decreased the expression level of senescence-associated ß-galactosidase in senescent fibroblasts. In addition, p53 phosphorylation and p21 expression were significantly reduced in senescent fibroblasts treated with hDSPC-CM. hDSPC-CM restored the expression levels of collagen type I, collagen type III, and tissue inhibitor of metalloproteinase, and antagonized the increase of matrix metalloproteinase 1 expression. Finally, we demonstrated that hDSPC-CM significantly reduced reactive oxygen species levels by specifically up-regulating the expression level of superoxide dismutase 2. Taken together, these data suggest that hDSPC-CM can be applied as a potential therapeutic agent for improving human aged skin.

Residual urinary volume is a predictor of overhydration in patients on peritoneal dialysis.

Fluid overload is linked to hypertension and cardiovascular diseases in patients on peritoneal dialysis (PD). It is important to monitor the residual urinary volume in patients with end-stage renal disease (ESRD). In fact, fluid overload and residual urinary volume have been considered the risk factors of mortality in ESRD patients on PD. However, the relationship between residual urinary volume and fluid overload was still controversial. Therefore, the objective of this cross-sectional study was to evaluate the association between residual urinary volume and the volume status of PD patients. Body composition was measured using a portable multifrequency whole-body bioimpedance assessment. Relative overhydration was defined when the ratio of overhydration to extracellular water was > 0.15. We examined 75 patients, with a mean age of 50.7 years and mean body mass index of 23.5 kg/m(2). Dialysis vintage was 46.5 months. The patients were divided into the anuric group (n = 30; urine output ≤ 100 mL/day) and the group of urine output > 100 mL/day (n = 45). The anuric group showed higher degree of relative overhydration compared to the patients with the urine output of > 100 mL/day (p = 0.020). In a multivariable linear regression analysis, anuria, diabetes, and serum albumin level were independently associated with relative overhydration. In conclusion, volume status should be closely monitored in anuric patients, and the preservation of residual urinary volume is one of important goals to maintain volume status in PD patients.

Epigallocatechin-3-O-(3-O-methyl)-gallate-induced differentiation of human keratinocytes involves klotho-mediated regulation of protein kinase-cAMP responsive element-binding protein signaling.

(-)-Epigallocatechin-3-O-gallate (EGCG) has long been known as a potent inducer of keratinocyte differentiation. Although its molecular mechanisms have been extensively studied, its actions on human skin remain to be elucidated. In this study, we demonstrated that methylated EGCG and EGCG increase the expression of klotho, and that klotho functions as a downstream target of EGCG and methylated EGCG in keratinocyte differentiation. We demonstrated that methylated EGCG3 and EGCG induce morphological changes in normal human epidermal keratinocytes (NHEKs) that are related to up-regulation of klotho expression. We also demonstrated that a klotho-induced keratinocyte differentiation marker in NHEKs is inhibited by H-89, a protein kinase (PKA) inhibitor. These results suggest that methylated EGCG and EGCG may function as inducers of keratinocyte differentiation via transcriptional regulation of the klotho protein.