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

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

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

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

Coronary artery calcium and risk of chronic kidney disease in young and middle-aged adults.

BACKGROUND: The role of the coronary artery calcium score (CACS) in incident chronic kidney disease (CKD) in asymptomatic young populations remains unclear. The aim of this study was to evaluate the association between CACSs and CKD development in adults. METHODS: A cohort study of 113 171 Korean adults (mean age 40.6 years) without CKD and proteinuria at baseline who underwent a cardiac tomography estimation of CACSs during health screening examinations was performed (median follow-up 4.2 years). The outcome was CKD, defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 and/or the presence of proteinuria. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CKD were estimated using Cox proportional hazards regression analyses. RESULTS: A higher CACS was moderately associated with an increased risk of CKD in a dose-dependent manner. The multivariable-adjusted HRs for CKD comparing CACSs 1-100, 101-300 and >300 with a CACS of 0 were 1.15 (95% CI 1.05-1.25), 1.37 (95% CI 1.13-1.66) and 1.71 (95% CI 1.32-2.22), respectively (P for trend <.001). When CKD was defined using low eGFR and proteinuria separately, corresponding HRs for low eGFR were 1.31 (95% CI 1.05-1.62), 1.41 (95% CI 0.95-2.11) and 1.86 (95% CI 1.16-3.00), respectively (P for trend = .001), while the HRs for proteinuria were 1.11 (95% CI 1.02-1.21), 1.32 (95% CI 1.07-1.64) and 1.57 (95% CI 1.16-2.12), respectively. CONCLUSIONS: A higher CACS was progressively associated with an increased risk of CKD, even at low CACSs. Individuals with a CACS >0 appear to have an increased risk of CKD and may benefit from preventive measures to reduce CKD risk.

Association between physical activity and risk of renal function decline and mortality in community-dwelling older adults: a nationwide population-based cohort study.

BACKGROUND: Physical activity (PA) is an important risk factor associated with health outcomes. However, the relationship between PA and kidney function decline in older adults remains unclear. We examined the influence of PA on kidney function decline and mortality in community-dwelling older adults. METHODS: Adults aged ≥ 65 years with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 who had available health checkup data from 2009 to 2010 were included. The cohort was followed annually through December 2015 for anthropometric, sociodemographic, and medical information including outcomes and biennially for laboratory information from the health checkup. We divided these patients into three groups according to self-reported PA (Inactive group: no leisure-time PA, Active group: vigorous activity for at least 80 min/week or a sum of moderate-intensity activity and walking for at least 300 min/week, Low-active group: level of PA between the definitions of the other two groups). Associations between the intensity of PA and death, cardiovascular death, and ≥ 50% eGFR decline were investigated. RESULTS: Among 102,353 subjects, 32,984 (32.23%), 54,267 (53.02%), and 15,102 (14.75%) were classified into the inactive, low-active, and active groups, respectively. The active group was younger, contained a higher proportion of men, and had higher frequencies of hypertension, diabetes mellitus, drinking, and smoking than the other groups. The active group had significantly lower incidence rates of mortality, cardiovascular mortality, and kidney function decline than the other groups (all p < 0.001). The active group also showed lower all-cause (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.70-0.82) and cardiovascular mortality (HR, 0.64; 95% CI, 0.53-0.78) and protection against ≥ 50% eGFR decline (HR, 0.81; 95% CI, 0.68-0.97) compared with the inactive group in the fully adjusted Cox proportional hazards regression model. CONCLUSIONS: High PA was an independent modifiable lifestyle factor for reducing mortality and protecting against declines in kidney function in older adults.

Serum creatinine to cystatin C ratio and clinical outcomes in adults with non-dialysis chronic kidney disease.

Background: Studies have suggested that the serum creatinine/cystatin C (Cr/CysC) ratio is a surrogate marker for muscle wasting is associated with adverse outcomes in several disease conditions. To clarify the utility of the Cr/CysC ratio as a prognostic marker in chronic kidney disease (CKD) we evaluated the association between the Cr/CysC ratio clinical outcomes in patients with non-dialysis CKD. Methods: This prospective observational cohort study included 1,966 participants of the KoreaN cohort study Outcomes in patients With CKD (KNOW-CKD). We evaluated associated factors with the serum Cr/CysC ratio and association between the serum Cr/CysC ratio and composite outcomes of all-cause death and cardiovascular events (CVEs). Results: The mean age was 54 ± 12 (SD) years and 61% were men. The mean serum Cr/CysC ratio was 10.97 ± 1.94 in men and 9.10 ± 1.77 in women. The Cr/CysC ratio correlated positively with urinary creatinine excretion, a marker of muscle mass. In the fully adjusted Cox proportional hazard model, the Cr/CysC ratio was associated with the occurrence of adverse outcomes through a median follow-up of 5.9 years [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.85-0.99 for the composite outcomes, HR = 0.87, 95% CI, 0.78 - 0.97 for all-cause death, and HR = 0.93; 95% CI, 0.84-1.04 for CVEs]. In subgroup analyses, there were interactions of the Cr/CysC ratio with age and sex for risk of the clinical outcomes, but not eGFR group. Conclusion: A higher Cr/CysC ratio is associated with a lower risk of the composite outcomes, especially all-cause mortality, even after adjusting for eGFR. These suggest that the Cr/CysC ratio is a useful prognostic marker in CKD.

Urine creatinine concentration influences the prognostic value of proteinuria for MACE prediction from the findings of the KNOW-CKD study.

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 m2 (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 m2 (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.

Association between Secondhand Smoke Exposure and Metabolic Syndrome in 118,609 Korean Never Smokers Verified by Self-Reported Questionnaire and Urine Cotinine.

BACKGROUND: No study has reported the association between secondhand smoke (SHS) exposure and metabolic syndrome (MetS) in self-reported never smokers verified by both self-reported questionnaire and urine cotinine. METHODS: A total of 118,609 self-reported and cotinine-verified never smokers (38,385 male; age 34.8±7.1 years) who participated in the Kangbuk Samsung Health Study between 2011 and 2016 were included. Cotinine-verified never smokers were defined as individuals with urinary cotinine <50 ng/mL. SHS exposure was defined as current exposure to passive smoking indoors at home or workplace. RESULTS: Prevalence of SHS exposure in the overall population was 22.6% (27.4% for males and 20.3% for females (P<0.001). The overall prevalence of MetS was 6.8% and was higher in males than in females (10.7% vs. 4.9%, P<0.001). In both genders, MetS prevalence was higher in the SHS exposure group than the non-SHS exposure group (11.3% vs. 10.4%, P=0.010 for males; 5.8% vs. 4.6%, P<0.001 for females). However, there was significant gender interaction for the association between SHS exposure and MetS (P for interaction=0.010). In the multivariate regression analyses, SHS exposure was associated with increased MetS odds only in females (odds ratio [95% confidence interval], 1.02 [0.94 to 1.11] in male vs. 1.17 [1.06 to 1.29] in female). In particular, females with SHS exposure of ≥1 hour/day and ≥3 times showed increased odds of MetS compared with those without SHS exposure (1.22 [1.02 to 1.45], 1.30 [1.14 to 1.49]). CONCLUSION: This cross-sectional study showed that SHS exposure was significantly associated with prevalence of MetS in self-reported and cotinine-verified female never smokers.

Solitary kidney and risk of chronic kidney disease.

The renal outcome of solitary kidney remains controversial. We examined the longitudinal association of congenital or acquired solitary kidney with the development of chronic kidney disease (CKD). A cohort study was performed involving 271,171 Korean men and women free of CKD at baseline who underwent a health screening program and who were followed annually or biennially for an average of 5.4 years. Solitary kidney was determined based on ultrasonographic findings. CKD was defined as an estimated glomerular filtration rate of < 60 ml/min/1.73 m2 and/or the presence of proteinuria in two or more consecutive visits. During 1,472,519.6 person-years of follow-up, 2989 participants developed CKD (incidence rate: 2.0 per 1000 person-years). After adjustment for potential confounders, the aHR (95% CIs) for incident CKD comparing solitary kidney to the control was 3.26 (1.63-6.54). In analyses of cause-specific solitary kidney, aHR (95% CIs) for CKD comparing unilateral nephrectomy and congenital solitary kidney to the control were 6.18 (2.31-16.49) and 2.22 (0.83-5.92), respectively. The association between solitary kidney and CKD was stronger in men. Having a solitary kidney was independently associated with an increased risk of CKD development. Therefore, preventive strategies for reducing the risk of CKD are required in individuals with a solitary kidney.

eGFR and coronary artery calcification in chronic kidney disease.

BACKGROUND: The independent association between eGFR and coronary artery calcification (CAC) is complex and not clear. The aim of this study was to investigate the relationship between eGFR calculated from different equations and CAC in predialysis CKD patients in Korea. METHODS: In this cross-sectional study, we analysed 1533 patients from the KNOW-CKD cohort. eGFR was calculated by a four-variable MDRD equation (eGFRMDRD ), CKD-EPI creatinine equations (eGFRCr ), CKD-EPI cystatin C equation (eGFRCys ) and CKD-EPI creatinine-cystatin equation (eGFRCrCys ). Participants were divided into eGFR categories (<30, 30-59, 60-89, ≥90 mL/min/1.73 m2 ). CACS (coronary artery calcium score) was measured using cardiac computed tomography. CAC was defined as CACS >100. RESULTS: Coronary artery calcification was found in 334 (21.8%) patients and was more prevalent in the lower eGFR groups (P < 0.001). In multivariate Tobit regression, CACS increased gradually as eGFRCrCys decreased (P for trend = 0.034). In multivariate logistic regression, there were gradual associations between lower eGFR and CAC when an eGFRCys or eGFRCrCys was used. The adjusted OR for CAC in the group with eGFR <30 mL/min/1.73 m2 compared to the group with eGFR ≥90 mL/min/1.73 m2 was 2.64 (95% CI, 1.09-3.60) when eGFRCrCys was used. Of the four eGFR formulas, only adding eGFRCrCys significantly improved CAC prediction models without eGFR (P = 0.046). CONCLUSIONS: There was a gradual and independent association between low eGFR and CAC in a predialysis CKD cohort in Korea. eGFRCrCys predicted CAC better than other equations in this population.

High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin: analysis from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD) study.

Background: The association between fibroblast growth factor 23 (FGF23) and coronary artery calcification (CAC) was inconclusive. Recently it was shown that adiponectin modulates renal handling of calcium and phosphorus. We hypothesized that adiponectin plays a role in the effect of FGF23 on CAC and explored whether the association between FGF23 and CAC is modified by serum adiponectin level in chronic kidney disease (CKD) patients. Methods: This cross-sectional study analyzed 1435 predialysis CKD patients from the Korean Cohort Study for Outcome in Patients with CKD cohort. Participants were divided into two groups according to their serum adiponectin (upper half and lower half). Each group was further divided into three groups according to their FGF23 levels as follows: low (<5.0 RU/mL), middle (5.0-29.9 RU/mL) and high (≥30.0 RU/mL). The coronary artery calcium score (CACS) was assessed using cardiac computed tomography and CAC was defined as a CACS >100. Results: The median CACS did not differ between the low and high adiponectin groups {3.2 [interquartile range (IQR) 0.0-98.1] versus 0.5 [0.0-99.5], P = 0.988}. The CACS ratio comparing high FGF23 to low FGF23 was significantly increased in the high adiponectin group, but not in the low adiponectin group [2.35 (IQR 1.14-4.85) versus 1.10 (0.60-2.03)]. The odds ratio for CAC in the high FGF23 group compared with the low group was 1.97 (IQR 1.10-3.53). The association between FGF23 and CAC was modified significantly by adiponectin level (P for interaction = 0.023). Conclusions: High serum FGF23 was associated with CAC in CKD patients with high adiponectin, but not in those with low adiponectin. Further studies are warranted to verify the role of adiponectin in FGF23-related CAC.

Association Between Sonographically Diagnosed Nephrolithiasis and Subclinical Coronary Artery Calcification in Adults.

BACKGROUND: Although recent studies suggest an association between nephrolithiasis and clinical cardiovascular events, this association has been underexplored. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 62,091 asymptomatic adults without known coronary heart disease who underwent a screening health examination that included cardiac tomography. PREDICTOR: Nephrolithiasis. OUTCOME: Coronary artery calcification (CAC). MEASUREMENTS: Nephrolithiasis assessed using ultrasonography of the abdomen. CAC scoring assessed using cardiac computed tomography. RESULTS: The prevalence of CAC scores > 0 was 13.1% overall. Participants with nephrolithiasis had a higher prevalence of coronary calcification than those without (19.1% vs 12.8%). In Tobit models adjusted for age and sex, the CAC score ratio comparing participants with nephrolithiasis with those without nephrolithiasis was 1.56 (95% CI, 1.19-2.05). After further adjustment for screening center, year of screening examination, physical activity, alcohol intake, smoking status, education level, body mass index, family history of cardiovascular disease, total energy intake, glucose concentration, systolic blood pressure, triglyceride concentration, high-density lipoprotein cholesterol concentration, uric acid concentration, and estimated glomerular filtration rate, the CAC score ratio was attenuated, but remained significant (CAC score ratio, 1.31; 95% CI, 1.00-1.71). LIMITATIONS: Computed tomographic diagnosis of nephrolithiasis was unavailable. CONCLUSIONS: Nephrolithiasis was associated with the presence of CAC in adults without known coronary heart disease, supporting the hypothesis that these 2 health conditions share a common pathophysiology.

High estimated glomerular filtration rate is associated with coronary artery calcification in middle-aged Korean men without chronic kidney disease.

BACKGROUND: High estimated glomerular filtration rate (eGFR) as well as low eGFR is associated with cardiovascular morbidity and mortality. Vascular calcification is a suggested link between low eGFR and worse cardiovascular outcome. However, the association between high eGFR and vascular calcification is not known. The aim of this study is to investigate the relationship between high eGFR and coronary artery calcification (CAC). METHODS: This cross-sectional study analyzed middle-aged Korean men in whom coronary artery calcium scores (CACS) and eGFR were measured as part of a health examination program in Korea. Participants with underlying chronic kidney disease (CKD), cardiovascular disease (CVD) and cancer were excluded. CAC was defined as a CACS >100. RESULTS: Among 6986 subjects [age 48.1 (46.5-50.5) years], 321 (4.6%) participants had CAC. The percentages of participants with CAC were 5.7, 3.8, 4.9 and 6.6 in groups with eGFR (mL/min/1.73 m(2)) of 60 ∼ 74, 75 ∼ 89, 90 ∼ 104 and 105 ∼ max, respectively. According to multivariate analysis, the odds ratio for CAC in the group with eGFR of 105 ∼ max compared with the group with eGFR of 75 ∼ 89 was 2.52 (1.67-3.79, P < 0.001) after adjustment for age, body mass index, diabetes, hypertension, systolic blood pressure, glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, hsCRP, calcium, phosphorus, current smoking, alcohol intake and vigorous exercise frequency. CONCLUSIONS: High eGFR is associated with CAC in middle-aged Korean men without CKD. Further studies are needed to verify a causal relationship and clarify the role of high eGFR in the development of CVD.

Environmental heavy metal exposure and chronic kidney disease in the general population.

Lead (Pb), mercury (Hg), and cadmium (Cd) are common heavy metal toxins and cause toxicological renal effects at high levels, but the relevance of low-level environmental exposures in the general population is controversial. A total of 1,797 adults who participated in the KNHANES (a cross-sectional nationally representative survey in Korea) were examined, and 128 of them (7.1%) had chronic kidney disease (CKD). Our study assessed the association between Pb, Hg, Cd exposure, and CKD. Blood Pb and Cd levels were correlated with CKD in univariate logistic regression model. However, these environmental heavy metals were not associated with CKD after adjustment for age, sex, BMI, smoking, hyperlipidemia, hypertension, diabetes, and these metals in multivariate logistic regression models. We stratified the analysis according to hypertension or diabetes. In the adults with hypertension or diabetes, CKD had a significant association with elevated blood Cd after adjustment, but no association was present with blood Pb and Hg. The corresponding odds ratio [OR] of Cd for CKD were 1.52 (95% confidence interval [CI], 1.05-2.19, P=0.026) in adults with hypertension and 1.92 (95% CI, 1.14-3.25, P=0.014) in adults with diabetes. Environmental low level of Pb, Hg, Cd exposure in the general population was not associated with CKD. However, Cd exposure was associated with CKD, especially in adults with hypertension or diabetes. This finding suggests that environmental low Cd exposure may be a contributor to the risk of CKD in adults with hypertension or diabetes.

Novel three-dimensional imaging volumetry in autosomal dominant polycystic kidney disease: comparison with 2D volumetry.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) volumetry is an important marker for evaluating the progression of disease. Three-dimensional (3D) volumetry is generally more timesaving than 2D volumetry, but its reliability and accuracy are uncertain. METHODS: Small and large phantoms simulating polycystic kidneys and 20 patients with ADPKD underwent magnetic resonance imaging (MRI) volumetry. We evaluated the total kidney volume (TKV) and total cyst volume (TCV) using a novel 3D volumetry program (XelisTM) and compared 3D volumetry data with the conventional 2D method (the reference volume values). After upload and threshold setting, the other organs surrounding the kidney were removed by picking and sculpting. The novel method involves drawing of the kidney or cyst and automatic measurement of kidney volume and cyst volume in 3D images. RESULTS: The 3D volume estimation of the small and large phantoms differed from the actual values by 6.9% and -8.2%, respectively, for TKV and by 2.1% and 1.4% for TCV. In ADPKD patients, the intra-reader reliability of 3D volumetry was 30 ± 180 mL (1.3 ± 10.3%) and 25 ± 113 mL (1.2 ± 9.4%), respectively, for TKV and TCV. Correlation between 3D volumetry and 2D volumetry of TKV and TCV resulted in a high correlation coefficient and a regression slope approaching 1.00 (r = 0.97 - 0.98). The mean of the volume percentage differences for 3D vs. 2D for TKV : TCV were -6.0 ± 8.9% : 2.0 ± 11.8% in large ADPKD and -16.1 ± 10.4% : 13.2 ± 21.9% in small ADPKD. CONCLUSION: Our study showed that 3D volumetry has reliability and accuracy compared with 2D volumetry in ADPKD. 3D volumetry is more accurate for TCV and large ADPKD.

The association between underweight and the development of albuminuria is different between sexes in relatively healthy Korean subjects.

BACKGROUND: There are limited data on the association between underweight and albuminuria. The aim of this study is to verify the effect of underweight on the development of albuminuria. METHODS: Participants who underwent two health check-ups with a 2-year interval at a tertiary hospital in Korea between 2002 and 2009 were studied. After exclusion of participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or dipstick albuminuria ≥1+ at the first check-up, 53 876 participants were enrolled. We measured the incidence of albuminuria at the second check-up and calculated the odds ratio (OR) for the development of albuminuria according to body mass index (BMI). RESULTS: After 2 years, 746 cases of incident albuminuria were observed among 53 876 participants. The effect of BMI on the development of albuminuria was modified by sex in a multivariate logistic model with adjustment for age, diabetes, hypertension, dyslipidaemia, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, uric acid, eGFR, current smoking status and alcohol intake (P-value for interaction <0.001). Compared with participants in the normal weight range (BMI, 18.5-22.9), the ORs for incident albuminuria were 1.93 [95% confidence interval (CI), 1.35-2.76; P ≤ 0.001], 1.19 (0.84-1.67; P = 0.329) and 0.71 (0.43-1.17; P = 0.177) in underweight (BMI, <18.5), overweight (BMI, 23.0-24.9) and obese (BMI, ≥25) women. However, the ORs were 0.9 (95% CI, 0.39-2.05; P = 0.794), 1.08 (0.84-1.38; P = 0.567) and 1.38 (1.09-1.75; P = 0.007) for each corresponding group of men. CONCLUSIONS: Underweight was significantly associated with the development of albuminuria after 2 years in relatively healthy Korean females, but this relationship was not significant in males. This study suggests the need for more studies on the role of underweight in renal injury in men and women.

Fat mass gain predicts estimated GFR decline in a relatively healthy Korean population.

BACKGROUND: Previous studies have shown that obesity is a risk factor for estimated glomerular filtration rate (eGFR) decline and chronic kidney disease (CKD). However, the relationship between fat mass directly measured by bioimpedance analysis and eGFR is not well known. METHODS: We analyzed 21,859 participants without CKD at baseline who underwent two health checkups at a 5-year interval during 2002-2009. Fat mass was measured by Inbody 3.0 (Biospace, Seoul, Korea). eGFR decline was defined as eGFR <60 ml/min/1.73 m(2) at second checkup. Logistic regression analysis was used to analyze factors related to eGFR decline. RESULTS: Participants were divided into tertiles according to their fat mass change over 5 years: lower tertile (n = 7,042; <-0.7 kg), middle tertile (n = 7,478; -0.7 to 1.2 kg) and higher tertile (n = 7,339; >1.2 kg). After 5 years, 246 cases of eGFR decline were observed. Multivariate logistic analysis revealed that age (OR 1.03, 95% CI 1.02-1.05, p < 0.001), diabetes mellitus (OR 2.04, 95% CI 1.22-3.40, p = 0.007), baseline eGFR (OR 0.80, 95% CI 0.78-0.83, p < 0.001) and higher tertile of fat mass change (OR 1.58, 95% CI 1.16-2.13, p = 0.003) were associated with eGFR decline after adjustment for sex, hypertension, dyslipidemia, cardiovascular disease, smoking status, body mass index, and high-density lipoprotein cholesterol level. CONCLUSIONS: Fat mass gain over 5 years was independently associated with eGFR decline to <60 ml/min/1.73 m(2) in a relatively healthy Korean population. This finding suggests that lifestyle changes to prevent fat mass gain could be protective against the development of CKD.

Effects of Toll-like receptor antagonist 4,5-dihydro-3-phenyl-5-isoxasole acetic acid on the progression of kidney disease in mice on a high-fat diet.

BACKGROUND: Obesity-related metabolic disorders are closely associated with inflammation induced by innate immunity. Toll-like receptors (TLRs) play a pivotal role in the innate immune system by activating proinflammatory signaling pathways. GIT27 (4,5-dihydro-3-phenyl-5-isoxasole acetic acid) is an active immunomodulatory agent that primarily targets macrophages and inhibits secretion of tumor necrosis factor α [as well as interleukin (IL)-1ß, IL-10, and interferon γ]. However, the effect of TLR antagonist on kidney diseases has rarely been reported. We investigated whether the TLR antagonist GIT27 has beneficial effects on the progression of kidney disease in obese mice on a high-fat diet (HFD). METHODS: Six-week-old male C57BL/6 mice were divided into three groups: mice fed with normal chow diet (N=4); mice fed with a HFD (60% of total calories from fat, 5.5% from soybean oil, and 54.5% from lard, N=4); and GIT27-treated mice fed with a HFD (N=7). RESULTS: Glucose intolerance, oxidative stress, and lipid abnormalities in HFD mice were improved by GIT27 treatment. In addition, GIT27 treatment decreased the urinary excretion of albumin and protein in obesity-related kidney disease, urinary oxidative stress markers, and inflammatory cytokine levels. This treatment inhibited the expression of proinflammatory cytokines in the kidneys and adipose tissue, and improved extracellular matrix expansion and tubulointerstitial fibrosis in obesity-related kidney disease. CONCLUSION: TLR inhibition by administering GIT27 improved metabolic parameters. GIT27 ameliorates abnormalities of lipid metabolism and may have renoprotective effects on obesity-related kidney disease through its anti-inflammatory properties.

Sulodexide improves renal function through reduction of vascular endothelial growth factor in type 2 diabetic rats.

AIMS: Sulodexide is a promising therapeutic drug for the management of diabetic nephropathy. Although sulodexide has demonstrated a renoprotective effect through its ability to restore glomerular ionic permselectivity, the exact mechanism is still not clear. We investigated the effects of long-term sulodexide treatment on diabetic nephropathy in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats. MAIN METHODS: Diabetic rats were treated with or without sulodexide at 10mg/kg/day in the drinking water for nine months. Renal morphology and changes in VEGF and p38 mitogen-activated protein kinase (p38 MAPK), urinary levels of albumin (UAE) and urinary VEGF excretion were determined. To define the direct effects of sulodexide, we performed an in vitro experiment using podocytes. KEY FINDINGS: UAE was significantly higher in OLETF rats than in control LETO rats, and the sulodexide group showed significantly decreased UAE after six months of treatment. Interestingly, urinary VEGF levels were also significantly decreased in the sulodexide-treated group. In accordance with UAE and urinary VEGF changes, the renal expression of profibrotic molecules was significantly decreased after sulodexide treatment. In addition, the activation of p38 MAPK, assessed by measuring the level of phospho-specific p38 MAPK, increased in diabetic renal tissues and was markedly suppressed by sulodexide treatment. In cultured podocytes, sulodexide treatment significantly decreased high glucose-induced p38 MAPK activation and VEGF synthesis. SIGNIFICANCE: Sulodexide directly suppresses VEGF synthesis through the p38 MAPK pathway in podocytes, and these results suggest that sulodexide may provide renoprotection via suppression of renal VEGF synthesis independently of glomerular basement membrane ionic permselectivity in type 2 diabetic rats.

Glucocorticoids attenuate septic acute kidney injury.

BACKGROUND: The incidence and mortality of septic acute kidney injury (AKI) remains high, whereas our understanding of pathogenesis for septic AKI is still limited. Glucocorticoids (GCs) have been clinically recommended for treatment of septic shock and also have showed favorable effect on septic AKI in several animal experiments. The aim of this study is to investigate the pathophysiology of septic AKI and the effect of GCs on septic AKI. METHODS: We induced septic AKI using cecal ligation and puncture (CLP) model in 8-10 wk-old male C57BL/6 mice. Saline or dexamethasone (2.5 mg/kg) dissolved in saline was administered after surgery. Hemodynamic, biochemical and histological changes were examined in a time-course manner. RESULTS: CLP resulted in hyperdynamic warm shock with multiple organ dysfunction including AKI. Despite renal dysfunction, light microscopy showed scanty acute tubular necrosis and inflammation. Instead, CLP induced significant increase in apoptosis of the kidney and spleen cells. In addition, septic kidneys showed mitochondrial injury and alterations in Bcl2 family proteins in the renal tubular cells. Dexamethasone treatment attenuated renal dysfunction, but it was not associated with improvement of hemodynamic parameters. Dexamethasone-induced organ protective effect was associated with reduced mitochondrial injury with preserved cytochrome c oxidase and suppression of proapoptotic proteins as well as reduced cytokine release. CONCLUSIONS: Mitochondrial damage and subsequent apoptosis are thought to play important role in the development of septic AKI. GCs might be a useful therapeutic strategy for septic AKI by reducing mitochondrial damage and apoptosis.

Adipose-derived stem cells improve renal function in a mouse model of IgA nephropathy.

T-cell dysregulation plays an important role in the pathogenesis of immunoglobulin A nephropathy (IgAN). Adipose-derived stem cells (ASCs) have been reported to be able to prevent tissue damage through immune-modulating effects. To evaluate the effects of ASCs in high IgA ddY (HIGA) mice, ASCs were isolated from HIGA mice with different stages of IgAN before and after disease onset. ASCs were injected at a dose of 5×10(6) cells/kg body weight through the tail vein every 2 weeks for 3 months. Although the administered ASCs were rarely detected in the glomeruli, 24-h proteinuria was markedly decreased in all ASC-treated groups. Although glomerular deposition of IgA was not significantly different among groups, mesangial proliferation and glomerulosclerosis were dramatically decreased in most ASC treatment groups. In addition, levels of fibrotic and inflammatory molecules were markedly decreased by ASC treatment. Interestingly, ASC therapy significantly decreased Th1 cytokine activity in the kidney and caused a shift to Th2 responses in spleen T-cells as determined by FACS analysis. Furthermore, conditioned media from ASCs abrogated aggregated IgA-induced Th1 cytokine production in cultured HIGA mesangial cells. These results suggest that the beneficial effects of ASC treatment in IgAN occur via paracrine mechanisms that modulate the Th1/Th2 cytokine balance. ASCs are therefore a promising new therapeutic agent for the treatment of IgAN.