Risk factors and renal outcomes of low bone mineral density in patients with non-dialysis chronic kidney disease.

Bone disorder is a common complication of chronic kidney disease (CKD). The clinical usefulness of bone mineral density (BMD) in CKD is not well known. Our study shows that low BMD is associated with physical activity and dietary Na/K intake ratio and can predict poor renal outcome in non-dialysis CKD. PURPOSE: Despite evidence of a link between bone mineral disorders and chronic kidney disease (CKD), the clinical implications of bone mineral density (BMD) in CKD are not well established. We investigated risk factors and renal outcomes of low BMD in CKD. METHODS: We analyzed data from the KNOW-CKD. BMD measured by dual-energy x-ray absorptiometry was classified by T score: normal (T score ≥ - 1.0), osteopenia (- 1.0 > T score > - 2.5), and osteoporosis (T score ≤ - 2.5) of the lumbar spine, hip, or femoral neck. Logistic regression analysis to assess risk factors of low BMD (T score < - 1.0) and Cox proportional hazards models to estimate risk of incident end-stage renal disease (ESRD). RESULTS: Low BMD was prevalent (osteopenia 33%; osteoporosis 8%) in 2128 adults with CKD (age 54 ± 12 years; male 61%). Over a median follow-up of 4.3 years, there were 521 cases of incident ESRD. Lower BMD was associated with female sex, older age, low eGFR, low BMI, and lifestyle factors of physical activity (odds ratio (OR) = 0.62, 95% confidence interval (0.49-0.77)) and spot urine Na/K ratio (1.07 (1.00-1.15)). In adjusted Cox models, low BMD was associated with increased incident ESRD (hazard ratio (HR) = 1.14 (0.92-1.41) for osteopenia; 1.43 (1.01-2.04) for osteoporosis, P for trend < 0.05) compared with the reference of normal BMD. The association between low BMD and ESRD was similar according to T score discordance classification. CONCLUSIONS: Low BMD was associated with modifiable lifestyle factors including low physical activity and high dietary Na/K intake ratio. The presence of low BMD is associated with poor renal outcomes in non-dialysis CKD.

DASH dietary pattern and chronic kidney disease in elderly Korean adults.

BACKGROUND/OBJECTIVES: Dietary patterns are linked to risk and outcomes in chronic kidney disease (CKD). Dietary intake varies by race, region and age. The relationship between a Dietary Approaches to Stop Hypertension (DASH) diet and CKD in elderly Koreans is unclear. SUBJECTS/METHODS: We conducted cross-sectional analyses of 2408 community-dwelling elderly participants from the Korean National Health and Nutrition Examination Survey (2011-2012). DASH dietary patterns for six nutrients (protein, fiber, calcium, potassium, total fat and sodium) were collected by 24 h recall. DASH-US (based on the US recommendations) and DASH-KQ (Korean quartile) scores were generated by summing the scores for the six nutrients. Multivariate logistic regression analysis was used to calculate odds ratio (OR) for the association between a DASH diet and CKD. RESULTS: Mean subject age was 72.4±5.1 years, 13.9% had CKD and 23.8% had diabetes. Protein, fiber, calcium and potassium intake was lower in CKD than non-CKD participants. In multivariate logistic regression analysis adjusted for age, sex, body mass index, comorbid conditions and other factors, a high DASH score was associated with a low odds for CKD based on DASH-US (OR=0.78, 95% confidence interval (CI), 0.65-0.94, P=0.009) and DASH-KQ (OR=0.95, 95% CI, 0.91-0.99, P=0.022). In six nutrients of DASH diet, high fiber intake showed a low odds for CKD in the DASH-KQ model (P for trend=0.010). CONCLUSIONS: Our findings suggest that higher adherence to a DASH diet and higher fiber intake are associated with lower odds of CKD in elderly Koreans. These results should be corroborated through longitudinal studies of the association between a DASH diet and high-fiber diet on the risk of developing CKD.

Chronic kidney disease and high eGFR according to body composition phenotype in adults with normal BMI.

BACKGROUND AND AIMS: Body composition contributes to the risk of chronic kidney disease (CKD) and glomerular hyperfiltration. In adults with normal body mass index (BMI), the relationships of body composition with CKD and high estimated glomerular filtration rate (eGFR) are largely unknown. METHODS AND RESULTS: We analyzed 10,734 adults from the Korean National Health and Nutrition Examination Survey (KNHANES), whose body mass index (BMI) was within the normal range (18.5-24.9 kg/m2). Body composition was categorized into four phenotypes (normal, sarcopenia alone, obesity alone, and sarcopenic obesity) based on appendicular lean mass index (ALMI) and total body fat percentage (TBF%) measured by dual-energy X-ray absorptiometry (DXA). We examined the relationship of CKD and high eGFR (eGFR ≥ 120 ml/min per 1.73 m2) with body composition phenotypes. Sarcopenia alone (14.3%), obesity alone (16.0%), and sarcopenic obesity (10.7%) were prevalent. The association between sarcopenia alone and eGFR was J-shaped, while that between sarcopenic obesity and eGFR was U-shaped. In multivariate logistic regression analysis compared with the normal phenotype, sarcopenic obesity had an elevated odds ratio (OR) for CKD (OR: 1.59, 95% CI: 1.16-2.19). Sarcopenia alone (OR: 1.87; 95% CI: 1.41-2.47) and sarcopenic obesity (OR: 2.37, 95% CI: 1.68-3.36) had elevated OR for high eGFR. CONCLUSION: These findings suggest that decreased muscle mass and coexistence with excess adiposity show associations with CKD and high eGFR even in adults with normal BMI. Body composition measured by DXA could provide information on the relationship of body composition with CKD and high eGFR.

Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease.

BACKGROUND AND AIMS: Previous studies suggested an association between low serum magnesium levels and metabolic or cardiovascular disease. Additionally, several studies have shown that low serum magnesium is associated with vascular calcification, but there are no studies exploring its relation to coronary artery calcification (CAC). We investigated the relationship between low serum magnesium and CAC by using health examination data. METHODS AND RESULTS: We cross-sectionally analyzed 34,553 participants who underwent coronary multi-detector computed tomography and serum magnesium level measurement in 2010-2012 as part of a health examination program at a tertiary hospital in Korea. CAC was defined as a coronary artery calcium score > 100. Participants were divided into three groups according to their serum magnesium level as follows: low < 1.9 mg/dL (n = 931), normal = 1.9-2.3 mg/dL (n = 32,341), and high > 2.3 mg/dL (n = 1281). The percentages of participants with CAC were 3.7, 1.5, and 2.3 in each group, respectively. According to multivariate analysis, low serum magnesium was associated with CAC after adjustment for age, sex, BMI, diabetes, hypertension, cardiovascular disease, systolic BP, LDL cholesterol, HDL cholesterol, eGFR, serum calcium and phosphorus, hsCRP, current smoking status, alcohol intake and vigorous exercise frequency. The odds ratio for CAC in the low serum magnesium group compared to the normal group was 2.10 (1.40-3.15, P < 0.001). CONCLUSION: Low serum magnesium level is associated with CAC in a Korean population at low risk for cardiovascular disease. Further studies are needed to generalize this finding and to verify the causal relationship between low serum magnesium and CAC.

Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice.

Despite the emerging importance of fibroblast growth factor 21 (FGF21) as a metabolic hormone regulating energy balance, its direct effects on renal function remain unexplored. FGF21 was injected ip daily for 12 weeks into db/db mice. Compared with control vehicle injection, FGF21 treatment significantly improved lipid profiles and insulin resistance and resulted in significantly higher serum adiponectin levels. In contrast, serum insulin and 8-isoprostane levels were significantly decreased. Interestingly, FGF21 and its receptor components in the kidneys were found to be significantly up-regulated in db/db mice, which suggests an FGF21-resistant state. FGF21 treatment significantly down-regulated FGF21 receptor components and activated ERK phosphorylation. FGF21 administration also markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic molecule synthesis. Furthermore, FGF21 improved renal lipid metabolism and oxidative stress injury. In cultured renal cells, FGF21 was mainly expressed in mesangial cells, and knockdown of FGF21 expression by stealth small interfering RNA further aggravated high-glucose-induced profibrotic cytokine synthesis in mesangial cells. Our results suggest that FGF21 improves insulin resistance and protects against renal injury through both improvement of systemic metabolic alterations and antifibrotic effects in type 2 diabetic nephropathy. Targeting FGF21 could therefore provide a potential candidate approach for a therapeutic strategy in type 2 diabetic nephropathy.

Renal protective effects of toll-like receptor 4 signaling blockade in type 2 diabetic mice.

Chronic inflammation caused by high glucose and high free fatty acid (FFA) concentrations is a major contributor to the pathogenesis of type 2 diabetes. Recent evidence suggests that activation of Toll-like receptor (TLR) signaling induces peripheral insulin resistance and mediates central insulin and leptin resistance. In this study, we investigated the renal effects of TLR4 signaling blockade in type 2 diabetic mice. Eight-week-old db/db mice were treated for 12 weeks with (S,R)-3-phenyl-4,5-dihydro-5-isoxasole acetic acid (GIT27), which targets macrophages through the inhibition of TLR4- and TLR2/6-mediated signaling pathways. Although GIT27 treatment improved glycemic control and insulin tolerance, which is associated with a lower lipid profile, it did not impact body weight or food consumption. GIT27 treatment also markedly decreased urinary albumin excretion, decreased proinflammatory cytokine synthesis, improved tissue lipid metabolism, induced oxidative stress, and improved glomerulosclerosis compared with the control db/db group. In cultured podocytes and adipocytes, high glucose levels with FFA stimulation increased TLR4 expression and proinflammatory cytokine synthesis, but the effects were abolished by GIT27 treatment. In addition, knockdown of TLR4 expression by stealth small interfering RNA abolished FFA-induced proinflammatory cytokine synthesis in cultured podocytes. In conclusion, our results suggest that GIT27 treatment improves insulin resistance and protects against the renal injury that occurs in type 2 diabetic nephropathy through both metabolic and antiglomerulosclerotic mechanisms. These results suggest that TLR pathway inhibition might play a direct protective role in diabetic kidney disease.

Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice.

The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy.