Intestinal alkaline phosphatase modulation by food components: predictive, preventive, and personalized strategies for novel treatment options in chronic kidney disease.

Alkaline phosphatase (AP) is a ubiquitous membrane-bound glycoprotein that catalyzes phosphate monoesters' hydrolysis from organic compounds, an essential process in cell signaling. Four AP isozymes have been described in humans, placental AP, germ cell AP, tissue nonspecific AP, and intestinal AP (IAP). IAP plays a crucial role in gut microbial homeostasis, nutrient uptake, and local and systemic inflammation, and its dysfunction is associated with persistent inflammatory disorders. AP is a strong predictor of mortality in the general population and patients with cardiovascular and chronic kidney disease (CKD). However, little is known about IAP modulation and its possible consequences in CKD, a disease characterized by gut microbiota imbalance and persistent low-grade inflammation. Mitigating inflammation and dysbiosis can prevent cardiovascular complications in patients with CKD, and monitoring factors such as IAP can be useful for predicting those complications. Here, we review IAP's role and the results of nutritional interventions targeting IAP in experimental models to prevent alterations in the gut microbiota, which could be a possible target of predictive, preventive, personalized medicine (PPPM) to avoid CKD complications. Microbiota and some nutrients may activate IAP, which seems to have a beneficial impact on health; however, data on CKD remains scarce.

Phenotypic features of vascular calcification in chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease stage 5 (CKD5) are predisposed to vascular calcification (VC), but the combined effect of factors associated with VC was sparsely investigated. We applied the relaxed linear separability (RLS) feature selection model to identify features that concomitantly associate with VC in CKD5 patients. METHODS: Epigastric arteries collected during surgery from living donor kidney transplant recipients were examined to score the histological extent of medial VC. Sixty-two phenotypic features in 152 patients were entered into RLS model to differentiate between no-minimal VC (n = 93; score 0-1) and moderate-extensive VC (n = 59; score 2-3). The subset of features associated with VC was selected on the basis of cross-validation procedure. The strength of association of the selected features with VC was expressed by the absolute value of 'RLS factor'. RESULTS: Among 62 features, a subset of 17 features provided optimal prediction of VC with 89% of patients correctly classified into their groups. The 17 features included traditional risk factors (diabetes, age, cholesterol, BMI and male sex) and markers of bone metabolism, endothelial function, metabolites, serum antibodies and mitochondrial-derived peptide. Positive RLS factors range from 1.26 to 4.05 indicating features associated with increased risk of VC, and negative RLS factors range from -0.95 to -1.83 indicating features associated with reduced risk of VC. CONCLUSION: The RLS model identified 17 features including novel biomarkers and traditional risk factors that together concomitantly associated with medial VC. These results may inform further investigations of factors promoting VC in CKD5 patients.

Comparison of three PET methods to assess peritoneal membrane transport.

The peritoneal equilibration test (PET) is the most widespread method for assessing water and solute transport across the peritoneal membrane. This study compared three methods: traditional PET (t-PET), mini-PET, and modified PET (mod-PET). Non-diabetic adults (n=21) who had been on peritoneal dialysis (PD) for at least three months underwent t-PET (glucose 2.5%-4 h), mini-PET (glucose 3.86%-1 h), and mod-PET (glucose 3.86%-4 h) to determine dialysate-to-plasma concentration ratio (D/P) for creatinine and dialysate-to-baseline dialysate concentration ratio (D/D0) for glucose. Agreement between methods regarding D/P creatinine and D/D0 glucose was assessed using analysis of variance (ANOVA), Pearson's correlation coefficient, and Bland-Altman analysis. D/P creatinine differed between t-PET and mini-PET (P<0.001) and between mod-PET and mini-PET (P<0.01) but not between t-PET and mod-PET (P=0.746). The correlation of D/P creatinine with t-PET vs mod-PET was significant (r=0.387, P=0.009) but not that of t-PET vs mini-PET (r=0.088, P=0.241). Estimated bias was -0.029 (P=0.201) between t-PET and mod-PET, and 0.206 (P<0.001) between t-PET and mini-PET. D/D0 glucose differed between t-PET and mod-PET (P=0.003) and between mod-PET and mini-PET (P=0.002) but not between t-PET and mini-PET (P=0.885). The correlations of D/D0 glucose in t-PET vs mod-PET (r=-0.017, P=0.421) or t-PET vs mini-PET (r=0.152, P=0.609) were not significant. Estimated bias was 0.122 (P=0.026) between t-PET and mod-PET, and 0.122 (P=0.026) between t-PET and mini-PET. The significant correlation of D/P creatinine between t-PET and mod-PET suggested that the latter is a good alternative to t-PET. There was no such correlation between t-PET and mini-PET.

Effects of Probiotic Supplementation on Trimethylamine-N-Oxide Plasma Levels in Hemodialysis Patients: a Pilot Study.

Components present in the diet, L-carnitine, choline, and betaine are metabolized by gut microbiota to produce metabolites such as trimethylamine-N-oxide (TMAO) that appear to promote cardiovascular disease in chronic kidney disease (CKD) patients. The objective of this pilot study was to evaluate the effects of probiotic supplementation for 3 months on plasma TMAO levels in CKD patients on hemodialysis (HD). A randomized, double-blind trial was performed in 21 patients [54.8 ± 10.4 years, nine men, BMI 26.1 ± 4.8 kg/m2, dialysis vintage 68.5 (34.2-120.7) months]. Ten patients were randomly allocated to the placebo group and 11 to the probiotic group [three capsules, totaling 9 × 1013 colony-forming units per day of Streptococcus thermophilus (KB19), Lactobacillus acidophilus (KB27), and Bifidobacteria longum (KB31). Plasma TMAO, choline, and betaine levels were measured by LC-MS/MS at baseline and after 3 months. While TMAO did not change after probiotic supplementation, there was a significant increase in betaine plasma levels. In contrast, the placebo group showed a significant decrease in plasma choline levels. Short-term probiotic supplementation does not appear to influence plasma TMAO levels in HD patients. Long-term studies are needed to determine whether probiotics may affect TMAO production in CKD patients.

Comparison of three PET methods to assess peritoneal membrane transport

The peritoneal equilibration test (PET) is the most widespread method for assessing water and solute transport across the peritoneal membrane. This study compared three methods: traditional PET (t-PET), mini-PET, and modified PET (mod-PET). Non-diabetic adults (n=21) who had been on peritoneal dialysis (PD) for at least three months underwent t-PET (glucose 2.5%-4 h), mini-PET (glucose 3.86%-1 h), and mod-PET (glucose 3.86%-4 h) to determine dialysate-to-plasma concentration ratio (D/P) for creatinine and dialysate-to-baseline dialysate concentration ratio (D/D0) for glucose. Agreement between methods regarding D/P creatinine and D/D0 glucose was assessed using analysis of variance (ANOVA), Pearson's correlation coefficient, and Bland-Altman analysis. D/P creatinine differed between t-PET and mini-PET (P<0.001) and between mod-PET and mini-PET (P<0.01) but not between t-PET and mod-PET (P=0.746). The correlation of D/P creatinine with t-PET vs mod-PET was significant (r=0.387, P=0.009) but not that of t-PET vs mini-PET (r=0.088, P=0.241). Estimated bias was −0.029 (P=0.201) between t-PET and mod-PET, and 0.206 (P<0.001) between t-PET and mini-PET. D/D0 glucose differed between t-PET and mod-PET (P=0.003) and between mod-PET and mini-PET (P=0.002) but not between t-PET and mini-PET (P=0.885). The correlations of D/D0 glucose in t-PET vs mod-PET (r=−0.017, P=0.421) or t-PET vs mini-PET (r=0.152, P=0.609) were not significant. Estimated bias was 0.122 (P=0.026) between t-PET and mod-PET, and 0.122 (P=0.026) between t-PET and mini-PET. The significant correlation of D/P creatinine between t-PET and mod-PET suggested that the latter is a good alternative to t-PET. There was no such correlation between t-PET and mini-PET.

Lipophilic index, kidney function, and kidney function decline.

BACKGROUND AND AIMS: Unhealthy dietary fats are associated with faster kidney function decline. The cell membrane composition of phospholipid fatty acids (FAs) is a determinant of membrane fluidity and rheological properties. These properties, which have been linked to kidney damage, are thought to be reflected by the lipophilic index (LI). We prospectively investigated the associations of LI with kidney function and its decline. METHODS AND RESULTS: Observational study from the Prospective Investigation of Vasculature in Uppsala Seniors including 975 men and women with plasma phospholipid FAs composition and cystatin-C estimate glomerular filtration rate (eGFR). Of these, 780 attended re-examination after 5 years, and eGFR changes were assessed. Participants with a 5-year eGFR reduction ≥30% were considered chronic kidney disease (CKD) progressors (n = 198). LI was calculated as the sum of the products of the FA proportions with the respective FAs melting points. Blood rheology/viscosity measurements were performed in a random subsample of 559 subjects at baseline. Increased LI showed a statistically significant but overall weak association with blood, plasma viscosity (both Spearman rho = 0.16, p < 0.01), and erythrocyte deformability (rho = -0.09, p < 0.05). In cross-sectional analyses, LI associated with lower eGFR (regression coefficient 3.00 ml/min/1.73 m2 1-standard deviation (SD) increment in LI, 95% CI: -4.31, -1.69, p < 0.001). In longitudinal analyses, LI associated with a faster eGFR decline (-2.13 [95% CI -3.58, -0.69] ml/min/1.73 m2, p < 0.01) and with 32% increased odds of CKD progression (adjusted OR 1.32 [95%, CI 1.05-1.65]). CONCLUSIONS: A high LI was associated with lower kidney function, kidney function decline, and CKD progression.

Excess protein intake relative to fiber and cardiovascular events in elderly men with chronic kidney disease.

BACKGROUND AND AIMS: The elevated cardiovascular (CVD) risk observed in chronic kidney disease (CKD) may be partially alleviated through diet. While protein intake may link to CVD events in this patient population, dietary fiber has shown cardioprotective associations. Nutrients are not consumed in isolation; we hypothesize that CVD events in CKD may be associated with dietary patterns aligned with an excess of dietary protein relative to fiber. METHODS AND RESULTS: Prospective cohort study from the Uppsala Longitudinal Study of Adult Men. Included were 390 elderly men aged 70-71 years with CKD and without clinical history of CVD. Protein and fiber intake, as well as its ratio, were calculated from 7-day dietary records. Cardiovascular events were registered prospectively during a median follow-up of 9.1 (inter-quartile range, 4.5-10.7) years. The median dietary intake of protein and fiber was 66.7 (60.7-71.1) and 16.6 (14.5-19.1) g/day respectively and the protein-to-fiber intake ratio was 4.0 (3.5-4.7). Protein-to-fiber intake ratio was directly associated with serum C-reactive protein levels. During follow-up, 164 first-time CVD events occurred (incidence rate 54.5/1000 per year). Protein-fiber intake ratio was an independent risk factor for CVD events [adjusted hazard ratio, HR per standard deviation increase (95% confidence interval, CI) 1.33 (1.08, 1.64)]. Although in opposing directions, dietary protein [1.18 (0.97, 1.44)], dietary fiber alone [0.81 (0.64, 1.02)], were not significantly associated with CVD events. CONCLUSIONS: An excess of dietary protein relative to fiber intake was associated with the incidence of cardiovascular events in a homogeneous population of older men with CKD.

Epicardial fat accumulation, cardiometabolic profile and cardiovascular events in patients with stages 3-5 chronic kidney disease.

BACKGROUND: It has been hypothesized that epicardial adipose tissue (EAT) exerts pathogenic effects on cardiac structures. We analysed the associations between EAT and both cardiovascular (CV) disease risk factors and CV events in patients with chronic kidney disease (CKD). PATIENTS AND METHODS: We included 277 nondialysed patients [median age 61, interquartile range (IQR) 53-68 years; 63% men] with stages 3-5 CKD in this cross-sectional evaluation. EAT and abdominal visceral adipose tissue (VAT) were assessed by computed tomography. Patients were followed for median 32 (IQR 20-39) months, and the composite of fatal and nonfatal CV events was recorded. RESULTS: With increasing EAT quartiles, patients were older, had higher glomerular filtration rate, body mass index, waist, VAT and coronary calcification, higher levels of haemoglobin, triglycerides, albumin, C-reactive protein and leptin and higher prevalence of left ventricular hypertrophy and myocardial ischaemia; total and high-density lipoprotein cholesterol, 25-hydroxy-vitamin D and 1, 25-dihydroxy-vitamin D progressively decreased. Associations between EAT and cardiac alterations were not independent of VAT. During follow-up, 58 CV events occurred. A 1-SD higher EAT volume was associated with an increased risk of CV events in crude [hazard ratio (HR) 1.41, 95% confidence interval (CI) (1.12-1.78) and adjusted (HR 1.55, 95% CI 1.21-1.99) Cox models. However, adding EAT to a standard CV disease risk prediction model did not result in a clinically relevant improvement in prediction. CONCLUSION: Epicardial adipose tissue accumulation in patients with CKD increases the risk of CV events independent of general adiposity. This is consistent with the notion of a local pathogenic effect of EAT on the heart or heart vessels, or both. However, EAT adds negligible explanatory power to standard CV disease risk factors.

Dietary acid load, kidney function, osteoporosis, and risk of fractures in elderly men and women.

SUMMARY: Because kidney dysfunction reduces the ability to excrete dietary acid excess, we hypothesized that underlying kidney function may have confounded the mixed studies linking dietary acid load with the risk of osteoporosis and fractures in the community. In a relatively large survey of elderly men and women, we report that dietary acid load did neither associate with DEXA-estimated bone mineral density nor with fracture risk. Underlying kidney function did not modify these null findings. Our results do not support the dietary acid-base hypothesis of bone loss. INTRODUCTION: Impaired renal function reduces the ability to excrete dietary acid excess. We here investigate the association between dietary acid load and bone mineral density (BMD), osteoporosis, and fracture risk by renal function status. METHODS: An observational study was conducted in 861 community-dwelling 70-year-old men and women (49% men) with complete dietary data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The exposure was dietary acid load as estimated from 7-day food records by the net endogenous acid production (NEAP) and potential renal acid load (PRAL) algorithms. Renal function assessed by cystatin C estimated glomerular filtration rate was reduced in 21% of the individuals. Study outcomes were BMD and osteoporosis state (assessed by DEXA) and time to fracture (median follow-up of 9.2 years). RESULTS: In cross-section, dietary acid load had no significant associations with BMD or with the diagnosis of osteoporosis. During follow-up, 131 fractures were validated. Neither NEAP (adjusted hazard ratios (HR) (95% confidence interval (CI)), 1.01 (0.85-1.21), per 1 SD increment) nor PRAL (adjusted HR (95% CI), 1.07 (0.88-1.30), per 1 SD increment) associated with fracture risk. Further multivariate adjustment for kidney function or stratification by the presence of kidney disease did not modify these null associations. CONCLUSIONS: The hypothesis that dietary acid load associates with reduced BMD or increased fracture risk was not supported by this study in community-dwelling elderly individuals. Renal function did not influence on this null finding.

Sarcopenia in chronic kidney disease on conservative therapy: prevalence and association with mortality

BACKGROUND:In chronic kidney disease (CKD), multiple metabolic and nutritional abnormalities contribute to the impairment of skeletal muscle mass and function thus predisposing patients to the condition of sarcopenia. Herein, we investigated the prevalence and mortality predictive power of sarcopenia, defined by three different methods, in non-dialysis-dependent (NDD) CKD patients.METHODS:We evaluated 287 NDD-CKD patients in stages 3-5 [59.9 ± 10.5 years; 62% men; 49% diabetics; glomerular filtration rate (GFR) 25.0 ± 15.8 mL/min/1.73 m(2)]. Sarcopenia was defined as reduced muscle function assessed by handgrip strength (HGS <30th percentile of a population-based reference adjusted for sex and age) plus diminished muscle mass assessed by three different methods: (i) midarm muscle circumference (MAMC) <90% of reference value (A), (ii) muscle wasting by subjective global assessment (B) and (iii) reduced skeletal muscle mass index (<10.76 kg/m² men; <6.76 kg/m² women) estimated by bioelectrical impedance analysis (BIA) (C). Patients were followed for up to 40 months for all-cause mortality, and there was no loss of follow-up.RESULTS:The prevalence of sarcopenia was 9.8% (A), 9.4% (B) and 5.9% (C). The kappa agreement between the methods were 0.69 (A versus B), 0.49 (A versus C) and 0.46 (B versus C). During follow-up, 51 patients (18%) died, and the frequency of sarcopenia was significantly higher among non-survivors. In crude Cox analysis, sarcopenia diagnosed by the three methods was associated with a higher hazard for mortality; however, only sarcopenia diagnosed by method C remained as a predictor of mortality after multivariate adjustment...

Epicardial fat accumulation, cardiometabolic profile andcardiovascular events in patients with stages 3–5 chronickidney disease

Cordeiro AC, Amparo FC, Oliveira MAC,Amodeo C, Smanio P, Pinto IMF, Lindholm B,Stenvinkel P, Carrero JJ (Karolinska Institutet,Stockholm, Sweden; Dante Pazzanese Institute ofCardiology, S~ao Paulo; Dante Pazzanese Institute ofCardiology, S~ao Paulo; Dante Pazzanese Instituteof Cardiology, S~ao Paulo; Dante Pazzanese Instituteof Cardiology, S~ao Paulo, Brazil). Epicardialfat accumulation, cardiometabolic profile andcardiovascular events in patients with stages3–5 chronic kidney disease.

Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (χ 2=14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease.

Elevated levels of plasma osteoprotegerin are associated with all-cause mortality risk and atherosclerosis in patients with stages 3 to 5 chronic kidney disease.

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and plays a role in vascular calcification. We evaluated the relationship between osteoprotegerin levels and inflammatory markers, atherosclerosis, and mortality in patients with stages 3-5 chronic kidney disease. A total of 145 subjects (median age 61 years, 61% men; 36 patients on hemodialysis, 55 patients on peritoneal dialysis, and 54 patients with stages 3-5 chronic kidney disease) were studied. Clinical characteristics, markers of mineral metabolism (including fibroblast growth factor-23 [FGF-23]) and inflammation (high-sensitivity C-reactive protein [hsCRP] and interleukin-6 [IL-6]), and the intima-media thickness (IMT) in the common carotid arteries were measured at baseline. Cardiac function was assessed by color tissue Doppler echocardiography. After 36 months follow-up, the survival rate by Kaplan-Meier analysis was significantly different according to OPG levels (χ ² =14.33; P=0.002). Increased OPG levels were positively associated with IL-6 (r=0.38, P<0.001), FGF-23 (r=0.26, P<0.001) and hsCRP (r=0.0.24, P=0.003). In addition, OPG was positively associated with troponin I (r=0.54, P<0.001) and IMT (r=0.39, P<0.0001). Finally, in Cox analysis, only OPG (HR=1.07, 95%CI=1.02-1.13) and hsCRP (HR=1.02, 95%CI=1.01-1.04) were independently associated with increased risk of death. These results suggested that elevated levels of serum OPG might be associated with atherosclerosis and all-cause mortality in patients with chronic kidney disease.

Serum fatty acid patterns, insulin sensitivity and the metabolic syndrome in individuals with chronic kidney disease.

OBJECTIVES: The causes of the multiple metabolic disorders of individuals with chronic kidney disease (CKD) are not fully known. We investigated the relationships between dietary fat quality, the metabolic syndrome (MetS), insulin sensitivity and inflammation in individuals with CKD. SUBJECTS: Two population-based surveys were conducted in elderly Swedish individuals (aged 70 years) with serum cystatin C-estimated glomerular filtration rate <60 mL min(-1) /1.73 m2: the Uppsala Longitudinal Study of Adult Men (ULSAM) and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) surveys. The present population comprised 274 men and 187 subjects (63% women) from the ULSAM and PIVUS cohorts, respectively. DESIGN: Factor analyses of serum fatty acids were used to evaluate dietary fat quality. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance (IR) and, in ULSAM, also by euglycaemic clamp. RESULTS: Factor analyses generated two fatty acid patterns of (i) low linoleic acid (LA)/high saturated fatty acid (SFA) or (ii) high n-3 polyunsaturated fatty acid (n-3 PUFA) levels. In both surveys, the low LA/high SFA pattern increased the odds of having MetS [adjusted odds ratio 0.60 [95% confidence interval (CI) 0.44-0.81] and 0.45 (95% CI 0.30-0.67) per SD decrease in factor score in the ULSAM and PIVUS surveys, respectively] and was directly associated with both IR and C-reactive protein. The n-3 PUFA pattern was not consistently associated with these risk factors. CONCLUSIONS: A serum fatty acid pattern reflecting low LA and high SFA was strongly associated with MetS, IR and inflammation in two independent surveys of elderly individuals with CKD. At present, there are no specific dietary guidelines for individuals with CKD; however, these findings indirectly support current recommendations to replace SFAs with PUFAs from vegetable oils.

Clinical determinants and mortality predictability of stearoyl-CoA desaturase-1 activity indices in dialysis patients.

BACKGROUND: Stearoyl-CoA desaturase-1 (SCD-1) converts dietary saturated fatty acids to monounsaturated fatty acids. Elevated SCD-1 activity thus signifies impaired fatty acid metabolism and excess saturated fat intake. In the general population, increased SCD-1 activity is associated with cardiovascular disease and mortality. The determinants and implications of SCD-1 activity in dialysis patients are unknown. SUBJECTS: A total of 222 dialysis patients (39% women) with prospective follow-up, median age of 57 years and an average of 12 months of dialysis. DESIGN: Fatty acid compositions in plasma phospholipids and free fatty acids (FFAs) were assessed by gas-liquid chromatography. SCD-1 activity indices were calculated as the product-to-precursor fatty acid ratio (palmitoleic acid/palmitic acid) in each fraction to reflect SCD-1 activities in the liver and adipose tissue. RESULTS: Median hepatic and adipose tissue SCD-1 activity indices were 0.016 and 0.150, respectively. In multivariate analyses, SCD-1 was positively associated with age, female sex and serum interleukin-6 level. During 18.4 (interquartile range 5.5-37.3) months of follow-up, there were 61 deaths and 115 kidney transplants. The cut-off level for high SCD-1 indices was determined by receiver operating characteristic curve analyses. In fully adjusted competing risk models, patients with high SCD-1 indices in both phospholipids and FFAs had more than twofold increased mortality risk before kidney transplantation [hazard ratio (HR) 2.29, 95% confidence interval (CI) 1.28-4.11 and HR 2.36, 95% CI 1.38-4.03, respectively], compared with patients with low SCD-1 indices. CONCLUSIONS: Both hepatic and adipose tissue SCD-1 activity indices independently predict mortality in dialysis patients. Further studies are warranted to determine whether reducing SCD-1 activity by dietary intervention (limiting saturated fat) could improve survival in dialysis patients.

Zoledronate inhibits phosphate and bone morphogenetic protein 2-induced extracellular calcification of vascular smooth muscle cells in vitro.

The aim of this study was to explore the effects of the bisphosphonate zoledronate on calcification induced by inorganic phosphate (Pi) and/or bone morphogenetic protein 2 (BMP-2) and the underlying mechanisms. Primary vascular smooth muscle cells (VSMCs) from rats were treated with 3 mM Pi or 3 mM Pi/BMP-2, with and without addition of zoledronate; 1.4 mM Pi served as a control. Calcium deposits, expression of core binding factor α-1 (Cbfa-1), osteopontin (OPN), parathyroid pituitary-specific transcription factor (Pit)-1 and Pit-2, and Pi uptake of VSMCs was determined. The calcification of VSMCs induced by elevated Pi or Pi/BMP-2 was significantly inhibited by zoledronate. The expression of Cbfa-1, OPN and Pit-1 was increased significantly after treatment with an elevated level of Pi or Pi/BMP-2, and this expression was significantly suppressed by addition of zoledronate. Pi uptake of VSMCs increased following treatment with elevated Pi and significantly decreased by addition of zoledronate. These results indicated that zoledronate effectively inhibited calcification induced by Pi/BMP-2, and this may have been achieved by means of the downregulation of expression of calcification-related proteins and uptake of Pi.

The role of epigenetics in kidney diseases.

Epigenetics is the study of changes in gene expression that occur without changes in DNA sequence. These reversible modifications include DNA methylation, histone acetylation and RNA interference. Epigenetic changes are fundamental for the regulatory physiological processes that regulate gene activity; therefore, these changes are altered in response to environmental factors or disease states, but, in many circumstances, they are also believed to contribute to disease occurrence and progression. So far, studies of the epigenome have been scarce in nephrology. However, there is evidence that in the uremic milieu, several features such as inflammation, dyslipidaemia, hyperhomocysteinaema, oxidative stress as well as vitamin and nutritional deficiencies may affect the epigenome, and impact patient outcome. The present review describes the current knowledge on epigenetic alterations in the course of various kidney disease states. Although the science of epigenetics is still in its infancy, it seems that it may help elucidate the pathogenic mechanisms in uraemia, and allow novel treatment strategies to be developed.

Plasma osteoprotegerin, arterial stiffness, and mortality in normoalbuminemic Japanese hemodialysis patients.

UNLABELLED: A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome. INTRODUCTION: A high circulating OPG level is reported to be a risk factor for vascular calcification and mortality in Western chronic kidney disease (CKD) patients but it is not known if this is true for Japanese CKD patients, where a different risk profile may operate. METHODS: OPG and PWV were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients (median age 62 years) who were prospectively followed for 6 years. RESULTS: OPG levels were associated in multivariate analysis with age, dialysis vintage, history of cardiovascular disease (CVD) and parathyroid hormone levels. C-reactive protein levels did not correlate with OPG. Patients with clinical history of CVD had significantly higher OPG levels and OPG levels were positively correlated to PWV, an index of arterial stiffness. These associations were independent of age, sex, dialysis vintage, and diabetes. During the follow-up period, 40 deaths, including 25 cardiovascular deaths, were recorded. In crude analysis, each unit of increase in OPG was associated with increased all-cause (hazard ratios 1.14, 95% confidence interval 1.08-1.20) and CVD mortality (1.14 [1.07-1.21]), which persisted after adjustment for age, sex, dialysis vintage, diabetes, and baseline CVD (1.12 [1.05-1.19] and 1.11 [1.02-1.19], all-cause and CVD mortality, respectively). CONCLUSIONS: In long-term normoalbuminemic Japanese hemodialysis patients, with low prevalence of inflammation, OPG levels were strongly linked with both arterial stiffness and worse outcome.

Increased expression of pro-inflammatory genes in abdominal subcutaneous fat in advanced chronic kidney disease patients.

OBJECTIVES: Low-grade systemic inflammation, oxidative stress and peripheral insulin resistance are intimately associated and contribute to the increased risk of cardiovascular complications in advanced chronic kidney disease (CKD). Because altered adipose tissue activities have previously been linked to pathophysiological processes in various inflammatory and metabolic diseases we hypothesized that the uraemic milieu in patients with CKD may interact with the adipose tissue, provoking an unfavourable shift in its transcriptional output. DESIGN: Twenty-one adipokine mRNAs were quantified in abdominal subcutaneous adipose tissue (SAT) biopsies and serum/plasma concentrations of inflammatory markers and related protein products were measured. SETTING: The study was conducted at the Karolinska University Hospital, Huddinge, and Karolinska Institutet, Stockholm, Sweden. SUBJECTS: Thirty-seven patients with CKD [15 women, median 58 (interquartile range 49-65) years] and nine nonuraemic individuals [four women, age 62 (45-64) years] were recruited prior to initiation of peritoneal dialysis catheter insertion or elective hernia repair/laparoscopic cholecystectomy, respectively. RESULTS: Even after correction for body mass index, SAT from patients showed a significant upregulation of inflammatory pathway genes interleukin 6 (3.0-fold, P=0.0002) and suppressor of cytokine signalling 3 (2.5-fold, P=0.01), as well as downregulation of leptin (2.0-fold, P=0.03) and the oxidative stress genes uncoupling protein 2 (1.5-fold, P=0.03) and cytochrome b-245, alpha polypeptide (1.5-fold, P=0.005), in relation to controls. CONCLUSIONS: These gene expression differences suggest that inflammatory and oxidative stress activities may be important features of the intrinsic properties of uraemic adipose tissue, which may have significant effects on the uraemic phenotype.

Adiponectin in chronic kidney disease has an opposite impact on protein-energy wasting and cardiovascular risk: two sides of the same coin.

Adiponectin, an anti-inflammatory, anti-atherogenic and insulin sensitizing adipokine exists in several isoforms in the circulation. In patients with chronic kidney disease (CKD), circulating levels of total as well as high-molecular-weight adiponectin are elevated. In contrast to initial studies, several recent and larger studies on outcomes do not support a protective effect of high adiponectin on cardiovascular disease (CVD) and overall mortality in CKD patients. Paradoxically, high adiponectin predicts increased overall and cardiovascular mortality in CKD patients. This effect seems unrelated to a direct effect of adiponectin, but rather due to a process of protein-energy (PEW) wasting. This review summarizes recent conflicting findings on adiponectin in relation to outcomes and discusses the pathophysiologic roles of adiponectin in PEW, insulin resistance and vascular injuries of CKD patients.