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Weight excess is a risk factor for progressive renal function loss, not only in subjects with renal disease or renal transplant recipients, but also in the general population. Considering the increasing prevalence of obesity worldwide, weight excess may become the main renal risk factor on a population basis, all the more so because the risk is not limited to morbid obesity, but is already apparent in the overweight range. The mechanism of the renal risk is multifactorial. In addition to the role of comorbid conditions such as hypertension and diabetes, current evidence supports a pathogenetic role for renal hemodynamics, specifically glomerular hyperfiltration, and also glomerular hypertension. Weight excess is associated with an elevated glomerular filtration rate and a less pronounced rise in renal plasma flow, resulting in an elevated filtration fraction. This suggests glomerular hypertension due to afferent-efferent dysbalance, which impairs glomerular protection from systemic hypertension. Data in renal transplant recipients support the pathogenetic role of elevated glomerular pressure for long-term renal prognosis. Blockade of the renin-angiotensin-aldosterone system can reverse the renal hemodynamic abnormalities. The obesity-associated renal risk is unfavourably affected by high sodium intake. This may be due to the effects of sodium on blood pressure, which is often sodium-sensitive in obesity, but direct renal effects are also present. Interestingly, sodium restriction ameliorates overweight-associated hyperfiltration in overweight subjects. More focus on weight excess as a renal risk factor is warranted. Preventive measures should focus on weight excess as well as on specific protection against renal damage, by renin-angiotensin-aldosterone system-blockade and moderate sodium restriction.

Background: To evaluate the effectiveness and sustainability of self-managed sodium restriction in patients with chronic kidney disease.Study Design: Open randomized controlled trial.Setting & Participants: Patients with moderately decreased kidney function from 4 hospitals in the Netherlands.Intervention: Regular care was compared with regular care plus an intervention comprising education, motivational interviewing, coaching, and self-monitoring of blood pressure (BP) and sodium.Outcomes: Primary outcomes were sodium excretion and BP after the 3-month intervention and at 6-month follow-up. Secondary outcomes were protein excretion, kidney function, antihypertensive medication, self-efficacy, and health-related quality of life (HRQoL).Results: At baseline, mean sodium excretion rate was 163.6 +/- 64.9 (SD) mmol/24 h; mean estimated glomerular filtration rate was 49.7 +/- 25.6 mL/min/1.73 m(2); median protein excretion rate was 0.8 (IQR, 0.4-1.7) g/24 h; and mean 24-hour ambulatory systolic and diastolic BPs were 129 +/- 15 and 76 +/- 9 mm Hg, respectively. Compared to regular care only (n = 71), at 3 months, the intervention group (n = 67) showed reduced sodium excretion rate (mean change, -30.3 [95% CI, -54.7 to -5.9] mmol/24 h), daytime ambulatory diastolic BP (mean change, -3.4 [95% CI, -6.3 to -0.6] mm Hg), diastolic office BP (mean change, -5.2 [95% CI, -8.4 to -2.1] mm Hg), protein excretion (mean change, -0.4 [95% CI, -0.7 to -0.1] g/24h), and improved self-efficacy (mean change, 0.5 [95% CI, 0.1 to 0.9]). At 6 months, differences in sodium excretion rates and ambulatory BPs between the groups were not significant, but differences were detected in systolic and diastolic office BPs (mean changes of -7.3 [95% CI, -12.7 to -1.9] and -3.8 [95% CI, -6.9 to -0.6] mm Hg, respectively), protein excretion (mean changes, -0.3 [95% CI, -0.6 to -0.1] g/24h), and self-efficacy (mean change, 0.5 [95% CI, 0.0 to 0.9]). No differences in kidney function, medication, and HRQoL were observed.Limitations: Nonblinding, relatively low response rate, and missing data.Conclusions: Compared to regular care only, this self-management intervention modestly improved outcomes, although effects on sodium excretion and ambulatory BP diminish over time. (C) 2016 by the National Kidney Foundation, Inc.

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP

Aim The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension. Methods A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15). Results Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9–42] mg/d) was reduced by DRI only (12 [5–28] mg/d, P = 0.030). Conclusions In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension. Trial Registration Dutch trial register, registration number: 2532 www.trialregister.nl

Objectives: Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a key regulator of low density lipoprotein (LDL) receptor processing, but the PCSK9 pathway may also be implicated in the metabolism of triglyceride-rich lipoproteins. Here we determined the relationship of plasma PCSK9 with very low density lipoprotein (VLDL) and LDL subfractions.Design and methods: The relationship of plasma PCSK9 (sandwich enzyme-linked immunosorbent assay) with 3 very low density lipoprotein (VLDL) and 3 low density lipoprotein (LDL) subfractions (nuclear magnetic resonance spectroscopy) was determined in 52 subjects (30 women).Results: In age-and sex-adjusted analysis plasma PCSK9 was correlated positively with total cholesterol, non-high density lipoprotein cholesterol and LDL cholesterol (r=0.516 to 0.547, all p Conclusions: This study suggests that plasma PCSK9 predominantly relates to IDL, a triglyceride-rich LDL subfraction. The PCSK9 pathway may affect plasma triglycerides via effects on the metabolism of triglyceriderich LDL particles. (C) 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Background: The cholesterol esterifying enzyme, lecithin: cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE).Methods: Two-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13-1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay.Results: Plasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p Conclusion: In acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added to RAAS blockade on residual albuminuria in patients with type 2 diabetic nephropathy.In this multicentre, double-blind, placebo-controlled, crossover randomised trial, we included patients with type 2 diabetic nephropathy. Main entry criteria were microalbuminaria or macroalbuminuria, and creatinine clearance of 30 mL/min or higher with less than 6 mL/min decline in the previous year. We tested the separate and combined effects of sodium restriction (dietary counselling in the outpatient setting) and hydrochlorothiazide (50 mg daily), added to standardised maximal angiotensin-converting enzyme (ACE) inhibition (lisinopril 40 mg daily), on albuminuria (primary endpoint). Patients were given hydrochlorothiazide (50 mg per day) or placebo during four treatment periods of 6 weeks. Both treatments were combined with regular sodium diet or sodium restriction (target sodium intake 50 mmol Na(+) per day). The 6-week treatment periods were done consecutively in a random order. Patients were randomised in blocks of two patients. The trial was analysed by intention to treat. The trial is registered with TrialRegister.nl, number 2366.Of 89 eligible patients, 45 were included in the study. Both sodium restriction and hydrochlorothiazide significantly reduced albuminuria, irrespective of treatment sequence. Residual geometric mean albuminuria with baseline treatment was 711 mg per day (95% CI 485-1043); it was significantly reduced by sodium restriction (393 mg per day [258-599], p=0·0002), by hydrochlorothiazide (434 mg per day [306-618], p=0·0003), and to the greatest extent by their combination (306 mg per day [203-461], p0·0001). Orthostatic complaints were present in two patients (4%) during baseline treatment, five (11%) during addition of sodium restriction, five (11%) during hydrochlorothiazide treatment, and 12 (27%) during combination treatment. No serious adverse events occurred.We conclude that sodium restriction is an effective non-pharmacological intervention to increase RAAS blockade efficacy in type 2 diabetic nephropathy.None.

Objective:Sodium restriction potentiates the efficacy of the rennin-angiotensin-aldosterone system (RAAS)-blockade and improves long-term cardiovascular and renal protection, even independent of the better blood pressure control. The mechanisms underlying the potentiation of cardiorenal protection by sodium restriction are incompletely understood. RAAS-blockade with angiotensin-converting enzyme (ACE) inhibitors increases circulating levels of the anti-inflammatory and antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which is assumed to contribute to its therapeutic effects. We hypothesized that sodium restriction on top of RAAS-blockade further increases AcSDKP, as a possible explanation for the enhanced effects of RAAS-blockade during sodium restriction.Methods:To test this hypothesis, we performed a secondary analysis of a randomized clinical trial investigating 46 nondiabetic chronic kidney disease (CKD) patients (age 5013 years, 80% men) with overt proteinuria and mild to moderate renal insufficiency. Patients were subjected, in a crossover design, to four double-blind 6-week study periods with either regular sodium diet (19449mmol Na(+/)day) or low sodium diet (102 +/- 52mmol Na+/day) on top of either lisinopril (40mg/day; single RAAS-blockade) or lisinopril plus valsartan (320mg/day; dual RAAS-blockade).Results:Sodium restriction significantly increased circulating levels of AcSDKP during single and dual RAAS-blockade (P=0.032 and 0.042, respectively). Linear mixed-model analysis confirmed that AcSDKP levels were increased in response to sodium restriction, irrespective of sex, age, creatinine clearance, blood pressure, BMI, single or dual RAAS-blockade, treatment sequence and other dietary factors, that is calcium and protein (P=0.020).Conclusion:In patients with nondiabetic CKD, we demonstrated that sodium restriction, on top of single and dual RAAS-blockade, increases circulating levels of the anti-inflammatory and antifibrotic peptide AcSDKP. The rise in AcSDKP may contribute to the increased protection of RAAS-blockade during sodium restriction.

Weight excess and/or central body fat distribution are associated with increased long-term renal risk, not only in subjects with renal disease or renal transplant recipients, but also in the general population. As the prevalence of weight excess is rising worldwide, this may become a main renal risk factor on a population basis, even more so because the risk extends to the overweight range. Understanding the mechanisms of this detrimental effect of weight excess on the kidneys is needed in order to design preventive treatment strategies. The increased risk associated with weight excess is partly attributed to associated comorbid conditions, such as hypertension, dyslipidaemia, insulin resistance and diabetes; however, current evidence supports a direct pathogenetic role for renal haemodynamics as well. Weight excess is associated with an altered renal haemodynamic profile, i.e. an increased glomerular filtration rate relative to effective renal plasma flow, resulting in an increased filtration fraction (FF). This renal haemodynamic profile is considered to reflect glomerular hyperfiltration and glomerular hypertension, resulting from a dysbalance between afferent and efferent arterial vasomotor balance. This unfavorable renal haemodynamic profile was found to be associated with renal outcome in experimental models and in human renal transplant recipients, and is associated with a blunted sodium excretion, and reversible by weight loss, renin-angiotensin-aldosterone system blockade or by dietary sodium restriction. More recent evidence showed that a central body fat distribution is also associated with an increased FF, even independent of overall weight excess. In this review, we provide an overview on current literature on the impact of weight excess and central body fat distribution on the renal haemodynamic profile in humans, and its possible role in progressive renal damage.

Objectives Low normal thyroid function may promote the development of atherosclerotic cardiovascular disease by thus far poorly defined mechanisms. We tested the impact of thyroid function on HDL antioxidative capacity, a metric of its anti-atherogenic functionality, in euthyroid subjects with varying degrees of glucose tolerance.Design and Subjects Seventy subjects with Type 2 diabetes mellitus (T2DM), 37 subjects with impaired fasting glucose (IFG) and 31 subjects with normal fasting glucose (NFG) (revised NCEP-ATPIII criteria) participated in a cross-sectional study.Measurements HDL antioxidative capacity (standardized for HDL cholesterol) was measured as the percentage inhibition of low-density lipoprotein oxidation in vitro.Results TSH, free T4 and HDL antioxidative capacity were not different among NFG, IFG and T2DM subjects (P > 0.25 for each). HDL antioxidative capacity was correlated positively with free T4 (r = 0.320, P = 0.007), and negatively with plasma glucose (r = -0.394, P Conclusions In the context of chronic hyperglycaemia, low free T4 within the euthyroid range confers diminished HDL antioxidative capacity, a pathophysiologically relevant metric of HDL functionality.

Background: High density lipoproteins (HDL) contain paraoxonase-1 (PON-1), which has strong anti-oxidative properties. Apolipoprotein E (apoE) may enhance PON-1 activity in vitro, but the extent to which PON-1 activity is determined by circulating apoE levels is unknown. Here we determined relationships of serum PON-1 activity with apoE in subjects without and with metabolic syndrome (MetS).Methods: We measured PON-1 activity (arylesterase activity), plasma apoE and serum amyloid A (SAA) in 93 subjects without and in 75 subjects with MetS (25 and 54 subjects with Type 2 diabetes mellitus (T2DM), respectively; p Results: PON-1 activity was lower in MetS (p Conclusion: Higher apoE levels may confer higher PON-1 activity. The relationship of PON-I activity with total plasma apoE is apparently abrogated in MetS. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Background: Plasma cholesteryl ester transfer (CET), reflecting endogenous transfer of cholesteryl esters from HDL to very low and low density lipoproteins, is elevated in Type 2 diabetes mellitus (T2DM), and may predict (subclinical) cardiovascular disease. Low normal thyroid function may adversely affect lipoprotein metabolism and atherosclerosis development. We tested whether plasma CET is related to thyroid function in euthyroid T2DM and non-diabetic subjects.Subjects and methods: Plasma CET was measured in 74 T2DM and 82 non-diabetic subjects with thyroid-stimulating hormone (TSH) and free thyroxine levels within the reference range.Results: Plasma CET was 20% higher in T2DM (P = 0.003) coinciding higher cholesteryl ester transfer protein (CETP) mass (P = 0.009) and triglycerides (P = 0.02). In univariate analysis, plasma CET was correlated positively with TSH in T2DM only (r = 0.330, P = 0.004). Multiple linear regression analysis revealed a positive interaction between the presence of T2DM and TSH on plasma CET after controlling for age, sex, body mass index, non-HDL cholesterol, triglycerides and CETP mass (beta = 0.167, P = 0.030). The relationship of plasma CET with TSH was also positively modified by plasma glucose and HbA1c (interaction terms: beta = 0.119, P = 0.036, beta = 0.170, P = 0.001, respectively). Additionally, plasma triglycerides interacted positively with TSH on plasma CET in T2DM (beta = 0.198, P = 0.011).Conclusions: Low normal thyroid function, as inferred from higher TSH, confers increased plasma CET in the context of chronic hyperglycemia. Effects of thyroid function on plasma CET may be particularly relevant in hypertriglyceridemic T2DM. Low normal thyroid function could influence atherosclerosis susceptibility in T2DM by affecting the plasma cholesteryl ester transfer process. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Central distribution of body fat is associated with a higher risk of renal disease, but whether it is the distribution pattern or the overall excess weight that underlies this association is not well understood. Here, we studied the association between waist-to-hip ratio (WHR), which reflects central adiposity, and renal hemodynamics in 315 healthy persons with a mean body mass index (BMI) of 24.9 kg/m(2) and a mean I-125-iothalamate GFR of 109 ml/min per 1.73 m(2). In multivariate analyses, WHR was associated with lower GFR, lower effective renal plasma flow, and higher filtration fraction, even after adjustment for sex, age, mean arterial pressure, and BM I. Multivariate models produced similar results regardless of whether the hemodynamic measures were indexed to body surface area. Thus, these results suggest that central body fat distribution, independent of BMI, is associated with an unfavorable pattern of renal hemodynamic measures that could underlie the increased renal risk reported in observational studies.

OBJECTIVE The creatinine excretion rate (CER) is inversely associated with mortality in the general and renal transplant population. The CER is a marker for muscle mass. It is unknown whether the CER is associated with outcome in diabetes. We therefore investigated whether the CER is a determinant of all-cause mortality in diabetic patients. RESEARCH DESIGN AND METHODS We used data from the combined Reduction of Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy Trial (IDNT) studies. A total of 1,872 patients (58% of the overall population) with type 2 diabetes and nephropathy with valid 24-h urinary creatinine excretion data were included. The primary end point of the analyses was all-cause mortality. RESULTS Mean age was 60 ± 8 years and median CER was 1,407 (total range 400–3,406) mg/day. Body surface area, hemoglobin, black race, and albuminuria were positive independent determinants of the CER, whereas female sex and age were inverse independent determinants of the CER. During a median follow-up of 36 (29–45) months, 300 patients died. In a Kaplan-Meier analysis of sex-stratified tertiles of the CER, risk for all-cause mortality increased with decreasing CER (P < 0.001). In a multivariable Cox regression analysis, lower CER (as a continuous variable) was independently associated with increased risk for all-cause mortality (hazard ratio 0.39 [95% CI 0.29–0.52], P < 0.001). Adjustment for potential collection errors did not materially change these associations. CONCLUSIONS Lower CER was strongly associated with increased all-cause mortality in patients with type 2 diabetes and nephropathy. As the CER can be considered a proxy for muscle mass, this puts renewed emphasis on physical condition and exercise in this population.

Background: Effects of thyroid function status on lipoprotein metabolism may extend into the euthyroid range. Low-density lipoprotein (LDL) metabolism is governed by proprotein convertase subtilisin-kexin type 9 (PCSK9), which down-regulates LDL receptor expression, resulting in higher LDL cholesterol (LDL-C). Here, we tested whether plasma PCSK9 correlates with thyroid function in nonobese and obese euthyroid subjects.Methods: We assessed the extent to which plasma PCSK9 is determined by thyrotropin (TSH) in 74 euthyroid subjects (31 women; TSH between 0.5 and 4.0mU/L and free thyroxine [FT4] between 11.0 and 19.5 pM) with varying degrees of obesity (body mass index [BMI] ranging from 20.2 to 40.4 kg/m(2)).Results: TSH, FT4, PCSK9, non-high-density lipoprotein cholesterol (non-HDL-C), LDL-C, and apolipoprotein B (apoB) levels were not different between 64 nonobese subjects (BMI = 30 kg/m2; p > 0.20 for each). PCSK9 correlated positively with TSH in nonobese subjects (r = 0.285, p = 0.023). In contrast, PCSK9 was not associated positively with TSH in obese subjects (r = -0.249, p = 0.49). The relationship of PCSK9 with TSH was different between nonobese and obese subjects when taking age, sex, FT4, and the presence of anti-thyroid antibodies into account (multiple linear regression analysis: beta = -0.320, p = 0.012 for the interaction term between the presence of obesity and TSH on PCSK9), and was also modified by BMI as a continuous trait (beta = -0.241, p = 0.062 for the interaction term between BMI and TSH on PCSK9). Non-HDL-C, LDL-C, and apoB levels were dependent on PCSK9 in nonobese subjects (p 0.50), Accordingly, BMI interacted negatively with PCSK9 on non-HDL-C (p = 0.028) and apoB (p = 0.071).Conclusions: This study suggests that circulating PCSK9 levels correlate with thyroid function even in the normal range. This relationship appears to be blunted by obesity. Thyroid functional status may influence cholesterol metabolism through the PCSK9 pathway.

Fibroblast growth factor 23 (FGF-23) rises progressively in chronic kidney disease and is associated with adverse cardiovascular outcomes. FGF-23 putatively induces volume retention by upregulating the sodium-chloride cotransporter (NCC). We studied whether, conversely, interventions in volume status affect FGF-23 concentrations.We performed a post hoc analysis of 1) a prospective saline infusion study with 12 patients with arterial hypertension who received 2L of isotonic saline over 4 hours, and 2) a randomized controlled trial with 45 diabetic nephropathy (DN) patients on background angiotensin-converting enzyme -inhibition (ACEi), who underwent 4 6-week treatment periods with add-on hydrochlorothiazide (HCT) or placebo, combined with regular sodium (RS) or low sodium (LS) diet in a cross-over design. Plasma C-terminal FGF-23 was measured by ELISA (Immutopics) after each treatment period in DN and before and after saline infusion in hypertensives.The patients with arterial hypertension were 45 +/- 13 (mean +/- SD) years old with an estimated glomerular filtration rate (eGFR) of 101 +/- 18mL/min/1.73m(2). Isotonic saline infusion did not affect FGF-23 (before infusion: 68 median [first to third quartile: 58-97] relative unit (RU)/mL, after infusion: 67 [57-77] RU/mL, P=0.37). DN patients were 65 +/- 9 years old. During ACEi+ RS treatment, eGFR was 65 +/- 25mL/min/1.73m(2) and albuminuria 649mg/d (230-2008mg/d). FGF23 level was 94 (73-141) RU/mL during ACEi therapy. FGF-23 did not change significantly by add-on HCT (99 [74-148] RU/mL), LS diet (99 [75-135] RU/mL), or their combination (111 [81-160] RU/mL, P= 0.15).Acute and chronic changes in volume status did not materially change FGF-23 in hypertensive patients and DN, respectively. Our data do not support a direct feedback loop between volume status and FGF-23 in hypertension or DN.

Background and aims: Both a high dietary sodium and high phosphate load are associated with an increased cardiovascular risk in patients with chronic kidney disease (CKD), and possibly also in non-CKD populations. Sodium and phosphate are abundantly present in processed food. We hypothesized that (modulation of) dietary sodium is accompanied by changes in phosphate load across populations with normal and impaired renal function.Methods and Results: We first investigated the association between sodium and phosphate load in 24-h urine samples from healthy controls (n = 252), patients with type 2 diabetes mellitus (DM, n = 255) and renal transplant recipients (RTR, n = 705). Secondly, we assessed the effect of sodium restriction on phosphate excretion in a nondiabetic CKD cohort (ND-CKD: n = 43) and a diabetic CKD cohort (D-CKD: n = 39). Sodium excretion correlated with phosphate excretion in healthy controls (R = 0.386, P Conclusions: Dietary exposure to sodium and phosphate are correlated across the spectrum of renal function impairment. The concomitant reduction in phosphate intake accompanying sodium restriction underlines the off-target effects on other nutritional components, which may contribute to the beneficial cardiovascular effects of sodium restriction. (C) 2016 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.

Item does not contain fulltext Urinary proteins that leak through the abnormal glomerulus in nephrotic syndrome may affect tubular transport by interacting with membrane transporters on the luminal side of tubular epithelial cells. Patients with nephrotic syndrome can develop nephrocalcinosis, which animal models suggest may develop from impaired transcellular Ca(2+) reabsorption via TRPV5 in the distal convoluted tubule (DCT). In nephrotic-range proteinuria, filtered plasminogen reaches the luminal side of DCT, where it is cleaved into active plasmin by urokinase. In this study, we found that plasmin purified from the urine of patients with nephrotic-range proteinuria inhibits Ca(2+) uptake in TRPV5-expressing human embryonic kidney 293 cells through the activation of protease-activated receptor-1 (PAR-1). Preincubation with a plasmin inhibitor, a PAR-1 antagonist, or a protein kinase C (PKC) inhibitor abolished the effect of plasmin on TRPV5. In addition, ablation of the PKC phosphorylation site S144 rendered TRPV5 resistant to the action of plasmin. Patch-clamp experiments showed that a decreased TRPV5 pore size and a reduced open probability accompany the plasmin-mediated reduction in Ca(2+) uptake. Furthermore, high-resolution nuclear magnetic resonance spectroscopy demonstrated specific interactions between calmodulin and residues 133-154 of the N-terminus of TRPV5 for both wild-type and phosphorylated (S144pS) peptides. In summary, PAR-1 activation by plasmin induces PKC-mediated phosphorylation of TRPV5, thereby altering calmodulin-TRPV5 binding, resulting in decreased channel activity. These results indicate that urinary plasmin could contribute to the downstream effects of proteinuria on the tubulointerstitium by negatively modulating TRPV5.

Background. Recent experimental findings demonstrate vascular endothelial growth factor C (VEGF-C)-mediated water-free storage of salt in the interstitium, which prevents a salt-sensitive blood pressure state. It is unknown whether this mechanism plays a role in salt homeostasis and regulation of blood pressure in humans as well. Therefore, we investigated circulating VEGF-C levels and blood pressure during different well-controlled salt intake in chronic kidney disease (CKD) patients and in healthy subjects.Methods. In two crossover studies, non-diabetic proteinuric CKD patients (n = 32) and healthy subjects (n = 31) were treated with consecutively a low-sodium diet (LS, aim 50 mmol Na+/day) and a high-sodium diet (HS, aim 200 mmol Na+/day) in random order, during two 6-week (CKD patients) and two 1-week periods (healthy subjects).Results. We found that VEGF-C levels are higher during HS than during LS in CKD patients (P = 0.034) with a trend towards higher VEGF-C in healthy subjects as well (P = 0.070). In CKD patients, HS was associated with higher NT-proBNP levels (P = 0.005) and body weight (P = 0.013), consistent with extracellular volume (ECV) expansion and with higher blood pressure (P Discussion. Our findings support a role for VEGF-C-mediated salt homeostasis in humans. Considering the salt sensitivity of blood pressure, this buffering mechanism appears to be insufficient in proteinuric CKD patients. Future studies are needed to provide causality and to substantiate the clinical and therapeutic relevance of this VEGF-C regulatory mechanism in humans.

Obesity is a risk factor for renal graft loss. Higher body mass index (BMI) in native kidneys is associated with glomerular hyperfiltration. Whether higher BMI in renal transplants is associated with hyperfiltration is unknown. We investigated the impact of BMI on renal hemodynamics 1 year post-transplant. We analyzed glomerular filtration rate (GFR, I-125-iothalamate) and effective renal plasma flow (ERPF, I-131-hippurate) in 838 kidney transplants. Data were analyzed for all patients and for the subpopulation without diabetes. Long-term impact of BMI and renal hemodynamics were explored by Cox-regression. With higher BMI GFR and filtration fraction (FF) increased significantly. Multivariate analysis supported impact of BMI on GFR (adjusted r(2) of the model 0.275) and FF (adjusted r(2) of the model 0.158). This association was not explained by diabetes mellitus. On Cox-regression analysis, lower GFR and higher FF were independent determinants of overall graft loss and graft loss by patient mortality. Lower GFR and higher BMI were determinants of death-censored graft loss, with borderline contribution of higher FF. In renal transplants higher BMI is independently associated with higher GFR and FF one year posttransplant, suggesting glomerular hyperfiltration with altered afferent-efferent balance. Mechanisms underlying the long-term prognostic impact of hyperfiltration deserve further exploration.

Plasma cholesteryl ester transfer (CET), reflecting transfer of cholesteryl esters from high density lipoproteins (HDL) towards apolipoprotein B-containing lipoproteins, may promote atherosclerosis development, and is elevated in Type 2 diabetes mellitus (T2DM). We determined the extent to which the relationship of plasma CET with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions is modified in T2DM. Plasma CET, cholesteryl ester transfer protein (CETP) mass, as well as VLDL and LDL subfractions (nuclear magnetic resonance spectroscopy) were determined in 62 T2DM patients and 53 non-diabetic subjects. Plasma CET and CETP mass were increased in T2DM, coinciding higher triglycerides and large VLDL particles (all P 0.15). Abnormalities in the concentration and composition of large VLDL particles are likely to contribute to elevated plasma CET in T2DM. This article is protected by copyright. All rights reserved

Proprotein convertase subtilisin-kexin type 9 (PCSK9), a key regulator of low density lipoprotein receptor expression, has recently been reported to be upregulated by resistin in HepG2 cells and human primary hepatocytes. Whether this translates into a positive relationship of plasma PCSK9 with resistin levels in humans with varying degrees of obesity is unknown.We assessed the extent to which plasma PCSK9 levels are determined by resistin in individuals with varying degrees of obesity.In 80 subjects (35 women; no diabetes mellitus) with body mass index ranging from 19.4 to 40.4 kg/m(2), plasma PCSK9 levels were not positively related to resistin (r=-0.161, p=0.154). Despite positive correlations of non-high density lipoprotein cholesterol (r=0.378, p0.001), low density lipoprotein (r=0.292, p0.01) and apolipoprotein B (apoB) (r=0.266, p0.05) with PCSK9, none of these apolipoprotein (apo) B-containing lipoprotein measures was positively related to resistin (p0.10 for all). In subjects with BMI25.0 kg/m(2) (n=38), PCSK9 was even inversely related to resistin (r=-0.322, p=0.049), and this relationship remained present after controlling for either leptin (p=0.027) or insulin resistance (P=0.031). In subjects with BMI ≥ 25.0 kg/m(2) (n=42), PCSK9 was unrelated to resistin (r=-0.064, p=0.69).This study demonstrates that there is no positive association of plasma PCSK9 with resistin in lean and moderately obese individuals. Our data question whether circulating resistin is a physiologically important determinant of higher PCSK9 levels.

BACKGROUND: The strong anti-oxidative properties of bilirubin largely explain its cardioprotective effects. Insulin resistance is featured by low circulating bilirubin. Thyroid hormone affects both bilirubin generation and its biliary transport, but it is unknown whether circulating bilirubin is associated with thyroid function in euthyroid subjects. Aim is to determine relationships of bilirubin with TSH, free T4 and free T3 in euthyroid subjects without type 2 diabetes mellitus (T2DM), and to assess whether such a relationship would be modified by the degree of insulin resistance. METHODS: Total bilirubin, TSH, free T4, free T3, glucose, insulin, lipids and transaminases were measured in 1854 fasting euthyroid subjects without T2DM, recruited from the general population (PREVEND cohort). Insulin resistance was assessed by homeostasis model assessment. RESULTS: Bilirubin was positively related to free T4 (β = 0.116, P

Bilirubin may confer cardiovascular protection because of its strong antioxidative properties. Both thyroid dysfunction and the diabetic state affect bilirubin metabolism. Here we tested whether low-normal thyroid function affects serum bilirubin among euthyroid subjects with and without type 2 diabetes mellitus (T2DM).Serum total bilirubin, thyrotropin and free thyroxine (free T4), transaminases, insulin sensitivity (homeostasis model assessment), and lipids were measured in 74 T2DM and 82 nondiabetic subjects with thyrotropin and free T4 levels within the euthyroid range.Bilirubin was positively related to free T4 in T2DM subjects (r = 0.370, p0.001), but not in nondiabetic subjects (r = 0.047, p = 0.68). In age- and sex-adjusted multiple linear regression analysis, free T4 was found to interact positively with the presence of T2DM on serum bilirubin (interaction term: β = 0.251, p = 0.024). This interaction remained present after additional adjustment for alcohol intake, aspartate aminotransferase and insulin sensitivity (interaction term: β = 0.222, p = 0.043), or alternatively for cholesterol and triglycerides (interaction term: β = 0.203, p = 0.057).Lower free T4 levels within the euthyroid range confer decreased bilirubin in T2DM. Low-normal thyroid function could enhance atherosclerosis susceptibility in T2DM by decreasing serum bilirubin.

Objective LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin–kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. Methods Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m 2 , proteinuria 1.9 [0.9–3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na + /day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3–1.1] g/day ( P Results Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161–314] vs. 143 [113–190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline ( R = 0.399, P = 0.018) and at maximal antiproteinuric treatment ( R = 0.525, P = 0.001), but did not decrease during proteinuria reduction ( P = 0.84). Individual changes in total cholesterol ( R = 0.365, P = 0.024), non-HDL cholesterol ( R = 0.333, P = 0.041), and LDL cholesterol ( R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment ( P = 0.04). Conclusion Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects.

Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p

Hypertension and proteinuria are important mediators of renal damage. Since H2S has vasodilatory, anti-inflammatory and antioxidant properties, we investigated its effects in Angiotensin II (Ang II)-induced hypertensive renal disease in rats. Treatment with H2S donors (NaHS or sodium thiosulfate (STS)) during three weeks of Ang II infusion reduced hypertension by 22% and 18% resp (p

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk., Author Summary Hypertension is the leading contributor to global mortality with a global prevalence of 26.4% in 2000, projected to increase to 29.2% by 2025. While 50%–60% of population variation in blood pressure can be attributable to additive genetic factors, all the genetic variants robustly identified so far explain only 1%–2% of the population variance indicating the presence of additional undiscovered risk variants. Using an extreme case-control strategy, we have discovered a SNP in the promoter region of the uromodulin gene (UMOD) to be associated with hypertension (minor allele protective against hypertension). We then validated this association using large-scale population and case-control studies, where similar extreme criteria for selection of cases and controls have been used (21,466 cases and 18,240 controls). As the locus was related to uromodulin, a protein exclusively expressed in the kidneys, we show that the association is independent of renal dysfunction. We also show preliminary evidence that the SNP allele which is protective against hypertension is also protective against cardiovascular events in 26,654 Swedish subjects followed-up for 12 years. The newly discovered UMOD locus for hypertension has the potential to give unique insights into the role of uromodulin in BP regulation and to identify novel drugable targets.