Effects of atorvastatin on red-blood cell Na(+)/Li(+) countertransport in hyperlipidemic patients with and without hypertension

BACKGROUND: To explore the effect of short-term cholesterol-lowering treatment with atorvastatin on erythrocyte sodium-lithium countertransport (Na(+)/Li(+) CT) activity. METHODS: Group A consisted of 30 patients (14 men) with mild essential hypertension (systolic blood pressure (SBP), 140-159 mm Hg and/or diastolic BP, 90-99 mm Hg) and primary hypercholesterolemia low-density lipoprotein (LDL) cholesterol >4.1 mmol/l and triglycerides (TG) <2.8 mmol/l), group B of 30 normotensive patients (16 men) with primary hypercholesterolemia, while 37 (18 men) healthy volunteers comprised the control group. After a 6-week dietary lead-in, all eligible patients were prescribed 20 mg/day of atorvastatin. Anthropometric data, blood-pressure (BP) measurements and determinations of lipid, non-lipid metabolic parameters (including homeostasis model assessment index, (HOMA-IR)) and erythrocyte Na(+)/Li(+) CT activity were collected at baseline and after 12 weeks of treatment. RESULTS: At baseline Na(+)/Li(+) CT activity was significantly higher in group A and B compared with the control group and correlated directly with obesity indices, systolic and diastolic BP, total cholesterol, LDL-cholesterol, TG, apolipoprotein B (apoB), HOMA-IR, uric acid and inversely with high-density lipoprotein (HDL)-cholesterol and apoA1. Systolic and diastolic BP levels, HOMA-IR and Na(+)/Li(+) CT activity were significantly decreased after atorvastatin treatment in both patient groups. The reduction in Na(+)/Li(+) CT activity correlated with baseline Na(+)/Li(+) CT activity and the changes in HOMA-IR values. CONCLUSIONS: Short-term treatment with atorvastatin for patients with hypercholesterolemia, and with or without essential hypertension, is associated with a significant reduction in the erythrocyte Na(+)/Li(+) CT activity, BP levels and insulin resistance independent of concomitant changes in lipid parameters.     

The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium countertransport in NIDDM

Summary Increased erythrocyte sodium-lithium countertransport rate is found in non-diabetic subjects with essential hypertension, and in insulin-dependent diabetic subjects with nephropathy. However, relationships between these variables in non-insulin-dependent diabetic subjects are ill-defined. In order to characterise the relationships between blood pressure, urinary albumin excretion, and erythrocyte sodium-lithium countertransport, 66 subjects with non-insulin-dependent diabetes were studied. Urinary albumin excretion rate correlated with mean 24-h ambulatory systolic blood pressure (r=0.57; p<0.001), but not with sodium-lithium countertransport (r=0.06; p=0.31). No significant relationship was observed between 24-h systolic blood pressure and erythrocyte sodium-lithium countertransport (r = 0.16; p=0.17). The principal differences between microalbuminuric and normoalbuminuric subjects (albumin excretion rate >15 g·min^–1 [n=20], and <15 g·min^–1, [n=46]) were: higher 24-h systolic blood pressure (145.9 [16.8] mm Hg vs 131.9 [16.8] mm Hg; p=0.006), nocturnal heart rate (72.4 [8.9] vs 67.4 [8.9] beats·min^–1; p=0.042), and HbA₁ (11.3 [1.5]% vs 10.1 [2.0]%; p=0.028), and a longer median duration of diabetes (10.0 vs 5.0 years; p = 0.02). In contrast, there was no significant difference in sodium-lithium countertransport rate between microalbuminuric (0.41 [0.18] mmol·l^–1·h^–1) and normoalbuminuric subjects (0.39 [0.15] mmol·l^–1· h^–1; p=0.687). In multiple regression analysis controlling for race, age, body mass index and HbA₁, the significant determinants of albumin excretion rate were 24-h systolic blood pressure (B [regression coefficient]=0.029, SE[B] [standard error of B]=0.009, t=2.95, p=0.005), duration of diabetes (B=0.430, SE[B]=0.169, t=2.54, p=0.016) and male gender (B=–1.170, SE[B]=0.457, t=–2.56, p=0.015). In conclusion, albumin excretion rates in non-insulin-dependent diabetic subjects are linked to hypertension and glycaemic exposure, but show no relationship to erythrocyte sodium-lithium countertransport.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin dependent diabetes mellitus - SLC sodium lithium countertransport - AER albumin excretion rate - B regression - SE coefficient; standard error of B     

Urinary albumin excretion is associated with nocturnal systolic blood pressure in resistant hypertensives

Microalbuminuria is a known marker of subclinical organ damage. Its prevalence is higher in patients with resistant hypertension than in subjects with blood pressure at goal. On the other hand, some patients with apparently well-controlled hypertension still have microalbuminuria. The current study aimed to determine the relationship between microalbuminuria and both office and 24-hour ambulatory blood pressure. A cohort of 356 patients (mean age 64 ± 11 years; 40.2% females) with resistant hypertension (blood pressure ≥ 140 and/or 90 mm Hg despite treatment with ≥ 3 drugs, diuretic included) were selected from Spanish hypertension units. Patients with estimated glomerular filtration rate <30 mL/min/1.73 m(2) were excluded. All patients underwent clinical and demographic evaluation, complete laboratory analyses, and good technical-quality 24-hour ambulatory blood pressure monitoring. Urinary albumin/creatinine ratio was averaged from 3 first-morning void urine samples. Microalbuminuria (urinary albumin/creatinine ratio ≥ 2.5 mg/mmol in males or ≥ 3.5 mg/mmol in females) was detected in 46.6%, and impaired renal function (estimated glomerular filtration rate <60 mL/min/1.73 m(2)) was detected in 26.8%. Bivariate analyses showed significant associations of microalbuminuria with older age, reduced estimated glomerular filtration rate, increased nighttime systolic blood pressure, and elevated daytime, nighttime, and 24-hour diastolic blood pressure. In a logistic regression analysis, after age and sex adjustment, elevated nighttime systolic blood pressure (multivariate odds ratio, 1.014 [95% CI, 1.001 to 1.026]; P=0.029) and reduced estimated glomerular filtration rate (multivariate odds ratio, 2.79 [95% CI, 1.57 to 4.96]; P=0.0005) were independently associated with the presence of microalbuminuria. We conclude that microalbuminuria is better associated with increased nighttime systolic blood pressure than with any other office and 24-hour ambulatory blood pressure monitoring parameters.     

Decrease in urinary albumin excretion associated with the normalization of nocturnal blood pressure in hypertensive subjects

Previous results have indicated that valsartan administration at bedtime as opposed to on wakening improves the diurnal/nocturnal ratio of blood pressure without loss in efficacy and therapeutic coverage. We hypothesized that increasing this ratio could reduce microalbuminuria. We conducted a prospective, randomized, open-label, blinded endpoint trial on 200 previously untreated nonproteinuric patients with grade 1 to 2 essential hypertension, assigned to receive valsartan (160 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured by ambulatory monitoring for 48 consecutive hours before and after 3 months of treatment. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of blood pressure on a per-subject basis. The significant blood pressure reduction after 3 months of therapy was similar for both treatment times. The diurnal/nocturnal blood pressure ratio was unchanged after valsartan on awakening, but significantly increased from 7.5 to 12.2 (P<0.001) when valsartan was administered at bedtime. Urinary albumin excretion was significantly reduced by 41% after bedtime treatment. This reduction was independent of the 24-hour blood pressure decrease but highly correlated with the decrease in nocturnal blood pressure and mainly with the increase in diurnal/nocturnal ratio (P<0.001). Bedtime valsartan administration improves the diurnal/nocturnal blood pressure ratio to a more dipper profile. This normalization of the circadian blood pressure pattern is associated with a significant decrease in urinary albumin excretion and plasma fibrinogen, and could thus reduce the increased cardiovascular risk in nondipper hypertensive patients.     

Serum uromodulin is associated with urinary albumin excretion in adolescents with type 1 diabetes

Early diabetic kidney disease (DKD) occurs in adolescents with type 1 diabetes (T1D). Lower serum uromodulin (SUMOD) predicts DKD progression in adults with T1D. In this study, we demonstrate that lower SUMOD is associated with urinary albumin excretion in adolescents with T1D, suggesting a potential relationship between SUMOD and early kidney dysfunction in T1D youth.     

Urinary albumin excretion is associated with impaired flow- and nitroglycerin-mediated brachial artery dilatation in hypertensive adults

We investigated whether the urinary albumin/creatinine ratio (UACR), a measure of albuminuria, is associated with non-invasive measures of arterial function in hypertensive adults without known coronary heart disease (CHD) or stroke. UACR was measured in the first voided morning urine sample in 469 non-Hispanic white hypertensive individuals (mean age 62.2+/-9.8 years, 41% men) belonging to hypertensive sibships. High-resolution ultrasonography of the brachial artery was used to assess flow-mediated dilatation (FMD)--an endothelium-dependent response--and nitroglycerin-mediated dilatation (NMD)--an endothelium-independent response. Because of skewed distribution, UACR was log transformed after addition of 0.1. The association of log (UACR+0.1) with FMD and NMD, before and after adjustment for CHD risk factors, serum creatinine, and hypertension medication and statin use was assessed using linear regression analyses. In univariable analyses, variables associated with lower FMD were greater age, male sex, history of smoking, lower high-density lipoprotein (HDL) cholesterol, higher serum creatinine and higher log (UACR+0.1); variables associated with lower NMD were greater age, male sex, higher systolic blood pressure, lower HDL cholesterol, higher serum creatinine and higher log (UACR+0.1). In separate stepwise multivariable regression analyses that adjusted for conventional CHD risk factors, serum creatinine and hypertension medication and statin use, higher log (UACR+0.1) was associated with lower brachial artery FMD (P=0.035) and NMD (P=0.0002). These findings highlight the association of increased urinary albumin excretion with impaired vascular reactivity in hypertensive individuals.     

Dysglycemia but not lipids is associated with abnormal urinary albumin excretion in diabetic kidney disease: a report from the Kidney Early Evaluation Program (KEEP)

ABSTRACT: BACKGROUND: The relationship between glycemic control and lipid abnormalities with urinary albumincreatinine ratio (ACR) in chronic kidney disease (CKD) patients with diabetes mellitus (DM) is unknown. We sought to investigate the association of dyslipidemia and glycemic control with levels of albuminuria in the National Kidney Foundation (NKF) Kidney Early Evaluation Program (KEEP) participants with DM and CKD stage 3 or higher. METHODS: We performed a cross-sectional study of 6639 eligible KEEP patients with DM and CKD Stage 3 to 5 from June 2008 to December 2009. Multivariate logistic regression was used to evaluate the association of lipid parameters (per 10 mg/dl change in serum level) and glycosylated hemoglobin (HbA1c) values with three degrees of albuminuria normo (<30 mg g), micro (30 to 300 mgg) and macro (>300 mgg). RESULTS: 2141 KEEP participants were included. HbA1c levels were strongly associated with microalbuminuria (compared to normo-albuminuria) and macro-albuminuria (compared to normoalbuminuria and micro-albuminuria). Each 1.0% increase in HbA1c increased the odds of micro-albuminuria by 32% (OR 1.32, 95% CI 1.23-1.42) and the odds of macro-albuminuria (vs. microalbuminuria) by 16% (OR 1.16, 95% CI 1.05-1.28). Only increases in serum HDL were associated with decreased odds of micro-albuminuria; otherwise, the association between other components of the serum lipid profile with urinary ACR did not reach statistical significance. CONCLUSION: In this cross-sectional study of 2141 KEEP participants with DM and CKD stages 3-5, overall glycemic control but not lipids were associated with abnormal urinary albumin excretion, a marker of increased risk for progressive disease.     

Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects

BACKGROUND: Elevated urinary albumin excretion (UAE) predicts atherosclerotic cardiovascular disease. It is hypothesized that elevated UAE is associated with a generalized vascular dysfunction. This study tested this hypothesis for conduit arteries. METHODS AND RESULTS: Clinically healthy subjects were selected: 19 with UAE >90th percentile in the background population (6.6 microgram/min相似文献   

培哚普处比硝苯地平能更有效降低高血压病患者的尿蛋白排泄

目的 探讨硝苯地平和培哚早长期治疗对高血压病患肾功能的影响。方法 ５２例高血压病患发为两组：硝苯地平组（２６例）和培哚普利组（２６例）,疗程２４周,治疗前后观察肾功能指标变化。结果 （１）两种药物能同等程度降低各组高血压病患的动脉血压,培哚普处组高血压病患治疗后能显降低尿蛋白排泄量,升高肾小球滤过率「２４小时尿白蛋白（ｍｇ／２４ｈ）;１０４．５±４１．８降至６６．７±２５．９,Ｐ〈０．０     

培哚普利比硝苯地平能更有效降低高血压病患者的尿蛋白排泄

目的探讨硝苯地平和培哚普利长期治疗对高血压病患者肾功能的影响。方法５２例高血压病患者随机分为两组：硝苯地平组（２６例）和培哚普利组（２６例）,疗程２４周,治疗前后观察肾功能指标变化。结果（１）两种药物能同等程度降低各组高血压病患者的动脉血压,但培哚普利组高血压病患者治疗后能显著降低尿蛋白的排泄量,升高肾小球滤过率［２４小时尿白蛋白（ｍｇ／２４ｈ）：１０４５±４１．８降至６６．７±２５．９,Ｐ＜０．０１;２４小时尿蛋白（ｇ／Ｌ）：０．２４±０．０６４降至０．１７±０．０３９,Ｐ＜００１;肾小球滤过率（ｍｌ／ｍｉｎ）：１１２．２±１３．２升至１２５．５±１５．２,Ｐ＜０．０５］,而硝苯地平组治疗前后无明显变化（Ｐ＞０．０５）。（２）两组治疗后尿白蛋白下降幅度与收缩压和舒张压下降幅度均无显著相关（ｒ值分别为：０．２６９和０．２７８,Ｐ＞０．０５,与０．１８２和０．１８８,Ｐ＞０．０５）。结论对高血压病合并早期肾损害患者,培哚普利比硝苯地平更有效地降低尿蛋白排泄;培哚普利减少尿白蛋白排泄是不依赖于动脉血压的有效降低,其可能机制是肾内血流量或肾小球通透性的改变所致。     

Activation of the Na(+)/H(+) exchanger is required for reperfusion-induced Ins(1,4,5)P(3) generation

Post-ischemic reperfusion causes a change in inositol phosphate responses to norepinephrine from primary generation of inositol(1,4) bis phosphate (Ins(1,4)P(2)) to generation of inositol(1,4,5) tris phosphate (Ins(1,4,5)P(3)) that is required for the initiation of reperfusion arrhythmias. The current study was undertaken to investigate the role of Na(+)/H(+)exchange in facilitating this transient change in inositol phosphate response. Rat hearts were subjected to 20 min ischemia followed by 2 min reperfusion and Ins(1, 4,5)P(3)content was measured by mass analysis or by anion-exchange HPLC following [(3)H]inositol labeling. Reperfusion caused generation of [(3)H]Ins(1,4,5)P(3)(1732+/-398 to 3103+/-214, cpm/g tissue, mean+/-S.E.M., n=5, P<0.01) and the development of arrhythmias. Inhibition of Na(+)/H(+)exchange, by reperfusing at pH 6.3 or by pretreating with HOE-694 (10 n M-3 microM) or HOE-642 (3 microM) prevented the [(3)H]Ins(1,4,5)P(3)generation, without causing any suppression of norepinephrine release. Increases in Ins(1,4,5)P(3)mass were similarly reduced by inhibition of Na(+)/H(+)exchange. Thus, activation of Na(+)/H(+)exchange is required for the enhanced Ins(1,4,5)P(3)response observed under reperfusion conditions, and prevention of Ins(1,4,5)P(3)generation may be an important contributor to the anti-arrhythmic actions of inhibitors of Na(+)/H(+)exchange.     

First morning urinary albumin concentration is a good predictor of 24-hour urinary albumin excretion in children with Type I (insulin-dependent) diabetes

Summary Twenty-four hour urinary albumin excretion was measured in 97 children with Type 1 (insulin-dependent) diabetes and found to have a geometric mean of 6 mg/day (range 1–38 mg/d). The same geometric mean of 6 mg/day (range 1–45 mg/d) was found in 120 normal children. The relationship of 24-h urinary albumin excretion to the albumin concentration (mg/1) and to the ratio of albumin: creatinine (mg: mmol) on first morning urine samples in 64 patients was highly significant (r=0.93 and r=0.62 respectively, p < 0.001). In 41 patients, the relationship between 24-h urinary albumin excretion and albumin concentration upon urine samples at various times was assessed. The correlation was highest on the first morning sample (r=0.86); 09.00h to 13.00 h, 0.51; 13.00 h to 18.00 h, 0.68; 18.00 h to 23.00 h, 0.32. High sensitivity and moderate specificity was obtained using a first morning albumin concentration of greater than 20 mg/l to detect increased albumin excretion. These results show that the measurement of albumin concentration on the first morning urine sample can be used for a screening test for micro-albuminuria in children.     

Increased urinary albumin excretion is associated with a cluster of metabolic alterations in type 2 diabetes mellitus

The relationship between urinary albumin excretion rate (UAE) and some metabolic and haemodynamic characteristics was studied in 62 (50 male, 12 female) type 2 (non-insulin-dependent) diabetic patients, with (26 male, 5 female) and without (24 male, 7 female) ischaemic heart disease (IHD), free from overt diabetic nephropathy. The overall population was subdivided into quartiles on the basis of UAE values (mg/24h): group 1 (16 subjects), 3.3–7 (range); group 2 (15 subjects), 7.22–11.8; group 3 (15 subjects), 11.9–30; group 4 (16 microalbuminuric subjects), 31.7–226. The groups were comparable with regard to age, duration of diabetes and prevalence of smokers. From group 1 to group 4 we found increasing levels of body mass index (BMI) (24.2±0.6, 26.6±0.7, 27.6±0.7, 27.6±0.9 kg/m²;P=0.007), HbA_1c (5.99±0.2, 6.45±0.35, 7.02±0.41, 7.4±0.39%;P=0.017), total cholesterol (5.30±0.26, 5.51±0.34, 6.14±0.21, 6.32±0.26 mmol/l;P=0.026), triglycerides (1.37±0.20, 1.67±0.21, 2.07±0.29, 2.55±0.45 mmol/l;P=0.034) and prevalence of hypertension (50%, 67%, 67%, 81%;P=0.088). No significant differences were found between C-peptide, insulin resistance (K index of insulin tolerance test) and high-density lipoprotein (HDL)-cholesterol levels. Groups 1+2 had a lower prevalence of IHD in comparison with groups 3+4 (42% vs 58%,P=0.069). Using multiple regression analysis, only HbA_1c was independently associated with log₁₀ UAE in the overall population (P=0.002), including as independent variables age, duration of diabetes, BMI, total cholesterol, triglycerides and mean arterial pressure. In conclusion: (1) type 2 diabetic patients show higher BMI, HbA_1c, total cholesterol, triglyceride levels and prevalence of hypertension with increasing UAE, even in the normoalbuminuric range; (2) the prevalence of IHD is higher in the groups with elevated UAE; (3) glycaemic control is the only metabolic characteristic independently associated with UAE.     

Is there increased cardiovascular risk in essential hypertensive patients with abnormal kinetics of red blood cell sodium-lithium countertransport?

Na+ transport kinetics were studied in red blood cells (RBCs) from 50 essential hypertensive patients and 30 normotensive controls. Seven hypertensive patients were characterized by the following: (1) a maximal rate of Na+-Li+ countertransport higher than an upper normal limit of 525 mumol.litre cells-1.h-1; (2) an apparent dissociation constant for internal Na+ higher than an upper normal limit of 20.4 mmol.litre cells (in only five of the seven hypertensives); (3) no other kinetic abnormality in Na+,K+ pump, Na+,K+ cotransport or passive Na+ permeability. Clinically, hypertensives with abnormal countertransport were characterized by high serum low-density lipoprotein (LDL) cholesterol levels and the presence of electrocardiographic left ventricular hypertrophy (LVH). Conversely, mean values of these two clinical parameters were normal in the remaining hypertensive patients, independently of the presence of other abnormalities in Na+,K+ pump, Na+,K+ cotransport or passive Na+ permeability. In conclusion, the presence of abnormal Na+-Li+ countertransport kinetics in erythrocytes may be associated with an enhanced cardiovascular risk in hypertension.     

Cardiovascular remodelling and red blood cell Li+/Na+ countertransport in patients with type 1 diabetes and essential hypertension

Patients with type 1 (insulin-dependent) diabetes may develop a specific cardiac disease characterized by functional and structural abnormalities. The pathogenesis of the cardiac disease is poorly understood but cardiac and renal complications may coexist. Patients with overt diabetic nephropathy have increased red cell Li⁺/Na⁺ countertransport (CT), which reflects abnormal kinetic properties of the red cell membrane Na⁺/H⁺ exchange. Since the activation of Na⁺/H⁺ exchange has a key role in cell proliferation and cell growth, as well as in the regulation of cell sodium and cell pH and in the renal reabsorption of Na⁺ and bicarbonate, we have looked for relationships between red cell Li⁺/Na⁺ CT, Na⁺/H⁺ exchange and cardiovascular remodeling in patients with type 1 diabetes, essential hypertension and idiopathic familiar cardiomyopathy. In type 1 diabetes the maximal velocity of Li⁺/Na⁺ CT is positively correlated with interventricular septum thickness and the left ventricular wall to lumen ratio. Similar results were obtained in patients with essential hypertension. In these patients an increased Li⁺/Na⁺ CT is also associated with severe and drug-resistant hypertension and with significant vascular remodelling, estimated by the minimal post-ischaemic vascular resistance in the calf. Finally, Li⁺/Na⁺ CT is negatively correlated with diastolic relaxation of the left ventricle in familiar hypertrophic cardiomyopathy. From these data it appears that widespread abnormal kinetic properties of Na⁺/H⁺ exchange, estimated by increased red cell Li⁺/Na⁺ CT, may have epistatic effects on the pathogenesis of cardiac complications of type 1 diabetes and essential hypertension.     

Reduction of albumin urinary excretion is associated with reduced cardiovascular events in hypertensive and/or diabetic patients. A meta-regression analysis of 32 randomized trials

Background

The association between renal dysfunction and risk of cardiovascular (CV) events and mortality has been reported in several studies. However, it is unclear whether reduction in urinary albumin excretion (UAE) is associated with reduced risk of clinical events. Therefore, we sought to investigate, in a meta-regression analysis of randomized studies enrolling hypertensive and/or diabetic patients, whether changes in UAE are associated with changes in CV outcomes and all-cause mortality.

Methods

MEDLINE, ISI Web of Science, Cochrane Database and Scopus were searched for randomized trials enrolling more than 200 diabetic and/or hypertensive patients, reporting UAE at baseline and at end of follow-up and CV events [CV death, myocardial infarction (MI), and stroke], as well all-cause mortality.

Results

Thirty-two trials enrolling 80,812 participants were included in analyses. Meta-regression analysis showed that each 10% reduction of UAE was significantly associated with 13% reduction of MI (Regression Coefficient [RC]:0.0055; 95% Confidence Interval [CI]:0.0014 to 0.0095; p = 0.010), with 29% reduction of stroke (RC:0.0124; CI:0.0030 to 0.0218; p = 0.013) and with 14% reduction of the composite outcome (CV death, MI, stroke)(RC:0.0059; CI:0.0027 to 0.0090; p = 0.001), whereas not significantly associated with all-cause (RC:0.0028; CI:− 0.0047 to 0.0103; p = 0.486) and CV mortality (RC:0.0028; CI:− 0.0047 to 0.0103; p = 0.447). Results were mostly confirmed by sensitivity analysis. No heterogeneity or publication bias was detected.

Conclusions

Reduction in UAE is associated with reduced risk of MI and stroke in diabetic and/or hypertensive patients. These findings suggest that UAE changes may represent a valuable intermediate end-point for CV risk evaluation in clinical practice.