Changes in Kidney Function in a Population With Essential Hypertension in Real Life Settings.

INTRODUCTION: Hypertension has been identified as one of the commonest modifiable determinants for chronic kidney disease progression. A variety of antihypertensive drugs are available and their effect on kidney function has been investigated by a large number of randomized controlled trials. Observational studies, although scarcely been used, outpatient can reflect everyday practice, where drug exposures vary over time, and may provide an alternative for detecting longitudinal changes in kidney function. MATERIALS AND METHODS: We applied mixed model repeated measures analysis to investigate the effect of antihypertensive drug categories and their combinations on kidney function change over time in a cohort of 779 patients with essential hypertension, using the data from a Greek hypertension outpatient clinic. Antihypertensive drugs were grouped in 5 categories. Their effect was evaluated and their combinations with and without renin-angiotensin-system inhibitors (RASI) to each other. In addition, the combination of RASI with calcium channel blockers (CCBs) was studied. RESULTS: Diuretics, RASI, CCBs, and beta-blockers had a significant renoprotective and blood pressure lowering effect. Combinations with RASI had a smaller beneficial effect on kidney function compared to CCBs (0.75 mL/min/1.73 m2 per year of drug use versus 0.97 mL/min/1.73 m2). There was no additional effect when combining RASI with CCBs. However, the lowering effect on systolic blood pressure was greater (-0.83 mm Hg per year of drug use, P < .001). CONCLUSIONS: RASI were found to have a smaller, although significant, renoprotective effect. There was no additional effect on kidney function when combining RASI with CCBs.

Echocardiographic Parameters During Long and Short Interdialytic Intervals in Hemodialysis Patients.

BACKGROUND: The long interdialytic interval in thrice-weekly hemodialysis is associated with excess cardiovascular risk. However, the mechanisms behind these adverse consequences are not fully understood. This study investigated the interdialytic changes in right and left ventricular function during the 2- and 3-day intervals. STUDY DESIGN: Observational study with 2 random crossover sequences of recordings: 3-day followed by 2-day interval or vice versa. SETTINGS & PARTICIPANTS: 41 stable patients with end-stage renal disease on standard thrice-weekly hemodialysis therapy. PREDICTOR: 3-day (long) versus 2-day (short) interdialytic interval. OUTCOME: Interdialytic change in echocardiographic indexes of left and right ventricular function. MEASUREMENTS: 2-dimensional echocardiographic and tissue Doppler imaging studies were performed with a Vivid 7 cardiac ultrasound system at the start and end of the 3- and 2-day interdialytic intervals. RESULTS: During both intervals studied, elevations in cardiac output, stroke volume, left ventricular mass index, and peak early diastolic velocities of the left ventricle were evident. Interdialytic weight gain (3.0±1.7 vs 2.4±1.3 [SD] kg) and inferior vena cava diameter increase (0.54±0.3 vs 0.25±0.3) were higher during the 3-day versus the 2-day interval (P<0.001). Left ventricular systolic and diastolic function indexes were generally no different between interdialytic intervals. In contrast, interdialytic increases in left and right atrial volume, right ventricular systolic pressure (RVSP; 15.3±10.2 vs 4.7±5.2mmHg; P<0.001), and tricuspid regurgitation maximum velocity (0.46±0.45 vs 0.14±0.33m/s; P=0.001) were significantly greater during the 3- versus the 2-day interval. Multivariable analysis suggested that changes in interdialytic weight gain, right ventricle diastolic function, and pulmonary vascular resistance were determinants of the change in RVSP. LIMITATIONS: Observational study design. CONCLUSIONS: Excess volume accumulation over the long interdialytic interval in hemodialysis patients results in higher left and right atrial enlargement and RVSP elevation, which clinically corresponds to pulmonary circulation overload, providing one plausible pathway for the excess mortality risk during this period.

Ambulatory recording of wave reflections and arterial stiffness during intra- and interdialytic periods in patients treated with dialysis.

BACKGROUND AND OBJECTIVES: Wave reflections and arterial stiffness are independent cardiovascular risk factors in ESRD. Previous studies in this population included only static recordings before and after dialysis. This study investigated the variation of these indices during intra- and interdialytic intervals and examined demographic, clinical, and hemodynamic variables related to arterial function in patients undergoing hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between February 2013 and May 2014, a total of 153 patients receiving maintenance hemodialysis in five dialysis centers of northern Greece underwent ambulatory BP monitoring with the newly introduced Mobil-O-Graph device (IEM, Stolberg, Germany) over a midweek dialysis session and the subsequent interdialytic period. Mobil-O-Graph is an oscillometric device that records brachial BP and pulse waves and estimates, via generalized transfer function, aortic BP, augmentation index (AIx) as a measure of wave reflections, and pulse wave velocity (PWV) as an index of arterial stiffness. RESULTS: AIx was lower during dialysis than in the interdialytic period of dialysis-on day (Day 1) (mean±SD, 24.7%±9.7% versus 26.8%±9.4%; P<0.001). In contrast, PWV remained unchanged between these intervals (9.31±2.2 versus 9.29±2.3 m/sec; P=0.60). Both AIx and PWV increased during dialysis-off day (Day 2) versus the out-of-dialysis period of Day 1 (28.8%±9.8% versus 26.8%±9.4% [P<0.001] and 9.39±2.3 versus 9.29±2.3 m/sec [P<0.001]). Older age (odds ratio [OR], 1.09; 95% confidence interval [95% CI], 1.02 to 1.15), female sex (OR, 7.56; 95% CI, 1.64 to 34.81), diabetic status (OR, 8.84; 95% CI, 1.76 to 17.48), and higher mean BP (OR, 1.17; 95% CI, 1.09 to 1.27) were associated with higher odds of high AIx; higher heart rate was associated with lower odds (OR, 0.71; 95% CI, 0.63 to 0.80) of high AIx. Older age (OR, 2.04; 95% CI, 1.61 to 2.58) and higher mean BP (OR, 1.15; 95% CI, 1.05 to 1.27) were independent correlates of high PWV. CONCLUSIONS: This study showed a gradual interdialytic increase in AIx, whereas PWV was only slightly elevated during Day 2. Future studies are needed to elucidate the value of these ambulatory measures for cardiovascular risk prediction in ESRD.

Arterial stiffness: a novel cardiovascular risk factor in kidney disease patients.

Prospective observational studies have shown that arterial stiffness is a strong and independent predictor of cardiovascular disease in hemodialysis patients. Recent evidence further supports that arterial hardening predicts cardiovascular and all-cause mortality in peritoneal dialysis patients, renal transplant recipients and patients with chronic kidney disease (CKD) not on dialysis. Of note, dissociation of arterial stiffness with blood pressure reduction were related to worsened cardiovascular outcome in kidney disease patients, suggesting that arterial stiffness may not only be a predictor, but also a true risk factor, representing a specific and potentially reversible pattern of outward arterial remodeling in these individuals. On this basis, arterial stiffness has emerged as a novel therapeutic target for cardiovascular risk reduction in patients with CKD; specific interventions, such as renin-angiotensin-system blockade, use of statins, and decrease of calcium- phosphate product may delay the progression of arteriosclerotic process. This article summarizes the accumulated evidence from clinical and epidemiological studies regarding the prognostic significance of arterial stiffening on cardiovascular outcomes and provides insights on possible treatment strategies for arterial stiffness attenuation in patients with CKD.

Hemodiafiltration does not have additional benefits over hemodialysis on arterial stiffness, wave reflections and central aortic pressures.

BACKGROUND/AIMS: The hypothesis that dialytic modality affects arterial stiffness was never investigated. This study includes comparative evaluation of hemodiafiltration versus hemodialysis on arterial function during first and second weekly dialysis sessions. METHODS: 24 patients receiving hemodiafiltration and another 24 age- and sex-matched controls receiving hemodialysis were included. Patients were evaluated before and after first and second weekly dialysis sessions. Applanation tonometry of peripheral arteries was applied to determine aortic and brachial pulse wave velocity and heart rate-adjusted augmentation index (AIx(75)). RESULTS: Hemodiafiltration and hemodialysis reduced AIx(75), but not aortic and brachial pulse wave velocity. Intradialytic reductions in AIx(75) did not differ between hemodiafiltration and hemodialysis in first and mid-week dialysis. In multivariate linear regression, predictors of intradialytic reduction in AIx(75) were changes in body weight and central aortic systolic blood pressure, but not dialytic modality. CONCLUSION: This study showed that hemodiafiltration has similar effects with hemodialysis on wave reflections and stiffness.

Diverse effects of interdialytic intervals on central wave augmentation in haemodialysis patients.

BACKGROUND: Increased arterial stiffness is a common finding and independent predictor of mortality in end-stage renal disease (ESRD) patients. A long interdialytic interval was associated with increased risk of cardiovascular death in patients receiving conventional haemodialysis (HD). This is the first study to examine the effects of a long (3-day) versus short (2-day) interdialytic period on arterial elasticity in HD patients. METHODS: Seventy ESRD patients receiving standard HD three times per week were studied at the start and end of a 3-day and a 2-day interdialytic interval. At each time point, applanation tonometry of peripheral arteries was performed to assess arterial stiffness and wave reflection parameters. Aortic and brachial pulse wave velocities (PWV) were recorded as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflections. RESULTS: AIx, heart-rate-adjusted AIx and augmentation pressure were significantly increased during both interdialytic intervals, whereas aortic and brachial PWVs remained unchanged. The interdialytic increases in all the three AIx parameters were significantly higher during the 3-day interval in comparison to the 2-day interval (P < 0.001 for all comparisons). In contrast, no significant differences in interdialytic changes of aortic (P = 0.355) and brachial (P = 0.319) PWVs were noted between the two intervals. Mixed linear model analysis revealed that central aortic systolic blood pressure (SBP) and body weight, but not aortic or brachial PWV, were independent determinants of the change in heart-rate-adjusted AIx throughout the study. CONCLUSIONS: AIx is increased between HD sessions, whereas arterial elasticity is not. This interdialytic increase in central wave augmentation is more pronounced during the 3-day interval, suggesting a mechanism possibly involved in the elevated cardiovascular risk of HD patients at this time point.

Effects of low-dose atorvastatin on arterial stiffness and central aortic pressure augmentation in patients with hypertension and hypercholesterolemia.

BACKGROUND: Experimental and clinical data suggest that statins exert anti-inflammatory and antiproliferative actions on vasculature beyond their lipid-lowering properties. Whether these pleiotropic effects of statins translate into a beneficial effect on arterial stiffness is not clear. This study aimed to evaluate the potential effects of low-dose atorvastatin treatment on arterial stiffness and central arterial pressure waveforms in patients with mild hypertension and hypercholesterolemia. METHODS: In a double-blind, randomized, placebo-controlled fashion, 50 hypertensive and hypercholesterolemic patients were allocated to receive 10 mg of atorvastatin or placebo for 26 weeks. Arterial stiffness was assessed by aortic pulse-wave velocity (PWV) using a Sphygmocor device. Central arterial pressure waveform parameters were estimated by radial artery applanation tonometry. Heart rate-adjusted augmentation index (AIx(75)) was used as measure of wave reflections. RESULTS: At study end, aortic PWV (9.0 ± 1.5 vs. 10.9 ± 2.6 m/sec; P < 0.001) and AIx(75) (24.9% ± 9.7% vs 28.8% ± 11.8%; P < 0.001) were significantly lower in the atorvastatin group than that placebo group. Furthermore, decreases in central aortic systolic blood pressure and pulse pressure were evident at study-end with atorvastatin but not with placebo (130 ± 8 vs. 138 ± 6 mm Hg, P < 0.001; 48 ± 7 vs. 53 ± 6 mm Hg, P < 0.05, respectively). Atorvastatin-induced reductions in aortic PWV during follow-up showed significant associations with changes in AIx(75) and central aortic systolic blood pressure and pulse pressure. CONCLUSIONS: This study shows that low-dose atorvastatin treatment improves arterial stiffness and exerts a reduction on central aortic pressures. These effects may represent a potential mechanism of cardiovascular risk reduction observed with statin use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Database Identifier Number: NCT01126684.

The effect of antihypertensive drugs on chronic kidney disease: a comprehensive review.

Data from randomized clinical trials and epidemiological evidence identify systemic hypertension as the second most common modifiable risk factor for chronic kidney disease (CKD) progression after diabetes mellitus. CKD may progress silently over the years and early diagnosis and control of hypertension is of major importance in delaying renal function decline. Recent guidelines for the treatment of hypertension suggest the use of a variety of antihypertensive drugs in order to achieve the desired blood pressure levels. Renin-angiotensin system inhibitors have been undoubtedly studied the most and are suggested by guidelines and experts as first choice in patients with hypertension and renal injury, particularly in those with diabetes, as they have repeatedly shown to significantly reduce proteinuria. Other classes of antihypertensive drugs have been studied to a lesser extent and they have their own unique properties and effects. However, it is now common knowledge that adequate blood pressure control is the most important factor for the preservation of renal function, so every drug that effectively lowers hypertension is believed to be renoprotective. The present article will review the latest data on the role and properties of each class of antihypertensive drugs on CKD.

Hypertension and symptomatic hypokalemia in a patient with simultaneous unilateral stenoses of intrarenal arteries and mesangioproliferative glomerulonephritis.

We present the case of a young patient with hypertension and unprovoked symptomatic hypokalemia. His workup uncovered secondary aldosteronism, moderate proteinuria, and, quite unusually, concurrent chronic hepatitis B. Detailed investigations, including renal angiography, renal vein sampling, and kidney biopsy, showed unilateral renin hypersecretion due to intrarenal arterial stenoses and mesangioproliferative glomerulonephritis, presumed to be secondary to hepatitis B infection. Targeted pharmacotherapy reversed all clinical manifestations, normalizing blood pressure and serum potassium level and achieving full remission of proteinuria and loss of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and a dramatic decrease in viral load.

Hemodialysis reduces augmentation index but not aortic or brachial pulse wave velocity in dialysis-requiring patients.

BACKGROUND/AIMS: Arterial stiffening characterizes the vasculature of end-stage renal disease (ESRD) patients and is a strong predictor of their cardiovascular morbidity and mortality. Previous studies evaluating the effect of hemodialysis on large artery elasticity gave contradictory results. This study aimed to investigate the impact of hemodialysis on arterial stiffness and wave reflections on chronic hemodialysis patients. METHODS: A total of 51 stable ESRD patients on maintenance hemodialysis were evaluated before and after the first and second dialysis session of the week. Arterial stiffness was assessed by measuring aortic and brachial pulse wave velocity (PWV). Central arterial pressure waveform parameters were estimated by radial artery applanation tonometry. Heart rate-adjusted augmentation index [AIx(75)] was used as measure of wave reflections. RESULTS: During both dialysis sessions systolic blood pressure (SBP) and pulse pressure (PP) at brachial artery and central aorta were reduced. AIx(75) was decreased in first and second weekly dialysis session (27.5 ± 1.2 vs. 21.0 ± 1.5, p < 0.001 and 24.7 ± 1.2 vs. 20.5 ± 1.5, p < 0.001, respectively). In contrast, aortic and brachial PWV remained unchanged during both dialysis sessions. Changes in AIx(75) during hemodialysis were associated with changes in central aortic SBP, PP and ejection duration. CONCLUSIONS: This study shows that hemodialysis does not acutely affect arterial stiffness, but reduces wave reflections from periphery. This dissociation between effects of hemodialysis on PWV and AIx(75) may reflect differential impact on large and small branches of the arterial tree.

PPAR-γ agonism for cardiovascular and renal protection.

Diabetes mellitus is an established risk factor for cardiovascular disease and the leading cause of end-stage renal disease in the Western World. Thiazolidinediones (TZDs) represent a class of antidiabetic agents that exert their glucose-lowering effects by reducing insulin resistance, through stimulation of a type of nuclear receptor, called peroxisome proliferator-activated receptor-γ. Apart from improving glycemic control, TZDs were shown to exert beneficial effects on several components of the metabolic syndrome and cardiovascular risk markers. Furthermore, background and human studies have shown that TZDs reduce urinary albumin and protein excretion and interfere with most of the pathogenentic pathways involved in the development and progression of diabetic nephropathy. On the other hand, currently used TZDs have side effects, most important of which is fluid retention leading to wait gain and heart failure deterioration. With regards to cardiovascular outcomes, the anticipated benefit of TZDs was demonstrated for pioglitazone, whereas a series of previous meta-analyses linking rosiglitazone treatment with increased risk of myocardial infarction and cardiovascular death raised uncertainty around the cardiovascular safety of rosiglitazone. This article will discuss the effects of TZDs on established and emerging cardiovascular risk factors, the data on possible beneficial renal effects of these compounds, and the existing evidence from large-scale clinical trials and meta-analyses on their effects on cardiovascular outcomes, aiming to provide an overview of the cardio- and renoprotective properties of these drugs.

Effect of hospitalization on 24-h ambulatory blood pressure of hypertensive patients.

The aim of this study is to assess the effect of hospital admission on 24-h ambulatory blood pressure (ABP) in hypertensive subjects. Treated or untreated hypertensive adults with open-angle glaucoma underwent inpatient and outpatient 24-h ABP monitoring in a random order 4 weeks apart. Awake ambulatory hours, awake in-bed hours and sleep hours were reported by participants. The nighttime-to-daytime ABP dip (%) and the sleeping-to-awake dip (ambulatory and in-bed) were determined using the two ABP recordings. A total of 40 subjects were analyzed (mean age 65.7 ± 8.4 (s.d.) years, n=19 men). Daytime systolic BP (SBP) was lower in the hospital than in the outpatient setting (mean difference 4.3 ± 10.4 mm Hg, P=0.01), as was the awake ambulatory SBP (mean difference 5.0 ± 11.1 mm Hg, P=0.008). No differences were detected in 24 h, nighttime or sleeping SBP or in any of the respective diastolic outpatient vs. inpatient ABP measurements. The nighttime SBP dip (vs. daytime) was larger in the outpatient setting (8.9 ± 7.5% and 5.2 ± 4.7%, respectively; P=0.003). Sleeping SBP dip (vs. awake ambulatory and awake in-bed) was also larger in the outpatient setting (11.1 ± 7.3 and 7.8 ± 5.9%, respectively; P=0.02) with no difference in diastolic ABP. These data suggest that inpatient 24-h ABP monitoring does not reflect the usual BP level during routine daily life, nor does it represent the usual diurnal pattern of an individual. Relying on the 24-h ABP monitoring performed in the hospital environment may lead to an underestimation of ABP and an overdiagnosis of non-dippers. Therefore, 24-h ABP monitoring for decision making regarding diagnosis and treatment of hypertension should be performed only in the routine daily conditions of each individual.

Beneficial effects of oral magnesium supplementation on insulin sensitivity and serum lipid profile.

BACKGROUND: Epidemiological studies have associated low dietary Mg2+ intake with insulin resistance (IR) and increased risk for metabolic syndrome; however, the effect of Mg2+ supplementation on IR has not been adequately investigated. This study aimed to investigate the effects of oral Mg2+ supplementation on insulin sensitivity (IS) and serum lipids.
MATERIAL/METHODS: Forty-eight patients with mild uncomplicated hypertension participated in the study. Among them, 24 subjects were assigned to 600 mg of pidolate Mg2+ daily in addition to lifestyle recommendations for a 12-week period, and another 24 age- and sex-matched controls were only given lifestyle recommendations. At baseline and study-end, blood sampling for determination of fasting glucose and insulin levels, serum lipids and other standard laboratory tests, as well as an oral glucose tolerance test (OGTT) for estimation of IS indices, were performed in all subjects.
RESULTS: In the Mg2+ supplementation group the OGTT-derived IS indices of Stumvoll, Matsuda and Cedercholm in were increased between baseline baseline and study-end. In contrast, none of these parameters were changed in the control group. Reductions in total cholesterol, LDL-cholesterol and triglyceride levels, along with a parallel increase in HDL-cholesterol levels, were evident at study-end in the intervention group, but not in the control group.
CONCLUSIONS: This study suggests that oral Mg2+ supplementation improves IS and lipid profile in mildly hypertensive patients. These potential beneficial effects of Mg2+ on associated metabolic factors could be helpful for patients with hypertension in terms of overall cardiovascular risk reduction.

Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy.

IMPORTANCE OF THE FIELD: As with all potent therapeutic agents, the use of diuretic compounds has been linked with several adverse effects that may reduce quality of life and patient compliance and, in some cases, may be associated with considerable morbidity and mortality. Among the various types of adverse effects, disturbances of electrolyte and acid-base balance are perhaps the most common, and some of them are the aetiological factors of other side effects (i.e., hypokalaemia causing ventricular arrhythmias or glucose intolerance). The mechanism and site of action and, therefore, the pharmacological effects of each diuretic class largely determine the specific electrolyte or acid-base abnormalities that will accompany the use of each diuretic agent. AREAS COVERED IN THE REVIEW: This article reviews the major electrolyte disturbances (hypokalaemia, hyperkalaemia, hyponatraemia, disorders of magnesium and calcium balance), as well as the acid-base abnormalities complicating the use of the various diuretic agents. WHAT THE READER WILL GAIN: The reader will gain insights into the pathogenesis of the diuretic-induced electrolyte and acid-base disorders together with considerations for their prevention and treatment. TAKE HOME MESSAGE: Knowledge of the pharmacologic properties of each diuretic class and appropriate monitoring of patients under diuretic treatment represent the most important strategies to prevent the development of diuretic-related adverse events and their consequences.

Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds.

IMPORTANCE OF THE FIELD: Diuretics are among the most important drugs of our therapeutic armamentarium and have been broadly used for > 50 years, providing important help towards the treatment of several diseases. Although all diuretics act primarily by impairing sodium reabsorption in the renal tubules, they differ in their mechanism and site of action and, therefore, in their specific pharmacological properties and clinical indications. Loop diuretics are mainly used for oedematous disorders (i.e., cardiac failure, nephrotic syndrome) and for blood pressure and volume control in renal disease; thiazides and related agents are among the most prescribed drugs for hypertension treatment; aldosterone-blockers are traditionally used for primary or secondary aldosteronism; and other diuretic classes have more specific indications. AREAS COVERED IN THIS REVIEW: This article discusses the mechanisms of action, pharmacological effects and clinical indications of the various diuretic classes used in everyday clinical practice, with emphasis on recent knowledge suggesting beneficial effects of certain diuretics on clinical conditions distinct from the traditional indications of these drugs (i.e., heart protection for aldosterone blockers). WHAT THE READER WILL GAIN: Reader will gain insights into the effective use of diuretic agents for various medical conditions, representing their established or emerging therapeutic indications. TAKE HOME MESSAGE: Knowledge of the pharmacologic properties and mechanisms of action of diuretic agents is a prerequisite for the successful choice and effective clinical use of these compounds.

Effect of thiazolidinediones on albuminuria and proteinuria in diabetes: a meta-analysis.

BACKGROUND: Because of the major clinical and economic burden of diabetic nephropathy, new therapeutic tools to delay its progression are needed. Recent studies suggest that thiazolidinediones have renal benefits. We aimed to evaluate the effect of thiazolidinediones on urinary albumin and protein excretion in patients with diabetes mellitus. STUDY DESIGN: Systematic review and meta-analysis by searching MEDLINE/PubMed, EMBASE, and Cochrane CENTRAL databases (1991 to September 2009). SETTING & POPULATION: Patients with diabetes mellitus. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials. INTERVENTION: Thiazolidinediones (rosiglitazone and pioglitazone) compared with placebo or other antidiabetic agents. OUTCOMES: Weighted (WMDs) and standardized mean differences (SMDs) for changes in urine albumin or protein excretion between the thiazolidinedione and control groups. RESULTS: Of 171 originally identified articles, 15 studies (5 with rosiglitazone and 10 with pioglitazone) involving 2,860 patients were included in the analysis. In participants with baseline normo- or microalbuminuria, the WMD of proportional changes between the thiazolidinedione and control groups in urinary albumin excretion measured using time-specified collections was -64.8% (95% CI, -75.6 to -53.9) and the WMD of changes in albumin-creatinine ratio was -24.8% (95% CI, -39.6 to -10.0). Overall, in participants with normo- and microalbuminuria, thiazolidinedione treatment was associated with a significant decrease in urinary albumin excretion (SMD, -0.6 units of standard deviation [SD]; 95% CI, -0.8 to -0.4). Similarly, thiazolidinediones were associated with a significant decrease in urinary protein excretion in patients with proteinuria (SMD, -1.1 units of SD; 95% CI, -1.8 to -0.4). LIMITATIONS: Significant heterogeneity across included studies in several subgroup analyses; patient-level data not available. CONCLUSIONS: Treatment with thiazolidinediones significantly decreases urinary albumin and protein excretion in patients with diabetes. This finding calls for clinical trials with hard renal outcomes to elucidate the potential benefits of thiazolidinediones on diabetic nephropathy.

Oral calcium supplementation ambulatory blood pressure and relation to changes in intracellular ions and sodium-hydrogen exchange.

BACKGROUND: Calcium (Ca2+) supplementation has been shown paradoxically to reduce intracellular Ca2+ and induce vascular relaxation. The aim of the study was to assess 24-h blood pressure (BP) change after Ca2+ supplementation and to investigate its relation to changes in intracellular ions and the activity of the first isoform of sodium-hydrogen exchange (NHE-1) in subjects with hypertension and type 2 diabetes. METHODS: This parallel, randomized controlled, single-blinded trial, consisted of 31 patients with type 2 diabetes, and hypertension who were allocated to receive 1,500 mg of Ca2+ per day (n = 15) or no treatment (n = 16) for 8 weeks. RESULTS: In the Ca2+ group a decrease of 1.7 +/- 2.7 mm Hg (mean +/- SE) P = 0.52 for mean 24-h systolic BP (SBP) and 2.1 +/- 1.5 mm Hg, P = 0.19 for mean 24-h diastolic BP (DBP) was recorded. Whereas in the control group an increase of 1.4 +/- 2.7 mm Hg, P = 0.59 for mean 24-h SBP and 1.2 +/- 2.8 mm Hg, P = 0.83 for mean 24-h DBP was observed. Intraplatelet Ca2+ decreased whereas intraplatelet magnesium (Mg2+) and erythrocyte K+ increased in the intervention group. Change in mean 24-h SBP in the pooled group correlated with both change in intraplatelet Ca2+ (r = 0.49, P < 0.05) and NHE-1 activity (r = 0.6, P < 0.001). The contribution of intraplatelet Ca2+ was attenuated when both parameters were entered in a multivariate regression model. CONCLUSIONS: The present study shows a weak, statistically nonsignificant trend towards association of Ca2+ supplementation on 24-h BP in hypertensive subjects with type 2 diabetes. However, our results indicated an interrelation of [Ca2+]i levels and NHE-1 activity on BP in patients with hypertension and type 2 diabetes.

Oral magnesium supplementation reduces ambulatory blood pressure in patients with mild hypertension.

BACKGROUND: Accumulating evidence implicates a role of Mg(2+) in the pathophysiology of essential hypertension. Previous studies evaluating the antihypertensive efficacy of Mg(2+) supplementation gave contradictory results. This study aimed to investigate the effect of oral Mg(2+) supplementation on 24-h blood pressure (BP) and intracellular ion status in patients with mild hypertension. METHODS: A total of 48 patients with mild uncomplicated hypertension participated in the study. Among them, 24 subjects were assigned to 600 mg of pidolate Mg(2+) daily in addition to lifestyle recommendations for a 12-week period and another 24 age- and sex-matched controls were only given lifestyle recommendations. At baseline and study-end (12 weeks) ambulatory BP monitoring, determination of serum and intracellular ion levels, and 24-h urinary collections for determination of urinary Mg(2+) were performed in all study subjects. RESULTS: In the Mg(2+) supplementation group, small but significant reductions in mean 24-h systolic and diastolic BP levels were observed, in contrast to control group (-5.6 +/- 2.7 vs. -1.3 +/- 2.4 mm Hg, P < 0.001 and -2.8 +/- 1.8 vs. -1 +/- 1.2 mm Hg, P = 0.002, respectively). These effects of Mg(2+) supplementation were consistent in both daytime and night-time periods. Serum Mg(2+) levels and urinary Mg(2+) excretion were significantly increased in the intervention group. Intracellular Mg(2+) and K(+) levels were also increased, while intracellular Ca(2+) and Na(+) levels were decreased in the intervention group. None of the intracellular ions were significantly changed in the control group. CONCLUSION: This study suggests that oral Mg(2+) supplementation is associated with small but consistent ambulatory BP reduction in patients with mild hypertension.

The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality.

Cardiovascular morbidity and mortality in patients with type 2 diabetes are a major problem in clinical practice. Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated receptor gamma which improve glycaemic control by reducing insulin resistance. TZDs also seem to have beneficial effects on various cardiovascular risk factors and consequently may have the potential to reduce the risk of cardiovascular disease (CVD). Although the first large-scale clinical trial evaluating the effect of a TZD on secondary prevention of major adverse cardiovascular outcomes supported this hypothesis, a recently published meta-analysis raised substantial uncertainty about the cardiovascular safety of rosiglitazone. This article summarises the evidence from completed and ongoing outcome trials with TZDs, as well as the recent meta-analytic data on their cardiovascular safety, aiming to provide an up-to-date and balanced view of a very important field. Data from clinical trials consistently indicate that treatment with glitazones significantly increase the risk of heart failure. Despite the fact that rosiglitazone and pioglitazone have much more similarities than differences with regards to their effects on cardiovascular risk factors, pioglitazone seems to have more favourable effects on major cardiovascular outcomes. This issue also highlights the potential hazards involved in using surrogate end-points for drug approval.