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

Association of antihypertensive monotherapy with serum sodium and potassium levels in Chinese patients

<b>Background</b> International guidelines on management of hypertension recommend any major classes of antihypertensive drugs. However, the low prescribing rate of thiazides has been attributed to concerns about electrolyte disturbances and studies between antihypertensive drug classes and hyponatremia/hypokalemia among Chinese patients were scarce. <p></p> <b>Methods</b> From clinical databases we included 2,759 patients who received their first-ever antihypertensive monotherapy from January 2004 to June 2007 in a large territory of Hong Kong. We studied the plasma sodium and potassium levels 8 weeks after prescriptions and factors associated with hyponatremia and hypokalemia by multivariable regression analyses. <p></p> <b>Results</b> Among major antihypertensive drug classes, thiazide users had the lowest sodium level (139.6 mEq/l, 95% confidence interval (CI) 139.3, 140.0, P < 0.001) and patients-prescribed calcium channel blockers (CCBs; 3.92 mEq/l, 95% CI 3.89, 3.95) or thiazide diuretics (3.99 mEq/l, 95% CI 3.93, 4.04) had the lowest potassium levels (P < 0.001). Multivariate analysis reported that advanced age (>/=70 years, odds ratio (OR) 7.49, 95% CI 2.84, 19.8, P < 0.001), male gender (OR 2.38, 95% CI 1.45, 3.91, P < 0.001), and thiazide users (OR 2.42, 95% CI 1.29, 4.56, P = 0.006) were significantly associated with hyponatremia, while renin-angiotensin system (RAS) (OR 0.31, 95% CI 0.13, 0.73, P = 0.008) and beta-blockers (BBs) (OR 0.35, 95% CI 0.23, 0.54, P < 0.001) users were less likely to present with hypokalemia. However, the proportions having normonatremic (95.1%) and normokalemic (89.4%) levels were high. <p></p> <b>Conclusions</b> In view of the low prevalence of hyponatremia and hypokalemia associated with thiazides, physicians should not be deterred from prescribing thiazide diuretics as first-line antihypertensive agents as recommended by most international guidelines

Anti-diabetic effect of a preparation of vitamins, minerals and trace elements in diabetic rats: a gender difference

BACKGROUND: Although multivitamin products are widely used as dietary supplements to maintain health or as special medical food in certain diseases, the effects of these products were not investigated in diabetes mellitus, a major cardiovascular risk factor. Therefore, here we investigated if a preparation of different minerals, vitamins, and trace elements (MVT) for human use affects the severity of experimental diabetes. METHODS: Two days old neonatal Wistar rats from both genders were injected with 100 mg/kg of streptozotocin or its vehicle to induce diabetes. At week 4, rats were fed with an MVT preparation or vehicle for 8 weeks. Well established diagnostic parameters of diabetes, i.e. fasting blood glucose and oral glucose tolerance test were performed at week 4, 8 and 12. Moreover, serum insulin and blood HbA1c were measured at week 12. RESULTS: An impaired glucose tolerance has been found in streptozotocin-treated rats in both genders at week 4. In males, fasting blood glucose and HbA1c were significantly increased and glucose tolerance and serum insulin was decreased at week 12 in the vehicle-treated diabetic group as compared to the vehicle-treated non-diabetic group. All of the diagnostic parameters of diabetes were significantly improved by MVT treatment in male rats. In females, streptozotocin treatment resulted in a less severe prediabetic-like phenotype as only glucose tolerance and HbA1c were altered by the end of the study in the vehicle-treated diabetic group as compared to the vehicle-treated non-diabetic group. MVT treatment failed to improve the diagnostic parameters of diabetes in female streptozotocin-treated rats. CONCLUSION: This is the first demonstration that MVT significantly attenuates the progression of diabetes in male rats with chronic experimental diabetes. Moreover, we have confirmed that females are less sensitive to STZ-induced diabetes and MVT preparation did not show protection against prediabetic state. This may suggest a gender difference in the pathogenesis of diabetes

Suppression of SIRT1 in Diabetic Conditions Induces Osteogenic Differentiation of Human Vascular Smooth Muscle Cells via RUNX2 Signalling

Vascular calcification is associated with significant morbidity and mortality within diabetes, involving activation of osteogenic regulators and transcription factors. Recent evidence demonstrates the beneficial role of Sirtuin 1 (SIRT1), an NAD+ dependant deacetylase, in improved insulin sensitivity and glucose homeostasis, linking hyperglycaemia and SIRT1 downregulation. This study aimed to determine the role of SIRT1 in vascular smooth muscle cell (vSMC) calcification within the diabetic environment. An 80% reduction in SIRT1 levels was observed in patients with diabetes, both in serum and the arterial smooth muscle layer, whilst both RUNX2 and Osteocalcin levels were elevated. Human vSMCs exposed to hyperglycaemic conditions in vitro demonstrated enhanced calcification, which was positively associated with the induction of cellular senescence, verified by senescence-associated β-galactosidase activity and cell cycle markers p16 and p21. Activation of SIRT1 by SRT1720 reduced Alizarin red staining by a third, via inhibition of the RUNX2 pathway and prevention of senescence. Conversely, inhibition of SIRT1 via Sirtinol and siRNA increased RUNX2 by over 50%. These findings demonstrate the key role that SIRT1 plays in preventing calcification in a diabetic environment, through the inhibition of RUNX2 and senescence pathways, suggesting a downregulation of SIRT1 may be responsible for perpetuating vascular calcification in diabetes

Effects of calcium supplementation on blood pressure insulin resistance and intracellular ions in patients with hypertension and the metabolic syndrome

The aim of the present doctoral study was to investigate the effect of Ca²⁺ supplementation per os in hypertension and insulin resistance (IR) in patients with stage 1 arterial hypertension and type 2 diabetes who met the criteria of the metabolic syndrome. Furthermore, the thesis aimed to investigate the effect of Ca²⁺ supplementation on changes in intracellular Ca²⁺ [Ca²⁺]i and Mg²⁺ [Mg²⁺]i and changes in the activity of the first isoform of the Na⁺-H⁺ exchange, 24 hour urine albumin and 24 hour urine ions, serum electrolytes (Na⁺, K⁺, Ca²⁺, Mg²⁺), total cholesterol, triglycerides, LDL and HDL cholesterol, apolipoprotein A1 (ApoA1) and B (Apo B) and lipoprotein (a) Lp(a), fibrinogen, C-reactive protein (CRP), renal function, uric acid levels, fasting glucose and insulin and glycated haemoglobin (HbA1c), body composition, body weight, and the usual anthropometric indices. The study population consisted of 31 patients with hypertension and type 2 diabetes. All subjects were receiving sulfonylurea for the treatment of diabetes (15mg of glibenclamide) per day. All patients that were included in the study had stage 1, newly diagnosed hypertension and received no antihypertensive treatment.. After completing all these tests, patients were randomized to receive 1500mg elemental Ca²⁺ per os daily (n=15), or nothing (n=16) for 8 weeks. After 8 weeks (two months) of follow-up, participants visited again our laboratory for the repeat of all the above tests. This study yielded a series of important results. At the end of the study, addition of supplementary Ca²⁺ in the intervention group resulted in a significant improvement of IS compared with baseline. In contrast, in the control group IS did not show a significant change. All parameters of the euglycemic clamp increased in the Ca²⁺ group (M-value from 2.51±0.94 to 2.83±0.94 mmol * min-1 P0.05). In contrast, in the control group there was a small, non significant increase of all the above parameters which reached 1.4±2.7 mmHg, (P=0.59), for 24-hour SBP and 1.2±2.8 mmHg, (P=0.83), for 24-hour DBP respectively. Compared with the control group, Ca²⁺ supplementation group showed a significant fall in mean free intraplatelet Ca²⁺ ([Ca²⁺]i) (-44.7±20.0 nmol/L, m±SEΜ, P0,05). Αντίθετα, στην ομάδα ελέγχου, παρατηρήθηκε μία μικρή, μη σημαντική αύξηση των παραπάνω παραμέτρων της τάξης του 1,4±2,7 mmHg, (P=0,59), για την 24ωρη ΣΑΠ και 1,2±2,8 mmHg, (P=0,83), για την 24ωρη ΔΑΠ αντίστοιχα. Σε σύγκριση με την ομάδα ελέγχου, η ομάδα της συμπληρωματικής χορήγησης Ca²⁺ παρουσίασε σημαντική πτώση στη μέση τιμή του ελεύθερου ενδοαιμοπεταλιακού Ca²⁺, ([Ca²⁺]i) (-44,7±20,0 nmol/L, m±SEΜ, P<0,05). Αντίθετα η μέση τιμή του ενδοαιμοπεταλιακού Mg²⁺, ([Mg²⁺]i) στην ομάδα της παρέμβασης παρουσίασε σημαντική άνοδο (259,5±63,2 μmol/L, P<0,05), ενώ δεν μεταβλήθηκε στην ομάδα ελέγχου. Τα παραπάνω ευρήματα υποδηλώνουν έναν μηχανισμό ινσουλινικής αντίστασης, δηλαδή αυτόν της ενδοκυττάριας αύξησης του Ca²⁺, σε υπερτασικούς ασθενείς. Τονίζεται επίσης ο σημαντικός ρόλος της ανταλλαγής Na⁺-H⁺ στην παθοφυσιολογία της υπέρτασης και η αλληλεπίδρασή του με το ενδοκυττάριο Ca²⁺. Η συμπληρωματική χορήγηση Ca²⁺ είναι μία οικονομική παρέμβαση που μπορεί να βελτιώσει την ευαισθησία στην ινσουλίνη σε ασθενείς με σακχαρώδη διαβήτη τύπου 2 και υπέρταση

Can antihypertensive medication interfere with the vicious cycle between hypertension and vascular calcification?

Vascular calcification is a phenomenon of disturbed calcium deposition, as part of the calcium that is supposed to be deposited to our bones, is lodged to our vessels. There are two forms of vascular calcification, each with a distinct anatomical distribution and clinical relevance, namely the intimal and medial calcification. Studies have demonstrated that hypertension may cause vascular calcification but also that both types of calcification, especially medial, promote arterial rigidity and hence hypertension. Implications of this two-way road are largely unknown as there is no consensus yet on their exact clinical value. However, several antihypertensive medications seem to be able to interfere with the cycle of high blood pressure and vascular calcium deposits. The present review summarizes the up-to-date data regarding the effect of antihypertensive medication on vascular calcification

The Role of MicroRNAs in Arterial Stiffness and Arterial Calcification. An Update and Review of the Literature

Arterial stiffness is an independent risk factor for fatal and non-fatal cardiovascular events, such as systolic hypertension, coronary artery disease, stroke, and heart failure. Moreover it reflects arterial aging which in many cases does not coincide with chronological aging, a fact that is in large attributed to genetic factors. In addition to genetic factors, microRNAs (miRNAs) seem to largely affect arterial aging either by advancing or by regressing arterial stiffness. MiRNAs are small RNA molecules, ~22 nucleotides long that can negatively control their target gene expression posttranscriptionally. Pathways that affect main components of stiffness such as fibrosis and calcification seem to be influenced by up or downregulation of specific miRNAs. Identification of this aberrant production of miRNAs can help identify epigenetic changes that can be therapeutic targets for prevention and treatment of vascular diseases. The present review summarizes the specific role of the so far discovered miRNAs that are involved in pathways of arterial stiffness