Hypertension and nephrology

[Direct renin inhibitors]

FARSANG Csaba

FEBRUARY 28, 2011

Hypertension and nephrology - 2011;15(01)

[The mechanisms of action of direct renin inhibitors and the important clinical findings gained by the first, clinically approved drug, aliskiren are discussed. The relative lack of side effects and the very long-lasting antihypertensive action of aliskiren is emphasized. Investigations showing efficacy and protective effects of aliskiren and its combinations with other antihypertensive drugs (diuretics, calcium antagonists, angiotensin converting enzyme inhibitors, angiotensin receptor blockers) against hypertension-induced subclinical organ damage as well as still ongoing clinical trials are also described.]

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[It is well known, that there is a difference between peripheral and central systolic and pulse pressure. As the pressure wave travels distally from the heart, there is a significant increase, which is called pressure amplification. Central blood pressure can be measured easily and non-invasively, and the result shows a positive correlation with cardiovascular end-points. Several antihypertensive drugs can differently decrease central and peripheral blood pressure. The effect of diuretics on central systolic and pulse pressure is neutral or negative. While traditional β-blockers (e.g. atenolol) have a definitive negative effect, nebivolol shows a positive one. The calcium antagonists tend to have a favorable effect, while the clear beneficial effect of the angiotensin converting enzime inhibitors is well documented. There are only few data on angiotensin receptor blockers, however, the results seem to be promising.]

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[The clinical significance of peripheral and central blood pressure form the neurologist’s point of view]

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[Hypertension - affecting both the large and the small cerebral vessels - is the most frequent risk factor for cerebrovascular disorders manifesting in stroke, hypertensive encephalopathy or vascular dementia. The central pressure measured at the proximal part of the aorta has more important role in the development of vascular hypertrophy and carotid atherosclerosis than the pressure measured in the brachial artery. Central aortic pressure more accurately reflects the filling conditions of the left ventricle and thus the pressure conditions affecting the cerebral vascular system, than brachial pressure values, therefore possibly predicts more reliably the risk of cardiovascular events than brachial pressure values. Features of the stiffness of large arteries (like pulse wave velocity) more directly reflect the chronic effect of ageing, hypertension and diabetes than brachial or even central aortic pressure. Therefore in upcoming clinical trials arterial stiffness and central aortic pressure should be considered as possible surrogate endpoints. Antihypertensive treatment is an important part of primary and secondary stroke prevention. Decreasing blood pressure in hypertensive subjects significantly decreases the risk of stroke and other vascular events, and the extent of risk reduction primarily depends on the extent of the decrease in blood pressure. Several factors should be considered when choosing from treatment options. The use of traditional β blockers - partly due to their smaller effects on central blood pressure - decreased recently. Further observations will decide on the role of third generation β blockers in the prevention of cardiovascular mortality and morbidity.]

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[Annual citations in the PubMed database on vitamin D were approximately 5000, this represents a doubling in the last decade and a 20% increase in the last year. There is renewed interest in vitamin D synthesis, metabolism and action. The two principal reasons for increased interest can be: 1. new knowledge regarding the nonhormonal, autocrine, and paracrine actions of 1,25-dihydroxylated vitamin D metabolites in man, 2. the worsening, worldwide trend to vitamin D insufficiency. Clinical vitamin D research in last years has confirmed the presence of a worldwide problem of vitamin D depletion, a problem that appears to be worsening. Largescale population based studies bear out long-held concerns that low serum 25(OH)D levels are associated with a number of adverse outcomes in the human musculoskeletal, innate immune, and cardiovascular systems. In fact, low vitamin D levels are significantly associated with all-cause mortality in the U.S. population and Hungary respectively. It is hypothesized that the global rise in incidence of obesity contributes to the worsening of the problem of vitamin D deficiency, amplifying adverse impacts on the host skeleton, immunoreactivity to microbes, and metabolic status. Finally, it should be remembered that treatment of vitamin D deficiency has two phases: restoration of 25(OH)D levels up to more than 30 ng/ml; and maintenance of the serum 25(OH)D level in that range. The present upper level (UL) of vitamin D intake that is deemed to be safe (2000 IU/day) must be re-evaluated considering data acquired over the past 15 years.]

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[Epithelial-mesenchymal transition (EMT) plays a central role in physiological and pathological processes of embryogenesis, carcinogenesis and tissue fibrosis. During EMT epithelial cells may transform to myofibroblasts, which are the effector cells of fibrosis. In our summary the process of EMT and its medical importance will be reviewed in relation to renal fibrosis. Regardless of the initiating cause the final common mechanism of organ fibrosis is similar in the different chronic renal diseases. It always involves major inflammatory responses, however the molecular mechanisms involved are still elusive. The EMT now takes centre stage as the point of convergence between inflammation and the progression of degenerative fibrotic diseases. Understanding the pathomechanism of EMT and the significance of signalling pathways involved in this process may lead to a new therapeutic approach in the treatment of chronic renal diseases.]

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[INTRODUCTION - International and Hungarian (JNC-7, ESH/ESC2007 és 2009, MHT 2009) Guidelines suggest a target blood pressure <140/90 mmHg for hypertensive patients, and <130/80 mmHg for those with high/very high cardiovascular risk (e.g. patients with diabetes mellitus, chronic renal disease). It was proved that for achieving the most efficient antihypertensive effect and reducing side effects, thd use of drug combinations is needed in most patients. In Hungary, ACE-inhibitor plus diuretic combination is one of the most frequently used one in Hungary. The aim of the PICASSO study was to evaluate the efficacy and metabolic effects of the fixed combination of high-dose perindopril plus indapamide (Coverex-AS Komb Forte®) in clinical practice of hypertonologists, cardiologists and general practicioners. PATIENTS AND METHODS - Patients with uncontrolled, grade 1 or 2 primary hypertension, age, >18years were involved in the open, 3-month, multicentre, prospective, observational, non-interventional clinical study if the treating physician indicated a combination treatment with higher dose antihypertensive drugs. Blood pressure (also with ABPM), heart rate, metabolic parameters (plasma lipids, blood sugar, Na, K, creatinine, uric acid, GGT) were measured by routine methods, medical history and quality of life parameters were registered on a validated questionnaire. Changes in the above parameters were also separately evaluated in patients with different risk factors or with concomitant diseases. RESULTS - Data of 9683 patients were evaluated (54% women, 46% men, average age 61.8 years). By the end of the therapy used in the study, blood pressure average decreased from 159/93 to 131/80, by ABPM from 145/83 to 126/74 mmHg (24hr averages, systolic/diastolic blood pressure, respectively), the heart rate from 79 to 73 beats/min (p<0,001). Target blood pressure was achieved in 75,4% of patients with no major concomitant disease, but only in 14% of those with a concomitant disease characterised by lower target blood pressure. The diurnal index by ABPM did not change substantially. Clinically significant decreases were found in the plasma levels of total cholesterol, LDL-cholesterol, triglycerides, fasting glucose and uric acid levels, but there were no major changes in serum levels of HDL-cholesterol, Na, K, and GGT. Quality of life parameters significantly improved by the end of the study. CONCLUSIONS - Combinations of perindopril and indapamide can be successfully and safely used in everyday practice.]

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[Perindopril plus Indapamid CombinAtion blood preSSure reductiOn study (PICASSO)]

[INTRODUCTION - International and Hungarian (JNC-7, ESH/ESC2007 és 2009, MHT 2009) Guidelines suggest a target blood pressure <140/90 mmHg for hypertensive patients, and <130/80 mmHg for those with high/very high cardiovascular risk (e.g. patients with diabetes mellitus, chronic renal disease). It was proved that for achieving the most efficient antihypertensive effect and reducing side effects, thd use of drug combinations is needed in most patients. In Hungary, ACE-inhibitor plus diuretic combination is one of the most frequently used one in Hungary. The vérnyomáscsökaim of the PICASSO study was to evaluate the efficacy and metabolic effects of the fixed combination of high-dose perindopril plus indapamide (Coverex-AS Komb Forte®) in clinical practice of hypertonologists, cardiologists and general practicioners. PATIENTS AND METHODS - Patients with uncontrolled, grade 1 or 2 primary hypertension, age, >18 years were involved in the open, 3-month, multicentre, prospective, observational, non-interventional clinical study if the treating physician indicated a combination treatment with higher dose antihypertensive drugs. Blood pressure (also with ABPM), heart rate, metabolic parameters (plasma lipids, blood sugar, Na, K, creatinine, uric acid, GGT) were measured by routine methods, medical history and quality of life parameters were registered on a validated questionnaire. Changes in the above parameters were also separately evaluated in patients with different risk factors or with concomitant diseases. RESULTS - Data of 9683 patients were evaluated (54% women, 46% men, average age 61.8 years). By the end of the therapy used in the study, blood pressure average decreased from 159/93 to 131/80, by ABPM from 145/83 to 126/74 mmHg (24hr averages, systolic/diastolic blood pressure, respectively), the heart rate from 79 to 73 beats/min (p<0,001). Target blood pressure was achieved in 75,4% of patients with no major concomitant disease, but only in 14% of those with a concomitant disease characterised by lower target blood pressure. The diurnal index by ABPM did not change substantially. Clinically significant decreases were found in the plasma levels of total cholesterol, LDL-cholesterol, triglycerides, fasting glucose and uric acid levels, but there were no major changes in serum levels of HDLcholesterol, Na, K, and GGT. Quality of life parameters significantly improved by the end of the study. CONCLUSIONS - Combinations of perindopril and indapamide can be successfully and safely used in everyday practice.]