Clinical and pathogenetic substantiation of the use of the angiotensin II receptor blocker eprosartan in the therapy of chronic glomerulonephritis

The dissertation is devoted to the clinical and pathogenetic substantiation of the use of the angiotensin II receptor blocker eprosartan in patients with chronic glomerulonephritis. The work is aimed at evaluating the effect of long-term eprosartan therapy on arterial hypertension, microcirculation, vasoactive hormone levels, filtration function of the kidneys, proteinuria, functional renal reserve, parameters of electrolyte, purine, lipid and protein metabolism, and hemostasis. The metabolism of connective tissue biopolymers (glycosaminoglycans, hydroxyproline fractions, hyaluronidase activity) as markers of nephrosclerosis and the dynamics of these indicators during treatment are considered separately. A comparative analysis of the effects of eprosartan and the ACE inhibitor enalapril is carried out, and the influence of prolonged therapy on the rate of progression of chronic glomerulonephritis is assessed.

Relevance of the study. The relevance of studying the problem of glomerulonephritis and the unflagging interest of researchers in it is due to the fact that the course of chronic glomerulonephritis (CGN) is inevitably characterized by the development of renal failure and disability at a young age [67,68,78,112,118,125,135,159,238,278]. Among patients with chronic glomerulonephritis, about 90% die from renal failure.

The effectiveness of measures aimed at preventing or slowing the progression of chronic renal failure (CRF) directly depends on the targeted influence on the factors of progression of renal failure, which, according to fundamental studies of clinical pathophysiologists, are associated with the activation of the systemic and/or local renal renin-angiotensin system (RAS) and increased production of the vasoconstrictor hormone angiotensin II (AT II). The main pathophysiological manifestations of the activation of the systemic and local renal RAS are systemic arterial hypertension (AH), intraglomerular hypertension and hyperfiltration, the development and/or increase of pre-existing proteinuria, and the intensification of sclerotic processes in the kidney due to stimulation of proliferative processes [2,10,21,31,37,53,70,81,108,111,134,168,180,257,262]. Given that each of the listed properties of AT II individually, and especially their combination, leads to rapid sclerosis of the kidney and loss of its functions, it becomes obvious that the potential means of protecting the kidney is pharmacological blockade of AT II. At the present stage, this can be achieved through the use of angiotensin-converting enzyme (ACE) inhibitors, the effectiveness of which in slowing the rate of progression of chronic kidney diseases has been repeatedly proven in major multicenter randomized studies (AIPRI, REIN, MDRD, EUCLID, etc.).

AT1-receptor blockers (ARBs) are a relatively new class of antihypertensive drugs that, by selectively blocking AT1-receptors, more completely suppress the RAS and cause significantly fewer side effects characteristic of ACE inhibitors (cough, angioneurotic edema, etc.).

Most clinical studies have been conducted in patients with diabetes mellitus, in which the important role of ACE inhibitors and ARBs in reducing proteinuria and the progression of kidney lesions has been shown. The results of these studies cannot be fully applied to patients with kidney diseases of other etiologies. In patients with nondiabetic hypertensive nephropathy, the question of choosing an antihypertensive drug remains open.

Among the AT1-angiotensin receptor blockers currently available, eprosartan (Teveten®, Solvay Pharma) stands out, which differs from other drugs of this class not only in its chemical structure but also in a number of pharmacodynamic properties that allow this drug to be considered the first representative of a new generation of AT1-receptor blockers [48,60,99,161,177,200,215,268,284,297]. Eprosartan has a unique dual mechanism of action, due to which it controls the activity of the RAS and the sympathoadrenal system (SAS). This property is the main advantage over other drugs of this class. In a number of studies, not only the high clinical efficacy of eprosartan was observed, but also its excellent tolerability compared with ACE inhibitors [20,48,183].

By the present time, a number of studies have been carried out on the antihypertensive effect of eprosartan in patients with essential hypertension [82,140,162,207,248,259,297]. Experimental and clinical data suggest its high efficacy in the treatment of AH, including in patients with CGN. However, it should be noted that, despite the great current interest in eprosartan, data on its use in kidney diseases are scarce and in many respects contradictory, devoted mainly to diabetic nephropathy with an assessment of no more than two or three indicators of renal function. The nephroprotective effect of the drug still remains unproven. It is known that chronic glomerulonephritis is accompanied by destruction of connective tissue [27,44,90,94,141,208,247,291,273]. Given the nature of the pathological process, substantial interest in changes in the metabolism and functional state of the connective tissue system of the body under the influence of pathogenetic therapy with eprosartan is natural. All of the above dictates the need for a more detailed study of the mechanisms of action of eprosartan in the treatment of chronic glomerulonephritis and in preventing the development or slowing of chronic renal failure.

Aim of the study. To evaluate the effectiveness and substantiate the expediency of using the angiotensin II receptor blocker eprosartan in the therapy of chronic glomerulonephritis.

Objectives of the study.

1. To study the antihypertensive effectiveness of eprosartan in the therapy of chronic glomerulonephritis with the syndrome of arterial hypertension using modern approaches to blood pressure monitoring.

2. To evaluate the effect of eprosartan on the functional state of the kidneys, the level of proteinuria, renal hemodynamics, the state of microcirculation, the level of vasoactive hormones, and the lipid, purine, and electrolyte spectrum of blood in the studied category of patients.

3. To carry out a comparative analysis of the effects of the AT1-receptor blocker eprosartan and the ACE inhibitor enalapril on the controlled clinical and functional indicators.

4. To assess the degree of nephrosclerosis, to analyze the possibilities of using tests for determining hyaluronidase activity of blood, fractions of glycosaminoglycans and hydroxyproline in blood and urine, and to study their dynamics under the influence of pathogenetic therapy with eprosartan in CGN patients.

5. To evaluate the effect of prolonged eprosartan therapy on the rate of progression of chronic glomerulonephritis.

Scientific novelty of the work. New data have been obtained on the effect of prolonged administration of eprosartan on the parameters of arterial pressure (AP) in CGN patients. A reliable positive dynamics of 24-hour AP monitoring indicators was established: average 24-hour systolic and diastolic AP, the magnitude of the morning rise and variability of AP, and the time index of arterial hypertension. Normalization of 24-hour AP profiles was observed.

For the first time, the positive effect of eprosartan on the state of the microcirculatory bed and microcirculatory hemodynamics and on the level of vasoactive hormones in CGN patients has been proven.

For the first time in this work, the nephroprotective effect of eprosartan in patients with chronic glomerulonephritis has been proven, and the possibility of improving the functional state of the kidneys has been shown.

For the first time, a natriuretic effect and a tendency toward improvement of the blood lipid spectrum under the influence of prolonged eprosartan therapy were revealed in the studied patients. It was established that in CGN patients combined with hyperuricemia, six-month eprosartan therapy reduces the level of uric acid in blood serum.

For the first time, the advantage of ARBs (eprosartan) over the ACE inhibitor (enalapril) in certain controlled indicators has been established. Eprosartan exerts a more significant antihypertensive effect due to a greater reduction in systolic AP, variability, and morning rise of AP. Eprosartan also has an advantage over enalapril in its effect on the level of vasopressor hormones, the elevated level of uric acid, total serum cholesterol, and the ability to correct microcirculation disorders and intrarenal hemodynamics.

For the first time, the dependence of indicators of connective tissue biopolymer metabolism on the stage of CRF has been established. At the biochemical level, it has been proven that in CGN patients at the preclinical stage of CRF, increased breakdown of endogenous glycosaminoglycans (GAG) and hydroxyproline indicates the formation of renal dysfunctions and the gradual development of nephrosclerosis. For the first time, it has been established that a prolonged course of treatment with eprosartan causes positive changes in the metabolism of glycosaminoglycans and hydroxyproline fractions in blood and urine, and in hyaluronidase activity of blood.

For the first time, the role of eprosartan in slowing the progression of the disease and renal failure in CGN patients has been proven, and the mechanism of this action has been clarified.

Practical significance of the work. The conducted study substantiates the use of eprosartan as a pathogenetic therapy in CGN patients. Eprosartan has a pronounced antihypertensive effect (with respect to systemic and intraglomerular hypertension), an antiproteinuric effect, and slows the rate of disease progression, which determines the need for its use regardless of the initial AP level. The tactics of eprosartan use have been developed, the doses have been substantiated, and the duration of treatment has been established.

Tests for the determination of GAG, hydroxyproline, and hyaluronidase activity can be used for diagnostic purposes to assess the severity of sclerotic processes in renal tissue in chronic glomerulonephritis, including the early preclinical stage of CRF development. The study of connective tissue markers can serve as an additional test in assessing the effectiveness of the therapy being carried out.

Implementation of the results of the work. The results of the work have been introduced into the practical activity of the nephrological department and into the work of the outpatient unit of the nephrological service of the municipal healthcare institution medical and sanitary unit "Izmash", as well as into the treatment process of the nephrological department of RKB No. 1. The materials of the dissertation are used in teaching topics on nephrology in the course of internal diseases at the State Educational Institution of Higher Professional Education "Izhevsk State Medical Academy".

Main propositions put forward for defense.

1. Prolonged therapy with eprosartan in CGN patients contributes to the improvement of AP monitoring indicators, microcirculation, the functional state of the glomerular and tubular apparatus of the kidneys, and intrarenal hemodynamics, exerts a hypolipidemic effect, a natriuretic effect, favorably affects the level of vasoactive hormones and the metabolism of connective tissue biopolymers.

2. Chronic glomerulonephritis is characterized by specific changes in the content of hyaluronidase activity of blood, glycosaminoglycans, and hydroxyproline fractions in blood and urine, which warn of the development of nephrosclerosis earlier than conventional (clinical and laboratory) methods.

3. Long-term therapy with eprosartan, due to its nephroprotective properties, reduces the rate of progression of chronic glomerulonephritis.

Approbation of the work. The main propositions of the work were reported and discussed at the annual international nephrological conference "White Nights" (Saint Petersburg, 2003, 2004); the republican scientific and practical conference with international participation devoted to problems of gerontology and geriatrics (Syktyvkar, 2004); the III Conference of Young Scientists of Russia with international participation, dedicated to the 60th anniversary of the RAMS (Moscow, 2004); the V Scientific Conference of Young Scientists "Postgraduate Readings - 2004" (Samara, 2004); the II, III, IV Interuniversity Scientific Conferences of Young Scientists (Izhevsk, 2002, 2003, 2004); and at meetings of the republican society of nephrologists and therapists.

Publications. On the topic of the dissertation, 12 works have been published, of which 8 are in central press and 1 in peer-reviewed journals of the Higher Attestation Commission.

Volume and structure of the dissertation. The dissertation consists of an introduction, a literature review, a description of materials and methods of the study, three chapters of original research, a conclusion, conclusions, practical recommendations, and a list of references (164 domestic and 137 foreign sources). The dissertation is set out on 180 pages of typewritten text, illustrated with 26 tables and 19 figures.