Influence of arterial hypertension and dyslipidemia on the cardiorenal continuum at the stages of progression of chronic glomerulonephritis

The dissertation is devoted to studying the influence of arterial hypertension and dyslipidemia on the formation of the cardiorenal continuum in patients with chronic glomerulonephritis at different stages of chronic kidney disease. It examines the clinical and functional relationships between impaired renal function, arterial hypertension, dyslipidemia, and the state of the cardiovascular system, including left ventricular hypertrophy and chronic heart failure.

The work evaluates the nephro- and cardioprotective effects of angiotensin-converting enzyme inhibitors and statins, as well as the pleiotropic anti-inflammatory action of simvastatin in patients with chronic glomerulonephritis. The findings are intended to substantiate an integrated approach to the management of patients with combined renal and cardiovascular involvement.

Relevance of the study. At the present stage, chronic glomerulonephritis (CGN) is interpreted as an immune-inflammatory disease with predominant involvement of the glomeruli and involvement of all renal structures, characterized by a wave-like course with an outcome in nephrosclerosis. CGN accounts for up to 71% of cases of terminal chronic renal failure (tCRF). In 1999–2003, CGN occupied the leading place in the structure of causes of tCRF among patients receiving renal replacement therapy [1]. Dialysis helps to extend the lives of patients by an average of 4–5 years [30]. Provision of dialysis treatment is a socio-economic problem, as the number of patients requiring this expensive method of renal replacement therapy is steadily increasing [29]. Therefore, modern nephrology devotes considerable attention to studying the mechanisms of progression of glomerulonephritis [13, 43, 53, 72, 94, 151, 255, 318], as well as to seeking methods of slowing progression [208, 220, 295] that allow lengthening the pre-dialysis period of the disease.

The immune-inflammatory mechanism underlies the activity of CGN and plays an important role in its development and progression [60, 63, 71, 296]. However, CGN also progresses under the influence of non-immune factors, among which arterial hypertension, intraglomerular hypertension, proteinuria, dyslipidemia, and metabolic disorders are of primary importance [19, 52, 165].

It has been proven that one of the leading causes of death among patients on renal replacement therapy is cardiovascular disease, which develops long before the onset of terminal CRF [30, 61]. The risk of death from cardiac and vascular diseases in patients with CRF is 10–15 times higher than in the general population. Numerous risk factors for the progression of renal disease and cardiovascular disease are shared. Thus, the formation and development of cardiovascular disease and the progression of renal disease are in direct and parallel relationship. The so-called cardiovascular continuum is formed [30], later termed the cardiorenal continuum [67]. Therefore, patients suffering from chronic kidney disease require an integrated approach in terms of studying the patterns of development, assessing the progression of renal and cardiovascular diseases, and the principles of therapy, which will substantially improve the prognosis.

Aim of the study. To investigate the patterns of formation of the cardiorenal continuum in patients with chronic glomerulonephritis at the stages of progression of chronic kidney disease under the influence of arterial hypertension, dyslipidemia, and impaired renal function, and to substantiate methods of cardio- and nephroprotection.

Objectives of the study.

1. To investigate the influence of arterial hypertension and hyperlipidemia on renal function in CGN patients at the stages of CKD progression.

2. To evaluate the state of the cardiovascular system in CGN patients under the influence of AH and HLP at the stages of disease progression.

3. To study the influence of the factors of AH, HLP, and impaired renal function on the patterns of CGN progression and left ventricular remodeling.

4. To analyze the cardio- and nephroprotective effects of ACE inhibitors and statins in CGN patients.

5. To study the pleiotropic action of simvastatin in CGN patients.

Scientific novelty of the work.

For the first time, the features of the clinical and functional manifestations of the cardiorenal continuum at the stages of CKD progression have been studied in CGN patients. The influence of AH, HLP, and CGN progression on the formation of left ventricular hypertrophy (LVH) has been revealed. For the first time, the development of diastolic chronic heart failure (CHF) at early CKD stages has been demonstrated, independently of the presence of AH, LVH, and ischemic heart disease (IHD), as well as the aggravation of CHF as CGN progresses under the influence of AH. The frequency and structure of cardiovascular diseases in CGN patients at CKD stages have been studied. The influence of isolated and combined factors of AH, HLP, and the baseline level of renal function on CGN progression has been proven.

The greatest nephroprotective effect has been proven, consisting in stabilization of GFR (Δ ≥2 ml/min over 3 years), reduction of proteinuria by 25.9%, associated with the hypolipidemic action – reduction of total cholesterol by 5.5%, LDL cholesterol by 10.0%, improvement of renoscintigraphy indices – and the cardioprotective effect – consisting in reduction of LVMI by 12.3% and improvement of left ventricular systolic and diastolic function – under the influence of ACE inhibitor therapy in CGN patients with AH upon reaching target blood pressure levels during a 3-year follow-up. In CGN patients taking hypotensive drugs irregularly or without reaching the target blood pressure level, a minimal nephroprotective effect was observed in the absence of a cardioprotective one.

It has been established that statin treatment of HLP in CGN patients, with achievement of target lipid levels during 3-year therapy, leads to a slowing of the decline in GFR and the increase in proteinuria, Tmax, and T1/2 compared with untreated patients. The cardioprotective action was expressed in slowing the progression of diastolic heart failure, manifested as normalization of the transmitral flow parameter. The pleiotropic effect of simvastatin (simvahexal), consisting in reductions in immunoglobulins A and M, circulating immune complexes, C-reactive protein, and ESR in CGN patients with HLP, is observed after 1 month of therapy.

Practical significance of the work.

The study revealed a high frequency of IHD and diastolic CHF in CGN patients. At CKD stages 1–2, the frequency of CHF is the same in patients with AH and normal BP. As renal function declines, its frequency increases in patients with AH. When the rate of GFR decline is >4.03±1.1 ml/min/year, LVH develops in CGN patients, which allows these rates of progression to be considered an independent factor leading to myocardial remodeling. Therefore, in CGN patients, regardless of the BP level and/or the rate of disease progression >4.03±1.1 ml/min/year, echocardiography with assessment of left ventricular diastolic function is indicated.

In CGN patients with AH and/or a progressive course of CGN at CKD stages 1–2, continuous administration of ACE inhibitors with achievement of target BP levels leads to stabilization of GFR (Δ GFR = +1.1 ml/min over 3 years), a reduction of proteinuria by 25.9%, a reduction of total cholesterol by 5.5%, LDL cholesterol by 10.0%, improvement of renoscintigraphy indices, reduction of LVMI by 12.3%, and improvement of left ventricular systolic and diastolic function.

Prescription of statins in the observed CGN patients with AH and HLP, upon achievement of target lipid levels corresponding to the high cardiovascular risk group, exerts an antiproteinuric effect, reducing 24-hour proteinuria by 15.6% over 3 years of therapy, improves the functional state of the kidneys, slows the decline in GFR by 4.9% over 3 years compared with untreated patients, improves renoscintigraphy indices, and additionally reduces the progression of CHF by normalizing left ventricular diastolic function.

The pleiotropic anti-inflammatory effect of statins may serve as an additional component in the treatment of patients with CGN.

Implementation of the results. The results of the work have been implemented in the practice of the Nephrology Department of the Republican Clinical Hospital No. 1 in Kazan and the Outpatient Department of the Consultative and Diagnostic Center of the Aviastroitelny District of Kazan. The materials of the dissertation are used in teaching topics on therapy, nephrology, and cardiology in the course of general medical practice and therapy at the State Educational Institution of Higher Professional Education "Kazan State Medical University of the Federal Agency for Healthcare and Social Development."

Main statements defended.

1. AH and HLP in CGN patients, when acting in isolation, lead to a comparable decrease in GFR and impairment of tubular function, which increase when these factors are combined. HLP and AH are independent factors of CGN progression at CKD stages 1–2 and lead to acceleration of the rates of CGN progression at stages 3–4. With the combination of AH and HLP, the rates of CGN progression are higher than with the isolated action of each of them.

2. The determining factors of LVH formation in CGN patients are AH and the rates of CKD progression. The frequency of LVH detection in CGN patients without AH at CKD stages 1–2 is 12%, without increasing as CKD progresses. At CKD stages 1–4, the predominant type of LVH is concentric. With the appearance of AH at the stage of tCRF, the eccentric type of LVH dominates.

3. CHF occurs with equal frequency in CGN patients at CKD stage 1–2 with and without AH. AH at CKD stages 3–5 contributes to a higher frequency and severity of CHF. In 20.0% of CGN patients without AH, LVH, and IHD at CKD stages 1–2, diastolic CHF is recorded, which increases as renal function declines (at CKD stages 3–4) to 36.0%.

4. Treatment with ACE inhibitors for 3 years in CGN patients with AH, with achievement of target BP, leads to a reduction of proteinuria, total cholesterol, and LDL cholesterol, stabilizes GFR, slowing CKD progression, improves left ventricular systolic and diastolic function, and reduces LVMI.

5. Statin therapy for 3 years in CGN patients with AH exerts an antiproteinuric effect, improves renal function by slowing the decline in GFR and reducing CHF progression, and normalizes left ventricular diastolic function. The pleiotropic anti-inflammatory action of simvastatin is observed after the first month of treatment of CGN patients with HLP.

Approval of the work. The main scientific results of the dissertation were reported at a meeting of the Society of Therapists of Kazan (Kazan, 2005), at the X All-Russian Scientific and Practical Conference "Young Scientists in Medicine" (Kazan, 2005), at the Scientific and Practical Conference "Current Issues in Nephrology" (Naberezhnye Chelny, 2005), at the Republican Scientific and Practical Conference "CRF, Mechanisms of Progression. Treatment and Management of Patients at the Pre-Dialysis Stage" (Kazan, 2005), at the VI Congress of the Scientific Society of Nephrologists of Russia (Moscow, 2005), at the Scientific and Practical Conference "Modern Approaches to the Diagnosis, Classification, and Treatment of CKD" (Nizhnekamsk, 2006), at the XI All-Russian Scientific and Practical Conference "Young Scientists in Medicine" (Kazan, 2006), at the Interdistrict Scientific and Practical Conference "Chronic Renal Failure – Early Diagnosis, Management, Principles of Nephroprotection" (Chistopol, 2006), and at the Interdistrict Scientific and Practical Conference "Modern Approaches to the Treatment of CKD" (Zelenodolsk, 2006).

Publications. Eleven publications have been issued on the topic of the dissertation, of which 1 is in a peer-reviewed journal of the Higher Attestation Commission.

Scope and structure of the dissertation. The dissertation is set out on 157 pages of typewritten text and consists of an introduction, a literature review, a description of the material and methods of the study, two chapters of the results of the author's own investigations, a conclusion, conclusions, and practical recommendations. The bibliography includes 379 sources, including 296 foreign authors. The dissertation is illustrated with 36 tables, 12 figures, and 1 chart.