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Рогачова Т.А. Влияние коррекции дислипидемии на состояние почечной гемодинамики у больных эссенциальной гипертензией в сочетании с остеоартр
14.05.2014, 09:13

Резюме
Рогачова Т.А. Вплив корекції дисліпідемії на стан ниркової гемодинаміки у хворих на есенціальну гіпертензію у поєднанні з остеоартрозом.
Вивчено вплив корекції дисліпідемії аторвастатином на ниркові механізми обміну кальцію у 96 хворих на есенціальну гіпертензію в поєднанні з остеоартрозом. Вивчали ліпідний спектр крові, кальційуретичну функцію нирок, стан транспорту кальцію між нирками, позаклітинною рідиною і кістками, нирковий кровотік і судинний опір нирок до та після місяця терапії лізиноприлом в дозі 20-40 мг на добу і 3 месяців терапії аторвастатином в дозі 20 мг на добу. Крім ефективної корекції дисліпідемії аторвастатин зменшив ниркову екскрецію кальцію після кальцієвого навантаження на 24,6% внаслідок підвищення (р<0,05) канальцевої реабсорбції на 1,45%, що сприяло прискоренню транспорту кальцію з позаклітинної рідини до кісток. Механізм канальцевих змін полягає в покращенні перитубулярної гемодинаміки внаслідок збільшення (р<0,05) ниркового кровотоку і зменшення (р<0,05) еферентної судинної резистентності.
Ключові слова: есенціальна гіпертензія, остеоартроз, аторвастатин, кальцій-уретична функція нирок, ниркова гемодинаміка.
Резюме
Рогачова Т.А. Влияние коррекции дислипидемии на состояние почечной гемодинамики у больных эссенциальной гипертензией в сочетании с остеоартрозом.
Изучено влияние коррекции дислипидемии аторвастатином на почечные механизмы обмена кальция в 96 больных эссенциальной гипертензией в сочетании с остеоартрозом. Изучали липидный спектр крови, кальцийуретическую функцию почек, состояние транспорта кальция между почками, внеклеточной жидкостью и костями, почечный кровоток и сосудистое сопротивление почек до и после месяца терапии лизиноприлом в дозе 20-40 мг в сутки и 3 месяцев терапии аторвастатином в дозе 20 мг в сутки. Кроме эффективной коррекции дислипидемии аторвастатин уменьшил почечную экскрецию кальция после кальциевой нагрузки на 24,6% в результате повышения (р<0,05) канальцевой реабсорбции на 1,45%, что способствовало ускорению транспорта кальция из внеклеточной жидкости в кости. Механизм канальцевых изменений заключается в улучшении перитубулярной гемодинамики в результате увеличения (р<0,05) почечного кровотока и уменьшения (р<0,05) эфферентной сосудистой резистентности.
Ключевые слова: эссенциальная гипертензия, остеоартроз, аторвастатин, кальцийуретическая функция почек, почечная гемодинамика.
Summary
Rogachova Т.А. The effect of the dyslipidaemia correction on the state of renal hemodynamics in patients with essential hypertension and osteoarthritis.
Influence of the dyslipidaemia correction of atorvastatin is studied on the kidney mechanisms of exchange of calcium in 96 patients with essential hypertension and osteoarthritis. Studied the lipid spectrum of blood, calciuretic renal function, state of calcium transport (CaT) between the extracellular fluid and the bone (EF-B) and between the kidneys and the extracellular fluid (K-EF), renal blood flow and renal vascular resistance before and after a month therapy with lizinoprilom in the dose of 20-40 mg / day, and then 3-month therapy with atorvastatin in dose 20 mg a day.
Key words: essential hypertension, osteoarthritis, atorvastatin, renal calciuretic function, renal hemodynamics.

UDC 616.12-008.331.1+616.72-018.3-007.17/.248]+616.153.215-085+612.13

Донецкий национальный медицинский университет им. М.Горького

83003, Украина, г. Донецк, пр. Ильича 16

M. Gorky Donetsk National Medical University

Illicha Av. 16, Donetsk, 83003, Ukraine

vvkolomiyets@i.ua
         A study from 1988 to 1994, which included 77714 people in the United States of America has shown that in patients with osteoarthritis (OA) essential hypertension (EH) was diagnosed more frequently (in 75% of cases) than in the general population (38% of cases) [2, 7, 8]. Despite the significant progress in the study of the EH and the OA within recent years, there still remain open questions regarding the activation of their common pathogenetic mechanisms and the peculiarities of therapy incase of their joint course. Vascular disorders, including due to endothelial dysfunction, are considered as the most important pathogenetic mechanism of joint damage in OA - the cartilage and the subchondral bone [4]. Disturbances of lipid metabolism contribute to the development of degenerative changes in the vascular wall and articular cartilage and are a common pathogenetic mechanism of these diseases [5].

            Under the action of proinflammatory cytokines resorption of the extracellular matrix by chondrocytes and erosion of the cartilage occurs in the articular cartilage tissue, which increases the load on the subchondral bone, wherein microfractures occur, which leads to more severe cartilage tissue degradation and progression of joints lesions [6]. Osteoporosis is an integral part of the OA. At EG disturbances of calcium metabolism are revealed. They characterized by a tendency to a deficiency of extracellular calcium and activation of the parathyroid hormone (PTH) synthesis, which also contributes to the acceleration of resorptive processes in the bone tissue [1]. A pathogenetically justified drugs in this situation are ACE inhibitors and statins. Statins due to their lipid and nonlipid mechanisms can reduce endothelial dysfunction, manifestations of systemic inflammation and improve the condition of the bone tissue.
        The purpose of research: to study the effect of dyslipidemia correction with atorvastatin on the renal mechanisms of calcium exchange in patients with EH in combination with OA.

Materials and methods

The study included 96 patients with EH stage II in combination with OA of the knee joints I-II x-ray stage by Kellgrenn in ages from 52 to 75 years before and after a month  therapy with  lizinoprilom in the dose of 20-40 mg / day, and then 3-month therapy with atorvastatin in dose 20 mg a day. Serum lipid profile was determined with the help of colorimetric method: total cholesterol (TC), high-density lipoprotein- cholesterol (HDL-C) and low-density lipoprotein- cholesterol (LDL-C), triglycerides (TG). The comparison group consisted of 25 healthy individuals of the same age. Calciuretic renal function was  studied in the conditions of the oral calcium tolerance test (CTT). The concentration of calcium in the blood serum and urine were determined by atomic absorption spectrophotometry on spectrophotometer «Specord». The state of calcium transport (CaT) between the extracellular fluid and the bone (EF-B) and between the kidneys and the extracellular fluid (K-EF) was characterized in accordance with the algebraic margin between the variation of the calcium concentration in the blood serum of the patients from the calcium concentration in healthy individuals  and the value of calcium proceeds in the blood from the kidneys by tubular reabsorption, which is equal to the amount of calcium receipt from the extracellular sector to the bone one. Renal blood flow (RBF) was estimated with the help of Doppler study of the renal arteries diameter with an ultrasound unit Ultima PA. Total (TRVR), afferent (AfRVR) and efferent (EfRVR) renal vascular resistance was calculated using the formulae D.Gomez.

The obtained results were processed statistically using Microsoft Excel software package and the program “Biostatistics 4.03” (USA).

Results and their Discussion

         In all examined patients atorvastatin caused a significant decrease in the concentrations of TC and LDL cholesterol.  The initial levels of TC fluctuated whithin the range of: 4.69 - 7.5 mmol/l. The average levels of TC and it fractions are presented in the table. However, not only the mean but also the minimum content of  TC exceeded the recommended level for persons with the presence of at least 1 risk factor (EG) - < 4.5 mmol/l. In both groups there was an increase in the level of LDL cholesterol. The level of HDL cholesterol was 1.09 ± 0.06 mmol/l. Therapy with ACE inhibitor does not modify the state of lipid metabolism. Treatment with atorvastatin contributed to the correction of dyslipidaemia. The level of TC decreased and in all patients does not exceed 4.50 mmol/l. The level of LDL cholesterol did not exceed  2.60 mmol/l. No significant changes of the level of HDL cholesterol were  observed. Atherogenic index decreased (p <0,05) to 2.62±0.13. Our previous studies have shown that in the patients with EH in combination with OA, there is an increase renal excretion of calcium. This study

Table


Effect of lisinopril and atorvastatin on lipid metabolism, renal hemodynamics and calciuresis in patients with essential hypertension in combination with osteoarthritis (M±m)

Indicators

Phase of the survey

Before treatment

After treatment

Lisinopril

Lisinopril+ atorvastatin

TC, mmol/l

5,97±0,14

5,92±0,10

4,11±0,11*

LDL-C, mmol/l

3,78±0,12

3,67±0,11

2,12±0,09*

TRVR, dyn×sec×cm-5

9915±119

7022±90*

6519±94*

AfRVR,dyn×sec×cm-5

6418±87

4510±74*

4371±66*

EfRVR, dyn×sec×cm-5

3497±39

2512±31*

2148±33*

RBF, l/(min×1,73m2)

642±22

817±13*

      919±16*

GFR, ml/min

104,3±2,1

106,5±2,4

108,1±3,3

CaE, mmol

1,18±0,03

1,14±0,03

0,86±0,02*

EFСа,%

4,96±0,17

4,68±0,16

3,23±0,11*

CaT K-EF, mmol/l

+0,089±0,010

+0,085±0,009

+0,099±0,011

CaT EF-B, mmol/l

-0,047±0,007

-0,044±0,008

-0,092±0,008

Note: * - present fairly, in comparison with the previous phase of treatment (p<0.05).

showed a decrease in total calcium excretion (CaE) within 240 min CTT after treatment with atorvastatin. The table also shows, that the excessive renal excretion of calcium obtained in the CTT is confirmed by the slow transport of calcium between the kidneys and the extracellular fluid, in comparison with the transport of calcium in healthy people (+0,108±0,009 mmol/l). Kidney calcium losses lead to slower movement of calcium from the extracellular sector to the bone, which contributes to osteoporosis and consequently to the progression of OA. Renal calcium losses exacerbate its deficit in the organism of patients with EH and OA, due to the low intestinal absorption. For understanding the reasons of the reduction in excessive renal calcium losses in patients taking atorvastatin, it is necessary to establish a mechanism, through which changes in lipid metabolism may lead to a decrease in renal calcium excretion. Considering the fact, that at the same time with the shifts of renal calcium excretion decrease in excreting calcium fraction (EFCa) has been noted on the background of constant glomerular filtration, the most reasonable to assume change in intrarenal hemodynamic, in particular supplying for the tubular reabsorption. The improvement of intrarenal hemodynamic under the influence of atorvastatin using is evidenced by the growing value of the RBF. Increase of  the RBF is due to the decrease in renal vascular resistance. Vascular resistance is decreased primarily due to a decrease in resistance of efferent arterioles. The explanation for this phenomenon, apparently, is identified previously positive effects of atorvastatin on the endothelial synthesis of nitric oxide, and in particular in the renal arterioles. The increase in the RBF increases the flow rate of ultrafiltrate in the tubules of the nephron, including in the area of  «tight spots», which starts with greater intensity to reabsorb sodium and chloride ions, which suppresses secretion of renin, and therefore also angiotensin II, which causes dilatation of efferent arterioles and returns  GFR to the initial level [3]. From the table it can be seen that the GFR on the background of the therapy did not change. Taking into account the role of the renin-angiotensin system in the regulation of efferent tone, the most reasonable is the simultaneous use of ACE inhibitor and atorvastatin. The mechanism of anticalciuretic action of atorvastatin is caused, probably by the change of the passive transmembrane flow of calcium ions in the cells of the capillaries around the distal tubules, due to vasodilatation effect of nitric oxide, which is stimulated by atorvastatin. Reduction of tubular loss of calcium may also be done by intensification of  its active transcellular transport as a result of increased synthesis of transport proteins and kalbindina in the cells of peritubular capillaries.

Summary

         1. In patients with EH in combination with OA atorvastatin along with cholesterol-lowering effect has hypocalciuretic and antiresorptive effect.

         2. Anticalciuretic  effect of atorvastatin is due to its favorable effect on renal hemodynamics - the increase in renal blood flow due to reduced intrarenal efferent vascular resistance.

         3. Renal effects of atorvastatin are enhanced by simultaneous administration of an ACE inhibitor.

         Prospects for further research

 It is advisable to assess the relationship between hypocalciuretic  effect of atorvastatin and its hypotensive and positive articular influence.

Литература
1. Коломієць В.В. Обмін кальцію у хворих на остеоартроз із супутньою артеріальною гіпертензією / В.В. Коломієць, К.Ю. Сімбірцева, М.П. Чисников // Медицина транспорту України. – 2009. - № 3 (31). – Р. 83-87.
2. Мендель О.И.Остеоартроз как фактор риска кардиоваскулярных катастроф / О.И. Мендель, А.В. Наумов, Л.И. Алексеева [и др.] // Укр. Ревматол. журн. - 2010. - № 3 (41). – Р. 68-73.
3. Протеинурическое ремоделирование тубулоинтерстиция – мишень нефропротективной терапии при хронических заболеваниях почек / Н.А. Мухин, Л.В. Козловская, И.М. Кутырина [и др.] // Тер. арх. – 2002. – № 6. – С. 5-11.
4. Grynpas M.D. Subchondral bone in osteoarthritis / M.D. Grynpas // Calcified tissue international. – 2010. – Vol. 1 (49). - Р. 20-26.
5. Hofman A. The Rotterdam Study: objectives and design update / A. Hofman, M.M. Breteler, C.M. van Duijn [et al.] // Eur J Epidemiol. - 2010. - Vol. 24. – Р. 553–572.
6. Masuko K. A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation / K. Masuko, M. Murata, N. Suematsu [et al.] // Clin Exp Rheumatol. - 2009. - Vol. 27. – Р. 347–353.
7. Rosenberg L. The Black Women’s Health Study: a follow-up study for causes and preventions of illness / L. Rosenberg, L. Adams-Campbell, J.R. Palmer // J Am Med Womens Assoc. - 1995. - Vol. 2 (50). – Р. 56-58.
8. Zoler M.L. Cardiovascular disease, osteoarthritis linked in 30-years study / M.L. Zoler // Health publications. - 2009. - Vol. 9 (168). – Р. 357-362.

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