Resistant and refractory arterial hypertensions are two distinct clinical phenotypes of uncontrolled arterial hypertension (AH), which differ in their sensitivity to antihypertensive drug therapy. The review presents data obtained in clinical studies devoted to elucidating the involvement of disorders of neurohormonal status and renal function in the formation of resistant and refractory arterial hypertension, to and the development of new approaches to increasing the effectiveness of antihypertensive therapy in these patient’s populations. The results of these studies have shown that in patients with uncontrolled arterial hypertension, despite prolonged intake ≥ 3 antihypertensive drugs with different mechanisms of action, including a diuretic, excess sodium reabsorption persists in the distal segments of nephron due to increased aldosterone activity and sympathetic nervous system hyperactivity. In this regard, special attention has been paid to the data of PATHWAY-2, PATHWAY-3 and ReHOT trials that in patients with resistant AH tested the clinical efficacy of spironolactone, amiloride, and antiadrenergic drugs bisoprolol, doxazosin and clonidine, suppressing activity of the sympathetic nervous system.
Arterial hypertension (AH) resistant to drug therapy is the phenotype of uncontrolled AH, in which patients receiving at least 3 antihypertensive drugs, including a diuretic, maintain blood pressure above the target level. Initially, the term refractory hypertension was also used to refer to resistant hypertension. Recently, however, refractory hypertension has been isolated into a separate phenotype of difficult to treat hypertension, which is defined as insufficient control of target blood pressure, despite the use of at least 5 different mechanisms of antihypertensive drugs, including long-acting diuretic and antagonist of mineralcorticoid receptors. Resistant hypertension is detected in 10–15 % of all hypertensive patients receiving drug therapy, and is often found in patients with chronic kidney disease. Hypertension can be a cause and/or consequence of kidney damage and is typical of most patients with chronic kidney disease. The lack of control of target blood pressure in a significant proportion of hypertensive patients with CKD who receive at least 3 antihypertensive drugs of different mechanisms of action indicates a lack of effectiveness of antihypertensive therapy, which not only accelerates the loss of renal function, but also significantly worsens the prognosis, contributing to such people risk of cardiovascular and renal complications. The review presents data on the prevalence, prognostic value of resistant hypertension in patients with chronic kidney disease, features of its formation and approaches to increasing the effectiveness of antihypertensive therapy in this patient population.
РЕФЕРАТ ЦЕЛЬ: выяснить возможность применения биомаркеров NGAL и KIM-1 мочи для раннего выявления повреждения проксимальных канальцев (ПК) и тубулоинтерстиция у недиабетических больных с АГ с ХБП. ПАЦИЕНТЫ И МЕТОДЫ. В исследовании участвовали 60 больных (16 мужчин и 44 женщин, в возрасте 60,4±8,37 года) с первичной или нефрогенной АГ II-III степени, которые были разделены на группы: 1-я группа с СКФ>90 мл/мин/1,73 м 2 , n = 27, 2-я группа с СКФ 60-74 мл/мин/1,73 м 2 , (n=18), 3-я группа с СКФ<60 мл/мин/1,73 м 2 (n = 15). Группу контроля составили 15 нормотензивных лиц (6 мужчин и 9 женщин, средний возраст 49,8±9,68 года) без явных признаков заболеваний почек и сердечно-сосудистой системы. Всем пациентам проведено комплексное обследование с определением содержания в моче NGAL («Human NGAL ELISA kit») и KIM-1 («Human KIM-1 Immunoassay ELISA»). РЕЗУЛЬТАТЫ. В моче больных 2-й и 3-й группы выявлено повышенное по сравнению с контрольной группой содержание NGAL в 2,62 и 7,22 раза соответственно. Прирост концентрации KIM-1 мочи в этих же группах пациентов составил 2,12 и 3,14 раза соответственно. Похожие результаты были получены и в выделенной группе (n = 30) больных с АГ с хронической сердечной недостаточностью с сохранной фракцией выброса (ХСНсФВ). Концентрация NGAL мочи в группе таких больных с легкой дисфункцией почек (СКФ 67,2±5,93 мл/мин/1,73 м 2 ) превышала показатели группы сравнения в 2,36 раза, а в группе пациентов с выраженным нарушением функции почек (СКФ 53,6±6,67 мл/мин/1,73 м 2 ) -в 9,09 раза (р < 0,05). Аналогичные данные прироста содержания KIM-1 в моче больных с ХСНсФВ составили 1,84 и 6,87 раза соответственно (р < 0,05). ЗАКЛЮЧЕНИЕ. Прирост NGAL мочи более чем в 2,5 раза или прирост KIM-1 мочи более чем в 2 раза по сравнению с нормальными значениями может быть диагностическим маркером раннего повреждения ПК и тубулоинтерстиция у недиабетических больных с АГ с С2 стадией ХБП.Ключевые слова: артериальная гипертензия, хроническая болезнь почек, NGAL, KIM-1.ABSTRACT THE AIM: to investigate the possibility of the use of urine biomarkers NGAL (neutrophil gelatinase-associated lipocalin) and KIM-1 (kidney injury molecule-1) for early detection of damage to proximal tubules (PT) and tubulointerstitium in nondiabetic hypertensive patients with CKD stage 2. PATIENTS AND METHODS. The research involved 60 patients (16 men and 44 women, mean age 60,4±8,37 years) with primary and nephrogenic hypertension, which were divided into 3 groups: 1 gr. with GFR>85 ml/min/1,73 m 2 ), 2 gr. with GFR 60-74 ml/min/1,73 m 2 ), and 3 gr. with GFR<60 ml/min/1,73 m 2 ), The control group consisted 15 normotensive individuals (6 men and 9 women, mean age 49,8±9,68 years) without overt signs of kidney and cardiovascular diseases. All patients carried out a comprehensive survey with determination the content of urine NGAL («Human NGAL ELISA kit») and KIM-1 («Human KIM-1 Immunoassay ELISA»). RESULTS. Increased NGAL content In the urine of patients 2 and 3 gr. were identified respectively in 2,62 and 7,22 times compared with the control...
The review summarized data on the diagnostic and prognostic value of biomarkers of kidney injury NGAL (neutrophil gelatinaseassociated lipocalin), KIM-1 (kidney injury molecule-1) and L-FABP (liver type fatty acid-binding protein) in patients with CKD. The most studied of these is NGAL, increase of its level in urine reflects the severity of CKD. Elevated levels of urinary NGAL evaluated also as a prognostic criterion which allows identifying patients with high risk of unfavorable course of disease. Elevated levels of urinary KIM-1 inpatients with CHF can detect individuals with tubulointerstitial kidney injury, having an adverse prognostic value, and to assess their risk of death or rehospitalization about CHF. Data obtained in large populations of patients with diabetes type 1 and 2 with CKD show that high levels of urinary L-FABP is associated with an increased risk of diabetic nephropathy progression. High levels of this biomarker in urine of patients with diabetes type 2 and stage1-2 CKD is also unfavorable prognostic marker of increased risk of coronary heart disease and other cardiovascular complications. In general, diagnostic and prognostic value of urine KIM-1 and L-FABP in CKD patients with varying severity poorly understood and needs further clinical studies.
Refractory arterial hypertension is characterized by a lack of control of target blood pressure, despite the prolonged use >5 antihypertensive drugs with different mechanisms of action, including longacting diuretic chlorthalidone and the mineralcorticoid receptor antagonists (spironolactone or eplerenone). The review presents the results of clinical studies devoted the elucidating peculiarities of the neurohormonal status and water-salt balance in such patients and developing new approaches to antihypertensive drug therapy based on them. According to these studies, individuals with refractory hypertension differ from patients with resistant hypertension with the higher of sympathetic nervous system activity and the absence of an increased of intrathoracic fluid volume, which indirectly indicates a significant decrease in the intravascular fluid volume. In this regard, the review focuses on the data obtained in assessing the clinical efficacy of sympatholytics clonidine and reserpine in patients with resistant and refractory hypertension, as well as renal sodium-glucose co-transporter type 2 inhibitors, which suppress the sympathetic nervous system activity and can be used to overcome refractory hypertension in patients with type 2 diabetes.
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