Nephrology for the Family Physician - O.I. Bakaliuk 2003

Modern approaches to the treatment of specific pathological conditions associated with kidney damage
Treatment of renal arterial hypertension

Before outlining the principles of Treatment for Renal Arterial Hypertension (RAH), let us quote Ye.M. Tareyev (1953): "Most people imagine that a pill is a sniper bullet that hits the target without missing. In reality, it is much more like shrapnel that strikes an entire 'area'." Until recently, treating RAH indeed resembled striking an "area".

Numerous randomized trials have revealed no significant differences among various classes of antihypertensive agents in terms of the degree of Blood pressure (BP) reduction. The primary criterion for choosing an antihypertensive drug is its ability to reduce cardiovascular morbidity and mortality while maintaining a normal quality of life. Controlled clinical trials indicate indisputable advantages of beta-blockers and Diuretics in this regard. However, strictly adhering to the recommendation to prioritize these specific groups of antihypertensive drugs when other highly effective and well-tolerated agents are available remains unjustified (see: Profilaktika, diagnostika i lechenie pervichnoy arterialnoy gipertonii v Rossiyskoy Federatsii. Russkiy meditsinskiy zhurnal. - 2000. - No. 8. - P. 318-338).

Antihypertensive therapy is indicated for patients with RAH when diastolic BP exceeds 100 mmHg. Determining the exact BP level required to ensure optimal renal function in a given patient is challenging; however, in most cases, clinical deterioration is driven not by excessive BP lowering, but by too rapid a reduction. According to WHO recommendations (1996), the target should be the normalization of BP to no higher than 140/90 mmHg (Appendix No. 1 to the Order of the Ministry of Health of Ukraine dated August 10, 1998, No. 247). For instance, research by H. Ritz (1998) demonstrates that to slow the progression of Chronic Kidney Disease, BP should be maintained at 125/75 mmHg. The author notes that with proteinuria (PU) at 1 g/day and BP at 140/90 mmHg, the decline in Glomerular Filtration rate (GFR) is 9 mL/min/year, whereas with the same PU level and BP restricted to 120/75 mmHg, it is only 3 mL/min/year. Based on the completed MDRD (Modification of Diet in Renal Disease) study, in the presence of chronic renal failure (CRF), BP should be 130/85 mmHg, and when PU exceeds 1 g/day, it should be 125/75 mmHg (including in patients with Diabetes Mellitus, as shown by the UKPDS - UK Prospective Diabetes Study).

The regimen and diet are the same as for Essential Hypertension, and any additional restrictions (e.g., protein, potassium) are solely related to the Specific features of the kidney disease or the degree of impairment in renal function. The only recommendation that might provoke Structure/133.html">Discussion or even objection is the allowance for alcohol consumption—no more than 30 g of pure alcohol per day interspersed with several alcohol-free days per week, as reported by E.I. Taran (2001).

When treating RAH, alongside the antihypertensive effect, it is crucial to consider whether the drug possesses a nephroprotective effect, which can be evaluated by the reduction in PU and the response of renal hemodynamics (effective renal plasma flow, GFR). Indeed, it is well known that when renal blood flow autoregulation and GFR have been impaired by prolonged hypertension, further BP reduction or specific pharmacodynamic properties of a drug may impair renal perfusion (sympatholytics, certain peripheral vasodilators) and thereby accelerate disease progression (D.D. Ivanov, 1999). From this perspective, the choice of antihypertensive agents for RAH is rather limited.

Based on the Pathogenesis of RAH, it becomes clear that preference should be given to agents capable of inhibiting local and/or systemic RAS activity by blocking The formation of AT-II or by blocking type 1 AT-II receptors (K. Tsunoda et al., 1993; H.P. Brunner et al., 1993; MacFadyen et al., 1994; P.V. Kang et al., 1994; D. Harold et al., 1995; A. Awan Najam et al., 1996; M.I. Oliverio et al., 1997). However, given the high cost of these drug classes, let us briefly characterize other groups of antihypertensive agents that can be utilized in this clinical scenario.

Drugs capable of partially reducing AT-II production through the inhibition of renin synthesis include beta-blockers and calcium antagonists.

Beta-blockers. This group is considered foundational for treating hypertension of any Etiology (T.T. Arabidze et al., 1997) due to the competitive and selective inhibition of catecholamine binding to beta-adrenergic receptors. Depending on the specific features of this inhibition, beta-blockers are divided into selective and non-selective, with or without intrinsic sympathomimetic activity. For RAH, selective beta-blockers without intrinsic sympathomimetic activity are preferred.

Below are the most common agents from these groups approved for use in Ukraine.

Selective beta-blockers without intrinsic sympathomimetic activity: atenolol (50–200 mg/day; trade names: atenolol, athenova, atenobene, blocotenol, catemol, tenormin, uniloc, fallitonzin), metoprolol (50–400 mg/day; trade names: betaloc, vasocardin, corvitol, lopresol, metolol, metoprolol), betaxolol (10–20 mg/day; trade name: lokren); selective beta-blockers with intrinsic sympathomimetic activity: acebutolol (400–1000 mg/day; trade name: sectral), talinolol (100–400 mg/day; trade name: cordanum).

Third-generation selective beta-1-receptor blockers include Nebilet (nebivolol, Berlin-Chemie, Germany) and celiprolol (Léčiva, Czech Republic). Nebilet produces a pronounced antihypertensive effect through its action on endothelial nitric oxide release and the blockade of endothelin synthesis (I.M. Dyakov et al., 2001; O.V. Sinyachenko et al., 2001; P.M. Janssen et al., 1999). Celiprolol is a highly selective beta-blocker with partial beta-2-agonist activity and vasodilating properties, making it suitable for patients prone to bradycardia, lipid and Carbohydrate METABOLISM disorders, Heart Failure, obstructive airway disease, or peripheral arterial disease (Yu.N. Sirenko et al., 2002; D. Modersohn et al., 1994; T.J. Cleophas et al., 1996; H. Mathys et al., 1996). Furthermore, it has been shown to significantly increase effective renal plasma flow without inducing glomerular hyperfiltration while reducing proteinuria (J. Bohier et al., 1993; K. Malminiemi et al., 1998).

Recently, a group of agents has been identified that, alongside beta-blocking activity, can also inhibit alpha-adrenergic receptors: labetalol, bucindolol, and carvedilol. Carvedilol (6.25–50 mg/day; trade names: carvedilol, dilatrend), based on ongoing studies, promises to become the drug of choice when severe hypertension—including RAH—is complicated by heart failure.

Combinations of beta-blockers and diuretics are quite common: Viscardix (pindolol 10 mg + clopamide 5 mg), Metopress (metoprolol 100 mg + hydrochlorothiazide 12.5 mg), Tenoretic (atenolol 100 mg + chlorthalidone 20 mg), Trasitensin (oxprenolol 80 mg + chlorthalidone 10 mg), and Trepress (oxprenolol 80 mg + chlorthalidone 10 mg + hydralazine 25 mg).

Side effects of varying severity are quite frequent (6–20%): bronchospasm, cold hands and feet, worsening of Raynaud's syndrome, depression, insomnia, hypertriglyceridemia, bradycardia, hypotension, onset or progression of heart failure, and heart blocks.

It is worth noting reports on the efficacy of the beta-2-adrenergic agonist partusisten at a dose of 5 mg/day in treating RAH and Cytology/cytology/16.html">Early stages of chronic kidney disease. Its antihypertensive effect correlated with positive changes in renal blood flow, alongside a decrease in clinical and laboratory markers of inflammatory activity (M.S. Komadenko, 1998).

Calcium channel blockers. Without dwelling in detail on the Structure and function of various voltage-gated neuronal calcium channels (N-, P-, Q-types), we note the crucial role of low-voltage-activated (T) and high-voltage-activated (L) types in the genesis of hypertension. These types are the most prevalent in myocardial Cells. The function of T-type channels is still under investigation, but their vital role in maintaining a regular heart rhythm is already well recognized.

L-type channels are directly responsible for the excitation-contraction coupling of cardiomyocytes; these are precisely the channels blocked by various classes of calcium channel antagonists. The pharmacokinetics of calcium channel blockers allow them to be used at any stage of chronic kidney disease without dose adjustment.

Among the three classes of calcium channel blockers (dihydropyridines, benzothiazepines, phenylalkylamines), sustained-release dihydropyridines are preferred for treating RAH: amlodipine (norvasc, 2.5–10 mg/day), felodipine (5–20 mg/day), isradipine (2.5–10 mg/day), nisoldipine (5–20 mg/day), Adalat SL (30–90 mg/day), nitrendipine (10–40 mg/day), and lercanidipine (2–4 mg/day). Alongside their antihypertensive action, these agents also exhibit a certain nephroprotective effect, clinically manifested as a reduction in proteinuria.

The renal effect of this drug group is mediated by an increase in GFR alongside the inhibition of tubular sodium and Water reabsorption (inhibition of calcium-dependent mechanisms of transtubular sodium transport, primarily in the proximal nephron segment; W. Colucci, 1996; S.N. Rasmusen et al., 1997). Their use is also associated with marked antihypoxic, antiarrhythmic (especially verapamil and diltiazem in supraventricular arrhythmias), antiallergic, and antiplatelet effects, as well as a favorable impact on pulmonary hypertension and bronchobstructive syndrome.

A fundamentally novel agent in this group is mibefradil, which completely blocks T-type channels and 25% of L-type channels. When administered, vasodilation occurs alongside a reduced heart rate without changes in myocardial contractility. Unlike other agents, mibefradil does not cause reflex sympathetic activation or tachycardia; additionally, it possesses an antiproliferative effect, which is important for suppressing vascular wall fibrosis in RAH.

Recently, reports have emerged regarding the favorable antihypertensive, anti-sclerotic, and nephroprotective effects of Diacordin (diltiazem hydrochloride by Léčiva, Czech Republic) in the treatment of RAH, even in the presence of chronic kidney disease and during hemodialysis (D.D. Ivanov, 1999; V.S. Kushnirenko, 2000).

Adverse effects of calcium antagonists include fluctuating BP levels with non-sustained-release formulations, negative effects on myocardial conductivity and contractility, tachycardia, angioedema, weakness, constipation, and headache.

ACE inhibitors. They exert a pronounced antihypertensive effect by blocking the formation of AT-II. Captopril and enalapril are the most widely used.

Capoten (25–100 mg/day) belongs to the Class of captopril-like ACE inhibitors that directly block The conversion of AT-I to AT-II, whereas Renitec (5–40 mg/day) is a prodrug that must be metabolized in the body into an active substance—in this case, enalaprilat—to exert its effect. Clinically, these agents should not be pitted against one another; simply put, Capoten is taken 3–4 times daily, while Renitec is taken 1–2 times. The latter is more convenient for patients given the necessity of long-term (months to years) therapy.

A third class of ACE inhibitors is also distinguished—water-soluble agents, represented by lisinopril (5–20 mg/day). The latter is not metabolized, does not penetrate Tissues, and is excreted unchanged by the Kidneys (I. Drinovac, 1998).

As noted above, ACE inhibitors—acting as a type of kininase—not only participate in the conversion of Ang I to Ang II, but are also capable of breaking down bradykinin, a potent vasodilating substance with favorable clinical effects. Consequently, The Use of ACE inhibitors increases the body's bradykinin levels. Notably, the accumulation of bradykinin in the Lungs is specifically linked to one of the side effects of ACE inhibitors: a dry cough. Thus, to date, ACE inhibitors—particularly renitec—represent the sole group of agents (emphasized by us, O.B.) capable of adequately and appropriately increasing systemic and tissue-level bradykinin in the body (R.D. Fahry et al., 1993). Compared to other antihypertensive drugs, ACE inhibitors have a much greater impact on Left Ventricular Hypertrophy, reducing it by 44.7% with renitec, compared to 26.9% for calcium antagonists, 22.8% for beta-blockers, and 21.4% for diuretics.

The administration of renitec is accompanied by a more pronounced nephroprotective effect compared to other classes of antihypertensives (reducing proteinuria by 40-50%, H.R. Brunner, 1992). This effect is based on renitec's ability to lower intraglomerular pressure by dilating the lumen of the efferent glomerular arteriole (an effect also attributed to bradykinin), improve effective renal blood flow, and decrease renal vascular resistance.

A series of recent experimental and clinical studies has demonstrated that, at equivalent antihypertensive efficacy, diuretics and beta-blockers are inferior to ACE inhibitors specifically in their nephroprotective properties. For instance, A. Remuzzi (1990) showed that despite a similar blood pressure-lowering effect, structural glomerular damage was lesser in rats with experimental renal pathology and renovascular hypertension (RVH) treated with renitec, compared to a group receiving reserpine, beta-blockers, diuretics, or hydralazine. ACE inhibitors also preserve the kidney's residual autoregulatory capacity, which is lost when calcium antagonists are used (K. Griffin et al., 1995).

In addition to influencing glomerular hemodynamics and proteinuria, ACE inhibitors reduce cytokine expression, the degree of interstitial infiltration, and Collagen deposition in the mesangium (S. Ishidoya, 1996). These findings can significantly tip the scales in favor of ACE inhibitors as the drugs of choice for RVH, since it has long been noted that tubulointerstitial changes correlate better with impaired renal function than glomerular alterations. Today, it is becoming evident that preventing or slowing the progression of renal failure is largely associated with the pharmacological blockade of renal glomerular and tubular RAAS (A.L. Kamper et al., 1995).

Other drugs in this group (prodrugs) differ in their chemical structure (presence of sulfhydryl, phenyl, or phosphorus-containing groups), The Need for metabolic conversion to form the active moiety, duration of action, affinity for ACE, and tissue penetration. These include benazepril (10-40 mg/day), quinapril (5-20 mg/day), ramipril (1.25-20 mg/day), spirapril (12.5-50 mg/day), fosinopril (10-40 mg/day), and cilazapril (2.5-10 mg/day); however, their nephroprotective effect is less pronounced than that of renitec (S.M. Skupoy et al., 1994).

Second-generation long-acting ACE inhibitors are considered promising, with prestarium (perindopril) being a prominent representative. According to N.N. Petrova et al. (1999) and L. Vaur et al. (1995), its use not only provides high antihypertensive efficacy (81.5%), but also significantly improves renal hemodynamic parameters.

Among the side effects of ACE inhibitors (occurring in 2-4% of cases) are cough, taste disturbances, neutropenia, hyperkalemia, transient hypercreatininemia, Skin reactions, and angioedema. It should also be noted that ACE inhibitors must be used with caution in cases of RVH caused by renal artery stenosis (I.M. Kutyrina et al., 1996). ACE inhibitors are contraindicated in bilateral renal artery stenosis or equivalent lesions, severe aortic stenosis, obstructive cardiomyopathy, and Pregnancy.

Currently, the literature actively discusses The impact of ACE Gene polymorphism on responsiveness to ACE inhibitor therapy, though the results of these studies remain contradictory (H. Yoshida et al., 1995; H.H. Parving et al., 1996; G.G. Van Essen et al., 1996).

AT-II Receptor Antagonists. A fundamentally new approach to treating hypertension, including RVH, has emerged quite recently.

In 1982, Y. Furukawa et al. described a new class of chemical compounds that neutralized the effects induced by Ang II in rabbit aorta strips (development of fibrosis and hypertrophy of vascular smooth Muscle cells). Since 1988, active research has been underway to develop a well-tolerated and orally bioavailable pharmacological agent based on this foundation.

In 1990, the potassium salt of this compound was synthesized (losartan potassium, trade name Cozaar) and its pharmacodynamics were described (P.C. Wong et al., 1990; P.B.M.W.M. Timmerman et al., 1991).

This is the first precision-acting agent from a fundamentally new class of antihypertensives that selectively blocks type 1 AT-II receptors in the vascular wall (B.A. Sidorenko, 1996; E.P. Svyshchenko, 1996; E.N. Amosova et al., 1997; E.G. Nesukay, 1997, 1998; R.D. Smith et al., 1994; B.M.W.M. Pieter et al., 1995). Its antihypertensive and nephroprotective effects (in terms of reducing proteinuria and altering renal hemodynamics) are equivalent to those of ACE inhibitors (Y.X. Wang et al., 1992; M. Burnier et al., 1995). Unlike renitec, the pharmacokinetics of Cozaar do not depend on renal function, making it suitable for treating hypertension even in patients undergoing hemodialysis (Yu.M. Sirenko, 1995; R.T. Gansevoort et al., 1994; D.A. Sica et al., 1995).

The MECHANISM OF ACTION of this class of drugs is also linked to increased nitric oxide synthesis, improved endothelial function, and the accumulation of angiotensin, which stimulates prostaglandin production and enhances the antihypertensive effect. Additionally, a reduction in left ventricular hypertrophy, beneficial effects on Cardiac Arrhythmias, and improved hemodynamics and metabolic parameters are observed in patients with left ventricular dysfunction.

Cozaar is prescribed at a dose of 50 mg once daily, regardless of prior therapy. The clinical effect of Cozaar develops within 1-2 weeks, peaks at 3-6 weeks, and persists for 2-3 weeks after discontinuation; resistance is observed in only 15.3% of patients. In such cases, Cozaar is administered (J.A. Schoenberger, 1995) in combination with diuretics (noting that the combination drug Hyzaar—50 mg Cozaar + 12.5 mg hydrochlorothiazide—currently exists), beta-blockers, calcium antagonists, and other antihypertensives. The use of Cozaar is not accompanied by adverse changes in lipid and glucose metabolism (L. Harrison, 1995).

We should also mention its hypouricemic and uricosuric effects, detailed in the section "Renal Involvement in Gout," along with a minimal side effect profile compared to other antihypertensive classes. The only established side effect of Cozaar is dizziness (W. Shaw et al., 1993, 1994; R.L. Simpson et al., 1994; L.P. Gasdick et al., 1994).

Data on the use of Cozaar in renal pathology were reviewed at the International Congress of Nephrology, "New Therapies for Renal Diseases: AT-II Antagonists" (Sydney, Australia, 1997). Specifically, we highlight the Conclusions of Prof. D. de Zeeuw et al., a meta-analysis of studies evaluating the renoprotective effects of ACE inhibitors and other antihypertensives in 1,100 patients with nephropathies of various origins. At equivalent blood pressure-lowering effects, ACE inhibitors reduced proteinuria by an average of 40%, whereas other agents (calcium antagonists, beta-blockers, diuretics, vasodilators) reduced it by 10%.

The authors hypothesized that the antiproteinuric effect of ACE inhibitors is mediated not only through the bradykinin system, but also via the suppression of local glomerular and tubular RAAS. To test this, D. de Zeeuw et al. conducted an experiment combining 14 days of ACE inhibitor therapy (lisinopril at 100 mg/day) with a concurrent counteracting infusion of a bradykinin antagonist or exogenous Ang II. The addition of the bradykinin antagonist affected neither blood pressure nor proteinuria, whereas the addition of exogenous Ang II raised blood pressure and restored proteinuria to baseline levels. The researchers concluded that the inhibition of renal RAAS, rather than merely the accumulation of proteinuria-controlling bradykinin, is the decisive factor. This was brilliantly confirmed when they studied The Effect of losartan potassium on proteinuria levels in patients with non-diabetic RVH.

According to their findings and those of other researchers (F.N. Hutchison et al., 1992), administering 100 mg of Cozaar daily produced virtually no additional hypotensive effect, yet significantly reduced proteinuria further (by another 15-20%). Blood pressure and proteinuria returned to baseline levels 12 weeks after drug withdrawal.

It is possible that part of losartan potassium's nephroprotective effect stems specifically from its favorable impact on the progression rate of tubulointerstitial renal lesions via the inhibition of tubular RAAS (R.A. Lafayette et al., 1992, 1993; K. Kohara et al., 1993).

The renal hemodynamic response—effective renal plasma flow and glomerular filtration rate—was identical for both drug classes (ACE inhibitors and AT-II type 1 receptor blockers). Furthermore, given that losartan potassium does not tend to accumulate in the blood regardless of the glomerular filtration rate, and can be used in patients with any stage of chronic renal failure (A. Domenic Sica et al., 1995), the future of RVH treatment may belong exclusively to this agent.

This class of antihypertensives also includes valsartan (Diovan), candesartan, irbesartan, enprosartan, and others. All of them are prodrugs, meaning their metabolites exhibit significantly greater affinity for receptors than the parent compound.

Thus, recalling the words of E.M. Tareyev quoted above, we can say that AT-II type 1 receptor antagonists are the first "sniper bullet" for treating hypertension, characterized by high antihypertensive efficacy, excellent tolerability, ease of use, absence of a rebound phenomenon, minimal side effects, and target-organ protection.

Let us briefly describe other classes of medications that lack a direct, defined effect on RAAS activity. Nevertheless, they can be utilized in the treatment of RVH for step-by-step titration of the antihypertensive effect.

Diuretics. The Mechanism of action of diuretics involves reducing Cardiac Output, circulating blood volume, and vascular wall resistance to vasodilating agents. In cases of RVH, these agents are typically used in combination with other antihypertensive medications.

Among thiazide diuretics, preference is given to benzthiazide (12.5-50 mg/day), hydrochlorothiazide (12.5-25 mg/day), and cyclothiazide (1-2 mg/day); among thiazide-like diuretics, chlorthalidone (12.5-50 mg/day), clopamide (10-60 mg/day), and quinethazone (0.5-2 mg/day) are preferred.

Side effects of thiazide and loop diuretics include hypokalemia, hyperuricemia, hypercalcemia, decreased libido, Insulin resistance, negative impacts on Lipid Metabolism, and blood rheological properties.

Among thiazide-like diuretics, arifon (indapamide, synonyms: fludex, tertensif) stands out. Its hypotensive effect is observed at a dose of 2.5 mg/day (A. Harrower, 1995). This drug is quite effective as monotherapy for hypertension, does not affect blood Cholesterol levels or tissue glucose tolerance, does not impair renal hemodynamics, does not cause a rebound effect upon withdrawal, and can be used in renal failure.

Loop diuretics (ethacrynic acid (25-100 mg/day), furosemide (20-320 mg/day)) are rarely used for the long-term treatment of refractory arterial hypertension (primarily in emergency situations or renal failure) due to their ability to activate powerful counterregulatory vasoconstrictor mechanisms.

Since 1999, the saluretic torasemide (Trifas, Berlin-Chemie — 50-200 mg orally in the morning) has been used in Ukraine, even in patients with significantly reduced creatinine clearance (less than 20 mL/min).

Potassium-sparing diuretics (amiloride (5-10 mg/day), veroshpiron (25-100 mg/day)) have limited antihypertensive and natriuretic effects; furthermore, they are contraindicated when creatinemia exceeds 0.221 mmol/L.

Alpha-adrenoreceptor blockers are also included by WHO experts in the first-line treatment group for hypertension. They are capable of lowering blood pressure (primarily diastolic) through the blockade of postsynaptic alpha-1 adrenoreceptors and the vasodilation mediated by this blockade.

While matching other drugs in antihypertensive activity, long-acting agents of this group — terazosin (hytrin, 1-20 mg/day), doxazosin (cardura, 1-16 mg/day) — practically lack the negative first-dose effect, unlike prazosin (adversuten, 1-20 mg/day).

At the same time, other quite important effects of these agents are noted: a positive impact on lipid and carbohydrate metabolism, the degree of Urinary Tract obstruction in Prostatic Adenoma, and The ability to increase tissue sensitivity to insulin (G. Bartsh et al., 1997).

Drugs that simultaneously block alpha-1 and beta-2 adrenoreceptors include carvedilol (6.25-50 mg/day) and labetalol (200-800 mg/day), while those blocking alpha-1 and serotonin adrenoreceptors include urapidil (15-120 mg/day).

Among other groups of hypotensive agents not included in the list of first-line antihypertensive drugs, we should mention centrally acting alpha-2 receptor agonists (clonidine), sympatholytics with central and peripheral action (reserpine), and direct arterial vasodilators (hydralazine, diazoxide, minoxidil).

These drug groups are used only when the patient has contraindications for prescribing other hypotensive agents. They are characterized by a rather high frequency of side effects that impair the patient's quality of life — depression and dry Mouth with clonidine; depression, drowsiness, bronchospasm, cardiac arrhythmias, and impotence with reserpine; RAAS stimulation, reflex tachycardia, and a tendency toward fluid retention with direct vasodilators.

A distinctive feature of refractory arterial hypertension is resistance to hypotensive therapy.

One of the possible regimens for stepwise escalation of hypotensive therapy intensity in refractory arterial hypertension can be structured as follows:

Stage I: a single drug — beta-blocker, ACE inhibitor, angiotensin II receptor antagonist, or calcium channel blocker. A diuretic can be added to each of these agents (e.g., hypothiazide 12.5 mg/day or arifon 2.5 mg/day);

Stage II: two drugs — beta-blocker + alpha-blocker (prazosin); ACE inhibitor + calcium channel blocker; beta-blocker + hydralazine; angiotensin II receptor antagonist + any other hypotensive drug;

Stage III: three drugs — diuretic + vasodilator + sympatholytic; beta-blocker + diuretic + vasodilator; ACE inhibitor + diuretic + prazosin; ACE inhibitor + diuretic + beta-blocker; beta-blocker + diuretic + apresoline; beta-blocker + diuretic + angiotensin II receptor antagonist.

If three components are insufficiently effective, ganglion blockers such as guanethidine are added.

It is worth addressing the treatment of refractory and malignant hypertension. The criterion for hypertension refractoriness is a reduction in systolic blood pressure by less than 15% and diastolic blood pressure by less than 10% from baseline levels under an appropriate regimen and rational therapy using adequate doses of three or more hypotensive agents. It should be noted that in 2/3 of cases, so-called "pseudoresistance" occurs, meaning non-adherence to the prescribed treatment regimen. The remaining 1/3 of refractoriness cases are caused by low doses of hypotensive drugs, their irrational combinations, concomitant use of other substances (NSAIDs, sympathomimetics, oral contraceptives, antidepressants, etc.), and the presence of underlying diseases and conditions (smoking, obesity, Sleep apnea, insulin resistance, alcohol abuse).

The criterion for malignant hypertension (primary or any form of symptomatic) is a blood pressure elevation exceeding 220 and 130 mmHg combined with Keith-Wagener-Barker grade III-IV retinopathy, as well as fibrinoid arteriolosclerosis on renal biopsy. These patients are often diagnosed with hypertensive heart disease, a propensity for ventricular fibrillation, strokes, myocardial infarction, progressive heart failure, chronic renal failure; however, these clinical criteria are not decisive in establishing this Diagnosis. Notably, among all cases of malignant hypertension, 40% are attributed to pheochromocytoma, 30% to renovascular hypertension, 12% to primary aldosteronism, 10% to parenchymal renal diseases, 6% to scleroderma, polyarteritis nodosa, or Renal Tumors, and 2% to essential hypertension.

In addition to the mandatory prescription of a combination of 3-5 antihypertensive agents in sufficiently high doses to such patients, the treatment regimen may additionally include (G.G. Aribidze et al., 1997; A.V. Shabalin et al., 1999):

- minoxidil (5 mg 1-2 times daily);

- PGE₂ (prostenon), intravenous drip with an initial rate of 90-110 ng/kg body weight/min (2-3 infusions);

- sodium nitroprusside, intravenous drip with an initial rate of 0.5-1.5 mg/kg body weight/min (3-5 infusions);

- hemadsorption or plasmapheresis (2-3 Procedures in heart failure);

- hemodialysis or hemofiltration in renal failure;

- Immunosorption (in severe hypercholesterolemia);

- isolated blood ultrafiltration for refractory edema.

Treatment for renovascular hypertension (RVH) is generally surgical. To achieve successful surgical outcomes, it is crucial to prove that hypertension is specifically linked to unilateral renal ischemia. In most cases, the affected segment of the renal artery is replaced with a graft. Another approach is widening the renal artery lumen via balloon angioplasty. The outcomes of this method are superior in fibromuscular Dysplasia; however, positive results have also been achieved in atherosclerotic renal artery stenosis. If hypertension is caused by unilateral renal disease, nephrectomy remains the treatment of choice.

If there are contraindications to the Surgical treatment of RVH, standard antihypertensive therapy is employed, with an emphasis on type 1 angiotensin II receptor blockers (ARBs) or ACE inhibitors. When using the latter, one must keep in mind the potential risk of impaired function in the ischemic kidney due to a reduction in the filtration pressure gradient.

Finally, we should highlight promising new areas in the treatment of hypertension in general and renovascular hypertension in particular, which are currently under active development: potassium channel openers (pinacidil, nicorandil), imidazoline receptor agonists (moxonidine, rilmenidine), neutral endopeptidase inhibitors (candoxatril, mixanpril), renin inhibitors (zankiren, remikiren, enalkiren, Ro-42-5892), endothelin antagonists (bosentan, BQ-123), prostacyclin synthesis activators (cicletanine, epoprostenol), and serotonin receptor blockers (ketanserin, urapidil, indoramin). More detailed information on these topics can be found in the reviews by M. Schlachter (1995), J.R. Gregori et al. (1995), and L.I. Olbinskaya et al. (1998).