In 2005, the II Congress of Nephrologists of Ukraine approved the terms "chronic kidney disease" (CKD) for adult patients and "chronic kidney disease" for children. These terms are collective in nature and are similar to the concepts of coronary heart disease (CHD) and chronic nonspecific lung disease.

D.D. Ivanov, Department of Nephrology, National Academy of Postgraduate Education named after P.L. shupik

The expediency of their introduction in nephrology is due to the need to indicate the progressive course of kidney diseases lasting more than 3 months or initially accompanied by a decrease in kidney function.

The stages of CKD according to the glomerular filtration rate (GFR), calculated on the basis of determining the level of blood creatinine, are presented in table 1. It should be noted that the formulas for calculating GFR (C-G, MDRD) exclude the possibility of detecting hyperfiltration, which is observed in the early stages of renal dysfunction and is considered as functional compensation. For example, hyperfiltration is characteristic of the first stage of diabetic nephropathy and is diagnosed by renal scintigraphy or in the traditional Roberg-Tareev test.

The annual increase in the number of patients with dialysis chronic renal failure (CRF) - CKD 5th st. is about 100 people per 1 million population (60-150). At the same time, there are about 100 times more patients with all degrees of CKD. For example, data on the prevalence of CKD in the UK are available from the NeoERICA study (The New Opportunities for Early Renal Intervention by Computerized Assessment) (Table 2).

If CKD is suspected, the NKF KDOQI guidelines recommend:

1. determine the level of blood creatinine for the subsequent calculation of GFR;
2. urinalysis for the presence of albuminuria.

These recommendations proceed from the fact that CKD is most often accompanied by a decrease in GFR and the presence of microalbuminuria. According to the results of the NHANES III (National Health and Nutrition Examination Survey), 20% of people with diabetes and 43% of patients with hypertension in the absence of proteinuria have a GFR of less than 30 ml/min. 20% of patients with diabetes and 14.2% of those with hypertension without diabetes have a GFR of less than 60 ml/min, and the number of such patients increases with age. The results of the study indicate that the true prevalence of CKD is much higher. In this case, the indication for referring the patient to a nephrologist is the level of creatinine 133-177 mmol/l (or GFR less than 60 ml/min).

To determine the stage of CKD, it is recommended to use the derivative of the blood creatinine level, namely the estimated GFR. There are several rationales for using GFR rather than serum creatinine. The relationship between creatinine concentration and GFR is non-linear; therefore, in the early stages of CKD, with very close values ​​of serum creatinine levels, GFR values ​​can differ by almost a factor of two (figure). In this regard, GFR should be considered as a much more sensitive indicator of the functional state of the kidneys.

In nephrology, a number of principles have been formulated that are followed in the treatment of patients with CKD:

1. Achievement of the target level of blood pressure<130/80 мм рт. ст. или САД<98 мм рт. ст. при протеинурии до 1 г/сут и АД<125/75 мм рт. ст. и САД<92 мм рт. ст. при протеинурии, превышающей 1 г/сут .
2. There is no target level for proteinuria, it should be minimal or absent. The terms for reducing proteinuria by half should not exceed 6 months (J. Redon, 2006).
3. Achieving the target level of blood pressure and the elimination of proteinuria are independent tasks and involve the use of all possible antihypertensive drugs in a certain sequence.
4. Drugs of choice (usually in combination) in the following sequence: angiotensin-converting enzyme inhibitors (ACE inhibitors), sartans, diuretics / moxonidine, selective calcium channel blockers, selective β-blockers. Among calcium blockers, preference is given to diltasem (verapamil), felodipine, lercandipine, among β-blockers - nevibolol, carvedilol, bisoprolol and metoprolol succinate.

There are three possible outcomes of CKD treatment:

1. reverse development of CKD (if eGFR> 60 ml/min);
2. stabilization of CKD with a significant lengthening of the pre-dialysis period;
3. ongoing progression of CKD to dialysis CKD.

Patients with CKD 1-4th stage. have a 6-12 times greater risk of dying than surviving to the terminal stage. In a five-year follow-up of 27,998 patients with CKD stage 3. death occurred in 24.3% of patients. At the same time, the risk of death from cardiovascular events is higher than the possibility of progression to terminal CRF. The risk of developing cardiovascular events increases with a decrease in GFR below 90 ml/min.

What are the main causes of patient death? The answer to this question was obtained in the HOT study (Hypertension Optimal Treatment Study) (Tables 3, 4).

The European Society of Cardiology (ESC) 2006 guidelines initially suggest the use of non-invasive methods such as exercise ECG, stress echo, or perfusion myocardial scintigraphy to confirm the diagnosis of CAD. Obviously, these methods can be implemented for patients with CKD to assess the risk of cardiovascular events.

The need to prevent the development of complications from the cardiovascular system should be taken into account when selecting drugs for antihypertensive therapy and eliminating proteinuria (i.e., slowing down the progression of CKD). In this regard, ACE inhibitors as the main group of choice are likely to be ranked taking into account not only their class renoprotective effect, but also intraclass differences based on the evidence base regarding the prevention of cardiovascular events. Therefore, when prescribing ACE inhibitors with preserved kidney function, preference should obviously be given to drugs that have an evidence base for the prevention of cardiovascular events, and as kidney function decreases, ACE inhibitors with nephroprotective properties.

The NKF (2004) and ESC (2004) guidelines define ACE inhibitors as the drugs of choice for the treatment of hypertension in diabetes, diabetic nephropathy, left ventricular dysfunction, and all chronic kidney diseases. This actually recognizes the class effect of ACE inhibitors in reducing blood pressure (ESC, 2004; NKF, 2004) and proteinuria (NKF, 2004).

The evidence base for ACE inhibitors in CKD is presented for ramipril (MICROHOPE, REIN, DIABHYCAR, TRENDY), lisinopril (ALLHAT, CALM, EUCLID, BRILLIANT), trandolapril (COOPERATE), benazepril (AIPRI), enalapril (DETAIL). For these ACE inhibitors (except benazepril), the guidelines of the European Society of Cardiology indicate the initial and target doses for the treatment of heart failure.

In patients with initial nephropathy in type 1 diabetes mellitus, captopril, lisinopril, enalapril, perindopril and ramipril have an evidence base (level of evidence 1A). In late type 1 diabetes mellitus nephropathy, only captopril has an evidence base. In early type 2 diabetic nephropathy, ramipril and enalapril reduce the combined endpoint of myocardial infarction, stroke, or cardiovascular death.

Ramipril and perindopril are recommended for secondary prevention of cardiovascular disease without heart failure or left ventricular dysfunction (ESC, 2004), as well as stable angina, asymptomatic or suspected CAD (ACP, 2004; ESC, 2004). The latter shows good efficacy in the elderly (PREAMI). However, one should be aware of the subclinical impairment of kidney function, detected by the estimated GFR, in this category of patients. In this regard, the appointment of perindopril requires the consultation of a nephrologist. At the same time, the combination of ACE inhibitors with drugs that do not belong to the nephroprotective group (amlodipine - ASCOT, atenolol / nitrendipine; G.M. London, 2001) leads to a decrease in the risks of developing non-fatal myocardial infarction, fatal coronary events, kidney damage and mortality.

Thus, the appointment of an ACE inhibitor in CKD is due to the effect of the drug on cardiovascular risks that determine the patient's survival. Practical criteria for the effectiveness of ACE inhibitors are the normalization of blood pressure and the elimination of proteinuria/albuminuria as one of the manifestations of endothelial dysfunction. Evidence-based drugs include enalapril, ramipril, and perindopril in Ukraine. All of them have a predominantly renal route of elimination, which obviously determines their high inhibitory activity on tissue angiotensin II (an analogy with non-selective β-blockers) and at the same time is their weakness in a progressive decrease in GFR, forcing a dose reduction with blood creatinine more than 221 mmol / l (ESC, 2004) or switch to ACE inhibitors with extrarenal excretion (monopril, quadropril, moexipril). Continuation of ACE inhibitor therapy at a therapeutic dose with severe renal dysfunction also reduces cardiovascular risks and proteinuria, but is accompanied by an increase in blood creatinine levels. In this regard, if there is a suspicion of impaired renal function, it is advisable to calculate the glomerular filtration rate. ACE inhibitors should be used early in the development of CKD, which makes it reversible and reduces cardiovascular mortality.

Summarizing the above, we can conclude that the choice of ACE inhibitors in chronic kidney disease is determined by the risks of cardiovascular or renal events. With preserved kidney function and the presence of hypertension, heart failure and coronary artery disease, as well as in post-infarction patients, the evidence base allows the use of ramipril and perindopril to increase patient survival. In CKD with renal risks (lower GFR, diabetes), an ACE inhibitor with a dual kidney/liver elimination route should be preferred. Despite the decrease in effect, drugs with a non-renal route of excretion (moexipril) are the safest. Strengthening of antihypertensive and antiproteinuric action is achieved by a combination of ACE inhibitors and sartan.

Literature

1. Ivanov D.D. Renal continuum: is CKD reversal possible? // Nephrology. - 2006. - T. 10. - No. 1. - S. 103-105.
2. Dratwa M., Sennesael J., Taillard F. et al. Long-term tolerance of perindopril in hypertensive patients with impaired renal function. J Cardiovasc Pharm 1991; 18 (Suppl 7): 40-44.
3. Guerin A.P., Blacher J., Pannier B. et al. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation 2001; 103:987-992.
4. Guidelines on the management of stable angina pectoris. The task Force on the Management of Stable Angina Pectoris of European Society of Cardiology // ESC, 2006. - 63 p.
5. Gnanasekaran I., Kim S., Dimitrov V., Soni A. SHAPE-UP – A management program for Chronic Kidney Disease // Dialysis @ Transplantation, May, 2006. – P. 294-302.
6. De Zeeuw D., Remuzzi G., Parving H.H. et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int 2004; 65:2309-2320.
7. Ruilope L., Segura J. Blood pressure lowering or selection of antihypertensive agent: which is more important? Nephrol Dial Transplant 2006; 21(4): 843-846.
8. Shlipak M. Diabetic nephropathy. Clinical Evidence Concise by BMJ Publishing Group. Am Fam Physician 2005; 72(11): 2299-2302.
9. Snyder S., Pendergraph B. Detection and Evaluation of Chronic Kidney Disease. Am Fam Physician 2005; 72(9): 1723-1732.
10. Van Biesen W., de Bacquer D., Verbeke F. et al. The glomerular filtration rate in an apparently healthy population and its relation with cardiovascular mortality during 10 years. Eur Heart J 2007; 28(4):478-483.
11. www.aakp.org (American Association of Kidney Patients).
12. www.kidney.org/professionals/kdoqi/guidelines_bp/index.htm (National Kidney Foundation).
13. www.InfoPOEMs.com.
14. www.nephrology.kiev.ua (First Ukrainian nephrology site).
15. www.niddk.nih.gov (National Institute of Diabetes and Digestive and Kidney Diseases).

Chronic renal failure (CKD) often leads to the development of severe forms in patients arterial hypertension requiring special treatment.

Unlike malignant essential hypertension, it leads to nephrosclerosis and CRF much less frequently, however, renal hypertension, the frequency of which increases as kidney function decreases, is one of the factors that determine not only the progression of CRF, but also mortality. In 90% of patients with chronic renal failure, hypertension is associated with hyperhydration due to a delay in the release of sodium and fluid.

Diuretic drugs for chronic renal failure

The removal of excess sodium and fluid from the body is achieved by the appointment of saluretics, the most effective of which are furosemide (lasix), ethacrynic acid (uregit), bufenox (domestic analogue of bumetanide). With chronic renal failure, the dose of furosemide increases to 160-240 mg / day, uregit ≈ up to 100 mg / day, bufenox ≈ up to 4 mg / day. The drugs slightly increase CF and significantly increase potassium excretion.

Diuretics are usually prescribed in tablets, with pulmonary edema and other urgent conditions - intravenously. It should be remembered that in high doses, furosemide and ethacrynic acid can reduce hearing, increase the toxic effect of tseporin, bufenox can induce muscle pain and stiffness.

With chronic renal failure, spironolactone (veroshpiron), triamterene, amiloride and other drugs that promote potassium retention are carefully used. Minoxidil causes secondary hyperaldosteronism with water and sodium retention, so it is advisable to combine it with ß-blockers and diuretics.

In severe chronic renal failure, in conditions of an increase in the filtration load on functioning nephrons due to the competitive transport of organic acids, the flow of diuretics into the luminal space of the tubules is disrupted, where they, by binding to the corresponding carriers, inhibit sodium reabsorption.

By increasing the luminal concentration of drugs, such as loop diuretics by increasing the dose or continuous intravenous administration of the latter, the diuretic effect of furosemide (Lasix), bufenox, toresemide and other drugs of this class can be enhanced to a certain extent.

Thiazides, the site of action of which are the cortical distal tubules, with normal kidney function, have a moderate sodium and diuretic effect (only 5% of filtered sodium is reabsorbed in the nephron at their site of action), with CF less than 20 ml / min they become little or completely ineffective.

At a glomerular filtration rate of 100 ml/min, 144 liters of blood passes through the kidneys per day and 200 meq Na (1%) is excreted. In patients with a glomerular filtration rate of 10 ml / min, 14.4 l / day of blood is perfused through the kidneys and, in order to eliminate 200 meq of Na, the excreted fraction should be 10%. To double the excretion of Na, its fractional excretion in healthy people should increase by 1%, and in patients by ≈ 10%. Thiazides, even at high doses, cannot provide such a pronounced inhibition of Na reabsorption.

In severe hypertension refractory to treatment in patients with chronic renal failure, renin activity and plasma aldosterone levels increase.

Blockers of ß-adrenergic receptors in chronic renal failure

Blockers of ß-adrenergic receptors - propranolol (anaprilin, obzidan, inderal), oxyprenolol (trazikor), etc. - are able to reduce renin secretion. Since CKD does not affect the pharmacokinetics of ß-blockers, they can be used at high doses (360-480 mg/day). The blocker of α- and ß-adrenergic receptors labetolol at a dose of 600-1000 mg / day also significantly reduces plasma renin activity. In hypertension and heart failure, ß-blockers should be prescribed with caution, combining them with cardiac glycosides.

Calcium channel blockers in chronic renal failure

Calcium channel blockers (verapamil, nifedipine, diltiazem) are now increasingly used to treat renal hypertension in patients with chronic renal failure. As a rule, they do not have a negative effect on renal hemodynamics, and in some cases they can slightly increase CF by reducing the resistance of preglomerular vessels.

In patients with chronic renal failure, the excretion of nifedipine (Corinfar) slows down in proportion to the decrease in creatinine clearance, and the hypotensive effect increases. The pharmacokinetics and hypotensive effect of verapamil in patients with varying degrees of impaired renal function and healthy individuals are almost the same and do not change during hemodialysis.

With uremia, the pharmacokinetics of mibefradil, which is a new class of calcium channel blockers, does not change. Being a derivative of tetralol, the drug has 80% bioavailability after oral administration and an average half-life of 22 hours, which allows it to be taken once a day. Mibefradil is metabolized mainly in the liver, and in serum it is 99.5% bound to plasma proteins (mainly acid α1-glycoprotein), so its elimination during hemodialysis is negligible.

Angiotensin-converting enzyme inhibitors

Most ACE inhibitors (captopril, enalapril, lisinopril, trandolapril) are eliminated from the body by the kidneys, which must be taken into account when prescribing them to patients with chronic renal failure. Fosinopril, ramipril, temocapril, etc. are excreted unchanged and in the form of metabolites not only with urine, but also with bile, and in chronic renal failure, their hepatic elimination pathway increases compensatory. For such drugs, dose reduction is not required when administered to patients, even with severely impaired renal function, although the frequency of adverse reactions may increase slightly. The most serious of these are hyperkalemia (hyperreninemic hypoaldosteronism) and deterioration of kidney function, which primarily threatens patients with renovascular hypertension (often with bilateral renal artery stenosis) and kidney transplant recipients with the development of arterial stenosis of the transplanted kidney.

Z.Wu and H.Vao (1998) found that the ACE inhibitor benazepril at a dose of 10-20 mg / day, along with a decrease in blood pressure, also reduces insulin resistance and glucose intolerance in patients with preterminal uremia.

Most ACE inhibitors, by reducing the concentration of AN II in the circulation, are not able to block the formation of AN II at the tissue level, since in the heart without the participation of ACE under the action of serine proteinases (chymase) up to 80% of AN II is formed, and in the arterial wall 70% of AN II is generated under the influence of the chymase-like enzyme CAGE (chymosin-sensitive angiotensin II - generating enzyme).

Undesirable activation of the renin-angiotensin system, including at the tissue level, can be weakened by blocking specific receptors (AT1) that mediate the action of AN II.

The first AT1 peptide blocker synthesized was saralazine, which caused a persistent decrease in blood pressure in rats with one occluded renal artery and in humans when administered intravenously at a dose of 0.1 to 10 mg/kg.

In 1982, the ability of imidazole derivatives to block some of the effects of AN II was revealed, which served as the basis for the subsequent development and clinical use of non-peptide AT1 blockers. One of the first drugs of this group, which have an antihypertensive effect when taken orally, was losartan. Subsequently, he and similar drugs, as well as ACE inhibitors, began to be widely used not only in arterial hypertension, but also in heart failure, to prevent the progression of chronic renal failure and reduce proteinuria. In the experiment, AT1 blockers improved myocardial function in its hypertrophy, viral damage, etc.

Patients with chronic renal failure practically do not need to reduce the dose of AT1 blockers and rarely experience side effects (cough, angioedema, etc.) characteristic of ACE inhibitors.

Currently, drug therapy for arterial hypertension is so effective that it allows, in combination with non-drug methods (ultrafiltration, hemodiafiltration), to abandon the recently practiced in patients taken for hemodialysis, binephrectomy or embolization of the renal arteries.

Relief of a hypertensive crisis

For the relief of hypertensive crises in severe chronic renal failure, in addition to traditional ganglioblockers, sympatholytics, etc., the calcium antagonist verapamil (Isoptin) and peripheral vasodilators: diazoxide and sodium nitroprusside can be used parenterally. The hypotensive effect of these drugs occurs within minutes after administration, but does not last long. Isoptin is administered intravenously by bolus at a dose of 5-10 mg, its effect can be prolonged by drip administration up to a total dose of 30-40 mg. The most powerful vasodilator, sodium nitroprusside, is prescribed only intravenously (50 mg in 250 ml of 5% glucose solution) for 6-9 hours with constant monitoring of blood pressure and regulation of the rate of administration. Diazoxide (hyperstat, odemin) 300 mg is administered intravenously by stream for 15 seconds, the hypotensive effect lasts up to 6-12 hours. Multiple use of vasodilators is limited due to the risk of side effects (sodium nitroprusside can be administered no more than 3 times due to the accumulation metabolite ≈ thiocyanate, and diazoxide can reduce, albeit reversibly, renal blood flow and CF).

Often, rapid relief of a hypertensive crisis is observed with sublingual use of 5-10 mg of nifedipine or 12.5-25 mg of captopril.

CKD and heart failure

Prolonged hypertension in combination with uremic intoxication, hyperhydration, acidosis, anemia, electrolyte and other shifts cause damage to the heart muscle, which leads to heart failure, in which cardiac glycosides are indicated. When prescribing cardiac glycosides, it is necessary to take into account the ways and speed of their excretion from the body and the content of potassium in the plasma. Strofantin is excreted mainly by the kidneys, therefore, with severe chronic renal failure, its half-life increases by more than 2 times, and the dose should be reduced to 50-75% of the usual one. The daily dose of digoxin in chronic renal failure should not exceed 50-60% of the normal, i.e. not more than 0.5 mg / day, more often 0.125 mg / day. Digitoxin is mainly metabolized in the liver, its half-life in chronic renal failure almost does not differ from the norm, however, due to a change in the sensitivity of the myocardium to glycosides, it is recommended to prescribe 60-80% of the usual dose (0.15 mg / day).

However, a violation of the systolic function of the heart is rarely observed in moderately severe chronic renal failure. Diastolic dysfunction is corrected by the appointment of ACE inhibitors, AT1 receptor blockers, nitrates.

Anabolic steroids ≈ methandrostenolone (nerobol) 5 mg 1-2 times a day, retabolil, methylandrostenediol, nonsteroidal anabolic substances (potassium orotate), B vitamins, etc. can bring some benefit in terms of correcting cardiopathy.

acidosis in CKD

Acidosis usually does not cause severe clinical symptoms. The main reason for its correction is the prevention of the development of bone changes with a constant retention of hydrogen ions, as well as hyperkalemia. In moderate acidosis, protein restriction helps. To correct severe acidosis, sodium bicarbonate is recommended at 3-9 g / day, in acute situations - intravenous administration of a 4.2% sodium bicarbonate solution (inject slowly). Its amount depends on the deficiency of buffer bases (RBD).

Taking into account that 1 ml of a 4.2% sodium bicarbonate solution contains 0.5 mmol of bicarbonate, it is possible to calculate the volume of solution required to replenish DBO, however, the administration of more than 150 ml of the solution at a time is undesirable because of the danger of inhibition of cardiac activity and development heart failure. Calcium carbonate is somewhat less effective (2 g 4-6 times a day). Taking large doses of calcium carbonate can cause constipation.

Urgent correction of acidosis is necessary with increasing hyperkalemia that develops with oliguria or the appointment of potassium-sparing diuretics (veroshpiron, triamteren). An increase in serum potassium up to 6 mmol / l is usually not accompanied by clinical symptoms. With severe hyperkalemia, muscle paralysis may develop and, which is especially dangerous, cardiac arrhythmias, up to a complete cardiac arrest.

Hyperkalemia in chronic renal failure

Treatment of acute, life-threatening hyperkalemia begins with the infusion of a physiological potassium ≈ calcium antagonist, which is administered intravenously at a dose of 2 g in the form of a 10% solution of calcium gluconate every 2-3 hours. The transition of potassium from the extracellular fluid to the cells is achieved by intravenous administration of bicarbonate (it is necessary to increase the concentration bicarbonate in serum up to 15 mmol / l) and crystalline zinc-insulin (15-30 IU, every 3 hours with 2-5 g of glucose per unit of insulin to prevent hypoglycemia). Insulin increases the activity of the sodium-potassium cellular pump and the entry of potassium into cells.

The removal of potassium from the body is achieved by taking an ion exchange resin at 40-80 mg / day, which reduces the concentration of potassium in the serum by 0.5-1 mmol / l. This drug is often combined with sorbitol, which causes diarrhea. The purpose of the resin is recommended for the prevention of hyperkalemia and acute renal failure. With intractable hyperkalemia, hemodialysis or peritoneal dialysis is performed.

The use of antibiotics in chronic renal failure

Due to the potential nephrotoxicity of many drugs, the correct treatment of uremia of various infectious complications is important. For local bacterial infections, such as pneumonia, it is advisable to prescribe penicillins and cephalosporins, which have little toxicity even with significant plasma accumulation. Aminoglycosides, which have a "narrow safety margin" - a small gap between the therapeutic and toxic dose, can cause deterioration in kidney function, neuromuscular block, neuritis of the auditory nerves. Their use is justified in severe septic conditions. The concentration of gentamicin, tobramycin and other drugs of this group in the serum can be reduced to subtherapeutic when used together with carbenicillin or heparin. Elimination of tetracyclines in patients with chronic renal failure is slowed down, which requires a corresponding reduction in the usual dose by about 1/3. It should be remembered that drugs in this group can aggravate azotemia and increase acidosis.

Similarly, it is necessary to reduce the dose of fluoroquinolones, although they are partially metabolized in the liver.

In urinary tract infections, preference is also given to penicillin and cephalosporins, which are secreted by the tubules. Due to this, their sufficient concentration is ensured even with a decrease in CF. This applies equally to sulfonamides, including prolonged action. It is impossible to achieve a therapeutic concentration of aminoglycosides in the urinary tract with CF less than 10 ml / min.

Catad_tema Type II diabetes mellitus - articles

Catad_tema Kidney pathology - articles

The use of the angiotensin-converting enzyme inhibitor spirapril in chronic renal failure, hypertension and diabetic nephropathy

G. L. Elliot
Faculty of Medicine and Therapy, University of Glasgow, Scotland

Summary

Data from modern clinical studies on arterial hypertension (AT) and the recommendations of national and international societies for its treatment indicate the importance of strict regulation of blood pressure (BP). This, in particular, is well illustrated by the fact that in the treatment of patients with diabetes mellitus (DM) with strict regulation of blood pressure, clinical outcomes are markedly improved with a decrease in the incidence of fatal and non-fatal cardiovascular complications.

Clinical trials for the treatment of hypertension have shown that a number of antihypertensive drugs successfully reduce blood pressure, but there is a significant amount of information that the optimal treatment of diabetic nephropathy and (micro)albuminuria should be based on the use of ACE inhibitors. Despite ongoing debate over whether the benefits of treating diabetic and hypertensive patients are related to BP reduction per se, it is widely believed that inhibition of the intrarenal renin-angiotensin system provides more success than achieving hemodynamic changes alone. Thus, hypertension and nephropathy in DM and other forms of kidney disease can be managed with ACE inhibitors.

For the selection of a specific ACE inhibitor in diabetic nephropathy, there are no direct comparisons between them. There is evidence that spirapril is at least as effective as the reference ACE inhibitor enalapril, but with a trend towards greater reductions in diastolic BP.

Clearly, patients with diabetic nephropathy and/or chronic renal failure are at potential risk of drug accumulation if clearance is achieved solely by glomerular filtration. In this regard, spirapril has advantages. Data have been published showing that spirapril(at) does not produce marked changes in end-point concentrations (24 hours post-dose) of the drug, even in advanced renal failure (GFR).< 20 мл/мин). Таким образом, не требуется модификации лечебного режима и можно не беспокоиться о кумуляции препарата, возможных избыточных действиях и неблагоприятных побочных эффектах его. Можно сказать, что ингибиторы АПФ являются интегральным компонентом лекарственной терапии для пациентов с диабетической нефропатией. При почечной недостаточности желательно назначать такие препараты, как спираприл, поскольку он обладает и внепочечным механизмом выведения, не кумулируется и не дает неблагоприятных побочных эффектов.

Keywords: spirapril, chronic renal failure, diabetic nephropathy, arterial hypertension, angiotensin-converting enzyme inhibitors

THE ACE INHIBITOR SPIRAPRIL IN CHRONIC RENAL FAILURE, HYPERTENSION AND DIABETIC NEPHROPATHY

H. L. Elliott

The evidence from recent clinical outcome trials in arterial hypertension (AH) and the treatment guidelines from national and international authorities have placed a clear emphasis on "tight" blood pressure (BP) control. This has been particularly well illustrated in the treatment of patients with diabetes mellitus and AH where "tight" BP control clearly improves the outcome with reduced numbers of fatal and non-fatal cardiovascular events. Whilst the clinical trials in AH have identified benefits through BP reduction with a range of antihypertensive drugs there is a considerable volume of evidence to suggest that the optimal treatment for diabetic nephropathy and microalbuminuria should be based upon ACE inhibition. It is widely held that inhibition of intra-renal renin angiotensin systems leads to greater benefit than can be achieved by hemodynamic changes alone. Thus, management of AH and nephropathy in both DM and other forms of renal disease revolves around BP reduction through an ACE inhibitor-based treatment regimen.

Where there is renal failure it may be prudent to administer a drug such as spirapril which has non-renal elimination mechanisms and which has been shown to have no accumulation problems or increased adverse effects.

key words: spirapril, chronic renal failure, diabetic nephropathy, hypertension, ACE inhibitors

Arterial hypertension (AH) is found in about 50% of cases with parenchymal kidney disease, regardless of the underlying diagnosis. However, quantitatively, diabetes mellitus (DM) is the most common cause of renal dysfunction, and the prevalence of both diabetic nephropathy and elevated blood pressure increases with age and duration of the disease. At any level of blood pressure, a patient with diabetes is significantly more at risk of cardiovascular disease, and this is an obvious indication for effective antihypertensive therapy.

The benefit of lowering blood pressure in hypertensive patients with diabetes is supported by the results of a number of recent clinical studies, and there is a significant amount of evidence in favor of the use of antihypertensive treatment regimens based on the use of angiotensin-converting enzyme (ACE) inhibitors.

In a seminal study by E. J. Lewis et al. the benefits of treatment of patients with type 1 diabetes based on the use of captopril have been confirmed in terms of not only reducing the rate of further deterioration of kidney function, but also a significant reduction in mortality and slowing the need for renal replacement therapy using dialysis or transplantation (Table 1). Captopril has also been used in the United Kingdom Prospective Diabetes Study (UK-PDS), which examined the benefits of tight and loose blood pressure regulation in the treatment of patients with type 2 diabetes. Based on the data obtained for captopril and similar results of studies on other ACE inhibitors, most national and international recommendations for the treatment of hypertension have identified ACE inhibitors as the drugs of choice for patients at high risk of cardiovascular morbidity and death due to the combination of hypertension and diabetes.

Table 1
Results of treatment with ACE inhibitors in patients with insulin-dependent DM (type 1) with diabetic nephropathy

Kidney disease, BP regulation, and choice of antihypertensive drug therapy

It has long been known that the decline in glomerular filtration rate in patients with diabetic nephropathy can be slowed down by effective antihypertensive therapy and BP reduction. The result of clinical studies on the use of ACE inhibitors is the current widespread recognition that ACE inhibitors are the main treatment for patients with a combination of hypertension, diabetes and diabetic nephropathy or kidney disease. However, in routine clinical practice, a number of additional tasks and aspects arise: a) patient compliance with prescribed treatment; b) strict regulation of blood pressure; c) mechanisms of non-renal elimination; d) safety and tolerability.

Patient compliance with prescribed treatment. Regardless of whether patients are diabetic or have other diseases, they are equally poor adherence to prescribed drug therapy. For this reason, an ACE inhibitor that can be taken once a day has a clear advantage. Given this, and despite the good results of clinical studies, captopril with the need to prescribe it 2 or 3 times a day is probably not the drug of choice.

Strict regulation of blood pressure. Obviously, regardless of the frequency of drug administration, it is necessary to achieve reliable round-the-clock regulation of blood pressure. Although this may often require a combination of different drugs, the treatment regimen should be based on an ACE inhibitor that is capable of providing a consistent and long-term antihypertensive effect. With regard to the quality of BP regulation, the results of a recent study show that spirapril is at least as effective as enalapril, both in magnitude and in the consistency of its antihypertensive effect.

Mechanisms of non-renal elimination. In patients with impaired renal function, reduced renal clearance may lead to excessive accumulation of the drug (or active metabolite), which in turn may increase the risk of adverse effects and possible drug toxicity. Therefore, the most preferred is a drug that is completely or partially eliminated by the non-renal route (ie, through the liver).

Safety and portability. Obviously, what is required is a drug that does not in itself cause deterioration of kidney function. In addition, in patients with impaired renal function, the incidence of side effects or reduced tolerability of the drug should not increase.

The use of spirapril in patients with renal insufficiency

Spirapril is an ACE inhibitor with two routes of elimination, with approximately 50% hepatic metabolism and 50% renal excretion. The effect of kidney damage of varying severity on the pharmacokinetics of spirapril was studied in detail in patients with creatinine clearance from 11 to 126 ml/min. In this study, 34 patients were divided into 4 groups according to creatinine clearance: in group I, the average creatinine clearance was 102 ml/min, in II, III and IV - 63, 32 and 17 ml/min, respectively. Although a statistically significant increase in the maximum concentration (C max) and the area under the plasma concentration-time curve (AUC) was proved in accordance with the decrease in glomerular filtration rate, it was not possible to detect a significant increase in the minimum plasma concentration of the drug (C min ) both after a single dose of spirapril (6 mg) and at constant plasma concentrations after 4 weeks of treatment with spirapril when taken once a day at 6 mg. Thus, there is no evidence of significant drug accumulation even in patients with creatinine clearance below 20 ml/min.

An additional feature of this clinical pharmacological study is the evidence that the degree of ACE inhibition and blood pressure reduction was maintained in all ranges of renal function, both with a single dose of spirapril and with treatment with it at a constant concentration in the blood. For example, under constant concentration conditions, a significantly higher level of ACE inhibition was noted during both the maximum and minimum concentrations of the drug in patients with more severe kidney damage (Table 2). However, no changes in kidney function were found; there was no increase in the frequency of side effects, as well as significant differences in the achieved blood pressure levels (Table 3).

The antihypertensive efficacy of spirapril has been documented in many clinical studies. Of particular interest is a comparative study with the ACE inhibitor enalapril, which assessed the response to 6 weeks of treatment. In general, the degree of reduction in blood pressure was almost the same, namely by 13/7 mm Hg. Art. (compared with placebo) for enalapril and 12/10 mm Hg. Art. for spirapril. A greater decrease in diastolic blood pressure during treatment with spirapril was statistically significant (p< 0,01).

table 2
Inhibition of ACE activity at the maximum and minimum concentration of the drug after a single dose of spirapril and under conditions of constant concentration

* R< 0,01 по сравнению с исходными.

Table 3
BP in the sitting position of patients after 4 weeks of treatment with spirapril

* R< 0,01 по сравнению с исходными.

A feature of this study was the determination of the T/P ratio (final and peak hypotensive effects) as an indicator of the duration of action of drugs (Table 4). For spirapril at a dose of 6 mg, the T / P ratio was 83%, for enalapril at a dose of up to 10 mg - only 71%. When the dose of enalapril was increased to 20 mg, the T/P ratio increased to 82% and the corresponding comparative value for spirapril 6 mg was 84%. Spirapril at the standard dosage of 6 mg gives a satisfactory T/P ratio consistently above that achieved with enalapril treatment. This study found another important practical advantage - neither titration nor dynamic dose adjustment is required to achieve the optimal antihypertensive effect of spirapril.

Table 4
Comparison of the action of spirapril and enalapril - end effect / peak effect for diastolic BP

There have been no studies on spirapril involving a large number of patients with diabetic nephropathy, but the available information is fully consistent with the results of studies of other ACE inhibitors. For example, a comparative study of spirapril and isradipine in a small number of patients showed that spirapril significantly reduces proteinuria and does not affect the glomerular filtration rate (Table 5). On the contrary, the use of isradipine was associated with a significant increase in proteinuria and with a tendency to worsen glomerular filtration.

Table 5
Treatment of diabetic nephropathy: comparative results of spirapril and isradipine after 6 months of treatment

Combined treatment with spirapril.

It is well known that combination drug treatment is needed in more than 50% of patients with essential hypertension (hypertension). The benefits of combination treatment were proven in the UKPD study, in which those patients who received strict BP control experienced a significant 24% reduction in the sum of diabetes-related endpoints compared with those in patients who received less strict BP control (p< 0,005). Это включало достоверное снижение (на 44%) случаев инсульта, а также недостоверное снижение (на 21%) частоты возникновения инфаркта миокарда, уменьшение на 18% общей смертности . Чтобы достигнуть этих успехов более чем у 60% пациентов, требовалось применение двух лекарственных препаратов или более. Комбинации ингибиторов АПФ и диуретиков были широко использованы при лечении больных СД с АГ.

Recently, combinations of ACE inhibitors and calcium channel blockers have become more widespread due to the combination of their antihypertensive effect and the absence of long-term undesirable metabolic effects.

We studied the effect of treatment with spirapril in combination with the calcium channel blocker isradipine on blood pressure, left ventricular hypertrophy and renal function. Based on ambulatory blood pressure measurements in one of these studies, this combination resulted in the lowest levels of blood pressure, especially systolic blood pressure, which was significantly lower than either drug alone. The average (approximate) levels of blood pressure achieved when combining spirapril with isradipine were 132/88 mm Hg in daily measurements. Art. and at night measurements 130/80 mm Hg. Art. Monotherapy with each of these drugs did not allow to achieve the level of systolic blood pressure below 140 mm Hg. Art.

Conclusion.

Patients with a combination of hypertension and diabetes are at high risk of cardiovascular disease. There is evidence that antihypertensive therapy not only inhibits further progression of kidney damage, but also improves outcomes by reducing cardiovascular morbidity and mortality. This is not as obvious for other kidney diseases, but the available evidence is consistent with the concept that sound BP control is a central part of the management of patients with hypertension and kidney disease.

The advantage of spirapril is the possibility of taking it once a day, as well as the fact that it does not accumulate to any noticeable degree in the presence of impaired renal function. For this reason, a drug with a dual elimination mechanism is preferred as the drug of choice, and spirapril has been shown to show no significant drug accumulation even in patients with moderate to severe renal insufficiency.

Thus, spirapril is a first-line drug for patients with hypertension and kidney damage, including patients with diabetic nephropathy.

LITERATURE
1. Lewis E. J., Hunsicker L. G., Bain R. P, Rohde R. D. for the Collaborative Group. The effect of angiotensin-converting-en-zyme inhibition on diabetic nephropathy. N. Engl. J. Med. 1993; 329: 1456-1462.
2. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular complications in type 2 diabetes: UKPDS 38 Br. Med. J. 1998; 317:703-713.
3. Guitard C., Lohmann F. W., Alflero R. et al. Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension. Cardiovasc. Drags Ther. 1997; 11:449-457.
4. Grass P., Gerbeau C., Kutz K. Spirapril: pharmacokinetic properties and drug interactions. Blood Pressure 1994; 3 (suppl. 2): 7-13.
5. Meredith P. A., Grass P., Guitard C., Elliott H. L. Pharmacokinetics of spirapril in renal impairment. Ibid. 1993 (suppl. 2): 14-19.
6. Norgaard K., Jensen T., Christensen P., Feldt-Rasmusen B. A comparison of spirapril and isradipine in patients with diabetic nephropathy and hypertension. Ibid. 1993; 2:301-308.
7. Maccariella E. R., Geneldu de Abreu Fagundes V., Francischetti E. A. The effects of isradipine and spirapril as monotherapy and combined therapy on blood pressure, renal haemodynam-ics, natriuresis and urinary kallikrein in hypertensive nephropathy. Am. J. Hypertens. 1997; 10:541-545.
8. Manolis A. J., Beldekos D., Handanis S. et al. Comparison of spirapril, isradipine, or combination in hypertensive patients with left ventricular hypertrophy. Effects on LVH regression and arrhythmogenic propensity. Ibid. 1998; 11:640-648.

Catad_tema Type II diabetes mellitus - articles

Fixed combinations of antihypertensive drugs and risk management of nephropathy in type 2 diabetes mellitus

Published in the magazine:
"CARDIOLOGY"; No. 10; 2012; pp. 110-114.

V.V. Fomin
GBOU VPO First Moscow State Medical University. THEM. Sechenov Ministry of Health and Social Development of the Russian Federation, 119992 Moscow, st. Trubetskaya, 8, building 2

Fixed Dose Combinations Of Antihypertensive Drugs And Management Of Risk Of Development Nephropathy In Type 2 Diabetes Mellitus

V.V. Fomin
I.M. Sechenov First Moscow Medical State University, ul. Trubetckay 8 str. 2, 119992 Moscow, Russia

The importance of lowering blood pressure (BP) as one of the main tools for managing the risk of developing organ damage in type 2 diabetes mellitus (DM) is currently beyond doubt, and in general, from this point of view, as one of the decisive evidence is still UKPDS results may be considered. Despite the fact that the results of some controlled clinical trials published over the past 5 years have become the basis for another discussion on the extent to which the maximum possible reduction in blood pressure is necessary in type 2 diabetes and, in general, whether special standards are needed for patients in this category target blood pressure, there is no reason to believe that it is possible to avoid the appearance of signs of organ damage in them without the help of antihypertensive drugs. Obviously, there will be no "revolutionary" changes in the tactics of managing a patient with type 2 diabetes in the near future, and the main positions of the generally accepted recommendations of experts will remain the same.

The problem of diabetic nephropathy has become an independent object of major clinical research due to a number of circumstances: firstly, its epidemic prevalence and the leading role in the structure of the causes of end-stage renal failure have become apparent; secondly, its signs, in particular, microalbuminuria (MAU) - a relatively early and potentially removable factor - can be considered as one of the most reliable markers of an unfavorable long-term prognosis; From a practical standpoint, we can say that among all patients with type 2 diabetes, the risk of death is maximum, and life expectancy is minimal in those who can detect signs of kidney damage. It should be emphasized that this statement can rightly be extrapolated to the general population: large epidemiological studies and meta-analyses based on them have clearly shown that the risk of developing cardiovascular complications (CVD) is maximum in the presence of signs of chronic kidney disease (CKD). ) - albuminuria and / or a decrease in the estimated glomerular filtration rate. There are a lot of such patients: these signs of CKD can be detected in 5-15% of the general population, depending on the ethnic and age composition of the examined. In turn, arterial hypertension (AH) and type 2 diabetes, especially in combination, retain their leading positions among the determinants of CKD in the general population, and therefore the importance of controlled clinical trials aimed at improving the tactics of its prevention in this category of patients is very important. great.

What results of controlled clinical trials that evaluated the "renal" component of the effectiveness of antihypertensive drugs in type 2 diabetes can be considered not subject to revision? First of all, the results of those studies that demonstrated the ability of angiotensin-converting enzyme inhibitors - ACE (for example, one of the earliest - EUCLID) and, somewhat later, angiotensin II receptor blockers (well-known RENAAL, IDNT, etc.) to significantly reduce urinary albumin excretion . The dynamics of this indicator was significantly associated with an increase in renal survival (UNCLEAR!) and a decrease in the risk of further deterioration of kidney function up to the end stage of renal failure. From this point of view, the results of the HOPE study and its part MICRO-HOPE turned out to be particularly instructive, demonstrating that the use of an ACE inhibitor in patients with type 2 diabetes can reduce albuminuria and significantly improve renal prognosis (UNCLEAR!), including if they also have other risk factors for the development of CVD, which are also determinants of CKD, in particular, in the absence of documented hypertension. Nevertheless, in the combination of type 2 diabetes and hypertension, the combined use of a renin-angiotensin-aldosterone system blocker and, if possible, reaching its maximum dose are considered as starting and absolutely necessary elements of kidney protection tactics.

Obviously, antihypertensive therapy used in patients with type 2 diabetes and including an ACE inhibitor or an angiotensin II receptor blocker should suggest the possibility of their combination. From a pathogenetic standpoint, the combination of an ACE inhibitor with a non-dihydropyridine calcium antagonist can claim to be one of the most justified. The BENEDICT study showed the ability of this combination of antihypertensive drugs to slow down the progression of the early stages of diabetic nephropathy. Of course, the combination of an ACE inhibitor (it should be emphasized that angiotensin II receptor blockers have not been studied in such a combination) with a non-dihydropyridine calcium antagonist deserves widespread use in patients with type 2 diabetes, but it cannot claim to be the only possible one, if only because it itself a non-dihydropyridine calcium antagonist (verapamil or diltiazem) may not always be used. So, the presence of chronic heart failure and / or intracardiac conduction disorders can become a significant limitation.

The question of the priority combination of antihypertensive drugs in terms of improving renal prognosis in type 2 DM has long been one of the most acute, and the answer to it was largely due to the ADVANCE study. In this study, the combination of perindopril and indapamide reduced the risk of all types of diabetic kidney disease by 21% (p<0,0001) по сравнению с таковым у пациентов, принимавших плацебо; на ту же величину уменьшилась вероятность возникновения МАУ (p<0,0001). Снижение риска вновь возникающего или прогрессирующего диабетического поражения почек, достигнутое при применении комбинированного препарата периндоприла с индапамидом по сравнению с плацебо, составило 18%, различие между группами было близким к статистически значимому (p=0,055). Ориентируясь на результаты исследования ADVANCE, можно утверждать, что благодаря использованию периндоприла с индапамидом у 1 из 20 больных СД 2-го типа в течение 5 лет можно предупредить диабетическую нефропатию, особенно ее III стадию, характеризующуюся появлением МАУ. Специально предпринятый анализ эффективности комбинированного препарата периндоприла и индапамида в зависимости от скорости клубочковой фильтрации в исследовании ADVANCE выявил, что при ХБП III и последующих стадий (расчетная скорость клубочковой фильтрации <60 мл/мин/1,73 м 2) выраженность положительного влияния этого комбинированного препарата на прогноз ССО, как минимум, удваивается. Благодаря комбинации периндоприла с индапамидом в группе с ХБП III и последующих стадий (n=2033, т. е. примерно каждый пятый больной из включенных в исследование) в течение 5 лет удается предотвратить 12 осложнений на 1000 пациентов, в то время как в группе с сохранной фильтрационной функцией почек - 6 осложнений на 1000 пациентов. Необходимо подчеркнуть, что нефропротективный эффект комбинированного препарата периндоприла с индапамидом в исследовании ADVANCE оказался ассоциированным со снижением риска развития ССО. Основные микро- и макрососудистые осложнения были констатированы в течение периода наблюдения у 15,5% больных, принимавших периндоприл с индапамидом, и у 16,8% представителей группы, в которой назначали плацебо. Таким образом, комбинация периндоприла с индапамидом обеспечивала достоверное снижение риска развития осложнений СД 2-го типа на 9% (p=0,041). Это означает, что их удается предупредить благодаря применению названных препаратов в течение 5 лет у 1 из 66 подобных пациентов.

Particularly instructive were the results of a specially conducted analysis of data from the ADVANCE study from the point of view of the effect of the dynamics of blood pressure achieved as a result of treatment on the signs of diabetic nephropathy. At the start of the study, blood pressure in the included patients averaged 145/81 mm Hg, in 20% of them initially did not exceed 130/80 mm Hg. During treatment, in the group receiving the combined preparation of perindopril with indapamide, blood pressure of 134.7 / 74.8 mm Hg was achieved, in the placebo group - 140.3 / 77.0 mm Hg. (p<0,0001). У получавших комбинированный препарат периндоприла с индапамидом за время исследования масса тела уменьшилась в среднем на 0,3 кг, в то время как у получавших плацебо увеличилась на 0,2 кг (p<0,0001). Практически одинаковое (74 и 73%) число представителей обеих групп к завершению исследования продолжали принимать назначенную терапию. Достигли исхода, относящегося к комбинированному показателю функции почек (дебют МАУ, признаков нефропатии, удвоение уровня креатинина до ≥200 мкмоль/л или терминальная стадия почечной недостаточности), 22,3% из принимавших комбинированный препарат периндоприла и индапамида и 26,9% из принимавших плацебо (p<0,0001). Таким образом, использование комбинации периндоприла с индапамидом позволяет предупредить наступление неблагоприятного почечного исхода в течение 5 лет у 1 из 20 больных СД 2-го типа; вероятность его развития, таким образом, снижается на 21%. Комбинированный препарат периндоприла с индапамидом снижал вероятность дебюта МАУ на 21% (p<0,0001), вероятность появления альбуминурии при исходной нормо- или МАУ - на 22% (p<0,0001). Развитие тяжелой нефропатии, которую констатировали при появлении альбуминурии, констатировано у 2,1% принимавших комбинированный препарат периндоприла с индапамидом и у 3% получавших плацебо (p=0,003). У пациентов, получавших комбинированный препарат периндоприла с индапамидом, чаще отмечался регресс МАУ вплоть до ее исчезновения. Скорость снижения расчетной скорости клубочковой фильтрации в обеих группах оказалась практически одинаковой.

The antialbuminuric effect of the combination of perindopril with indapamide persisted regardless of the initial level of systolic blood pressure (SBP), including in the group of patients in whom it was initially less than 120 mm Hg. This effect was maintained in all groups of patients, divided depending on the initial level of SBP (for example, less and more than 130/80 mm Hg, less and more than 140/90 mm Hg). However, the risk of composite renal function outcomes was significantly reduced in the groups with minimal achieved SBP, being lowest in patients with a mean SBP at the end of treatment of 106 mmHg. A similar pattern was obtained in the analysis of the relationship between renal risk and diastolic blood pressure (DBP).

Analysis of the results of the ADVANCE study in terms of the effect of the achieved BP dynamics on the risk of progression of diabetic nephropathy is very instructive and allows us to draw a number of practical conclusions. First of all, it is obvious that the combination of perindopril with indapamide has a positive effect on renal prognosis, regardless of the initial level of blood pressure, and this allows us to discuss the expansion of the group of patients with type 2 diabetes, in which its use can be considered indicated, towards people with normal blood pressure. Nevertheless, comparison of the dynamics of blood pressure with the risk of increased albuminuria and deterioration of the filtration function of the kidneys indicates that in type 2 diabetes, it is still necessary to strive for the maximum possible reduction in blood pressure, which, in turn, indicates the advisability of using the combined drug perindopril with indapamide in maximum doses. In favor of the expediency of achieving the maximum dose level in this combination is evidenced, in particular, by the experience of the combined analysis of data from the PIXCEL and PREMIER studies. Along with the greatest reduction in SBP and DBP achieved with the use of the maximum dose of perindopril and indapamide, the use of this combination made it possible to achieve the most pronounced decrease in the mass index of the left ventricular myocardium. In the PREMIER study, the combination of perindopril with indapamide at the maximum dose caused the greatest decrease in albumin / creatinine levels (it should be noted that this was not achieved in the group of patients who received enalapril 40 mg). Therefore, it can be argued that the combination of perindopril with indapamide in terms of nephroprotection in type 2 diabetes has significant advantages over monotherapy with an ACE inhibitor at the maximum dose, especially since it is often not well tolerated by patients.

The tactics of increasing doses to the maximum when using a combined preparation of an ACE inhibitor with a thiazide-like diuretic is recognized as rational. An example is the British guidelines for the management of hypertension, which, as you know, differ in one of the most stringent approaches to the analysis of the evidence base that justifies the use of one or another tactic of antihypertensive therapy. The combination of perindopril with indapamide at the highest (10 mg/2.5 mg) dose currently available in a fixed (Noliprel A Bi-Forte) form has been the subject of a number of controlled trials. The FALCO-FORTE study included 2237 patients with BP >140/90 mmHg. or with BP >130/85 mmHg and 3 or more risk factors who were prescribed a combination drug of perindopril with indapamide at a dose of 2.5 mg/0.625 mg per day (noliprel A) or 5 mg/2.5 SPECIFY!! mg per day (noliprel A forte); within 3 months of treatment, it was allowed to increase the dose to 10 mg / 2.5 mg per day (Noliprel A Bi-forte). Of the patients included in the FALCO-FORTE study, 69% of patients had previously received other antihypertensive drugs that turned out to be ineffective, 4.6% did not tolerate previous therapeutic regimens, and 26.8% of AH was diagnosed for the first time. In 52.6% of the included patients, hypertension was identified, which belonged to the category of high or very high risk of developing CVD (for example, 24.3% had 2, and 21.9% - 3 concomitant risk factors for developing CVD). After 3 months of treatment, the mean blood pressure was 132.3±10.6/81.3±6.3 mm Hg, compared with the initial level, its difference was highly significant. Target BP was achieved in 81.7% of patients. The dynamics of blood pressure was distinct and its severity did not depend on the presence of DM (19.2% of patients), metabolic syndrome (32.7% of patients), and left ventricular hypertrophy (31.6% of patients). The degree of blood pressure reduction increased as the dose of drugs increased: for example, in those receiving perindopril / indapamide at a dose of 2.5 mg / 0.625 mg per day (Noliprel A), SBP decreased by an average of 21.5 ± 11.5 mm Hg, and in those who received perindopril / indapamide at a dose of 10 mg / 2.5 mg per day (Noliprel A Bi-forte) - by 29.7 ± 14.5 mm Hg. Antihypertensive therapy with the combined preparation of perindopril with indapamide also made it possible to achieve a clear improvement in the quality of life of patients. Thus, the results of the FALCO-FORTE study allow us to conclude that the combination of perindopril with indapamide is highly effective in lowering blood pressure in patients with high-risk hypertension, in particular, associated with diabetes, but the greatest efficiency can be achieved when these drugs are used at maximum doses. Therefore, it is from the combination of perindopril with indapamide in maximum doses that one can expect the most pronounced organoprotective, including nephroprotective, action.

At present, it can already be stated that the combined preparation of perindopril and indapamide with their fixed maximum doses has a nephroprotective effect in type 2 diabetes. In particular, this is supported by the results of the VECTOR LIFE study carried out in Ukraine, which included 2747 patients with poorly controlled hypertension and type 2 diabetes. All patients were prescribed a combination drug with a fixed dose of perindopril and indapamide 10 mg/2.5 mg per day (Noliprel A Bi-forte), the duration of treatment was 60 days. The average age of the patients included in the VECTOR OF LIFE study was about 60 years, more than 50% of them had diabetes duration of more than 5 years, all received hypoglycemic therapy (more than 80% - oral drugs, less than 15% - insulins, including in combination with oral hypoglycemic agents). Initially, blood pressure levels were very high (174.4±0.3/62.0±0.3 mm Hg) with a tendency towards the predominance of isolated systolic hypertension, which has a very high risk of complications, including kidney damage, even in the absence of type 2 diabetes. During the initial examination, it was noted that there was a pronounced relationship between the increase in blood pressure and an increase in body weight, as well as the duration of diabetes; with increasing age, a clear increase in SBP was noted with a decrease in DBP. Most patients initially received monotherapy with an ACE inhibitor, about 10% - a calcium antagonist, almost 8% - p-blockers, about 3% - diuretics. Monotherapy, as well as combination therapy, in patients included in the VECTOR LIFE study, did not provide the necessary control of blood pressure.

A distinct change in blood pressure was achieved through therapy with a combination of perindopril with indapamide at the maximum dose (10 mg / 2.5 mg per day) already on the 14th day of treatment: SBP decreased by an average of 26.4 mm Hg, DBP - at 11.9 mm Hg. After 60 days of taking the drug, SBP decreased by 39.5 mm Hg, DBP - by 18.2 mm Hg. Thus, by the end of the study, normalization of blood pressure (134.9±0.8/82.4±0.1 mm Hg) was noted in the group as a whole. In 6%, by the end of the study, blood pressure remained within<130/80 мм рт. ст. Нормализации АД в целом удалось достичь у 57,5% пациентов. На антигипертензивную эффективность комбинации периндоприла с индапамидом в дозе 10 мг/ 2,5 мг в сутки не оказывало заметного влияния наличие ожирения. Прием комбинированного препарата периндоприла и индапамида в максимальных фиксированных дозах хорошо переносился больными. Таким образом, согласно результатам исследования ВЕКТОР ЖИЗНИ, фиксированная комбинация периндоприла с индапамидом обусловливает четкое снижение (у большинства больных - нормализацию) АД при исходно очень высоких его уровнях и низкой эффективности предшествующей терапии. С точки зрения органопротекции, в том числе нефропротекции, особое значение имеют полученные в исследовании ВЕКТОР ЖИЗНИ результаты, указывающие на существенные возможности Нолипрела А Би-форте в снижении САД, в том числе при исходном изолированном систолическом варианте АГ.

The strategy of nephroprotection in type 2 diabetes will obviously be further improved. At the same time, there is no doubt that the strategy of antihypertensive therapy based on the use of a combination of an ACE inhibitor with a thiazide-like diuretic will retain priority positions in this regard. At present, it is quite possible to achieve the maximum effect from the use of this combination drug due to the combination of perindopril and indapamide in the maximum fixed doses. The use of this combination is justified in all situations where there are signs of diabetic kidney disease and / or the risk of their occurrence is significant, including when other fixed full-dose combinations of antihypertensive drugs have not been effective enough.

Information about authors:
GBOU VPO First Moscow State Medical University. THEM. Sechenov, Moscow
Fomin V.V. - MD, prof. Department of Therapy and Occupational Diseases of the Medical and Preventive Faculty, Dean of the Faculty of Medicine.

LITERATURE

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2. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-1585.
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5. Matsushita K, van der Velde M., Astor B.C. et al. Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 2010;375:2073-2081.
6. Chen J., Muntner P., Hamm L. et al. The metabolic syndrome and chronic kidney disease in US Adults. Ann Intern Med 2004;140 167-174.
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