Chronic Renal Failure - Treatment

Conservative treatment of chronic renal failure is divided into symptomatic and pathogenetic. Its tasks include:

• inhibition of the progression of chronic renal failure (nephroprotective effect);
• slowing down the formation of left ventricular hypertrophy (cardioprotective effect);
• elimination of uremic intoxication, hormonal and metabolic disorders;
• elimination of infectious complications of chronic renal failure.

The drug is optimal for monotherapy of chronic renal failure; it has a nephroprotective and cardioprotective effect, is metabolically neutral, and has no side effects.

The main directions of conservative treatment of chronic renal failure are correction of nitrogen and water-electrolyte homeostasis, treatment of arterial hypertension and anemia.

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Correction of homeostasis and metabolic disorders

Low-protein diet (LPD) eliminates symptoms of uremic intoxication, reduces azotemia, gout symptoms, hyperkalemia, acidosis, hyperphosphatemia, hyperparathyroidism, stabilizes residual renal function, inhibits the development of terminal uremia, improves well-being and lipid profile. The effect of a low-protein diet is more pronounced when used in the early stages of chronic renal failure and with initially slow progression of chronic renal failure. A low-protein diet, limiting the intake of animal proteins, phosphorus, sodium, maintains the level of serum albumin, preserves nutritional status, enhances the nephroprotective and cardioprotective effect of pharmacotherapy (ACE inhibitors). On the other hand, treatment with epoetin drugs, having an anabolic effect, contributes to long-term adherence to a low-protein diet.

The choice of a low-protein diet as one of the priority methods of treating chronic renal failure depends on the etiology of nephropathy and the stage of chronic renal failure.

• In the early stages of chronic renal failure (creatinine less than 0.25 mmol/l), a diet with moderate protein restriction (1.0 g/kg of body weight) and a caloric content of at least 35-40 kcal/kg is acceptable. In this case, vegetable soy proteins (up to 85%) are preferable, enriched with phytoestrogens, antioxidants and containing less phosphorus than meat, fish, and milk protein - casein. In this case, products from genetically modified soy should be avoided.
• In chronic renal failure with a creatinine level of 0.25-0.5 mmol/l, a greater restriction of protein (0.6-0.7 g/kg), potassium (up to 2.7 g/day), phosphorus (up to 700 mg/day) is indicated with the same caloric content (35-40 kcal/kg). For the safe use of a low-protein diet, prevention of nutritional status disorders, the use of ketoanalogues of essential amino acids is recommended [ketosteril at a dose of 0.1-0.2 g/(kg x day)].
• In severe chronic renal failure (creatinine over 0.5 mmol/l), protein and energy quotas are maintained at 0.6 g protein per 1 kg of patient body weight, 35-40 kcal/kg, but potassium is limited to 1.6 g/day and phosphorus to 400-500 mg/day. In addition, a full range of essential keto/amino acids is added [ketosteril 0.1-0.2 g/(kg x day)]. "Ketosteril" not only reduces hyperfiltration and PTH production, eliminates negative nitrogen balance, but also reduces insulin resistance.
• In chronic renal failure in patients with gouty nephropathy and type 2 diabetes (NIDDM), a low-protein diet with hypolipidemic properties, modified by food additives with a cardioprotective effect, is recommended. The diet is enriched with PUFAs: seafood (omega-3), vegetable oil (omega-6), soy products, food cholesterol sorbents (bran, cereals, vegetables, fruits), folic acid (5-10 mg / day) are added. An important way to overcome uremic insulin resistance is the use of a set of physical exercises that normalize excess body weight. At the same time, an increase in tolerance to physical activity is provided by epoetin therapy (see below).
• To reduce phosphorus intake, in addition to animal proteins, limit the consumption of legumes, mushrooms, white bread, red cabbage, milk, nuts, rice, and cocoa. If there is a tendency toward hyperkalemia, exclude dried fruits (dried apricots, dates), crispy, fried, and baked potatoes, chocolate, coffee, and dried mushrooms; limit juices, bananas, oranges, tomatoes, cauliflower, legumes, nuts, apricots, plums, grapes, black bread, boiled potatoes, and rice.
• A sharp restriction of phosphate-containing products (including dairy products) in the diet of a patient with chronic renal failure leads to malnutrition. Therefore, together with a low-protein diet that moderately limits phosphate intake, drugs that bind phosphates in the gastrointestinal tract (calcium carbonate or calcium acetate) are used. An additional source of calcium are essential keto/amino acids in the form of calcium salts. If the blood phosphate level achieved in this case does not completely suppress the hyperproduction of PTH, it is necessary to add active metabolites of vitamin D ₃ - calcitriol to the treatment, and also correct metabolic acidosis. If complete correction of acidosis with a low-protein diet is impossible, citrates or sodium bicarbonate are prescribed orally in order to maintain the SB level within 20-22 mEq/l.

A 1g serving of food contains 5g of protein

Products	Portion weight, g
Bread	60
Rice	75
Cereals (buckwheat, oatmeal)	55-75
Chicken egg (one)	50
Meat	25
Fish	25
Cottage cheese	30
Cheese	15-25
Lard (fat)	300
Milk	150
Sour cream, cream	200
Butter	500
Potato	300
Beans	25
Fresh peas	75
Fresh mushrooms	150
Chocolate	75
Ice cream cream	150

Enterosorbents (povidone, hydrolytic lignin, activated carbon, oxidized starch, oxycellulose) or intestinal dialysis are used in the early stages of chronic renal failure or when it is impossible (unwilling) to follow a low-protein diet. Intestinal dialysis is performed by perfusing the intestine with a special solution (sodium chloride, calcium, potassium together with sodium bicarbonate and mannitol). Taking povidone for 1 month reduces the level of nitrogenous waste and phosphates by 10-15%. When taken orally 3-4 hours before, 6-7 liters of intestinal dialysis solution removes up to 5 g of non-protein nitrogen. As a result, the blood urea level decreases by 15-20% per procedure, and acidosis decreases.

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Treatment of arterial hypertension

Treatment of chronic renal failure consists of correction of arterial hypertension. The optimal level of arterial pressure, maintaining sufficient renal blood flow in chronic renal failure and not inducing hyperfiltration, varies within the range of 130/80-85 mm Hg in the absence of severe coronary or cerebral atherosclerosis. At an even lower level - 125/75 mm Hg, it is necessary to maintain arterial pressure in patients with chronic renal failure with proteinuria exceeding 1 g / day. At any stage of chronic renal failure, ganglionic blockers are contraindicated; guanethidine, systematic use of sodium nitroprusside, diazoxide is inappropriate. Saluretics, ACE inhibitors, angiotensin II receptor blockers, beta-blockers, and centrally acting drugs best meet the objectives of hypotensive therapy for the conservative stage of chronic renal failure.

Centrally acting drugs

Centrally acting drugs reduce blood pressure by stimulating adrenergic receptors and imidazoline receptors in the central nervous system, which leads to blockade of peripheral sympathetic innervation. Clonidine and methyldopa are poorly tolerated by many patients with chronic renal failure due to worsening depression, induction of orthostatic and intradialytic hypotension. In addition, the involvement of the kidneys in the metabolism of these drugs dictates the need for dosage adjustment in chronic renal failure. Clonidine is used to relieve hypertensive crisis in chronic renal failure, blocks diarrhea in autonomous uremic neuropathy of the gastrointestinal tract. Moxonidine, unlike clonidine, has a cardioprotective and antiproteinuric effect, a smaller central (depressant) effect and enhances the hypotensive effect of drugs of other groups without disturbing the stability of central hemodynamics. The dosage of moxonidine should be reduced as chronic renal failure progresses, since 90% of the drug is excreted by the kidneys.

Saluretics

Saluretics normalize blood pressure by correcting hypervolemia and removing excess sodium. Spironolactone, used in the initial stage of chronic renal failure, has a nephroprotective and cardioprotective effect by counteracting uremic hyperaldosteronism. With CF less than 50 ml/min, loop and thiazide-like diuretics are more effective and safe. They increase potassium excretion, are metabolized by the liver, therefore, with chronic renal failure, their dosages are not changed. Of the thiazide-like diuretics, indapamide is the most promising for chronic renal failure. Indapamide controls hypertension both due to the diuretic effect and by vasodilation - reducing OPSS. With severe chronic renal failure (CF less than 30 ml/min), a combination of indapamide with furosemide is effective. Thiazide-like diuretics prolong the natriuretic effect of loop diuretics. In addition, indapamide, due to the inhibition of hypercalciuria caused by loop diuretics, corrects hypocalcemia and thereby slows the development of uremic hyperparathyroidism. However, saluretics are not used for monotherapy of hypertension in chronic renal failure, since with prolonged use they aggravate hyperuricemia, insulin resistance, hyperlipidemia. On the other hand, saluretics enhance the hypotensive effect of central antihypertensive agents, beta-blockers, ACE inhibitors and ensure the safety of spironolactone in the early stages of chronic renal failure - due to the excretion of potassium. Therefore, periodic (1-2 times a week) administration of saluretics against the background of constant intake of the above groups of antihypertensive drugs is more beneficial. Due to the high risk of hyperkalemia, spironolactone is contraindicated in patients with diabetic nephropathy in the initial stage of chronic renal failure, and in patients with non-diabetic nephropathy - with a CF of less than 50 ml / min. Loop diuretics, indapamide, xipamide are recommended for patients with diabetic nephropathy. In the political stage of chronic renal failure, the use of loop diuretics without adequate control of water and electrolyte balance often leads to dehydration with acute-chronic renal failure, hyponatremia, hypokalemia, hypocalcemia, cardiac arrhythmias and tetany. Loop diuretics also cause severe vestibular disorders. Ototoxicity increases sharply with a combination of saluretics with aminoglycoside antibiotics or cephalosporins. In hypertension associated with cyclosporine nephropathy, loop diuretics may worsen and spironolactone may reduce the nephrotoxicity of cyclosporine.

ACE inhibitors and angiotensin II receptor blockers

ACE inhibitors and angiotensin II receptor blockers have the most pronounced nephro- and cardioprotective effect. Angiotensin II receptor blockers, saluretics, calcium channel blockers and statins enhance, and acetylsalicylic acid and NSAIDs weaken the hypotensive effect of ACE inhibitors. If ACE inhibitors are poorly tolerated (painful cough, diarrhea, angioedema), they are replaced by angiotensin II receptor blockers (losartan, valsartan, eprosartan). Losartan has a uricosuric effect that corrects hyperuricemia. Eprosartan has the properties of a peripheral vasodilator. Preferred are prolonged-release drugs metabolized in the liver and therefore prescribed to patients with chronic renal failure in slightly changed doses: fosinopril, benazepril, spirapril, losartan, valsartan, eprosartan. Doses of enalapril, lisinopril, perindopril, cilazapril should be reduced in accordance with the degree of decrease in CF; they are contraindicated in ischemic kidney disease, severe nephroangiosclerosis, hyperkalemia, terminal chronic renal failure (blood creatinine over 6 mg/dl), and after transplantation - in hypertension caused by cyclosporine nephrotoxicity. The use of ACE inhibitors in conditions of severe dehydration (against the background of long-term use of high doses of saluretics) leads to prerenal acute renal failure. In addition, ACE inhibitors sometimes reduce the antianemic effect of epoetin drugs.

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Calcium channel blockers

The advantages of calcium channel blockers include a cardioprotective effect with inhibition of coronary artery calcification, a normalizing effect on the circadian rhythm of arterial pressure in chronic renal failure, and the absence of Na and uric acid retention. At the same time, due to the negative inotropic effect, calcium channel blockers are not recommended for chronic heart failure. In hypertension and cyclosporine nephrotoxicity, their ability to influence afferent vasoconstriction and inhibit glomerular hypertrophy is useful. Most drugs (except isradipine, verapamil, and nifedipine) are used in chronic renal failure in normal doses due to their predominantly hepatic metabolism. Calcium channel blockers of the dihydropyridine series (nifedipine, amlodipine, isradipine, felodipine) reduce the production of endothelin-1, but compared to ACE inhibitors, they have less effect on the disturbances of glomerular autoregulation, proteinuria and other mechanisms of progression of chronic renal failure. Therefore, in the conservative stage of chronic renal failure, dihydropyridine calcium channel blockers should be used in combination with ACE inhibitors or angiotensin II receptor blockers. Verapamil or diltiazem, which have a distinct nephroprotective and antianginal effect, are more suitable for monotherapy. These drugs, as well as felodipine, are the most effective and safe in the treatment of hypertension in acute and chronic nephrotoxicity of cyclosporine and tacrolimus. They also have an immunomodulatory effect that normalizes phagocytosis.

Antihypertensive therapy of renal hypertension depending on the etiology and clinical features of chronic renal failure

Etiology and characteristics of chronic renal failure	Contraindicated	Shown
IHD	Ganglionic blockers, peripheral vasodilators	Beta-blockers, calcium channel blockers, nitroglycerin
Ischemic kidney disease	ACE inhibitors, angiotensin II receptor blockers	Beta-blockers, calcium channel blockers, peripheral vasodilators
Chronic heart failure	Non-selective beta-blockers, calcium channel blockers	Loop diuretics, spironolactone, ACE inhibitors, beta-blockers, carvedilol
Diabetic nephropathy	Thiazide diuretics, spironolactone, non-selective beta-blockers, ganglionic blockers, methyldopa	Loop, thiazide-like diuretics, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, moxonidine, nebivolol, carvedilol
Gouty nephropathy	Thiazide diuretics	ACE inhibitors, angiotensin II receptor blockers, beta-blockers, loop diuretics, calcium channel blockers
Benign prostatic hyperplasia	Ganglionic blockers	A1-Adrenergic blockers
Cyclosporine nephropathy	Loop, thiazide diuretics, ACE inhibitors	Calcium channel blockers, spironolactone, beta-blockers
Hyperparathyroidism with uncontrolled hypercalcemia	Thiazide diuretics, beta-blockers	Loop diuretics, calcium channel blockers

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Beta-blockers, peripheral vasodilators

Beta-blockers, peripheral vasodilators are used in severe renin-dependent renal hypertension with contraindications to the use of ACE inhibitors and angiotensin II receptor blockers. Most beta-blockers, as well as carvedilol, prazosin, doxazosin, terazolin are prescribed for chronic renal failure in normal dosages, and propranolol is used to relieve hypertensive crisis even in dosages significantly higher than the average therapeutic ones. Dosages of atenolol, acebutolol, nadolol, betaxolol, hydralazine should be reduced, since their pharmacokinetics are impaired in chronic renal failure. Beta-blockers have a pronounced antianginal and antiarrhythmic effect, so they are used to treat hypertension in patients with chronic renal failure complicated by coronary heart disease and supraventricular arrhythmias. Beta-selective drugs (atenolol, betaxolol, metoprolol, bisoprolol) are indicated for systematic use in chronic renal failure. In diabetic nephropathy, nebivolol and carvedilol are preferable, as they have little effect on carbohydrate metabolism, normalize the daily rhythm of arterial pressure and NO synthesis in the endothelium. Metoprolol, bisoprolol and carvedilol effectively protect the myocardium from the effects of increased sympathetic innervation tone and catecholamines. In severe uremic cardiomyopathy (ejection fraction less than 30%), they reduce cardiac mortality by 30%. When prescribing alpha1-adrenergic blockers (doxazosin, alfuzosin, terazosin), it should be taken into account that, along with the hypotensive effect, they delay the development of benign prostatic hyperplasia.

Contraindications to the use of beta-blockers, in addition to the well-known ones (severe bradycardia, impaired atrioventricular conduction, unstable diabetes mellitus), in chronic renal failure include hyperkalemia, decompensated metabolic acidosis, and severe uremic hyperparathyroidism, when there is a high risk of calcification of the cardiac conduction system.

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Immunosuppressive therapy

It is used in patients with primary and secondary nephritis.

In chronic renal failure, extrarenal systemic signs of secondary glomerulonephritis are often absent or do not reflect the activity of the renal process. Therefore, with a rapid increase in renal failure in patients with primary or secondary glomerulonephritis with normal kidney sizes, one should think about an exacerbation of nephritis against the background of chronic renal failure. Detection of signs of severe exacerbation of glomerulonephritis during kidney biopsy requires active immunosuppressive therapy. Dosages of cyclophosphamide should be adjusted in chronic renal failure. Glucocorticosteroids and cyclosporine, metabolized primarily by the liver, should also be prescribed in reduced doses in chronic renal failure due to the risk of worsening hypertension and intrarenal hemodynamic disorders.

Treatment of anemia

Since neither a low-protein diet nor antihypertensive drugs correct renal anemia (ACE inhibitors sometimes worsen it), the use of epoetin drugs in the conservative stage of chronic renal failure is often necessary. Indications for treatment with epoetin. In the conservative stage of chronic renal failure, epoetin is administered subcutaneously at a dose of 20-100 U/kg once a week. It is necessary to strive for complete early correction of anemia (Ht over 40%, Hb 125-130 g/l). Iron deficiency that developed against the background of epoetin therapy in the conservative stage of chronic renal failure is usually corrected by oral administration of iron fumarate or iron sulfate together with ascorbic acid. By eliminating anemia, epoetin has a pronounced cardioprotective effect, slowing down left ventricular hypertrophy and reducing myocardial ischemia in coronary heart disease. Epoetin normalizes appetite and increases albumin synthesis in the liver. At the same time, the binding of drugs to albumin increases, which normalizes their effect in chronic renal failure. However, in case of nutritional disorders, hypoalbuminemia, resistance to antianemic and other drugs may develop, so rapid correction of these disorders with essential keto/amino acids is recommended. Provided that hypertension is fully controlled, epoetin has a nephroprotective effect by reducing renal ischemia and normalizing cardiac output. With insufficient blood pressure control, epoetin-induced hypertension accelerates the rate of progression of chronic renal failure. In the development of relative resistance to epoetin caused by ACE inhibitors or angiotensin II receptor blockers, treatment tactics should be selected individually. If ACE inhibitors are used to correct arterial hypertension, it is advisable to replace them with calcium channel blockers or beta-blockers. If ACE inhibitors (or angiotensin II receptor blockers) are used to treat diabetic nephropathy or uremic cardiomyopathy, treatment is continued while increasing the dose of epoetin.

Treatment of infectious complications

In acute pneumonia and urinary tract infection, semisynthetic penicillins or second- and third-generation cephalosporins are preferable, providing a bactericidal concentration in the blood and urine and having moderate toxicity. Macrolides (erythromycin, azithromycin, clarithromycin), rifampicin and synthetic tetracyclines (doxycycline) metabolized by the liver and requiring no significant dose adjustment may be used. In polycystic disease with cyst infection, only lipophilic drugs (chloramphenicol, macrolides, doxycycline, fluoroquinolones, clindamycin, co-trimoxazole) administered parenterally are used. In generalized infections caused by opportunistic (usually gram-negative) flora, drugs from the fluoroquinolone group or aminoglycoside antibiotics (gentamicin, tobramycin) are used, characterized by high general and nephrotoxicity. The doses of these drugs metabolized by the kidneys should be reduced in accordance with the severity of chronic renal failure, and the duration of their use should be limited to 7-10 days. Dosage adjustment is necessary for many antiviral (acyclovir, ganciclovir, ribavirin) and antifungal (amphotericin B, fluconazole) drugs.

Treatment of chronic renal failure is a very complex process and requires the involvement of doctors of many specialties.