Treatment of diabetic nephropathy

The basis for the effective treatment of diabetic nephropathy is the early diagnosis and treatment carried out in accordance with the stage of the disease. Primary prevention of diabetic nephropathy is aimed at preventing the appearance of mycoalbumiuria, i.e. Influence on its modifiable risk factors (the level of compensation of carbohydrate metabolism, the state of intramural hemodynamics, lipid metabolism disorder, smoking).

Basics of treatment of diabetic nephropathy

The main principles of the prevention and treatment of diabetic nephropathy in stages I-III include:

• glycemic control;
• control of blood pressure (blood pressure level should be <135/85 mm Hg in patients with diabetes mellitus in the absence of mycoralbuminuria <130/80 mm Hg in the presence of microalbuminuria and <120/75 mm Hg in patients with proteinuria) ;
• control of dyslipidemia.

Hyperglycemia is the triggering factor of structural and functional changes in the kidneys. Two of the largest studies, the DCCT (United Kingdom Prospective Diabetes Study, 1998), and the UKPDS (United Kingdom Prospective Diabetes Study, 1998) showed that the tactics of intensive glycemic control lead to a significant decrease in the frequency of microalbuminuria and albuminuria in patients with diabetes mellitus 1 and 2 th type. Optimal compensation of carbohydrate metabolism, which prevents the development of vascular complications, suggests normal or close to normal values of glycemia and HbA _1c <7%.

Control of blood pressure in diabetes mellitus provides prevention of nephropathy and slowing the rate of its progression.

Non-medicamentous treatment of hypertension includes:

• restriction of consumption with sodium food to 100 mmol / day;
• increased physical activity;
• maintaining optimal body weight,
• restriction of alcohol intake (less than 30 g per day);
• to give up smoking,
• reduction in intake of saturated fat from food;
• reduction of mental stress.

[1], [2], [3], [4],

Hypotensive therapy for diabetic nephropathy

When choosing antihypertensive drugs for the treatment of patients with diabetes mellitus, their effects on carbohydrate and lipid metabolism, on the course of other abnormalities of diabetes mellitus and safety in cases of kidney dysfunction, the presence of nephroprotective and cardioprotective properties should be taken into account.

ACE inhibitors have pronounced nephroprotective properties, reduce the severity of intra-cerebral hypertension and microalbuminuria (according to BRILLIANT, EUCLID, REIN, etc.). Therefore, ACE inhibitors are shown in microalbuminuria, not only at elevated, but also at normal arterial pressure:

• Captopril orally 12.5-25 mg 3 times a day, continuously or
• Perindopril inside 2-8 mg once a day, constantly or
• Ramipril inside 1,25-5 mg once a day, constantly or
• Trandolapril inside 0.5-4 mg once a day, constantly or
• Fosinopril inside 10-20 mg once a day, constantly or
• Hinapril inside 2.5-10 mg once a day, constantly or
• Enalapril inside 2.5-10 mg 2 times a day, constantly.

In addition to ACE inhibitors, nephroprotective and cardioprotective effects are possessed by calcium antagonists from the verapamil group.

An important role in the treatment of hypertension is played by angiotensin II receptor antagonists. Their nephroprotective activity in type 2 diabetes and diabetic nephropathy is shown in three large studies - IRMA 2, IDNT, RENAAL. This medication is prescribed in case of side effects of ACE inhibitors (especially in patients with type 2 diabetes):

• Valsartan inside 8O-160 mg once daily, continuously or
• Irbesartan inside 150-300 mg once a day, constantly or
• Condesartan tsileksetil inside 4-16 mg once a day, constantly or
• Losartan inside 25-100 mg once a day, constantly or
• Telmisatran inside 20-80 mg once a day, constantly.

It is advisable to use ACE inhibitors (or angiotensin II receptor blockers) in combination with a nephroprotective sulodexide, which restores the impaired permeability of the basal membranes of the glomeruli of the kidneys and reduces the loss of protein in the urine.

• Sulodexide 600 LE intramuscularly once a day 5 days a week with a 2-day break, 3 weeks, then inside 250 LE once a day, 2 months.

This treatment is recommended 2 times a year.

At high arterial pressure, it is advisable to use combination therapy.

Therapy of dyslipidemia in diabetic nephropathy

70% of patients with diabetes mellitus with diabetic nephropathy of stage IV and above have dyslipidemia. When lipid metabolism disorders are detected (LDL> 2.6 mmol / L, TG> 1.7 mmol / L), correction of hyperlipidemia (hypolipidemic diet) is mandatory, with insufficient effectiveness - lipidemic drugs.

When LDL> 3 mmol / l shows a constant reception of statins:

• Atorvastatin - inside 5-20 mg once a day, the duration of therapy is determined individually or
• Lovastatin 10-40 mg once a day, the duration of therapy is determined individually or
• Simvastatin inside 10-20 mg once a day, the duration of therapy is determined individually.
• Doses of statins are corrected to achieve the target LDL level <2.6 mmol / l, TG - <1.7 mmol / l.
• With isolated hypertriglyceridemia (> 6.8 mmol / L) and normal GFR, fibrates are shown:
• Fenofibrate inside 200 mg once a day, the duration is determined individually or
• Ciprofibrate inside 100-200 mg / day, the duration of therapy is determined individually.

Restoration of impaired intraclinal hemodynamics at the stage of microalbuminuria can be achieved by limiting the intake of animal protein to 1 g / kg / day.

Treatment of severe diabetic nephropathy

The goals of treatment remain the same. However, there is a need to take into account the decline in kidney function and severe, difficult to control hypertension.

Hypoglycemic therapy

At the stage of expressed diabetic nephropathy, it remains extremely important to achieve the optimal compensation of carbohydrate metabolism (HLA _1c <7%). In patients with type 2 diabetes mellitus who received MTCT, the appearance of proteinuria introduces a number of limitations in the choice of medications, as the risk of their nephrotoxic action increases. The safest in this regard are drugs with a low percentage of renal excretion, in particular some second generation PSM (glycidone, glycazide) and meglitinides (repaglinide):

• Glikvidon inside 15-60 mg 1-2 times a day or
• Gliklazid inside 30-120 mg once a day or
• Repaglinide inside 0.5-3.5 mg 3-4 times a day.

The use of these drugs is possible even at the initial stage of chronic renal failure (serum creatinine level up to 250 μmol / l) provided adequate control of glycemia. With GFR <30 ml / min, patients must be transferred to insulin administration.

Hypotensive therapy

With insufficient effectiveness of antihypertensive monotherapy, a combination therapy is prescribed:

• Captopril orally 12.5-25 mg 3 times a day, continuously or
• Perindopril inside 2-8 mg once a day, constantly or
• Ramipril inside 1,25-5 mg once a day, constantly or
• Trandolapril inside 0.5-4 mg once a day, constantly or
• Fosinopril inside 10-20 mg once a day, constantly or
• Hinapril inside 2.5-40 mg once a day, constantly
• Enalapril vsrpri 2,5-10 mg 2 times a day, constantly.

+

• Amlodipine inside 5-10 mg once a day, constantly or
• Atenolol inside 25-50 mg 2 times a day, constantly or
• Bisoprolol is administered orally 5-10 mg once daily, continuously or
• Verapamil inside 40-80 mg 3-4 times a day, constantly or
• Diltiazem inside 60-180 mg 1-2 times in the knocking, constantly or
• Indapamide inside 2.5 mg once a day (morning on an empty stomach), constantly or
• Metoprolal inside 50-100 mg 2 times a day, constantly or
• Moxonidine inside 200 mcg once a day, constantly or
• Nebivolol orally 5 mg once a day, continuously or
• Furosemide inside 40-160 mg in the morning on an empty stomach 2-3 times a week, constantly.

Combinations of several drugs are also possible, for example:

• Captopril orally 12.5-25 mg 3 times a day, continuously or
• Perindopril inside 2-8 mg once daily, continuously or
• Ramipril inside 1,25-5 mg once a day, constantly or
• Trandolapril inside 0.5-4 mg once a day, constantly or
• Fosinopril inside 10-20 mg once a day, constantly or
• Hinapril inside 2.5-40 mg once a day, constantly or
• Enalapril inside 2.5-10 mg twice a day, constantly

+

• Amlodipine inside 5-10 mg once a day, constantly or
• Indapamide inside 2.5 mg once a day (morning on an empty stomach), constantly or
• Furosemide inside 40-160 mg on an empty stomach 2-3 times a week, constantly

+

• Atenolol inside 25-50 mg 2 times a day, constantly or
• Bisoprolol is administered orally 5-10 mg once daily, continuously or
• Metoprolol inside 50-100 mg 2 times a day, constantly or
• Moxonidine inside 200 mcg once a day, constantly or
• Nebivolol inside 5 mg once a day, constantly.

At a serum creatinine level <300 μmol / l, the dose of ACE inhibitor is reduced by a factor of 2 Also, as the GFR decreases and the level of creatinine and urea nitrogen increases, most other antihypertensive drugs are reconsidered in the blood. At a creatinine level> 300 μmol / L, ACE inhibitors are canceled before dialysis.

Correction of metabolic and electrolyte disorders in chronic renal failure

When proteinuria appears, low-protein and low-salt diets are prescribed, limiting the intake of animal protein to 0.6-0.7 g / kg of body weight in (on average, up to 40 g protein) with sufficient caloric intake (35-50 kcal / kg / day) salt restriction up to 3-5 g / day.

At a level of creatinine in the blood of 120-500 μmol / l, symptomatic therapy of chronic renal failure is carried out, including treatment of renal anemia, osteodystrophy, hyperkalemia, hyperphosphataemia, hypocalcemia, etc. With the development of chronic renal failure, there are known difficulties in controlling carbohydrate metabolism associated with changes in insulin requirements. This control is quite complex and must be carried out in an individual mode.

With hyperkalemia (> 5.5 meq / L), patients are prescribed:

• Hydrochlorothiazide inside 25-50 mg in the morning on an empty stomach or
• Furosemide inside 40-160 mg in the morning on an empty stomach 2-3 times a week.

+

• Polysterolsulfonate sodium inside 15 g 4 times a day to achieve and maintain a level of potassium in the blood no more than 5.3 meq / l.

After reaching the level of potassium in the blood of 14 meq / L, the medication can be stopped.

In the case of a potassium concentration in the blood of more than 14 meq / l and / or signs of severe hyperkalemia on the ECG (prolongation of the PQ interval, expansion of the QRS complex, smoothing of the P waves), under the monitor ECG monitoring,

• Calcium gluconate, 10% solution, 10 ml intravenously struined for 2-5 minutes once, in the absence of changes on the ECG, repetition of the injection is possible.
• Insulin soluble (human or porcine) short-acting 10-20 units in glucose solution (25-50 g glucose) intravenously struino (in the case of normoglycemia), with hyperglycemia, only insulin is administered in accordance with the level of glycemia.
• Sodium bicarbonate, 7.5% solution, 50 ml intravenously struino, for 5 minutes (in case of concomitant acidosis), in the absence of effect after 10-15 minutes, repeat the introduction.

If these measures are ineffective, hemodialysis is performed.

In patients with azotemia, enterosorbents are used:

• Activated charcoal inside 1-2 g 3-4 days, the duration of therapy is determined individually or
• Povidone, powder, inside 5 g (dissolved in 100 ml of water) 3 times a day, the duration of therapy is determined individually.

If the phosphorus-calcium metabolism is disturbed (usually hyperphosphataemia and hypocalcaemia), a diet is prescribed, phosphate in the food is limited to 0.6-0.9 g / day, with its inefficiency use calcium preparations. The target level of phosphorus in the blood is 4.5-6 mg%, calcium - 10.5-11 mg%. The risk of ectopic calcification is minimal. The use of aluminum gels that bind phosphate should be limited in view of the high risk of intoxication. Inhibition of endogenous synthesis of 1,25-dihydroxyvitamin D and bone tissue to parathyroid hormone resistance exacerbate hypocalcemia, for controlling a prescribed metabolites of vitamin D. In severe hyperparathyroidism shown surgical removal of hyperplastic parathyroid glands.

Patients with hyperphosphatemia and hypocalcemia are prescribed:

• Calcium carbonate, at an initial dose of 0.5-1 g of elemental calcium orally 3 times a day during meals, if necessary, increase the dose every 2-4 weeks (up to 3 g 3 times per day) until the level of phosphorus in the blood 4, 5-6 mg%, calcium 10.5-11 mg%.

±

• Calcitriol 0.25-2 μg orally once a day under the control of calcium in the serum twice a week. In the presence of renal anemia with clinical manifestations or concomitant cardiovascular pathology appoint.
• Epoetin-beta subcutaneously 100-150 units / kg once a week until the hematocrit value reaches 33-36%, the hemoglobin level is 110-120 g / l.
• Iron sulphate inside 100 mg (in terms of ferrous iron) 1- 2 times a day for 1 hour of food, long or
• Iron (III) hydroxide sucrose complex (solution 20 mg / ml) 50-200 mg (2.5-10 ml) before infusion dissolve in a solution of sodium chloride 0.9% (for each 1 ml of the drug 20 ml solution), intravenously drip , injected at a rate of 100 ml for 15 minutes 2-3 times a week, the duration of therapy is determined individually or
• Iron (III) hydroxide saccharose complex (solution 20 mg / ml) 50-200 mg (2.5-10 ml) intravenously struino at a rate of 1 ml / min 2-3 times a week, the duration of therapy is determined individually.

Indications for carrying out extracorporeal methods of treatment of chronic renal failure in diabetes mellitus are determined earlier than in patients with other renal pathology, as in diabetes mellitus fluid retention, disruption of nitrogen and electrolyte balance develop at higher values of GFR. With a GFR reduction of less than 15 ml / min and an increase in creatinine levels of up to 600 μmol / l, it is necessary to evaluate the indications and contraindications to the use of substitution therapy methods: hemodialysis, peritoneal dialysis and kidney transplantation.

[5], [6], [7], [8], [9], [10]

Treatment of uremia

Increase serum creatinine levels in the range from 120 to 500 μmol / l characterizes the conservative stage of chronic renal failure. At this stage, symptomatic treatment aimed at eliminating intoxication, cupping of hypertensive syndrome, correction of water-electrolyte disorders is carried out. Higher values of serum creatinine (500 μmol / L and higher) and hyperkalemia (more than 6.5-7.0 mmol / L) indicate the onset of the terminal stage of chronic renal failure, which requires extracorporeal dialysis methods of blood purification.

Treatment of patients with diabetes in this stage is carried out jointly by endocrinologists and nephrologists. Patients in the terminal stage of chronic renal failure are hospitalized in specialized nephrological units equipped with dialysis machines.

Treatment of diabetic nephropathy in the conservative stage of chronic renal failure

In patients with diabetes mellitus type 1 and type 2, who are on insulin therapy, the progression of chronic renal failure is often characterized by the development of hypoglycemic conditions requiring a reduction in the dose of exogenous insulin (Zabroda phenomenon). The development of this syndrome is due to the fact that with pronounced damage to the renal parenchyma, the activity of renal insulin, which participates in insulin degradation, decreases. Therefore, exogenously introduced insulin is slowly metabolized, circulates for a long time in the blood, causing hypoglycemia. In some cases, the need for insulin is reduced so much that doctors are forced to cancel insulin injections for a while. All changes in the dose of insulin should be made only with the obligatory control of the level of glycemia. Patients with type 2 diabetes mellitus, who received oral hypoglycemic drugs, should be transferred to insulin therapy in the course of development of chronic renal insufficiency. This is due to the fact that with the development of chronic renal failure, the removal of almost all drugs of sulfonylurea (except for glycazide and glycidone) and preparations from the biguanide group decreases drastically, which leads to an increase in their concentration in the blood and an increased risk of toxic effects.

Correction of blood pressure becomes the main method of treatment of progressive kidney pathology, which can slow the onset of terminal renal failure. The purpose of antihypertensive therapy, as well as the proteinuric stage of diabetic nephropathy, is maintaining blood pressure at a level not exceeding 130/85 mm Hg. The first choice, as in other stages of diabetic nephropathy, is considered ACE inhibitors. At the same time, one should remember the need to use these drugs cautiously at a pronounced stage of chronic renal failure (serum creatinine level more than 300 μmol / L) due to possible transient deterioration of the filtration function of the kidneys and the development of hyperkalemia. In the stage of chronic kidney failure, as a rule, monotherapy does not lead to stabilization of the blood pressure level, therefore, it is recommended that combined therapy with antihypertensive drugs belonging to different groups (ACE inhibitors + loop diuretics + calcium channel blockers + selective beta adrenoblockers + central action drugs) . Often, only a 4-component scheme for the treatment of hypertension in chronic renal failure allows you to achieve the desired level of blood pressure.

The main principle of treating the nephrotic syndrome is to eliminate hypoalbuminemia. When the concentration of albumin in the blood serum is less than 25 g / l, it is recommended that infusion of albumin solutions is recommended. At the same time, loop diuretics are used, and the dose of injected furosemide (for example, lasix) can reach 600-800 and even 1000 mg / day. Potassium-sparing diuretics (spironolactone, triamterene) in the stage of chronic renal failure are not used because of the danger of developing hyperkalemia. Thiazide diuretics are also contraindicated in renal failure, as they contribute to a decrease in the filtration function of the kidneys. Despite the massive loss of protein in the urine with nephrotic syndrome, it is necessary to continue the principle of a low protein diet in which the protein content of animal origin should not exceed 0.8 g per 1 kg of body weight. For nephrotic syndrome is characterized by hypercholesterolemia, so the treatment regimen necessarily includes lipid-lowering drugs (the most effective drugs from the group of statins). The prognosis of patients with diabetes mellitus with diabetic nephropathy in the stage of chronic renal failure and with nephrotic syndrome is extremely unfavorable. Such patients need to be prepared without delay for extracorporeal methods of treating chronic renal failure.

Patients with chronic renal failure, when the serum creatinine exceeds 300 μmol / L, it is necessary to limit the animal protein to the maximum (up to 0.6 g per 1 kg of body weight). Only in the case of a combination of chronic renal failure and nephrotic syndrome is it possible to consume protein in a volume of 0.8 g per kg of body weight.

If you need a lifelong compliance with a low-protein diet in patients with reduced nutrition may have problems associated with the catabolism of their own proteins. For this reason, it is recommended to use ketone analogues of amino acids (for example, ketosteril preparation). When treating this drug, it is necessary to monitor the level of calcium in the blood, as often hypercalcemia develops.

Anemia, which often occurs in patients with chronic renal failure, is usually associated with a decreased synthesis of renal erythropoietin, a hormone that provides erythropoiesis. For the purpose of replacement therapy, recombinant human erythropoietin (epoetin alfa, epoetin beta) is used. Against the backdrop of treatment, iron deficiency is often increased, so it is advisable to combine therapy with erythropoietin for more effective treatment with iron-containing drugs. Among the complications of therapy with erythropoietin are the development of severe arterial hypertension, hyperkalemia, and a high risk of thrombus formation. All these complications are easier to control if the patient is on hemodialysis treatment. Therefore, only 7-10% of patients receive erythropoietin therapy in the pre-dialysis stage of chronic renal failure, and about 80% start this treatment when dialysis is switched. With uncontrolled arterial hypertension and severe coronary artery disease, treatment with erythropoietin is contraindicated.

The development of chronic renal failure is characterized by hyperkalemia (more than 5.3 mmol / l) due to a decrease in renal excretion of potassium. For this reason, patients are recommended to exclude from food products rich in potassium (bananas, dried apricots, citrus fruits, raisins, potatoes). In those cases when hyperkalemia reaches values threatening cardiac arrest (more than 7.0 mmol / L), a physiological potassium antagonist - 10% calcium gluconate solution is intravenously administered. To remove potassium from the body, ion exchange resins are also used.

Disturbances of phosphorus-calcium metabolism in chronic renal failure are characterized by the development of hyperphosphataemia and hypocalcemia. For the correction of hyperphosphataemia, the restriction of consumption of foods rich in phosphorus (fish, hard and processed cheeses, buckwheat, etc.) and the introduction of drugs that bind phosphorus in the intestine (calcium carbonate or calcium acetate) are used. To correct hypocalcemia, prescribe calcium preparations, colcalciferol. If necessary, perform operative removal of hyperplastic parathyroid glands.

Enterosorbents - substances that can bind toxic products in the intestines and remove them from the body. The action of enterosorbents in chronic renal insufficiency is aimed at, on the one hand, to cause the reverse absorption of uremic toxins from the blood into the intestine; on the other hand, reduce the flow of intestinal toxins from the intestine into the bloodstream. As enterosorbents, activated carbon, povidone (for example, enterodesis), minisorb, ion exchange resins can be used. Enterosorbents should be taken in the intervals between meals, 1.5-2 hours after taking the main drugs. When treating with sorbents, it is important to monitor the regularity of the intestinal activity, if necessary, prescribe laxatives or perform cleansing enemas.

Treatment of diabetic nephropathy in the terminal stage of chronic renal failure

In the United States and a number of European countries (Sweden, Finland, Norway), diabetes mellitus came in first place in the overall structure of kidney diseases requiring extracorporeal therapy. At the same time, the survival rate of such patients also increased significantly. General indications for carrying out extracorporeal methods of treatment of chronic renal failure in diabetes mellitus appear earlier than in patients with other kidney diseases. Indications for dialysis in patients with diabetes mellitus are a decrease in GFR to 15 ml / min and a serum creatinine level of more than 600 μmol / l.

Currently, three methods of substitution therapy for patients with terminal stage of chronic renal failure - hemodialysis, peritoneal hemodialysis and kidney transplantation - are used.

Advantages of permanent dialysis:

• The apparatus method of blood purification is performed 3 times a week (not daily);
• regularity of supervision by medical personnel (3 times a week);
• Availability of the method for patients who have lost sight (not capable of independent maintenance).

Disadvantages of permanent dialysis:

• difficulty in providing vascular access (due to the fragility of damaged vessels);
• aggravation of hemodynamic disorders;
• difficulty in managing systemic arterial pressure;
• rapid progression of cardiovascular pathology;
• progression of retinopathy;
• difficulty in controlling glycemia;
• permanent attachment to the hospital.

Survival of patients with diabetes by hemodialysis after 1 year is 82%, after 3 years - 48%, after 5 years - 28%.

Advantages of peritoneal dialysis:

• does not require in-patient treatment (adapted to household conditions);
• provides more stable indicators of systemic and renal hemodynamics;
• provides a high clearance of toxic medium molecules;
• allows you to inject insulin intraperitoneally;
• no vascular access required;
• 2-3 times cheaper than hemodialysis.

Disadvantages of peritoneal dialysis:

• daily routine (4-5 times a day);
• impossibility of self-fulfillment of procedures in case of loss of vision;
• risk of recurrent peritonitis;
• progression of retinopathy.

According to the United States and Europe, the survival rate of patients with diabetes mellitus on peritoneal dialysis is not inferior to that of hemodialysis, and in patients with diabetes mellitus is even higher than when using hemodialysis. Survival of patients with diabetes mellitus on permanent ambulatory peritoneal dialysis (CAPD) during the first year is 92%, 2 years - 76%, 5 years - 44%.

Benefits of kidney transplantation:

• complete cure for renal failure for the period of graft function;
• stabilization of retinopathy;
• reverse development of polyneuropathy;
• good rehabilitation;
• satisfactory survival.

Disadvantages of kidney transplantation:

• the need for prompt intervention;
• risk of graft rejection;
• difficulty in providing metabolic control when taking steroid drugs;
• high risk of infectious complications due to taking cytotoxic drugs;
• re-development of diabetic glomerulosclerosis in the transplanted kidney.

Survival of patients with kidney transplantation for 1 year is 94%, 5 years - 79%, 10 years - 50%.

Combined kidney and pancreas transplantation

The idea of such a combined operation is justified by the possibility of complete clinical rehabilitation of the patient, since successful organ transplantation involves the elimination of manifestations of renal insufficiency and the diabetes itself, which caused kidney pathology. At the same time, the survival rate of patients with diabetes and graft after such operations is lower than with an isolated kidney transplant. This is due to great technical difficulties in performing the operation. Nevertheless, by the end of 2000, more than 1,000 combined kidney and pancreas transplants had been performed in the United States of America. The 3-year survival rate of patients was 97%. A significant improvement in the quality of life of patients, a suspension of the progression of target organ damage in diabetes mellitus, insulin dependence was detected in 60-92% of patients. With the development of new technologies in medicine, it is possible that in the coming years this type of substitution therapy will take the lead.

[11], [12], [13], [14], [15], [16], [17]

New in the treatment of diabetic nephropathy

Currently, the search for new ways to prevent and treat diabetic nephropathy is under way. The most promising of these are the use of drugs that affect the biochemical and structural changes in the basal membrane of the glomeruli of the kidneys.

Restoration of selectivity of the glomerular basement membrane

It is known that an important role in the development of diabetic nephropathy is played by the broken synthesis of glycosaminoglycan heparan sulfate, which is part of the basal membrane of the glomeruli and ensures the charge-selectivity of the renal filter. Replenishment of the stocks of this compound in the vascular membranes could restore the disturbed permeability of the membrane and reduce the loss of protein in the urine. The first attempts to use glycosaminoglycans for the treatment of diabetic nephropathy were undertaken by G. Gambaro et al. (1992) on the model of rats with streptozotocin diabetes. It is established that his early appointment - in the onset of diabetes mellitus - prevents the development of morphological changes in kidney tissue and the appearance of albuminuria. Successful experimental studies have made it possible to proceed to clinical trials of preparations containing glycosaminoglycans for the prevention and treatment of diabetic nephropathy. More recently, the drug glycosoaminoglycan company Alfa Wassermann (Italy) appeared in the Russian pharmaceutical market. Vesel Duet F (INN - sulodexide). The drug contains two glycosaminoglycan - low molecular weight heparin (80%) and dermatan (20%).

Scientists have investigated the nephroprotective activity of this drug in patients with type 1 diabetes mellitus with various stages of diabetic nephropathy. In patients with microalbuminuria, the excretion of albumin with urine decreased significantly after 1 week after the start of treatment and remained at the reached level within 3-9 months after the drug was discontinued. In patients with proteinuria, the excretion of protein in the urine significantly decreased after 3-4 weeks after the start of treatment. The achieved effect was also preserved after the drug was discontinued. There were no complications of treatment.

Thus, drugs from the group of glycosaminoglycans (in particular, sulodexide) can be considered effective, without the side effects of heparin, simple in the use of pathogenetic treatment of diabetic nephropathy.

Effects on non-enzyme glycosylated proteins

Non-enzyme glycosylated structural proteins of the glial basement membrane in hyperglycemia conditions lead to a disruption in their configuration and loss of normal selective permeability for proteins. A promising direction in the treatment of vascular complications of diabetes mellitus is the search for drugs that can interrupt the response of nonenzymatic glycosylation. An interesting experimental finding was the detected ability of acetylsalicylic acid to reduce glycosylated proteins. However, its purpose as a glycosylation inhibitor has not found wide clinical spread, since the doses in which the drug has an effect should be quite large, which is fraught with the development of side effects.

To interrupt the response of nonenzymatic glycosylation in experimental studies since the late 1980s, the drug aminoguanidine, which irreversibly reacts with carboxyl groups of reversible glycosylation products, is successfully used, stopping this process. More recently, a more specific inhibitor of the formation of the final products of glycosylation, pyridoxamine, has been synthesized.

[18], [19], [20], [21], [22], [23]

Effects on the polyol glucose exchange pathway

Increased glucose metabolism in the polyol pathway under the influence of the aldose reductase enzyme leads to the accumulation of sorbitol (osmotically active substance) in insulin-independent tissues, which also contributes to the development of late complications of diabetes mellitus. To interrupt this process, clinics use drugs from the group of aldose reductase inhibitors (tolestat, statil). A number of studies have demonstrated a decrease in albuminuria in patients with type 1 diabetes mellitus who received aldose reductase inhibitors. However, the clinical efficacy of these drugs is more pronounced in the treatment of diabetic neuropathy or retinopathy and less in the treatment of diabetic nephropathy. Perhaps this is due to the fact that the polyol glucose exchange pathway plays a lesser role in the pathogenesis of diabetic kidney damage than the vessels of other non-insulin-dependent tissues.

[24], [25], [26], [27], [28], [29], [30], [31],

Effects on the activity of endothelial cells

In experimental and clinical studies, the role of endothelin-1 as a mediator of the progression of diabetic nephropathy was clearly established. Therefore, the attention of many pharmaceutical companies is directed towards the synthesis of drugs that can block the increased production of this factor. At present, drugs that block receptors for endothelin-1 are being tested experimentally. The first results indicate a lower effectiveness of these drugs compared with ACE inhibitors.

[32], [33], [34], [35], [36], [37], [38],

Evaluation of treatment effectiveness

Criteria for the effectiveness of the prevention and treatment of diabetic nephropathy include general criteria for effective treatment of diabetes mellitus, as well as prevention of clinically pronounced stages of diabetic nephropathy, and a slowing down of the rate of decrease in the filtration function of the kidneys and the progression of chronic renal failure.

[39], [40], [41], [42], [43], [44]

Complications and side effects of treatment

Most complications and side effects of therapy for diabetic nephropathy develops as a result of the fact that medications are prescribed without taking into account contraindications and dose adjustment depending on the kidney function.

[45], [46], [47], [48],

Errors and unreasonable appointments

The most common mistakes in the treatment of diabetic nephropathy are the appointment of atypypertensive agents and the reduction in arterial pressure to an optimal level, the withdrawal from therapy with ACE inhibitors in patients with normal arterial pressure, the use of potassium-sparing diuretics, and the appointment of so-called angioprotectors (trental, compliance) .

[49], [50], [51]

Forecast

Mortality from uremia in type 2 diabetes is about 5-10%. Intensive insulin therapy with the achievement of compensation for carbohydrate metabolism reduces the risk of developing diabetic nephropathy by 60%, inhibiting the gradual course and can prevent or at least significantly delay the onset of renal failure. Early initiation of therapy with ACE inhibitors significantly reduces the rate of progression, as well as the rates of total and cardiovascular mortality.

Over the last decade, the quality of life of patients with diabetic nephropathy has improved. The slowdown in the rate of decline in GFR allowed us to extend the pre-dialysis period. The importance of diabetes in hemodialysis for 5 years exceeds 60%, survival after kidney transplantation for 10 years exceeds 50%. The problem of providing extracorporeal methods for treatment of patients with diabetes mellitus with terminal renal insufficiency remains acute, which makes it necessary to direct efforts to the earliest diagnosis of diabetic nephropathy and the timely administration of adequate pathogenetic therapy.

[52], [53], [54], [55]