Treatment of diabetic nephropathy

The basis of effective treatment of diabetic nephropathy is early diagnosis and treatment carried out in accordance with the stage of the disease. Primary prevention of diabetic nephropathy aims to prevent the occurrence of mycoalbuminuria, i.e., to influence its modifiable risk factors (the level of carbohydrate metabolism compensation, the state of intraglomerular hemodynamics, lipid metabolism disorders, smoking).

Basics of Diabetic Nephropathy Treatment

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

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

Hyperglycemia is a trigger factor for structural and functional changes in the kidneys. Two major studies - DCCT (Diabetes Control and Complication Study, 1993) and UKPDS (United Kingdom Prospective Diabetes Study, 1998) - have shown that intensive glycemic control tactics lead to a reliable decrease in the frequency of microalbuminuria and albuminuria in patients with type 1 and type 2 diabetes. Optimal compensation of carbohydrate metabolism, which allows preventing the development of vascular complications, assumes normal or close to normal glycemic values and an HbA _1c level of < 7%.

Controlling blood pressure in diabetes mellitus ensures the prevention of nephropathy and slows down the rate of its progression.

Non-drug treatment of arterial hypertension includes:

• limiting sodium intake with food to 100 mmol/day;
• increase physical activity;
• maintaining optimal body weight,
• limiting alcohol intake (less than 30 g per day);
• quitting smoking,
• reducing dietary intake of saturated fats;
• reduction of mental stress.

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Antihypertensive therapy for diabetic nephropathy

When choosing antihypertensive drugs for the treatment of patients with diabetes mellitus, one should take into account their effect on carbohydrate and lipid metabolism, the course of other deviations of diabetes mellitus and safety in case of renal dysfunction, the presence of nephroprotective and cardioprotective properties.

ACE inhibitors have pronounced nephroprotective properties, reduce the severity of intraglomerular hypertension and microalbuminuria (according to studies BRILLIANT, EUCLID, REIN, etc.). Therefore, ACE inhibitors are indicated for microalbuminuria not only with elevated, but also with normal arterial pressure:

• Captopril orally 12.5-25 mg 3 times a day, continuously or
• Perindopril orally 2-8 mg once a day, continuously or
• Ramipril orally 1.25-5 mg 1 time per day, continuously or
• Trandolapril orally 0.5-4 mg 1 time per day, continuously or
• Fosinopril orally 10-20 mg 1 time per day, continuously or
• Quinapril orally 2.5-10 mg 1 time per day, continuously or
• Enalapril orally 2.5-10 mg 2 times a day, constantly.

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

Angiotensin II receptor antagonists play an important role in the treatment of arterial hypertension. Their nephroprotective activity in type 2 diabetes mellitus and diabetic nephropathy has been demonstrated in three large studies - IRMA 2, IDNT, RENAAL. These drugs are prescribed in case of development of side effects of ACE inhibitors (especially in patients with type 2 diabetes mellitus):

• Valsartan orally 80-160 mg 1 time per day, continuously or
• Irbesartan orally 150-300 mg 1 time per day, continuously or
• Condesartan cilexetil orally 4-16 mg once daily, continuously or
• Losartan orally 25-100 mg 1 time per day, continuously or
• Telmisatran orally 20-80 mg once a day, continuously.

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

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

It is recommended to carry out this course of treatment twice a year.

For high blood pressure, it is advisable to use combination therapy.

Therapy of dyslipidemia in diabetic nephropathy

70% of patients with diabetes mellitus with diabetic nephropathy stage IV and higher have dyslipidemia. If lipid metabolism disorders are detected (LDL> 2.6 mmol/l, TG> 1.7 mmol/l), hyperlipidemia correction (lipid-lowering diet) is mandatory; if ineffective, hypolipidemic drugs are used.

If LDL > 3 mmol/l, continuous use of statins is indicated:

• Atorvastatin - orally 5-20 mg once a day, the duration of therapy is determined individually or
• Lovastatin orally 10-40 mg 1 time per day, the duration of therapy is determined individually or
• Simvastatin orally 10-20 mg once a day, the duration of therapy is determined individually.
• Statin doses are adjusted to achieve target levels of LDL <2.6 mmol/l, TG <1.7 mmol/l.
• In isolated hypertriglyceridemia (> 6.8 mmol/l) and normal SCF, fibrates are indicated:
• Fenofibrate orally 200 mg 1 time per day, duration is determined individually or
• Ciprofibrate orally 100-200 mg/day, duration of therapy is determined individually.

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

Treatment of severe diabetic nephropathy

The goals of treatment remain the same. However, it is necessary to take into account the decline in renal function and severe, difficult to control arterial hypertension.

Hypoglycemic therapy

At the stage of pronounced diabetic nephropathy, it remains extremely important to achieve optimal compensation of carbohydrate metabolism (HbA _1c < 7%). In patients with type 2 diabetes mellitus who received PSSS, the appearance of proteinuria introduces a number of restrictions in the choice of drugs, since the risk of their nephrotoxic effect increases. The safest in this regard are drugs with a low percentage of renal excretion, in particular some second-generation PSMS (gliquidone, gliclazide) and meglitinides (repaglinide):

• Glicvidone orally 15-60 mg 1-2 times a day or
• Gliclazide orally 30-120 mg 1 time per day or
• Repaglinide orally 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 that glycemia is adequately controlled. With SCF < 30 ml/min, it is mandatory to transfer patients to insulin administration.

Antihypertensive therapy

If antihypertensive monotherapy is insufficiently effective, combination therapy is prescribed:

• Captopril orally 12.5-25 mg 3 times a day, continuously or
• Perindopril orally 2-8 mg once a day, continuously or
• Ramipril orally 1.25-5 mg 1 time per day, continuously or
• Trandolapril orally 0.5-4 mg once a day, continuously or
• Fosinopril orally 10-20 mg 1 time per day, continuously or
• Quinapril orally 2.5-40 mg 1 time per day, constantly
• Enalapril 2.5-10 mg 2 times a day, constantly.

+

• Amlodipine orally 5-10 mg 1 time per day, continuously or
• Atenolol orally 25-50 mg 2 times a day, constantly or
• Bisoprolol orally 5-10 mg 1 time per day, continuously or
• Verapamil orally 40-80 mg 3-4 times a day, constantly or
• Diltiazem orally 60-180 mg 1-2 times a day, continuously or
• Indapamide orally 2.5 mg 1 time per day (in the morning on an empty stomach), continuously or
• Metoprolal orally 50-100 mg 2 times a day, constantly or
• Moxonidine orally 200 mcg once a day, continuously or
• Nebivolol orally 5 mg once daily, continuously or
• Furosemide orally 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 orally 2-8 mg once a day, continuously or
• Ramipril orally 1.25-5 mg 1 time per day, continuously or
• Trandolapril orally 0.5-4 mg 1 time per day, continuously or
• Fosinopril orally 10-20 mg 1 time per day, continuously or
• Quinapril orally 2.5-40 mg 1 time per day, continuously or
• Enalapril orally 2.5-10 mg 2 times a day, constantly

+

• Amlodipine orally 5-10 mg 1 time per day, continuously or
• Indapamide orally 2.5 mg 1 time per day (in the morning on an empty stomach), continuously or
• Furosemide orally 40-160 mg on an empty stomach 2-3 times a week, constantly

+

• Atenolol orally 25-50 mg 2 times a day, constantly or
• Bisoprolol orally 5-10 mg 1 time per day, continuously or
• Metoprolol orally 50-100 mg 2 times a day, continuously or
• Moxonidine orally 200 mcg 1 time per day, continuously or
• Nebivolol orally 5 mg once a day, continuously.

If the serum creatinine level is < 300 μmol/l, the ACE inhibitor dose is reduced by half. Also, as the SCF decreases and the creatinine and urea nitrogen levels in the blood increase, the intake of most other antihypertensive drugs is reviewed. If the creatinine level is > 300 μmol/l, ACE inhibitors are discontinued before dialysis.

Correction of metabolic and electrolyte disturbances in chronic renal failure

When proteinuria appears, a low-protein and low-salt diet is prescribed, limiting the consumption of animal protein to 0.6-0.7 g/kg of body weight (on average up to 40 g of protein) with sufficient caloric content of food (35-50 kcal/kg/day), limiting salt to 3-5 g/day.

At a blood creatinine level of 120-500 μmol/l, symptomatic therapy of chronic renal failure is carried out, including treatment of renal anemia, osteodystrophy, hyperkalemia, hyperphosphatemia, hypocalcemia, etc. With the development of chronic renal failure, certain difficulties arise in the control of carbohydrate metabolism associated with changes in the need for insulin. This control is quite complex and should be carried out on an individual basis.

For hyperkalemia (> 5.5 mEq/L), patients are prescribed:

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

+

• Sodium polystyrene sulfonate orally 15 g 4 times a day until the blood potassium level is reached and maintained at no more than 5.3 meq/l.

Once the blood potassium level reaches 14 mEq/L, medication can be stopped.

If the blood potassium concentration is greater than 14 mEq/L and/or there are signs of severe hyperkalemia on the ECG (prolongation of the PQ interval, widening of the QRS complex, smoothing of the P waves), the following is urgently administered under ECG monitoring:

• Calcium gluconate, 10% solution, 10 ml intravenously by jet stream over 2-5 minutes once; in the absence of changes on the ECG, the injection may be repeated.
• Soluble insulin (human or porcine) short-acting 10-20 U in a glucose solution (25-50 g of glucose) intravenously by jet stream (in case of normoglycemia); in case of hyperglycemia, only insulin is administered in accordance with the glycemia level.
• Sodium bicarbonate, 7.5% solution, 50 ml intravenously by jet stream, within 5 minutes (in case of concomitant acidosis), if there is no effect, repeat the administration after 10-15 minutes.

If the above measures are ineffective, hemodialysis is performed.

In patients with azotemia, enterosorbents are used:

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

In case of phosphorus-calcium metabolism disorders (usually hyperphosphatemia and hypocalcemia), a diet is prescribed, limiting phosphate in food to 0.6-0.9 g/day, and if it is ineffective, calcium preparations are used. The target level of phosphorus in the blood is 4.5-6 mg%, calcium - 10.5-11 mg%. In this case, the risk of ectopic calcification is minimal. The use of aluminum gels that bind phosphate should be limited due to the high risk of intoxication. Suppression of endogenous synthesis of 1,25-dihydroxyvitamin D and resistance of bone tissue to parathyroid hormone aggravate hypocalcemia, which is treated with vitamin D metabolites. In severe hyperparathyroidism, surgical removal of hyperplastic parathyroid glands is indicated.

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, the dose is increased every 2-4 weeks (maximum up to 3 g 3 times a day) until the blood phosphorus level reaches 4.5-6 mg%, calcium - 10.5-11 mg%.

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• Calcitriol 0.25-2 mcg orally once a day under the control of serum calcium content twice a week. In the presence of renal anemia with clinical manifestations or concomitant cardiovascular pathology, it is prescribed.
• Epoetin-beta subcutaneously 100-150 U/kg once a week until hematocrit reaches 33-36%, hemoglobin level - 110-120 g/l.
• Iron sulfate orally 100 mg (in terms of divalent iron) 1-2 times a day 1 hour before meals, long-term or
• Iron (III) hydroxide sucrose complex (solution 20 mg/ml) 50-200 mg (2.5-10 ml) before infusion dilute in 0.9% sodium chloride solution (for each 1 ml of the drug 20 ml of solution), intravenously by drip, administer 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 sucrose complex (solution 20 mg/ml) 50-200 mg (2.5-10 ml) intravenously by jet stream at a rate of 1 ml/min 2-3 times a week, the duration of therapy is determined individually.

Indications for extracorporeal methods of treating chronic renal failure in diabetes mellitus are determined earlier than in patients with other renal pathologies, since in diabetes mellitus fluid retention, nitrogen and electrolyte imbalance develop at higher values of SCF. If SCF decreases to less than 15 ml/min and creatinine levels increase to 600 μmol/l, it is necessary to evaluate the indications and contraindications for the use of replacement therapy methods: hemodialysis, peritoneal dialysis and kidney transplantation.

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Treatment of uremia

An increase in the serum creatinine level within the range from 120 to 500 μmol/l characterizes the conservative stage of chronic renal failure. At this stage, symptomatic treatment is carried out aimed at eliminating intoxication, stopping the hypertensive syndrome, and correcting water-electrolyte disturbances. Higher values of serum creatinine (500 μmol/l and above) 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 at this stage is carried out jointly by endocrinologists and nephrologists. Patients in the terminal stage of chronic renal failure are hospitalized in specialized nephrology departments equipped with dialysis machines.

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

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

Correction of blood pressure is becoming the main method of treatment of progressive kidney pathology, capable of slowing down the onset of terminal renal failure. The goal of antihypertensive therapy, as well as the proteinuric stage of diabetic nephropathy, is to maintain blood pressure at a level not exceeding 130/85 mm Hg. The first-choice drugs, as in other stages of diabetic nephropathy, are ACE inhibitors. At the same time, it should be remembered that these drugs must be used with caution in the severe stage of chronic renal failure (serum creatinine level over 300 μmol/l) due to possible transient deterioration of renal filtration function and development of hyperkalemia. In the stage of chronic renal failure, monotherapy usually does not lead to stabilization of the blood pressure level, therefore, it is recommended to conduct combined therapy with antihypertensive drugs belonging to different groups (ACE inhibitors + loop diuretics + calcium channel blockers + selective beta-blockers + centrally acting drugs). Often, only a 4-component treatment regimen for arterial hypertension in chronic renal failure allows achieving the desired blood pressure level.

The main principle of treating nephrotic syndrome is to eliminate hypoalbuminemia. When the serum albumin concentration drops below 25 g/l, albumin solution infusions are recommended. Loop diuretics are used at the same time, with the dose of furosemide (e.g., lasix) reaching 600-800 and even 1000 mg/day. Potassium-sparing diuretics (spironolactone, triamterene) are not used in the stage of chronic renal failure due to the risk of developing hyperkalemia. Thiazide diuretics are also contraindicated in renal failure, since they contribute to a decrease in the filtration function of the kidneys. Despite the massive loss of protein in the urine in nephrotic syndrome, it is necessary to continue to adhere to the principle of a low-protein diet, in which the content of animal protein should not exceed 0.8 g per 1 kg of body weight. Hypercholesterolemia is characteristic of nephrotic syndrome, so the treatment regimen necessarily includes hypolipidemic drugs (the most effective drugs are from the statin group). 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 must be immediately prepared for extracorporeal methods of treating chronic renal failure.

Patients with chronic renal failure, when serum creatinine exceeds 300 μmol/l, need to limit animal protein as much as possible (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 protein consumption permissible in the amount of 0.8 g per kg of body weight.

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

Anemia, which often occurs in patients with chronic renal failure, is usually associated with reduced synthesis of renal erythropoietin, a hormone that ensures erythropoiesis. Recombinant human erythropoietin (epoetin alpha, epoetin beta) is used for replacement therapy. During treatment, serum iron deficiency often increases, so for more effective treatment, erythropoietin therapy should be combined with iron-containing drugs. Complications of erythropoietin therapy include the development of severe arterial hypertension, hyperkalemia, and a high risk of thrombosis. All these complications are easier to control if the patient is on hemodialysis. Therefore, only 7-10% of patients receive erythropoietin therapy in the pre-dialysis stage of chronic renal failure, and about 80% begin this treatment when transferred to dialysis. In case of uncontrolled arterial hypertension and severe coronary heart disease, erythropoietin treatment is contraindicated.

The development of chronic renal failure is characterized by hyperkalemia (more than 5.3 mmol/l) due to decreased renal excretion of potassium. For this reason, patients are advised to exclude potassium-rich foods (bananas, dried apricots, citrus fruits, raisins, potatoes) from their diet. In cases where hyperkalemia reaches values threatening cardiac arrest (more than 7.0 mmol/l), a physiological potassium antagonist is administered intravenously - 10% calcium gluconate solution. Ion-exchange resins are also used to remove potassium from the body.

Disturbances of calcium-phosphorus metabolism in chronic renal failure are characterized by the development of hyperphosphatemia and hypocalcemia. To correct hyperphosphatemia, limit the consumption of foods rich in phosphorus (fish, hard and processed cheeses, buckwheat, etc.) and administer drugs that bind phosphorus in the intestine (calcium carbonate or calcium acetate). To correct hypocalcemia, calcium preparations and cholecalciferol are prescribed. If necessary, surgical removal of hyperplastic parathyroid glands is performed.

Enterosorbents are substances capable of binding toxic products in the intestine and removing them from the body. The action of enterosorbents in chronic renal failure is aimed at, on the one hand, causing reabsorption of uremic toxins from the blood into the intestine; on the other hand, reducing the flow of intestinal toxins from the intestine into the blood. Activated carbon, povidone (for example, enterodesis), minisorb, ion-exchange resins can be used as enterosorbents. Enterosorbents should be taken between meals, 1.5-2 hours after taking the main drugs. When treating with sorbents, it is important to monitor the regularity of bowel activity; if necessary, laxatives are prescribed or cleansing enemas are performed.

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

In the United States of America and a number of European countries (Sweden, Finland, Norway), diabetes mellitus has become the leading cause of kidney disease requiring extracorporeal therapy. At the same time, the survival rate of such patients has increased significantly. General indications for extracorporeal methods of treating 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 SCF to 15 ml/min and a serum creatinine level of more than 600 μmol/l.

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

Benefits of continuous dialysis:

• hardware method of blood purification is performed 3 times a week (not daily);
• regular monitoring by medical personnel (3 times a week);
• accessibility of the method for patients who have lost their sight (not capable of independent care).

Disadvantages of continuous dialysis:

• difficulty in providing vascular access (due to the fragility of damaged vessels);
• worsening of hemodynamic disorders;
• difficulty in managing systemic arterial pressure;
• rapid progression of cardiovascular pathology;
• progression of retinopathy;
• difficulty in glycemic control;
• permanent hospitalization.

The survival rate of patients with diabetes on hemodialysis is 82% after 1 year, 48% after 3 years, and 28% after 5 years.

Benefits of peritoneal dialysis:

• does not require inpatient treatment (adapted to home conditions);
• provides more stable indicators of systemic and renal hemodynamics;
• ensures high clearance of toxic medium molecules;
• allows for intraperitoneal administration of insulin;
• no vascular access required;
• 2-3 times cheaper than hemodialysis.

Disadvantages of peritoneal dialysis:

• daily procedures (4-5 times a day);
• inability to perform procedures independently due to vision loss;
• risk of developing 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 on hemodialysis, and in patients with diabetes mellitus it is even higher than when using hemodialysis. The survival rate of patients with diabetes mellitus on continuous ambulatory peritoneal dialysis (CAPD) during the first year is 92%, 2 years - 76%, 5 years - 44%.

Benefits of kidney transplant:

• complete cure for renal failure during the period of transplant functioning;
• stabilization of retinopathy;
• reversal of polyneuropathy;
• good rehabilitation;
• satisfactory survival rate.

Disadvantages of kidney transplant:

• the need for surgical intervention;
• risk of transplant rejection;
• difficulty in maintaining metabolic control when taking steroid drugs;
• high risk of infectious complications due to taking cytostatics;
• recurrence of diabetic glomerulosclerosis in the transplanted kidney.

The survival rate of patients after kidney transplantation is 94% within 1 year, 79% within 5 years, and 50% within 10 years.

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 failure and diabetes mellitus itself, which caused the kidney pathology. At the same time, the survival rate of patients with diabetes mellitus and the transplant after such operations is lower than with an isolated kidney transplant. This is due to the great technical difficulties in performing the operation. Nevertheless, by the end of 2000, more than 1,000 combined kidney and pancreas transplants were performed in the United States of America. The three-year survival rate of patients was 97%. A significant improvement in the quality of life of patients, a halt in the progression of target organ damage in diabetes mellitus, insulin independence was detected in 60-92% of patients. As new technologies in medicine improve, it is possible that in the coming years this type of replacement therapy will take a leading position.

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

New in the treatment of diabetic nephropathy

Currently, new ways of preventing and treating diabetic nephropathy are being sought. The most promising of them are considered to be the use of drugs that affect the biochemical and structural changes in the basal membrane of the glomeruli of the kidneys.

Restoration of glomerular basement membrane selectivity

It is known that an important role in the development of diabetic nephropathy is played by the impaired synthesis of glycosaminoglycan heparan sulfate, which is part of the glomerular basement membrane and ensures charge selectivity of the renal filter. Replenishment of this compound in the vascular membranes could restore the impaired membrane permeability and reduce protein loss with urine. The first attempts to use glycosaminoglycans for the treatment of diabetic nephropathy were made by G. Gambaro et al. (1992) on a model of rats with streptozotocin diabetes. It was found that its early administration - at the onset of diabetes mellitus - prevents the development of morphological changes in kidney tissue and the appearance of albuminuria. Successful experimental studies made it possible to move on to clinical trials of drugs containing glycosaminoglycans for the prevention and treatment of diabetic nephropathy. Relatively recently, a glycosaminoglycan preparation from Alfa Wassermann (Italy) Vesel Due F (INN - sulodexide) appeared on the Russian pharmaceutical market. The preparation contains two glycosaminoglycans - low-molecular heparin (80%) and dermatan (20%).

Scientists studied the nephroprotective activity of this drug in patients with type 1 diabetes mellitus with different stages of diabetic nephropathy. In patients with microalbuminuria, albumin excretion in urine significantly decreased as early as 1 week after the start of treatment and remained at the achieved level for 3-9 months after the drug was discontinued. In patients with proteinuria, protein excretion in urine significantly decreased 3-4 weeks after the start of treatment. The achieved effect also remained after the drug was discontinued. No complications of treatment were noted.

Thus, drugs from the glycosaminoglycan group (in particular, sulodexide) can be considered as effective, free of the side effects of heparin, easy-to-use means of pathogenetic treatment of diabetic nephropathy.

Effect on non-enzymatic glycosylation of proteins

Non-enzymatic glycosylation of structural proteins of the glomerular basement membrane under hyperglycemia conditions leads to disruption of 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 capable of interrupting the reaction of non-enzymatic glycosylation. An interesting experimental finding was the ability of acetylsalicylic acid to reduce protein glycosylation. However, its use as a glycosylation inhibitor has not found wide clinical distribution, since the doses in which the drug has an effect must be quite large, which is fraught with the development of side effects.

To interrupt the reaction of non-enzymatic glycosylation in experimental studies since the end of the 80s of the 20th century, the drug aminoguanidine has been successfully used, which irreversibly reacts with the carboxyl groups of reversible glycosylation products, stopping this process. More recently, a more specific inhibitor of the formation of end products of glycosylation, pyridoxamine, was synthesized.

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

Effect on the polyol pathway of glucose metabolism

Increased glucose metabolism via the polyol pathway under the influence of the enzyme aldose reductase leads to the accumulation of sorbitol (an osmotically active substance) in insulin-independent tissues, which also contributes to the development of late complications of diabetes mellitus. To interrupt this process, drugs from the group of aldose reductase inhibitors (tolrestat, statil) are used in the clinic. 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. This may be due to the fact that the polyol pathway of glucose metabolism plays a lesser role in the pathogenesis of diabetic kidney damage than in the vessels of other insulin-independent tissues.

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

Effect on endothelial cell activity

Experimental and clinical studies have clearly established the role of endothelin-1 as a mediator of diabetic nephropathy progression. Therefore, the attention of many pharmaceutical companies is directed toward the synthesis of drugs capable of blocking the increased production of this factor. Currently, experimental trials of drugs blocking receptors to endothelin-1 are underway. The first results indicate that these drugs are less effective than ACE inhibitors.

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

Evaluation of treatment effectiveness

The criteria for the effectiveness of the prevention and treatment of diabetic nephropathy include general criteria for the effective treatment of diabetes mellitus, as well as the prevention of clinically expressed stages of diabetic nephropathy and slowing the rate of decline in renal filtration function 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 diabetic nephropathy therapy develop as a result of medications being prescribed without taking into account contraindications and dose adjustments depending on kidney function.

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

Errors and unjustified appointments

The most common errors in the treatment of diabetic nephropathy include late administration of antihypertensive drugs and reduction of blood pressure to a suboptimal level, refusal of therapy with ACE inhibitors in patients with normal blood pressure, the use of potassium-sparing diuretics and the administration of so-called angioprotectors (trental, complamin).

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Forecast

Mortality from uremia in type 2 diabetes mellitus is approximately 5-10%. Intensive insulin therapy with carbohydrate metabolism compensation reduces the risk of diabetic nephropathy by 60%, slowing down the progradient course and can prevent or at least significantly delay the onset of renal failure. Early initiation of ACE inhibitor therapy significantly reduces the rate of progression, as well as overall and cardiovascular mortality.

Over the past decade, the quality of life of patients with diabetic nephropathy has improved. Slowing the rate of decline in SCF has allowed to extend the pre-dialysis period. The survival rate of patients with diabetes on hemodialysis for 5 years exceeds 60%, the survival rate after kidney transplantation for 10 years exceeds 50%. The problem of providing extracorporeal methods of treatment for patients with diabetes with terminal renal failure remains acute, which forces us to focus on the earliest possible diagnosis of diabetic nephropathy and timely administration of adequate pathogenetic therapy.

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