Strategies for the treatment of diabetic nephropathy

The strategy in the treatment of diabetic nephropathy can be conditionally divided into three stages:

• primary prevention of diabetic nephropathy, aimed at preventing the development of renal pathology in patients with normoalbuminuria;
• secondary prevention of diabetic nephropathy (treatment of patients with microalbuminuria to prevent a pronounced proteinuric stage of diabetic nephropathy);
• tertiary prevention of diabetic nephropathy (treatment measures in patients with diabetes mellitus with proteinuria in order to slow the decrease in the filtration function of the kidneys and the progression of chronic renal failure).

Primary prevention

The purpose of primary prevention of diabetic nephropathy is to prevent the appearance of microalbuminuria in patients with diabetes mellitus with normoalbuminuria belonging to the group at high risk of developing diabetic kidney damage. The risk group for microalbuminuria is composed of patients with diabetes mellitus with:

• inadequate compensation of carbohydrate metabolism (HbA1c> 7%);
• duration of diabetes more than 5 years;
• hyperfiltration and depleted functional renal reserve;
• the presence of retinopathy;
• the presence of hyperlipidemia.

Compensation of carbohydrate metabolism is achieved through a rational choice of hypoglycemic drugs. Data from large studies indicate that optimal compensation of carbohydrate metabolism (reducing HbA1c to less than 7.5%) reduced the risk of microalbuminuria by 34%, and proteinuria by 43% in the DCCT study and reduced the risk of developing microangiopathies by 25% in the UKPDS study.

The use of ACE inhibitors for the normalization of intrarenal hemodynamics in a subpressor dose (5 mg / day) is discussed. In the studies of M.V. Shestakova in patients with diabetes mellitus with hyperfiltration and the absence of a functional renal reserve treatment with ACE inhibitors in a suppressor dose for 1 month led to the restoration of intraclubic hemodynamics. However, for the final development of treatment tactics, large, controlled, randomized trials are needed.

Thus, the main principles of primary prevention of diabetic nephropathy consider ideal (optimal) compensation of carbohydrate metabolism - maintenance of HbA1c <7.5% and the appointment of ACE inhibitors in the presence of signs of intramedular hypertension (in the absence of functional renal reserve) even at normal blood pressure level

Secondary prevention

Secondary prevention of diabetic nephropathy involves the implementation of therapeutic measures aimed at preventing the progression of pathological changes in the kidneys in diabetic patients with diabetic nephropathy in the stage of microalbuminuria. As noted earlier, this is the last, reversible stage of diabetic nephropathy, so it is extremely important to diagnose it in time and take all the necessary preventive measures.

There are several most important risk factors for the rapid progression of diabetic nephropathy in the stage of microalbuminuria:

• HbA1c> 7.5%; albuminuria more than 100 mg / day;
• arterial pressure> 130/85 mm Hg;
• total serum cholesterol more than 5.2 mmol / l.

As in the previous stage, as the main therapeutic principles aimed at preventing the transition of micro-albuminuria to proteinuria, consider the compensation of carbohydrate metabolism, correction of intracenal hemodynamics, if necessary, antihypertensive and hypolipidemic therapy.

To compensate for carbohydrate metabolism in patients with type 1 diabetes, the practice of intensive insulin therapy should be fundamental to achieving qualitative metabolic control. To date, more than 5 large, multicenter, randomized trials have been conducted that have confirmed the benefits of intensive insulin therapy compared with traditional in achieving good diabetes mellitus and preventing the progression of diabetic nephropathy in the microalbuminuria stage.

When analyzing the results of studies it turned out that not every level of microalbuminuria is reversible even with the optimal compensation of carbohydrate metabolism. Thus, in Steno studies, it was shown that at a microalbuminuria level of less than 100 mg / day, the compensation of diabetes mellitus led to a decrease in urinary albumin excretion to normal values, with microalbuminuria> 100 mg / day, even with prolonged compensation of diabetes mellitus, albumin excretion did not decrease .

A large number of randomized, double-blind, controlled studies on the nephroprotective activity of ACE inhibitors lasting from 2 to 8 years in normotensive patients with type 1 diabetes mellitus with diabetic nephropathy in the stage of microalbuminuria. All studies without exception allowed to come to a common opinion that ACE inhibitors effectively inhibit the progression of diabetic nephropathy at the stage of microalbuminuria. The largest study found that of 235 patients with type 1 diabetes mellitus with microalbuminuria after 2 years of treatment, proteinuria developed in only 7% of patients receiving captopril and 21% of patients receiving placebo (The Microalbuminuria Captopril Study Group, 1996) . Long-term treatment (more than 8 years) with ACE inhibitors in patients with microalbuminuria also allows preserving the filtration function of the kidneys, preventing an annual decrease in GFR.

Data of foreign and domestic authors on the use of ACE inhibitors in patients with type 2 diabetes mellitus is slightly less than in patients with type 1 diabetes mellitus, but they are no less convincing. The expressed nephroprotective effect from the use of drugs of this group was obtained in such patients. The first long-term, randomized, double-blind study of the use of an ACE inhibitor in patients with type 2 diabetes mellitus with microalbuminuria showed that after 5 years of treatment with the drug, only 12% of patients developed proteinuria, while placebo treatment in 42% of patients. The annual rate of reduction in GFR in patients treated with ACE inhibitors slowed down 5-fold compared with patients receiving placebo.

When detecting dyslipidemia (hypercholesterolemia and / or hypertriglyceridemia) in patients with microalbuminuria, a set of measures is needed to normalize lipid metabolism, since hyperlipidemia is one of the main factors in the progression of diabetic nephropathy. These measures include both non-drug therapy and prescribing active medicines. Successful lipid-lowering therapy can significantly slow the rate of development of diabetic nephropathy.

Restoration of impaired intrarenal hemodynamics can be achieved also by non-drug methods, in particular by restricting the consumption of animal protein. In experimental studies, it has been shown that a high-protein diet leads to an increase in intralobular hypertension and, consequently, to the rapid progression of glomerulosclerosis. For this reason, in the stage of microalbuminuria, it is recommended that the consumption of protein with food be moderately reduced to reduce intra-cerebral hypertension. The optimal protein content in the diet in this stage of kidney damage should not exceed 12-15% of the total daily calorie content of food, which is not more than 1 g of protein per kilogram of body weight.

Basic principles of secondary prevention of diabetic nephropathy:

• ideal (optimal) compensation of carbohydrate metabolism - maintenance of HALAc <7.5%;
• the use of ACE inhibitors in subpressor doses at a normal level of arterial pressure and at medium therapeutic doses with increasing blood pressure;
• carrying out lipid-lowering therapy (with severe hyperlipidemia);
• a diet with a moderate restriction of animal protein (not more than 1 g of protein per 1 kg of body weight).

Tertiary prevention

Prevention of a rapid decrease in the filtration function of the kidneys and the development of chronic renal failure in diabetic patients in the proteinuric stage of diabetic nephropathy is called tertiary prevention of diabetic nephropathy.

Risk factors for the rapid decrease in renal nitrogen excretion in patients with diabetes mellitus in the stage of proteinuria: HLA1c> 8%, arterial pressure> 130/85 mm Hg, hyperlipidemia (total serum cholesterol more than 5.2 mmol / l, serum triglycerides> 2, 3 mmol / l), proteinuria more than 2 g / day, high protein diet (more than 1 g protein per 1 kg body weight), the lack of systematic treatment of hypertension (in particular, ACE inhibitors).

Proceeding from the listed risk factors for the rapid development of chronic renal failure, the main therapeutic principles at this stage are the compensation of carbohydrate metabolism, correction of blood pressure, lipid lowering therapy, low-protein diet.

In patients with type 1 diabetes, the most rational method of maintaining compensation / subcompensation of carbohydrate metabolism in the stage of proteinuria is the method of intensive insulin therapy; in patients with type 2 diabetes mellitus - the use of oral hypoglycemic drugs. With their ineffectiveness, patients are transferred to insulin therapy.

In the stage of proteinuria from the successful selection of antihypertensive drugs, the future fate of the patient with diabetes depends. If a patient with severe diabetic nephropathy succeeds in stabilizing blood pressure at a level not exceeding 130/85 mm Hg, the rate of decrease in the filtration function of the kidneys slows down 3-5 times, which significantly pushes the onset of terminal renal failure. The most effective in patients with diabetic nephropathy in the stage of proteinuria are ACE inhibitors, which have a powerful antihypertensive and nephroprotective effect. To enhance the antihypertensive effect, drugs of this group can be combined with calcium channel blockers, diuretics, beta-blockers.

To begin active lipid-lowering therapy in diabetes mellitus should only after the achievement of compensation (or subcompensation) of carbohydrate metabolism. If the level of cholesterol is maintained after this, within 5.2-6.2 mmol / l, non-drug-induced lipid lowering therapy is prescribed, which includes adherence to a low-cholesterol diet, expansion of physical activity, restriction of alcohol intake, etc. If within 3 months such activities are not lead to a decrease in the level of cholesterol, then prescribe medicinal lipid-lowering therapy.

Active medicinal lipid-lowering therapy is prescribed immediately in case of very high serum cholesterol levels (more than 6.5 mmol / l), since such cholesterol values are associated with a risk of high mortality from cardiovascular pathology.

In the stage of pronounced proteinuria, a more severe decrease in the intake of animal protein is introduced - up to 0.7-0.8 g per 1 kg of body weight. Such restrictions are necessary to reduce the hemodynamic load on the kidneys, provoked by a high-protein diet, and reduce the filtration load of the protein on the kidneys. The effectiveness of a low protein diet in diabetic patients has been proven for a long time in numerous clinical studies showing a decrease in proteinuria, a slowing down of the progressive decrease in the filtration function of the kidneys, stabilization of blood pressure in patients with a marked stage of diabetic nephropathy. Such restriction of animal protein intake should be observed not only for patients with moderate proteinuria, but also for patients with developed nephrotic syndrome, when protein losses in the urine exceed 3.5 g / day.