Treatment strategies for diabetic nephropathy

The strategy for treating diabetic nephropathy can be divided into three stages:

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

Primary prevention

The goal of primary prevention of diabetic nephropathy is to prevent the development of microalbuminuria in patients with diabetes mellitus with normoalbuminuria, who are at high risk of developing diabetic kidney disease. The risk group for developing microalbuminuria includes patients with diabetes mellitus with:

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

Compensation of carbohydrate metabolism is achieved through rational selection of hypoglycemic drugs. Data from large studies indicate that optimal compensation of carbohydrate metabolism (reduction of HbA1c to a level of less than 7.5%) allowed to reduce the risk of microalbuminuria by 34%, and proteinuria by 43% in the DCCT study and to reduce the risk of microangiopathy by 25% in the UKPDS study.

The use of ACE inhibitors for 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 lack of functional renal reserve, treatment with ACE inhibitors in a suppressor dose for 1 month led to restoration of intraglomerular hemodynamic parameters. However, for the final development of treatment tactics, large controlled randomized studies are necessary.

Thus, the main principles of primary prevention of diabetic nephropathy are considered to be ideal (optimal) compensation of carbohydrate metabolism - maintaining HbA1c <7.5% and prescribing ACE inhibitors in the presence of signs of intraglomerular hypertension (in the absence of functional renal reserve) even with normal blood pressure.

Secondary prevention

Secondary prevention of diabetic nephropathy involves therapeutic measures aimed at preventing the progression of pathological changes in the kidneys in patients with diabetes mellitus with diabetic nephropathy at 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 a timely manner and take all necessary preventive measures.

Several of the most important risk factors for rapid progression of diabetic nephropathy in the microalbuminuria stage can be identified:

• HbA1c>7.5%; albuminuria more than 100 mg/day;
• blood pressure > 130/85 mmHg;
• total serum cholesterol greater than 5.2 mmol/l.

As in the previous stage, the main therapeutic principles aimed at preventing the transition of microlbuminuria to proteinuria include compensation of carbohydrate metabolism, correction of intrarenal hemodynamics, and, if necessary, antihypertensive and lipid-lowering therapy.

To compensate for carbohydrate metabolism in patients with type 1 diabetes mellitus, the practice of intensive insulin therapy should be fundamental in achieving high-quality metabolic control. To date, more than 5 large multicenter randomized studies have been conducted, confirming the advantages of intensive insulin therapy compared to traditional therapy in achieving good compensation of diabetes mellitus and preventing the progression of diabetic nephropathy at the stage of microalbuminuria.

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

A large number of randomized, double-blind, controlled studies have been conducted to study the nephroprotective activity of ACE inhibitors lasting from 2 to 8 years in normotensive patients with type 1 diabetes mellitus and diabetic nephropathy in the microalbuminuria stage. All studies without exception have led to a consensus that ACE inhibitors effectively inhibit the progression of diabetic nephropathy in the microalbuminuria stage. The largest study found that out 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 in 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 SCF.

There are fewer data from foreign and domestic authors on the use of ACE inhibitors in patients with type 2 diabetes mellitus compared to patients with type 1 diabetes mellitus, but they are no less convincing. A pronounced nephroprotective effect from the use of drugs in this group was also obtained in such patients. The first long-term randomized double-blind study on 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, proteinuria developed in only 12% of patients, while with placebo treatment - in 42% of patients. The annual rate of decrease in SCF in patients treated with ACE inhibitors slowed down 5 times compared to patients receiving placebo.

When dyslipidemia (hypercholesterolemia and/or hypertriglyceridemia) is detected in patients with microalbuminuria, it is necessary to carry out a set of measures aimed at normalizing lipid metabolism, since hyperlipidemia is one of the main factors in the progression of diabetic nephropathy. These measures include both non-drug therapy and the administration of active drugs. Successful lipid-lowering therapy can significantly slow the rate of development of diabetic nephropathy.

Restoration of impaired intrarenal hemodynamics can be achieved by non-drug methods, in particular by limited consumption of animal protein. Experimental studies have shown that a high-protein diet leads to an increase in intraglomerular hypertension and, consequently, to rapid progression of glomerulosclerosis. For this reason, at the stage of microalbuminuria, it is recommended to moderately limit protein intake with food to reduce intraglomerular hypertension. The optimal protein content in the diet at this stage of kidney damage should not exceed 12-15% of the total daily caloric intake of food, which is no more than 1 g of protein per 1 kilogram of body weight.

Basic principles of secondary prevention of diabetic nephropathy:

• ideal (optimal) compensation of carbohydrate metabolism - maintaining HbA1c <7.5%;
• the use of ACE inhibitors in subpressor doses at normal blood pressure levels and in average therapeutic doses when blood pressure increases;
• conducting lipid-lowering therapy (in case of severe hyperlipidemia);
• a diet with moderate restriction of animal protein (no more than 1 g of protein per 1 kg of body weight).

Tertiary prevention

Prevention of rapid decline in renal filtration function and development of chronic renal failure in patients with diabetes mellitus in the proteinuric stage of diabetic nephropathy is called tertiary prevention of diabetic nephropathy.

Risk factors for rapid decline in renal nitrogen excretion function in patients with diabetes mellitus in the proteinuria stage: HbA1c>8%, blood pressure>130/85 mmHg, hyperlipidemia (total serum cholesterol over 5.2 mmol/l, serum triglycerides over 2.3 mmol/l), proteinuria over 2 g/day, high-protein diet (over 1 g protein per 1 kg body weight), lack of systematic treatment of arterial hypertension (in particular, with ACE inhibitors).

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

In patients with type 1 diabetes mellitus, the most rational method of maintaining compensation/subcompensation of carbohydrate metabolism at the stage of proteinuria remains the method of intensive insulin therapy; in patients with type 2 diabetes mellitus, the use of oral hypoglycemic drugs. If they are ineffective, patients are transferred to insulin therapy.

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

Active hypolipidemic therapy for diabetes should be started only after compensation (or subcompensation) of carbohydrate metabolism has been achieved. If the cholesterol level remains within 5.2-6.2 mmol/l, non-drug hypolipidemic therapy is prescribed, which includes following a low-cholesterol diet, increasing the volume of physical activity, limiting alcohol intake, etc. If such measures do not lead to a decrease in cholesterol levels within 3 months, then drug hypolipidemic therapy is prescribed.

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

At the stage of pronounced proteinuria, a more stringent reduction in animal protein consumption is introduced - to 0.7-0.8 g per 1 kg of body weight. Such restrictions are necessary to reduce the hemodynamic load on the kidneys caused by a high-protein diet and to reduce the filtration load of protein on the kidneys. The effectiveness of a low-protein diet in patients with diabetes mellitus has long been proven in numerous clinical studies that have shown a decrease in proteinuria, a slowdown in the progressive decline in the filtration function of the kidneys, and stabilization of blood pressure in patients with an pronounced stage of diabetic nephropathy. Such a restriction of animal protein consumption must be observed not only by patients with moderate proteinuria, but also by patients with developed nephrotic syndrome, when protein losses in the urine exceed 3.5 g / day.