Pathogenesis of chronic renal failure

It has been established that in most patients with SCF of about 25 ml/min and below, terminal chronic renal failure inevitably occurs, regardless of the nature of the disease. There is an adaptive response of intrarenal hemodynamics to the loss of mass of functioning nephrons: a decrease in resistance in the afferent (more pronounced) and efferent arterioles of functioning nephrons, leading to an increase in the rate of intraglomerular plasma flow, i.e. to hyperperfusion of glomeruli and an increase in hydraulic pressure in their capillaries. This results in hyperfiltration, and subsequently - glomerulosclerosis. Dysfunction of the tubular epithelium (primarily proximal) is closely associated with the development of tubulointerstitial fibrosis. Tubular epithelium is capable of synthesizing a wide range of cytokines and growth factors. In response to injury or overload, it enhances the expression of adhesion molecules, synthesis of endothelin and other cytokines that promote tubulointerstitial inflammation and sclerosis. In concomitant arterial hypertension under conditions of impaired autoregulation of intrarenal hemodynamics, systemic arterial pressure affects glomerular capillaries, aggravating hyperperfusion and increasing intraglomerular hydraulic pressure. Tension of the capillary wall leads to disruption of the integrity and permeability of the basement membrane, and subsequently to the extravasation of protein molecules into the mesangium. Mechanical injury is accompanied by dysfunction of glomerular cells with the release of cytokines and growth factors, the action of which stimulates proliferation of the mesangium, synthesis and expansion of the mesangial matrix and, ultimately, leads to glomerulosclerosis. Any damage to the vessel wall stimulates platelet aggregation with the release of thromboxane, a powerful vasoconstrictor that plays an integral role in the development of arterial hypertension. Increased reactivity and platelet aggregation is stimulated by hyperlipidemia, the combination of which with arterial hypertension is accompanied by even more pronounced changes in the glomeruli.

The morphological substrate of chronic renal failure is glomerulosclerosis, characterized, regardless of the primary renal pathology, by glomerular depletion, mesangial sclerosis, and expansion of the extracellular matrix, which includes laminin, fibronectin, heparan sulfate proteoglycan, type IV collagen, and interstitial collagen (normally absent from the glomeruli). The increase in the extracellular matrix replacing functionally active tissue is a complex process involving various growth factors, cytokines, and heat shock proteins.

Factors of progression of chronic renal failure: arterial hypertension, decrease in the mass of functioning nephrons by more than 50%, formation of fibrin in the glomerulus, hyperlipidemia, persistent nephrotic syndrome. In chronic renal failure, there is a violation of osmo- and volume regulation, ionic composition of the blood, acid-base balance. At the same time, the excretion of the end products of nitrogen metabolism, foreign substances, metabolism of proteins, carbohydrates and lipids is disrupted and the secretion of excess organic substances and biologically active substances increases.

A decrease in glomerular filtration in chronic renal failure to 30-20 ml/min leads to a violation of acidoammoniogenesis and depletion of the alkaline reserve. Due to a decrease in the release of hydrogen ions in the form of ammonium in conditions of preserved ability to acidify urine, acidosis and a violation of the processes of reabsorption of bicarbonates in the tubular apparatus of the kidneys develop. Changes in the acid-base balance contribute to the development of osteopathy, hyperkalemia and anorexia. Deterioration of renal function is accompanied by hyperphosphatemia and hypocalcemia, an increase in the activity of alkaline phosphatase and hypersecretion of parathyroid hormone by the parathyroid glands.

As kidney function deteriorates, the production of active metabolites of vitamin D decreases. As a result, calcium absorption in the intestine and reabsorption in the kidneys decrease, which leads to the development of hypocalcemia. A direct correlation has been noted between the decline in kidney function and a decrease in the concentration of 1,25(OH) ₂ vitamin D3 _in the blood.

In high concentrations, phosphate acts as a uremic toxin, which determines an unfavorable prognosis. Hyperphosphatemia also contributes to the development of hypocalcemia, secondary hyperparathyroidism, osteoporosis, arterial hypertension, and atherosclerosis. Hyperparathyroidism in combination with impaired production of the active metabolite of vitamin D [1,25(OH) ₂ vitamin D3 _] contributes to increased osteoclast activity in bones, which leads to calcium leaching from them and the development of renal osteodystrophy.

The kidneys are the source of endogenous erythropoietin (about 90%), so chronic renal failure leads to a pathogenetically significant deficiency of renal erythropoietin. In this case, the formation of erythroblasts and globin synthesis are disrupted, and anemia develops. A direct relationship has been found between the level of creatinine and hemoglobin in the blood. In adults, anemia occurs at later stages of chronic renal failure than in children. In addition, the latter often experience growth retardation, and the earlier chronic renal failure occurs, the more pronounced it is. The most significant deviations in physical development are observed in children with congenital pathology of the urinary system.

The pathogenesis of growth disorders is not fully understood. Its possible causes in chronic renal failure:

• endogenous (renal disease or syndrome);
• lack of protein or decreased energy value of food;
• water-electrolyte imbalance;
• acidosis;
• renal osteodystrophy;
• renal anemia;
• hormonal disorders.

It has been proven that growth retardation in chronic renal failure in children is not associated with a decrease in growth hormone secretion or a deficiency of insulin-like growth factor-1. It is assumed that it is due to an increase in the content of proteins that bind the latter due to a decrease in glomerular filtration, which, in turn, leads to a decrease in the biological activity of insulin-like growth factor-1.

Delayed puberty and hypogonadism are found in 50% of all children of pubertal age with chronic renal failure. Uremia occurring before and during puberty causes more pronounced changes in exocrine testicular function than chronic renal failure that develops after gonadal maturation.

Unhealthy nutrition of children quickly leads to the development of protein-energy deficiency, which is usually combined with signs of osteodystrophy.

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