Pathogenesis of chronic renal failure

It was found that in the majority of patients with GFR of about 25 ml / min and below, terminal chronic renal failure is inevitable, regardless of the nature of the disease. There is an adaptive response of intrarenal hemodynamics to the loss of mass of the active nephrons: a decrease in the resistance in the afferent (more pronounced) and efferent arterioles of functioning nephrons, leading to an increase in the rate of intra-cell plasma flow, i.e., hyperperfusion of the glomeruli and increased hydraulic pressure in their capillaries. As a result, there is hyperfiltration, and subsequently - glomerulosclerosis. Dysfunction of the tubular epithelium (primarily proximal) is closely related to the development of tubulointerstitial fibrosis. The tubular epithelium is capable of synthesizing a wide range of cytokines and growth factors. In response to damage or overload, it enhances the expression of adhesion molecules, the synthesis of endothelin and other cytokines that promote tubulointerstitial inflammation and sclerosis. With concomitant arterial hypertension in conditions of impaired autoregulation of intrarenal hemodynamics, systemic arterial pressure affects glomerular capillaries, exacerbating hyperperfusion and increasing intra-cerebral hydraulic pressure. The voltage of the capillary wall leads to a violation of the integrity and permeability of the basal membrane, and further to the transudation of protein molecules into mesangium. Mechanical damage is accompanied by dysfunction of the glomerulus cells with release of cytokines and growth factors, the action of which stimulates the proliferation of mesangium, the 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 potent vasoconstrictor that plays an integral role in the development of arterial hypertension. Strengthening the reactivity and aggregation of platelets stimulates hyperlipidemia, the combination of which with arterial hypertension is accompanied by even more pronounced changes in the glomeruli.

Morphological substratum of chronic renal failure is glomerulosclerosis, characterized by glomerulosclerosis independent of the primary pathology of the kidneys, mesangia sclerosis, extracellular matrix expansion, which includes laminin, fibronectin, heparan sulfate proteoglycan, type IV collagen and interstitial collagen (normally absent in glomeruli). The increase in the extracellular matrix replacing the functionally active tissue is a complex process that involves the participation of various growth factors, cytokines and thermal shock proteins.

Factors of progression of chronic renal failure: arterial hypertension, a decrease in the mass of functioning nephrons by more than 50%, the formation of fibrin in the glomerulus, hyperlipidemia, persistent nephrotic syndrome. With chronic renal failure, there is a violation of osmo- and volumoregulation, ionic blood composition, acid-base state. In this case, the excretion of the final products of nitrogen metabolism, foreign substances, the metabolism of proteins, carbohydrates and lipids is disrupted and the secretion of excess organic substances and biologically active substances is increased.

Reduction of glomerular filtration in chronic renal failure to 30-20 ml / min leads to disruption of acido-ammoniogenesis and depletion of the alkaline reserve. Due to the decrease in the release of hydrogen ions in the form of ammonium, in the conditions of a preserved urine acidification, acidosis and violation of the processes of reabsorption of bicarbonates in the tubular apparatus of the kidneys develop. The change in CBS promotes the development of osteopathy, hyperkalemia and anorexia. Impairment of kidney function is accompanied by hyperphosphatemia and hypocalcemia, increased activity of alkaline phosphatase and hypersecretion of parathyroid hormone by parathyroid glands.

As the kidney function worsens, 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 between a drop in renal function and a decrease in blood concentration of 1,25 (OH) ₂ vitamin D _{3 was} noted .

In high concentrations, phosphate acts as a uremic toxin, which determines the unfavorable prognosis. Hyperphosphatemia also promotes the development of hypocalcemia, secondary hyperparathyroidism, osteoporosis, arterial hypertension, atherosclerosis. Hyperparathyroidism in combination with impaired production of the active metabolite of vitamin D [1,25 (OH) ₂ vitamin D ₃ ] promotes an increase in the activity of osteoclasts in the bones, which leads to the elution of calcium from them and the development of renal osteodystrophy.

The kidneys are the source of endogenous erythropoietin (about 90%), so chronic renal insufficiency leads to a pathogenetically significant deficiency of renal erythropoietin. This breaks the formation of erythroblasts, the synthesis of globin and develops anemia. A direct relationship was found between the level of creatinine and hemoglobin in the blood. In adults, anemia occurs at later stages of chronic kidney failure than in children. In addition, the latter are often noted for growth retardation, and the earlier chronic renal failure appeared, 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 has not been fully understood. Its possible causes for chronic renal failure:

• endogenous (kidney disease or syndrome);
• lack of protein or a decrease in the energy value of food;
• violation of water-electrolyte balance;
• acidosis;
• renal osteodystrophy;
• renal anemia;
• hormonal disorders.

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

In 50% of all puberty children with chronic renal failure, delayed puberty and hypogonadism are detected. Uremia, which occurs before and during puberty, causes more pronounced changes in exocrine testicular function than chronic renal failure, which developed after the maturation of the gonads.

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

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]