Chronic renal failure: causes and pathogenesis

The main causes of chronic renal failure are endocrine and vascular diseases. The percentage of patients with diabetic nephropathy, atherosclerotic and hypertensive nephroangiosclerosis is constantly growing among all patients on chronic dialysis.

Causes of chronic kidney failure:

• Inflammatory: chronic glomerulonephritis, chronic pyelonephritis, kidney damage in systemic connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, necrotizing vasculitis, hemorrhagic vasculitis), tuberculosis, HIV-nephropathy, HCV-nephritis, HBV-nephritis, malarial nephropathy, schistosomal Nephropathy.
• Metabolic and endocrine: diabetes mellitus type 1 and type 2, gout, amyloidosis (AA, AL), idiopathic hypercalciuria, oxalose, cystinosis.
• Vascular diseases: malignant hypertension, ischemic kidney disease, hypertension.
• Hereditary and congenital diseases: polycystic disease, segmental hypoplasia, Alport syndrome, reflux-nephropathy, Fanconi nephronophytosis, hereditary onyarthrosis, Fabry's disease.
• Obstructive nephropathy: nephrolithiasis, tumors of the urinary system, hydronephrosis, urogenital schistosomiasis.
• Toxic and medicinal nephropathies: analgesic, cyclosporine, cocaine, heroin, alcoholic, lead, cadmium, radiation, caused by germanium dioxide.

[1], [2], [3], [4], [5], [6]

Pathogenesis of chronic renal failure

Chronic renal failure is primarily caused by disturbing homeostasis by renal water retention and low molecular weight substances. The most important violations of homeostasis include:

• hyperhydration;
• sodium retention;
• volume-Cа ⁺ -dependent arterial hypertension;
• hyperkalemia;
• hyperphosphatemia;
• hypermagnesia;
• metabolic acidosis;
• azotemia with hyperuricemia.

Simultaneously, chronic renal failure accumulates uremic toxins from the "medium molecules" fractions that cause uremic encephalopathy and polyneuropathy, as well as beta _2- microglobulin, glycosylated proteins, and many cytokines. In response to a decrease in the filtration function with a delay in the body of sodium, potassium, phosphorus, H ⁺ ions, the production of aldosterone, antidiuretic (ADH), natriuretic and parathyroid (PTH) hormones acquiring the properties of uremic toxins increases.

Wrinkling of the renal parenchyma leads to a deficiency of erythropoietin (epoetin), metabolites of vitamin D ₃, vasodepressor prostaglandins and activation of the RAAS of the kidneys, resulting in anemia, renin-dependent hypertension, uremic hyperparathyroidism. The pathogenesis of hypertension in chronic renal failure is also due to activation of the sympathetic nervous system of the kidneys, the accumulation of uremic inhibitors of NO synthetase (asymmetric dimethylarginine) and digoxin-like metabolites, as well as resistance to insulin and leptin. With uremic polyneuropathy, the absence of a night decrease in blood pressure in renal hypertension is associated.

Symptoms of chronic renal failure caused by water-electrolyte and hormonal imbalance

Systems	Clinical signs
Cardiovascular	Hypertension, left ventricular hypertrophy, cardiomyopathy, chronic heart failure, acute coronary syndrome
Endothelial	Progressive systemic atherosclerosis
Hemopoiesis	Anemia, hemorrhagic syndrome
Bone	Fibrous osteitis, osteomalacia
Gastrointestinal	Peptic ulcers, angiodysplasia of the gastrointestinal mucosa, malabsorption syndrome
Immune	Viruses and bacteriocarriers, infectious and oncological diseases, dysbacteriosis
Sexual	Hypogonadism, gynecomastia
Protein metabolism	Hypercatabolism, mal-nutrition syndrome *
Lipid metabolism	Hyperlipidemia, oxidative stress
Carbohydrate metabolism	Insulin resistance. De novo diabetes

* Mal-nutrition - a syndrome of protein-energy deficiency.

Cardiovascular pathology ranks first among causes of death in chronic renal failure.

• Uremic cardiomyopathy due to hypertension is represented by concentric hypertrophy of the left ventricle (LVH). With uremic cardiomyopathy caused by volume overload (hypervolemia, anemia), eccentric hypertrophy of the left ventricle develops with its steady gradual dilatation. Expressed uremic cardiomyopathy is characterized by systolic or diastolic dysfunction with chronic heart failure (CHF).
• Progression of atherosclerosis in chronic renal failure is caused by generalized endothelial dysfunction, hypertension, hyperphosphatemia, atherogenic hyperlipidemia, hyperinsulinemia, amino acid imbalance (arginine deficiency, excess homocysteine). Hyperphosphatemia not only accelerates the progression of chronic renal failure and induces hyperplasia of parathyroid glands, but also acts as a risk factor for mortality from cardiovascular complications of chronic renal failure independent of uremic hyperparathyroidism.

Progression: the leading role of nonspecific mechanisms

The rate of progression of chronic renal failure is proportional to the rate of sclerosis of the renal parenchyma and is largely predetermined by the etiology of nephropathy.

• Progression of chronic renal failure in chronic nephritis depends on its clinical variant and morphological type (see Glomerulonephritis). Chronic renal failure in nephrotic or mixed nephritis (FSGS or mesangiocapillary), usually develops in the 3-5th year of the disease.
• Chronic renal failure with AA-amyloidosis in terms of the rate of progression is comparable with diffuse nephritis. It develops against a background of persistent nephrotic syndrome in the framework of hepatolienal syndrome, syndrome of impaired absorption, adrenal insufficiency. Sometimes there is an acute thrombosis of the renal veins.
• Chronic renal failure in diabetic nephropathy is progressing more rapidly than latent nephritis and chronic pyelonephritis. The monthly rate of decrease in the filtration function for diabetic nephropathy is directly proportional to the degree of hyperglycemia, the severity of hypertension, and the magnitude of proteinuria. In 20% of patients with type 2 diabetes mellitus, the rapid formation of chronic renal failure is observed due to the development of irreversible acute renal failure: prerenal, renal, postrenal (see "acute renal failure").
• Chronic renal failure in chronic pyelonephritis and polycystic disease progresses slowly, therefore, osteodystrophy and uremic polyneuropathy sometimes occur even in the conservative stage of chronic renal failure, and the first clinical symptoms of chronic renal failure are polyuria, the syndrome of the salt-losing kidney.

Nonspecific, non-inflammatory mechanisms involved in the progression of chronic renal failure:

• hypertension;
• proteinuria (more than 1 g / l);
• bilateral stenosing atherosclerosis of the renal arteries;
• overloading of food with protein, phosphorus, sodium;

Factors contributing to accelerating the progression of chronic renal failure

Disrupting autoregulation of glomerular blood flow	The glomerular lesion causing glomerulosclerosis
Decreased functioning renal parenchyma Load with sodium chloride Activation of renal RAAS Hyperglycemia, ketonomia Hyperproduction of NO, prostaglandins, growth hormone Smoking Drinking alcohol, cocaine Oxidative stress	Hypertension with circadian rhythm disturbance Load of protein, phosphates Hyperproduction of angiotensin II, aldosterone Glycosylation of albumin, glomerular basement membrane proteins Hyperparathyroidism (CaxP> 60) Atherosclerosis of the renal arteries Proteinuria> 1 g / l Hyperlipidemia

• smoking;
• addiction;
• hyperparathyroidism;
• activation of RAAS;
• hyperaldosteronism;
• glycosylation of tissue proteins (with diabetic nephropathy).

To the factors aggravating the course of chronic renal failure, intercurrent acute infections (including urinary tract infection), acute obstruction of the ureter, pregnancy are also included. In addition, under conditions of uremic defect in autoregulation of the glomerular blood stream, water-electrolyte disturbances easily induce spasm of the afferent arteriolus. Therefore, in chronic renal failure, prerenal acute renal failure is especially frequent. In chronic renal failure, the risk of renal drug damage significantly increased with the development of renal acute renal failure.

In response to a progressive decrease in the functioning renal parenchyma, angiotensin II-dependent spasm of the efferent glomerular arteriolis occurs along with prostaglandin-dependent vasodilatation of the afferent arteriol, which contributes to hyperfiltration. Persistent hyperfiltration and intra-cerebral hypertension lead to glomerular hypertrophy with their damage, glomerulosclerosis and progression of chronic renal failure.