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 among all patients on chronic dialysis is constantly growing.

Causes of chronic renal 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 2, gout, amyloidosis (AA, AL), idiopathic hypercalciuria, oxalosis, cystinosis.
• Vascular diseases: malignant hypertension, ischemic kidney disease, hypertension.
• Hereditary and congenital diseases: polycystic disease, segmental hypoplasia, Alport syndrome, reflux nephropathy, Fanconi nephronophthisis, hereditary onychoarthrosis, Fabry disease.
• Obstructive nephropathy: nephrolithiasis, tumors of the urinary system, hydronephrosis, urogenital schistosomiasis.
• Toxic and drug-induced nephropathy: analgesic, cyclosporine, cocaine, heroin, alcohol, lead, cadmium, radiation, caused by germanium dioxide.

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Pathogenesis of chronic renal failure

Chronic renal failure is primarily caused by renal retention of water and low-molecular substances that disrupts homeostasis. The most important homeostasis disorders include:

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

At the same time, chronic renal failure causes accumulation of uremic toxins from the fractions of "medium molecules" causing uremic encephalopathy and polyneuropathy, as well as beta ₂ -microglobulin, glycosylated proteins, and many cytokines. In response to a decrease in filtration function with retention of sodium, potassium, phosphorus, and H ⁺ ions in the body, the production of aldosterone, antidiuretic (ADH), natriuretic, and parathyroid (PTH) hormones increases, acquiring the properties of uremic toxins.

Shrinkage of the renal parenchyma leads to a deficiency of erythropoietin (epoetin), vitamin D3 metabolites _, vasodepressor prostaglandins and activation of the renal RAAS, resulting in the development of anemia, renin-dependent hypertension, and uremic hyperparathyroidism. The pathogenesis of hypertension in chronic renal failure is also due to activation of the sympathetic nervous system of the kidneys, accumulation of uremic NO-synthetase inhibitors (asymmetric dimethylarginine) and digoxin-like metabolites, as well as resistance to insulin and leptin. The absence of a nocturnal decrease in blood pressure in renal hypertension is associated with uremic polyneuropathy.

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
Hematopoiesis	Anemia, hemorrhagic syndrome
Bone	Osteitis fibrosa, osteomalacia
Gastrointestinal	Peptic ulcers, angiodysplasia of the gastrointestinal mucosa, malabsorption syndrome
Immune	Virus and bacteria carriage, infectious and oncological diseases, dysbacteriosis
Sexual	Hypogonadism, gynecomastia
Protein metabolism	Hypercatabolism, malnutrition syndrome*
Lipid metabolism	Hyperlipidemia, oxidative stress
Carbohydrate metabolism	Insulin resistance. de novo diabetes

* Malnutrition - protein-energy deficiency syndrome.

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

• Uremic cardiomyopathy caused by hypertension is represented by concentric left ventricular hypertrophy (LVH). In uremic cardiomyopathy caused by volume overload (hypervolemia, anemia), eccentric left ventricular hypertrophy with its steady gradual dilation develops. Severe 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, homocysteine excess). Hyperphosphatemia not only accelerates the progression of chronic renal failure and induces hyperplasia of the 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 non-specific 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.

• The 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), as a rule, develops in the 3rd-5th year of the disease.
• Chronic renal failure in AA amyloidosis is comparable in its rate of progression to diffuse nephritis. It develops against the background of persistent nephrotic syndrome within the framework of hepatosplenic syndrome, malabsorption syndrome, adrenal insufficiency. Sometimes acute renal vein thrombosis occurs.
• Chronic renal failure in diabetic nephropathy progresses faster than in latent nephritis and chronic pyelonephritis. The monthly rate of decrease in filtration function in diabetic nephropathy is directly proportional to the degree of hyperglycemia, the severity of hypertension and the amount of proteinuria. In 20% of patients with type 2 diabetes mellitus, especially rapid development 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, so 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 and salt-wasting kidney syndrome.

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

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

Factors that contribute to the acceleration of the progression of chronic renal failure

Impairing autoregulation of glomerular blood flow	Causing damage to the glomeruli with the development of glomerulosclerosis
Decreased functioning renal parenchyma Sodium chloride loading Activation of renal RAAS Hyperglycemia, ketonemia Hyperproduction of NO, prostaglandins, growth hormone Smoking Use of alcohol, cocaine Oxidative stress	Hypertension with circadian rhythm disorder Loading with protein, phosphates Hyperproduction of angiotensin II, aldosterone Glycosylation of albumin, proteins of the glomerular basement membrane Hyperparathyroidism (CachP >60) Atherosclerosis of the renal arteries Proteinuria > 1 g/l Hyperlipidemia

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

Factors that aggravate the course of chronic renal failure also include intercurrent acute infections (including urinary tract infection), acute ureteral obstruction, pregnancy. In addition, under conditions of uremic defect of autoregulation of glomerular blood flow, water-electrolyte disturbances easily induce spasm of the afferent arteriole. Therefore, prerenal acute renal failure develops especially often in chronic renal failure. In chronic renal failure, the risk of drug-induced kidney damage with the development of renal acute renal failure is significantly increased.

In response to progressive reduction in functioning renal parenchyma, angiotensin II-dependent spasm of the efferent glomerular arteriole occurs together with prostaglandin-dependent vasodilation of the afferent arteriole, which promotes hyperfiltration. Persistent hyperfiltration and intraglomerular hypertension lead to glomerular hypertrophy with glomerular damage, glomerulosclerosis, and progression of chronic renal failure.