Proteinuria

Proteinuria is the excretion of proteins in the urine that exceeds normal (30-50 mg/day) values, usually a sign of kidney damage.

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Causes proteinuria

In the presence of pronounced leukocyturia and especially hematuria, a positive qualitative reaction for protein in the urine is due to the breakdown of cellular elements during prolonged standing of urine; in this situation, proteinuria exceeding 0.3 g/day is considered pathological.

Precipitation protein tests give false positive results in the presence of iodine-containing contrast agents, large amounts of antibiotics (penicillins or cephalosporins), and sulfonamide metabolites in the urine.

In the early stages of development of most nephropathies, low-molecular plasma proteins (albumin, ceruloplasmin, transferrin, etc.) predominantly penetrate into the urine. However, it is possible to detect high-molecular proteins (alpha2-macroglobulin, y-globulin), which are more typical for severe kidney damage with “large” proteinuria.

Selective proteinuria includes proteins with a low molecular weight of no more than 65,000 kDa, mainly albumin. Non-selective proteinuria is characterized by an increase in the clearance of medium- and high-molecular proteins: a ₂ -macroglobulin, beta-lipoproteins, and y-globulin predominate in the composition of urine proteins. In addition to plasma proteins, proteins of renal origin are determined in the urine - Tamm-Horsfall uroprotein, secreted by the epithelium of the convoluted tubules.

Glomerular proteinuria is caused by increased filtration of plasma proteins through glomerular capillaries. This depends on the structural and functional state of the glomerular capillary wall, the properties of protein molecules, pressure and blood flow velocity, which determine the SCF. Glomerular proteinuria is a mandatory sign of most kidney diseases.

The wall of the glomerular capillaries consists of endothelial cells (with rounded openings between them), a three-layer basement membrane - a hydrated gel, and epithelial cells (podocytes) with a plexus of pedunculated processes. Due to its complex structure, the glomerular capillary wall can "sift" plasma molecules from the capillaries into the space of the glomerular capsule, and this function of the "molecular sieve" largely depends on the pressure and speed of blood flow in the capillaries.

Under pathological conditions, the size of the "pores" increases, deposits of immune complexes cause local changes in the capillary wall, increasing its permeability for macromolecules. In addition to the size of the glomerular "pores", electrostatic factors are also important. The glomerular basement membrane is negatively charged; the pedunculated processes of podocytes also carry a negative charge. Under normal conditions, the negative charge of the glomerular filter repels anions - negatively charged molecules (including albumin molecules). The change in charge promotes albumin filtration. It is assumed that the fusion of the pedunculated processes is a morphological equivalent of a change in charge.

Tubular proteinuria is caused by the inability of the proximal tubules to reabsorb low-molecular plasma proteins filtered in normal glomeruli. Proteinuria rarely exceeds 2 g/day, excreted proteins are represented by albumin, as well as fractions with an even lower molecular weight (lysozyme, beta ₂ -microglobulin, ribonuclease, free light chains of immunoglobulins), which are absent in healthy individuals and in glomerular proteinuria due to 100% reabsorption by the epithelium of the convoluted tubules. A characteristic feature of tubular proteinuria is the predominance of beta ₂ -microglobulin over albumin, as well as the absence of high-molecular proteins. Tubular proteinuria is observed in cases of damage to the renal tubules and interstitium: tubulointerstitial nephritis, pyelonephritis, potassium-penic kidney, acute tubular necrosis, chronic rejection of a renal transplant. Tubular proteinuria is also characteristic of many congenital and acquired tubulopathies, in particular Fanconi syndrome.

"Overflow" proteinuria develops with an increase in the concentration of low-molecular proteins (immunoglobulin light chains, hemoglobin, myoglobin) in the blood plasma. In this case, these proteins are filtered by unchanged glomeruli in quantities exceeding the tubules' ability to reabsorb. This is the mechanism of proteinuria in multiple myeloma (Bence-Jones proteinuria) and other plasma cell dyscrasias, as well as myoglobinuria.

The so-called functional proteinuria is distinguished. The mechanisms of development and clinical significance of most of its variants are unknown.

• Orthostatic proteinuria occurs during prolonged standing or walking ("proteinuria en marche") and quickly disappears in a horizontal position. The amount of protein excretion in urine does not exceed 1 g/day. Orthostatic proteinuria is glomerular and non-selective and, according to long-term prospective studies, is always benign. When isolated, there are no other signs of kidney damage (changes in urinary sediment, increased blood pressure). It is most often observed in adolescence (13-20 years), and disappears in half of people 5-10 years after its onset. Characteristically, there is no protein in urine tests taken immediately after the patient has been in a horizontal position (including in the morning before getting out of bed).
• Proteinuria of tension, found after intense physical exertion in at least 20% of healthy individuals, including athletes, is apparently also benign. According to the mechanism of its occurrence, it is considered tubular, caused by redistribution of intrarenal blood flow and relative ischemia of the proximal tubules.
• In case of fever with a body temperature of 39-41 °C, especially in children and elderly and senile people, so-called febrile proteinuria is detected. It is glomerular, the mechanisms of its development are unknown. The occurrence of proteinuria in a patient with fever sometimes indicates the addition of kidney damage; this is evidenced by simultaneously occurring changes in the urinary sediment (leukocyturia, hematuria), large, especially nephrotic values of protein excretion in the urine, as well as arterial hypertension.

Proteinuria exceeding 3 g/day is a key sign of nephrotic syndrome.

Proteinuria and progression of chronic nephropathy

The importance of proteinuria as a marker of the progression of kidney damage is largely determined by the mechanisms of toxic action of individual components of the protein ultrafiltrate on the epithelial cells of the proximal tubules and other structures of the renal tubulointerstitium.

Components of protein ultrafiltrate that have nephrotoxic effects

Protein	Mechanism of action
Albumen	Increased expression of proinflammatory chemokines (monocyte chemoattractant protein type 1, RANTES*) Toxic effect on proximal tubular epithelial cells (overload and rupture of lysosomes with release of cytotoxic enzymes) Induction of synthesis of vasoconstriction molecules, aggravating hypoxia of tubulointerstitial structures Activation of apoptosis of proximal tubular epithelial cells
Transferrin	Induction of complement component synthesis by proximal tubular epithelial cells Increased expression of proinflammatory chemokines Formation of reactive oxygen radicals
Complement components	Formation of cytotoxic MAC** (C5b-C9)

• * RANTES (Regulated upon activation, normal T-lymphocyte expressed and secreted) - activated substance expressed and secreted by normal T-lymphocytes.
• **MAC - membrane attack complex.

Many mesangiocytes and vascular smooth muscle cells undergo similar changes, signifying the acquisition of the main properties of a macrophage. Monocytes from the blood actively migrate into the renal tubulointerstitium, also transforming into macrophages. Plasma proteins induce processes of tubulointerstitial inflammation and fibrosis, called proteinuric remodeling of the tubulointerstitium.

The severity of proteinuric remodeling of tubulointerstitium is one of the main factors determining the rate of progression of renal failure in chronic nephropathy. The dependence of the increase in serum creatinine concentration on the magnitude of proteinuria and the prevalence of tubulointerstitial fibrosis has been repeatedly demonstrated for various forms of chronic glomerulonephritis and renal amyloidosis.

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Symptoms proteinuria

Proteinuria is usually a sign of kidney disease. High ("large") proteinuria is also considered a marker of the severity and activity of kidney damage.

Forms

Based on the content of certain proteins in plasma and urine, the following types of proteinuria are conventionally distinguished:

• selective;
• non-selective.

By localization:

• glomerular;
• canalicular.

By etiology:

• "overflow" proteinuria;
• functional proteinuria:
  • orthostatic;
  • idiopathic;
  • tension proteinuria;
  • febrile proteinuria.

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Diagnostics proteinuria

Laboratory diagnostics of proteinuria

When quantitatively determining the urinary protein excretion rate in a range of values not exceeding 1 g/day, the pyrogallol method has advantages in sensitivity over the more common sulfosalicylic method.

Types of proteinuria are differentiated by determining individual protein fractions in urine using biochemical and immunohistochemical methods.

Orthostatic proteinuria is confirmed by the results of a special test: urine is collected in the morning before getting out of bed, then after being in a vertical position (preferably after walking with hyperlordosis) for 1-2 hours. An increase in the excretion of proteins with urine only in the second portion confirms orthostatic proteinuria.

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Differential diagnosis

Excretion of proteins in urine reaches significant values (more than 3 g/day) in chronic and, less commonly, acute glomerulonephritis, glomerulonephritis in systemic diseases (systemic lupus erythematosus, Henoch-Schonlein purpura), kidney damage in subacute infective endocarditis and paraproteinemia (multiple myeloma, mixed cryoglobulinemia), renal vein thrombosis, and also in diabetic nephropathy.

Moderate, including “trace” (less than 1 g/day) proteinuria is found not only in patients with chronic glomerulonephritis, Bright's disease or in the context of systemic diseases, but also in vascular nephropathies, including kidney damage in essential arterial hypertension, nodular polyarteritis and atherosclerotic stenosis of the renal arteries (ischemic kidney disease).

Important are the changes in urinary sediment and renal function accompanying proteinuria. In most chronic nephropathies, proteinuria is usually combined with erythrocyturia. Isolated proteinuria, often nephrotic, is characteristic of renal vein thrombosis and, especially, renal amyloidosis. Preservation of significant excretion of proteins in the urine with persistent or rapidly increasing deterioration of renal function is characteristic of renal amyloidosis, as well as diabetic nephropathy.

The presence of microalbuminuria in patients with diabetes mellitus types 1 and 2 with essential arterial hypertension reliably indicates the development of kidney damage.

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Treatment proteinuria

Treatment of proteinuria is based on the severity of the nephroprotective effect of most drugs (ACE inhibitors, angiotensin II receptor blockers, statins, calcium channel blockers), which is due to their antiproteinuric effect.

Impact on proteinuric remodeling of tubulointerstitium is one of the most effective ways to slow down the progression of chronic renal failure (“Nephroprotective strategy”).

Forecast

The dynamics of protein excretion with urine is important when prescribing pathogenetic therapy. A relatively rapid decrease in proteinuria is considered a favorable prognostic sign.

Timely diagnosis and treatment of proteinuria in most cases allows us to prevent or at least reduce the rate of progression of most chronic nephropathies.

Microalbuminuria is considered as a marker of generalized endothelial dysfunction, which indicates a significant deterioration not only in the renal prognosis, but also an increased risk of cardiovascular complications, including in individuals who do not suffer from carbohydrate metabolism disorders (see " Clinical examination of urine ").

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