Proteinuria

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

[1], [2], [3], [4]

Causes of the proteinuria

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

Sedimentary protein samples give false positive results in the presence of iodine-containing contrast substances in the urine, a large number of antibiotics (penicillins or cephalosporins), metabolites of sulfonamides.

In the early stages of development of most nephropathies, low-molecular plasma proteins (albumin, ceruloplasmin, transferrin, etc.) penetrate the urine. However, it is possible to detect high-molecular proteins (alpha2-macroglobulin, y-globulin), more typical for severe renal involvement with "large" proteinuria.

Selective refers to proteinuria, represented by proteins with a low molecular weight of not more than 65,000 kD, 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 urine proteins . In addition to plasma proteins in urine, proteins of renal origin are determined - uroprotein Tamm-Horsfall, secreted by the epithelium of convoluted tubules.

Glomerular (protein glomerular) proteinuria is caused by an increase in the filtration of plasma proteins through the glomerular capillaries. It depends on the structural and functional state of the wall of the glomerular capillaries, the properties of protein molecules, the pressure and blood flow velocity that determine GFR. Glomerular proteinuria is an indispensable sign of most kidney diseases.

The wall of the glomerular capillaries is made up of endothelial cells (with rounded holes between them), a three-layered basal membrane - a hydrated gel, as well as epithelial cells (podocytes) with a tangle of leg processes. Due to the complex structure, the glomerular capillary wall can "sift" the plasma molecules from the capillaries into the space of the capsule of the glomerulus, and this function of the "molecular sieve" depends to a large extent on the pressure and velocity of blood flow in the capillaries.

In pathological conditions, the "pore" sizes increase, the deposits of immune complexes cause local changes in the capillary wall, increase its permeability for macromolecules. In addition to the size of the glomerular "pores", electrostatic factors are also important. The glomerular basal membrane is negatively charged; A negative charge is borne by the foot pods of the podocytes. Under normal conditions, the negative charge of the glomerular filter repels anions - negatively charged molecules (including albumin molecules). Changing the charge contributes to the filtration of albumin. It is assumed that the merging of leg legs is the morphological equivalent of a change in charge.

Tubular (tubular) proteinuria is caused by the inability of the proximal tubules to reabsorb plasma low-molecular proteins filtered in normal glomeruli. Proteinuria rarely exceeds 2 g / day, excreted proteins are albumin, and also fractions with even lower molecular weight (lysozyme, beta _2- microglobulin, ribonuclease, free light chains of immunoglobulins), absent in healthy individuals and in glomerular proteinuria due to 100 % by reabsorption by epithelium of 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 lesions of the renal tubules and interstitium: with tubulointerstitial nephritis, pyelonephritis, potassium penicle, acute tubular necrosis, chronic rejection of the renal transplant. Tubular proteinuria is also characteristic of many congenital and acquired tubulopathies, in particular  Fanconi syndrome.

Proteinuria "overflow" develops with an increase in the concentration of low-molecular proteins (light chains of immunoglobulins, hemoglobin, myoglobin) in blood plasma. At the same time these proteins are filtered by unaltered glomeruli in an amount exceeding the ability of the tubules to reabsorb. This is the mechanism of proteinuria in multiple myeloma (Bens-Jones proteininuria) and other plasma-cell dyscrasia, as well as myoglobinuria.

The so-called functional proteinuria is allocated. The mechanisms of development and the clinical significance of most of its variants are not known.

• Orthostatic proteinuria occurs with prolonged standing or walking ("proteinuria en marche") with rapid disappearance in a horizontal position. The amount of excretion of proteins with urine does not exceed 1 g / day. Orthostatic proteinuria is glomerular and non-selective and, according to long prospective studies, is always benign. With its isolated nature, there are no other signs of kidney damage (changes in urinary sediment, increased blood pressure). More often observed in adolescence (13-20 years), half of people disappear after 5-10 years from the time of occurrence. Characteristic of the lack of protein in urine samples taken immediately after the patient's stay in a horizontal position (including in the morning before rising from bed).
• The stress proteinuria detected after intensive physical exertion in at least 20% of healthy individuals, including athletes, is apparently also benign. According to the mechanism of its origin, it is considered tubular, caused by redistribution of the intrarenal blood flow and relative ischemia of the proximal tubules.
• With a fever with a body temperature of 39-41 ° C, especially in children and elderly and elderly people, the so-called febrile proteinuria is found. It is glomerular, the mechanisms of its development are not known. Occurrence of proteinuria in a patient with fever sometimes indicates adherence of renal damage; in favor of this is evidence of simultaneously occurring changes in urinary sediment (leukocyturia, hematuria), large, especially nephrotic values of urinary protein excretion, and hypertension.

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

Proteinuria and progression of chronic nephropathies

The importance of proteinuria as a marker of the progression of kidney lesions is largely due to the mechanisms of the toxic effect of individual components of the protein ultrafiltrate on the epithelial cells of the proximal tubules and other structures of renal tubulointerstitium.

Components of the protein ultrafiltrate, which exert a nephrotoxic effect

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

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

Many mesangiocytes and smooth muscle cells of the vessels undergo similar changes, meaning the acquisition of the basic properties of the macrophage. In the renal tubulointerstitium, monocytes from the blood also actively migrate, also transforming into macrophages. Plasma proteins induce the processes of tubulointerstitial inflammation and fibrosis, called proteinuric remodeling tubulointerstitium.

The severity of proteinuric remodeling tubulointerstitcia is one of the main factors determining the rate of progression of renal failure in chronic nephropathies. 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 amyloidosis of the kidneys.

[5], [6], [7], [8], [9]

Symptoms of the proteinuria

Proteinuria, as a rule, is a sign  of kidney disease. High ("large") proteinuria is also seen as a marker of the severity and activity of kidney damage.

Forms

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

• selective;
• nonselective.

By localization:

• glomerular;
• tubular.

On the etiology:

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

[10], [11], [12], [13], [14], [15]

Diagnostics of the proteinuria

Laboratory diagnostics of proteinuria

When quantifying the excretion of proteins in the urine in the range of values not exceeding 1 g / day, the pyrogallol method has advantages in sensitivity to the more prevalent sulfosalicylic.

Types of proteinuria are differentiated by determining individual protein fractions in the urine by 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 staying in an upright position (preferably after walking with hyperlordosis) for 1-2 hours. Increasing the excretion of proteins with urine only in the second portion confirms orthostatic proteinuria.

[16], [17], [18], [19]

Differential diagnosis

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

Moderate, including "trace" (less than 1 g / day) proteinuria is detected not only in patients with chronic glomerulonephritis, 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 concomitant proteinuria changes in urinary sediment and kidney function. In most chronic nephropathies, proteinuria, as a rule, is combined with erythrocyte. The isolated nature of proteinuria, often nephrotic, is associated with thrombosis of the renal veins and, especially, amyloidosis of the kidneys. Preservation of significant excretion of proteins in the urine with persistent or rapidly increasing impairment of kidney function is characteristic of amyloidosis of the kidneys, as well as for diabetic nephropathy.

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

[20], [21], [22], [23]

Treatment of the 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 precisely to their antiproteinuric effect.

Impact on proteinuric remodeling tubulointerstition is one of the most effective ways that inhibit the progression of chronic renal failure ("Nephroprotective strategy").

Forecast

The dynamics of the excretion of proteins with urine is important in the appointment of pathogenetic therapy. The relatively rapid decrease in proteinuria is seen as a favorable prognostic sign.

Timely diagnosis and treatment of proteinuria can in most cases 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 in not only the kidney prognosis, but also an increase in the risk of cardiovascular complications, including in people who do not suffer from disorders of carbohydrate metabolism (see " Clinical Study of Urine " .

[24], [25], [26], [27], [28]