Proteinuria is the presence of protein in the urine, the level of which is higher than the standard values. Appears in newborns and children different ages, in young people and adults, regardless of gender. Normal for men and women consider the amount of protein (protein) from 0.15 g / l to 0.33 g / l. In the analysis of urine of healthy children, it is absent. For the smallest, the limit is 0.025 g / l, for the oldest - 0.33 g / l.
Classification criteria
Often proteinuria is accompanied by leukocytosis and erythrocytosis - an increased content of white and red blood cells. In this case, the presence of cylinders and bacteria can be detected.
A variety of proteins from the blood plasma enter the urine. Most of them are albumins, their predominance is albuminuria. Tissue proteins are represented by complex glycoproteins. They are produced by the renal tubules and mucous organs of the genitourinary system.
The underlying types of proteinuria are as follows:
- Renal.
- Postrenal (extrarenal).
Extrarenal proteinuria is called pseudoproteinuria because it does not depend on glomerular capillary permeability. The renal type is more often diagnosed, because it is a manifestation of diseases of the kidneys and other organs of the urinary system. It occurs when there is a violation of the process of reabsorption of proteins into the blood. This occurs when the renal filter is damaged due to impaired blood supply to the kidneys, hypoxia of its parenchyma, and epithelial tubular degeneration.
Normally, blood containing proteins enters the vessels of the renal glomeruli. big molecules negatively charged immunoglobulins and albumins do not pass through the glomerular filter and enter the proximal tubule. Light proteins with a low molecular weight and with a positive charge are filtered out, but in the convoluted tubules of the nephrons are reabsorbed into the blood.
Proteins do not pass into the urine. Waste products of organs and systems, toxic substances go there. Therefore, their level in urine is a defining symptom for making a diagnosis in pathology. The indicator of the presence of proteins over 1 g / l indicates a kidney disease with a violation of the permeability of the membranes of the renal glomeruli.
It is important! In newborns, the level of protein in the urine is increased due to some physiological features. If on the eighth day of life this indicator has not returned to normal, it is urgent to determine the cause.
Massive proteinuria is observed in other chronic diseases developing with renal manifestations. This may be diabetic nephropathy, atherosclerosis of the renal arteries against the background of hypertension, lipoid nephrosis and others.
High levels of protein (about 10 g / l) are detected in heart failure complicated by nephrotic syndrome. Hypertensive crises provoke proteinuria from 16 g / l. A large amount of protein in the urine is characteristic of some malignant neoplasms (myeloma, kidney carcinoma, bladder cancer).
But the level of protein in the urine does not always characterize the severity of kidney damage. So, low proteinuria can manifest itself with kidney failure. Small levels of protein in the urine are not always symptomatic. With high proteinuria, urine becomes foamy, swelling of the upper and lower extremities, faces.
Stages and non-pathological forms of the disease
The classification of proteinuria is ambiguous. There are several of them, but the main ones are two of them, which are associated with the names of scientists - Bernstein and Robson, who studied this topic in the 20th century. Allocate its types by origin:
- non-pathological (functional, physiological);
- pathological (organic).
Also, proteinuria can be permanent - manifestations of kidney pathologies, and transient (temporary) - physiological. There are three degrees of severity of manifestations of proteinuria:
If traces of protein or a small concentration of them are detected in the urine test, and the second study did not change the indicators of the previous one, this may be the first manifestation of a glomerular filter lesion.
Functional proteinuria temporary - a transient protein of low concentration (not more than 1 g / l) appears in the urine and disappears after the elimination of influencing factors. They do not depend on kidney disease, they are not treated.
The best known of these is orthostatic proteinuria.. It can appear in children at any age. Occurs most often with prolonged stay on the legs in motion. Her level is low. The kidneys are healthy. After sleep, rest and a horizontal position in the morning urine, protein is usually absent.
The exact reasons for its appearance are unknown. According to some medical scientists, this functional proteinuria is the result of compression of the left renal vein. It is determined using special tests. But it is important not to miss the onset of kidney disease.
Transient proteinuria is also functional. Protein in the urine is detected after hypothermia or overheating, nervous tension, dehydration, high temperature, large physical activity due to protein diet.
It is temporary, the protein disappears without treatment, symptoms of diseases are not observed. If the level of protein in the urine at the same time reaches 2 g/l, the analysis is repeated twice. The absence of protein will confirm the transient nature of proteinuria.
Sometimes physiological proteinuria of tension is isolated, which appears during physical overstrain and disappears after its impact, and feverish. Feverish proteinuria develops in childhood in diseases not associated with kidney damage and accompanied by a body temperature above 38 ° C. After its decrease, there is no protein in the urine.
Pathological proteinuria
In accordance with the source of protein in the urine, these types of organic proteinuria are called:
- prerenal;
- renal;
- postrenal.
prerenal type
The prerenal form occurs due to the active production of light immunoglobulins (Bence-Jones proteins), in an amount that the tubules cannot reabsorb, as well as the development of hemoglobinuria, accompanied by the breakdown of red blood cells and their appearance in the urine. This is observed in myeloma and some other malignant tumors, intravascular hemolysis, extensive tissue necrosis.
What are Bence-Jones proteins
At the same time, protein indicators can reach 20 g / day. It is imperative to carry out special study urine for the presence of Bence-Jones monoclonal protein in it. IN general analysis urine reveals red and white blood cells, a certain amount of free hemoglobin, specific tissue proteins. There is also a decrease in urine production, high blood pressure, swelling. In a blood test, anemia and a decrease in the level of bilirubin are determined.
Renal type of disease
Renal proteinuria can be:
- tubular (turbular).
- Glomerular (glomerular).
Tubular proteinuria accompanies congenital changes in them, nephritis, tubular necrosis and other kidney diseases associated with their defeat. In this case, the reverse absorption of the protein into the blood becomes impossible. The level of proteinuria is not higher than 2 g / day. Urine is dominated by light proteins, albumins. Absent - with a large molecular weight. It occurs less frequently than glomerular.
With the development of most pathologies of the kidneys with increased penetration of proteins through the glomerular filters (glomerulopathy), glomerular proteinuria is manifested.
It is especially pronounced in glomerulonephritis (primary and secondary). This is the most common form of proteinuria. The protein concentration can reach 20 g/day.
In nephrotic syndrome, the largest number protein in the urine. Albumin is significantly lost, which leads to tissue edema. Heavy proteins are present in the urine, as the basement membrane is also damaged. Glomerular proteinuria can be selective or non-selective.
Selective proteinuria is the presence of low molecular weight proteins (albumin, transferrin, ceruloplasmin) in the urine, which confirms a slight disturbance in the renal filter. At the same time, nephrotic manifestations are expressed slightly, timely treatment quickly restores its functions.
With non-selective proteinuria, the lungs and a large amount of high-molecular proteins enter the urine, which indicates a severe damage to the filter. If selective proteinuria shows signs of non-selective proteinuria, glomerulopathy develops and worsens.
A non-selective species, like a selective one, is a rather dangerous diagnosis.
Postrenal and isolated forms
The postrenal form is a false proteinuria. Protein enters the urine from the exudate inflammatory diseases urinary system and genital organs (cystitis, urethritis, vaginitis, colpitis).
With false proteinuria, casts, leukocytes and bacteria are found in the urine. Protein values are below 1 g/day.
You need to know that an increase in protein in the urine can trigger the intake of certain medications. In this case, extrarenal proteinuria of false origin occurs.
In addition to false proteinuria, isolated proteinuria has also been identified, which is diagnosed in a significant number of those who are examined (up to 10%). It can be benign - all kinds of physiological or permanent.
This proteinuria occurs against the background of minor functional disorders in the renal glomeruli, more often with glomerulonephritis. In the urine, 2 g / day of protein is determined, other indicators are normal. Its danger is that gradually, slowly, renal failure can develop.
Protein levels in urine fluctuate throughout the day. The most accurate data is in the study of urine collected per day. It is possible to determine the presence of protein in the urine only in a medical institution, only a doctor can make a correct diagnosis and prescribe treatment.
The term "proteinuria" refers to the appearance of any type of protein in the urine in excess of physiological (normal) values.
Revealing advanced level protein in the urine is the most studied and significant pathological symptom in the practice of a doctor, indicating a violation of the urinary system.
In different patients, the severity of proteinuria can vary significantly, depending on the disease underlying it. In addition, the detection of protein in the urine can be observed in isolation or in combination with other changes in TAM (hematuria, leukocyturia, bacteriuria).
- 1 The inner layer, represented by the endothelium, most of which is covered with pores with a diameter of 40 nm. The pores are covered by a diaphragm, so protein filtration is this stage determined by both the pore size and the state of this diaphragm;
- 2 Three-layer membrane (basal), located outside of the inner layer. Its permeability to protein molecules is determined by its electrical charge and the arrangement of collagen filaments;
- 3 Epithelial lining (podocyte apparatus) located on the urinary side of the basement membrane. This layer is responsible for the process of active filtration using microfilaments.
- 1 Severe psycho-emotional stress;
- 2 Eating a lot of protein;
- 3 Dehydration, electrolyte disturbances;
- 4 Chronic heart failure, hypertension;
- 5 fever;
- 6 Against the backdrop of debilitating exercise(marching proteinuria);
- 7 Against the background of hypothermia.
- 1 Prerenal, or overload, associated with increased protein breakdown and the appearance of an increased concentration of low molecular weight proteins in the blood plasma.
- 2 Renal, associated with damage to the filtration apparatus of the renal glomerulus and / or tubules of the kidneys, where protein molecules are reabsorbed.
- 3 Postrenal, due to pathology of the underlying urinary tract. Often due to inflammatory exudation.
- 1 plasmablastic leukemia;
- 2 multiple myeloma;
- 3 Connective tissue diseases;
- 4 Rhabdomyolysis;
- 5 Lymphoma with paraproteinemia;
- 6 Hemolytic anemia;
- 7 Macroglobulinemia.
- 1 Glomerulonephritis (acute or chronic);
- 2 Nephropathy in diabetes;
- 3 Nephropathy of pregnancy;
- 4 Amyloidosis;
- 5 Tumors of the kidneys;
- 6 Hypertensive nephrosclerosis;
- 7 Gout.
- 1 Renal glomerular (glomerular) proteinuria, which develops when the cortical substance of the kidney, in which the nephrons are located, is damaged.
- 2 Renal tubular proteinuria, which develops against the background of problems with reabsorption of proteins in the proximal tubules.
- 1 When lost negative charge basement membrane in the urine begin to predominate low molecular weight protein molecules (albumin and transferrin).
- 2 In case of violation of the integrity of the pores in the membranes, large molecular weight (immunoglobulin G) are determined in the urine.
- 1 Highly selective - excretion of low molecular weight proteins with a mass of up to 70 kDa (mainly albumin);
- 2 Selective - excretion of both low molecular weight and proteins weighing up to 150 kDa;
- 3 Non-selective - isolation of a protein with a mass of 830 to 930 kDa.
- 1 Interstitial nephritis;
- 2 Urinary infections;
- 3 Urolithiasis;
- 4 Toxic effects;
- 5 Wilson's disease;
- 6 Fanconi syndrome.
- 1 Inflammatory pathology urinary tract(cystitis, urethritis, prostatitis);
- 2 Bleeding from the urinary tract;
- 3 Polyps of the bladder;
- 4 Tumors of the urinary tract.
Show all
1. History of the discovery of the syndrome
The first information about the change chemical composition urine for some diseases were obtained as early as the 17th century. So, in 1694, the outstanding Leiden doctor F. Dekker first discovered protein in the urine of patients with proven kidney pathology.
In his research, he was able to demonstrate that urine contains a substance that coagulates and coagulates when heated, which in turn leads to the formation of "turbidity".
Based on the experiments, F. Dekker proposed specific methods for detecting this impurity using acetic acid.
As a pathological syndrome, proteinuria was described by D. Cotugno in 1764, identifying it in a patient with acute pyelonephritis. Finally connected proteinuria and renal pathology R. Bright.
To identify the protein, he used a fairly simple and specific technique - heating a small amount of urine in a spoon over a flame (the protein precipitated after denaturation). A number of experiments have used nitric acid to detect protein.
R. Bright reliably established the connection of proteinuria with chronic nephritis, which for some time was called "Bright's disease".
2. Limits of norm and pathology
Often, the question of the presence of protein in the urine of healthy individuals can be answered ambiguously. What is considered a normal range for diagnosing pathological proteinuria? There are conflicting data in the medical literature.
With the protein concentration in a single portion of urine, everything is quite simple, normally it should not exceed 0.03 g / l (in children up to a year up to 0.002 g / l, in children older than a year - 0.036 g / l).
The level of daily loss of protein in the urine should normally not exceed 0.15 g / day (up to 100 mg / day Pushkarev I.A. 1985; 150 mg / day Bergstein J., 1999; 200 mg / day B.M. Brenner, 2007) .
At the same time, the calculated concentrations of the level of daily proteinuria based on the given norms in healthy person(taking into account diuresis up to 1.5 l / day) show the possibility of removing up to 0.1 grams of protein.
Such discrepancies are explained by the individual and racial characteristics of protein excretion in the urine.
The vast majority of people are characterized by slight proteinuria (about 40-50 mg per day). In 10-15% of the population, the daily excretion of protein in the urine reaches 0.150 g / day without confirmation of the pathology of the urinary system.
To assess the degree of daily loss of protein in the urine great importance has a chosen diagnostic method.
Generally accepted methods, such as a test with sulfosalicylic acid or a biuret reaction, do not detect protein in the urine of a healthy population. When a single increase in the level of protein in the urine is detected, patients are often prescribed.
3. Protein composition of urine
To assess proteinuria correctly, you need to have an idea of the qualitative and quantitative composition of normal urine.
In a portion of the urine of a healthy person, up to 200 different proteins can be detected, filtered from the blood or secreted by the epithelial cells of the urinary system.
Approximately 50-70% of urine protein is uroromucoid (uromodulin) - a product of renal tissue synthesis. In the lumen of the renal tubules, uromodulin forms a specific gel-like structure that is impermeable to water, but permeable to ions.
Uromodulin is found in the renal tissue from the 16th day of embryogenesis. In daily urine, it is detected in the amount of 20-100 mg, and its synthesis increases with high salt intake, taking loop diuretics (furasemide, torasemide).
The appearance of tissue proteins may be the result of normal renal excretion and continuous renewal of kidney tissues.
Plasma proteins are second in terms of specific gravity.. When using high-quality diagnostic systems, about 30 plasma proteins can be detected in urine, the leading position among which is albumin.
In the urine, proteins of the tissues of the heart, pancreas, liver, and transplantation antigens can be detected. Damage to the heart tissue in patients is accompanied by myoglobinuria, and some tumors lead to increased excretion of low molecular weight proteins.
Almost all known human hormones are excreted in the urine. In pregnant women, proteins secreted by placental tissues can be detected in the urine.
4. Mechanism of appearance of protein in urine
Urine formation occurs in the main structural element of the kidney - the renal glomerulus (a network of arterial capillaries enclosed in a capsule).
Blood entering the capillaries of the glomerulus is filtered through a special glomerular membrane with the formation of primary urine. The glomerular filtration membrane has a rather complex structure and includes:
In a healthy person, the glomerular filter can pass proteins of a certain size (no more than 4 nm, weighing no more than 70 kDa). Proteins such as serum albumin, myoglobin, prealbumins, lysozyme, microglobulins, etc. are freely filtered.
In addition to size, the charge of the protein molecule plays an important role in the filtration process. The basement membrane is normally negatively charged and does not allow active filtration of plasma proteins that have the same charge.
Figure 1 - The structure of the nephron
If small plasma proteins manage to pass the renal filter, they are almost completely absorbed in the renal tubules.
Summarizing the above, physiological protein excretion is the result of the interaction of glomerular and tubular mechanisms, and damage to any of the departments of the nephron can lead to proteinuria.
Identification of transient or permanent proteinuria in a person requires a thorough examination. Next, we turn to the study of the main reasons for the increase in the level of protein in the urine.
5. Functional proteinuria
Functional proteinuria is not associated with renal tissue damage. It is based on a transient violation of protein filtration. This condition may occur when:
In infants, dehydration proteinuria is often found, which is based on violations of the feeding regimen, toxicosis, diarrhea, and vomiting. After removal of the provoking factor, such proteinuria stops.
In adolescents, the so-called orthostatic proteinuria can be detected - an increase in the excretion of protein in the urine during the transition to a standing position. In children predisposed to orthostatic proteinuria, active growth is diagnosed, small muscle mass, kyphosis, lumbar lordosis, low blood pressure, and absolutely normal kidney function.
Proteinuria occurs when a teenager is standing. Lordosis of the spine leads to the fact that the anterior surface of the liver goes down and slightly presses the inferior vena cava. Stagnation of blood in the renal veins and provokes the release of protein in the urine.
In physiological proteinuria, the largest proportion is low molecular weight proteins (up to 20 kDa), for example, Ig, 40% proteins with a high mass (65 kDa), 40% are uromodulin.
6. Pathological proteinuria
Pathological proteinuria develops when the renal glomeruli, where filtration occurs, or the renal tubules, where reabsorption of protein molecules occurs, are damaged.
Depending on the level of damage, three types of pathological proteinuria can be distinguished:
6.1. prerenal
Prerenal proteinuria is based on the appearance in the patient's blood plasma of proteins with a small molecule size, which can pass through a healthy renal filter and enter the urine in large quantities.
The appearance of such proteins in the plasma is associated either with their increased synthesis or with the breakdown of tissue structures and cells. This condition may occur when:
Most often, this type of proteinuria is due to an increase in the blood of light chains of Ig (Bence-Jones protein), myoglobin, hemoglobin, lysozyme.
Congestive forms of prerenal proteinuria are possible, which occur in decompensated heart disease, metastases, and tumors of the abdominal cavity.
In a separate category, neurogenic prerenal proteinuria can be distinguished, which can be provoked epileptic fit, traumatic brain injury, hemorrhage, autonomic crisis.
6.2. Renal
IN this case an increase in the level of protein in the urine is associated with damage to the renal parenchyma or renal interstitium. This is typical for the following conditions:
Depending on the location of the damage, the composition and volume of proteins excreted in the urine changes, which makes it possible to distinguish between:
6.2.1. Glomerular injury
With damage to the renal glomeruli, changes in the glomerular type are recorded in the urine:
Thus, the nature of damage to the renal filter affects the ability to pass protein molecules. different sizes and masses.
That is why, according to the composition of uroproteins, proteinuria is distinguished:
To determine the degree of selectivity, a special index is used, which is the ratio of isolation of proteins with high mass to low molecular weight (usually the ratio of IgG/albumin).
A ratio of up to 0.1 (selective) indicates a filtration defect associated with a violation of the ability to retain negatively charged molecules. An increase in the index of more than 0.1 indicates the non-selectivity and permeability of the filter pores for macromolecules.
Determination of the degree of selectivity of glomerular proteinuria is important for the development of patient management tactics.
The selective nature of protein loss in the urine indicates minimal damage, therefore, in such patients, the effectiveness of glucocorticosteroids is high.
Non-selectivity is associated with more severe changes in the renal filter (membranous nephropathy, glomerulosclerosis, proliferative glomerulonephritis), in the treatment, as a rule, resistance to steroids is observed.
An increase in glomerular hydrostatic pressure can also lead to increased protein filtration, which is a variant of glomerular proteinuria.
6.2.2. tubular protein loss
It develops against the background of impaired protein reabsorption in the renal tubules and is manifested by the release of low molecular weight proteins (weight below 40 kDa), which are normally completely reabsorbed.
Tubular proteinuria, as a rule, does not exceed 2 g / 1.73 mx2 / day.
Pathologies associated with tubular protein loss include:
Indicators of tubular proteinuria are B2-microglobulin, retinol-binding protein and/or alpha1-microglobulin.
The level of excretion of B2-microglobulin has the greatest diagnostic value. An increase in the level of albumin in the urine with a normal content of B2-microglobulin indicates damage to the glomeruli, while the predominance of B2-microglobulin indicates tubular pathology. However, one should not forget the possibility erroneous result analysis.
6.3. Postrenal
Postrenal proteinuria is caused by the ingestion of an inflammatory protein-rich exudate into the urine and is associated with damage to the underlying urinary tract. This condition may occur when:
Figure 1 - Differential diagnosis of proteinuria. Source -V.L. Emanuel. Problems of the pathology of the urogenital system // Journal of laboratory medicine. No. 7, 2015.
7. Gradations of proteinuria
By the amount of protein excretion, it is advisable to distinguish between the variability of proteinuria, which ranges from microproteinuria to a high, nephrotic degree (above 3 g / day).
The term MAU (microalbuminuria) is understood as the excretion of albumin in the urine in an amount above the physiological norm, but below the sensitivity of standard test systems.
It is customary to talk about MAU with a daily loss of 10 mg to 300 mg of albumin. UIA may be the only one early sign damage to the glomerulus, for example, in diabetic nephropathy.
MAU appears long before the start of a decrease in the level of GFR (glomerular filtration rate). Microalbuminuria also occurs in hypertension, kidney transplant rejection.
Proteinuria of low gradations (300 mg -1 g / day) can be detected with acute infections urinary tract obstruction, urolithiasis, nonspecific nephritis.
Moderate loss of proteins (1 g - 3 g / s) develops with acute tubular necrosis, glomerulonephritis, hepatorenal syndrome, amyloidosis.
A large loss of protein in the urine (more than 3 g / s) is actually always associated with a violation of the glomerular filter and a change in the "size-charge ratio" of proteins and membranes.
8. Clinical manifestations
Proteinuria occurring in mild form, usually has no clinical manifestations or masked by the symptoms of the underlying pathology.
With a significant increase in the concentration of protein in the urine, foaming during urination is observed. Such "foam" remains long enough.
Constant and significant loss proteins with urine can lead to the development of edema of the face, limbs, abdomen.
9. Kidney failure
Proteinuria is one of the most significant risk factors for the formation and progression of CKD ( chronic disease kidneys). The relationship between the increase in protein loss in the urine and the rate of decline in kidney function has been proven.
In one of the latest meta-analyses (Stoycheff, 2011), the role of proteinuria as an independent risk factor for CKD progression was once again proven.
Proteinuria (including MAU) are risk factors for the development of complications from the cardiovascular system.
In international expert recommendations, a normogram is used to determine the risk of an unfavorable prognosis for the development of CKD and renal failure (Figure 2). The higher the level of proteinuria, the higher the risk of fatal outcomes.
Fig. 2. Nomogram of risk of poor prognosis KDIGO-2012, 2013: green - low risk (if there are no other markers of renal pathology or the pathology itself), yellow - moderate risk, orange - high risk, red - very high risk
10. Treatment tactics
The tactics of managing a patient with proteinuria directly depend on the cause, the risk of an unfavorable outcome, the prognosis, which determines the need for dynamic monitoring by a therapist or a nephrologist.
Proteinuria (proteinuria) - the appearance of protein in the urine in concentrations that make it possible to identify it with qualitative methods.
Distinguish
- Renal proteinuria and
- Extrarenal (postrenal) proteinuria
Renal proteinuria
Renal proteinuria is caused by damage to the glomerular filter or dysfunction of the epithelium of the convoluted tubules.
Distinguish between selective and non-selective proteinuria depending on the ratio of certain plasma and urinary proteins, their molecular weight and charge.
Selective proteinuria
Selective proteinuria occurs with a minimal (often reversible) violation of the glomerular filter, represented by low molecular weight proteins (molecular weight not exceeding 68,000) - albumin, ceruloplasmin, transferrin.
Non-selective proteinuria
Non-selective proteinuria is more common with more severe filter damage, when large molecular proteins begin to be lost. The selectivity of proteinuria is an important diagnostic and prognostic feature.
Renal proteinuria can be:
- organic and
- functional (physiological).
Organic renal proteinuria
Organic renal proteinuria occurs with organic damage to the nephron. Depending on the predominant mechanism of occurrence, certain types of organic proteinuria can be distinguished.
Glomerular proteinuria
Glomerular proteinuria - due to damage to the glomerular filter, occurs with glomerulonephritis and nephropathy associated with metabolic or vascular diseases. (glomerulonephritis, hypertension, infectious and allergic factors, cardiac decompensation)
tubular proteinuria
Tubular proteinuria - associated with the inability of the tubules to reabsorb plasma low molecular weight proteins that have passed through an unchanged glomerular filter. (amyloidosis, acute tubular necrosis, interstitial nephritis, Fanconi syndrome)
Prerenal proteinuria
Prerenal proteinuria (excessive) - develops in the presence of an unusually high plasma concentration of a low molecular weight protein, which is filtered by normal glomeruli in an amount exceeding the physiological ability of the tubules to reabsorb. (myeloma, necrosis muscle tissue, erythrocyte hemolysis)
Functional renal proteinuria
Functional renal proteinuria is not associated with kidney disease and does not require treatment.
Functional proteinuria include:
- marching,
- emotional
- cold,
- intoxication,
- orthostatic (only in children and only in a standing position).
Extrarenal (postrenal) proteinuria
With extrarenal (postrenal) proteinuria, protein can enter the urine from the urinary and genital tract (with colpitis and vaginitis - with improperly collected urine). In this case, this is nothing more than an admixture of inflammatory exudate.
Extrarenal proteinuria usually does not exceed 1 g/day and is often transient.
Diagnosis of extrarenal proteinuria is helped by a three-cup test and urological examination.
Postrenal proteinuria occurs with cystitis, urethritis.
Methods for determining protein in urine
A prerequisite for conducting studies on the presence of protein is the absolute transparency of urine.
Quality samples
Sample with sulfosalicylic acid
3–4 ml of filtered urine is poured into two test tubes. Add 6–8 drops of a 20% solution of sulfosalicylic acid to an experimental test tube. The second tube is the control. On a dark background, compare the control tube with the experimental one. In the presence of protein in urine samples, an opalescent turbidity appears.
The result is indicated as follows:
- the reaction is weakly positive (+),
- positive (++),
- sharply positive (+++).
The sample is highly sensitive.
You can also use a dry test, when a few crystals of sulfosalicylic acid or a filter paper pre-soaked with a solution of this acid are added to several milliliters of urine.
False positive results may be due to the intake of iodine preparations, sulfa drugs, large doses of penicillin and the presence of uric acid in the urine in high concentrations.
Nitric acid test (Geller test)
1–2 ml of a 50% solution of nitric acid is poured into a test tube, then an equal amount of urine is layered on the acid. In the presence of protein, a white ring appears at the interface between two liquids. Sometimes a reddish ring is formed slightly above the boundary between the liquids. purple from the presence of urates. The urate ring, unlike the protein ring, dissolves with slight heating.
Bright sample
The Bright boil test and proteinuria screening tests (dry colorimetric samples) require virtually no reagents.
When urine containing protein is boiled, it denatures, forming a cloudy precipitate or flakes that do not dissolve in 6% acetic acid, unlike phosphate salts. Screening tests are based on the ability of a protein (albumin) to change the color of paper coated with an indicator (usually bromophenol blue) and a buffer. A direct relationship between the color intensity of the indicator paper (Albufan, Albutest - Czech Republic; Labstix, Multistix - USA; Comburtest - Germany) and the amount of protein makes it possible to roughly estimate the amount of proteinuria. However, currently used screening tests are not without drawbacks. In particular, bromophenol blue does not detect Bence-Jones protein.
Quantitative Methods
Brandberg-Roberts-Stolnikov method
The method is based on a qualitative sample with nitric acid. The course of the test is described above. The appearance of a thin ring at the border of two liquids between the 2nd and 3rd minutes after layering indicates the presence of 0.033 g / l of protein in the urine (protein concentration in urine is usually expressed in ppm, i.e., in grams per liter). If the ring appears earlier than after 2 minutes, the urine should be diluted with water. Such a dilution of urine is selected so that when it is layered on nitric acid, the ring appears at the 2-3rd minute. The degree of dilution depends on the width and compactness of the ring and the time of its appearance.
The protein concentration is calculated by multiplying 0.033 g/l by the degree of urine dilution (Table 8).
The Roberts-Stolnikov dilution method has a number of disadvantages: it is subjective, time-consuming, the accuracy of determining the protein concentration decreases as the urine is diluted.
The most convenient and accurate are the nephelometric and biuret methods.
Nephelometric method
It is based on the property of the protein to give turbidity with sulfosalicylic acid, the intensity of which is proportional to the concentration of the protein. 1.25 ml of filtered urine is poured into a graduated test tube and a 3% solution of sulfosalicylic acid is added to a volume of 5 ml, thoroughly mixed. After 5 minutes, the extinction is measured on the FEK-M (or any other photometer) at a wavelength of 590–650 nm (orange or red light filter) against the control in a cuvette with a layer thickness of 0.5 cm. For control, use 1.25 ml of filtered urine ( the same), to which a volume of 5 ml is added isotonic solution sodium chloride.
A calibration curve is preliminarily built depending on the extinction value on the protein concentration. Albumin standard solution (from human or bovine serum) is used to prepare various protein concentrations. Complete the worksheet.
Biuret method
It is based on the ability of the protein to give with copper sulfate and caustic alkali a violet biuret complex, the color intensity of which is directly proportional to the amount of protein. To 2 ml of urine add 2 ml of trichloroacetic acid solution to precipitate the protein and centrifuge. The supernatant is discarded. To the sediment (protein) add 4 ml of 3% NaOH solution and 0.1 ml of 20% copper sulfate solution, stir and centrifuge. The violet supernatant is photometered at a wavelength of 540 nm (green light filter) against distilled water in a cuvette with a layer thickness of 1.0 cm. The protein concentration is determined from a table obtained empirically (the calibration curve is built as in the previous method).
Orthostatic test
Indicated for suspected orthostatic proteinuria and nephroptosis. After complete emptying of the bladder, the subject maintains a horizontal position for 2 hours. Then, without getting up, he passes one (control) portion of urine. Over the next 2 hours, the subject walks continuously, maintaining the position of maximum lumbar lordosis (holds a stick behind the lower back), after which he passes the second portion of urine. In both portions of urine, the protein concentration and protein content in grams are determined, and in case of nephroptosis, the number of red blood cells in 1 ml. With orthostatic proteinuria, proteinuria or a 2–3-fold increase in the initial protein content in grams is detected in the second serving. The appearance of hematuria, often in combination with trace proteinuria in the second portion, is characteristic of nephroptosis.
Determination of Bence-Jones uroproteins
Bence-Jones proteins are thermolabile low molecular weight paraproteins (relative molecular weight 20,000–45,000) found mainly in multiple myeloma and Waldenström's macroglobulinemia. They are light L-chains of immunoglobulins. Due to their small molecular weight, L-chains easily pass from the blood through an intact renal filter into the urine and can be determined there using a thermoprecipitation reaction. The study is advisable to conduct only with a positive test with sulfosalicylic acid. The definition is carried out as follows. To 10 ml of urine, add 3–4 drops of a 10% solution of acetic acid and 2 ml of a saturated sodium chloride solution, gently heat in a water bath, gradually increasing the temperature. If there are Bence-Jones proteins in the urine, then at a temperature of 45–60 ° C diffuse turbidity appears or a dense white precipitate forms. On further heating to boiling, the precipitate dissolves and reappears on cooling. This sample is not sensitive enough and must be checked by electrophoresis and immunoelectrophoresis.
Proteinuria - the excretion of protein in the urine in an amount exceeding normal values(50 mg/day). This is the most common sign of kidney damage.
IN clinical practice usually standard strips and protein precipitation with sulfasalicylic or trichloroacetic acid are used, followed by nephelometry or refractometry, which determine protein in excess of 20 mg / day. Somewhat more accurate are the biuret method and the Kjeldahl method, which determine the amount of protein in tissues and liquids by nitrogen (azotometric method). Using such methods of protein chemistry and radioimmunoassays, various low molecular weight proteins (prealbumin, albumin, α1-acid glycoprotein, β2-microglobulin, α2-antitrypsin, α-lipoprotein, siderophilin, ceruloplasmin, haptoglobin, transferrin, immunoglobulin light chains) can be detected in urine. , as well as high-molecular (a2-macroglobulin, y-globulin) proteins.
The release of protein in the amount of 30-50 mg / day is considered physiological norm for an adult. This amount is 10-12 times less than what is normally filtered from blood plasma through the glomeruli (in healthy individuals, about 0.5 g of albumin is filtered per day), since most of the filtered protein is normally reabsorbed in the proximal tubules. Tubular reabsorption occurs by endocytosis of proteins by the brush border membrane of tubular cells. At the same time, some proteins are secreted into the urine by the cells of the tubular epithelium (for example, the Tamm-Horsfall uroprotein, a complex glycoprotein with a very high molecular weight, synthesized and secreted by the cells of the ascending loop of Henle and the distal tubules), and also come out of the dead cells of the urinary tract.
In kidney pathology (less often in extrarenal pathology), conditions arise that contribute to the appearance of a large amount of protein in the urine, primarily due to increased filtration of proteins through the glomerular capillary filter, as well as a decrease in tubular reabsorption of filtered proteins.
The filtration of blood plasma proteins through the wall of the glomerular capillaries depends on the structural and functional state walls of glomerular capillaries, its electric charge, properties of protein molecules, hydrostatic pressure and blood flow velocity, which determine the glomerular filtration rate.
Normally, the penetration of plasma proteins into the urinary space is prevented by the anatomical barrier (the structure of the glomerular filter), the electrostatic charge of the capillary wall, and hemodynamic forces.
The wall of the glomerular capillaries is made up of endothelial cells (with rounded holes between the cells - fenestra), a three-layer basement membrane (hydrated gel), as well as epithelial cells (podocytes) with a plexus of pedunculated processes and pores between them with a diameter of about 4 nm (slit-like diaphragm). Due to this complex structure, the glomerular capillary wall can "sieve" plasma molecules from the capillaries into the space of the glomerular capsule, and this function of the "molecular sieve" is largely dependent on the size and shape of the macromolecules.
Small-sized plasma proteins (lysozyme, β2-microglobulin, ribonuclease, free light chains of immunoglobulins, retinol-binding protein) easily pass through these pores into the space of the glomerular capsule (Bowman's capsule), and then are completely reabsorbed by the epithelium of the convoluted tubules. Under pathological conditions, pore sizes increase, deposits of immune complexes cause local changes in the capillary wall, increasing its permeability for macromolecules.
Albumin molecules have a diameter of 3.6 nm (smaller than the pore size), however, under physiological conditions, they, like most other macromolecules, practically do not reach the slit-like diaphragm of the BMC and linger at the level of the fenestra.
A functional barrier is created here, the integrity of which is ensured by a negative charge and normal capillary blood flow. The glomerular basement membrane and pedunculate processes of podocytes are also negatively charged.
Sialoglycoprotein and glycosaminoglycans rich in heparan sulfate are responsible for the negative charge of the glomerular filter. IN normal conditions the negative charge of the glomerular filter repels anions - negatively charged molecules (including albumin molecules). The loss of the negative charge aids in the filtration of albumin, which then passes freely through the pores in the slit-like diaphragm.
Thus, albumin excretion is associated primarily with the loss of negative charge by the glomerular filter; excretion of larger molecules occurs only when the basement membrane is damaged.
In addition to the negative charge, the functional barrier includes hemodynamic factors - normal capillary blood flow, the balance of hydrostatic and oncotic pressure, the difference in transcapillary hydrostatic pressure, and the glomerular ultrafiltration coefficient.
The permeability of the capillary wall increases, contributing to proteinuria, both with a decrease in the flow rate in the capillaries, and in conditions of glomerular hyperperfusion and angiotensin II-mediated intraglomerular hypertension. The introduction of angiotensin II or norepinephrine, which changes intraglomerular hemodynamics, increases protein excretion in the urine. The possible role of hemodynamic changes should be taken into account when evaluating abnormal proteinuria, especially transient or occurring in patients with circulatory failure. Reduction of intraglomerular hypertension by measures that cause dilatation of the efferent arteriole (ACE inhibitors) or constriction of the afferent arteriole (NSAIDs, cyclosporine, low protein diet) can significantly reduce proteinuria.
Glomerular proteinuria- the most common form of proteinuria associated with a violation of the permeability of the glomerular filter. It is observed in most kidney diseases - glomerulonephritis (primary and systemic diseases), amyloidosis of the kidneys, diabetic glomerulosclerosis, thrombosis of the renal vessels, as well as in hypertension, atherosclerotic nephrosclerosis, congestive kidney.
Depending on the content of certain proteins in the blood plasma and in the urine, selective and non-selective proteinuria is isolated (the term is conditional, it is more correct to speak of the selectivity of the isolation of protein fractions, the selectivity of their clearance). Selective proteinuria is called proteinuria, represented by proteins with a low molecular weight - not more than 65,000 (mainly albumin). Non-selective proteinuria is characterized by an increase in the clearance of medium and high molecular weight proteins (a2-macroglobulin, B-lipoproteins, and y-globulins predominate in the composition of urinary backs). To determine the glomerular selectivity index, the clearance of immunoglobulin G is compared with the clearance of albumin or transferrin. Selective proteinuria has a better prognosis than non-selective proteinuria. Currently, in clinical practice, the assessment of the selectivity index is rarely used, mainly in children.
Recently, the attention of researchers has been attracted by microalbuminuria - the excretion of a minimal amount of albumin in the urine, only slightly exceeding the physiological one. Microalbuminuria, the definition of which requires the use of highly sensitive methods, is the first symptom of diabetic nephropathy, kidney transplant rejection, kidney damage in hypertension; associated with intraglomerular hypertension.
tubular proteinuria. With a decrease in the ability of the proximal tubules to reabsorb plasma low molecular weight proteins filtered in normal glomeruli, tubular proteinuria develops. The amount of protein released exceeds 2 g/day, the protein is represented by fractions with a low molecular weight (lysozyme, β2-microhyobulin, ribonuclease, free light chains of immunoglobulins).
In addition, a special Tamm-Horsfall protein is determined in the urine (and is normal), secreted in an amount of 20-30 mg / day by intact tubules - a thick ascending knee of the loop of Henle and initial departments collecting ducts.
Tubular proteinuria is observed in interstitial nephritis, pyelonephritis, potassium kidney, acute tubular necrosis, chronic renal transplant rejection, congenital tubulopathies (Fanconi's syndrome).
To determine tubular proteinuria, the content of β-microglobulin in the urine (normally not exceeding 0.4 μg / l) is usually examined, less often - lysozyme; V last yearsα1-microglobulin was proposed as a marker of tubular damage.
Proteinuria overflow. Increased protein excretion can also be observed under the influence of extrarenal factors. So, overflow proteinuria develops with increased formation of plasma low molecular weight proteins (light chains of immunoglobulins, hemoglobin, myoglobin), which are filtered by normal glomeruli in an amount exceeding the ability of the tubules to reabsorb. This is the mechanism of proteinuria in multiple myeloma (Bene-Jones proteinuria), myoglobinuria, lysocymuria, described in patients with leukemia. Perhaps, changes in the physicochemical properties, the configuration of normal plasma proteins are also important. For example, multiple infusions of blood plasma due to bleeding disorders can cause transient proteinuria up to 5-7 g/day. The administration of albumin to patients with nephrotic syndrome may also lead to an increase in proteinuria (although changes in renal hemodynamics may occur with massive infusions).
Functional proteinuria. Functional proteinuria, the exact mechanisms of pathogenesis of which have not been established, include orthostatic, idiopathic transient, stress proteinuria, febrile proteinuria, and proteinuria in obesity.
Orthostatic proteinuria is characterized by the appearance of protein in the urine during prolonged standing or walking with its rapid disappearance when the body position changes to horizontal. Proteinuria usually does not exceed 1 g / day, is glomerular and non-selective, the mechanism of its occurrence is unclear. More often it is observed in adolescence, in half of the patients it disappears after 5-10 years. The mechanism of development may be associated with an inadequately enhanced response of intrarenal hemodynamics to changes in body position.
The diagnosis of orthostatic proteinuria is made when the following conditions are combined:
Age of patients 13-20 years;
The isolated nature of proteinuria, the absence of other signs of kidney damage (changes in urinary sediment, increased blood pressure, changes in the vessels of the fundus);
The exclusively orthostatic nature of proteinuria, when there is no protein in urine samples taken after the patient has been in a horizontal position (including in the morning before getting out of bed).
To prove this diagnosis, it is necessary to conduct an orthostatic test. To do this, urine is collected in the morning before getting out of bed, then after a 1-2-hour stay in an upright position (walking with a stick behind your back to straighten your spine). The test gives even more accurate results if the morning (night) portion of urine is poured out (since bladder there may be residual urine), and the first portion is collected after a 1-2 hour stay of the subject in a horizontal position.
In adolescence, idiopathic transient proteinuria can also be observed, found in healthy individuals with medical examination and absent in subsequent urine tests.
Tension proteinuria is detected in 20% of healthy individuals (including athletes) after a sharp physical exertion. Protein is detected in the first collected portion of urine. Proteinuria is tubular in nature. It is assumed that the mechanism of proteinuria is associated with the redistribution of blood flow and relative ischemia of the proximal tubules.
Feverish proteinuria observed in acute febrile conditions, especially in children and the elderly. It is predominantly glomerular in nature. The mechanisms of this type of proteinuria are poorly understood, and the possible role of increased glomerular filtration along with transient damage to the glomerular filter by immune complexes is discussed.
proteinuria in obesity. Proteinuria is often observed in morbid obesity (body weight over 120 kg). According to J.P.Domfeld (1989), among 1000 obese patients, 410 had proteinuria without changes in urine sediment; cases of a nephrotic syndrome are also described. It is assumed that the development of such proteinuria is based on changes in glomerular hemodynamics (intraglomerular hypertension, hyperfiltration) associated with an increase in the concentration of renin and angiotensin in obesity, which decreases during fasting. With weight loss, as well as treatment with ACE inhibitors, proteinuria may decrease and even disappear.
In addition, proteinuria may be of non-renal origin. In the presence of severe leukocyturia and especially hematuria, a positive reaction to protein may be the result of the breakdown of blood cells during prolonged standing of urine; in this situation, proteinuria exceeding 0.3 g / day is pathological. Sedimentary protein tests can give false positive results in the presence of iodine contrast agents, a large number of penicillin or cephalosporin analogues, sulfonamide metabolites in the urine.
Massive proteinuria undoubtedly has a glomerular nature, and the lesions of the tubules that are repeatedly described in it are secondary (this does not remove the question of the role of the tubules in its origin in connection with impaired protein reabsorption and cleavage of macromolecules in them). Light microscopy does not make it possible to describe morphological changes that are strictly specific for massive proteinuria, since focal and diffuse thickening of the basement membrane and thickening of capillary loops occur in it; massive proteinuria also occurs in diabetic glomerulosclerosis and amyloidosis. Strictly specific changes are not detected by electron microscopy. Vacuolization, swelling and thickening of endothelial cells are described. In integumentary cells, as a rule, fusion and disappearance of cell processes are detected. The basement membrane is altered, ill-defined, wrinkled, lamellar structures are sometimes disturbed, and appear "moth-eaten" (Churg et al., 1962; Dalgaard, 1958; Farquhar, 1957; Holle, 1960; Meriel et al., 1963; Miller, Bohle, 1956; Thoenes, 1961). Massive proteinuria is thus associated with morphological changes nephron and leads to changes in the protein spectrum of serum and to the most important consequence protein loss - hypoproteinemia. It should be borne in mind that when the basement membrane contacts the elements of the protein molecule, the latter can be enzymatically affected (Dubach and Regan, 1960, 1962, 1963). By itself, massive proteinuria does not yet determine the qualitative composition of the secreted proteins, since there is no direct relationship between the amount of protein lost per day and the uroproteinogram. A large daily loss of protein (over 2.5-3.5 g) is the main pathogenetic factor nephrotic syndrome. With massive proteinuria, as a rule, the uroproteinogram changes, and the ratio of albumin / globulins in the urine increases, reaching or exceeding the ratio in serum; according to Kühn (1966), it is equal to 2.7 for glomerulonephritis, i.e. the bulk of the lost protein is albumin (66% for amyloidosis, 60% for glomerulonephritis and 65% for diabetic glomerulosclerosis). By immunoelectrophoresis, Kühn (1966) showed that, depending on the degree of damage to the "molecular sieve" in massive proteinuria, there may be various proteins in the urine [prealbumins, albumins, α1-low molecular weight acidic protein - uromucoid, α2-glycoprotein (antitrypsin), α1-lipoprotein (doubtful), haptoglobin, ceruloplasmin, α2-macroglobulin (very rare), siderophilin, BA, 1c-globulin, β2-lipoprotein (doubtful); үа-glycoprotein, үm-globulin, ү2-globulin and even fibrinogen (?)].
The causes of massive proteinuria are different and similar to the causes of nephrotic syndrome (see Chapter VI).
Myeloma kidney can also lead to massive proteinuria (G. A. Alekseev, N. E. Andreeva, 1966). The release of a low molecular weight uroprotein (most often γ-protein) in it raises one theoretical problem: if the tubules reabsorb proteins selectively, and the normal glomerular filtrate contains 40 mg! 100 ml of protein, i.e. about 60 g per day, then it is unclear why the protein is not released in significant concentration when the tubules are saturated with myeloma protein. We must therefore accept that the indiscriminate reabsorption clause has an exception for the myelomatous protein.
