Hematuria

Hematuria is the presence of blood in the urine. A distinction is made between macro- and microhematuria.

In the urine of a healthy person, no more than 1-2 erythrocytes are found in the field of vision, or 10 ⁴ -10 ⁵ of these cells in a portion of urine collected over 12 hours. The presence of 3-5 or more erythrocytes in the field of vision is called hematuria.

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Causes hematuria

Normally, hematuria is observed extremely rarely. A relatively benign condition accompanied by microhematuria is considered to be the disease of the thin basement membranes of the glomerulus. As a rule, such patients can identify cases of this disease in relatives; microhematuria is isolated and renal failure does not develop.

Microhematuria occurs after prolonged walking or running, such as in long-distance runners or soldiers on long marches. Typically, the red blood cells disappear after exercise stops. The mechanism by which march microhematuria develops has not been established. Long-term prospective observation of people with march microhematuria suggests that its presence does not increase the likelihood of developing chronic progressive kidney disease.

Macrohematuria is never detected in healthy people. As a rule, the presence of macrohematuria indicates the severity of damage to the renal tissue and/or urinary tract.

Non-renal hematuria is most often caused by a disruption of the integrity of the mucous membrane of the urinary tract due to inflammation, tumor damage, and injuries, often accompanied by ulceration. One of the most common causes of non-renal hematuria is stone formation or passage of a stone through the ureters, bladder, and urethra. Bleeding from the mucous membrane of the urinary tract can be caused by an overdose of anticoagulants.

Renal hematuria is associated with destructive processes in kidney tissue, impaired venous outflow, and necrotizing vasculitis. Glomerular hematuria is usually caused by immune-inflammatory damage to the glomerular basement membrane (GBM) or its congenital anomalies. In addition, renal hematuria is observed in toxic and inflammatory lesions of the tubulointerstitium and tubules, as well as with increased renal intravascular coagulation [disseminated intravascular coagulation (DIC), antiphospholipid syndrome].

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Causes of non-renal hematuria

Cause	Source of hematuria
Stones	Ureters Urinary bladder
Tumors	Urinary tract Prostate adenocarcinoma Benign prostatic hyperplasia
Infections and parasitic infestations	Acute cystitis, prostatitis, urethritis caused by bacteria or Chlamydia trachomatis Tuberculosis, schistosomiasis of the urinary tract
Medicines	Cyclophosphamide (hemorrhagic cystitis) Sodium heparin Warfarin
Injuries	Foreign body in the urinary tract Contusions of the urinary tract Long walking/running

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Causes of glomerular hematuria

Group

Examples of diseases

Primary lesions of the glomeruli of the kidneys Secondary lesions (in systemic diseases) Hereditary/Family

IgA nephropathy Acute postinfectious glomerulonephritis Mesangiocapillary glomerulonephritis Rapidly progressive glomerulonephritis Fibrillary glomerulonephritis Minimal change nephropathy Focal segmental glomerulosclerosis Henoch-Schönlein purpura Systemic lupus erythematosus Goodpasture's syndrome Systemic vasculitis (especially ANCA-associated) Subacute infective endocarditis Essential and HCV-associated mixed cryoglobulinemia Thrombotic thrombocytopenic purpura (TTP) Hemolytic uremic syndrome Alport syndrome Thin basement membrane disease of the glomeruli (benign familial hematuria) Fabry disease Hereditary onychoarthrosis

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Causes of non-glomerular hematuria

Group	Examples of diseases
Tumors	Renal cell carcinoma
	Wilms tumor (nephroblastoma)
	Multiple myeloma
	Angiomyolipoma (tuberous sclerosis)
Vascular	Renal infarction
	Renal vein thrombosis
	Arteriovenous malformations
	Malignant hypertension
Metabolic	Hypercalciuria
	Hyperoxaluria
	Hyperuricosuria
	Cystinuria
Renal papillary necrosis	Taking analgesics
	Tuberculosis of the kidney
	Obstructive uropathy
	Sickle cell anemia
	Alcohol abuse
Medicines	Acute drug-induced tubulointerstitial nephritis
Hydronephrosis	Any origin
Cystic kidney disease	Autosomal dominant polycystic kidney disease
	Medullary cystic disease/familial juvenile nephronophthisis
	Medullary spongy kidney
Injury	Contusion or crushing of the kidney
	Long walk/run

In all variants of hematuria, it is necessary to search for its cause. In patients with already diagnosed chronic kidney and/or urinary tract disease, hematuria, especially macrohematuria, always indicates an increase in the activity or exacerbation of the disease.

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Pathogenetic factors of hematuria

The sudden appearance of an unusual, blood-like color of urine, sometimes in the midst of complete health, in the absence of any other painful manifestations, certainly frightens the patient, prompting him to seek emergency help. However, visually intense blood coloring of urine does not always indicate massive bleeding. Arterial bleeding from the kidney and urinary tract without prior trauma or surgery is an exception. Most bleeding manifested by hematuria is usually venous. Most often, they arise from the fornical plexuses surrounding the vaults of the renal calyces or varicose submucosal veins of the calyceal-pelvic system, ureters, bladder or urethra.

Intensive bleeding is indicated by the presence of clots in blood-stained urine; in particularly severe cases, their formation in front of the patient and doctor immediately after urination is a sign of massive bleeding that threatens the patient's life. In hematuria caused by a urological disease, proteinuria occurs, which, as a rule, is false and is associated primarily with the presence of hemoglobin in the urine, as well as blood plasma proteins. A level of false proteinuria of 0.015 g or more against the background of macrohematuria characterizes severe, life-threatening bleeding and requires emergency diagnostic and therapeutic measures.

In cases of massive bleeding from the kidney and upper urinary tract due to trauma and neoplasms, as well as in case of bladder and prostate tumors, the bladder can overflow with urine with a large admixture of blood and clots that obstruct the bladder neck area and the internal opening of the urethra, and the muscular elements of the wall are overstretched beyond the limit, making contraction of the detrusor and opening of the neck impossible. Acute urinary retention occurs due to bladder tamponade. Such patients require emergency urological intervention.

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Symptoms hematuria

Hematuria, along with edema and severe arterial hypertension, is considered an obligatory component of acute nephritic syndrome. It is characteristic of acute glomerulonephritis, including poststreptococcal, or indicates an increase in the activity of chronic glomerulonephritis. Macrohematuria is more characteristic of acute nephritic syndrome.

Acute nephritic syndrome in acute glomerulonephritis is sometimes combined with signs of acute renal failure - an increase in the concentration of serum creatinine and oligo- or anuria. Hypervolemia determines the severity of arterial hypertension. Often, dilation of the left heart with signs of congestion in the pulmonary circulation develops rapidly. Acute nephritic syndrome in acute glomerulonephritis is completely reversible in most cases, immunosuppressive therapy is usually not necessary.

A significant increase in urinary protein excretion is not characteristic of acute poststreptococcal glomerulonephritis and rather indicates an exacerbation of chronic glomerulonephritis. The disappearance of macrohematuria in patients with chronic glomerulonephritis indicates the achievement of remission, although microhematuria can persist for a very long time. The presence of hematuria in chronic glomerulonephritis always indicates the activity of kidney damage.

Hematuria is observed in various forms of chronic glomerulonephritis (IgA nephropathy), including in the context of systemic diseases (Schonlein-Henoch purpura). The combination of hematuria with deafness and a history of kidney disease indicates Alport syndrome (hereditary nephritis with deafness).

The frequency of hematuria in various types of chronic glomeruloneuritis in adults and children is not the same. Microhematuria is observed in 15-20% of children with minimal-change nephropathy; their nephrotic syndrome is usually sensitive to treatment with corticosteroids. Microhematuria is observed much less frequently in adult patients with minimal-change nephropathy.

Microhematuria is a characteristic sign of tubulointerstitial nephropathy, including metabolic nephropathy (hypercalciuria, hyperuricosuria). This sign can exist for a long time in isolation or be combined with a moderate decrease in the relative density of urine.

Hematuria and rapidly increasing renal failure, accompanied by bloody diarrhea, are characteristic of hemolytic uremic syndrome. In addition, these patients have hemolytic anemia and clinical signs of hypohydration.

Urinary tract infections and nephrolithiasis are also causes of hematuria. In elderly patients with isolated microhematuria, especially in combination with fever or subfebrile condition, it is necessary to exclude tumors of the urinary tract, including kidney cancer.

Asymptomatic total hematuria with intensely colored urine, accompanied by the release of clots, is a very serious symptom of neoplasms of the kidneys and bladder. Often, hematuria is absent for a long time or is intermittent. This should not reassure either the doctor or the patient. It is necessary to conduct a full range of special studies to confirm or exclude the diseases that caused hematuria. If the results of ultrasound and other objective methods do not provide information about the cause of hematuria, then to establish the source of bleeding, it is necessary to perform a cystoscopic examination at the height of hematuria. In addition to examining the bladder cavity, it is necessary to determine the nature and color of the urine released from the mouths of both ureters. This simple technique will allow you to establish not only the degree of hematuria, but also its unilateral or bilateral origin.

It is necessary to analyze various clinical symptoms. The combination of several signs, the timing of their occurrence allow the doctor to make an assumption about the possible etiology of hematuria with a high degree of probability. The analysis of the interdependence of the occurrence of pain and hematuria helps to determine the topical diagnosis. In urolithiasis, pain always precedes the latter, and the intensity of bleeding is most often small. At the same time, with intense hematuria with clots caused by a destructive process, pain occurs after it due to the disruption of the outflow of urine by the formed blood clot. Painful frequent urination with concomitant hematuria indicates a pathological process (tumor, stone, inflammation) in the bladder.

In case of bladder stones, hematuria occurs after intensive walking, bumpy rides in transport and is accompanied by frequent urination. Often the pain radiates to the head of the penis.

Hematuria is a very important symptom of urological diseases. Any patient who has had hematuria at least once (if it is not associated with acute cystitis) needs urgent urological examination.

In case of asymptomatic hematuria, if there is no absolute certainty about the localization of the pathological process, it is advisable to perform cystoscopy. It should be remembered that the wrong tactics of the doctor in case of hematuria can cause a delayed diagnosis of the tumor process.

Diagnostics hematuria

Macrohematuria in freshly excreted urine is determined visually. The color of urine varies from "meat slops" to scarlet, sometimes described by patients as "cherry color", "fresh blood". Macrohematuria in all cases is accompanied by microhematuria.

Microhematuria (erythrocyturia) is determined by microscopic examination of urine sediment. During external examination, blood may not be present in the urine. The condition of the cell wall of red blood cells is of great importance, for example, their leached forms are more often found in glomerulonephritis. The more distal the source of hematuria is located in the urinary tract, the less morphological changes the red blood cells of the urinary sediment undergo. The presence of blood in the urine is a serious sign of various diseases of the genitourinary system (for example, a tumor process in the kidneys, upper urinary tract, bladder, urethra).

In neoplasms of the upper and lower urinary tract, hematuria may be the only symptom of the disease or be combined with other signs.

The source of hematuria can often be determined by assessing the anamnestic data and macroscopic examination of the urine. Its examination is carried out using a two-glass test. The patient is asked to urinate into two vessels without interrupting the urine stream, so that approximately a third of the total volume is released into the first, and the remaining two-thirds into the second.

If blood is detected only in the first portion, then we are talking about the initial (beginning) form of hematuria. As a rule, it is observed when the pathological process is localized in the urethra (neoplasms, hemangiomas and inflammatory diseases of the urethra). Initial hematuria should be distinguished from urethrorrhagia. In this case, blood is released from the urethra involuntarily, outside the act of urination. Most often, urethrorrhagia is observed with injuries to the urethra.

In some diseases (for example, acute cystitis, posterior urethritis, prostate adenoma and cancer, bladder tumor located in the cervical area), blood is released at the end of urination (often in drops). In these cases, we speak of terminal (final) hematuria. Uniform blood content in all portions of urine is total hematuria. It is observed in diseases of the renal parenchyma, upper urinary tract (calyces, pelvis, ureters) and lower (bladder) urinary tract. Sometimes total hematuria occurs as a result of trauma to a large number of venous plexuses in the area of an enlarged prostate (for example, with adenoma).

Total hematuria can be of different intensity: from the color of "meat slops" to the color of cranberry juice and ripe cherries. Total hematuria is the most common, prognostically significant symptom, the main and not always the first sign of such serious diseases as tumors of the renal parenchyma, pelvis, ureter, bladder. Moreover, at present, hematuria in the listed nosological forms is considered a late clinical sign indicating an unfavorable prognosis. In addition, total hematuria can be a symptom of other destructive processes: renal tuberculosis, papillary necrosis, bladder ulcer, urolithiasis, acute cystitis. It should be borne in mind that in some patients total hematuria may be a sign of the hematuric form of glomerulonephritis, the visceral form of adenomyosis (endometriosis), and a number of parasitic diseases of the urinary bladder (schistosomiasis, bilharziasis). The intensity of total hematuria can be judged by the presence of clots in the excreted portion of urine. They may indicate erosion of more or less large vessels as a result of a destructive process in the kidneys and urinary tract.

The source of bleeding can also be judged by the shape of the clots. Long, worm-like clots are formed if the source of bleeding is localized in the kidney and/or upper urinary tract. Following the ureter, the blood coagulates, taking the shape of earthworms or leeches. However, a clot can also form in the bladder, in which case it takes on a shapeless appearance. Such clots are described as "pieces of torn liver." Thus, shapeless clots can occur as a result of bleeding from the upper urinary tract and bladder. It should be emphasized that when collecting anamnesis, the doctor should clarify not only the nature and possible source of hematuria, but also the shape of the clots released.

The clots described by patients in the form of films, fragments as thick as a sheet of paper, are fibrin films imbibed with erythrocytes. It should also be noted that vermiform clots are detected not only in cases where the source of hematuria is located above the internal sphincter of the urethra. In cases of non-intensive urethrorrhagia (especially with external compression of the urethra for the purpose of hemostasis), the emptying of the bladder may be preceded by the release of a vermiform clot.

Thus, in case of macroscopic hematuria, it is necessary to take into account its type (initial, terminal or total), intensity, presence and shape of clots.

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Inspection and physical examination

The connection between hematuria and chronic glomerulonephritis is confirmed by arterial hypertension and edema. The presence of skin rash (primarily purpura) and arthritis indicates kidney damage as part of systemic diseases.

An enlarged and palpable kidney is observed in cases of tumor damage.

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Laboratory diagnostics of hematuria

Hematuria, hemoglobinuria, and myoglobinuria are distinguished using specific tests. The most commonly used test is the ammonium sulfate test: 2.8 g of ammonium sulfate is added to 5 ml of urine. Hemoglobin precipitates and settles on the filter after filtration or centrifugation; myoglobin remains dissolved, and the urine remains colored.

Test strips that detect the peroxidase activity of hemoglobin are used as screening: erythrocytes are hemolyzed on indicator paper, and hemoglobin, causing oxidation of the organic peroxide applied to the test strip, changes its color. If there is a large amount of peroxides in the urine or massive bacteriuria, a false positive reaction is possible.

The presence of hematuria should be confirmed by microscopy of urinary sediment.

Unchanged and changed erythrocytes are found in urine. Unchanged erythrocytes are round, anuclear cells of yellow-orange color. Changed erythrocytes have the appearance of single- or double-contour bodies (shadows of erythrocytes), often practically colorless, or discs with uneven edges.

The detection of acanthocytes in urine - red blood cells with an uneven surface resembling a maple leaf - is considered one of the reliable signs of glomerular hematuria.

Quantitative methods are also used to determine microhematuria. One of the most commonly used is the Nechiporenko method, based on counting the number of formed elements (erythrocytes, leukocytes, cylinders) in 1 ml of urine; normally, the content of erythrocytes in 1 ml of urine does not exceed 2000.

Laboratory diagnostics can confirm the predominantly renal origin of hematuria.

Laboratory research methods used in the differential diagnosis of hematuria

General urine analysis	Biochemical blood test	Immunological blood test
Proteinuria Cylinders Leukocyturia Bacteriuria Crystals (urates, oxalates)	Hypercreatininemia Hyperkalemia Hypercalcemia Hyperuricemia Increased alkaline phosphatase activity	Hypocomplementemia Increased IgA levels Cryoglobulins Antinuclear antibodies ANCA Anti-glomerular basement membrane antibodies Antibodies to cardiolipin Markers of HBV, HCV infection

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Instrumental diagnostics of hematuria

Diagnosis of hematuria uses instrumental, including visualizing, research methods:

• ultrasound examination of the abdominal cavity and kidneys;
• ultrasound examination of the bladder and prostate gland;
• computed tomography of the abdominal cavity and pelvis;
• MRI;
• excretory urography;
• cystoscopy.

The combination of hematuria with significant proteinuria and/or progressive deterioration of renal function is considered an indication for kidney biopsy.

Renal hematuria is divided into glomerular and non-glomerular. Phase-contrast microscopy is used to differentiate these variants.

In microhematuria, light microscopy of urine sediment allows detecting both fresh and leached erythrocytes, which are an indirect sign of minor bleeding from the kidney and upper urinary tract. The phase-contrast microscopy method proposed in the clinic of therapy and occupational diseases of the Moscow Medical Academy named after I.M. Sechenov can provide some assistance in this regard.

A functional test with physical activity in combination with microhematuria and proteinuria also helps in the diagnostic search. An increase in the amount of protein and unchanged erythrocytes against the background of physical activity is more characteristic of urological causes of microhematuria (small calculus, "fornical" bleeding). An increase in the amount of protein with a sharp increase in the number of changed erythrocytes is an indirect sign of impaired venous blood outflow from the kidney, while a sharp increase in proteinuria with an insignificant increase in the titer of formed elements in the sediment is more characteristic of nephrological patients.

A detailed consideration of the causes of hematuria is due to diagnostic and tactical errors that can be observed in the outpatient and clinical practice of a nephrologist. The most tragic situations are those associated with late diagnosis of oncological diseases - tumors of the renal parenchyma, renal pelvis and ureter, bladder, etc. Rational diagnostic and therapeutic tactics are especially relevant in the case of sudden total painless macrohematuria. It should be considered an emergency condition requiring urgent diagnostic and therapeutic measures that should be carried out by a urologist.

If there is clinical evidence of an acute inflammatory process (acute cystitis in women, acute urethritis and prostatitis in men), the cause of hematuria may be clear based on the clinical data alone. In other cases, a 2-glass test should be performed urgently, which will help confirm the presence of macrohematuria at the time of examination, approximately (by eye) estimate its intensity, the presence and shape of blood clots. Vermiform clots indicate bleeding from the kidney and upper urinary tract; shapeless ones most likely form in the bladder. Visual assessment of the obtained 2 portions of urine allows you to clarify the nature of hematuria (initial, total or terminal). Subsequent emergency laboratory testing will allow you to differentiate hematuria from hemoglobinuria and approximately estimate the intensity of bleeding based on the level of false protein and the number of formed elements. Initial macrohematuria requires emergency urethroscopy and urethrography, and other types require ultrasound examination and urethrocystoscopy to clarify the source of bleeding. In urethrocystoscopy, it may be the urethra and bladder affected by the pathological process, the mouth of the right or left ureter, or both ureteral mouths.

Bilateral discharge of urine stained with blood is more typical for disorders of the blood coagulation system and diffuse inflammatory diseases of the kidneys. Urological diseases, as a rule, manifest themselves as unilateral bleeding. To reliably establish the source of bleeding, it is necessary to identify a steadily repeating rhythmic flow of urine portions, noticeably stained with blood from the corresponding ureteral orifice, or a pathological process on the mucous membrane of the bladder with a characteristic visual picture (tumor, inflammation, ulcer, calculus, varicose veins, etc.). It should be emphasized that for greater reliability and to prevent subjectivity in assessing the cystoscopic picture, at least two doctors should participate in such an emergency study, and if appropriate technical means are available, it is desirable to perform a video recording.

Modern research capabilities (if necessary against the background of drug-induced polyuria) using not only abdominal but also rectal and vaginal sensors make ultrasound examination especially indicated, necessary and informative, however, the pathological process in the kidney and bladder revealed during such examination should in no way be a reason for refusing an emergency cystoscopic examination in the case of acute total macrohematuria, since the patient may suffer from not one, but two or more diseases. Thus, with a kidney tumor, a bladder tumor is possible, and with prostate hyperplasia, in addition to a bladder tumor, pathological processes in the kidney and upper urinary tract, etc. may also occur.

Having appeared suddenly, hematuria may be short-lived and stop on its own. The absence of any noticeable clinical manifestations (pain, dysuria) can reassure the patient and the doctor, convincing them that there is no need for a detailed examination. The next episode of hematuria, the appearance of other symptoms of the disease as it progresses may indicate a delayed diagnosis; in this case, the prognosis is much worse.

The tactics of in-depth examination to clarify the cause of hematuria depends on a comprehensive assessment of clinical symptoms, physical, laboratory, ultrasound, endoscopic and other examination data. The principles of such examination should be the choice of optimal methods to obtain the maximum information necessary to establish the correct diagnosis and determine rational therapy, preventing unjustified treatment in case of incomplete or erroneous diagnosis, as well as the use of the entire necessary arsenal of diagnostic tools, especially for the detection or exclusion of surgical diseases.

Differential diagnosis of renal hematuria using phase-contrast microscopy

Hematuria	Microscopy results
Glomerular	More than 80% of red blood cells differ sharply in size and shape (dysmorphism), their membranes are partially torn, and their contours are uneven
Non-glomerular	More than 80% of red blood cells are of the same shape and size (isomorphism), little changed
Mixed	Absence of a clear predominance of dysmorphic or isomorphic erythrocytes

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Differential diagnosis

Before using special instrumental methods of examination, it is advisable to conduct a three-glass test. Blood clots often form when bleeding from the bladder, ureters and renal pelvis.

Interpretation of the three-glass test

Type of hematuria	Changes in urine analysis	Reasons
Initial hematuria Terminal hematuria Total hematuria	Blood in the first portion Blood in the third portion Blood in all portions	Inflammation, ulceration, trauma, tumor of the initial part of the urethra Inflammation, tumor of the prostate gland, cervical part of the bladder Lesions of the bladder (hemorrhagic cystitis), ureters, renal pelvis, renal parenchyma

Differential diagnostics of hematuria aims to establish its renal or non-renal origin. It is also necessary to differentiate between glomerular and non-glomerular hematuria.

Analysis of the course of the disease and complaints allows us to establish the duration of hematuria, its paroxysmal or constant nature. In addition, hematuria is sometimes combined with various pain syndromes (for example, pain in the lower back, abdomen) and urination disorders (pollakiuria, polyuria). When questioning, it is necessary to pay attention to the intake of medications, the relationship of hematuria with physical activity, a general tendency to bleeding, the presence of kidney disease in the family history. The combination of hematuria with dysuria indicates its extrarenal origin.

General factors, particularly gender and age, should be taken into account. Hematuria that first appears in the elderly is more often of non-glomerular origin; urinary tract diseases (bladder, prostate gland), including tumors, as well as kidney cancer, should be excluded. In addition, renal tuberculosis should be excluded at this time. If the results of most available research methods are of low informative value in a patient with persistent (6-12 months) hematuria, a renal biopsy should be considered.

Hematuria should be distinguished from hemoglobinuria, in which the urine contains not red blood cells, but free hemoglobin and fragments of its molecules, as well as urethrorrhagia - the release of blood from the external opening of the urethra outside the act of urination. It is necessary to remember that urine can acquire a color similar to blood due to the consumption of certain foods (beets), as well as taking a drug (madder extract). The use of phenolphthalein (purgen) with an alkaline reaction of urine can cause its pink and even crimson color. This is why hematuria as a symptom characterizing bleeding from the kidney (kidneys) and urinary tract is indicated only by the detection of red blood cells in the urine sediment by microscopy.

Blood may appear in urine when it enters from the female genital organs, from the preputial sac in men, or when it is introduced intentionally (artificial hematuria).

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Forecast

Persistent hematuria in combination with “large” proteinuria and severe arterial hypertension is a marker of an unfavorable renal prognosis.

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