Haematuria R31

In 1853, Teichmann was the first to detect haemoglobin as hydrochloric haematin in urine (Guder 1989). In 1858, Heller described a test for the detection of hemoglobin in urine by alkalizing and heating the urine. The benzidine test, still in use today, was developed in 1904 by R. and O. Adler (Guder 1989) and three years later the concept of the test strip still in use today was developed (Hofmann 2001).

Addis first examined cellular excretions in the collected urine of 74 healthy medical students in 1926, laying the groundwork for the definition of hematuria. He found an average of 131,500 erythrocytes per day, 645,000 leukocytes and 2,080 cylinders. These findings were later confirmed by other investigators (Guder 1989). In 1982, Fairley and Birch described a simple method of phase contrast microscopy for detecting the glomerular genesis of hematuria. They called the typical changes of the erythrocytes "dysmorphism" (Kuhlmann 2015)

(Significant) haematuria is the repeated occurrence of erythrocytes in the urine (2 out of 2 or 3 urine samples positive) exceeding the physiological level of ≤ 5 erythrocytes / µg urine (Kasper 2015 / Bald 2012).

Hematuria is divided into different categories:

1. according to pain sensation:

• dolent
• indolent (Herold 2020)

2. according to micro- and macrohaematuria:

• Microhematuria:
  • since this is not visible to the naked eye, the urine appears inconspicuous
  • microscopically there are ≥ 3 erythrocytes / field of view (in the so-called "high power field").
  • The condition is referred to as persistent non-visible haematuria (NSH) if 2 out of 2 or 3 rapid urine tests are positive for blood (Mainz 2019).
  • NSH is usually asymptomatic (Mainz 2019)
• Macrohematuria:
  • haematuria is visible to the naked eye
  • often accompanied by proteinuria (Manski (2020))
  • Immediate clarification should always be carried out (Herold 2020).

3. according to the cause of the haematuria:

• Glomerular hematuria:
  • in the phase contrast medium microscopic examination > 5 % acanthocytes can be detected
  • they are found in a typical ring shape with protuberances (so-called "Mickey Mouse ears")
• non-glomerular hematuria:
  • Microscopically, iso- or eumorphic erythrocytes are present (Herold 2020).

4. according to temporal occurrence:

• initial hematuria
  • haematuria occurring at the beginning of micturition
• terminal hematuria
  • haematuria occurring at the end of micturition (Manski 2020)

Hematuria can occur at any age, even in infants (Bald 2012). In everyday clinical practice, microhaematuria occurs in approx. 4 % - 5 % of all urine tests.

Isolated hematuria without proteinuria:

• Prostatitis
• Urethritis
• Tuberculosis
• Neoplasia
• Trauma
• idiopathic
• congenital anomaly
• Hypercalciuria
• hyperuricosuria (Kasper 2015)
• Microhematuria:
• 1. prerenal causes such as:
  • Coagulation disorders
  • Platelet dysfunction
• 2. renal causes such as:
  • Glomerulonephritis
  • Pyelonephritis
  • Renal embolism
  • Renal artery stenosis
  • interstitial nephritis
  • Cystic kidney
  • renal tuberculosis
  • papillary necrosis
  • renal infarction
  • Medullary sponge kidney
  • Renal cell carcinoma
• 3. postrenal causes such as:
  • Nephrolithiasis of the urinary tract
  • Prostatic hypertrophy
  • Tumors of the urinary tract
  • Cystitis
  • Endometriosis
  • Schistosomiasis

(Kasper 2015 / Herold 2020 / Fritze 2008)

Macrohematuria:

• this is of arterial origin in light red urine
• venous origin with dark or burgundy urine
• in older haemorrhages dark brown to black urine
• Myoglobinuria due to rhabdomyolysis (very rare); the urine is red or dark in colour; this can be caused by muscle trauma, for example.
• Haemoglobinuria due to haemolysis (also very rare); the urine is also red or dark in colour; this can be caused by e.g. haemolytic crisis in the context of haemolytic anaemia, incompatibility after administration of blood transfusion, long marches, soap abortions etc. (Bolenz 2018)

Glomerular hematuria:

• proliferative glomerular diseases:
  • primary glomerulonephritides such as:
    • IgA nephropathy
    • membranoproliferative glomerulonephritis
    • rapidly progressive glomerulonephritis (RPGN)
  • secondary glomerulonephritides e.g. in the context of:
    • vasculitides
    • systemic lupus erythematosus
    • post-infectious glomerulonephritis (e.g. after endocarditis)
    • Goodpasture syndrome
    • essential mixed cryoglobulinemia
• non-proliferative glomerular diseases:
  • membranous glomerulopathy
  • focal segmental glomerulosclerosis
  • diabetic glomerulosclerosis
• familial glomerular hemoglobinuria:
  • Alport syndrome (autosomal recessive inheritance or spontaneous mutation with alteration of basement membrane undextrarenal symptoms [Nagel 2016])
  • SLS (autosomal recessive inherited senior locomotive syndrome [Briese 2002])
  • Nephropathy with narrowing of the glomerular basement membrane (TBMN)

Non-glomerular hematuria:

• 16.3 % are caused by stone disease
• 4 % due to bleeding in the prostate area
• about 3 % occur in the context of a malignant disease
• 2,3 % are caused by an infection
• 0.9% are caused by glomerular kidney disease
• in about 2/3 of the cases a cause cannot be determined (Mainz 2019)

Initial hematuria:

• Prostate
• Seminal ducts
• Urethra (Manski 2020)

Terminal hematuria:

• Bleeding in the area of the trigonum vesicae (triangular, wrinkle-free, white-appearing area of the urinary bladder between the beginning of the urethra and the confluences of the ureters [Schiebler 2013]) (Manski 2020)

Artificial causes such as:

• Coagulation disorders
• increased physical stress (so-called "march hemoglobinuria")
• febrile infections
• menstruation
• Münchhausen syndrome (Kasper 2015 / Herold 2020 / Fritze 2008)

Urine discoloration without evidence of erythrocytesdue to:

• blueberries / blackberries
• beetroot
• food dyes
• chronic lead poisoning

drug-induced:

• as true hematuria due to e.g.:
  • ACE inhibitors
  • Allopurinol
  • Cyclophosphamide
  • Lithium
  • Penicillamine
• as pseudohematuria due to e.g.:
  • Quinidine
  • Chloroquine
  • Deferoxamine
  • Doxorubicin
  • parenteral iron
  • ibuprofen (especially in children)
  • Levodopa
  • Methyldopa
  • Metronidazole
  • Nitrofurantoin
  • Phenothiazine
  • Phenytoin
  • Primaquine
  • Rifampicin
  • Sulfonamides
  • vitamin B12
• not assignable:
  • Aminoglycosides
  • Cephalosporins
  • furosemide
  • oral contraceptives
  • Mesna (2-mercaptoethanesulfonate sodium)
  • penicillin and its derivatives
  • Phenazopyridine
  • Phenobarbital
  • Thiazides (Mainz 2019 / Soon 2012)

Sonography: Sonography of the kidneys and urinary bladder is part of the basic diagnosis of hematuria (Bolenz 2018).

Urethrocystoscopy: Urethrocystoscopy should be performed on a risk-adapted basis in patients with:

• older age
• male gender
• Tobacco smokers, etc. (Bolenz 2018 / Herold 2020)

CT and 4-phase- MSCT: Native CT for further diagnosis should be performed in patients under 30 years of age and in patients under 40 years of age with microhematuria to avoid higher radiation exposure.

In older patients and generally in cases of suspected malignant disease - irrespective of age - examination with 4-phase MSCT (multi-slice computed tomography) is recommended, which allows complete clarification of the cause of the haematuria. However, the radiation exposure is high (Töpker 2018).

Determination of inflammatory parameters

• Renal retention values (Bolenz 2018)
• Urine streak test: The urine streak test detects microhematuria due to the peroxidatic effect of hemoglobin and myoglobin. Microscopic sediment examination is required to differentiate hematuria, hemoglobinuria or myoglobinuria.
• Sediment examination for further differentiation

Caution: Taking high doses of Vit. C may give a false negative result on the urine strip test.

Microhaematuria: Inmicrohaematuria, the presence of:

- t; 5 % acanthocytes

- esence of red blood cells

- esence of marked albuminuria (> 500 mg / 24h) (Herold 2020).

If the rapid blood test strip is positive, the following diagnosis is recommended:

• microscopic examination
  • if erythrocytes are detected, further differentiation with regard to the origin:
    • renal origin if acanthocytes and erythrocytes are detected
    • postrenal haemorrhage if eumorphic erythrocytes are detected
  • if no erythrocytes are detectable, it is:
    • myoglobinuria (usually together with clear serum and CK elevation)
    • Hemoglobinuria (reddish serum and signs of hemolysis) (Herold 2020).

If the urine is red but the rapid test strip is negative, the following procedure is recommended:

• Reverse aldehyde test (so-called "Ehrlich's aldehyde test" [Bob 2001]).
• positive result = porphyria
• negative result = artificial causes (see "Etiology") (Herold 2020).

Isolated haematuria in children is never found in tumorous diseases such as Wilms' tumour. Therefore, in the absence of other symptoms, urological clarification is not necessary (Bald 2012).

3-Glass spec imen: The 3-Glass specimen can be helpful in localizing bleeding in the lower urinary tract. In the case of initial haematuria, the source of bleeding is found in the area of the urethra or prostate, in the case of terminal in the area of the bladder and in the case of total in the area of the bladder or supravesical (Fritze 2008).

Microhematuria: Diagnosis of microhematuria is confirmed by two positive rapid urine tests of a standard morning midstream urine sample (Mainz 2019).

In patients without risk factors (see below) with asymptomatic, non-glomerular microhematuria, up to 80% of cases may be so-called idiopathic, constitutional hematuria without disease value.

However, in patients with risk factors such as older age, male sex, tobacco smoking, etc., an extended diagnosis in the form of urine cytology, urethrocystoscopy and, if necessary, a CT scan should always be performed. In this case, no cause of microhematuria is found in 15% (Herold 2020).

Macrohaematuria: Any macrohaematuria should be clarified immediately (Manski 2020). The diagnosis is confirmed by quantitative and qualitative microscopic detection of erythrocytes (Bolenz 2018).

If the pH of the urine is low, hematin stains after prolonged standing, which makes the urine appear coffee-brown (Herold 2020).

The treatment of hematuria depends on the cause.

The prognosis also depends on the particular cause.

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