Diagnostic pathway for simple microscopic hematuria in children
Hematuria
Definition of hematuria: More than normal amount of RBCs in urine
・Centrifugal urine: RBC ³ 3/Hp
・Urine red blood cells > 8000/ml
・Addis count: RBC > 500,000
Degree of hematuria
・Microvolume: 2 to 10 RBC/Hp
・Moderate amount: In between
・Large amount: RBCs full field of view/Hp
Examination methods of hematuria
・Automated urine analyzer: Quick, sensitive, and crude. Primary screening
The false-negative rate for diagnosing hematuria is only 0.9%, and it is widely used. Among them, the degree of urinary occult blood is deduced by using the oxidation of hemoglobin in urine to discolor the pigment in question, and can be falsely negative or falsely positive due to the influence of reducing agents such as vitamin C and oxidizing agents such as myoglobin in urine, so it is relatively crude and only suitable for primary screening of hematuria.
・Conventional light microscopy: classical. Cannot distinguish the source of hematuria; results of centrifugal and non-centrifugal urine cannot be compared
・Phase contrast microscopy: Can distinguish the source of hematuria. Expensive equipment
・Automated hematocrit analyzer to check urinary RBC volume: Not yet commonly performed
Classification of hematuria
Flesh-eye hematuria or microscopic hematuria
Persistent hematuria or recurrent hematuria
Symptomatic hematuria or asymptomatic hematuria
Polycythemia vera or homogeneous hematuria or mixed hematuria
Glomerular hematuria or non-glomerular hematuria
Simple microscopic hematuria
– Increased amount of RBCs in the urine.
– Negative urine protein and normal white blood cells.
– No clinical symptoms, normal blood pressure, normal renal function
Overview
– Hematuria is a common symptom of kidney disease in children.
– Foreign statistics show that the incidence of asymptomatic hematuria in school-aged children ranges from 0.4 to 4.1%.
– Domestic, 1986, 224,291 urine screenings in healthy children: 0.42% incidence of asymptomatic hematuria
– Domestic, 1996, 14.7% of 2315 children with renal biopsies had simple hematuria
The importance of microscopic hematuria
– Microscopic hematuria is often an incidental finding
– Etiology, pathology, and prognosis of microscopic hematuria can be very different
– Doctors: often faced with confusion about what to diagnose and how to treat
– Parents: Consultations, multiple treatments, and high costs
How to diagnose hematuria
I. Is there definitely hematuria?
・Transient hematuria (minor sports injury, viral infection, allergy, etc.)
Vehaskari: Among 8,954 children aged 8 to 15 years, 4 urine specimens were taken from each of them, of which 4.1% were positive for one or more hematuria and 1.1% were positive for two or more, and the latter were examined twice more within six months, and only 0.4% were found to have hematuria for sure. Large-scale flow investigation found 4% once positive hematuria, 1% twice positive, 0.5% three times positive. ∴ Repeated multiple urine tests are necessary.
・Hemoglobinuria (HUS, etc.)
・Red urine (effect of drugs such as rifampin)
・External blood mixed with urine (menstruation, etc.)
Ideas for examination of microhematuria
II. Careful history taking
The circumstances of the onset of the disease (manifestations of urinary sensation, stones, nephritis)
Laboratory tests at the onset of the disease.
Special questioning of protein and WBC and tubular type in previous urinalysis.
family history.
Anticoagulation therapy such as Warfarin.
Basic laboratory tests for microscopic hematuria
– Urine routine
Is there pusuria/bacteriuria? Proteinuria? Tubular urine?
Amount of RBC in urine?
– Kidney function
– Ultrasound of both kidneys
– 24h urine protein quantification: if necessary
Localization of microscopic hematuria
Key step.
・Diagnose the nature of hematuria: Is it glomerular or non-glomerular hematuria?
・Conduct the next targeted examination
・Determine the prognosis
Localization of microscopic hematuria
Perform a comprehensive clinical evaluation based on the following.
– Ask about relevant medical history, drug history, and family history
– Physical examination and other urinalysis findings (e.g., tubular pattern, urine protein, specific crystals, etc.)
– Urinary RBC morphology and other urinary RBC localization methods.
Among them, urinary RBC localization occupies an important position, especially isolated hematuria, which is an important basis for diagnosis.
Localization of microscopic hematuria
Evidence of glomerular hematuria.
– 24h urine protein > 1.0g
– RBC tubular pattern
– Echinocytes > 5%
– Small deformed RBCs predominate
Glomerular hematuria or non-glomerular hematuria?
Urinalysis Glomerular hematuria Non-glomerular hematuria Tongliao Hospital Pediatrics Department Li Hongying
Protein ≥++ (> 1g/24h) <++ (<1g/24h)
Sediment RBC tubular pattern can be seen
Deformed RBC rate ≥ 70% < 30%
Severely deformed RBCs ≥ 30% < 15%
Erythrocytes > 5% < 5%
Mean RBC volume < 75fI ≥ 75fI
Urine phase contrast microscopy
The following do not support glomerular hematuria
l normal red blood cells
coarse spike-like red blood cells
fine spike-like red blood cells
l Shadow cells
Suggesting glomerular hematuria: l
l small deformed red blood cells
l Erythrocyte tubular type (specific, rather insensitive)
l Spiny red blood cells (bagel-like red blood cells with protruding cell membranes forming vesicles)
Large-scale studies on glomerulonephritis (confirmed by renal biopsy) have shown that this test detects glomerulonephritic hematuria with
Sensitivity 52-73% and
Specificity 98-100%
Mechanism of hematuria formation
・Glomerular hematuria: RBCs in capillaries are extruded from the narrow fissures of the diseased basement membrane; RBCs are affected by osmotic pressure and urinary enzymes over time as they pass through the renal tubules.
・Non-glomerular hematuria: Intravascular RBCs enter the urinary stream because the anatomical integrity of the urethral mucosa is disrupted
Limitations of hematuria localization by urine red blood cell morphology
– Must be fresh urine.
– reliable significance of this method of localization when a certain amount of RBCs are present in the urine (>10-15/Hp)
– Glomerulonephric hematuria may appear as normal RBCs in the case of naked eye hematuria.
– When “biphasic hematuria” is present, the source of hematuria should not be arbitrarily determined by the results of one or one urinary RBC localization method, and multiple or multiple localization methods should be used as much as possible.
Renal pathological changes in 341 children with simple hematuria from 2315 kidney biopsies in China in 1996
Of the 110 cases of carnal hematuria.
– IgA nephropathy in 39 cases (35.5%)
– Thylakoid hyperplasia in 23 cases (20.9%)
– Mild lesions 16 cases (14.5%)
– Thin basement membrane in 12 cases (10.9%)
Of the 231 cases of microscopic hematuria.
– Thylakoid hyperplasia 101 cases (43.7%)
– FSGS 31 cases (13.4%)
– IgA nephropathy 27 cases (11.7%)
– Mild lesions 23 cases (10.0%)
– Thin basement membrane 13 cases (5.6%)
Common glomerular diseases presenting as simple hematuria
– IgA nephropathy
– Mild thylakoid proliferative nephritis
– Thin basement membrane nephropathy
– Alport syndrome
– Others (minor lesions, etc.)
Further investigations for those with glomerular hematuria
– hepatic and renal lipid profile
– Excluding secondary causes: ANA, ANCA , HBV
– Excluding acute post-streptococcal nephritis: ASO, CH50, C3,
– Tests related to IgA nephropathy: Ig
– Electro auscultation (if necessary)
– Renal biopsy
Treatment of common glomerular diseases presenting as simple hematuria
– IgA nephropathy: Chinese medicine may be used as appropriate
– Mild thylakoid proliferative nephritis: appropriate herbal medicine may be used
– Thin basement membrane nephropathy: protect the kidneys; follow up
– Alport syndrome: kidney protection; follow up
– Other (mild lesions, etc.): kidney protection; follow-up
Diagnostic tools for common glomerular diseases presenting as simple hematuria
The question has been raised: is a renal puncture necessary?
– North America: Given that there is no effective treatment for IgA nephropathy, AS, TMN, etc., nephrostomy is not an effective diagnostic tool for children with negative family history of simple hematuria. By adulthood, a definitive diagnosis is needed to find a job, get insurance, and serve in the military, when it is easier to mobilize for a kidney puncture.
– Domestic: A clear diagnosis will help in proper treatment and avoid blindly seeking medical help.
Indications for renal biopsy in hematuria
– Isolated hematuria lasting ≥ 6 months.
– Isolated hematuria with a positive family history.
– Persistent carnituria for ≥ 2 to 4 weeks.
– hematuria combined with proteinuria (quantitative ≥ 1g/24h).
– Hematuria with unexplained hypertension or renal hypofunction.
Renal biopsy should be routinely performed with light microscopy, immunofluorescence and electron microscopy
Skin type IV collagen immunopathology screening may be performed first in children with a family history of hematuria.
Common non-glomerular diseases presenting as simple hematuria
– Urinary tract infections (pyelonephritis, cystitis, urethritis)
– Left renal vein compression syndrome (nutcracker phenomenon)
– Congenital renal malformations (polycystic kidney, medullary spongy kidney, hydronephrosis, renal arteriovenous malformation, etc.)
– Idiopathic hypercalcemia with or without renal calculi
– Others (parasites, tuberculosis, polyps, tumors, etc.)
Further diagnosis of non-glomerular hematuria
・Culture of clean middle urine
・Renal ultrasound, renal vascular ultrasound
・Venous pyelogram, abdominal plain film, abdominal CT
・UCa/Cr, 24-hour urine calcium
・ESR, PPD, chest X-ray, urine for antacid bacilli
Tests for blood disorders
IgA nephropathy One of the most common primary glomerulonephritis
– Immune complex disease
・More common in older children, male to female ratio 2:1
・Typical clinical manifestation: Sarcopenic hematuria with/without persistent microscopic hematuria synchronized with pharyngitis. (Hematuria + proteinuria, acute nephritis syndrome, nephrotic syndrome, etc. are seen)
・Laboratory tests are non-specific and dominated by deformed RBCs
・Must be diagnosed immunopathologically (IgA-dominated granular deposits in the thylakoid region)
・Excluding secondary IgA nephropathy
Mild thylakoid proliferative nephritis
・Mostly recovery from nephritis after various infections
・Clinical: Glomerular hematuria
・Pathology: Mild thylakoid hyperplasia under light microscopy; a few immune complex deposits under immunofluorescence
No specific treatment
Alport syndrome
・Progressive hereditary disease, 85% XD, a small proportion of AD or AR
(Mutation in the IV collagen a-chain gene encoding GBM, thus unable to form a normal IV collagen meshwork)
・Main clinical features: prevalent in boys; glomerular hematuria, may be accompanied by proteinuria, progressive hyperalgesia; neurogenic deafness; ocular abnormalities. Positive family history
Diagnosis: Uneven thickness, delamination, and fracture of the dense layer of GBM on electron microscopy; anti-a chain (IV) antibody staining shows negative a3, a4, and a5 chains. a5 chain in EBM is negative.
Thin basement membrane nephropathy (benign familial hematuria)
Heterogeneous disease, partly due to chromosome 2 COL4A3/COL4A4
Caused by mutations in the gene region.
・Most positive family history
・Clinical: All age groups, benign asymptomatic hematuria (mostly persistent microscopic, but also naked eye; glomerular hematuria, may be accompanied by mild proteinuria or hypertension), generally normal renal function. Susceptibility to other glomerular diseases
・Confirmation of diagnosis: GBM uniformly thin on electron microscopy, negative on light microscopy and immunofluorescence, preferably with a positive family history
・Prognosis is mostly good and long-term follow-up is required, with attention to exclude early Alport syndrome.
Common non-glomerular diseases in children with isolated hematuria
Left renal vein compression syndrome (Nutcracker phenomenon)
・Principle: The left renal vein system is stagnant and has abnormal traffic with the urine collection system (the left renal vein exits the kidney and travels in the angle between the abdominal aorta and superior mesenteric artery and then enters the inferior vena cava)
・Clinical: Most common in adolescent children; non-glomerular hematuria (microscopic or naked eye, persistent or recurrent), upright proteinuria
・Proposed diagnosis: Left renal vein diameter in the supine position differs by more than two times before and after the angle of entrapment
・Confirmed diagnosis: The diameter of the left renal vein in the posterior spinal extension position differs more than 4 times from the anterior to the posterior angle; cystoscopy shows hematuria from the left ureteral side
・Note: Non-exclusive diagnosis; hematuria + proteinuria is more likely to be occult nephritis
・Good prognosis, long-term follow-up, no specific treatment
Idiopathic hypercalcemia
・Etiology is unclear, and the onset is often familial.
・Clinical: (Microstones damage renal tubules) Non-glomerular hematuria (microscopic or naked eye, persistent or recurrent)
・Diagnosis.
Normal blood calcium.
Elevated urinary calcium (immediate urinary Uca/cr > 0.21 proposed diagnosis, 24-hour urinary calcium > 4 mg/kg confirmed diagnosis)
Idiopathic hypercalcemia (continued)
Calcium loading test: perform staging
Low calcium diet (≤300mg/d) for one week prior to test, 2-hour fasting urine collected on test day (specimen U1) with normal breakfast, along with oral calcium gluconate (elemental calcium 1g/1.73m2), 4-hour urine specimen collected U2), two specimens done separately for Uca/cr.
Normal values U1ca/cr < 0.21, U2ca/cr < 0.27
Typing: Absorption type (U1 normal, U2 elevated), the
Leaky type (both U1 and U2 elevated)
Recently, the two types have been found to be partially convertible or coexisting (mixed type).