Nephrology Krishan Chugh, Anupam Sachdeva, Ajay Gambhir, Satinder Aneja, AP Dubey, Shyam Kukreja
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Approach to Hematuria in ChildrenCHAPTER 1

Amish Udani,
Sangeetha G,
Vijayakumar M
 
Introduction
Hematuria signifies blood in the urine and it can be macroscopic (gross) or microscopic. Microscopic hematuria can be symptomatic or asymptomatic. Hematuria is a frightening situation for the child, parent and doctor as well. Proper detailed history taking, physical examination, relevant investigations help us to arrive at the cause. If hematuria is non-life-threatening and a cause is not ascertained in initial evaluation, the children can be kept under surveillance and re-evaluated periodically or when hematuria recurs. Prevalence of hematuria is 0.5–2.0% in normal school going children.1
 
Definition
Definitions used in association with hematuria in children are many and they are helpful in defining either the cause or the seriousness of the illness.2
Macroscopic hematuria: Child is brought with history of blood in urine. Dipstick examination (positive for true hematuria, myoglobinuria and hemoglobinuria; negative for pseudohematuria due to rifampicin, colored food and beetroot) and sediment examination (RBCs and RBC casts in true hematuria) are needed.
Microscopic hematuria: This indicates presence of abnormal number of red blood cells (RBCs) in urine. More than 5 RBC per mm3 in uncentrifuged urine and more than 5 RBC/HPF in a centrifuged specimen (10 mL urine, 2000 rpm for 5 minutes) will denote significant hematuria.3,4 It comes to notice when urine analysis is done as a screening test or for any other symptom.
Transient hematuria: Fever, infections, trauma and exercise are common causes and are usually microscopic.
Persistent hematuria: Presence of RBCs in urine done in three samples one week apart with or without other cellular deposits or recurrent macroscopic hematuria is defined as persistent hematuria and usually indicates renal disease.
Symptomatic hematuria: Hematuria in association with other symptoms such as hypertension, edema and urinary symptoms always indicates underlying disease and needs detailed evaluation.2
Asymptomatic hematuria: It can be macroscopic but is usually microscopic and may be the sole abnormality with neither history nor physical examination providing indication of systemic, renal or urological disorders. Long-term follow-up is necessary to identify a benign or a slowly progressive disease process.
Isolated hematuria: This definition includes both macroscopic and microscopic hematuria. Severe renal histologic abnormalities in children with persistent isolated hematuria are unusual. Persistent microhematuria interspersed with episodes of gross bleeding or with proteinuria signifies serious illness. These children need long-term follow-up as hematuria can disappear, or the child can develop additional renal or systemic abnormalities, or rarely isolated hematuria can persist.
 
Detection of Hematuria
Dipstick examination of urine can be used as a screening procedure but documentation of hematuria by microscopic examination is always mandatory. Dipsticks depends on peroxidase like chemical reaction between free hemoglobin or hemoglobin present in intact RBC or myoglobin in urine and a chemical tetramethylbenzidine present in the strip producing a blue color. It is capable of detecting 3–10 RBC/µL of uncentrifuged urine. It has 100% sensitivity and 99% specificity.1 They are relatively costly but good as screening test for hematuria.
Macroscopic hematuria is visible to the naked eye and can be associated with significant proteinuria or RBC casts. Presence of RBCs in urine should always be confirmed by microscopic examination of 10–15 mL of freshly collected sample centrifuged at 2000 rpm for 5 min, decanting the supernatant, then resuspending the sediment in remaining 0.5 mL.3,4 Microscopic hematuria seen in asymptomatic cases should be given importance in the presence of significant proteinuria.5
Absence of RBC on microscopic examination with positive dipstick test suggests hemoglobinuria or myoglobinuria, which can be distinguished by spectrophotometry. Bedside test to identify hemoglobinuria is by centrifugation of urine wherein the supernatant fluid is uniformly pink whereas in true hematuria it is dirty brown.5 Dipsticks can be false positive in alkaline urine pH >9.0 or contamination with menstrual blood or fever or exercise or contamination with oxidizing agents and false negative in the presence of formalin or ascorbic acid.1
 
Mechanism of Hematuria
Blood in urine can have its origin either from the glomeruli or from renal tubules and interstitium. It can also originate from the urinary tract including the collecting systems, ureters, bladder and urethra. In glomerular hematuria, RBCs cross the glomerular endothelial-epithelial barrier and enter the capillary lumen through structural discontinuities in the capillary wall. These discontinuities are supposed to be at the capillary wall–mesangial 3cell reflections.
One should note that the renal papillae are susceptible to necrotic injury from microthrombi and anoxia in children with a hemoglobinopathy like sickle cell disease or in those exposed to toxins. Episodes of transient microscopic or macroscopic hematuria during systemic infections or after moderate exercise are seen due to altered renal hemodynamic responses and may not signify a primary renal disease. Mechanical erosion of the mucosal surfaces in the urinary tract by the calculi or gravel can result in hematuria.6
 
Causes of Hematuria
Various conditions causing hematuria are given in Table 1.1. Common systemic conditions that can cause hematuria include disseminated intravascular coagulation (DIC) and bleeding diathesis.2
Table 1.1   Causes of hematuria
Systemic disease
Disseminated intravascular coagulation (DIC)
Anticoagulant therapy
Snake bite envenomation
Hemorrhagic disease
Thrombocytopenia
Glomerular disorders
Acute glomerulonephritis (ANS)
Chronic glomerulonephritis (membranoproliferative GN, membranous nephropathy)
IgA nephropathy
Henoch-Schonlein purpura (HSP)
Systemic lupus erythematosus (SLE)
Hemolytic uremic syndrome (HUS)
Renal vasculitis
Alport's syndrome
Benign familial hematuria
Renal vein thrombosis
Acute cortical necrosis
Non-glomerular disorders
Hypercalciuria
Hyperuricosuria
Hyperoxaluria
Urolithiasis
Cystitis (viral hemorrhagic, drug induced)
Genitourinary anomalies with infection
Tumors
Polycystic kidney disease
Trauma
Foreign body
Sickle cell hemoglobinopathy
Urinary tract infection
Conditions mimicking hematuria (pseudohematuria)
Foods containing beetroot
Drugs—furazolidone, pyridium, rifampicin
Pigmenturia—hemoglobinuria, myoglobinuria, bilirubinuria4
Glomerular diseases causing hematuria include post-infective glomerulonephritis (PIGN) which is the commonest followed by chronic glomerulonephritis like IgA glomerulonephritis (IgA GN) and membranoproliferative glomerulonephritis (MPGN) in our hospital. Adenovirus induced acute cystitis, hypercalciuric conditions, urolithiasis and lastly tumors are common causes of non-glomerular hematuria.
 
Features of Hematuria
One should look into various presenting features and clinical examination findings to determine glomerular or non-glomerular as the source of bleeding. Urine examination helps us to differentiate between the two as shown in Table 1.2.2,7 Some of the common presenting features of diseases causing hematuria is given in Table 1.3.2
In glomerular hematuria urine is usually tea colored and blood is seen throughout urinary stream and hence is termed total hematuria.7 Hematuria is usually painless and edema, hypertension and history of preceding or associated infection are commonly seen.
Table 1.2   Glomerular versus non-glomerular hematuria
Urinary finding
Glomerular
Non-glomerular
Color
Red or brown
Usually red
Clots
Absent
May be present
Proteinuria
2+ or more
Less than 2+
RBC morphology
Dysmorphic >15%
Eumorphic
Table 1.3   Presenting features of hematuria
Etiological condition
Associated features
Glomerular
Acute post-infective GN
Membranoproliferative GN
Henoch-Schonlein purpura
IgA nephropathy
Alport's syndrome
Non-glomerular
Acute interstitial nephritis
Urinary tract infection
Hypercalciuria, hyperuricosuria,
hyperoxaluria
Urolithiasis
Hydronephrosis
Wilms’ tumor
Hemorrhagic cystitis
Coagulation disorder
Polycystic kidney
AV malformations
Edema, hypertension, oliguria, mild proteinuria
Edema, proteinuria, hypertension
Purpura, arthralgia, abdominal symptoms
Recurrent hematuria, syn-pharyngitic
Ear, eye abnormalities, family history
Fever, rash, eosinophilia; history of drug intake
Fever, flank pain, dysuria
Colicky pain; family history of stones
Colicky pain, graveluria, family history
Flank pain, abdominal mass
Abdominal mass
Follows drug intake or viral infection with
suprapubic pain or passage of clots
Bleeding from other sites
Abdominal mass, hypertension
Passage of clots, malformations elsewhere5
Family history of renal failure and deafness can be present. History of recurrent or persistent fever, arthralgia, arthritis, recurrent wheeze, recurrent jaundice and abdominal pain may be present pointing towards secondary glomerulonephritis. Presence of RBC casts in urine signifies glomerular hematuria and is associated with persistent or heavy proteinuria of 2+ or more or spot urine protein to creatinine ratio of >0.5. The RBCs are dysmorphic by phase contrast microscopy and acanthocytes are common.8 Blood clots and crystals are absent.
In non-glomerular hematuria urine is bright red. Dysuria and increased frequency are noted. Prolonged irregular fever of UTI can be seen. Features of urolithiasis like abdominal pain, vomiting and passage of gravel may be present. Absence of RBC casts and less than 15% dysmorphic RBCs in urine may signify non-glomerular hematuria.2 Blood clots and crystals may be seen. Though proteinuria is seen it is not heavy and is less than 2+ or spot urine protein to creatinine ratio is <0.5.
Exercise related hematuria is seen in children following exercise which can be microscopic or macroscopic. Glomerular RBC and RBC casts are documented in few of them and otherwise urine analysis is normal at other times. Usually they are kept under surveillance.2
Benign familial hematuria is a condition in which children with hematuria will have first degree relative with hematuria without chronic kidney disease or sensorineural deafness. On the contrary children with Alport's syndrome of familial hematuria will have first degree relative with hematuria, chronic kidney disease and sensorineural deafness. Benign familial hematuria usually runs a non-progressive course and end stage renal disease is very rarely reported.2 Electron microscopy of kidney biopsy shows thin glomerular basement membrane.
 
Approach to Hematuria
A good history, physical examination and urine analysis helps to determine the type of hematuria (glomerular or non-glomerular) and the urgency of evaluation of the cause for hematuria. Special stress should be given to family history of renal disease/deafness, identification of anatomic abnormalities and presence of macroscopic hematuria.
Family history is important in the evaluation of hematuria in children. Alport's syndrome should be doubted in a child when there is a first degree relative of the child with hematuria, sensorineural deafness and renal failure. Other diseases that carry a genetic origin include lupus nephritis, hemophilia and sickle cell disease. Nephrolithiasis and IgA GN also can have a familial association. The thin glomerular basement membrane disease is a common cause of benign familial hematuria in children. Family members may not be aware that they have microscopic hematuria and should always be screened with a microscopic urinalysis.
Systemic diseases with thrombocytopenia or disseminated intravascular coagulation can present as hematuria. The use of furosemide for congenital 6heart disease can lead to hypercalciuria and subsequently, hematuria. Antibiotics and over-the-counter medications may cause interstitial nephritis and hematuria. Chemotherapy (cyclophosphamide) and radiation for malignancies can explain isolated hematuria in children.
In the neonatal period, hematuria due to thrombosis of the renal vein or artery can occur especially after umbilical catheterization. Predisposing factors for renal vein thrombosis include perinatal asphyxia, dehydration, septicemia, shock, and coagulopathies secondary to protein C deficiency. Clinically they present as gross hematuria with unilateral or bilateral renal mass. Renal ultrasonogram and Doppler studies of renal vessels help in the diagnosis.
Periorbital edema is frequently the first site of edema in children with glomerular disease. Raised jugular venous pressure (JVP), presence of gallop and basal lung fields with crackles indicating fluid overload denotes glomerulonephritis. Nephrotic edema may not have features of fluid overload as mentioned above. Ascites usually suggests nephrotic syndrome. Costovertebral angle tenderness may indicate upper urinary tract infection (UTI). Recent trauma can be detected by findings of flank bruises and pain. Examining the abdomen for masses is critical for the identification of tumors, polycystic kidneys or hydronephrosis. The examination of the skin can give evidence of pallor or rash. Pallor indicating anemia may signify either acute loss of blood as in hemolytic uremic syndrome (HUS) or a chronic kidney disease. Butterfly rash over the face or photosensitive rash points towards systemic lupus erythematosus whereas palpable purpuric rash over buttocks and extensor surface of the limbs suggest Henoch-Schonlein purpura. A fundoscopic examination of the retina, looking for evidence of long-standing hypertension or lenticonus as seen in Alport's syndrome, should be performed.
The presence of proteinuria and hematuria on urinalysis suggests glomerulonephritis. Proteinuria should not exceed 2+ if the only source of protein is from the blood.7 The presence of heavy proteinuria, hypoalbuminemia and hypercholesterolemia suggest nephrotic syndrome. Pertinent to glomerulonephritis, laboratory investigations include a complete blood count, throat culture, antistreptolysin O (ASO) titer, serum estimation of C3, C4 levels, albumin, creatinine and electrolytes. The complement C3 level is low in acute post-streptococcal glomerulonephritis, subset of membranoproliferative glomerulonephritis (MPGN), lupus nephritis and C3 nephropathy. Serum C4 can also be reduced in lupus nephritis. Microscopic hematuria which is persistent almost always warrants a referral to a pediatric nephrologist. Indications for renal biopsy in them include persistent microscopic hematuria for more than 1 year and recurrent gross hematuria with decreased renal function, proteinuria or hypertension.9
In crystalluria or renal stone disease, the initial work up consists of ultrasonogram and screening the urine for calcium excretion by Ca/Cr ratio or estimation of 24-hour urine calcium, uric acid, oxalate and citrate excretion, estimation of serum creatinine, electrolytes, uric acid, calcium and 7albumin levels. There have been reports of recurrent abdominal and flank pain in children with idiopathic hypercalciuria. In addition, non-calculous idiopathic hypercalciuria is an important contributing factor to recurrent UTI in children. If the kidney-ureter-bladder is negative for stones by abdominal ultrasonogram, abdominal and pelvic spiral computed tomography scan should be obtained in children with a clinical picture of renal stone disease for confirmation. A nephrology/ urology consultation is appropriate if a stone is detected. Rare causes include tumors and some anatomic or vascular problems.5 Arteriovenous malformation of the kidney can present with gross hematuria. Renal ultrasonogram and CT scan of the abdomen may locate the tumor or malformation. Renal angiography offers a definitive diagnosis as per need. Most of the conditions requiring advanced work-up should be referred to a pediatric nephrologist or urologist.
A simple practical approach towards laboratory evaluation is given in Figure 1.1. Algorithimic approach to microscopic and macroscopic hematuria is given in Figure 1.2 and 1.3 respectively.10 Stepwise approach to a child with hematuria is presented in Figure 1.4.2
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Fig. 1.1: Laboratory evaluation of hematuria
8
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Fig. 1.2: Algorithm for evaluation of microscopic hematuria
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Fig. 1.3: Algorithm for evaluation of macroscopic hematuria
9
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Fig. 1.4: Step-by-step approach to hematuria
 
Conclusion
A good detailed history and adequate clinical examination will direct us towards the cause of hematuria. Treatment should be according to the cause of hematuria. If no diagnosis is made initially with the available clinical picture and evaluation, it is always better to keep the child under surveillance as at a later date the presentation may direct us towards the correct diagnosis. Please note that the two important non-post infective causes of hematuria are IgA 10GN and hypercalciuric syndromes. Early detection and appropriate timely interventions delay the progression to end stage renal disease in them.
References
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  1. Amish Udani, Sangeetha P, Vijayakumar M. Approach to hematuria. In: Nammalwar BR, Vijayakumar M (eds), Principles and Practice of Pediatric Nephrology 2nd edn. Jaypee Brothers Medical Publishers (P) Ltd, New Delhi. 2013; pp 200-10.
  1. Diven SC, Travis LB. A practical primary care approach to hematuria in children. Pediatr Nephrol. 2000; 14:65–72.
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  1. Meyers KE. Evaluation of hematuria in children. Urol Clin N Am. 2004; 31:559–73.
  1. Butani L, Srivastava RN. Asymptomatic hematuria and proteinuria. In: Srivastava RN, Bagga A (Eds). Pediatric Nephrology, 5th edn. Jaypee Brothers Medical Publishers (P) Ltd, New Delhi. 2011; pp 187-94.
  1. Fogazzi GB, Verdesca S and Garigali G. Urinalysis - Core curriculum in Nephrology. Am J Kidney Dis. 2008; 51:1052–67.
  1. Quigley R. Evaluation of hematuria and proteinuria: how should a pediatrician proceed? Curr Opin Pediatr. 2008; 20:140–4.
  1. Moxey-Mims M. Hematuria and proteinuria. In: Kher K, Schnaper HW, Makker SP (Eds). Clinical Pediatric Nephrology, 2nd edn. Informa Health Care, UK, 2007; pp 129-41.