It is common to detect proteinuria during routine urinalysis in children. Although transient proteinuria and orthostatic proteinuria are common and benign conditions, it is important to differentiate them from clinically significant proteinuria associated with renal pathology or systemic diseases. Such differentiation can be made by considering the clinical presentation and appropriate use of laboratory tests.
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Definition

Proteinuria is defined as urinary protein excretion exceeding 100 mg/m2/day or > 4 mg/m2/hr.

Fixed proteinuria is defined as ≥ 1+ proteinuria on a urinary dipstick examination or a urine protein:creatinine ratio (UPr/UCr) of > 0.2 in the first morning urine sample on three consecutive days. Persistent proteinuria is defined as ≥ 1+ proteinuria on urinary dipstick examination (equivalent to ≥ 30 mg/dL) on at least three urine specimens separated by several weeks.

Isolated proteinuria is defined as asymptomatic proteinuria in otherwise healthy children with normal physical examination, normal blood pressure, and normal laboratory evaluation except for presence of proteinuria.

Epidemiology of Childhood Nephrotic Syndrome

Although 10 % of children may have proteinuria in a single void specimen of urine, only 0.1 of children have persistent proteinuria or pathologic proteinuria. Prevalence of proteinuria peaks during adolescence. 60 % of school-aged children and adolescents with persistent proteinuria have orthostatic proteinuria. The condition occurs in 3–5 % of adolescents.

Diabetic nephropathy is the most common cause of proteinuria representing up to 50 cases per million of the population.

The condition is more common among Americans of Asian or African origin due to the higher rates of diabetes among these groups.

Etiology of Childhood Nephrotic Syndrome

Benign proteinuria (High Yield)

  • Transient proteinuria: fever, exercise, dehydration, stress, seizure, exposure to cold, heart failure
  • Orthostatic (postural) proteinuria

Glomerular proteinuria

  • Minimal change (idiopathic) nephrotic syndrome
  • Focal segmental glomerulosclerosis (FSGS)
  • Mesangial proliferative glomerulonephritis
  • Membranous nephropathy
  • Membranoproliferative glomerulonephritis
  • IgA nephropathy
  • Acute post-infectious glomerulonephritis
  • Henoch-Schönlein purpura (HSP)
  • Hemolytic-uremic syndrome (HUS)
  • Lupus nephritis
  • Diabetic nephropathy
  • Sickle cell nephropathy
  • Amyloidosis
  • Alport syndrome

Tubular proteinuria

  • Acute tubular necrosis (ATN) is the most common cause. Hypovolemia or hypovolemic may lead to the development of acute tubular necrosis. ATN can also be caused by some drugs such as NSAIDs, aminoglycosides, amphotericin, lithium, etc.
  • Tubulointerstitial nephritis
  • Fanconi syndrome (Cystinosis, galactosemia, Wilson disease, Lowe syndrome)
  • X-linked recessive nephrolithiasis (Dent disease)
  • Renal dysplasia, polycystic kidney disease
  • Reflux nephropathy
  • Pyelonephritis
  • Mitochondrial disorders
  • Heavy metal poisoning

Overflow proteinuria

  • Myoglobinuria in rhabdomyolysis
  • Immunoglobulins in multiple myeloma (common in adults)

Pathophysiology of Childhood Nephrotic Syndrome

In children, urinary protein excretion up to 100 mg/m2/day or 150 mg/day is considered normal, while in neonates it can be as high as up to 300 mg/m2/day. Normally, excreted urinary proteins include Tamm-Horsfall protein (uromodulin, ca 50 %), albumin (ca 40 %), and low-molecular weight (LMW) proteins (ca 10 %)including β2-microglobulin and amino acids.

Normally, passage of proteins across the glomerular basement membrane is controlled by :

  1. Size of the molecules where proteins with molecular weight <25,000 Da cannot cross the glomerular basement membrane (GBM).
  2. Charge of the molecules as the GBM is negatively charged due to presence of heparan sulfate proteoglycans thus, it repels anions like albumin.

Majority of LMW proteins that are filtered at glomerulus are reabsorbed by proximal tubule. Proteinuria occurs when any of these mechanisms are disrupted.

Glomerular proteinuria occurs due to increased permeability of glomeruli, while tubular proteinuria occurs due to decreased reabsorption of LMW proteins by renal tubules. Glomerular proteinuria is usually dominant in albumin and can be of high degree, while tubular proteinuria is usually dominant in LMW proteins and is usually low grade (UPr/UCr < 1.0).

Overflow proteinuria occurs where proteins cannot be effectively reabsorbed by the proximal tubule due to an overproduction of proteins. Children with transient proteinuria do not have underlying renal parenchymal disease. One possible explanation for transient proteinuria are the hemodynamic changes in the glomerular blood flow causing an increased protein diffusion into the urine.

Possible mechanisms that explain orthostatic proteinuria include renal hemodynamic changes associated with postural change, partial renal vein occlusion, increased glomerular capillary wall permeability, or role of circulating immune complexes.

In renal diseases with persistent proteinuria, it is believed that proteinuria itself can cause injury to renal tubular cells, possibly by the generation of reactive oxygen species.

Some of the metabolic effects of hypoproteinemia include:

  • Edema results from two main pathogenic pathways which include a reduction in the amount of albumin that lowers the oncotic pressure and thus excessive fluid in third spaces. Moreover, the sodium retention due to kidney hypofunction leads to water retention causing edema.
  • Hypoproteinemia leads to the activation of the liver for lipoprotein synthesis leading to hyperlipidemia and overflow in urine to cause lipiduria.
  • A hypercoagulable state results from loss f smaller anticoagulant factors and retention of larger pro-coagulant factors such as fibrinogen.

Symptoms of Childhood Nephrotic Syndrome

Proteinuria is mostly asymptomatic and may be detected during routine screening urinalysis or during diagnostic evaluation.

In transient proteinuria proteinuria is present during a fever (temperature > 101 °F), dehydration, stress or heart failure, or following exercise, seizure or exposure to cold. Dipstick test shows 2+ or lower proteinuria, which resolves after resolution of the condition. Sometimes, exercise-induced proteinuria may last for as long as 48 hours following exercise.

In orthostatic proteinuria increased protein excretion (up to 1000 mg/day) is seen in an upright position, while normal protein excretion is seen in a supine position. The child does not have hypertension, edema, hematuria, hypoalbuminemia, or renal dysfunction.

Children with isolated proteinuria are otherwise healthy, asymptomatic children with normal physical examination, normal blood pressure, and normal other laboratory findings. Proteinuria is usually < 2 g/day.

When proteinuria is due to a specific disease, symptoms of the disease are the presenting symptoms of the child.

Nephrotic syndrome is characterized by nephrotic range proteinuria, hypoalbuminemia, hyperlipidemia and edema. The child may present with periorbital or pedal edema, ascites, anasarca, or abdominal pain. Hematuria or hypertension may be present in some patients.

Patients with systemic renal diseases usually have hematuria or hypertension in addition to proteinuria. Patients with post-infectious glomerulonephritis usually have a history of pharyngitis or impetigo 2–4 weeks prior and present with acute nephritic syndrome, hematuria, proteinuria, hypertension, and acute renal failure.

IgA nephropathy is characterized by episodes of macroscopic hematuria, proteinuria, abdominal or flank pain, and fever within 72 hours of a respiratory infection.

HSP is characterized by purpuric lesions, especially over buttocks and lower extremities, abdominal pain, edema, and arthralgia. HUS may present with history of bloody diarrhea, vomiting, abdominal pain, anemia, and renal failure.

Children with interstitial nephritis may have a history of recent exposure to antibiotics or other medications and may have allergic symptoms such as a skin rash.

Diagnosis of Childhood Nephrotic Syndrome

Collection of 24-hour urine is gold standard for urinary protein quantization but is often impractical or not possible in children. 24-hour urine protein > 100-150 mg/m2/day usually suggests proteinuria, but preterm infants and neonates may normally have an even higher protein excretion. Urinary protein excretion > 1000–2000 mg/day is usually pathologic in children, except in cases of orthostatic proteinuria.

  • Urinary protein excretion ≤ 4 mg/m2/h is considered normal
  • 4–40 mg/m2/h is considered as proteinuria
  • > 40 mg/m2/h is nephrotic-range proteinuria

Urine protein:creatinine ratio (UPr/UCr) is widely used to diagnose proteinuria. UPr/UCr > 0.5 (in children aged < 2 years) or > 0.2 (in children aged > 2 years) suggests proteinuria. However, in children < 6 months the ratio may be up to 0.8 is often considered normal. The ratio > 2.0 suggests nephrotic range proteinuria. (High Yield)

For measurement of UPr/UCr, freshly voided first morning urine (FMU) specimen is usually preferred, but a random sample is also acceptable. As the ratio is dependent on urinary creatinine, the ratio may be elevated in conditions with low creatinine excretion such as severe malnutrition or children with low muscle mass. In conditions with low glomerular filtration rate (GFR) an interpretation of the ratio is difficult.

The urinary dipstick test is the most common test used initially. The reagent strip is analyzed within 60 seconds after immersing it in freshly voided urine. Tetrabromophore is a chromatophore that is impregnated on the strip and changes color depending upon the amount of proteins in the urine. The dipstick method is most sensitive to albumin and less sensitive to other proteins.

It is a semiquantitative method, which can be interpreted according to the following table. 

Dipstick result   Amount of protein in urine
Negative < 10 mg/dL
Trace 10–29 mg/dL
1+ 30–100 mg/dL
2+ 100–300 mg/dL
3+ 300–1000 mg/dL
4+ > 1000 mg/dL

Causes for false-positive results in dipstick testing:

  • Alkaline urine (pH > 7.0)
  • Highly concentrated urine
  • Prolonged immersion of dipstick in urine
  • Pyuria
  • Macroscopic hematuria
  • Presence of antiseptic agents (hydrogen peroxide, chlorhexidine, benzalkonium chloride) in specimen
  • Phenazopyridine therapy

Causes for false-negative results are very dilute urine (specific gravity < 1.005) or when the predominant protein in urine is not albumin.

If urine specific gravity is < 1.010 ≥ trace proteinuria on dipstick should be considered clinically significant, while if the specific gravity is > 1.015 dipstick reading suggestive of ≥ 1+ proteinuria should be considered clinically significant.

Sulfosalicylic acid (SSA) turbidometric testing is a less commonly used qualitative test for proteinuria, but it can detect albumin, immunoglobulins, and Bence-Jones proteins in urine. As acidification of urine causes precipitation of urinary proteins, the turbidity results when SSA reagent (three parts) is added to freshly voided urine sample (one part). The degree of turbidity can be compared with a predetermined scale.

Urine protein electrophoresis is helpful to identify presence of proteins other than albumin in urine, such as β2-microglobulin, retinol binding protein, α-globulins, monoclonal proteins, etc. Urine immunofixation electrophoresis is helpful when there is overproduction of immunoglobulins as in certain malignancies.

Detection and quantification of microalbuminuria in children with diabetes mellitus is important as it is a predictor of diabetic nephropathy and cardiovascular morbidity. Urine microalbumin:creatinine ratio (MA:Cr) < 20–30 mg/g is considered normal. Urine albumin excretion 20–200 μg/min/1.73 m2 or MA:Cr 30–300 mg/g suggests microalbuminuria, while > 200 μg/min/1.73 m2 suggests frank proteinuria.

A microscopic examination of urine is helpful to diagnose other underlying medical conditions.

  • Presence of dysmorphic red blood cells (RBC) suggests glomerular disease
  • Presence of RBC casts suggests glomerulonephritis or vasculitis
  • Presence of white blood cells (WBC) and WBC casts in urine suggests infective etiology, exudative glomerulonephritis or interstitial nephritis
  • Fatty casts or oval fat bodies may present in nephrotic syndrome or lupus nephritis
  • Granular casts suggest chronic renal disease
  • Presence of eosinophils in urine is highly suggestive of interstitial nephritis. (High Yield)
  • Presence of glycosuria, phosphaturia, amino aciduria and bicarbonate wasting suggests Fanconi syndrome

The initial evaluation of an asymptomatic child with persistent proteinuria should include an FMU sample for complete urinalysis and UPr/UCr. Dipstick negative or trace proteinuria and UPr/UCr < 0.2 in the FMU sample for three consecutive days confirms the diagnosis of orthostatic proteinuria. For the collection of FMU, the child must empty the bladder before going to bed and the urine must be collected immediately upon rising in the morning.

Note: Children with transient or confirmed orthostatic proteinuria require no further diagnostic evaluation.

For children with persistent proteinuria, further laboratory evaluation is required to diagnose other underlying conditions. Such evaluations include

  • Complete blood counts (CBC)
  • Serum electrolytes
  • Renal function tests
  • Serum albumin
  • Serum complement levels (C3, C4)
  • Streptococcal markers (anti-streptolysin O and anti-DNAase B titers)
  • Serum antinuclear antibody (ANA) level
  • Serum cholesterol
  • Chest X-ray (to look for signs of volume overload)
  • Renal ultrasound (to diagnose renal structural abnormalities)

Indications for a referral to the pediatric nephrologist include

  • Persistent non-orthostatic proteinuria
  • Abnormal urine findings
  • Presence of hypertension or edema
  • Presence of systemic manifestations
  • Abnormal renal function or serum electrolytes
  • Abnormal imaging studies
  • Family history of renal disease

Possible indications for percutaneous renal biopsy include persistent microscopic or macroscopic hematuria, hypertension, increased serum creatinine, hypocomplementemia, or family history of chronic renal disease or end-stage renal disease. Renal biopsy is also considered if ANCA (anti-neutrophil cytoplasmic antibody) vasculitis is suspected or is indicated for management of nephrotic syndrome.

Differential Diagnoses of Childhood Nephrotic Syndrome

  • Proteinuria: transient proteinuria, orthostatic proteinuria, persistent proteinuria, isolated proteinuria
  • Nephrotic-range proteinuria: minimal change nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy (rare)
  • Proteinuria + hematuria: post-infectious glomerulonephritis, IgA nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, Alport syndrome
  • Proteinuria + systemic findings: HSP, HUS, lupus nephritis, Wegener’s granulomatosis or other ANCA vasculitis, Goodpasture’s disease

Therapy of Childhood Nephrotic Syndrome

Transient proteinuria and orthostatic proteinuria do not require any specific treatment. For children with orthostatic proteinuria, long-term periodic monitoring (every 6–12 months) of first morning urine and of blood pressure is required.

For children with isolated proteinuria, initial thorough diagnostic evaluation, periodic monitoring of FMU and blood pressure, and referral to a pediatric nephrologist are recommended. Proteinuria lowering medications may be considered.

Treatment of persistent proteinuria consists of management of the underlying disease and the use of proteinuria lowering medications.

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are proteinuria lowering agents. ACE inhibitors are helpful as primary or adjunctive treatment in patients with high grade or nephrotic-range proteinuria. They are often started in children with diabetes mellitus at the onset of microalbuminuria.

They have an additional advantage of lowering blood pressure in hypertensive patients. ARBs have similar effects, but they are more commonly used in older adolescents due to the lack of sufficient evidence in the pediatric population. A combination of ACE inhibitor and ARB may have additional advantages.

Progression and Prognosis of Childhood Nephrotic Syndrome

Transient proteinuria is a benign condition that resolves with the resolution of the associated factor/condition. Orthostatic proteinuria is also a benign condition with no long-term effects. However, the progression to glomerulosclerosis is seen in rare cases.

The long term prognosis of children with isolated proteinuria is good, however, ca 20 % of them have a risk of progressive renal disease within the next 10 years.

Exam Questions

1.    Which of the following is the most common cause of persistent proteinuria in school-aged children?

  1. Transient proteinuria
  2. Orthostatic proteinuria
  3. Minimal change nephrotic syndrome
  4. IgA nephropathy
  5. Acute post-infectious glomerulonephritis

2.     Which of the following conditions can give false-positive result for proteinuria on dipstick examination of urine?

  1. Urine specific gravity 1.003
  2. Urine pH 6.8
  3. Proteinuria with predominantly β2-microglobulin
  4. Gross hematuria

3.    In a child with fixed proteinuria, if microscopic examination of urine shows presence of eosinophils, which of the following is most possible diagnosis?

  1. Minimal change nephrotic syndrome
  2. Alport syndrome
  3. Interstitial nephritis
  4. Fanconi syndrome
  5. Galactosemia

Answers: 1. B; 2. D; 3. C

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