Overview
Definition:
Proteinuria is the presence of abnormal quantities of protein in the urine
In pediatrics, it's typically defined as a 24-hour urinary protein excretion > 4 mg/m²/hour, or a protein-to-creatinine ratio (PCR) on a spot urine sample > 0.2 mg/mg (or > 200 mg/g)
This can be transient, orthostatic (postural), or persistent, indicating underlying renal pathology.
Epidemiology:
Transient proteinuria is common, occurring in up to 10% of healthy children
Orthostatic proteinuria is the most common cause of persistent proteinuria in asymptomatic children and adolescents, affecting 1-5% of this population
Persistent, pathological proteinuria is less common and requires thorough investigation.
Clinical Significance:
Proteinuria in children can be an indicator of significant renal disease, including glomerular diseases (e.g., nephrotic syndrome, glomerulonephritis) and tubular disorders
Prompt and accurate diagnosis is crucial for initiating timely treatment, preventing progression to chronic kidney disease, and improving long-term outcomes
Distinguishing benign causes like orthostatic proteinuria from pathological proteinuria is paramount.
Clinical Presentation
Symptoms:
Many children with orthostatic or mild persistent proteinuria are asymptomatic
Symptoms, if present, may indicate underlying renal disease and can include edema (periorbital, pedal), hypertension, foamy urine, reduced urine output, flank pain, fever, rash, or joint pain
Growth failure may be a subtle sign in chronic conditions.
Signs:
Physical examination may reveal signs of fluid overload such as peripheral edema, ascites, pleural effusions, or hypertension
Pallor may suggest anemia secondary to chronic disease
In some cases of glomerulonephritis, a palpable kidney might be noted
However, in orthostatic proteinuria, physical examination is typically normal.
Diagnostic Criteria:
No formal diagnostic criteria for proteinuria itself, but thresholds define abnormality
Persistent proteinuria is often defined as proteinuria detected on at least two occasions separated by at least two weeks
Orthostatic proteinuria is characterized by significant proteinuria in the upright position and normal or near-normal protein excretion when supine.
Diagnostic Approach
History Taking:
Key history points include duration and any recent illness (e.g., fever, sore throat preceding glomerulonephritis), family history of renal disease, medication use, presence of edema, hypertension, or urinary symptoms
Ask about changes in posture and timing of urine voiding relative to protein detection
Red flags include significant edema, hypertension, hematuria, systemic symptoms, or a history of recurrent infections.
Physical Examination:
Perform a thorough physical examination, including blood pressure measurement (crucial for detecting hypertension), assessment for edema, hydration status, skin examination for rashes, and examination of other organ systems for signs of systemic illness
Assess growth parameters (height and weight).
Investigations:
Initial investigation involves a urinalysis to confirm proteinuria and assess for other abnormalities like hematuria, leukocytes, or casts
A quantitative assessment of proteinuria is then needed: 1
Spot Urine Protein-to-Creatinine Ratio (PCR): Preferred in pediatrics
normal <0.2 mg/mg
2
Twenty-four-hour Urine Protein Excretion: Gold standard
normal <4 mg/m²/hour
If proteinuria is confirmed, further workup includes: Serum creatinine and electrolytes to assess renal function
Complete Blood Count (CBC)
Urine microscopy to identify casts (e.g., red blood cell casts in glomerulonephritis, white blood cell casts in pyelonephritis)
Tests for specific etiologies if indicated: ANA, anti-dsDNA (lupus), C3/C4 complement levels, anti-GBM antibodies, ASO titer (post-streptococcal), hepatitis B/C serology, HIV testing
Renal ultrasound to assess kidney size, morphology, and rule out structural abnormalities.
Differential Diagnosis:
The differential diagnosis for proteinuria in children includes: 1
Benign causes: Transient proteinuria (fever, exercise, emotional stress), orthostatic proteinuria
2
Glomerular diseases: Nephrotic syndrome (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, MPGN), acute post-infectious glomerulonephritis, IgA nephropathy, lupus nephritis, vasculitis
3
Tubular disorders: Fanconi syndrome
4
Other: Urinary tract infection (less common cause of significant proteinuria without hematuria), certain medications, and systemic diseases.
Orthostatic Vs Persistent Workup
Orthostatic Workup:
If proteinuria is detected, especially in an otherwise healthy child, orthostatic proteinuria is a primary consideration
The key diagnostic step is to collect urine samples in both the upright (standing for >30 minutes) and supine (lying down for >30 minutes) positions
A diagnosis of orthostatic proteinuria is made if significant proteinuria is present in the upright sample and absent or markedly reduced in the supine sample
A 24-hour urine protein or spot PCR should confirm this distinction
Normal renal function, absence of edema, and no other urinary abnormalities on urinalysis support this diagnosis.
Persistent Workup:
Persistent proteinuria, defined as proteinuria present on multiple occasions regardless of posture, or significant proteinuria in the supine position, requires further investigation to identify the underlying renal pathology
This involves a detailed evaluation as outlined in the "Diagnostic Approach" section, including serological tests, complement levels, and potentially a renal biopsy if a specific glomerular disease is suspected and treatment decisions depend on it.
Interpretation Of Pcr And 24hr Protein:
A spot PCR > 0.2 mg/mg or 24-hour protein excretion > 4 mg/m²/hour is abnormal
A PCR between 0.2-1.0 mg/mg might be considered borderline and may warrant repeat testing
PCR > 2.0 mg/mg often indicates nephrotic range proteinuria
Persistent significant proteinuria necessitates evaluation for underlying renal disease, while transient or mild orthostatic proteinuria usually carries a benign prognosis.
Management
Orthostatic Management:
Orthostatic proteinuria is generally a benign condition with no specific treatment required
Reassurance of the patient and family is important
It typically resolves spontaneously in late adolescence or early adulthood
Regular monitoring of blood pressure and renal function is usually not necessary unless other risk factors are present.
Persistent Management:
Management of persistent proteinuria depends entirely on the underlying etiology
If due to a specific glomerular disease (e.g., nephrotic syndrome, glomerulonephritis), treatment targets the underlying condition
This may involve immunosuppressive therapy (corticosteroids, cyclophosphamide, etc.), ACE inhibitors or ARBs to reduce proteinuria and blood pressure, and supportive care to manage complications like edema and hypertension
For persistent non-nephrotic proteinuria without evidence of significant glomerular disease, ACE inhibitors or ARBs may be used to reduce proteinuria and protect renal function.
Supportive Care:
Supportive care in persistent proteinuria may include dietary modifications (low salt intake), fluid management for edema, and antihypertensive medications
Close monitoring of blood pressure, renal function, and urinary protein excretion is essential.
Prognosis
Factors Affecting Prognosis:
The prognosis for proteinuria in children is highly dependent on the underlying cause
Orthostatic proteinuria generally has an excellent prognosis with spontaneous resolution
Persistent proteinuria due to glomerular diseases varies widely
early diagnosis and appropriate treatment can significantly improve outcomes and reduce the risk of progression to chronic kidney disease
Factors influencing prognosis include the specific diagnosis, severity of proteinuria, presence of hypertension, and degree of renal dysfunction at diagnosis.
Outcomes:
Children with orthostatic proteinuria typically experience normal renal function and lifespan
For those with persistent proteinuria from glomerular diseases, outcomes range from complete remission to progressive loss of renal function, depending on the specific condition and treatment response
Some may develop end-stage renal disease requiring dialysis or transplantation.
Follow Up:
Children with diagnosed orthostatic proteinuria require minimal to no follow-up, unless new symptoms or concerns arise
Children with persistent proteinuria require regular and long-term follow-up by a pediatric nephrologist
This includes serial assessment of blood pressure, renal function (serum creatinine, eGFR), urinary protein excretion, and monitoring for disease-specific complications.
Key Points
Exam Focus:
Distinguishing orthostatic proteinuria from pathological persistent proteinuria is a high-yield concept for exams
Understand the diagnostic criteria and the role of spot PCR and 24-hour urine protein
Be familiar with the common causes of persistent proteinuria in pediatrics.
Clinical Pearls:
Always measure blood pressure in any child found to have proteinuria
A normal physical exam and normal renal function in a child with proteinuria should prompt consideration of orthostatic proteinuria
Renal biopsy is indicated for nephrotic syndrome or persistent significant proteinuria with suspected glomerular disease.
Common Mistakes:
Over-reliance on a single positive dipstick test without quantitative confirmation
Failure to distinguish between transient, orthostatic, and persistent proteinuria
Inadequate workup for persistent proteinuria, leading to delayed diagnosis of serious renal disease
Not considering systemic diseases that can cause proteinuria.