TOPIC 33: Proteinuria – Understand the differential diagnosis, evaluation, and management of proteinuria

MOCA-PBR – 2025 Edition TOPIC 33: Proteinuria – Understand the differential diagnosis, evaluation, and management of proteinuria

OFFICIAL ABP TOPIC:

Understand the differential diagnosis, evaluation, and management of proteinuria

BACKGROUND

While proteinuria is often benign and transient in children, persistent proteinuria may indicate underlying kidney disease. It is important for pediatricians to recognize when proteinuria requires further evaluation and treatment.

DIFFERENTIAL DIAGNOSIS OF PROTEINURIA

TYPE OF PROTEINURIA 

MECHANISM 

COMMON CAUSES 

Glomerular Proteinuria 

– Increased filtration of macromolecules (e.g., albumin) across the glomerular capillary wall due to anatomic or functional lesions. 

– Minimal change disease

– Focal segmental glomerulosclerosis

– Orthostatic proteinuria. 

Tubular Proteinuria 

– Impaired reabsorption of low molecular weight proteins in the proximal tubule. 

– Fanconi syndrome

– Acute tubular necrosis

– Drug toxicity (e.g., NSAIDs, aminoglycosides). 

Overflow Proteinuria 

– Overproduction of low molecular weight proteins exceeding tubular reabsorptive capacity. 

– Rare in children

– Often associated with plasma cell dyscrasias (e.g., multiple myeloma in adults). 

Childhood proteinuria presents in three main patterns:

  1. Transient/intermittent: Most common; can be induced by fever, exercise, stress, seizures, hypovolemia. Requires no further evaluation.
  2. Orthostatic: Increased protein excretion only in the upright position; normalizes when recumbent. Common in adolescent males. Benign condition.
  3. Persistent: Should be evaluated for underlying kidney disease.

THE DIFFERENTIAL DIAGNOSIS OF RENAL CAUSES OF PROTEINURIA

 

DIAGNOSIS 

KEY FEATURES 

DIAGNOSTIC TESTS 

Minimal Change Disease (MCD) 

– Most common cause of nephrotic syndrome

– Normal complement levels

– Responds to steroids

– No hematuria

– Biopsy rarely needed

Focal Segmental Glomerulosclerosis (FSGS) 

– Nephrotic-range proteinuria

– Hypoalbuminemia

– Often steroid-resistant

– May have microscopic hematuria

– Kidney biopsy shows segmental sclerosis of glomeruli

IgA Nephropathy 

– Episodic gross hematuria, often after URI

– Mild proteinuria

– Normal complement levels

– Biopsy shows mesangial IgA deposits

Post-Streptococcal GN 

– Recent strep infection

– Low C3, normal C4

– Hematuria with RBC casts

– Mild proteinuria

– Positive ASO/anti-DNase B

– Low C3 (normalizes in 8-12 weeks)

Lupus Nephritis 

– Proteinuria with active urine sediment

– Systemic signs of SLE (malar rash, arthritis, cytopenias)

– Positive ANA

– Low C3/C4

– Biopsy with positive immunofluorescence

Fanconi Syndrome 

– Tubular proteinuria with glycosuria

– Aminoaciduria

– Metabolic acidosis with low bicarbonate

– Low bicarbonate

– Urine amino acid levels elevated

Other causes of proteinuria include diabetes, IgA vasculitis, viral infections, malignancy, and toxins such as mercury.

EVALUATION OF PROTEINURIA

HISTORY AND PHYSICAL EXAM

  • Transient proteinuria: Suggested by febrile illness, intense exercise, seizure.
  • Persistent proteinuria: Findings suggestive of kidney disease include urine volume/color changes, edema, hypertension, recent strep infection, family history of kidney disease, hearing loss.

Quantitative Measurement of Proteinuria

  • Protein-to-creatinine ratio on first morning spot sample: Usually preferred over 24-hour urine collection. Normal: <0.2 (age >2 years), <0.5 (age 6-24 months).
  • 24-hour urine collection: Often difficult in young children. Abnormal if >100 mg/m²/day.

Evaluation Algorithm for ASYMPTOMATIC Proteinuria

  • Obtain first AM urine protein-to-creatinine ratio and urinalysis.
  • If protein-to-creatinine ratio <0.2 (age >2 years) or <0.5 (age 6-24 months) and urinalysis normal → transient proteinuria, repeat in 1 year.
  • If first AM protein-to-creatinine ratio normal but dipstick-positive proteinuria on second upright specimen → orthostatic proteinuria, repeat in 1 year.
  • If protein-to-creatinine ratio ≥0.2 (age >2 years) or ≥0.5 (age 6-24 months):
    • Repeat protein-to-creatinine ratio and urinalysis in 1-2 weeks.
    • If still elevated, check BMP, cholesterol, albumin, total protein.
    • Consider additional testing based on clinical suspicion: C3, C4, ASO/anti-DNase B, ANA, HIV, Hepatitis B, Hepatitis C.
    • Perform renal/bladder ultrasound if history of UTI, hypertension, or abnormal creatinine.
    • If abnormalities persist after 4 weeks, refer to pediatric nephrology.

Evaluation of SYMPTOMATIC Proteinuria

  • Nephrotic syndrome is characterized by all three of the following: nephrotic-range proteinuria (P/Cr ratio >3), edema, and albumin <3. Laboratory evaluation should include CBC, BMP, complement levels, lipids, and U/A. Children with nephrotic syndrome typically have hyperlipidemia as well.
  • A vasculitis evaluation should be done in children with palpable purpura or nonblanching rashes. Initial labwork should include CBC, U/A, LFTs, Cr, BUN, and ESR/CRP.
  • Pediatric nephrology referral and consideration of kidney biopsy is warranted for persistent proteinuria + hypertension, active urine sediment, or elevated creatinine.

MANAGEMENT OF PROTEINURIA

Management depends on the underlying etiology.

General Supportive Care

  • Monitor blood pressure, kidney function, proteinuria.
  • Treat edema with salt restriction and diuretics.
  • Maintain nutrition with adequate protein intake.
  • Prevent and promptly treat infections.

Transient and Orthostatic Proteinuria

  • Provide reassurance; repeat screening in 1 year to ensure no progression.

Persistent Proteinuria

Children with underlying kidney disease should usually be referred to nephrology for further management. Idiopathic nephrotic syndrome may be managed by the primary care pediatrician in consultation with a nephrologist.

DIAGNOSIS-SPECIFIC MANAGEMENT 

DIAGNOSIS 

FIRST-LINE THERAPY 

SECOND-LINE OR ADDITIONAL THERAPIES 

Minimal Change Disease 

Oral prednisone 60 mg/m²/day (max 60 mg) until urine protein negative for 3 consecutive days. 

Steroid-sparing agents: Levamisole, mycophenolate, calcineurin inhibitors (cyclosporine, tacrolimus). 

Post-Streptococcal GN 

Supportive care: Manage fluid/electrolyte balance; monitor complement levels (C3 normalizes in 8-12 weeks). 

Avoid immunosuppression unless severe crescentic disease. 

Lupus Nephritis 

Oral prednisone 60 mg/m²/day for proteinuria >500 mg/day or nephrotic-range proteinuria. 

Mycophenolate mofetil (MMF), IV cyclophosphamide (severe cases), maintenance therapy with azathioprine or MMF. 

Fanconi Syndrome 

Treat underlying cause; correct metabolic acidosis, electrolyte imbalances, and glycosuria. 

Supportive management and targeted treatment of primary disease (e.g., cystinosis). 

Chronic Kidney Disease 

ACE inhibitors or ARBs to reduce proteinuria and preserve kidney function. 

Address complications: bone health, anemia, nutrition; prepare for renal replacement therapy if progressive. 

REFERENCES

https://www.uptodate.com/contents/evaluation-of-proteinuria-in-children

https://www.uptodate.com/contents/treatment-of-idiopathic-nephrotic-syndrome-in-children

https://www.aafp.org/pubs/afp/issues/2017/0215/p248.html

https://www.uptodate.com/contents/iga-vasculitis-henoch-schonlein-purpura-kidney-manifestations 

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