Can malignancy and tuberculosis (TB) cause nephrotic-range proteinuria in pediatric patients?

Can Malignancy and TB Cause Renal Protein Losses in Children?

Yes, both malignancy and tuberculosis can cause nephrotic-range proteinuria in pediatric patients, though they represent secondary causes that require specific evaluation and management distinct from primary nephrotic syndrome.

Mechanisms and Clinical Context

Tuberculosis-Associated Proteinuria

TB can cause renal protein losses through multiple mechanisms:

• Direct renal involvement: TB can cause infiltrative diseases of the kidney, leading to glomerular dysfunction and proteinuria 1
• Drug-induced nephropathy: Anti-tuberculosis medications, particularly rifampicin and isoniazid, can trigger minimal change disease with nephrotic-range proteinuria and even acute renal failure during treatment 2
• Immune-mediated injury: TB infection can trigger secondary glomerular diseases through immune complex deposition or inflammatory responses 1

The proteinuria from TB-related causes can range from minimal to nephrotic-range (protein-to-creatinine ratio >2 g/g or >40 mg/m²/hour) 1, 3.

Malignancy-Associated Proteinuria

Malignancies are recognized secondary causes of nephrotic syndrome in children:

• Hematologic malignancies are specifically listed as secondary causes of nephrotic syndrome, capable of producing the full nephrotic triad of heavy proteinuria, hypoalbuminemia (<2.5 g/dL), and edema 4
• Paraneoplastic glomerulopathy: Malignancies can trigger immune-mediated glomerular injury through antibody production or cytokine release 1
• The mechanism may involve infiltrative disease of the kidney or systemic inflammatory responses affecting glomerular permeability 1

Diagnostic Approach for Secondary Causes

When evaluating proteinuria in children with suspected TB or malignancy:

Initial Laboratory Assessment

• Quantify proteinuria: First morning spot urine protein-to-creatinine ratio (normal <0.2 g/g; nephrotic-range ≥2 g/g) 1, 5
• Complete metabolic panel: Including total protein, serum albumin (hypoalbuminemia defined as ≤2.5 g/dL in children), and creatinine 1, 5
• Serological testing: Hepatitis B and C, complement levels (C3, C4), antinuclear antibody to exclude lupus 1, 5
• Infection screening: Urine cultures for bacteria or viral pathogens, particularly in TB-suspected cases 1

Imaging and Biopsy Considerations

• Renal ultrasound: Indicated when hematuria, infection, or renal insufficiency is present; may show echogenic kidneys or infiltrative changes 1, 5
• Renal biopsy: Warranted for persistent significant proteinuria (≥0.2 g/g on 3 specimens), especially when secondary causes like malignancy or TB are suspected, to determine histopathological diagnosis 1, 5

Key Distinguishing Features

Look for these specific clinical clues suggesting secondary causes rather than primary nephrotic syndrome:

• Non-nephrotic range proteinuria with hypoalbuminemia: Suggests secondary etiology including malignancy 3
• Active urinary sediments with hematuria: Requires immediate nephrology referral as this combination strongly suggests glomerular disease from secondary causes 5
• Systemic symptoms: Fever, weight loss, night sweats (TB), or constitutional symptoms (malignancy) 1
• Hypertension or renal insufficiency: More common with secondary causes 1, 5

Management Principles

TB-Related Proteinuria

• Treat underlying TB infection: Primary management focuses on appropriate anti-tuberculosis therapy 1
• Monitor for drug-induced nephropathy: Renal function and proteinuria should be monitored carefully during the first few months of rifampicin and isoniazid therapy 2
• Consider steroid therapy: If drug-induced minimal change disease develops, cessation of offending agent plus corticosteroids may be required 2

Malignancy-Related Proteinuria

• Treat underlying malignancy: Disease-specific therapy targeting the hematologic malignancy is the definitive treatment 4
• Supportive management: RAS inhibition with ACE inhibitors or ARBs to reduce proteinuria, dietary sodium restriction, and edema management with loop diuretics 3
• Avoid empiric immunosuppression: Unlike primary nephrotic syndrome in children <12 years where steroids are started without biopsy, secondary causes require biopsy confirmation before immunosuppressive therapy 1, 4

Referral Criteria

Immediate pediatric nephrology referral is warranted for:

• Persistent significant proteinuria (protein-to-creatinine ratio ≥0.2 g/g on 3 specimens) with suspected secondary causes 1, 5
• Combined hematuria and proteinuria, which strongly suggests glomerular disease 5
• Hypertension, edema, or elevated blood urea nitrogen/creatinine levels 1, 5
• Nephrotic syndrome features (heavy proteinuria, hypoalbuminemia <2.5 g/dL, edema) in the context of known or suspected TB or malignancy 5, 6

Common Pitfalls to Avoid

• Do not assume primary nephrotic syndrome: Children with systemic diseases like TB or malignancy require evaluation for secondary causes before initiating empiric steroid therapy 4
• Do not delay biopsy: Unlike typical minimal change disease in young children, suspected secondary causes warrant earlier biopsy to guide specific therapy 1
• Monitor for complications: Children with nephrotic syndrome from any cause have increased thromboembolism risk (29% risk for renal vein thrombosis when albumin is low), infection risk, and potential progression to end-stage renal disease 3