What are the possible causes of low Complement 3 (C3) and Fanconi syndrome in a patient?

Possible Causes of Low C3 and Fanconi Syndrome

The combination of low C3 and Fanconi syndrome most strongly suggests monoclonal gammopathy of renal significance (MGRS), particularly light chain-mediated proximal tubulopathy with concurrent immune complex glomerulonephritis or C3 glomerulopathy. 1, 2

Primary Diagnostic Consideration: Monoclonal Gammopathy

Monoclonal gammopathy is the leading cause to investigate when low C3 and Fanconi syndrome coexist in adults, especially in patients over 50 years old. 1, 2

• Monoclonal light chains (particularly kappa light chains from Vkappa1 or Vkappa3 subgroups) can directly cause Fanconi syndrome by accumulating in proximal tubular cells, with or without crystalline formation. 3
• The same monoclonal protein can trigger complement dysregulation leading to low C3 through immune complex formation or alternative pathway activation. 1, 2
• Waldenstrom's macroglobulinemia and smoldering myeloma are specific plasma cell disorders that can present with this dual pathology. 3

Required Workup for Monoclonal Gammopathy

• Serum and urine protein electrophoresis with immunofixation must be performed immediately. 1, 2
• Serum free light chain analysis is essential for detecting monoclonal proteins. 2
• Kidney biopsy with pronase digestion of paraffin-embedded tissue is critical, as standard immunofluorescence may miss masked monoclonal deposits in up to 5-10% of cases. 2
• Immunofluorescence studies must include staining for IgG, IgM, IgA, C1q, C3, and κ and λ light chains. 1

Secondary Causes to Exclude

Infection-Related Glomerulopathy with Tubular Injury

Bacterial infections, particularly invasive pneumococcal disease, can cause both low C3 (through classical pathway activation) and Fanconi-like syndrome simultaneously. 1, 4

• Pneumococcal disease has been documented to cause proximal renal tubulopathy with hypokalaemia, hypomagnesaemia, hypophosphataemia, and hypouricaemia during active infection. 4
• Post-infectious glomerulonephritis classically presents with low C3 that should normalize by 8-12 weeks; persistently low C3 beyond this timeframe suggests C3 glomerulopathy rather than infection-related disease. 1, 2
• Endocarditis and shunt nephritis can present with low complement and concurrent tubular dysfunction. 1

Hemosiderosis-Related Tubular Injury

Paroxysmal nocturnal hemoglobinuria with chronic hemolysis and transfusion-related iron overload can cause Fanconi syndrome through hemosiderin deposition in proximal tubules. 5

• This mechanism typically does not cause low C3 unless there is concurrent complement-mediated hemolysis or immune complex formation. 5
• Serum ferritin levels and renal MRI showing cortical iron deposition are diagnostic clues. 5

Genetic Disorders

Inherited metabolic disorders (cystinosis, tyrosinemia type I, mitochondrial disorders with HNF4A mutations) cause Fanconi syndrome but do not typically cause low C3 unless there is concurrent glomerular disease. 6, 7, 8

Diagnostic Algorithm

Immediate Laboratory Evaluation

• Serum complement levels: C3, C4, CH50 to determine pathway activation pattern. 2
• Low C3 with normal C4 suggests alternative pathway activation (C3 glomerulopathy); low C3 and low C4 suggest classical pathway activation (immune complex disease). 9, 2
• Complete urinalysis with sediment evaluation for dysmorphic hematuria and red blood cell casts. 2
• 24-hour urine protein quantification (significant if >500 mg/day), urine electrolytes, glucose, amino acids, phosphate, uric acid, and β2-microglobulin. 1, 6, 4

Essential Screening Tests

• Serum and urine protein electrophoresis with immunofixation. 1, 2
• Serum free light chain analysis. 2
• Blood and urine cultures if infection is suspected. 1, 4
• Serum ferritin and iron studies if hemolysis or transfusion history is present. 5

Kidney Biopsy Indications

Kidney biopsy is advised given the presence of Fanconi syndrome (hypouricaemia) combined with low C3 suggesting glomerular disease. 1

• Light microscopy with Congo red staining, immunofluorescence (including IgG subtyping if heavy chains are IgG), and electron microscopy are mandatory. 1
• Pronase digestion of paraffin-embedded tissue must be performed if monoclonal gammopathy is detected or suspected to unmask hidden monoclonal deposits. 2
• Mass spectrometry may be required for typing amyloidosis or detecting rare immunoglobulin deposits. 1

Critical Pitfalls to Avoid

• Do not assume infection-related glomerulonephritis if C3 remains low beyond 12 weeks; this mandates evaluation for C3 glomerulopathy or monoclonal gammopathy. 1, 2
• Do not rely solely on standard immunofluorescence in patients over 50 years old, as 60-80% may have monoclonal gammopathy requiring pronase digestion to detect masked deposits. 2
• Do not overlook active infections as triggers for complement dysregulation in genetically susceptible patients; treat the infection before labeling as primary autoimmune disease. 2, 4
• Do not delay kidney biopsy in the setting of declining renal function, as early diagnosis of MGRS-related lesions is critical for targeted therapy. 1