Which segment of the nephron is primarily affected in Fanconi syndrome associated with multiple myeloma?

Proximal Tubule is the Nephron Segment Affected in Fanconi Syndrome with Multiple Myeloma

The proximal renal tubule is the primary nephron segment affected in Fanconi syndrome associated with multiple myeloma. 1

Pathophysiology of Proximal Tubular Damage in Multiple Myeloma

In multiple myeloma-associated Fanconi syndrome, the pathophysiological process involves:

1. Free Light Chain Processing in Proximal Tubules:

   • Serum free light chains (FLCs) are normally filtered by glomeruli
   • FLCs are then endocytosed by proximal tubule cells and degraded within lysosomes 1
   • In multiple myeloma, excessive production of light chains (predominantly kappa type) overwhelms this normal processing mechanism 1, 2

2. Mechanism of Proximal Tubular Injury:

   • Excessive light chains form crystalline deposits within proximal tubular epithelial cells 3, 4
   • These crystalline inclusions cause direct injury to proximal tubular cells 1
   • The injury triggers inflammatory pathways with increased expression of NFκB and MAPK 1
   • This leads to transcription of inflammatory and profibrotic cytokines 1

3. Functional Consequences:

   • Failure of reabsorptive capacity of proximal tubules results in the characteristic features of Fanconi syndrome 1
   • Clinical manifestations include glucosuria, aminoaciduria, hypophosphatemia, and hypouricemia 1, 3, 4

Diagnostic Features

The diagnosis of multiple myeloma with Fanconi syndrome should be suspected when a patient presents with:

• Normoglycemic glycosuria (glucose in urine despite normal blood glucose)
• Generalized aminoaciduria
• Hypophosphatemia due to phosphaturia
• Hypouricemia due to uric acid wasting
• Normal anion gap metabolic acidosis 4
• Evidence of monoclonal gammopathy (particularly kappa light chains) 2, 3

Treatment Approach

Treatment should focus on the underlying multiple myeloma:

• Bortezomib-based chemotherapy regimens have shown superior outcomes in improving both hematological response and proximal tubular function 2
• Successful treatment of the underlying multiple myeloma can lead to improvement or resolution of the Fanconi syndrome features 5, 6
• Despite hematological response, renal tubular dysfunction may persist for extended periods (up to a year or more after treatment) 4

Clinical Pearls and Pitfalls

• Predominance of Kappa Light Chains: While both kappa and lambda light chains can cause renal damage in multiple myeloma, Fanconi syndrome is predominantly associated with kappa light chains (90.9% of cases) 2

• Diagnostic Pitfall: Don't overlook Fanconi syndrome in adults with unexplained renal tubular acidosis, glycosuria, and aminoaciduria, as it may be the first presentation of an underlying multiple myeloma 3

• Treatment Monitoring: When treating multiple myeloma with Fanconi syndrome, monitor both hematological response and tubular function parameters, as they may not improve simultaneously 2, 4

• Biopsy Findings: Kidney biopsy typically reveals crystalline inclusions within proximal tubular epithelial cells, which is pathognomonic for light chain-associated Fanconi syndrome 3, 4