What is Fanconi syndrome?

What is Fanconi Syndrome?

Fanconi syndrome is a generalized dysfunction of the proximal renal tubules characterized by impaired reabsorption leading to excessive urinary losses of phosphate, glucose, amino acids, bicarbonate, and other essential metabolites. 1, 2

Pathophysiology

The syndrome results from a transport defect in proximal tubular epithelial cells, causing a sodium-linked transport defect that affects multiple reabsorption pathways simultaneously. 2, 3 The underlying mechanism often involves:

• Inhibition of Na/K/ATPase activity in the proximal tubule, which disrupts the sodium gradient necessary for secondary active transport of multiple solutes 3
• Mitochondrial damage in proximal tubular cells, particularly in drug-induced cases 4
• Endocytosis dysfunction, as demonstrated in genetic models involving megalin and ClC-5 3

Cardinal Laboratory Features

The diagnosis requires recognizing the characteristic pattern of urinary losses despite normal or low serum levels:

• Hypophosphatemia from impaired phosphate reabsorption, leading to osteomalacia and bone pain 1, 5
• Normoglycemic glucosuria (glucose in urine despite normal blood glucose) 1, 5, 2
• Generalized aminoaciduria with excessive urinary amino acid excretion 1, 5
• Hypokalemia from increased urinary potassium losses, worsened by concurrent metabolic acidosis 1, 5
• Metabolic acidosis with elevated urinary pH (often >5.5) despite systemic acidosis, representing proximal renal tubular acidosis 5
• Phosphaturia causing renal phosphate wasting 1

Clinical Manifestations

Patients present with symptoms reflecting the electrolyte and metabolic derangements:

• Bone disease: rickets in children and osteomalacia in adults from chronic phosphate wasting 6, 1
• Muscle weakness and fatigue related to hypokalemia and metabolic acidosis 1
• Growth failure in affected children 1
• Bone pain and pathologic fractures from osteomalacia 4

Etiologies

Inherited Causes

• Tyrosinemia type I, where the tubulopathy is characterized by aminoaciduria, glucosuria, phosphaturia, and/or renal tubular acidosis 6, 1
• Cystinosis (CTNS gene mutations) 1
• Glycogen storage diseases including Fanconi-Bickel syndrome 1
• Fanconi anemia (multiple gene mutations) requiring additional monitoring for bone marrow failure and cancer risk 1, 7

Acquired Causes

• Multiple myeloma with light chain deposition, the most common adult form 1, 3
• Drug-induced: numerous medications including adefovir, which causes direct mitochondrial damage to proximal tubules 2, 4
• Heavy metal toxicity (cadmium, lead) 2, 8
• Lymphoma, particularly acute T cell leukemia/lymphoma (ATLL) related to HTLV1 infection, with intense proximal tubule infiltration by lymphomatous cells 9

Diagnostic Approach

At diagnosis, comprehensive assessment of renal involvement should include:

Blood Tests

• Serum creatinine and eGFR to assess kidney function 1
• Electrolytes including bicarbonate for RTA assessment 6
• Calcium and phosphate levels 6
• Alkaline phosphatase (elevated in rickets/osteomalacia) 1

Urine Tests

• Glucose, amino acids, calcium, phosphate 6
• Calcium:creatinine ratio and tubular reabsorption of phosphate 6
• Total protein, albumin, or β2-microglobulin 6
• Albumin:creatinine ratio and protein:creatinine ratio 1

Additional Studies

• Renal ultrasound to evaluate for dilated tubules, echogenicity, enlarged kidneys, cysts, and nephrocalcinosis 6
• Bone X-rays (wrist, chest) and densitometry for rachitic changes 6
• Genetic testing for inherited causes when clinically indicated 1
• Serum and urine protein electrophoresis to screen for multiple myeloma in adults 1

Kidney Biopsy Indications

Consider biopsy when Fanconi syndrome presents with hypouricemia, eGFR <60 mL/min/1.73m² with >2 mL/min/1.73m² per year decline, proteinuria with hematuria, or albumin:creatinine ratio >30 mg/mmol. 1

Management Principles

Treat the Underlying Cause

• For tyrosinemia type I: NTBC (nitisinone) with dietary restriction of phenylalanine/tyrosine reverses tubulopathy in nearly all cases within weeks 6, 7
• For cystinosis: cysteamine therapy starting at 1 mg/kg/day, potentially increasing to 2 mg/kg if no improvement 7
• For lymphoma-associated cases: successful treatment of the underlying lymphoma can lead to regression of Fanconi syndrome features 9

Supportive Care and Electrolyte Replacement

• Phosphate supplementation to address hypophosphatemia and prevent bone disease 1, 5
• Potassium supplementation for hypokalemia 1, 5
• Bicarbonate supplementation to correct metabolic acidosis 1, 5
• Fluid replacement: intravenous 10% dextrose/normal saline at 1.5-2.0 times maintenance rate to maintain normoglycemia in acute settings 7

Ongoing Monitoring

• Regular assessment of electrolytes, renal function, and bone health is crucial 1
• Periodic urine analysis for amino acids, glucose, phosphate, protein excretion, and calcium:creatinine ratios to assess tubulopathy recovery 6
• Post-transplant patients (in tyrosinemia type I) require periodic screening for renal disease as succinylacetone excretion continues despite liver transplantation 6, 7

Critical Pitfalls

A common pitfall is failing to recognize that glucosuria in Fanconi syndrome occurs despite normal serum glucose, distinguishing it from diabetes mellitus. 1, 5 Another is underestimating the severity of bone disease—early diagnosis and aggressive phosphate replacement are essential to prevent irreversible skeletal complications. 1 In drug-induced cases, continuation of the offending agent while treating symptoms will not resolve the syndrome; the causative drug must be discontinued. 2, 4