What is the appropriate management of Fanconi syndrome, including initial steps, supplementation, monitoring, and indications for renal replacement therapy?

Management of Fanconi Syndrome

Immediate Action: Identify and Remove the Causative Agent

The first and most critical step in managing Fanconi syndrome is to immediately discontinue any offending medication or toxin, as continued exposure leads to worsening renal function and potentially irreversible tubular damage. 1, 2

• For tenofovir disoproxil fumarate (TDF)-induced Fanconi syndrome: Stop TDF immediately upon diagnosis, as this is the most common drug-related cause in adults 3, 1
• Switch HIV patients to: Tenofovir alafenamide (TAF) if creatinine clearance >30 mL/min, abacavir in patients with significant renal impairment, or dolutegravir/raltegravir-based regimens 1, 2
• Switch hepatitis B patients to: Entecavir (minimal renal toxicity) or TAF where available 3, 1
• In children, investigate for inherited metabolic disorders (principally cystinosis) as the most common cause 4
• Review all medications and eliminate other potential nephrotoxins including deferasirox, aminoglycosides, cisplatin, ifosfamide, and expired tetracyclines 3, 5

Electrolyte and Metabolic Replacement Therapy

Phosphate Supplementation

• Administer oral phosphate supplementation to correct hypophosphatemia, which is a cardinal feature of Fanconi syndrome 3, 5, 4
• Monitor serum phosphate levels closely during replacement, as ongoing urinary losses require aggressive supplementation 3, 1

Bicarbonate Replacement

• Provide oral sodium bicarbonate or citrate to correct type II (proximal) renal tubular acidosis 5, 4
• Typical doses range from 1-3 mEq/kg/day divided into multiple doses 4

Potassium Supplementation

• Replace potassium losses, as hypokalemia is common due to impaired proximal tubular reabsorption 5, 6, 4
• Monitor serum potassium every 3-7 days initially until stable 1

Vitamin D and Calcium

• Supplement with vitamin D3 (cholecalciferol) or 25-OH-D3 (calcifediol) plus calcium (250-500 mg/day) for patients with low ionized calcium, elevated PTH, or low 25-OH-D3 levels 3
• Monitor ionized calcium (not total calcium, which is unreliable in the setting of hypoalbuminemia), 25-OH-D3, and PTH levels regularly 3

Volume and Sodium Replacement

• Replace sodium and volume losses, as sodium wasting and dehydration are common manifestations 4
• Avoid excessive fluid restriction that compromises nutritional intake 3

Monitoring Protocol

Initial Phase (First 3-6 Months)

• Electrolytes: Check serum phosphate, potassium, bicarbonate, and calcium weekly until stable, then every 2-4 weeks 1, 6
• Renal function: Monitor eGFR and serum creatinine every 2-4 weeks 3, 1, 2
• Urinalysis: Test for glycosuria, proteinuria, and aminoaciduria to assess tubular dysfunction 3, 1, 5
• Acid-base status: Measure serum bicarbonate and venous blood gas if metabolic acidosis is present 5, 4

Long-Term Monitoring (After Stabilization)

• Monitor renal function with eGFR, urinalysis, and testing for glycosuria and proteinuria every 6 months 1
• Continue checking electrolytes every 3-6 months or more frequently if supplementation is adjusted 1
• Assess for resolution of tubular dysfunction by checking for normalization of phosphate, glucose, and amino acid wasting 1
• For patients switched from TDF, monitor viral load (HIV or HBV) to ensure efficacy of alternative treatment 1

Special Considerations for Specific Populations

Children with Suspected Inherited Causes

• Exclude non-selective renal tubular phosphate wasting by looking for abnormal bicarbonate, amino acid, glucose, and uric acid losses in urine plus low molecular mass proteinuria 3
• Calculate tubular maximum reabsorption of phosphate per GFR (TmP/GFR) using spot urine tests 3
• Perform genetic testing if cystinosis or other inherited metabolic disorders are suspected 3, 4
• Provide high-energy (130 kcal/kg/day) and high-protein (4 g/kg/day) diet with low salt content 3

Adults with Drug-Induced Fanconi Syndrome

• TAF initiation: Do not start TAF if creatinine clearance is <30 mL/min; for active TDF-associated tubulopathy, ideally wait until tubulopathy resolves before initiating TAF 1
• Risk factors for TDF nephrotoxicity: Concurrent ritonavir-boosted protease inhibitors, preexisting renal disease, previous adefovir exposure 1, 2
• Consider combination therapy (e.g., entecavir plus TAF) for patients with multidrug-resistant viral infections 1

Patients with Concomitant Nephrotic Syndrome

• Monitor for hypothyroidism due to urinary loss of thyroxine-binding proteins; measure free T4 and TSH at disease onset 3
• Assess for anemia and provide iron supplementation plus erythropoietin if needed despite iron repletion 3
• Monitor reticulocyte count as a marker of erythropoiesis and response to therapy 3

Indications for Renal Replacement Therapy

• Initiate dialysis when: eGFR falls to <15 mL/min/1.73 m² with uremic symptoms, severe refractory metabolic acidosis, or life-threatening hyperkalemia despite medical management 3
• Peritoneal dialysis is the preferred modality in children to preserve central venous access for future transplantation 3
• Hemodialysis is an acceptable alternative with comparable outcomes 3
• For patients with autosomal recessive inherited Fanconi syndrome, parental kidney donation is usually accepted for transplantation 3

Common Pitfalls and How to Avoid Them

• Failing to discontinue the offending agent: Continued TDF or other nephrotoxin exposure will prevent recovery and may cause irreversible damage 1, 2
• Inadequate phosphate replacement: Ongoing urinary losses require aggressive supplementation; monitor levels frequently and adjust doses accordingly 3, 4
• Overlooking metabolic acidosis: Type II RTA requires bicarbonate replacement to prevent bone disease and growth failure in children 5, 4
• Using total calcium instead of ionized calcium: Total serum calcium underestimates true calcium status in the presence of hypoalbuminemia 3
• Premature TAF initiation: Starting TAF before tubulopathy resolves may lead to recurrence; monitor for resolution of tubular dysfunction first 1
• Inadequate viral suppression monitoring: After switching from TDF, ensure the alternative regimen maintains viral control 1