What is the treatment for primary hyperoxaluria?

Treatment of Primary Hyperoxaluria

All patients with suspected primary hyperoxaluria should immediately begin conservative therapy with aggressive hyperhydration (3.5-4 L/day in adults; 2-3 L/m² BSA in children) and potassium citrate (0.1-0.15 g/kg/day), while simultaneously pursuing genetic testing and pyridoxine responsiveness testing in PH1. 1

Immediate Conservative Management (All Patients)

Hyperhydration is the cornerstone of initial therapy and must be started promptly in all patients with suspected PH, even before genetic confirmation. 1

• Fluid intake targets: 3.5-4 liters daily for adults and 2-3 liters/m² body surface area for children, distributed throughout the entire 24-hour period 1, 2
• Infants may require gastrostomy tube placement to achieve adequate fluid intake 2
• Monitor hydration efficacy using urinary markers; frequency depends on disease severity 1

Potassium citrate should be administered orally at 0.1-0.15 g/kg/day in all patients with preserved kidney function. 1, 2

• This increases urinary citrate, which inhibits calcium oxalate crystallization 3
• Divide dosing into 3-4 daily administrations 2

Dietary management should be balanced, avoiding only extremely high oxalate foods (spinach, rhubarb, beetroot) rather than implementing strict oxalate restriction. 1, 2

• Maintain normal dietary calcium intake of 1,000-1,200 mg/day—calcium restriction paradoxically increases oxalate absorption 2, 4
• Avoid high-dose vitamin C supplements as they metabolize to oxalate 2

Type-Specific Pharmacological Therapy

Primary Hyperoxaluria Type 1 (PH1)

Test pyridoxine (vitamin B6) responsiveness in ALL patients with PH1 immediately upon diagnosis. 1, 2

• Dosing: Maximum 5 mg/kg/day 2
• Definition of responsiveness: ≥30% decrease in urinary oxalate after at least 3 months of treatment 2, 5
• Specific genotypes (c.508G>A and c.454T>A) are more likely to respond 5
• Titrate dose based on urinary oxalate excretion 1
• Approximately 30% of PH1 patients respond to pyridoxine 6, 7

RNA interference (RNAi) therapy is now indicated for patients with PH1 who have pyridoxine non-responsive mutations or inadequate response to pyridoxine. 1

• RNAi therapy (lumasiran, nedosiran) substantially lowers endogenous oxalate production 1, 5
• This represents a major advance approved in 2020 that may alter long-term outcomes 5

Primary Hyperoxaluria Types 2 and 3

PH2 and PH3 do not respond to pyridoxine; management relies on conservative therapy alone. 6, 7

• PH3 has not yet been reported to progress to end-stage renal disease 6, 7

Management of Advanced Kidney Disease (eGFR <30 ml/min/1.73 m²)

When eGFR falls below 30-40 ml/min/1.73 m², hepatic oxalate production exceeds renal clearance, leading to systemic oxalosis—this is a medical emergency requiring aggressive intervention. 1

Dialysis Strategy

Initiate intensified hemodialysis when plasma oxalate exceeds 30 μmol/L, even if GFR would not typically warrant dialysis. 5

• Use high-flux hemodialyzer (>1 m² capillary surface per 1 m² BSA) with maximal blood flow (>150-200 mL/min/m² BSA) 1
• Increase weekly session frequency rather than prolonging individual sessions, as oxalate removal effectiveness decreases during each session 1
• Target pre-dialysis plasma oxalate levels around 50-70 μmol/L (the range for dialysis patients without PH) 1
• Peritoneal dialysis alone is insufficient for oxalate clearance 5
• Consider daily hemodialysis combined with nocturnal peritoneal dialysis if tolerated 1

Transplantation Decisions

The transplantation strategy depends on PH type, pyridoxine responsiveness, eGFR, and access to RNAi therapy. 1

For PH1 with eGFR <30 ml/min/1.73 m²:

Combined liver-kidney transplantation is recommended for patients who do not respond to pyridoxine and have no access to RNAi therapy. 1

• Liver transplantation is the only cure for PH1, as it restores hepatic enzyme activity 1, 5
• The native liver must be completely removed—auxiliary liver transplantation is obsolete and inadequate 1
• Sequential versus simultaneous liver-kidney transplantation should be decided based on clinical situation and surgical preference 1

Isolated kidney transplantation should be considered for patients with PH1 who are homozygous for pyridoxine-responsive mutations and demonstrate adequate response. 1

• This avoids the risks of liver transplantation and immunosuppression 5
• Response to pyridoxine and/or RNAi therapy must be documented by plasma oxalate normalization 1

For PH2 with eGFR <30 ml/min/1.73 m²:

Liver transplantation may be suggested in patients with PH2 and advanced disease, though isolated kidney transplantation is generally preferred. 1

• The enzyme deficiency in PH2 is corrected by kidney transplantation alone 6, 7

Monitoring Protocol

Patients with Preserved Kidney Function:

• Monitor urinary oxalate, glycolate, citrate, calcium, and creatinine every 3-6 months during the first year, then every 6 months for 5 years 2
• Assess urinary oxalate on at least two occasions after 2 weeks of pyridoxine to evaluate responsiveness 2

Patients with CKD Stage 4 or Higher:

• Measure plasma oxalate levels (not urinary) every 3 months 1, 2
• Interpret plasma oxalate using reference values adjusted for kidney failure 1

Post-Transplantation:

• Monitor urinary and plasma oxalate every 6 months after liver transplantation until normalized on three occasions 1
• Monitor every 6 months after kidney transplantation for patients on pyridoxine/RNAi until normalization, then annually 1

Critical Pitfalls to Avoid

Delayed diagnosis is the most common and devastating pitfall—maintain high clinical suspicion in any patient with recurrent kidney stones, nephrocalcinosis, or unexplained kidney failure, especially in children. 1, 6

• Over 30% of PH1 patients progress to end-stage renal disease, often because diagnosis is missed or delayed 6
• Early intervention can delay or prevent ESRD 6

Never restrict dietary calcium—this paradoxically increases intestinal oxalate absorption and worsens hyperoxaluria. 2, 4

Do not delay dialysis initiation in advanced disease—waiting for traditional dialysis criteria allows systemic oxalosis to develop in bones, heart, vessels, nerves, and eyes. 1, 5

Avoid isolated kidney transplantation in pyridoxine non-responsive PH1 patients—3-year graft survival historically averaged only 20% due to recurrent oxalosis. 1