What is primary hyperoxaluria, how is it diagnosed, and what are the management options?

Primary Hyperoxaluria: Definition, Diagnosis, and Management

Primary hyperoxaluria is a group of autosomal recessive disorders causing endogenous oxalate overproduction that leads to recurrent kidney stones, nephrocalcinosis, kidney failure in over 70% of patients, and life-threatening systemic oxalosis when GFR falls below 30-40 ml/min/1.73 m². 1

What is Primary Hyperoxaluria?

Disease Mechanism:

• PH results from defects in hepatic glyoxylate metabolism, causing excessive oxalate production that cannot be adequately excreted by the kidneys. 1
• Calcium oxalate crystals deposit in renal tubules, causing intra-tubular and interstitial damage with chronic inflammation and obstruction. 1
• When GFR drops below 30-40 ml/min/1.73 m², hepatic oxalate production exceeds renal clearance, triggering systemic deposition in bone, heart, vessels, nerves, and eyes—a condition called systemic oxalosis. 1

Three Biochemical Types:

• Type 1 (PH1) is the most common and has the worst prognosis, caused by alanine/glyoxylate aminotransferase (AGT) deficiency. 1, 2
• Type 2 (PH2) and Type 3 (PH3) are rarer with generally better outcomes. 1
• PH1 accounts for the majority of cases progressing to end-stage renal disease. 1, 3

Diagnostic Approach

When to Suspect PH:

• Any patient with recurrent calcium oxalate kidney stones, nephrocalcinosis, or chronic kidney disease of unclear etiology—especially if presenting before age 25. 4
• End-stage kidney disease of uncertain cause, particularly with history of stones or nephrocalcinosis. 4
• Critical pitfall: Diagnosis is frequently delayed or missed until kidney failure occurs, which dramatically worsens outcomes. 1

Diagnostic Testing Algorithm:

1. Urinary oxalate measurement (24-hour collection):

   • Elevated urinary oxalate >1 mmol/1.73 m² body surface area per day (normal <0.5 mmol/1.73 m²/day) is diagnostic. 3
   • Must also measure urinary glycolate (elevated in PH1), citrate, calcium, and creatinine. 5

2. Genetic testing:

   • Should be pursued immediately in all suspected cases to confirm diagnosis and determine PH type. 5
   • Identifies specific mutations that predict pyridoxine responsiveness in PH1. 5

3. Plasma oxalate levels:

   • Essential when GFR <45 ml/min/1.73 m², as urinary measurements become unreliable. 5
   • Target monitoring every 3 months in CKD Stage 4 or higher. 5

4. Imaging findings:

   • Bilateral nephrocalcinosis and multiple renal stones on ultrasound or CT. 6, 7
   • In advanced disease: diffusely increased liver echogenicity, lytic bone lesions. 7

Management Strategy

Immediate Conservative Therapy (All Patients)

Aggressive hyperhydration is the cornerstone of initial management:

• Adults: 3.5-4 liters daily, distributed throughout the entire 24-hour period (including nighttime). 5
• Children: 2-3 liters/m² body surface area per day. 5
• This dilutes urinary oxalate concentration to reduce crystal formation. 5

Potassium citrate supplementation:

• Dose: 0.1-0.15 g/kg/day orally in all patients with preserved kidney function. 5
• Citrate inhibits calcium oxalate crystallization. 5, 3

Type-Specific Pharmacological Therapy

For PH1 patients—pyridoxine (vitamin B6) trial:

• Test responsiveness immediately upon diagnosis with maximum dose of 5 mg/kg/day. 5
• Approximately 30% of PH1 patients respond with normalized or reduced oxalate excretion. 3
• Response depends on specific genetic mutations. 5

RNA interference (RNAi) therapy:

• Indicated for PH1 patients who are pyridoxine non-responsive or have inadequate response. 5
• These therapies substantially lower endogenous oxalate production. 1
• Represents a major therapeutic advance introduced in recent years. 1

Management of Advanced Kidney Disease

Dialysis initiation criteria:

• Start intensified hemodialysis when plasma oxalate exceeds 30 μmol/L, even if GFR would not typically warrant dialysis. 5
• Use high-flux hemodialyzer with maximal blood flow. 5
• Increase weekly session frequency rather than prolonging individual sessions. 5
• Target pre-dialysis plasma oxalate levels around 50-70 μmol/L. 5
• Critical: Time on dialysis should be minimized to avoid overt systemic oxalosis. 3

Transplantation Decisions

Combined liver-kidney transplantation:

• Recommended for PH1 patients who do not respond to pyridoxine and lack access to RNAi therapy. 5
• The native liver must be completely removed to eliminate the source of oxalate overproduction. 5, 3
• This is the definitive treatment for enzyme deficiency. 6, 2

Isolated kidney transplantation:

• Consider for PH1 patients homozygous for pyridoxine-responsive mutations with adequate response. 5
• Preferred method for PH2 patients. 3
• Major pitfall: PH diagnosed after kidney transplant alone typically results in early graft loss due to recurrent disease. 4

Monitoring Protocol

For patients with preserved kidney function:

• Monitor urinary oxalate, glycolate, citrate, calcium, and creatinine every 3-6 months during the first year. 5
• Then every 6 months for 5 years. 5

For patients with CKD Stage 4 or higher:

• Measure plasma oxalate levels every 3 months using reference values adjusted for kidney failure. 5
• Serial imaging to assess for systemic oxalate deposition. 7

Critical Clinical Pitfalls

Delayed diagnosis is the most common and devastating error:

• Many patients are not diagnosed until end-stage renal disease develops, missing the window for kidney-protective interventions. 1
• Maintain high suspicion in any young patient with nephrocalcinosis, recurrent stones, or unexplained CKD. 4

Systemic complications when missed:

• Hypercalcemia from osteoclast-stimulating granulomas. 7
• Erythropoietin-resistant anemia from bone marrow oxalate deposition. 7
• Hypothyroidism from thyroid gland infiltration. 7
• Liver cirrhosis from long-term oxalate deposition (rare but reported). 2

Transplant-related errors:

• Performing isolated kidney transplant in undiagnosed PH1 leads to rapid graft failure. 4
• Inadequate dialysis intensity pre-transplant allows systemic oxalate burden to accumulate. 3