Genetics & disease subtypes
PH1 (AGXT — alanine-glyoxylate aminotransferase, peroxisome):
- Commonest and most severe (~70% of cases)
- Wide phenotype: infantile oxalosis to adult-onset stones
- Some mutations (G170R, F152I) respond to pyridoxine
- Untreated → ESKD often in childhood/teens
PH2 (GRHPR — glyoxylate reductase/hydroxypyruvate reductase, cytoplasmic):
- Milder than PH1 but still progressive
- Stones common; CKD develops over years
PH3 (HOGA1 — 4-hydroxy-2-oxoglutarate aldolase, mitochondrial):
- Most recent identification (2010)
- Variable severity; often presents as childhood stones with preserved eGFR for many years
- Some progress to advanced CKD
INHERITANCE: all autosomal recessive — siblings have 25% risk.
NHS GENETIC TESTING: National Genomic Test Directory R254 (Hyperoxaluria, primary) covers AGXT, GRHPR and HOGA1.
IMPORTANT DIFFERENTIAL: SECONDARY (enteric) hyperoxaluria from short-gut, bariatric surgery, IBD, chronic pancreatitis — clinically similar but mechanism is dietary oxalate over-absorption, not over-production. Treatment is different (calcium with meals, low-oxalate diet).
Clinical presentation & diagnosis
Presentation Spectrum
- Infant: failure to thrive, oxalosis, AKI, ESKD (most severe — PH1 infantile)
- Child/teen: recurrent stones, nephrocalcinosis, family history
- Young adult: 'unexplained' recurrent CaOx stones, slowly declining eGFR
- Late adult: rare, often missed; isolated stone disease then sudden ESKD
- Post-transplant disaster: kidney-alone transplant fails within months due to recurrent oxalate deposition
Suspect In
- First stone < 25 years
- Bilateral or recurrent stones
- Bilateral medullary nephrocalcinosis
- Family history of stones or unexplained ESKD
- CaOx monohydrate dominant on stone analysis
Investigations
- 24-h URINE OXALATE (timed, properly preserved with HCl):
- Normal: < 0.4 mmol/1.73 m²/day
- PH suggested: > 0.5 mmol/1.73 m²/day
- PH3 can have modest elevations
- 24-h urinary glycolate (high in PH1), glycerate (high in PH2), 4-OH-2-oxoglutarate (PH3)
- Plasma oxalate (only useful when eGFR < 30 — rises sharply in advanced CKD)
- Stone analysis: pure CaOx monohydrate
- Renal USS: nephrocalcinosis, stones
- GENETIC TESTING (R254 NHS panel)
- Echo (cardiac oxalosis screen if advanced)
- Eye review, bone X-rays if systemic oxalosis suspected
- Liver biopsy enzyme assay: now rarely needed
Treatment
CONSERVATIVE (all subtypes):
- Fluid intake > 3 L/m²/day round-the-clock (including overnight in older children/adults — set an alarm)
- Potassium citrate 0.1–0.15 g/kg/day (or 30–60 mEq/day adult)
- Neutral phosphate (where citrate insufficient and urinary calcium high)
- Avoid vitamin C megadoses (oxalate precursor)
- Avoid dehydration, prolonged immobilisation
Pyridoxine Trial (Ph1)
- 5 mg/kg/day, escalating to 20 mg/kg/day
- Response defined as ≥ 30% fall in urinary oxalate over 3–6 months
- Most likely to respond: G170R, F152I, I244T AGXT mutations
- Lifelong if responsive
Disease-modifying (NICE / Ema)
- LUMASIRAN (Oxlumo) — RNAi targeting HAO1 in hepatocytes
- NICE TA681 approved for PH1, all ages
- Subcutaneous injection monthly then 3-monthly
- Reduces urinary oxalate by 50–65%
- Started ideally before significant kidney damage
- NEDOSIRAN — RNAi targeting LDHA, broader (PH1, 2, 3)
- Approved in some jurisdictions; UK access via clinical trials
- Both delivered via UK specialist centres (renal genetics or stone clinics linked to liver transplant units)
Stone Interventions
- Standard urological care (SWL, ureteroscopy)
- AVOID PCNL in PH1 where possible (parenchymal trauma in already-vulnerable kidneys)
- Always send stone for composition analysis
Dialysis
- Standard HD is inadequate to clear oxalate (need 6+ sessions/week or daily extended HD)
- HDF or daily nocturnal HD preferred while awaiting transplant
- Plasma oxalate target as low as possible to prevent systemic deposition
Transplantation (Ph1)
- KIDNEY-ALONE: fails rapidly — recurrent oxalate destroys graft (NOT recommended)
- COMBINED LIVER–KIDNEY TRANSPLANT: definitive cure — corrects the enzyme defect
- PRE-EMPTIVE LIVER TRANSPLANT (before ESKD): considered in select children
- PH2 and PH3: kidney transplant may be considered (less aggressive disease) but data limited
- UK referral: National PH Centre — Birmingham, Manchester, Royal Free, GOSH (paediatric)
Family & Genetic Counselling
- Sibling testing (25% risk if AR)
- Cascade testing through R254
- Pre-implantation genetic diagnosis available for families with severe PH1
LIFE-LONG FOLLOW-UP under a specialist PH service is the standard of UK care.
