Primary Hyperoxaluria

Primary hyperoxaluria (PH) is a group of rare inherited disorders in which a faulty liver enzyme makes the body overproduce oxalate, a waste product cleared mainly by the kidneys. In the urine, oxalate binds calcium and forms calcium oxalate stones and deposits inside the kidney tissue (nephrocalcinosis). The 2023 ERKNet and OxalEurope consensus guideline reports that this leads to kidney failure in more than 70% of patients. Once kidney function falls below about 30-40 mL/min/1.73 m², the liver makes more oxalate than the kidneys can remove, and it builds up in bone, heart, blood vessels, nerves and eyes (systemic oxalosis). There are three types. Type 1 (PH1) accounts for about 80% of diagnosed cases and is the most severe; types 2 and 3 each account for about 10%, though genetic studies suggest both are underdiagnosed. In the Rare Kidney Stone Consortium registry of 355 patients, PH3 showed the slowest decline in kidney function but the earliest symptoms. The gravest form is infantile oxalosis, kidney failure from PH1 before the first birthday: in a European registry of 95 affected infants, 27 of the 89 followed up (30%) died, at a median age of 1.4 years, although survival was significantly better for children born after 2000. In PH, most oxalate comes from what the liver makes rather than from food, so diet changes alone can't control it. The one supplement with an established role is vitamin B6 (pyridoxine): the guideline recommends trying it in everyone with suspected PH or confirmed PH1, because certain PH1 gene variants respond, and in some people urine oxalate returns to normal. Oral Oxalobacter formigenes, an oxalate-degrading gut bacterium, did not lower oxalate in a 2025 meta-analysis of five randomised trials. Two prescription RNA interference (RNAi) drugs, lumasiran and nedosiran, substantially cut urine oxalate in randomised PH1 trials, though their long-term effect on stones and kidney function is still being established.

• •Recurrent kidney stones
• •Flank or groin pain
• •Blood in the urine
• •Frequent urinary infections
• •Painful urination
• •Bed-wetting or incontinence
• •Poor growth in infants
• •Fractures from bone oxalosis

• •AGXT variants (type 1)
• •GRHPR variants (type 2)
• •HOGA1 variants (type 3)
• •Autosomal recessive inheritance

All three types are autosomal recessive: a child is affected only when both parents pass on a faulty copy of the same gene. AGXT and GRHPR make enzymes that clear glyoxylate, a by-product of amino acid breakdown. PH1 is caused by variants in AGXT, which makes the liver enzyme alanine-glyoxylate aminotransferase (AGT); this enzyme depends on pyridoxal phosphate, the active form of vitamin B6, which is why B6 can help some people with PH1. PH2 is caused by variants in GRHPR. When either enzyme fails, glyoxylate is turned into oxalate, which the body gets rid of mainly through the kidneys. PH3 is caused by variants in HOGA1, an enzyme earlier in the same pathway; how its loss raises oxalate is not yet known. The p.Gly170Arg variant accounts for about 28-30% of PH1 variants in Western populations; it is a mistargeting variant linked to milder disease and to vitamin B6 response. Genetic analyses suggest PH is far more common than clinic records show, so many people with it are probably undiagnosed.