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A disorder of glyoxylate metabolism characterized by an excess of oxalate resulting in kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. There are 3 types of PH, types 1-3, all caused by liver-specific enzyme defects.
ORPHA:416Classification level: Disorder
Primary Hyperoxalurias (PH) prevalence ranges from 1-3/1 000 000 and the estimated incidence is between 1-2/10 000 000 per year with no differences between sexes. There are higher rates reported in isolated populations, especially in the Middle East and North Africa. A significant proportion of patients are diagnosed at adulthood which implies an important underdetection of patients. PH1 accounts for 85% of patients, PH2 8-10% and PH3 5-7%.
Hyperoxaluria may lead to kidney stones, nephrocalcinosis and ultimately renal failure and systemic oxalosis. Symptoms can appear at any age and may vary from infantile failure to thrive and cortical nephrocalcinosis with renal failure to hematuria, medullary nephrocalcinosis or sporadic stone disease, even within one family. PH1 is the most severe form; overall, more than 70% of PH1 patients develop end-stage kidney disease over time; this may even occur in patients with sporadic stone disease. Storage of oxalate occurs in severe renal failure and may affect bone, eyes, heart, arteries and peripheral nerves (systemic oxalosis). PH2 has a more benign course; no infantile oxalosis has been described and end-stage kidney disease occurs at relatively late age in about 20% of patients. PH3 is most benign with so far only a few reports of renal impairment and no end-stage kidney disease.
PH type 1 is caused by mutations of the AGXT gene causing dysfunction of the liver-specific peroxisomal enzyme alanine glyoxylate aminotransferase (AGT). Over 50 different mutations have been found, leading to either absence or dysfunction of AGT. Two common Western mutations (G170A, Phe152Ile) lead to a mitochondrial mistargeting of AGT. Type 2 is caused by mutations of GHRPR gene causing dysfunction of the cytosolic enzyme glyoxylate/hydroxypyruvate reductase, type 3 by mutations in HOGA1 causing dysfunction of the mitochondrial enzyme 4-hydroxy-2- oxoglutarate aldolase.
Diagnosis methods consist of an analysis of urine collection for 24h (at least 2 consecutive assessments) on oxalate, creatinine, glycolate (PH1), citrate (decreased in PH1), L-glycerate (PH2) and HOGA (PH3). Mutation analysis on AGTX gene can be done in case of hyperoxaluria. If negative or in case of high l-glycerate or HOGA mutation analysis on GRHPR or HOGA1 genes are realized. Assessment for systemic oxalosis in case of high plasma-oxalate and /or eGFR<40: fundoscopy, US heart, bone assessment.
Differential diagnosis includes hypercalciuria, hypocitraturia, cystinuria.
The disorder is inherited in an autosomal recessive manner. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 25% risk of passing the mutation to offspring.
Management and treatment
If eGFR>30 ml/min/1.73m2: the patient needs first high fluid intake (>3 liter/day/m2 body surface). Then pyridoxine challenge in PH1 starting dose 5 mg/kg/day, increase to max 20; reduction urine oxalate >30% = positive response (about 30% of patients in Europe). In third potassium-citrate 0,5 mmol/kg/day. If eGFR<30 ml/min/1.73m2 it is consider to direct combined liver-kidney transplantation, sequential liver-kidney transplantation in case of severe systemic oxalosis or kidney transplantation in B6 responsive PH1 patients. Dietary oxalate restriction is probably of limited use.
Severe infantile oxalosis has a poor prognosis quoad vitam. The prognosis for other PH1 B6 unresponsive patients is poor with respect to renal function (> 80% renal failure over time), better for B6 responsive patients, if timely diagnosed and treated. End-stage kidney disease has been found in 20% of PH2 patients, so far not in PH3.