Primary hyperoxalurias (PH)

Baby Detect > Nephrology > Primary hyperoxalurias (PH)

Includes:

– Primary hyperoxaluria type 1 – OMIM#259900 https://omim.org/entry/259900 – AGXT gene

Also known as: oxalosis I; glycolic aciduria; alanine-glyoxylate aminotransferase deficiency

– Primary hyperoxaluria type 2 – OMIM#260000 https://omim.org/entry/260000 – GRHPR gene

Also known as: oxalosis II; glyceric aciduria; glyoxylate reductase/ hydroxypyruvate reductase deficiency; D-glycerate dehydrogenase deficiency

– Primary hyperoxaluria type 3 – OMIM#613616 https://omim.org/entry/613616 – HOGA1 gene

1. The Disease:

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.

2. The Symptoms:

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. Lack of early signs or symptoms does not exclude the diagnosis.

  • 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.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (2 different mutations or 1 mutation in homozygosis in the AGXT, GRHPR or HOGA1 genes) should continue breastfeeding
  • Laboratory findings: 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).
  • The diagnosis is based on genetic and laboratorial results, familial history and clinical signs.
  • PH is a lifelong condition that requires lifetime management and regular follow-up with a nephrology specialist and a multidisciplinary approach to care, including paediatrics, nutrition, and genetics.
  • The primary strategy in prevention and treatment of the renal and systemic complications of PH1 is reduction of hepatic overproduction of oxalate. Hyper hydration (>3L/D/m2) even through tube feeding or gastrostomy feeding is used to reduced renal stones.
  • Until recently, the two options were pharmacologic doses of pyridoxine (limited to those individuals responsive to pyridoxine determined by their AGXT genotype) or liver transplantation (most often combined with or performed sequentially with kidney transplantation in persons with ESRD). In 2020 EMA approved lumasiran, an mRNAi therapeutic agent that reduces the amount of glyoxylate substrate available for metabolic conversion to oxalate by targeting the hepatic enzyme glycolate oxidase (an enzyme distinct from AGT that is in the same metabolic pathway). Since lumasiran targets glycolate oxidase, it is expected to be effective in all individuals with PH1, independent of AGXT genotype.
  • For PH2 and PH3 there is no indication of lumasiran, so it is needed strategies to minimize calcium oxalate crystal and stone formation by reducing urinary calcium oxalate supersaturation include: high oral fluid intake; alkalization of the urine using oral potassium citrate; and/or oral solutions that increase urinary pyrophosphate. Temporary intensive dialysis for ESRD, followed by transplantation.
  • Agents/circumstances to avoid: Intravascular volume contraction, delays in treatment of acute stone episodes, marked dietary oxalate excess, high-dose ascorbic acid, and nephrotoxic agents.
  • Genetic counselling is highly recommended for family planning and evaluation of at-risk family members such as siblings. As an autosomal recessive disorder, the recurrence risk in siblings is 25%.

4. For more information:

Orphanet: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=3529&Disease_Disease_Search_diseaseGroup=primary-oxaluria&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Primary-hyperoxaluria&title=Primary%20hyperoxaluria&search=Disease_Search_Simple

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