Primary hyperoxaluria type 2

Other Names: HP2; Oxalosis 2; Glyoxylate reductase/hydroxypyruvate reductase deficiency; Glyceric aciduria; D-glycerate dehydrogenase deficiency

Primary hyperoxaluria type 2 is a rare condition characterized by the overproduction of a substance called oxalate (also called oxalic acid). In the kidneys, the excess oxalate combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney stones. Deposits of calcium oxalate can lead to kidney damage, kidney failure, and injury to other organs.

Cause

Researchers have identified more than a dozen GRHPR mutations that cause this condition. These mutations either introduce signals that disrupt production of the glyoxylate reductase/hydroxypyruvate reductase enzyme or alter its structure. As a result, enzyme activity is absent or dramatically reduced. Glyoxylate builds up because of the enzyme shortage, and is converted to a compound called oxalate instead of glycolate. Oxalate, in turn, combines with calcium to form calcium oxalate, which the body cannot readily eliminate. Deposits of calcium oxalate can lead to the characteristic features of primary hyperoxaluria type 2.

Inheritance

Autosomal recessive inheritance, a 25% chance

Primary hyperoxaluria type 2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Primary hyperoxaluria type 2 is characterized by recurrent nephrolithiasis (deposition of calcium oxalate in the kidney and urinary tract), nephrocalcinosis (deposition of calcium oxalate in the kidney tissue), and end-stage renal disease (ESRD). After ESRD, oxalosis (widespread tissue deposition of calcium oxalate) usually develops. Presenting symptoms are typically those associated with the presence of kidney stones, including hematuria, renal colic (a type of abdominal pain caused by kidney stones), or obstruction of the urinary tract.

The symptoms of primary hyperoxaluria type 2 are typically less severe than primary hyperoxaluria type 1 and may be limited to kidney stone formation. Symptom onset may occur in childhood or adolescence. End stage renal disease is rarely observed in childhood.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Hyperoxaluria(High urine oxalate levels)
• Nephrocalcinosis(Too much calcium deposited in kidneys)
• Nephrolithiasis(Kidney stones)

30%-79% of people have these symptoms

• Recurrent urinary tract infections(Frequent urinary tract infections)
• Ureteral obstruction

5%-29% of people have these symptoms

• Renal insufficiency(Renal failure)

Diagnosis

Primary hyperoxaluria type 2 (PH2) should be suspected in individuals with the following clinical and laboratory features. Clinical features

• Symptoms of nephrolithiasis (e.g., hematuria, renal colic, obstruction of the urinary tract)
• Frequent recurrent nephrolithiasis
• Nephrocalcinosis
• End-stage renal disease with a history of nephrolithiasis

Laboratory features

• Kidney stone analysis. Kidney stones containing predominantly calcium oxalate
• Increased urinary oxalate, typically greater than 0.7 mmol/1.73 m2/24h (normal <0.46 mmol/1.73 m2/24h). A 24-hour collection in acid is preferable to a random sample.
• Increased urinary L-glycerate. This analyte may be detected on an organic acid screen, but there is considerable variability between methods and a specific method for glycerate is preferable.
• Increased plasma oxalate. After the onset of renal failure, measurement of plasma oxalate concentration may be helpful. In contrast to the elevated plasma oxalate concentrations in persons with renal failure from other causes, plasma oxalate concentrations in individuals with primary hyperoxaluria with glomerular filtration rate lower than 20 mL/min/1.73 m2 often exceed 50 μmol/L.

Establishing the Diagnosis The diagnosis of PH2 is established in a proband by identification of biallelic pathogenic variants in GRHPR by molecular genetic testing.

Treatment

The current management strategy includes high fluid intake, treatment with inhibitors of calcium oxalate crystallization, and temporary intensive dialysis for end-stage renal disease (ESRD) followed by kidney transplantation. Varying success has been reported following transplantation, with recurrence being a real possibility since hyperoxaluria and elevated L-glycerate levels persist. Careful management in the postoperative period, with attention to brisk urine output and use of calcium oxalate urinary inhibitors may help prevent complications.

To date, liver-kidney transplantation has not been used in primary hyperoxaluria type 2. This strategy may be considered, however, as there is more enzyme in the liver than in other tissues. More studies are needed before liver transplantation can be recommended. Other treatment modalities needing further investigation include liver cell transplantation and recombinant gene therapy to replace the missing enzyme.

Prognosis

While development of end-stage renal disease (ESRD) may be less common (and later occurring) in people with primary hyperoxaluria type 2 than in those with type 1, chronic and terminal renal insufficiency have been described. Prognosis depends on early treatment and management of hyperoxaluria and associated renal deterioration. Patients who develop ESRD and undergo kidney transplantation seem to carry a high risk of disease recurrence.

NIH genetic and rare disease info

• NIH info on Primary hyperoxaluria type 2

Primary hyperoxaluria type 2 is a rare disease.

Primary hyperoxaluria type 2 Resources
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