Primary hyperoxaluria (PH) is a rare genetic metabolic disorder marked by the body’s overproduction and buildup of oxalate. This accumulation primarily impacts the kidneys, potentially leading to significant kidney damage and, in severe instances, kidney failure. The condition is inherited, occurring when an individual receives two copies of a mutated gene, one from each parent.
Understanding Oxalate Accumulation
Oxalate is a natural chemical in the body, a waste product of metabolism with no known beneficial role. It enters the systemic circulation through dietary intake and endogenous production, mainly in the liver. In healthy individuals, kidneys filter oxalate, which is then excreted through urine. Normal daily urinary oxalate excretion ranges from 10 to 40 mg per 24 hours.
In primary hyperoxaluria, this process is disrupted due to enzyme deficiencies, leading to excessive oxalate production. The liver, responsible for most oxalate biosynthesis, overproduces this substance. When oxalate levels become high in the urine, it combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney stones. These calcium oxalate crystals can accumulate in the kidneys, causing damage and impairing their filtering ability. As kidney function declines, oxalate levels in the blood rise, leading to its deposition in other tissues throughout the body, known as systemic oxalosis.
Types and Genetic Roots
Primary hyperoxaluria is categorized into three types—PH1, PH2, and PH3—each stemming from distinct genetic mutations and associated enzyme deficiencies. These disorders are autosomal recessive, meaning an individual must inherit a mutated gene from both parents to develop the condition. The severity and specific organ involvement can vary among the types.
PH1 is the most prevalent and often the most severe form, accounting for 70% to 80% of PH cases. It results from mutations in the AGXT gene, which provides instructions for producing the liver-specific enzyme alanine-glyoxylate aminotransferase (AGT). A deficiency or dysfunction of AGT prevents the proper breakdown of glyoxylate, leading to its conversion into excessive oxalate.
PH2, caused by mutations in the GRHPR gene, accounts for 10% of PH cases. This gene encodes the enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR). A defect in GRHPR disrupts the processing of glyoxylate, leading to its accumulation and subsequent conversion to oxalate. While similar to PH1, PH2 presents with a less aggressive disease course, and kidney failure develops later in life.
PH3 is the most recently identified type, making up 8% to 10% of PH cases, and is caused by mutations in the HOGA1 gene. This gene is involved in the breakdown of a compound called 4-hydroxy-2-oxoglutarate into glyoxylate and pyruvate. While mutations in HOGA1 lead to increased oxalate, the precise biochemical mechanism is not fully understood. PH3 is milder than PH1 and PH2. Kidney stone formation may decrease by adulthood, and progression to kidney failure is rare.
Recognizing Symptoms and Diagnosis
The symptoms of primary hyperoxaluria typically begin with recurrent kidney stones. These stones can cause sharp pain in the back, side, lower stomach, or groin, and may lead to blood in the urine, frequent urges to urinate, or painful urination. Over time, continuous formation of calcium oxalate crystals can lead to nephrocalcinosis, the widespread deposition of calcium oxalate in kidney tissue. This accumulation progressively damages the kidneys, leading to a decline in kidney function and, eventually, chronic kidney disease or end-stage renal disease (ESRD).
As kidney function deteriorates, oxalate can no longer be efficiently cleared from the body, causing it to accumulate in the blood and deposit in other organs. This can affect bones, blood vessels, the heart, skin, and eyes.
Diagnosis of primary hyperoxaluria involves a combination of tests. Urine tests measure oxalate levels, with concentrations over 40-45 mg/day indicating hyperoxaluria. Blood tests assess kidney function and blood oxalate levels. Imaging tests, such as X-rays, ultrasound, or CT scans of the urinary tract, check for kidney stones or calcium oxalate deposits. Genetic testing confirms the diagnosis by identifying specific mutations in the AGXT, GRHPR, or HOGA1 genes.
Treatment Approaches
Treatment for primary hyperoxaluria focuses on preventing oxalate accumulation, reducing stone formation, and preserving kidney function. A primary strategy involves maintaining a high fluid intake, typically around 3 liters per day, to help flush oxalate from the kidneys and prevent crystals from forming. This approach is beneficial across all types of hyperoxaluria.
Specific medications also manage the condition. Pyridoxine, a form of vitamin B6, can be effective in some PH1 patients as it enhances the activity of the deficient AGT enzyme. Other medications, such as citrate and orthophosphate, are prescribed to inhibit calcium oxalate crystallization in the urine. Dietary adjustments, including limiting foods high in oxalate like spinach, rhubarb, and chocolate, and reducing salt and sugar intake, can further help manage oxalate levels.
When kidney function significantly declines, advanced interventions become necessary. Dialysis, either hemodialysis or peritoneal dialysis, removes waste products, including oxalate, from the blood when the kidneys can no longer do so effectively. For severe cases, particularly in PH1 where the enzyme defect originates in the liver, a combined liver and kidney transplantation may be considered. A liver transplant can correct the underlying enzyme deficiency, preventing further oxalate overproduction, while a kidney transplant addresses the existing kidney damage. In PH2, kidney transplantation alone may be an option, as the deficient enzyme is not solely liver-based.