Diseases In Depth - Primary Hyperoxaluria
What is Primary Hyperoxaluria?
Primary hyperoxaluria (PH) is the most severe of the hereditary causes of nephrolithiasis. Enzyme deficiency in the liver results in marked overproduction of oxalate that must be excreted by the kidneys. Oxalate in the urine in high concentrations is poorly insoluble when combined with calcium and thus leads to calcium oxalate crystals and stones. Primary hyperoxalurias are autosomal recessive disorders of glyoxylate metabolism characterized by excessive production and urinary excretion of oxalate and glycolate (PH type I, PH1), or oxalate and L-glycerate (PH type II, PH2). The urine oxalate excretion rate in affected patients is typically 3 to 6 times normal with severe clinical consequences. Urolithiasis and/or nephrocalcinosis occur in childhood or adolescence. Renal injury due to oxalate and consequences of urinary tract stones leads to renal failure. Loss of renal function leads to markedly increased plasma concentrations of oxalate, and if not addressed promptly by transplantation, results in deposition of calcium oxalate in body tissue (oxalosis). Resulting organ system dysfunction including ischemic ulcers of the skin, metabolic bone disease, refactory anemia, cardiomyopathy and cardiac conduction system abnormalities are the cause of severe morbidity and mortality. These rare diseases (PH1 and PH2) can be caused by defects in at least two glyoxylate-metabolizing enzymes. Recently, a third group of patients has been identified with an as-yet-unknown genetic cause of hyperoxaluria. Untreated, PH patient outcome is often poor, with death from renal failure and systemic oxalosis the norm. However, there is wide variability in outcome amongst patients, and with careful and aggressive treatment patient survival with preserved renal function to middle age (or older) is possible. The important factors that influence improved patient survival are currently poorly understood.
Who gets Primary Hyperoxaluria?
Primary hyperoxaluria causes not only stones of the urinary tract, but also loss of renal function. Stones recur frequently, with most patients requiring many stone procedures over the course of a lifetime. By 30 years of age, end stage renal failure is observed in approximately 40% of patients with type 1 PH, and by 50 years of age, 70% have lost renal function. Incidence and prevalence are unknown but have been estimated by surveys of nephrologists and urologists in France and Switzerland. Based on those studies, the incidence in central Europe is estimated at 1 in 120,000 live births and the prevalence at 1.05 to 2.9 per million population. No population based data are available from the U.S., though through the Mayo Clinic Hyperoxaluria Center we are aware of approximately 280 U.S. patients with PH. Some areas of the world, including Tunisia, the Canary Islands, and the Middle East appear to have a higher prevalence of PH.
What causes Primary Hyperoxaluria?
PH 1 and PH 2 are autosomal recessive disorders. These two well-defined subtypes of primary hyperoxaluria are both due to deficiencies of hepatic enzymes important in the metabolic disposition of glyoxylate. Type 1 (PH1) is due to deficiency or absence of alanine glyoxylate aminotransferase (AGT) enzyme and type 2 (PH2) is due to deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR). A small number of patients have been identified with clinical characteristics indistinguishable from type 1 or type 2, but with normal AGT and GRHPR liver enzyme activity. The etiology of the marked hyperoxaluria in such patients remains to be elucidated.
How is Primary Hyperoxaluria diagnosed?
All the pathological sequelae of the primary hyperoxalurias are related to the increased synthesis and excretion of oxalate. Marked hyperoxaluria is present from birth on, with 2 to 8 times the upper limit of normal urine oxalate being characteristic. Blood in the urine or pain related to stones, stone passage, or urinary tract infection are the most common symptoms of the disease. Over time, frequent stone recurrences and the need for multiple stone removal procedures are typical. The majority of patients are symptomatic before 10 years of age. In some cases, however, the disease may go unrecognized either due to the absence of symptoms or to incorrect diagnosis, until patients reach 30 to 50 years of age. Oxalate at high concentrations with calcium in the urine forms crystals that form in the urinary tract leading to stones, and also deposit in kidney tissue causing nephrocalcinosis. Calcium oxalate crystals are also directly injurious to renal cells and incite a granulomatous reaction in the renal interstitium. Over time the effects of such injury, often combined with intermittent obstruction or infection related to stones, lead to kidney failure. However, some patients present with kidney failure as the first manifestation of the disease, as early as 4 months of age. Patients with type 2 disease appear to have a milder course overall than those with type 1, including better preservation of renal function. The reasons for such variation in clinical expression are poorly understood, and if elucidated may provide valuable insights as to potentially remediable factors that can be exploited for therapeutic benefit. Once renal function declines to less than 30-40 ml/min/1.73 m2, plasma oxalate concentration rises, exceeding the supersaturation threshold for calcium oxalate and systemic oxalosis with associated morbidity and death result. Transplantation is required for satisfactory long term outcomes. Early diagnosis of primary hyperoxaluria is of vital importance so that treatment can be initiated as soon as possible. While molecular genetics can now provide definitive diagnosis for most patients, the lack of familiarity with the disease can result in delays of many years from onset of symptoms until diagnosis.
What is the treatment for Primary Hyperoxaluria?
Treatment strategies include careful dietary advice to minimize oxalate ingestion and maximize fluid intake, carefully titrated doses of pyridoxine for those patients in whom it is effective and neutral phosphate and/or citrate to reduce urinary saturation with calcium oxalate. Renal function must be monitored vigilantly and renal replacement therapy should be initiated promptly if renal clearance falls below a critical threshold, in order to prevent body-wide deposition of calcium oxalate. Kidney transplantation alone or combined kidney-liver transplantation is clearly the preferred treatment of renal failure for PH patients. If transplantation is not possible, patients must be aggressively dialyzed, often 6 or 7 days per week and/or using a combination of modalities, in order to remove enough oxalate to prevent body-wide oxalosis. The only definitive treatment for type 1 PH is liver transplantation to replace the missing AGT enzyme. All of these modalities have been in use for more than 20 years. Though long term outcomes have improved with earlier diagnosis and currently available treatment, more effective treatments are urgently needed. Promising new directions using molecular chaperones, oxalate degrading bacteria, and exploitation of oxalate transport physiology are in various stages of investigation.
