Primary Hyperoxaluria (PH)
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 soluble 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 1), oxalate and L-glycerate (PH type 2) and oxalate and hydroxyoxoglutarate (HOG) in PH type 3. The urine oxalate excretion rate in affected patients is typically 2 to 6 times normal with severe clinical consequences.The highest excretion rates are seen in PH1.
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, refractory anemia, cardiomyopathy and cardiac conduction system abnormalities are the cause of severe morbidity and mortality. These rare diseases can be caused by defects in at least three glyoxylate-metabolizing enzymes. Untreated, PH patient outcome is often poor, with death from renal failure and systemic oxalosis the norm in PH type 1, Kidney failure is less often seen in PH types 2 and 3, though does occur and oxalosis can be severe. However, there is wide variability in outcome amongst patients, and with careful longterm clinical management patient survival with preserved renal function to middle age (or older) is possible in patients of all PH types. 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 20 years of age, end stage renal failure is observed in approximately 25% of patients with type 1 PH, and by 40 years of age, 55% have lost renal function. By contrast, in PH 2 at age 40 years approximately 20% have lost kidney function, and in PH3 5% have reached end stage kidney failure. 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. Observations of clinically diagnosed disease in North America are similar. However, examination of publically available genetic data from the NHLBI ESP suggests a higher prevalence of 1 in 58,000 among European and African Americans. This discrepancy may indicate milder forms of the disease or underdiagnosis. 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?
PH1, PH2, and PH3 are autosomal recessive disorders. These three well-defined subtypes of primary hyperoxaluria are 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) and type 3 (PH3) to deficiency of hydroxyoxoglutarate aldolase. A small number of patients have been identified with clinical characteristics indistinguishable from known PH types, but with normal AGT, GRHPR, and HOGA 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 types 2 and 3 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 maximizing oral fluid intake, carefully titrated doses of pyridoxine for those PH type 1 patients in whom it is effective and citrate or neutral phosphate to reduce calcium oxalate crystal formation in the urine. 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 therapeutics with siRNA techniques and chaperone molecules, oxalate degrading bacteria, and exploitation of oxalate transport physiology are in various stages of investigation.