The primary hyperoxalurias are a group of autosomal recessive disorders involving the overproduction of oxalate. The latest review article in our Medical Progress series discusses the major biochemical, genetic, and therapeutic advances that have led to a better understanding of the disease.
• How is oxalate metabolized and what are the earliest symptoms of primary hyperoxaluria?
Oxalate, a dicarboxylic acid (HOOC-COOH), is a highly insoluble end product of metabolism in humans. It is excreted almost entirely by the kidney, particularly in the form of its calcium salt, and has a tendency to crystallize in the renal tubules. The main defect of inherited hyperoxaluria is the overproduction of oxalate, primarily by the liver, which results in increased excretion by the kidney. The earliest symptoms among those affected are urolithiasis and nephrocalcinosis, which lead to progressive renal involvement and chronic kidney disease.
• What is the clinical spectrum of primary hyperoxaluria?
Primary hyperoxaluria may occur at any age — from birth to the sixth decade of life — with a median age at onset of 5.5 years. The clinical presentation varies from infantile nephrocalcinosis and failure to thrive as a result of renal impairment to recurrent or only occasional stone formation in adulthood. However, 20 to 50% of patients have advanced chronic kidney disease or even ESRD [end-stage renal disease] at the time of diagnosis. Roughly 10% of patients receive a diagnosis of primary hyperoxaluria only when the disease recurs after kidney transplantation. In other cases, the disease is identified before symptoms appear in the course of family evaluations. Kidney injury, leading to a decrease in the GFR [glomerular filtration rate], results in chronic kidney failure and ultimately in ESRD, together with progressive systemic involvement. The major sites of crystal deposition are the kidneys, the blood-vessel walls, and the bones, with crystal deposits in bones often leading to fractures. However, oxalosis also affects the joints, retina, skin, bone marrow, heart, and central nervous system, leading to severe illness and death.
Morning Report Questions
Q: How is primary hyperoxaluria diagnosed?
A: Given its rarity, primary hyperoxaluria may go unrecognized for several years after the onset of symptoms. Because a majority of patients with primary hyperoxaluria present with symptoms related urolithiasis, assessment of the risk of kidney stones, based on measurements of urinary levels of oxalate, calcium, citrate, sodium, magnesium, and urate, as well as urinary pH and volume, is central to a good evaluation. In patients with primary hyperoxaluria, kidney stones usually consist of more than 95% calcium oxalate monohydrate (whewellite), and they are unusually pale in color and disorganized in appearance. Not all patients with primary hyperoxaluria have markedly elevated levels of urinary oxalate, but if symptoms are suggestive, an additional evaluation for primary hyperoxaluria should be considered. Measurements of other urinary metabolites, such as glycolate and l-glycerate, are helpful but nonspecific. Levels of glycolate are elevated in two thirds of patients with primary hyperoxaluria type 1 and may also be elevated in patients with type 3. Measurement of plasma levels of oxalate should be reserved for patients with stage 3b chronic kidney disease (estimated GFR, 30 to 45 ml per minute per 1.73 m2), since plasma levels remain relatively normal until kidney function is substantially impaired. A definitive diagnosis of primary hyperoxaluria in a patient with suggestive clinical signs and symptoms requires genetic testing.
Q: How is primary hyperoxaluria treated?
A: Once a diagnosis of primary hyperoxaluria is being entertained, supportive measures should be initiated, since long-term adherence to such treatment can dramatically improve the prognosis and slow the progression to ESRD. Fluid intake of more than 2 to 3 liters per square meter of body-surface area per day is essential for stone prevention, but in infants tube or gastrostomy feeding may be required to obtain appropriately dilute urine around the clock. Pyridoxine supplementation is helpful in primary hyperoxaluria type 1 (but not in other forms of primary hyperoxaluria). The intestinal oxalate load has a limited effect on disease progression in primary hyperoxaluria, since the main source of oxalate is endogenous. Consequently, oxalate-rich foods should be restricted only as a precaution, and normal calcium intake should be maintained. Probiotics that break down oxalate (e.g., Oxalobacter formigenes) may have a role in promoting intestinal oxalate excretion, although a recent clinical trial had disappointing results. Extracorporeal shock-wave lithotripsy (ESWL) is not recommended in patients with primary hyperoxaluria who have a heavy stone burden, both because calcium oxalate stones do not easily fragment and because the risk of parenchymal damage, particularly in small kidneys, is high. For affected patients with a high stone burden, minimally invasive methods (e.g., ureteroscopic laser lithotripsy with percutaneous stone removal) are preferable to ESWL.