Oxalate and Hyperoxaluria
Hyperoxaluria can be either primary or secondary. Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate and serine-pyruvate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, resulting in the formation of insoluble calcium oxalate crystals that accumulate in the kidney and eventually cause progressive renal failure. PPH1 is inherited as an autosomal recessive disorder. The majority of individuals with PH1 present in childhood or early adolescence with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function.
Secondary hyperoxaluria is caused by either increased intestinal oxalate absorption or excessive dietary intake of oxalate from eating foods such as rhubarb, spinach, parsley, and cocoa. Long-term supplementation with ascorbic acid increases the risk of plasma calcium oxalate supersaturation, particularly among patients undergoing hemodialysis. Increased intestinal oxalate absorption is most commonly caused by fat malabsorption, as has been well described in patients who have inflammatory bowel disease or who have undergone Roux-en-Y gastric bypass. In contrast to primary hyperoxaluria, in which systemic deposition of calcium oxalate is common, secondary hyperoxaluria follows a more benign course.
Secondary oxalate nephropathy is typically diagnosed late, by which time irreversible changes have often occurred within the renal parenchyma, such as interstitial infiltration, tubular injury, and mesangial-cell proliferation. More than half the patients with secondary oxalate nephropathy ultimately receive renal-replacement therapy, with none having a complete recovery.
Historically, the diagnosis of PH1 was confirmed by liver biopsy and AGT enzyme analysis. Enzyme analysis has been replaced by molecular testing.
More than 175 mutations in the AGXT gene have been found to cause PH1. PH1. Several common AGXT mutations have been identified including c.33dupC, p.Gly170Arg (c.508G->A), and p.Ile244Thr (c.731T->C). These mutations account for at least 1 of the 2 affected alleles in approximately 70% of individuals with PH1. Most of the AGXT gene mutations decrease or eliminate AGT activity. Other mutations cause the enzyme to be transported to mitochondria instead of to peroxisomes. While the mitochondrial enzyme retains activity, it cannot access glyoxylate which is in peroxisomes. The most common mistargeting mutation is G170R (gly170-to-arg). Direct sequencing of the AGXT gene is predicted to identify 99% of alleles in individuals who are known by enzyme analysis to be affected with PH1.
Measurement of two 24-hour urine specimens is recommended to confirm the diagnosis of hyperoxaluria. Urinary oxalate levels greater than 1 mmol per 24 hours characterize primary hyperoxaluria, whereas less-marked elevation is more suggestive of secondary hyperoxaluria. Urine testing is less sensitive in patients with chronic kidney disease because the deterioration in renal function leads to reduced urinary oxalate excretion. Plasma oxalate levels are useful for these patients. plasma oxalate levels. They are often higher than 80 µmol/L in patients with primary hyperoxaluria and between 20 and 80 µmol/L in patients with secondary hyperoxaluria.
Analysis of urinary metabolites is also helpful because primary hyperoxaluria is associated with elevated urinary levels of glycolate or L-glycerate in the presence of hyperoxaluria.
Reference Ranges
Urinary oxalate reference range 0.04 to 0.50 mmol per 24 hours.
Plasma oxalate reference range is 1 to 5 µmol per liter.
References
- Milliner DS: The primary hyperoxalurias: an algorithm for diagnosis. Am J Nephrol 2005;25(2):154-160
- Rumsby G, Williams E, Coulter-Mackie M: Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004;66(3):959-963
- Williams EL, Acquaviva C, Amoroso, A, et al: Primary hyperoxaluria type I: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-917.
- Forryan J et al. When the cause is not crystal clear. N Engl J Med 2020; 382:74-78
