Clinical Pearls & Morning Reports
Secondary hyperoxaluria almost always manifests later in life than primary disease, which typically manifests in childhood. Read the Clinical Problem-Solving Article here.
Q: Primary hyperoxaluria type 1 is associated with pathogenic variants in what gene?
A: Most cases of primary hyperoxaluria are associated with pathogenic variants in one of three genes (AGXT, GRHPR, and HOGA1 in disease types 1, 2, and 3, respectively) that encode for enzymes involved in glyoxylate metabolism; more than 200 different pathogenic variants have been described. The gene defects are autosomal recessive; all result in increased oxalate production.
Q: What are some of the causes of secondary hyperoxaluria?
A: Secondary hyperoxaluria is caused by increased intestinal oxalate absorption (enteric hyperoxaluria) or excessive dietary intake of oxalate (e.g., rhubarb, spinach, parsley, and cocoa) or its precursor, ascorbic acid; long-term supplementation with ascorbic acid has been reported to increase 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 (with a risk of heart block, synovitis, oxalate osteopathy, or crystalline retinopathy), secondary hyperoxaluria tends to follow a more benign course.
A: Measurement of two 24-hour urine specimens is recommended to confirm the diagnosis of hyperoxaluria (i.e., urinary oxalate levels above the reference range of 0.04 to 0.50 mmol per 24 hours). Values greater than 1 mmol per 24 hours characterize primary hyperoxaluria, whereas less-marked elevation is more typical of secondary hyperoxaluria. In patients with chronic kidney disease, however, 24-hour urine testing is less sensitive because the deterioration in renal function leads to reduced urinary oxalate excretion. Plasma oxalate levels are useful in this circumstance; relative to the normal range (1 to 5 µmol per liter), plasma oxalate levels are often higher than 80 µmol per liter in patients with primary hyperoxaluria and are between 20 and 80 µmol per liter in patients with secondary hyperoxaluria. A diagnosis of primary hyperoxaluria may be confirmed by whole-gene sequencing of AGXT, GRHPR, and HOGA1. Analysis of urinary metabolites is also helpful because primary hyperoxaluria is associated with elevated urinary levels of glycolate (type 1 disease) or l-glycerate (type 2 disease).
A: Treatment of secondary hyperoxaluria typically involves high fluid intake (3 to 4 liters per day) to counteract calcium oxalate supersaturation, as well as dietary modification (high-calcium, low-oxalate diet). Supplementation with pyridoxine (vitamin B6), which is routinely used in patients with primary hyperoxaluria, may also have a role in some cases of secondary hyperoxaluria; however, its effectiveness in this context has not been well studied. Urinary alkalinization with potassium citrate and sodium citrate has been suggested as a means of reducing calcium oxalate crystallization, because the citrate complexes with (and thus lowers the level of) urinary ionized calcium; although this treatment has been shown to reduce levels of urinary oxalate in patients with a propensity for the development of kidney stones, it has not been tested specifically in patients with enteric hyperoxaluria. Secondary oxalate nephropathy is typically diagnosed late, by which time irreversible changes have often occurred within the parenchyma, such as interstitial infiltration, tubular injury, and mesangial-cell proliferation. Case series suggest that more than half the patients with secondary oxalate nephropathy ultimately receive renal-replacement therapy, with none having a complete recovery.