A Primer on Primary Hyperoxaluria

Primary hyperoxalurias are a group of autosomal recessive disorders characterized by excess hepatic oxalate production and reduced kidney excretion.

They are classified into three types based on their enzymatic defect in glyoxylate metabolism

• Type 1 (80%): alanine glyoxylate aminotransferase (AGT) 
• Type 2 (10%): glyoxylate reductase/hydroxypyruvate reductase (GRHPR) 
• Type 3 (10%): mitochondrial 4-hydroxy-2-oxoglutarate aldolase enzyme (HOGA1)

Variable in presentation and severity, its true prevalence is likely underestimated. While it can occur at any age, the median age of onset is 5.5 years. In Europe, it has an estimated prevalence of 1-3 cases per 1 million, incidence of 1 case per 120,000 live births and account for 1-2% of pediatric ESKD Unfortunately 20-50% of patients have advanced CKD at diagnosis and 10% are diagnosed only after disease recurrence following transplantation.

Excreted almost entirely by the kidney, oxalate can cause kidney tubular toxicity, nephrocalcinosis and obstruction with superimposed infection. In type 1 primary hyperoxaluria as eGFR falls below 30, plasma oxalate rises resulting in oxalate deposition in various organs including the kidney, heart, joints, retina, skin, bone marrow, heart and CNS.

Given its rarity, clinical suspicion is required for diagnosis. Definitive diagnosis requires genetic testing. Clinically it presents with urolithiasis (greater than 95% calcium oxalate monohydrate), recurrent UTIs, metabolic acidosis, acute kidney failure or oxalate crystals on kidney biopsy. Labs can be notable for persistently elevated urine oxalate, serum L-glycerate or serum oxalate. For persons with a family history, prenatal diagnosis can be obtained through genetic screening in the first trimester.

Conservative treatment strategies should be employed early and include aggressive hydration and potassium citrate to inhibit crystallization. Pyridoxine supplementation can be used for primary hyperoxaluria type 1 Gly170Arg and Phe152Ile genotypes. Intestinal oxalate has limited effects on disease progression as oxalate is largely produced endogenously and studies using oxalate-metabolizing probiotics like Oxalobacter formigenes have been disappointing.

In primary hyperoxaluria type 1 conventional HD and PD are ineffective at removing sufficient levels of oxalate for patients with ESKD due to ongoing liver production. While the ultimate management is transplantation, dialysis may be required as a temporary therapy to reduce plasma oxalate levels. Strategies include short daily sessions of high-flux dialysis, nocturnal dialysis, or combinations of hemodialysis and nocturnal peritoneal dialysis.

Isolated liver transplantation corrects the enzyme defect and can be used in early stages of kidney disease. Isolated kidney transplantation can reduced plasma oxalate, but disease recurrence often leads to poor graft survival. Dual liver-kidney transplantation is thus commonly performed for patients with CKD stage 4. Limited data exists for organ transplantation in primary hyperoxaluria type 2 and type 3 has not yet been associated with ESKD.

Sapna Shah, MD
Nephrology Fellow
Mount Sinai, New York