Hereditary disorders of oxalate metabolism—the primary hyperoxalurias

Oxalate is an end-product of metabolism with no known useful biological function in humans. Anything that increases the body burden of oxalate, or elevates the concentration of oxalate in the urine, increases the risk of calcium oxalate deposition in the kidney and/or urinary tract, resulting in nephrocalcinosis and/or urinary stones.

Hyperoxaluria can be due to excessive dietary intake, enhanced gut absorption (e.g. after small intestinal resection or bypass), ill-defined multifactorial disease (as in idiopathic calcium oxalate urinary stone disease, see Chapter 21.14), or—less commonly—as a consequence of a number of inherited monogenic disorders, only two of which have been well characterized.

Primary hyperoxaluria type 1 (PH1, alanine:glyoxylate aminotransferase deficiency) and type 2 (PH2, glyoxylate/hydroxypyruvate reductase deficiency)

Clinical features and diagnosis—presentation is with symptoms or findings related to urolithiasis, usually in childhood but sometimes in adult life. Recurring stone formation is characteristic, and with progressive loss of kidney function (reaching endstage renal failure at median 30 years) a rising plasma oxalate level leads to deposition of calcium oxalate in many organs (systemic oxalosis), manifesting as painful, nonhealing skin ulcers, fracturing osteodystrophy, refractory anemia, complete heart block, and heart failure due to oxalate cardiomyopathy. Variability of clinical expression is marked, with some patients reaching end-stage renal failure in early childhood, while others retain renal function into late adulthood. Diagnosis is by DNA analysis of peripheral blood samples, or by enzyme assay of percutaneous liver biopsy tissue. Prenatal diagnosis can be accomplished in the first trimester by DNA analysis of chorionic villus samples.

Management—this initially involves (1) maintenance of high fluid intake; (2) medications to inhibit calcium oxalate crystallization—pharmacological doses of pyridoxine (vitamin B₆) are useful in some patients; and (3) urological procedures as required. Management of endstage renal failure is difficult: (1) haemodialysis and peritoneal dialysis are not capable of preventing progression of systemic oxalosis; (2) kidney transplantation alone is problematic in PH1—patients who respond fully to pyridoxine (with normalization or near normalization of urine oxalate) can do well, but otherwise the new kidney is at significant risk from oxalate deposition, particularly if there is delayed graft function; (3) combined liver and kidney transplantation—the treatment of choice in patients with PH1 who do not respond well to pyridoxine and are approaching endstage renal failure.