Primary hyperoxaluria: new directions for diagnosis and treatment

Abstract: Primary hyperoxaluria type 1 (PH1) is a rare genetic autosomal recessive disorder caused by deficient function of the liver-specific metabolic enzyme alanine:glyoxalate aminotransferase (AGT). AGT normally catalyzes the breakdown of glyoxalate to glycine; in PH₁, AGT function is abnormal and oxalate accumulates within the body. Oxalate can only be removed from the body by renal excretion, leading to hyperoxaluria with deposition of oxalate in the kidneys and progressive nephrocalcinosis, urolithiasis and renal failure. As renal function declines, oxalate deposition rapidly occurs in tissues throughout the body and results in systemic multiorgan dysfunction and early mortality. Diagnosis of PH1Sn the past was based on clinical presentation in conjunction with high plasma and urinary oxalate measurements. Confirmation of the diagnosis was made by examining liver biopsies for AGT activity. Treatment was primarily based on measures to increase urine flow and decrease oxalate crystallization within the kidney tubules. Pyridoxine therapy was empirically found to be helpful in a number of cases. Renal replacement therapy (dialysis and renal transplantation) met with limited success due to the low rate of oxalate clearance with both haemo- and peritoneal dialysis and the rapid deposition of oxalate within the transplanted kidney. Over the last 5 years, new understanding of the structure and function of AGT and the molecular basis of AGT dysfunction has resulted in the development of new diagnostic techniques which can in some cases eliminate the need for invasive liver biopsies. In addition, characterization of a known genetic polymorphism in combination with a specific amino acid mutation has been found to correlate with response to pyridoxine therapy in a third of patients. Improved long term results in patients who have progressed to renal failure have been reported with combined liver-kidney transplantation in conjunction with aggressive perioperative measures to reduce serum oxalate levels and systemic oxalate stores. Some experience with preemptive liver transplant prior to the development of renal failure has been reported. The role of pre-emptive liver transplantation remains uncertain given the unpredictability of the timing of renal failure and risks of liver transplantation and life-long immune suppression. Continuing efforts at developing specific gene therapy are ongoing.