Influence of Hydroxyproline Plasma Concentration on Its Metabolism to Oxalate

Location:

Rochester, Minn.

Trial status:

Open for Enrollment

Why is this study being done?

The purpose of this study is to determine the contribution of hydroxyproline metabolism to urinary oxalate and glycolate excretion in patients with primary hyperoxaluria. Oxalic acid (COOH)2 is an end product of metabolism that is synthesized mainly in the liver. We have estimated that 10 - 20 mg is synthesized in the body of healthy adults each day (1). The main precursor of oxalate is glyoxylate (CHO•COOH). The bulk of the glyoxylate formed is normally transaminated to glycine (NH2•CH2•COOH) by alanine: lyoxylate aminotransferase (AGT) or reduced to glycolate (CHOH•COOH) by glyoxylate reductase (GR). Less than 10% of the glyoxylate is oxidized to oxalate by lactate dehydrogenase (LDH). In individuals with the disease, primary hyperoxaluria, AGT, GR, or HOGA enzyme is deficient and the amount of oxalate synthesized by the liver increases to 80 - 300 mg per day. The increased oxalate excreted in urine can cause damage to kidney tissue. Calcium oxalate stones may form in the kidney or calcium oxalate crystals may deposit in renal tubules and the renal parenchyma (nephrocalcinosis). An increased rate of oxalate synthesis could also contribute to idiopathic calcium oxalate stone disease. Understanding the pathways of endogenous oxalate synthesis and identifying strategies that decrease oxalate production could be beneficial for individuals with these diseases. Hydroxyproline is the primary source of glyoxylate identified in the body (2). Daily collagen turnover of bone results in the formation of 300 - 450 mg of hydroxyproline, which cannot be re-utilized by the body and is broken down. This metabolism yields 180 - 250 mg of glyoxylate. Further hydroxyproline is obtained from the diet, primarily from meat and gelatin-containing products. The bulk of the glyoxylate formed is converted to glycine by the liver enzyme AGT, some to glycolate and a small amount to oxalate. The proportion of these metabolites is not known with any certainty. In this study, a quantitative estimate of the metabolites formed will provide estimates of the contribution of hydroxyproline turnover to daily oxalate production. These experiments will provide valuable information for the future assessment of the contribution of hydroxyproline metabolism to oxalate production in individuals with primary hyperoxaluria.

Who is eligible to participate?

Inclusion criteria: - Confirmed diagnosis of primary hyperoxaluria - eGFR (by serum creatinine) > 50ml/min/1.73m2 Exclusion criteria: - eGFR < 50 ml/min/1.73m2 - History of liver or kidney transplant - Primary hyperoxaluria patients who have responded to pyridoxine therapy with reduction of urine oxalate excretion to < 0.45 mmol/1.73m2/day. - Pregnancy

Last updated:

1/14/2014

NCT ID:

NCT02038543

IRB Number:

13-000150