Hydroxyproline Influence on Oxalate Metabolism
Condition: Hyperoxaluria
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Primary hyperoxaluria is an inborn error of metabolism that results in marked overproduction
      of oxalate by the liver. The excess oxalate causes kidney failure and can cause severe
      systemic disease due to oxalate deposition in multiple body tissues.

      Metabolic pathways that lead to oxalate are poorly understood, but recent evidence suggests
      that hydroxyproline may play a role. Sources of hydroxyproline include the diet and bone
      turnover. If hydroxyproline can be confirmed as a significant factor in primary
      hyperoxaluria, diet modification might be of value in reducing the severity of disease.

      This protocol, in which hydroxyproline labelled with a cold isotope is infused intravenously
      in patients with primary hyperoxaluria, will allow the researchers to measure the amount of
      oxalate produced from hydroxyproline. The contribution of hydroxyproline metabolism to the
      amount of oxalate excreted in urine in will be able to be determined for patients with each
      of the known types of primary hyperoxaluria.
    

Detailed description: 
      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.
      The researchers have estimated that 10 - 20 mg is synthesized in the body of healthy adults
      each day. 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: glyoxylate
      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 hydroxy-oxoglutarate
      aldolase (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. 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.
    

Intervention name(s): Hydroxyproline and Leucine
Intervention type(s): Drug
Intervention description(s): Subjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the CRTU. The metabolic flux of 2H3-leucine has been well characterized, and is used as a control when studying the metabolism of trace infusions of labeled amino acids 3. Blood samples will be obtained every 30 min to determine the enrichment of plasma with 13C5-hydroxyproline and 2H3-leucine. Urine collections will be obtained hourly. The fluxes of whole body hydroxyproline and leucine will be calculated
Other intervention name(s): 13C5-hydroxyproline; 2H3-leucine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hyperoxaluria; Oxalate; Primary Hyperoxaluria