Hydroxyproline Influence on Oxalate Metabolism
| Status: | Recruiting |
|---|---|
| Healthy: | No |
| Age Range: | 15 - 65 |
| Updated: | 4/21/2016 |
| Start Date: | September 2013 |
| End Date: | January 2017 |
| Contact: | Julie B Olson, RN |
| Email: | hyperoxlauriacenter@mayo.edu |
| Phone: | 800-270-4637 |
Influence of Hydroxyproline Plasma Concentration on Its Metabolism to Oxalate
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 signficant 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 us 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.
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 signficant 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 us 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.
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.
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.
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
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