Hydroxyproline Influence on Oxalate Metabolism

NCT ID: NCT02038543

Last Updated: 2017-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-30
• Study Completion Date: 2017-01-31

Brief 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.

Conditions

Hyperoxaluria

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Primary hyperoxaluria patients

Subjects will be infused with 13C5-hydroxyproline and 2H3-leucine for 6 hrs in the Clinical Research and Trials Unit (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

Group Type: EXPERIMENTAL

Hydroxyproline and Leucine

Intervention Type: DRUG

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

Interventions

Hydroxyproline and Leucine

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

Intervention Type: DRUG

Other Intervention Names

13C5-hydroxyproline; 2H3-leucine

Eligibility Criteria

Inclusion Criteria

• Confirmed diagnosis of primary hyperoxaluria (PH)
• Estimated Glomerular Filtration Rate (eGFR) (by serum creatinine) > 50ml/min/1.73m^2 - Patients with a diagnosis of PH I, PH II, PH III, or Non I/Non II/Non III PH (PH types will be confirmed by DNA)

Exclusion Criteria

• eGFR < 50 ml/min/1.73m^2
• 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/1.73m^2/day
• Pregnancy

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Rare Diseases Clinical Research Network

NETWORK

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

John Lieske

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

John C Lieske, MD

Role: PRINCIPAL_INVESTIGATOR

Mayo Clinic

Locations

Mayo Clinic Hyperoxaluria Center

Rochester, Minnesota, United States

Countries

United States

Other Identifiers

U54DK083908

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13-000150

Identifier Type: -

Identifier Source: org_study_id