Hydroxyproline Influence on Oxalate Metabolism

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 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.

Study Overview

• Status: Completed
• Conditions: Hyperoxaluria
• Intervention / Treatment: Drug: Hydroxyproline and Leucine

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Hyperoxaluria Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 61 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Drug: 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; Other Names: 13C5-hydroxyproline; 2H3-leucine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Oxalate (UOx)	The overall contribution of hydroxyproline catabolism to urinary oxalate (UOx) and glycolate (UGlc) excretion is determined by the excess mole percent enrichment of urine with 13C2-oxalate and glycolate corrected for the fraction of labelled [15N,13C5]-Hyp that is circulating in the plasma.	Participants will be followed for the duration of study infusion and observation, an average of 24 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Glycolate (UGIc)	The overall contribution of Hyp catabolism to urinary oxalate (UOx) and glycolate (UGlc) excretion is determined by the excess mole percent enrichment of urine with 13C2-oxalate and glycolate corrected for the fraction of labelled [15N,13C5]-Hyp that is circulating in the plasma.	Participants will be followed for the duration of the study infusion and observations, an average of 24 hours

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH); Rare Diseases Clinical Research Network
• Investigators: Principal Investigator: John C Lieske, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: December 19, 2013
• First Submitted That Met QC Criteria: January 14, 2014
• First Posted (Estimate): January 16, 2014

Study Record Updates

• Last Update Posted (Actual): July 2, 2017
• Last Update Submitted That Met QC Criteria: June 30, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Primary Hyperoxaluria; Oxalate; Hyperoxaluria
• Other Study ID Numbers: 13-000150; U54DK083908 (U.S. NIH Grant/Contract)