Clinical trial NCT02038543: Hydroxyproline Influence on Oxalate Metabolism
Official title: Influence of Hydroxyproline Plasma Concentration on Its Metabolism to Oxalate
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hyperoxaluria
Keywords: Hyperoxaluria
Oxalate
Primary Hyperoxaluria
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Rare Diseases Clinical Research Network
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2014-01-16
Enrollment: 22
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Oxalate (UOx)
timeFrame: Participants will be followed for the duration of study infusion and observation, an average of 24 hours.
Secondary outcomes:
measure: Mean Percent Conversion of Hydroxyproline (Hyp) to Urinary Glycolate (UGIc)
timeFrame: Participants will be followed for the duration of the study infusion and observations, an average of 24 hours
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic Hyperoxaluria Center
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: John C Lieske, MD
role: PRINCIPAL_INVESTIGATOR
References: