Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria

Study Overview
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Brief Summary
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This study will test the effectiveness of two medications: ACEI (angiotensin converting enzyme inhibitor)and ARB (angiotensin receptor blocker) in reducing the renal injury induced by hyperoxaluria in patients with Primary Hyperoxaluria. Hypothesis: Calcium oxalate crystal deposition in the kidney causes inflammation and resulting injury to kidney tissue. Angiotensin blockade will improve these changes, thus slowing the progression of renal insufficiency in patients with Primary Hyperoxaluria.

Detailed Description
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In patients with primary hyperoxaluria (PH), deficiency of hepatic enzymes important in disposition of glyoxylate results in marked hyperoxaluria. Calcium oxalate crystals and high oxalate concentrations in the renal filtrate result in inflammation and injury in the renal parenchyma. Loss of renal function over time is characteristic, with end stage renal failure occurring in half the patients by age 35 years, but as early as infancy in some patients. Experience in animal models of hyperoxaluria, and from other renal diseases, supports a role for ACEI and ARB medications in ameliorating inflammation and injury thus providing a renal protective effect. We propose to study the short-term effect of combined angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocking (ARB) therapy in patients with PH, in a controlled, randomized, two-year study. Primary endpoints will be urinary markers of renal tubular injury (retinol binding protein (RBP), alpha 1 microglobulin (α1m), γ-glutamyl transferase (GGT)) and interstitial fibrosis (transforming growth factor beta 1 (TGFβ1). Secondary endpoints will be the rates of change in renal tubular injury and renal function as determined by serum creatinine and creatinine clearance.

Official Title
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Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria

Conditions
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Hyperoxaluria

Intervention / Treatment
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* Drug: ACEI / Angiotensin converting enzyme inhibitor
* Drug: ARB /Angiotensin Receptor Blocker
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PH established by liver enzyme analysis in the patient or an affected sibling, DNA testing for mutations of the AGXT and GR/HPR gene, or meeting clinical criteria (Urine oxalate > 70 mg/1.73 m2/day in the absence of malabsorption or dietary excess of oxalate. Elevated urine glycolate or glycerate provides supporting evidence of type I or type II PH, respectively). Hyperoxaluria that persists during treatment with pyridoxine. Ten years of age or older. Glomerular filtration rate > 50 ml/min/1.73 m2 at the start of the study. Women of child bearing age will be required to use adequate contraception for 3 months before and throughout the study. Patients will be on a stable program of pyridoxine, neutral phosphate, or citrate medications - Exclusion Criteria: a. Age < 10 years. b. Glomerular filtration rate < 50 at start of study c. Hypersensitivity to ACEI or ARB medications d. Chronic use of ACEI or ARB medications prior to enrollment e. Hyperkalemia f. Previous renal transplant g. Homozygosity for the G170R mutation of AGXT h. Unwillingness to use adequate contraception during the study. i. Pregnancy -

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker. Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months. | Drug: ACEI / Angiotensin converting enzyme inhibitor<br>* Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker, Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.<br>* Other names: Lisinopril;Drug: ARB /Angiotensin Receptor Blocker<br>* Patients will be randomized to a combination of Angiotensin Converting Enzyme Inhibitor and Angiotensin Receptor Blocker,Patients will be randomized to a combination of ARB(losartan 50 mg daily in adult patients, 0.7 mg/kg/day in patients < 40 kg) ACE-I (lisinopril 10 mg daily in adult patients, 0.15 mg/kg/day in pediatric patients < 40 kg) to be taken for 24 months.<br>* Other names: Losartan;|
| Placebo Comparator: 2<br>Patients will take placebo for 24 months. | Drug: Placebo<br>* Patients will receive placebo for 24 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Two-year change in the urinary markers of renal tubular injury and interstitial fibrosis |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change in 1. Renal tubular injury markers and 2. Renal function as determined by serum creatinine and creatinine clearance. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Hyperoxaluria