Clinical trial NCT00280215: Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria
Official title: Renal Protective Effect of ACEI and ARB in Primary Hyperoxaluria
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Hyperoxaluria
Keywords: Primary Hyperoxaluria
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2006-01-20
Enrollment: 0
Sex: ALL
Minimum age (years): 10
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. Hyperoxaluria that persists during treatment with pyridoxine.
3. Ten years of age or older.
4. Glomerular filtration rate \> 50 ml/min/1.73 m2 at the start of the study.
5. Women of child bearing age will be required to use adequate contraception for 3 months before and throughout the study.
6. 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

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Primary outcomes:
measure: Two-year change in the urinary markers of renal tubular injury and interstitial fibrosis
timeFrame: 2 years
Secondary outcomes:
measure: Rate of change in 1. Renal tubular injury markers and 2. Renal function as determined by serum creatinine and creatinine clearance.
timeFrame: 2 years
Other outcomes:
Locations:
Study officials:
affiliation: Mayo Clinic Hyperoxaluria Center, Rochester MN
name: Dawn S Milliner, M.D.
role: PRINCIPAL_INVESTIGATOR
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