Renal Effects of an Angiotensin Converting Enzyme Inhibitor in Adults With Chronic Kidney Disease of Uncertain Aetiology (CKDu)

A Double Blind Clinical Trial to Examine the Renal Effects of an Angiotensin Converting Enzyme Inhibitor (Enalapril) in Adults With Chronic Kidney Disease of Uncertain Aetiology (CKDu)

Enalapril would significantly reduce progression of renal disease in patients with Chronic Kidney Disease of Uncertain aetiology.

Study Overview

• Status: Unknown
• Conditions: Renal Insufficiency, Chronic
• Intervention / Treatment: Drug: Enalapril; Drug: Calcium Supplement

Detailed Description

End Stage Kidney Disease (ESKD) results in reduced life expectancy, quality of life and increased consumption of health care resources. Chronic Kidney Disease of Uncertain aetiology (CKDu) is being increasingly recognized in the North Central Region of Sri Lanka and in certain regions over 25% (unpublished data) of general population is suspected as suffering from CKDu. The number of patients who reach ESKD that requires hemodialysis or transplantation is increasing, highlighting the need to find strategies that slow progression of kidney disease. The need for these strategies is even more critical in Sri Lanka where dialysis in not a preferred treatment option. Treatment strategies should be readily accessible and cheap.

The importance of proteinuria as a significant risk factor for ESKD is well recognized, and treatment that is targeted at reducing proteinuria has been shown to reduce progression of renal disease. The Renin - Angiotensin - Aldosterone - System (RAAS) is directly involved in the regulation of blood pressure, fluid volume, and vascular response to injury and inflammation. The inappropriate activation of this system causes hypertension, fluid retention, and inflammatory, thrombotic, and atherogenic effects that may contribute to end-organ damage in the long term. Angiotensin II mediates hemodynamic effects as well as inflammation and fibrosis in the kidney, heart, and vasculature.

Numerous clinical trials have established that interruption of the RAAS cascade with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) is beneficial in slowing progression of renal disease. Reduction of BP lowers proteinuria, but the use of an ACEI or an ARB reduces both proteinuria and the rate of deterioration of renal function beyond those seen with equivalent BP reduction from conventional antihypertensive agents. However, the use of these agents has limitations, with significant numbers of treated patients still demonstrating progressive renal disease. RAAS blockers have been shown to blunt the progression of advanced kidney disease. However the long-term renal effect of these agents in early renal disease is not well demonstrated. In fact the trials which showed benefits with RAAS blockers did show in glomerular disease and evidence is not so strong in tubulo-interstitial disease. The benefits of RAS inhibition seem to depend on the degree of proteinuria at baseline. It is marginal in those with low grade proteinuria.

In most forms of proteinuric chronic renal disease, glomerular filtration rate continues to decline even when the initial insult has been removed. The cause of CKDu is still unknown. CKDu is a tubulo-interstitial disease with low grade proteinuria. We believe that the place of ACEI for secondary prevention of CKDu progression needs investigation

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Selvarajah Mathu, MBBS, MD; Phone Number: 94-77-7390628; Email: mathuselvarajah@yahoo.com
• Study Contact Backup: Name: Navaratnasingam Janakan, MBBS, MSc, MD; Phone Number: 94-77-7489813; Email: navajanakan@yahoo.com

Study Locations

• Sri Lanka
  • North Central
    • Anuradhapura, North Central, Sri Lanka
      • General (Teaching) Hospital, Anuradhapura
      • Contact: Selvarajah Mathu, MBBS, MD; Phone Number: 94-77-7390628; Email: mathuselvarajah@yahoo.com
      • Principal Investigator: Selvarajah Mathu, MBBS, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females between 18-70 years of age
• CKDu Grade 1, 2, 3
• No contraindication for treatment with ACEI
• Informed consent given

Exclusion Criteria:

• Grade 4 CKDu
• Other chronic diseases
• Evidence or suspicion of non renal secondary hypertension
• Diabetes type 1 or 2
• Evidence or suspicion of renovascular disease, obstructive uropathy, or other renal disease
• Treatment with corticosteroids, non-steroidal anti-inflammatory drugs, or immune-suppressive drugs
• Acute myocardial infarction or cerebrovascular accident in the previous 6 months
• Severe uncontrolled hypertension (diastolic blood pressure ≥115 and/or systolic blood pressure ≥220 mm Hg)
• Suspicion or evidence of connective tissue disease, cancer, higher serum aminotransferase concentrations
• Chronic cough; drug or alcohol abuse; pregnancy and breast feeding
• Unwillingness to sign informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Enalapril, Proteinuria < 1g/day	Drug: Enalapril; 2.5-20 mg/day; Other Names: Angiotensin Converting Enzyme Inhibitor
Placebo Comparator: Calcium, Proteinuria < 1g/day	Drug: Calcium Supplement; Calcium 2.5-20 mg/day; Other Names: Calcium lactate
Active Comparator: Enalapril, Proteinuria > 1g/day	Drug: Enalapril; 2.5-20 mg/day; Other Names: Angiotensin Converting Enzyme Inhibitor
Placebo Comparator: Calcium, Proteinuria > 1g/day	Drug: Calcium Supplement; Calcium 2.5-20 mg/day; Other Names: Calcium lactate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proteinuria	Numerous clinical trials have established that angiotensin-converting enzyme inhibitors (ACEI) are beneficial in slowing progression of renal disease. However the long-term renal effect of these agents in early renal disease is not well demonstrated. In fact the trials which showed benefits with ACEI did show in glomerular disease and evidence is not so strong in tubulo-interstitial disease.	One year
Estimated GFR	In most forms of proteinuric chronic renal disease, glomerular filtration rate continues to decline even when the initial insult has been removed. The cause of CKDu is still unknown. CKDu is a tubulo-interstitial disease with low grade proteinuria. We believe that the place of ACEI for secondary prevention of CKDu progression needs investigation.	One year

Secondary Outcome Measures

Outcome Measure	Time Frame
Cardiovascular mortality	One year
All cause mortality	One year

Collaborators and Investigators

• Sponsor: Ministry of Health, Sri Lanka
• Collaborators: World Health Organization
• Investigators: Principal Investigator: Selvarajah Mathu, MBBS, MD, Ministry of Health; Principal Investigator: Shanthi Mendis, MBBS, MD, World Health Organization; Principal Investigator: Rezvi Sheriff, MBBS, MD, University of Colombo; Principal Investigator: Thilak Abeysekera, MBBS, MD, Ministry of Health; Principal Investigator: Saroj Jayasinghe, MBBS, MD, University of Colombo

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Anticipated): October 1, 2012
• Study Completion (Anticipated): October 1, 2013

Study Registration Dates

• First Submitted: June 16, 2012
• First Submitted That Met QC Criteria: June 19, 2012
• First Posted (Estimate): June 20, 2012

Study Record Updates

• Last Update Posted (Estimate): June 20, 2012
• Last Update Submitted That Met QC Criteria: June 19, 2012
• Last Verified: June 1, 2012

More Information

Terms related to this study

• Keywords: Renal Insufficiency, Chronic; ACEI; Uncertain aetiology
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Protease Inhibitors; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Calcium; Enalapril; Calcium, Dietary; Enzyme Inhibitors; Angiotensin-Converting Enzyme Inhibitors
• Other Study ID Numbers: NSF CKDu Research