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

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.

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(CKDu) is being increasingly recognized in the North Central Region of Sri Lanka and in certain regions over 25% (unpublished data) of general population is suspected as suffering from CKDu.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

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