Effect of Renin-angiotensin System Blockers on Glomerular Filtration Rate in Patients With Hypertension, Type 2 Diabetes With Normoalbuminuria

Phase 4

• Conditions: Hypertensive Disease; Diabetes
• Interventions: Drug: Renin-angiotensin system blockers; Drug: non-renin angiotensin system blockers

• Registration Number: NCT01500590
• Lead Sponsor: Hospital Authority, Hong Kong

Brief Summary

Diabetes is the leading cause of chronic kidney disease in developed countries. About 30-40% of patients with type 1 and type 2 diabetes mellitus will develop diabetic nephropathy. Microalbuminuria is often used as an early predictor of diabetic nephropathy. Many studies already demonstrated the renoprotective effect of Renin-angiotensin-system (RAS) blockers in patients with varying degree of albuminuria, few studies focus on studying the decline in glomerular filtration rate (GFR) among patients with normoalbuminuria. However a substantial number of diabetic patients exist with sub-normal GFR without microalbumin excretion. From literature, diabetes mellitus will have faster decline in GFR but the investigators do not know whether such decline can be slowed down by the use of RAS blockers as compared with other anti-hypertensive drugs. This Study investigate the effect of early treatment with RAS blockers on the decline rate of GFR in diabetic patients with normoalbuminuria.

Detailed Description

Renal excretory function, represented by GFR, deteriorates with age. After age 20-30 years, GFR declines by 1ml/min per year. This age related loss of renal function is proportional to blood pressure and glycemic level, and the rate of decline can accelerate up to 10-12 ml/min per year in poor BP and glycemia control.(1) Such rate of deterioration may lead to end-stage renal failure and the need for dialysis or transplantation.

Chronic kidney disease (CKD) is defined as either presence of kidney damage or GFR\< 60 ml/min/1.73 m2 for more than 3 months. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. Microalbuminuria is often an early and sensitive marker of kidney damage in many types of chronic kidney disease. Among patients with chronic kidney disease, the stage is divided into stage 1-5 by the level of GFR, with higher stages representing lower GFR levels.(2) Renin-Angiotensin System ( RAS) is an enzymatic cascade in which angiotensinogen is cleaved by renin to form angiotensin I, which in turn, is converted by angiotensin converting enzyme (ACE) to form angiotensin II. Angiotensin II produces renal vasoconstriction, so blocking the RAS is shown to be a useful approach to reduce the renovascular risk. Among the RAS blocking agents, angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARB) are most commonly used in clinical practice.

Many studies already demonstrated the renoprotective effect of ACEI and ARB. These studies include MicroHOPE study(3), IRMA(4), IDNT(5), RENNAL(6) with subjects having varying degree of albuminuria. With compelling benefit of RAS blockers in diabetic patients with albuminuria, current guideline from American diabetic Association (ADA) recommend the use of ACEI and ARB to delay the progression of renal disease in diabetic nephropathy.(7) According to the National Kidney Foundation guideline, the workgroup recommend hypertensive patients with diabetes and CKD stage 1-4 should be treated with an ACEI or ARB, usually in combination with a diuretic.(8) For patients with suboptimal GFR (\>= 60 ) without evidence of kidney damage like microalbuminuria, they are not considered as having CKD. There is lack of consensus on the selection of anti-hypertensive medication in this group of patients.

For subjects having normoalbuminuria, BENEDICT study demonstrates the delay in onset of microalbuminuria with the use of either trandolapril alone or trandolapril plus verapamil.(9) In ADVANCE trial, treatment with fixed combination of perindopril and indapamide reduced total renal event by 21%, defined as having new or worsening nephropathy or the development of new microalbuminuria.(10) However these studies mainly focus on using urinary albumin excretion as outcome measures. They seldom took the value of GFR into account.

However studies have found that significant decline in GFR in the absence of increase urine albumin excretion exists in a substantial percentage of adults with diabetes.(11) Decline in GFR should have diagnostic and prognostic value equivalent to urinary albumin excretion. However from literature, we cannot found the effect of RAS blockers on the decline in GFR. We therefore would like to carry out this study to investigate whether RAS blockers can delay the progress of renal disease, with particular attention to the value of GFR, in patients with GFR\>=60 but without microalbuminuria.

Study Timeline

• Study Start: 2011-11
• Study First Submitted: 2011-12-23
• Study First Submitted QC: 2011-12-27
• Study First Posted: 2011-12-28
• Status Verified: 2016-09
• Last Update Submitted: 2016-09-02
• Last Update Posted: 2016-09-05
• Primary Completion: 2018-08
• Study Completion: 2019-08

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 1400

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
renin-angiotensin system blockers	Renin-angiotensin system blockers	Those eligible patients will be randomized into 2 groups. One group use renin-angiotensin systems (RAS) blockers to control their blood pressure, the other group will use other types of anti-hypertensive agents other than RAS blockers
non-renin angiotensin system blockers	non-renin angiotensin system blockers	These includes norvasc adalat retard natrilix betaloc aldomet amlodipine 2.5 to 10 mg once daily nifedipine retard 20mg once daily to 40mg twice daily indapamide 2.5mg once daily metoprolol 25mg to 100mg daily methyldopa 125 mg once daily to 500mg twice daily

Primary Outcome Measures

Name	Time	Method
change of estimated GFR calculated by MDRD equation and onset of microalbuminuria	every 3 months	Diabetes mellitus patients assigned to have RAS blockers have slower decline in GFR and delay in onset of microalbuminuria compared with those using other anti-hypertensive drugs. We measure the value of eGFR at baseline and every 6 months period in both control group and intervention group. The eGFR is calculated by MDRD equation. GFR = 186 x {serum creatinine (umol/l) /88.4}-1.154 x (age) -0.203 x ( 0.742 if female); We than calculate the difference of eGFR value every 6 month from the baseline. We would like to compare this difference in both groups.

Trial Locations

Locations (1)

Hospital Authority, HKEC, FM&PHC; 🇨🇳 Hong Kong, China