1. Section I: RAS manipulation
E. Renal safety issues
HOPE: Any degree of proteinuria predicts CV risk
Content points:
Reduction in proteinuria is a desirable therapeutic outcome for two important reasons: prevention of dialysis and prevention of cardiovascular events. Microalbuminuria (generally defined as dipstick-positive proteinuria or an albumin to creatinine ratio [ACR] of >2 mg/mmol, equivalent to urinary protein excretion of 30 to 300 mg/day) is an independent predictor of cardiovascular events.
Gerstein et al used data from the HOPE study to clarify the relationship between different degrees of proteinuria and cardiovascular risk.29 Baseline urinary albumin measurements were available for 97% of the HOPE participants. Microalbuminuria was associated with a 1.83 relative risk for the primary outcome: combined cardiovascular death, MI, or stroke.
However, Gerstein et al found that any degree of proteinuria increases cardiovascular risk. A plot of the incidence of major cardiovascular events (primary outcome plus all-cause mortality and hospitalization for CHF) against ACR deciles revealed a continuous relation between proteinuria and cardiovascular risk. The risk extends well below threshold for microalbuminuria, which occurs in the 8th decile.
For every 0.4 mg/mmol increase in ACR, the risk of major cardiovascular events increased by 5.9%. This trend was observed in patients with and without diabetes.
It is relevant that in the HOPE study, ramipril reduced the primary outcome in patients with and without microalbuminuria.15

2. AASK: Study design Content points:
African Americans in the United States have a high prevalence of hypertension and as a result are at much higher risk for hypertension-related kidney disease than whites.1
The African American Study of Kidney Disease (AASK) examined the effects of three different antihypertensive drugs and two different intensities of blood pressure control in African Americans with hypertensive renal disease.30,31 AASK compared the effects of ACE inhibition (ramipril 2.5 to 10 mg daily), dihydropyridine calcium channel blockade (amlodipine 5 to 10 mg daily), and ß1-selective-blockade (metoprolol 50 to 200 mg daily) on renal function in 1094 African Americans with hypertensive renal disease (glomerular filtration rates [GFR] of 20 to 65 mL/min/1.73m2).
Each arm was also randomized to an aggressive blood pressure goal of 125/75 mm Hg or the more usual target of 140/90 mm Hg.
The primary study outcome was the rate of change in GFR and the secondary outcome was a composite outcome of >50% reduction in GFR, end-stage renal disease (ESRD), or death.
Follow-up was 4 years. There has been widespread belief that ACE inhibitors should be avoided in treatment of African Americans. However, after 3 years, the amlodipine arm of the study was discontinued based on demonstrated superior clinical efficacy with ramipril.31

3. AASK: Changes in GFR according to baseline UP/Cr (3-year data)
Content points:
Interim analysis of the ramipril and amlodipine arms of the AASK study indicated that ramipril was associated with a slower rate of renal disease progression despite comparable blood pressure reduction with both agents.31 The amlodipine arm of the study was therefore stopped at 3 years. The data appeared in an interim report.
This slide summarizes the changes in GFR at 3 years according to baseline urinary protein to creatinine ratios (UP/Cr) stratified as follows: <0.22 (corresponding to a protein excretion of <300 mg/d) or >0.22 (corresponding to a protein excretion of >300 mg/d, or microalbuminuria).
There was an acute rise in GFR in the amlodipine group with a baseline urinary protein to creatinine ratio of <0.22.
Among participants with a urinary protein to creatinine ratio of >0.22 the total decline in GFR at 3 years was 36% slower in the group treated with ramipril (P = 0.006).
Because a dihydropyridine calcium channel blocker-based antihypertensive drug regimen produced an acute rise in GFR among participants without proteinuria, in the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups. However, after adjustment for covariates, compared with the amlodipine group, the ramipril group had a 38% slower mean decline in GFR after 3 months (P = 0.002) and less proteinuria (P < 0.001).
The clinical outcomes of 4-year follow-up are summarized on the next slide.

4. AASK: Risk reduction in GFR decline, ESRD, or death with ACEI,
ß1-selective blockade, or CCB (dihydropyridine)
Content points:
The composite clinical outcome of the study was a decline in GFR of >50% from baseline (or 25 mL/min/1.73m2), end-stage renal disease (ESRD), or death.30
With the ACE inhibitor ramipril, there were 38% fewer composite clinical events than with amlodipine and 22% fewer than with the ß1-selective antagonist metoprolol. There were 19% fewer composite clinical events with metoprolol than with amlodipine.31
Progression of kidney disease was particularly rapid in patients with a urinary protein to creatinine ratio of >0.22. In these high-risk patients, the risk of composite clinical events was 46% lower with ramipril than with amlodipine, and 37% lower with metoprolol than with amlodipine.31

5. AASK: Clinical implications
Content points:
The results of AASK demonstrate that in African Americans with mild-to-moderate chronic renal insufficiency:
– ACE inhibition (ramipril) is effective initial antihypertensive therapy – ACE inhibition slows renal disease progression in patients with hypertensive renopathy and proteinuria more effectively than either dihydropyridine calcium channel blockade or ß1-selective blockade.30,31
The results of AASK demonstrate the benefit of controlling blood pressure in a high risk African American population with impaired renal function.
The results of AASK demonstrate that the renoprotective benefit of ACE inhibition extends to African Americans, dispelling the view that ACE inhibitors do not work well in this population.30,31

6. REIN post hoc analysis: Kidney survival by GFR tertile with ACEI
vs conventional therapy
Content points:
Background: Since the first ACE inhibitor, captopril, was approved for treatment of hypertension many physicians have been reluctant to offer the therapy to patients with renal failure.32 Reasons for potential concern have been acute renal function deterioration and hyperkalemia. Clinical trials have found ACE inhibitors can offer significant renal protection. However, many patients who might theoretically benefit from ACE inhibition are not currently offered the therapy that may delay progression of the disease.
A post hoc secondary analysis of the Ramipril Efficacy in Nephropathy (REIN) trial, assessed the risk/benefit profile of the ACE inhibitor ramipril in patients with nondiabetic, proteinuric chronic nephropathy and different degrees of renal insufficiency.32 Because the REIN trial did not use severe renal insufficiency as an exclusion criterion, this provided the opportunity for a post hoc study of the impact of renal function (GFR 10 to 100 ml/min/1.73 m2) on disease progression and response to treatment.
The study involved 322 patients who had at least three GFR evaluations that included a baseline measurement. There were 107 patients in the lowest GFR tertile, 108 in the middle tertile, and 107 in the highest tertile. Follow-up ranged from 21 to 49 months (mean 31 months).
The slide summarizes survival without ESRD by treatment and basal GFR. As expected, there were many more events in the lowest GFR tertile (50.5%, P < vs the second and third tertiles) and middle GFR tertile (17.6%, P < 0.01 vs the highest tertile). Regardless of treatment, progression to ESRD was relatively low among patients in the highest tertile.
The time-to-event analysis of ESRD showed a significant interaction of treatment effect with baseline proteinuria and GFR. Risk reduction was also strongly dependent on duration of treatment.

7. REIN post hoc analysis: Renoprotective effect of ACEI is independent
of renal failure severity
Content points:
Ramipril compared with the conventional treatment uniformly decreased the change in GFR by 22%, 22%, and 35% in the lowest, middle, and highest GFR tertiles respectively.32
Ramipril decreased the incidence of end-stage renal disease by 33%, 37%, and 100%, in the lowest, middle, and highest GFR tertile.

8. REIN post hoc analysis: Clinical implications
Content points:
This analysis establishes that the renoprotective effect of ACE inhibition in chronic nephropathies is independent of the severity of renal failure.32 ACE inhibition spared patients from dialysis in all three GFR subgroups, including those with very severe renal dysfunction, and was remarkably safe.
Renoprotection conferred by ACE inhibitors is time-dependent and treatment started at earlier stages of the disease considerably stabilizes renal function and prevents the need for dialysis:
– Maximal renal protection is achieved when treatment is started early in the course of the disease (GFR >50 mL/min)
– However, ACE inhibition is also renoprotective in patients with more severe renal disease (GFR between 10 and 30 mL/min).
ACE inhibition therapy should be offered to all patients with proteinuric chronic nephropathies, regardless of renal function (except those with prior allergic reaction or angioedema).

9. Multidrug approach to patients with chronic nephropathy
and nephrotic-range proteinuria
Content points:
Ruggenenti et al have developed this algorithm for a multidrug approach to optimize blood pressure control in patients with chronic renal disease and nephrotic-range proteinuria.33 The blood pressure target is <125/75 mm Hg.
Early interventions include a low-sodium diet, diuretic therapy, or both, and improved glucose control in diabetic patients.
ACE inhibition is initiated at a low dose and titrated to maximal doses. Additional antihypertensive agents (angiotensin type 1 receptor blockers, nondihyropyridine calcium channel blockers, and other agents) are added as needed to achieve the blood pressure target with choices tailored to the patient. In practice, a combination of antihypertensive agents is often necessary to achieve target blood pressure values.
Addition of a statin is also advised to treat lipid abnormalities of chronic renal insufficiency that are present in the early stages of renal function impairment and could promote progression of renal disease.

10. Targets of multidrug approach in chronic nephropathy or nephrotic-range proteinuria patients
Content points:
The notion of renoprotection is developing into a combined approach to renal disease, the main measures being pharmacologic control of blood pressure and reduction in proteinuria.33 Lowering blood lipids, smoking cessation, and tight glucose control for patients with diabetes also form part of the multimodal protocol for management of patients with renal impairment.
The targets of the multidrug approach to patients with chronic nephropathy and persistent nephrotic-range proteinuria are a reduction in multiple risk factors:
– Systolic or diastolic blood pressure: <125/75 mm Hg, as measured in the morning, prior to treatment
– 24-hour urinary protein excretion rate of <0.3 grams
– LDL-C of <2.6 mmol/L (<100 mg/dL)
– LDL-C and very low density lipoprotein (VLDL) cholesterol of <3.4 mmol/L (<132 mg/dL)
– Hemoglobin A1c of <7.5% in patients with diabetes

11. Renal disease progression after diagnosis of type 1 and type 2 diabetes
Content points:
In the past two decades the incidence of end-stage renal disease among patients with diabetes has increased, particularly with type 2 diabetes. One reason is as treatment of hypertension and CHD has improved, more patients with type 2 diabetes live long enough for nephropathy to develop.34
Although in the past, the risk of renal complications was thought to be considerably lower among patients with type 2 diabetes than among those with type 1 diabetes, abundant evidence shows that the risk of nephropathy with progression to end-stage renal disease is similar in the two groups.
As the duration of the illness increases, proteinuria develops to a similar extent among patients with type 1 and type 2 diabetes. By 10 to 15 years after diagnosis, both groups show an increase in the prevalence of proteinuria.
Within 5 years after the onset of proteinuria, progression to renal failure approaches 60% in patients with type 1 and type 2 diabetes.
Microvascular complications and macrovascular (atherosclerotic) complications are particularly frequent in high-risk patients with type 2 diabetes and renal failure.

12. Microalbuminuria progression rate predicts CHD mortality in diabetic patients
 Content points:
In patients with type 2 diabetes, microalbuminuria is associated with an increase in cardiovascular mortality. The rate at which microalbuminuria progresses varies considerably among patients. This study showed that the rate at which microalbuminuria progresses, rather than baseline level of microalbuminuria, is related to cardiovascular prognosis.35
The study involved 58 microalbuminuric patients with diabetes who were followed-up for 7-years. Five of the seven deaths during follow-up were from CHD. Cox's regression analysis identified progression of microalbuminuria as a significant predictor of all-cause mortality, CHD mortality, and macroalbuminuria. Adjustment for multiple risk factors did not affect these results.
An identical analysis showed that baseline microalbuminuria was not a significant predictor of cardiovascular outcomes.
Clinical implications: Compared with simply assessing the presence of microalbuminuria, monitoring the rate of progression may be a better method of identifying patients at risk for cardiovascular disease or decline in renal function

13. Effect of ARBs in patients with type 2 diabetes and nephropathy
Content points:
Two recently completed clinical trials investigated the effects of angiotensin II type 1 receptor blockers (ARBs) on progression of renal disease and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.37,38
Lewis et al in the Irbesartan Diabetic Nephropathy Trial (IDNT) studied 1715 patients with type 2 diabetes, hypertension and nephropathy followed-up for a mean of 2.6 years:36
- Irbesartan 300 mg reduced the primary outcome (composite of doubling of baseline serum creatinine concentration, end-stage renal disease, or all-cause mortality) by 20% vs placebo (P = 0.02) and by 23% vs amlodipine (P = 0.006). These effects were not explained by differences in the blood pressures that were achieved.
- There were no significant differences between treatments in the rates of cardiovascular composite outcomes or death.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study (RENAAL) assessed the effect of losartan in 1514 patients with type 2 diabetes and nephropathy.37 Patients also received conventional antihypertensive therapy (excluding ACE inhibitors) as needed. Mean follow-up was 3.4 years:
Compared with placebo, losartan was associated with a 16% risk reduction in the primary outcome (composite of doubling of baseline serum creatinine concentration, end-stage renal disease, or all-cause mortality), P = 0.02.
The rate of cardiovascular morbidity and mortality was similar between the two groups.

14. Trials of RAS inhibition in patients with type 2 diabetes and microalbuminuria
Content points:
The impact of renin-angiotensin system (RAS) inhibition in patients with type 2 diabetes and microalbuminuia was studied in two recent trials.38,28
The Irbesartan in patients with type 2 Diabetes and Microalbuminuria Study (IRMA-2) assessed the effect of the ARB irbesartan (150 mg or 300 mg daily) on diabetic nephropathy.38 IRMA-2 involved 590 patients with type 2 diabetes, hypertension, and microalbuminuria. Mean follow-up was 2 years.
MICRO-HOPE, a substudy of the HOPE trial, examined the effect of the ACE inhibitor ramipril on cardiovascular outcomes and diabetic nephropathy.28 The study involved 3496 patients with type 2 diabetes and 81 patients with type 1 diabetes. There were 1160 patients with microalbuminuria. Mean follow-up was 4.5 years.
The outcomes of these studies are discussed in the following slides.

15. IRMA-2: Primary outcome
Content points:
The baseline characteristics of the three treatment groups in IRMA-2 study were similar.38 In the group taking irbesartan 300 mg, 5.2% developed diabetic nephropathy compared with 9.7% in the 150-mg irbesartan group, and 14.9% in the placebo group. The Kaplan Meier curves in the treatment groups separated at three months and continued to diverge.
The 44% difference in progression to diabetic nephropathy with 150 mg daily of irbesartan was not significantly different from the placebo group. In the group taking irbesartan 300 mg/daily, there was a significant 68% difference in progression to nephropathy compared with the placebo group (P < 0.001).
The outcomes were adjusted for baseline level of microalbuminuria and the blood pressure reduction achieved with treatment.
The investigators concluded that irbesartan is renoprotective independent of its blood-pressure lowering effect in patients with type 2 diabetes and microalbuminuria.

16. MICRO-HOPE: Effect of ACE inhibition on renal and CV outcomes
Content points:
MICRO-HOPE, a substudy of HOPE, included 3496 patients with type 2 diabetes (98%) and 81 patients with type 1 diabetes (2%) and at least 1 other cardiovascular risk factor (hypertension or on antihypertensive treatment, dyslipidemia, smoking, or microalbuminuria) who were randomly assigned to ramipril 10 mg or placebo.28
As shown on the slide, the risk for overt nephropathy was reduced by 24% after 4.5 years (P = 0.027). Diagnosis was based on a positive 24-h urine collection or an albumin to creatinine ratio >36 mg/mmol. Ramipril 10 mg lowered the risk of nephropathy in those who did and did not have baseline microalbuminuria.
The cardiovascular benefits included significant reductions of 22% in MI (P = 0.01), 33% in stroke (P = 0.007), and 37% in cardiovascular death (P = ).
Ramipril 10 mg also was associated with significant reductions in the albumin-creatinine ratio at 1 year (P = 0.001) and at the end of the study (P = 0.02).
These findings demonstrate that ACE inhibition (ramipril 10 mg) has vasculoprotective and renoprotective effects in individuals with type 2 diabetes.