1. Hypertension Control and Progression of Renal Disease
In clinical trials, a slower rate of decline in GFR is noted in those who achieved a BP of 130/80 or less
In the MDRD study (nondiabetics), a subset analysis found that in those with proteinuria >1 gram/day had a slower rate of progression when BP was <125/75 (MAP 92)
To achieve this will require multiple medications (>2 on average)

2. Relationship Between Achieved BP in Clinical Trials and Decline in GFR
From Bakris et al AJKD 2000
From Bakris et al AJKD 2000

3. Blood Pressure Goals
*Caution advised if creatinine >3mg/dl

4. MDRD and BP Control on Progression of Renal Disease
In addition to the protein restriction arm, there was an arm to look at 2 levels of BP (MAP  107 vs  92)
In both Blacks and Whites, higher protein excretion was associated with a greater effect from tighter BP control
Overall, the lower BP treatment arm was associated with a greater benefit in Blacks (11.87.3 difference between 2 treatment groups in Blacks vs 0.31.3 in Whites)
Hebert et al, Hypertens 1997

5. AASK trial
Study of African Americans, age 18-70, with renal insufficiency secondary to hypertension
GFR (by iothalamate) between ml/min/1.73m2
Designed to compare (2x3 design)
2 levels of BP (MAP  92 vs usual Map of )
3 initial antihypertensive regimens (enalapril (ACEI), amlodipine (calcium-channel blocker), atenolol (beta-blocker))
Rate of decline in GFR

6. AASK
Trial is still on-going, but the amlodipine arm has been discontinued
Amlodipine led to an initial improvement in GFR and then a faster decline compared to enalapril
This difference was mainly seen in those with a urine protein excretion >1 gram/day
Overall, the group with a urine protein excretion > 1 gram/day was a higher risk subgroup
This suggests that for those with significant proteinuria and hypertension, ACEI are the first drug of choice and that African Americans benefit from ACEI

7. ACEI
ACEI are effective in diabetic and nondiabetic renal disease in slowing progression of renal disease
The effect of ACEI appears to be in addition to their blood pressure lowering effect
Their effect is greater in those with proteinuria
They should be the first line agent in any patient with hypertension and proteinuria
Would consider use in normotensive patients with proteinuria

8. ACEI in Diabetic Renal Disease
ACEI decrease progression from microalbuminuria to overt proteinuria in Type 1 diabetes
All Type 1 diabetics with microalbuminuria should be on an ACEI, irregardless of BP
There is less data in Type 2 DM with microalbuminuria, however ACEI decrease mortality in high risk individuals with DM (HOPE study) and slow progression once overt nephropathy has developed
In my opinion, all Type 2 DM with nephropathy should be on an ACEI (or ARB) unless not tolerated

9. ACEI in Nondiabetic Renal Disease
Recent meta-analysis (Jafar et al)
11 studies in English language
1860 subjects (941 ACEI, 919 control)
92% hypertensive
Baseline creatinine (mean) 2.31.2 mg/dl
Baseline proteinuria (mean) 1.8 2.3 g/day
Follow-up duration mean 2.2 years
Pooled analysis of individual patient data
Annals Int Med 2001

10. ACEI in Nondiabetic Renal Disease: Jafar et al Results
Those in ACEI group did have a greater mean decrease in systolic and diastolic BP
5.5 mm systolic (95% CI 3.0 to 6.1)
2.3 mm diastolic (CI 1.4 to 3.2)
ACEI decreased proteinuria to a greater degree
After adjustment for baseline characteristics, BP and proteinuria during follow-up, ACEI decreased progression to end-stage renal disease (7.4% ACEI, 11.6% control; RR 0.69, CI )

11. Angiotensin Receptor Blockers and Progression of Diabetic Nephropathy
3 recently published randomized trials examining the effect of ARB on progression of nephropathy in Type 2 diabetes (NEJM 2001)
All 3 studies aimed for equivalent BP control in all groups
Compared to other antihypertensive regimes, ARB’s slowed progression from microalbuminuria to overt proteinuria (Parving et al) and slowed progression to ESRD (Lewis et al, Brenner et al)
There isn’t data on head-to-head comparison of ACEI and ARB on progression of renal disease

12. Diabetes Control
Tighter glucose control decreases the development of microalbuminuria and overt proteinuria
There is not convincing data that it delays progression of renal disease once overt nephropathy develops
Unclear whether this reflects the relative importance of various risk factors in each stage of diabetic nephropathy or whether no trial has been of long enough duration

13. Control of Diabetes on Diabetic Nephropathy: DCCT
Intensive therapy decreased the development of sustained microalbuminuria by 60% (95% CI 37 to 74)
Intensive therapy decreased the risk of developing sustained overt albuminuria by 51% (CI 2 to 75%)
There were too few patients with a decline in GFR to evaluate
Kidney Int 1995

14. Intensive Glucose Control in Type II DM on Diabetic Nephropathy: UKDPS
Intensive control was associated with a decrease in the development of microalbuminuria and proteinuria
Not a significant difference in the development of renal failure (RR 0.45, 95% CI )

15. Lipids and Progression of Renal Disease
Mesangial cells resemble smooth muscle cells and respond to many of the same stimuli
In many, but not all, epidemiologic studies, hyperlipidemia predicts decline in renal function
In animal studies, treatment of hyperlipidemia ameliorates damage from renal disease (e.g. diabetic models, other renal disease models)
Treatment trial data is sparse

16. Meta-analysis of Lipid Reduction on Progression of Renal Disease
Randomized trials >3 months
13 trials found, able to obtain individual patient data from 5
11/13 used statins
Most short term and small
Examined change in GFR and proteinuria/albuminuria
Fried et al, Kidney Int 2001

17. Effect of Lipid Reduction on Loss of GFR
Treatment Worse
Treatment Better
Smulders (15)
Aranda (16)
Rayner (16)
Thomas (17)
Nielsen (18) Tonolo (19)
Buemi (21)
Hommel (21)
Scanferla (24) Lam (34)
Olbricht (43)
Nishimura (118)
Total (362)
p = 0.008

18. Effect of Lipid Reduction on Protein Excretion
Treatment Better
Treatment Worse
Smulders(15)
Aranda (16)
Rayner (16)
Nielsen (18) Tonolo (19)
Zhang (20)
Hommel (21)
Buemi (21)
Thomas (23)
Lam (34)
Olbricht (43)
Total (246)
p = 0.068

19. Lipid Reduction in Early Diabetic Nephropathy
Pilot Study in 39 Type 1 diabetics with normal or microalbuminuria
Randomized trial of simvastatin + diet (n=19) /placebo +diet (n=20) in those with LDL mg/dl
LDL decline by at least 25% by un-blinded pharmacist
Planned as 2-year study, but discontinued early, when recommendation of LDL threshold for starting medication lowered
Fried et al, JDC 2001

20. Effect of Lipid Reduction on Albuminuria
Data are medians and interquartile range

21. Poor Control of Hypertension and Low Use of ACEI in Renal Disease
In NHANES III, 75% of those with an elevated creatinine ( 1.6 in men or 1.4 in women) and hypertension were on medication
Only 27% had a BP <140/90
Only 11% had a BP <130/85 (JNC VI target)
In a recent study, 33% of nondiabetics and less than 50% of diabetics with CRI, in a large HMO, were on ACEI
Coresh et al, Arch Intern Med 2001; Nissenson et al JASN 2000

22. Use of Cardioprotective Medications in Chronic Renal Disease: Tonelli et al*
*Prospective Study of Patients seen by Nephrologists in 4 Canadian centers

23. Summary
Renal Failure is a growing public health problem that disproportionately affects the elderly and minorities
Early identification is possible by screening people for proteinuria or a mildly elevated creatinine
In current practice, many people with renal disease are diagnosed late and are under-treated
Early identification would allow greater attention at risk factors to decrease both progression of renal disease and cardiovascular disease, as similar risk factors are involved in the progression of both