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)

Relationship Between Achieved BP in Clinical Trials and Decline in GFR

Blood Pressure GoalsJNC VI ADA NKF

Diabetes <130/85 <130/85with ACEI

<130/80with ACEI

DiabeticNephropathy

<130/85with ACEI

<130/85with ACEI

<130/80with ACEI

RenalInsufficiency

<130/85with ACEI*

Not stated <130/80with ACEI

>1 gram urinaryprotein/day

<125/75with ACEI

Not stated <125/75with ACEI

*Caution advised if creatinine >3mg/dl

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 (11.87.3 difference between 2 treatment groups in Blacks vs 0.31.3 in Whites)

Hebert et al, Hypertens 1997

AASK trial Study of African Americans, age 18-70, with renal

insufficiency secondary to hypertension GFR (by iothalamate) between 25-70 ml/min/1.73m2

Designed to compare (2x3 design)– 2 levels of BP (MAP 92 vs usual Map of 102-107) – 3 initial antihypertensive regimens (enalapril (ACEI),

amlodipine (calcium-channel blocker), atenolol (beta-blocker))

Rate of decline in GFR

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

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

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

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) 2.31.2 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

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 0.51-0.94)

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

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

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

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 0.25-2.14)

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

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

-7.0 -5.0 -3.0 -1.0 1.0 3.0 5.0 7.0

Difference in GFR Decline (ml/min/mo)

Treatment Worse Treatment BetterSmulders (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

Effect of Lipid Reduction on Loss of GFR

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0

Difference in Albuminuria or Proteinuria [ln(treatment)- ln(control)]

Treatment WorseTreatment BetterSmulders(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

Effect of Lipid Reduction on Protein Excretion

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 100-160 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

Effect of Lipid Reduction on Albuminuria

6 mos 12 mos 18 mos

% change compared to baseline % change/mo

Placebo -0.12%(-0.23,0.56)

0.14%(-0.33, 0.56)

0.07%(-0.18,3.47)

0.77%(-1.71, 4.74)

Simvastatin 0.13(-0.29,0.31)

0.09(-0.12, 0.48)

-0.01(-0.18,0.099)

0.0805(-1.93, 3.69)

Data are medians and interquartile range

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

Use of Cardioprotective Medications in Chronic Renal Disease: Tonelli et al*

Total Group(n= 304)

Established CVD(n= 117)

Aspirin 27.3% 45.3%

Beta Blockers 33.9% 50.4%

ACEI 58.2% 57.3%

ARB 6.3% 6%

Statin (ifhyperlipidemic) 35.6% 49%

BP > 140/90 29.9% 35%

*Prospective Study of Patients seen by Nephrologists in 4 Canadian centers

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