Transcript Causes of Death by PET

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 Goals
JNC VI
<130/85
ADA
<130/85
with ACEI
NKF
<130/80
with ACEI
Diabetic
Nephropathy
<130/85
with ACEI
<130/85
with ACEI
<130/80
with ACEI
Renal
Insufficiency
<130/85
Not stated
with ACEI*
<130/80
with ACEI
>1 gram urinary
protein/day
<125/75
with ACEI
<125/75
with ACEI
Diabetes
*Caution advised if creatinine >3mg/dl
Not stated
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
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 102107)
– 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
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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
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
Effect of Lipid Reduction on Loss of GFR
Treatment Worse
Treatment Better
Smulders
Aranda
Rayner
Thomas
Nielsen
Tonolo
(15)
(16)
(16)
(17)
(18)
(19)
Buemi
(21)
Hommel (21)
Scanferla (24)
Lam
(34)
Olbricht
(43)
Nishimura (118)
Total
(362)
-7.0
-5.0
p = 0.008
-3.0
-1.0
1.0
3.0
Difference in GFR Decline (ml/min/mo)
5.0
7.0
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)
-2.0
p = 0.068
-1.5
-1.0
-0.5
0.0
Difference in Albuminuria or Proteinuria
[ln(treatment)- ln(control)]
0.5
1.0
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%
0.14%
0.07%
(-0.23,0.56) (-0.33, 0.56) (-0.18,3.47)
0.77%
(-1.71, 4.74)
Simvastatin
0.13
0.09
-0.01
0.0805
(-0.29,0.31) (-0.12, 0.48) (-0.18,0.099) (-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 (if
hyperlipidemic)
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