Transcript Recent advances in management of diabetic nephropathy

Recent advances in
management of
Diabetic Nephropathy
…Tiger by the tail
Normal Kidney
Diabetic Kidney
Diabetic nephropathy
Diabetic nephropathy is progressive kidney disease
 Most common cause of ESRD
 More likely to die than progress to ESRD
 Multi-risk factor intervention is critical
 Lowering blood pressure with RAAS blockade is critical
 Combinations of ACEi + ARB or MRA sensible
 No long term efficacy or safety data
 Prevent cardiovascular morbidity and mortality

Why is Diabetic
Nephropathy Important?
Diabetes: The Most Common Cause
of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other
Glomerulonephritis
No. of dialysis patients
(thousands)
10%
700
13%
Hypertension
27%
Diabetes
50.1%
600
No. of patients
Projection
95% CI
500
400
520,240
300
281,355
200
243,524
100
0
r2=99.8%
1984
1988
1992
United States Renal Data System. Annual data report. 2000.
1996
2000
2004
2008
Annual Cardiovascular Mortality (%)
Cardiovascular Death is Major
Cause of Mortality in ESRD
100
ESRD Population
GP Male
10
GP Female
GP Black
1
GP White
General Population
0.1
Dialysis Male
Dialysis Female
Dialysis Black
0.01
Dialysis White
0.001
25-34
35-44
45-54
55-64
65-74
Age (years)
Sarnak MJ and Levey AS. Am J Kidney Dis. 2000;35(4)(suppl1):S117-S131.
Foley RN. Am J Kidney Dis. 1998;32(S3):S112-119.
75-84
> 85
What is the Natural
History of Diabetic
Nephropathy?
Definition of Diabetic
Nephropathy
Clinical diagnosis based on Hx, Exam and urine
albumin/creatinine ratio in most cases
 Longstanding History of diabetes + retinopathy
 Macroalbuminuria (a.k.a “overt nephropathy”)
defined as random urine albumin/creatinine ratio
> 300 mg/g
 Hypertension (> 90%)
 Renal Biopsy confirmation is rare

Development of Macroalbuminuria Heralds Rapid
Decline in Glomerular Filtration in Type II Diabetes
Time
1
1.5
2
years
2.5
3
3.5
4
Change in GFR ml/min
0
-10
-20
-30
Microalbuminuria
-40
Macroalbuminuria
-50
Nelson RG. et al NEJM, 1996
Diabetics with Nephropathy (DM/CKD) are More
Likely to Die than to Progress to ESRD
5% Medicare sample , 1996-1997 cohort, 2 year follow-up
N=1,045,263
188,596
33,586
19,335
100
Event Free
Percent of Patients
ESRD
80
65.12
73.18
60
85.04
90.53
40
5.85
2.25
0.31
20
0
All Cause
Death
0.07
9.40
NDM/Non-CKD
24.57
29.04
NDM/CKD
DM/CKD
14.65
DM/Non-CKD
Status in the entry period
Diabetics with Macroalbuminuria are More Likely to
Die than Develop ESRD
The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics)
Newly diagnosed, predominantly white, medically treated
No albuminruia
1.4%
2.0%
C
V
3.0%
Microalbuminruia
2.8%
4.6%
Macroalbuminruia
2.3%
19%
Elevated Serum Creatinine
D
E
A
T
H
Adler et al. Kid Int, 2003
What are Diabetics with Nephropathy
Dying From?
Stroke
Sudden
Death
Myocardial
Infarction
Heart
Failure
Diabetic Nephropathy
Improving Outcomes
in Diabetic Nephropathy
Prevention of
Cardiovascular
Events
Prevention of
End-Stage Renal Disease
What is the Proper Therapy
of Kidney Disease in
patients with Diabetes?
The Renal Injury Triad
Angiotensin II
Hypertension
Proteinuria
Definition of Abnormal Albuminuria
in Diabetes Mellitus
Microalbuminuria
Macroalbuminuria
(Nephropathy)
Detected by dipstick
Urine Albumin / Cr
Renal Risk
Cardiovascular Risk
No
Yes
30 - 299 mg Alb / g Cr > 300 mg Alb / g Cr
Marker of future
nephropathy in some
Marker progressive
renal disease
Increased
Increased
* Random (Spot) urine preferably A.M. recommended
ADA Guidelines:
Diabetic Nephropathy
 A-Level Evidence (well done RCTs)
–
To reduce the risk and/or slow the progression of
nephropathy, optimize glucose control.
–
To reduce the risk and/or slow the progression of
nephropathy, optimize blood pressure control.
ADA: Screening Guidelines
 Expert Consensus
–
–
Perform an annual test for the presence of microalbuminuria in (1)
type 1 diabetic patients who have had diabetes >5 years and (2) all
type 2 diabetic patients starting at diagnosis.
Acceptable samples to test for increased urinary albumin excretion
are timed (e.g., 12 or 24 h) collections for measurement of albumin
concentration and timed or untimed samples for measurement of
the albumin:creatinine ratio. For screening, an untimed sample for
albumin measurement (without creatinine) may be considered if a
concentration cutoff is used that allows high sensitivity for
detection of an increased albumin excretion rate. Level of
evidence: E
ADA: Treatment Guidelines
 A-Level Evidence (well done trials)
—
—
—
—
—
In the treatment of albuminuria/nephropathy both angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers
(ARBs) can be used:
In hypertensive and nonhypertensive type 1 diabetic patients with any
degree of albuminuria, ACE inhibitors have been shown to delay the
progression of nephropathy. (1a)
In hypertensive and non hypertensive type 2 diabetic patients with
microalbuminuria, ACE inhibitors and ARBs have been shown to delay
the progression to macroalbuminuria. (Cochrane 1a DOE)
In patients with type 2 diabetes, hypertension, macroalbuminuria, and
renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have been
shown to delay the progression of nephropathy.
If one class is not tolerated, the other should be substituted.
ADA: Treatment
 B-Level Evidence (well done cohort
studies)
— With
the onset of overt nephropathy, initiate
protein restriction to <0.8 g • kg-1 body weight •
day-1 (approximately 10% of daily calories), the
current adult recommended daily allowance for
protein. Further restriction may be useful in
slowing the decline of glomerular filtration rate in
selected patients.
ADA: Treatment
 Expert Consensus
If ACE inhibitors or ARBs are used, monitor serum
potassium levels for the development of hyperkalemia.
— Consider referral to a physician experienced in the care of
diabetic renal disease when the glomerular filtration rate
has fallen to either <60 mL • min-1 • 173 m-2 or
difficulties have occurred in the management of
hypertension or hyperkalemia.
— Consider the use of non-dihydropyridine calcium channel
blockers or beta-blockers in patients unable to tolerate
ACE inhibitors or ARBs.
—
ACE-I is More Renoprotective than Conventional
Therapy in Type 1 Diabetes (Total N = 409)
0
% with
Doubling of
Baseline
Creatinine
Captopril
Conventional therapy
25
50
75
Baseline creatinine > 1.5 mg/dl
100
-2–
0
1
2
4
- 40 –
0–
- 20 –
Decrease in
Mean Blood- 2 –
Pressure
(mm Hg) - 4 –
% Reduction 0 –
in
Proteinuria - 20 –
-6–
-8–
3
- 40 –
NS
Lewis et al. N Engl J Med. 1993;329:1456-1462.
- 60 –
P <.001
ARB (losartan) Reduces Risk of ESRD in
Diabetic Nephropathy
Reduction in Endpoints in NIDDM with Angiotensin Antagonist
Losartan (RENAAL) Trial: 1513 type 2 Diabetics with Nephropathy
ESRD
30
% with event
Placebo
BP 142 / 74
Risk Reduction: 28%
p=0.002
20
10
Losartan
BP 140 / 74
• Avg: 3.5 BP drugs/pt
• 90% in both groups
received a CCB
0
0
12
24
36
48
347
375
42
69
Months
P (+ CT)
L (+ CT)
762
751
715
714
610
625
Brenner et al. New Engl J. Med Sept 20 2001
Irbesartan in Diabetic Nephropathy Trial:
Time to Doubling of Serum Creatinine, ESRD, or Death
1,715 Type 2 Diabetics with Nephropathy
70
Irbesartan
BP 140/77
60
BP 141/77
50
Placebo
40
BP 144/80
Change in Proteinuria
5
30
0
Percent Reduction
Subjects (%)
Amlodipine
RRR 23%
P=.006 RRR 20%
P=.02
P=NS
20
10
-5
-10
-15
Irbesartan
Amlodipine
Placebo
-20
-25
-30
0
-35
0
6
12
18
Lewis EJ, et al. N Engl J Med. 2001;345:851-860.
24
30
36
Follow-up
(mo)
42
48
54
60
Albuminuria at Baseline Predicts ESRD in Type
2 Diabetics with Nephropathy: RENAAL Trial
(N=1513)
% with ESRD end point
100
Baseline Albuminuria
80
≥3.0 g/g
HR
8.10
60
≥1.5<3.0 g/g
40
20
<1.5 g/g
0
0
12
de Zeeuw et al. Kid. Int. June 2004
24
Month
36
48
3.23
1.0
Reduction in Proteinuria is Associated with Reduced
Risk for End-Stage Renal Disease in Diabetic
Nephropathy
4.0
Relative Risk for
ESRD
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
<-40
de Zeeuw et al. Kid. Int. June 2004
≥-40
≥-10
<-10
<10
≥10
<40
≥40
<60
Change in Albuminuria %
≥60
RENAAL; Proteinuria Reduction (<0% versus
>30%) determines the cardiovascular outcome
% with CV endpoint
<0%
>30%
30
20
10
Heart Failure
40
% with heart failure
CV Endpoint
40
30
20
<0%
10
>30%
0
0
0
12
24
36
Month
De Zeeuw et al; Circulation, in press
48
0
12
24
Month
36
48
% with ESRD event
Continuation of Losartan After Serum
Creatinine Doubles Reduces Incidence of
ESRD
80 Risk Reduction: 30%
p=0.013
60
P
L
40
20
0
0
6
12
18
24
11
19
4
3
Months
P (+CT) 198
L (+CT) 162
111
104
48
43
RENAAL; Contribution of Baseline Systolic BP
or Proteinuria to ESRD in diabetic nephropathy
20
15.4
Hazard Ratio
15.7
17.1
13.2
15
10
5.5
5
6.7
2.4
0
2.0
1.8
1.4
3.6
1.6
1.0
1.1
0.9
1.0
SBP Quartile at
Baseline (mm Hg)
unpublished
Proteinuria Quartile at
Baseline (g/g)
Combination Therapy for BP Control:
Rule Rather Than Exception
Trial/Systolic Blood Pressure Achieved (mm Hg)
ALLHAT
138
IDNT
138
RENAAL
141
UKPDS
144
ABCD
132
MDRD
132
HOT
138
AASK
128
1
2
3
Number of BP Medications
Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.
4
How I do get My Patient’s BP to the
Goal of <130 / < 80 mmHg?






ACE Inhibitor / AII Receptor Antagonist
(maximum dose)
Low ( 2 gram ) Sodium Diet
Diuretic
 eGFR > 50 ml/min, thiazide
 eGFR < 50 ml/min, loop diuretic
Long-Acting CCB or b-blocker
Long-acting a-blocker vs clonidine
Minoxidil
Renal Effects of CCBs: Comparison
NDHP-CCBs show greater reductions in proteinuria in hypertensive
adults with proteinuria, with or without diabetes.
5
Proteinuria
Systolic Blood Pressure
N=510
N=1,338
2%
0
Change (%)
-5
-10
-15
-13%
-20
-18.5%
-25
-30
-30%
NS
DHP-CCB
-35
P=0.01
Bakris GL et al. Kidney Int. 2004. In press.
NDHP-CCB
Systematic Review of 28 Studies
17
Combination ACEi and Non-Dihydropyridine CCB
Reduces Proteinuria Further in Type 2 Diabetics
With Nephropathy
Percent reduction from baseline
Trandolapril
5.5 mg/d
Verapamil SR
314 mg/d
Trandolapril (2.9 mg/d) +
Verapamil SR (219 mg/d)
0
-20
-40
-60
Proteinuria
Blood Pressure
Bakris, et al. Kid Int. 1998;54:1283.
NKF Kidney Disease Outcomes Quality
Initiative: Pharmacologic Treatment
Type of CKD
BP Goal
Preferred Agents
for CKD, +
HTN
Other Agents to
Reduce CVD
Risk and Reach
BP Goal
Diabetic
< 130/80
ACEi or ARB
Diuretic
Preferred, then bBlocker or CCB
Non-Diabetic with Spot Urine Total Prot-to-Cr
ratio > 200 mg/g
< 130/80
ACEi or ARB
Diuretic
Preferred, then bBlocker or CCB
Non-diabetic with Spot Urine Total Prot-to-Cr
ratio < 200 mg/g
< 130/80
None Preferred
Diuretic
Preferred, then
ACEi, ARB, Bblocker or CCB
Transplanted
< 130/80 None Preferred
KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004
CKD
CCB, diuretic, bblocker ACEi,
ARB
Steno-2: Multiple Risk Factor Intervention Improves
Outcomes in Type 2 diabetics with
Microalbuminuria
 Randomized, open-label, target driven, long-term
intensified intervention trial aimed at multiple risk
factors in patients with type 2 diabetes and
microalbuminuria
 BP < 130/80, (all treated with an ACEi or ARB)
 A1c < 6.5%
 Total Cholesterol < 175 mg/dl
 Total Triglyceride 150 mg/dl
 Aspirin 81 mg daily
 Exercise program
Gaede et al N.Engl.Med. 3448:383. 2003
 Smoking Cessation
Intensive Multi-risk Factor Intervention
Improves Outcomes in Type 2 Diabetes
Primary Composite End Point (%)
Composite outcome: CV death, MI, coronary or
peripheral revascularization, CVA, amputation
60
P=0.007
50
Conventional therapy
40
30
20
Intensive therapy
10
0
0
12
24
36
48
60
72
84
96
Months of Follow-up
No. at Risk
Conventional 80
therapy
80
Intensive
therapy
72
70
63
59
50
44
41
13
78
74
71
66
63
61
59
19
Gaede et al N.Engl.Med. 3448:383. 2003
Risk of Death after AMI is Reduced across all
Levels of Kidney Function with Recommended
Interventions
Hazard ratio
1.20
1.10
Aspirin
1.00
Beta Blocker
0.90
ACE-I
0.80
0.70
0.61
0.60
0.50
0.40
0.62
0.52
0.40
0.45
0.58
0.52
0.41
0.44
0.30
0.20
< 1.5
1.5-2.4
2.5-3.9
Serum creatinine (mg/dl)
Shlipak et al., Ann Int Med 2002;137:555-62
Diabetic Nephropathy:
Important Message
 Lower
blood pressure < 130 / 80 mmHg
 Reducing Proteinuria
 Inhibition of Renin-Angiotensin System
 Multiple risk factor intervention





Glycemia
Dyslipidemia
Physical activity
Aspirin
Smoking cessation
Is Combination Therapy With
An ACE Inhibitor And An ARB
Safe And Effective For Patients
With Diabetic Renal Disease?
ACEi- or ARB-Based Regimens for
Diabetic Nephropathy Do Not Go Far
Enough!
50
RAAS blockade + Other?
40
ACEi or ARB
DGFR = - 6 ml/min/yr
Time to ESRD 6.6 yrs
30
20
10
ACEi + ARB
DGFR = - ? ml/min/yr
Time to ESRD ?
No ACEi/ARB
or BP control
DGFR = - 10 ml/min/yr
Time to ESRD 4 yrs
ESRD
2
4
6
Time (yrs)
8
10
Combining an ACEi and an ARB is more
Renoprotective than Either Agent alone in NonDiabetic Nephropathy
Treatment
N
Baseline
BP mmHg
DBP from
baseline
mmHg*
Primary
Endpoint
Hazard
Ratio**
P value
Combinatio
n
85
130 / 75
5.2 / 2.9
10 (11%)*
-
-
Trandolapril
86
130 / 76
5.3 / 3.0
20 (23%)
0.40
0.016
Losartan
85
130 / 74
5.1 / 2.9
20 (23%)
0.38
0.018
*Average number of medications 3.2 per pt, 90% in all groups on dihydropyridine CCB
** Hazard Ratio comparing combination with either agent alone
Nakao et al. Lancet 361:117-124, 2003
Summary of Studies combining ACEi and ARB in
Diabetic nephropathy: Effects on Proteinuria and BP
DM Type
Design
N
Duratio
n
Intervention
Results
1Type
2
DRBCT
4
4 weeks
40 mg Lisinopril /
50 Losartan
No effect
2Type
2
DRBCT
18
8 weeks
8 mg candesartan
25% Prot and
BP
3Type
1
DBRPCT
21
8 weeks
300 mg irbesartan
43% Prot and
BP
4Type
1
DBRCT
20
8 weeks
20 mg Benazepril/
ACEi / Valsartan 80 mg
15 % Prot and
BP
5Type
1
DBRCT
24
8 weeks
20 mg Enalapril/300 mg
Irbesartan
25% Prot and
BP
1 Agarwal et al. Kid Int 59:2282, 2002; 2 Rossing et al. Diab Care. 25:95-100, 2002; 3 Jacobsen et al
6Type
Neph. 2
Dial. Transplant
17:1019-1024,20
2002;48Jacobsen
J. Am./Soc.
Neph. 14:992-999,
DBRCT
weeks et al.ACEi
Candsartan
16 mg2003;5 Rossing
29%
Et al. Kid Int 63:1874-80, 2003 ; 6 Rossing et al. Diab Care 26:2268-2274, 2003.
Prot
Diabetic Nephropathy:
Important Message
Small short-term studies suggest combinations of ACEi
and ARB reduce proteinuria synergistically
 Greater reductions in proteinuria with or without
additional lowering in blood pressure
 Hyperkalemia and Increased creatinine not well
documented
 Safety and Efficacy of combination ACEi and ARB in
diabetic with nephropathy not well established

Is There a Role for Spironolactone
(or Eplerenone) in Combination
with Other Drugs in Patients with
Diabetic Nephropathy?
Role of Aldosterone in the Pathogenesis
of Diabetic Nephropathy
Angiotensin II
Hemodynamic
Glomerular
Hypertension
Aldosterone
Non-Hemodynamic
Capillary wall injury
Inflammation
O2- , TGF-b1 / PAI-1
Proteinuria
Injury to Glomerular Cells
Glomerular and Tubular Scarring
Progressive Renal Failure
Sclerosis and
Fibrosis
Adverse Renal and Cardiovascular
Effects of Aldosterone
Aldosterone
Glomerulosclerosis
Interstitial Fibrosis
Proteinuria
Ventricular Hypertrophy Endothelial dysfunction
Cardiac Fibrosis
Inflammation
Contractile Dysfunction
Renal Failure
Heart Failure
Oxidative Stress
Mineralocorticoid Receptor Blockade Improves
Cardiac Outcomes: Placebo Controlled Trials
10
1.00
P=0.03
9 RR=0.79 (95% Cl, 0.64-0.97)
Placebo
Probability of Survival
Cumulative Incidence of (%)
Eplerenone reduces sudden cardiac death Spironolactone improves survival in
Chronic Heart Failure
Post myocardial infarction
8
7
Eplerenone
6
5
4
3
2
1
0
0
3
6
9
12 15
18 21 24 27
30 33
36
P=0.001
RR=0.70 (95% Cl, 0.60-0.82
0.95
0.90
0.85
0.80
0.75
0.70
Spironolactone
0.65
0.60
0.55
Placebo
0.50
0.45
Months since Randomization
0.00
0
3
6
9 12 15 18 21 24 27 30 33 36
Months
Can Dual Blockade of the RAAS Improve
Renal Outcomes in Diabetic Nephropathy?
Ang I
Non-ACE
Pathways
ACE
ACEi
+
Ang II
ARB
AT1 Receptor
Aldosterone
+
Renal Injury
and Proteinuria
Progressive Diabetic Nephropathy
MRA
Study Design and
Objectives






Study Design: Randomized double-blind placebo controlled trial
Study Population: Diabetics with macroalbuminuria despite
maximally dosed ACE inhibitor
Intervention: Lisinopril 80 mg/d + losartan 100 mg/d or +
Aldactone 25 mg/d or + placebo
Primary Outcome: Change in albuminuria
Secondary Outcomes: Safety especially serum creatinine and
hyperkalemia
Follow up: 52 weeks
Study Hypothesis
Blockade of the renin-angiotensin system beyond ACE
inhibition decreases proteinuria and slows progression of
renal disease in diabetics with overt nephropathy by
suppressing aldosterone synthesis or blocking the
aldosterone receptor.
Combined Inhibition of the RAAS Pathway: ACEi + ARB
vs ACEi + MRA in Diabetic Nephropathy
Diabetics with SBP > 130 mmHg
Scr < 3, female, < 4, male
Lisinopril 80 mg/d +
Urine albumin/Cr ratio > 300
Losartan 100 mg p.o qd
on ACE inhibitor + CT
Lisinopril 80 mg/d
Lisinopril 80 mg/d + Placebo Maintain SBP 120-129 mmHg
With conventional
antihypertensives
D/C Study
Drug
Control to SBP < 130
Lisinopril 80 mg/d +
then Randomize
Aldactone 25 mg p.o. qd
Run-in
Period
-4
-2
48- 52 56
0
ABPM, aldosterone
Kidney Function
Lipids, Inflammation
24-26
ABPM, aldosterone
Kidney Function
Lipids, Inflammation
Time, weeks
BP blood pressure, potassium and serum creatinine measurement
RF renal function-GFR, RPF, 24 hour urine sodium, creatinine,potassium, protein and urea
ABPM, aldosterone
Kidney Function
Lipids, Inflammation
Diabetic Nephropathy:
Important Message
 Role
for spironolactone or eplerenone in
diabetics with nephropathy not established
 Small, short-term studies suggest adding on
is efficacious for lowering proteinuria
 Not clear if combinations are safe in larger
population
 No long-term trials with cardiovascular or
renal endpoints
Beyond RAAS
Blockade
Hypothesis: Anemia is an Important
CV Risk Factor in Chronic Kidney
Disease
Chronic Kidney
Disease
Anemia
Cardiovascular
disease
Baseline Hemoglobin Predicts ESRD in
Type 2 Diabetics with Nephropathy:
RENAAL Trial (N=1513)
End-stage renal disease, %
60
50
Hb < 11.3*
Adjusted
HR*
P
value
< 11.3
1.99
0.001
11.3-12.5
1.61
0.02
12.5-13.8
1.85
0.002
> 13.8
1.00
-
Hb g/dl
40
Hb 11.4-12.5*
30
20
Hb 12.5-13.8*
10
Hb > 13.8
0
1
2
3
Time, years
Mohanram et al. Kid. Int. Sept 2004
4
* Age, gender, GFR, Race, Proteinuria,
CV disease, A1c, lipids, BP, Ca, P, albumin
Is Anemia Causing
Cardiovascular And Renal
Disease In Diabetics, Or is it
Just A Marker?
Trial to Reduce Cardiovascular Events
with Aranesp (Darbepoietin) Therapy
Patient Population: 4000 Type 2 diabetics with
Chronic Kidney Disease (estimated GFR 20-60) and
Hb < 11 g/dl
 Study Design: Randomized, double-blind, placebocontrolled, multicenter international trial
 Intervention: Aranesp (darbepoetin alfa) to
increase Hb to 11-13 g/dl
 Primary Outcome: time to all-cause mortality and
cardiovascular morbidity, including: myocardial
infarction, acute myocardial ischemia, congestive
heart failure and stroke
Funded by Amgen
 Follow-up: 4 years

Diabetic Nephropathy: Some Novel
Therapies
Under Investigation
 Pirfenidone
–antifibrotic agent
 Aliskerin anti-renin agent
 Robuxistaurin- Protein Kinase C Beta-1
antagonist
 Advanced Glycation Endproduct
antagonists
 Others
How Should I Manage
My Patient With Diabetic
Nephropathy Today?
Diabetic Nephropathy Management
Parameter
 Lower
BP………………………
 Block
RAAS……………………
 Improve glycemia
…………….
 Lower LDL
cholesterol………..
 Anemia management
………...
 Endothelial
protection…………
 Smoking…………………
Target
< 130/80 mmHg
ACEi or ARB to max tolerated
A1c < 6.5% (Insulin/TZD)
< 100 (70) mg/dl statin + other
Hb 11-12 g/dl (Epo + iron)
Aspirin daily
Cessation
Diabetic Nephropathy: What
about proteinuria?

Lower BP to goal with max dose ACEi or ARB

Consider Adding: ACEi to ARB, mineralocorticoid receptor
antagonist to ACEi or ARB

Calcium Channel Blockers
 Non-dihydropyridine
 Dihydropyridine
LOCKING THE STABLE DOOR
…after the horse has bolted
Thank You