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Page 1: Diabetic Nephropathy 2009

Diabetic Nephropathy

Joel Michels Topf, MDClinical Nephrologist

Page 2: Diabetic Nephropathy 2009

Year Capacity

1926 84,401

1927 85,753

1949 97,239

1956 101,001

1991 102,501

1998 107,501

1999 107,501

2006 107,501

2009 106,201

Incident ESRD

0

0

0

0

56,103

87,179

91,275

110,854

117,632

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0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004

Diabetes Hypertension Glomerulonephritis

Etiologies of ESRD

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Diabetes, diabetic nephropathy and the epidemic raging in the U.S.

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USRDS Atlas 2005http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7

Diabetics on Dialysis: 183,706Total no of Diabetics: 23,600,000

0.78%0.78%

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ESRD

CV Mortality

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Finne, P. JAMA 2005; 294:1782-87.

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Diabetic nephropathy

Progressive renal damage as a result of diabetis mellitus type I or II

Initially, patients have increased GFR (2x normal)

Followed by proteinuria Followed by progressively

deteriorating GFR

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Diabetic nephropathy

Progressive renal damage as a result of diabetis mellitus type I or II

Initially, patients have increased GFR (2x normal)

Followed by proteinuria

Followed by progressively deteriorating GFR

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5-10 years

15-20 years

20 years

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220 g 240 g

Size MattersNormal kidney weight is 150 g

Diseases with large kidneys:• Multiple Myeloma • Hydronephrosis• Amyloidosis • Renal Cell Cancer• ADPKD/ARPKD • Not HIVAN

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nodular glomerulosclerosis

Kimmelstiel-Wilson lesions

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One in five diabetic patients on dialysis do not have this “classic” pathology.

They have ischemic nephropathy, with non-specific vascular and interstitial lesions

Ritz E, Orth SR. N Eng J Med 1999; 341:1127-33.

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Diabetic Nephropathy No

NephropathyDiabetic

Nephropathy

No Nephropathy

Type I Diabetes Type II Diabetes

No difference in glycemic control between people who get

nephropathy and those who don’t

Ritz E, et al. N Engl J Med 1999;341 :1127-33.

Incidence of proteinuria at 25 years after diagnosis

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Genetics

Familial clusteringDiabetic family members of patients

with diabetic nephropathy have an OR of 4.0

RaceESRD is 5 times more likely in African

Americans with family members on dialysis from DN

Pima indians have very high rates of diabetic nephropathy

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Transforming Growth Factor Beta

3

2407

0

500

1000

1500

2000

2500

1990199119921993199419951996199719981999200020012002200320042005

TGFß

Angiotensin II

Hyperglycemia

Extracellular matrix

Fibrosis

Scientific studies on TGFß and renal disease

Huang Y, Et al. Kidney International 2006; 69: 1713-4.

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Hyperfiltration

Early finding Renal vasodilation

Causes early increases in GFR Later

Nephron loss results in compensatory hyperfiltration

No increase in GFR

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Pathology

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A B C

0 years 5 years 10 years

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Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

DiabetesWhat is microalbuminuria?

a.Any albumin in the urine

b.Trace protein on dipstick in a first morning specimen

c.20-200 µg/min on a timed specimen

d.30-300 mg albumin/g creatinine

e.30-300 mg/L

What is macroalbuminuria?

a.1+ protein on a dipstick in a first morning specimen

b.1+ protein on a dipstick at any time

c.>250 mg in 24 hours

d.>3.5 g per 24 hours

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Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Diabetes

MicroalbuminuriaDipstick negative

MacroalbuminuriaDipstick positive

30 300 mg/d0

Patients with diabetes mellitus (N=3,498)

1.0 0.9

1.4

2.4

0.0

1.0

2.0

3.0

4.0

<2 2-5 5-14.3 >14.3

Relative Risk

MI, CVA, CV Death

All-cause

mortality

CHF

hospitalization

Gerstein, H. C. et al. JAMA 2001;286:421-426.

Albuminuria (mg/d)

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Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

Perkins BA, Et al. N Engl J Med 2003;348:2285-93.

Cholesterol < 198

Triglycerides < 145

Glycemic control (hgb a1c <8)

Blood pressure (sbp<115)

ACEi

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Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type II

Diagnosis

Diagnosis

Diagnosis

Perkins BA, Et al. N Engl J Med 2003;348:2285-93.

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U/A at Diagnosis(Type 2 patients)

Random spot collectionAlbumin:creatinineRepeat 3x in 3-6 months

2 of 3 ≥ 30mg/g creatinine

Microalbuminuria,begin treatment

NephropathyQuantify µalb:CrConsider referral

Modified from the American Diabetes Association. Diabetes Care. 2002; 25 Suppl 1: S85-S89.

No microalbuminuriaRe-screen yearly

Negative

Positive

No Yes

Differential of microalbuminuria• Early diabetic nephropathy • Obesity • Hypertension• Endothelial dysfunction• Metabolic syndrome• Atherosclerosis

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When is proteinuria not diabetic nephropathy?

When does a diabetic need a biopsy?

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Suspicious for non-diabetic nephropathy

Onset within 5 years of dx of diabetes Acute onset Active sediment Unusual review of systems Serologies

ANA, Hep B, Hep C, HIV

Absence of retinopathy or neuropathy

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TREATMENT

1. Blood pressure control

2. Glycemic control3. Angiotensin 2 control4. Proteinuria control5. Cholesterol control

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Intensive therapy

1. Low fat (<30%) diet2. 30 minutes exercise

3-5 days/week3. Smoking cessation4. ACEi regardless of

blood pressure5. Vitamin6. Aspirin7. A1c <6.58. Blood pressure control9. Cholesterol control

Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

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Primary end point

1. CV Death2. Non fatal MI3. CABG/PCI4. Nonfatal stroke5. Amputation6. Peripheral

revascularization

Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

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Treatment

1. Blood pressure control

2. Glycemic control3. Angiotensin 2 control4. Proteinuria control5. Cholesterol control

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Randomized prospective trial of treatment strategies in type two diabetes

ukpds

• Protocol written in 1976

• Recruitment from 1977-1991

• End of study 1997

• Type 2 diabetic patients 5,102

• Person years follow-up 53,000

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Favorsconventional

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes related endpoint

Diabetes related deaths

All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p

Favorsintensive

Relative Risk

Microvascular EndpointsAny Diabetes Related Endpoint

0

10

20

30

40

50

0 3 6 9 12 15

Pro

por

tion

of p

atie

nts

(%)

Years from randomisation

Hypoglycemia: any episode

0

1

2

3

4

5

0 3 6 9 12 15

Hypoglycemia: major episodes

Pro

por

tion

of p

atie

nts

(%)

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60

80

100

140

160

180

0 2 4 6 8

mm

Hg

Years from randomisation

144

154

8782

Blood pressure: Tight vs less tight control Blood pressure: Bad vs worse control

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0%

10%

20%

30%

40%

50%

0 3 6 9

% o

f pat

ient

s w

ith e

vent

s

Tight blood pressure control (758)

Less tight blood pressure control (390)

risk reduction24% p=0.0046

Years from randomisation

risk reduction32% p=0.019

Diabetes-related deaths

Stroke

0%

5%

10%

15%

20%

0 3 6 9

% p

atie

nts

with

eve

nt

Years from randomisation

risk reduction44% p=0.013

0%

5%

10%

15%

20%

0 3 6 9

% p

atie

nts

with

eve

nt

Years from randomisation

risk reduction37% p=0.0092

Microvascular endpoints

Any diabetes-related endpoints

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UK Prospective Diabetes Study

An intensive glucose control policy HbA1c 7.0 % vs 7.9 %

reduces risk of

any diabetes-related endpoints 12% p=0.030 microvascular endpoints 25% p=0.010 myocardial infarction 16% p=0.052

A tight blood pressure control policy 144/82 vs 154/87mmHg reduces risk of

any diabetes-related endpoint 24% p=0.005 microvascular endpoint 37% p=0.009 stroke 44% p=0.013

The benefit from tight glycemic control is less

than the benefit from lousy blood pressure control

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24.4

18.6

11.9

0

5

10

15

20

25

MI, CVA, CV mortality / 1,000 patient-

years

≤90 mmHg(n=501)

≤85 mmHg(n=501)

≤80 mmHg(n=499)

Hypertension Optimal Treatment trial (HOT Trial) randomized 18,790 patients to one of three diastolic blood pressure goals

8% of the original cohort was diabetic

The first line agent was felodipine

Harrison L, Et al. Lancet 1998; 351: 1755-1762.

HOT Diabetics

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Home blood pressure is the hemoglobin A1c of blood pressure

management.

Dr Whitey routinely

checks Hgb A1c to

make sure my

diabetes is on track.

Dr Whitey asks me

check my home BP to verify my BP is on track.

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Treatment

Blood pressure control Glycemic control3. Angiotensin 2 control4. Proteinuria control5. Cholesterol control

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Lewis, E. J. et al. N Engl J Med 1993;329:1456-1462

Cumulative Incidence of Events in Patients with Diabetic Nephropathy in the Captopril and Placebo Groups

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RENAAL Trial1513 type II DM with nephropathyCr 1.9Randomized to placebo or losartanPrimary outcome: composite of doubling serum Cr, ESRD, or death

Brenner BM, Et al. NEJM 2001; 343: 861-9.

50 mg

100 mg

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Picture of world with/without electricity

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ACEi are good,ARB are good…

in patients with albuminuria.

What about in normotensive patients without albuminuria?

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Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

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Multicenter, randomized, double blind controlled trial

285 normotensive patients with type I dm and albuminuria < 20 µg/min

Randomized to placebo, enalepril 10/20 mg or losartan 50/100 mg

Primary endpoint was change in mesangial volume on renal biopsy

Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

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Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

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Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

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Progression of diabetic retinopathy (2 steps)

Odds ratio vs placebo

Placebo 38% 1

Enalepril 25% 0.35 (65% reduction)

Losartan 21% 0.30 (70% reduction)

Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

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ACEi are goodARB are good

What about both together?

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CALM Study

N= 200 Type II DM with

microalbuminuria Randomized to:

Lisinopril 20 mg qd Candesartan 16 mg

qd Combination of

lisinopril 20 mg and candesartan 16 mg

24

39

50

0

10

20

30

40

50

Reduction in Albuminuria (%)

Candesartan Lisinopril Combination

Mogensen CE, Et al. BMJ 2000; 321: 1440-4.

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Combination ACEi & ARB:the Meta analysis

10 studies of patients with diabetic nephropathy

315 patients randomized to ACEi or ACEi and ARB

Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

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Problem: Too shortWrong target

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Studies use change in proteinuria as the primary endpoint

Most were 8-12 weeks in duration

Significant reduction in proteinuria compared to ACEi (p=0.01)

Reduced GFR (3.9 ml/min, p=0.03)

Increase in potassium (0.2 mmol/L, p<0.01)

Reduction in BP (5.2/5.3, p<0.01)

Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

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STUDIES OF ACEI + ARB IN NON-DIABETICS

What about the data of dual therapy in non-diabetics

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On Target

Telmisartan + ramipril vs ramipril vs telmisartan

Outcome: CV death, MI, CVA, hospitalization for CHF

25,620 patients were randomized Study population: age >55,

coronary, peripheral or cerebrovascular disease or diabetes with end-organ damage

ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

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37% had diabetes 13% had microalbuminuria 50% had prior MI 22%had prior CABG 68% had history of hypertension

56 months of follow-up

ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

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Primary outcome

ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

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Renal outcomes

Renal impairment:13.5% with combo tx10.2% ramipril10.6% telmisartanRR 1.33 for combination tx (p=<0.001)

Initiation of dialysis0.8% with combination therapy0.6% with monotherapyRR 1.37 (p=0.1)

ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

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Renal outcomes

Second publication with data focused on renal outcomes

Primary outcome for this publication was dialysis, death or doubling of serum creatinine

Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008

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Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008

0.037

0.038

0.020

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Increased renal outcomes despite better proteinuria

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Cooperate Trial: ACEi+ARB in non-diabetics263 patients with non-diabetic renal diseaseAverage GFR 37.5 mL/minAverage protein excretion 2.5 g/dayRandomized to losartan 100mg, trandolapril 3mg, or both

Nakao N, Et al. Lancet 2003; 361: 117-24.

Endpoint: doubling of serum creatinine or dialysis

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PotassiumPotassium

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RESOLVD 768 patients with heart failure (NYHA II to IV)Potassium rose 0.11 mmol/L (p<0.05 vs

Candesartan alone and enalepril alone) ValHeFT

5010 patients with heart failure (NYHA II to IV and EF<40%)

Potassium rose 0.12 mmol/L (p<0.001) CHARM-Added trial

2548 patients with heart failure (NYHA II to IV and EF<40%)

No significant change in potassium

McKelvie RS, Et al. Circulation 1999; 100: 1056-64.Cohn JN, Et al. N Eng J Med 2001; 345: 1667-75.McMurray JJ, Et al. Lancet 2003; 362: 767-71.

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Any addition ofACEiARBAldosterone antagonistDiuretic

Must check electrolytes one week later

High potassiumStop the drugLow potassium

dietLoop diureticThiazide diureticLiberalize sodium

restriction

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Treatment

Blood pressure control Glycemic control Angiotensin 2 control4. Proteinuria control5. Cholesterol control

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Theory: reduce proteinuria, reduce cardiovascular events

High High | High Low | Low High | Low Low

Ibsen H, Et al. Hypertension 2005; 45: 198-202.

Pre-specified subanalysis of the LIFE trial8206 men and women ages 55-80 with hypertension and LVH13% were diabeticsPrimary analysis was Atenolol vs LosartanComposite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI

…Reduction in albuminuria during treatment translates to a reduction in

cardiovascular events…

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…Interestingly, suppression of albuminuria was the strongest predictor of long-term protection

from cardiovascular events…

De Zeeuw D, Et al. Circulation 2004; 110: 921-927.

Theory: reduce proteinuria, reduce cardiovascular events and renal end-pointsReanalysis of the RENAAL trial. Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or reduction in proteinuria.The reduction in albuminuria at 6 months predicted outcomes at 42 months

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Conclusion: reduction in proteinuria reduces CV complications and renal complications

Implications: reduction in proteinuria can be used as an intermediate end-point, i.e. interventions which reduce proteinuria are good.

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Calcium channel blockers Verapamil does not delay

development of microalbuminuria Verapamil does reduce

proteinuria in diabetics independent of changes in blood pressure

Ruggenenti P, Et al. N Eng J Med 2004; 351: 1941-51.

% C

hang

e in

Pro

tein

uria

Blo

od p

ress

ure

Bakris GL, Et al. Kidney Int 1998; 58: 1283-9.

Aldosterone antagonists

Spironolactone reduces proteinuria in diabetics Change in proteinuria is

independent of blood pressure

All patients were treated with an ACEi or ARB

24-Hr ambulatory BP fell 6/2

Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.

Carvedilol RCT of metoprolol vs.

carvedilol, improved A1c and albuminuria

Bakris GL, Et al. JAMA 2004; 292: 2227-36.

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Aliskiren in addition to losartan in DM2 and nephropathy

RCT double blind, multicenter N=599 Placebo vs 150 mg aliskiren for 3

months Followed by doubling of the dose

of the placebo and aliskiren (300 mg)

Study duration 6 months

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Use of aliskiren 150 mg for 3 months and 300 mg for 3 months lowered albuminuria 20% compared to placebo

150 mg 300 mg

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Treatment

Blood pressure control Glycemic control Angiotensin 2 control Proteinuria control5. Cholesterol control

0

5,000,000

10,000,000

15,000,000

20,000,000

25,000,000

Diabetics Diabetics on Dialysis

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Run-inACEi or ARBACEi + ARB

AtorvastatinGroup A

PlaceboGroup B

20 mg

40 mg

10 mg

Randomization

Bianchi S, Et al. Am J Kidney Dis 2003; 41:565-570.

A Controlled, Prospective Study of the Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease56 men and women with non-diabetic GNCrCl 53 mL/min and proteinuria = 2.5 g/d

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Atorvastatin Dose80 mg

20 mg

40 mg

10 mg

GREACE Study1541Greek men and womenAge < 75, LDL > 100 and hx CHD20% DM3 year follow-upCHD events:

Study:12% vs control: 24.5%

Athyros VG, Et al. J Clin Pathol 2004; 57: 728-34.

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Conclusions

Diabetic nephropathy is the most common cause of ESRD in the world

ESRD is a rare out-come among diabetics

Just over half of diabetics will develop nephropathy

Blood pressure control Glycemic control Angiotensin 2

reduction Proteinuria reduction

ACEi + ARB Statins Aldosterone antagonists Dihydropyridine calcium

channel blockers Endothelin antagonists

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157 150

625 610

0

100

200

300

400

500

600

700

1980 1985 1990 1995 2000 2005

Incidence per 1,000,000

30-59

60+

under 30

Incidence of ESRD due to diabetic nephropathy

IDNTRENALL

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fin