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Recent advances in management of Diabetic Diabetic Nephropathy Nephropathy

Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

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Page 1: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Recent advances in management of

Diabetic Diabetic NephropathyNephropathy

Page 2: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

……Tiger by the tailTiger by the tail

Page 3: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Kidney

Normal Kidney

Page 4: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic nephropathyDiabetic nephropathy Diabetic nephropathy is progressive kidney Diabetic nephropathy is progressive kidney

diseasedisease Most common cause of ESRD Most common cause of ESRD More likely to die than progress to ESRDMore likely to die than progress to ESRD Multi-risk factor intervention is criticalMulti-risk factor intervention is critical Lowering blood pressure with RAAS blockade Lowering blood pressure with RAAS blockade

is criticalis critical Combinations of ACEi + ARB or MRA sensibleCombinations of ACEi + ARB or MRA sensible

No long term efficacy or safety dataNo long term efficacy or safety data Prevent cardiovascular morbidity and mortalityPrevent cardiovascular morbidity and mortality

Page 5: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Why is Diabetic Why is Diabetic Nephropathy Nephropathy Important?Important?

Page 6: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetes: The Most Diabetes: The Most Common Cause of ESRDCommon Cause of ESRD

Primary Diagnosis for Patients Who Start Dialysis

Diabetes50.1%

Hypertension27%

Glomerulonephritis

13%

Other

10%

United States Renal Data System. Annual data report. 2000.

No. of patientsProjection95% CI

1984 1988 1992 1996 2000 2004 20080

100

200

300

400

500

600

700

r2=99.8%243,524

281,355520,240

No

. o

f d

ialy

sis

pat

ien

ts

(th

ou

san

ds)

Page 7: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Cardiovascular Death is Major Cardiovascular Death is Major

Cause of Mortality in ESRDCause of Mortality in ESRD

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74 75-84 > 85

Age (years)

An

nu

al C

ard

iova

scu

lar

Mo

rtal

ity

(%)

GP Male

GP Female

GP Black

GP White

Dialysis Male

Dialysis Female

Dialysis Black

Dialysis White

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.

General Population

ESRD Population

Page 8: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

What is the What is the Natural History Natural History

of Diabetic of Diabetic Nephropathy?Nephropathy?

Page 9: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Definition of Diabetic Definition of Diabetic Nephropathy Nephropathy

Clinical diagnosis based on Hx, Exam and Clinical diagnosis based on Hx, Exam and urine albumin/creatinine ratio in most casesurine albumin/creatinine ratio in most cases

Longstanding History of diabetes Longstanding History of diabetes ++ retinopathyretinopathy

Macroalbuminuria (a.k.a “overt Macroalbuminuria (a.k.a “overt nephropathy”) defined as random urine nephropathy”) defined as random urine albumin/creatinine ratio albumin/creatinine ratio >> 300 mg/g 300 mg/g

Hypertension (> 90%)Hypertension (> 90%) Renal Biopsy confirmation is rareRenal Biopsy confirmation is rare

Page 10: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Development of Macroalbuminuria Heralds Rapid Decline in Glomerular Filtration in Type II

Diabetes

-50

-40

-30

-20

-10

0

1 1.5 2 2.5 3 3.5 4

Time yearsC

hang

e in

GFR

ml/m

in

Microalbuminuria

Macroalbuminuria

Nelson RG. et al NEJM, 1996

Page 11: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetics with Nephropathy (DM/CKD) Diabetics with Nephropathy (DM/CKD) are More Likely to Die than to Progress are More Likely to Die than to Progress

to Eto ESRDSRD

Status in the entry period

DM/CKDDM/Non-CKD NDM/CKDNDM/Non-CKD

19,335188,596 33,586N=1,045,263

0.070.31

2.255.85

Per

cen

t o

f P

atie

nts

Event Free

ESRD

All CauseDeath

5% Medicare sample , 1996-1997 cohort, 2 year follow-up

9.40 14.6529.04

85.0473.18

65.12

24.57

90.53

0

20

40

60

80

100

Page 12: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetics with Macroalbuminuria are Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRDMore Likely to Die than Develop ESRD

CV

DEATHElevated Serum Creatinine

19%

No albuminruia1.4%

2.0%

Microalbuminruia3.0%

2.8%

Macroalbuminruia4.6%

2.3%

The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated

Adler et al. Kid Int, 2003

Page 13: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

What are Diabetics with What are Diabetics with Nephropathy Dying From?Nephropathy Dying From?

Stroke MyocardialInfarction

HeartFailure

SuddenDeath

Page 14: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Improving Outcomes in Diabetic Nephropathy

Prevention of Cardiovascular

Events

Prevention of End-Stage Renal Disease

Diabetic Diabetic NephropathyNephropathy

Page 15: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

What is the Proper What is the Proper Therapy of Kidney Therapy of Kidney Disease in patients Disease in patients

with Diabetes?with Diabetes?

Page 16: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

The Renal Injury The Renal Injury TriadTriadAngiotensin II

ProteinuriaHypertension

Page 17: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Definition of Abnormal Definition of Abnormal Albuminuria in Diabetes Albuminuria in Diabetes

MellitusMellitusMicroalbuminuriaMicroalbuminuria MacroalbuminurMacroalbuminur

iaia(Nephropathy)(Nephropathy)

Detected by Detected by dipstickdipstick

NoNo YesYes

Urine Albumin / Urine Albumin / CrCr

30 - 299 mg Alb / 30 - 299 mg Alb / g Cr g Cr

>> 300 mg Alb / 300 mg Alb / g Crg Cr

Renal RiskRenal Risk Marker of future Marker of future nephropathy in nephropathy in

somesome

Marker Marker progressive progressive

renal diseaserenal diseaseCardiovascular Cardiovascular RiskRisk

IncreasedIncreased IncreasedIncreased* Random (Spot) urine preferably A.M. recommended

Page 18: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ADA Guidelines: ADA Guidelines: Diabetic NephropathyDiabetic Nephropathy

– To reduce the risk and/or slow the To reduce the risk and/or slow the progression of nephropathy, progression of nephropathy, optimize optimize glucose controlglucose control. .

– To reduce the risk and/or slow the To reduce the risk and/or slow the progression of nephropathy, progression of nephropathy, optimize optimize blood pressure controlblood pressure control..

A-Level Evidence (well done RCTs)

Page 19: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ADA: Screening ADA: Screening GuidelinesGuidelines

– Perform an annual test for the presence of Perform an annual test for the presence of microalbuminuriamicroalbuminuria in (1) type 1 diabetic patients who in (1) type 1 diabetic patients who have had diabetes >5 years and (2) all type 2 have had diabetes >5 years and (2) all type 2 diabetic patients starting at diagnosis.diabetic patients starting at diagnosis.

– Acceptable samples to test for increased urinary Acceptable samples to test for increased urinary albumin excretion are timed (e.g., 12 or 24 h) albumin excretion are timed (e.g., 12 or 24 h) collections for measurement of albumin collections for measurement of albumin concentration and timed or untimed samples for concentration and timed or untimed samples for measurement of the albumin:creatinine ratio. For measurement of the albumin:creatinine ratio. For screening, an untimed sample for albumin screening, an untimed sample for albumin measurement (without creatinine) may be measurement (without creatinine) may be considered if a concentration cutoff is used that considered if a concentration cutoff is used that allows high sensitivity for detection of an increased allows high sensitivity for detection of an increased albumin excretion rate. Level of evidence: Ealbumin excretion rate. Level of evidence: E

Expert Consensus

Page 20: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ADA: Treatment ADA: Treatment GuidelinesGuidelines

— In the treatment of albuminuria/nephropathy both In the treatment of albuminuria/nephropathy both angiotensin-converting enzyme (ACE) inhibitors and angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBsangiotensin receptor blockers (ARBs) can be used: ) can be used:

— In hypertensive and nonhypertensive type 1 diabetic In hypertensive and nonhypertensive type 1 diabetic patients with any degree of albuminuria, ACE inhibitors patients with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. have been shown to delay the progression of nephropathy. (1a)(1a)

— In hypertensive and non hypertensive type 2 diabetic In hypertensive and non hypertensive type 2 diabetic patients with microalbuminuria, ACE inhibitors and ARBs patients with microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to have been shown to delay the progression to macroalbuminuria. (Cochrane 1a DOE)macroalbuminuria. (Cochrane 1a DOE)

— In patients with type 2 diabetes, hypertension, In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have been shown to delay the >1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy.progression of nephropathy.

— If one class is not tolerated, the other should be substituted.If one class is not tolerated, the other should be substituted.

A-Level Evidence (well done trials)

Page 21: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ADA: TreatmentADA: Treatment

— With the onset of overt nephropathy, With the onset of overt nephropathy, initiate initiate protein restriction to <0.8protein restriction to <0.8 g • kg-1 g • kg-1 body weight • day-1 (approximately 10% body weight • day-1 (approximately 10% of daily calories), the current adult of daily calories), the current adult recommended daily allowance for protein. recommended daily allowance for protein. Further restriction may be useful in Further restriction may be useful in slowing the decline of glomerular filtration slowing the decline of glomerular filtration rate in selected patients.rate in selected patients.

B-Level Evidence (well done cohort studies)

Page 22: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ADA: TreatmentADA: Treatment

— If ACE inhibitors or ARBs are used, monitor If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of serum potassium levels for the development of hyperkalemia. hyperkalemia.

— Consider Consider referralreferral to a physician experienced in to a physician experienced in the care of diabetic renal disease when the the care of diabetic renal disease when the glomerular filtration rate has fallen to either <60 glomerular filtration rate has fallen to either <60 mL • min-1 • 173 m-2 or difficulties have mL • min-1 • 173 m-2 or difficulties have occurred in the management of hypertension or occurred in the management of hypertension or hyperkalemia. hyperkalemia.

— Consider the use of non-dihydropyridine calcium Consider the use of non-dihydropyridine calcium channel blockers or beta-blockers in patients channel blockers or beta-blockers in patients unable to tolerate ACE inhibitors or ARBs.unable to tolerate ACE inhibitors or ARBs.

Expert Consensus

Page 23: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)

ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)

- 40 –

- 20 –

0 –

- 20 –

- 40 –

- 60 –

% Reduction in

Proteinuria

P <.001

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

% with Doubling of

Baseline Creatinine

Baseline creatinine > 1.5 mg/dl

0

25

50

75

100

0 1 2 3 4

Captopril

Conventional therapy

- 2 –

0 –

- 2 –

- 4 –

- 6 –

- 8 –

Decrease in Mean Blood

Pressure (mm Hg)

NS

Page 24: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ARB (losartan) Reduces Risk of ESRD in ARB (losartan) Reduces Risk of ESRD in Diabetic NephropathyDiabetic Nephropathy

ESRD

Months

% w

ith

eve

nt

0 12 24 36 48

0

10

20

30

p=0.002Risk Reduction: 28%

Placebo

Losartan

P (+ CT)

L (+ CT) 751 714 625 375 69762 715 610 347 42

Brenner et al. New Engl J. Med Sept 20 2001

BP 142 / 74

BP 140 / 74

Reduction in Endpoints in NIDDM with Angiotensin Antagonist Losartan (RENAAL) Trial: 1513 type 2 Diabetics with Nephropathy

• Avg: 3.5 BP drugs/pt• 90% in both groups received a CCB

Page 25: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Irbesartan in Diabetic Nephropathy Trial: Irbesartan in Diabetic Nephropathy Trial: Time to Doubling of Serum Creatinine, ESRD, Time to Doubling of Serum Creatinine, ESRD,

or Deathor Death

Lewis EJ, et al. N Engl J Med. 2001;345:851-860.

Su

bje

cts

(%)

0 6 12 18 24 30 36 42 48 54

Follow-up (mo)

60

0

10

20

30

40

50

60

70

RRR 20%P=.02P=NS

RRR 23%P=.006

Irbesartan

Amlodipine

Placebo

1,715 Type 2 Diabetics with Nephropathy

Change in Proteinuria

-35

-30

-25

-20

-15

-10

-5

0

5

Per

cen

t R

edu

ctio

n

IrbesartanAmlodipinePlacebo

BP 141/77

BP 144/80

BP 140/77

Page 26: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

% w

ith

ES

RD

en

d p

oin

t

80

100

40

60

20

048362412

Month

≥3.0 g/g

≥1.5<3.0 g/g

<1.5 g/g

HR

8.10

3.23

1.0

0

Albuminuria at Baseline Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial

(N=1513)

Baseline Albuminuria

de Zeeuw et al. Kid. Int. June 2004

Page 27: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Reduction in Proteinuria is Associated Reduction in Proteinuria is Associated with Reduced Risk for End-Stage Renal with Reduced Risk for End-Stage Renal

Disease in Diabetic NephropathyDisease in Diabetic Nephropathy

0.5

1.0

3.5

4.0

2.5

3.0

1.5

2.0

0.0<-40 ≥10 ≥60≥-10≥-40 ≥40

<60<-10 <10 <40

Change in Albuminuria %

Re

lati

ve

Ris

k f

or

ES

RD

de Zeeuw et al. Kid. Int. June 2004

Page 28: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

RENAAL; Proteinuria Reduction RENAAL; Proteinuria Reduction (<0% versus >30%) determines the (<0% versus >30%) determines the

cardiovascular outcome cardiovascular outcome CV Endpoint Heart Failure

0 12 24 36 48

Month

0

10

20

30

40

% w

ith C

V e

ndpo

int >30%

<0%

0 12 24 36 48

Month

0

10

20

30

40

% w

ith h

eart

failu

re

<0%

>30%

De Zeeuw et al; Circulation, in press

Page 29: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Continuation of Losartan After Continuation of Losartan After Serum Creatinine Doubles Serum Creatinine Doubles

Reduces Incidence of ESRDReduces Incidence of ESRD

Months

% w

ith E

SR

D e

vent

0 6 12 18 240

20

40

60

80p=0.013

Risk Reduction: 30%

198 111 48 11 4P (+CT)

LP

L (+CT) 162 104 43 19 3

Page 30: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

RENAAL; Contribution of Baseline RENAAL; Contribution of Baseline Systolic BP or Proteinuria to ESRD Systolic BP or Proteinuria to ESRD

in diabetic nephropathyin diabetic nephropathy

<140140 - 151151 - 165

>165

<.5

>2.51.25 - 2..5

.5 – 1.2

Proteinuria Quartile at Baseline (g/g)

SBP Quartile atBaseline (mm Hg)

Haz

ard

Rat

io

15.4

5.5

2.4

1.4

13.2

6.7

1.8

1.0

15.7

2.0

1.6

0.9

17.1

3.6

1.1

1.0

0

5

10

15

20

unpublished

Page 31: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Combination Therapy for BP Combination Therapy for BP Control: Control:

Rule Rather Than ExceptionRule Rather Than Exception

1 2 3 4

Number of BP Medications

ALLHAT

IDNT

RENAAL

UKPDS

ABCD

MDRD

HOT

AASK

Trial/Systolic Blood Pressure Achieved (mm Hg)

Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.

138

138

141

144

138

128

132

132

Q050240
M54_1803_Sec II
Page 32: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

How I do get My Patient’s BP How I do get My Patient’s BP to the Goal of <130 / < 80 to the Goal of <130 / < 80

mmHg?mmHg? ACE Inhibitor / AII Receptor ACE Inhibitor / AII Receptor

Antagonist (maximum dose)Antagonist (maximum dose) Low ( 2 gram ) Sodium DietLow ( 2 gram ) Sodium Diet Diuretic Diuretic

eGFR eGFR >> 50 ml/min, thiazide 50 ml/min, thiazide eGFR < 50 ml/min, loop diureticeGFR < 50 ml/min, loop diuretic

Long-Acting CCB or Long-Acting CCB or -blocker-blocker Long-acting Long-acting -blocker vs clonidine-blocker vs clonidine MinoxidilMinoxidil

Page 33: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Bakris GL et al. Kidney Int. 2004. In press.

NDHP-CCBs show greater reductions in proteinuria in hypertensive adults with proteinuria, with or without diabetes.

DHP-CCB NDHP-CCB

Ch

ang

e (

%)

P=0.01-35

-30

-25

-20

-15

-10

-5

0

5

ProteinuriaN=510

Systolic Blood PressureN=1,338

NS

2%

-30%

-13%

-18.5%

Renal Effects of CCBs: Renal Effects of CCBs: ComparisonComparison

Systematic Review of 28 Studies 17

Page 34: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Combination ACEi and Non-Combination ACEi and Non-Dihydropyridine CCB Reduces Dihydropyridine CCB Reduces Proteinuria Further in Type 2 Proteinuria Further in Type 2 Diabetics With NephropathyDiabetics With Nephropathy

0

-20

-40

-60

Trandolapril5.5 mg/d

Verapamil SR314 mg/d

Trandolapril (2.9 mg/d) +Verapamil SR (219 mg/d)

Per

cent

red

uctio

n fr

om b

asel

ine

Proteinuria

Blood Pressure

Bakris, et al. Kid Int. 1998;54:1283.

Page 35: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

NKF Kidney Disease Outcomes NKF Kidney Disease Outcomes Quality Initiative: Quality Initiative:

Pharmacologic TreatmentPharmacologic Treatment

KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004

Type of CKDType of CKD BP GoalBP Goal Preferred Preferred Agents for Agents for CKD, CKD, ++ HTN HTN

Other Agents Other Agents to Reduce to Reduce CVD Risk and CVD Risk and Reach BP Reach BP GoalGoal

DiabeticDiabetic < < 130/80130/80

ACEi or ARBACEi or ARB Diuretic Diuretic Preferred, Preferred, then then --Blocker or Blocker or CCBCCB

Non-Diabetic with Spot Urine Total Non-Diabetic with Spot Urine Total Prot-to-Cr ratio Prot-to-Cr ratio >> 200 mg/g 200 mg/g

< < 130/80130/80

ACEi or ARBACEi or ARB Diuretic Diuretic Preferred, Preferred, then then --Blocker or Blocker or CCBCCB

Non-diabetic with Spot Urine Total Non-diabetic with Spot Urine Total Prot-to-Cr ratio Prot-to-Cr ratio << 200 mg/g 200 mg/g

< < 130/80130/80

None None PreferredPreferred

Diuretic Diuretic Preferred, Preferred, then ACEi, then ACEi, ARB, B-ARB, B-blocker or blocker or CCBCCB

Transplanted Transplanted

CKDCKD< < 130/80130/80

None None PreferredPreferred

CCB, CCB, diuretic, diuretic, --blocker ACEi, blocker ACEi, ARBARB

Page 36: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Steno-2: Multiple Risk Factor Steno-2: Multiple Risk Factor Intervention Improves Outcomes in Intervention Improves Outcomes in

Type 2 diabetics with Microalbuminuria Type 2 diabetics with Microalbuminuria Randomized, open-label, target driven, long-term Randomized, open-label, target driven, long-term

intensified intervention trial aimed at multiple risk intensified intervention trial aimed at multiple risk factors in patients with type 2 diabetes and factors in patients with type 2 diabetes and microalbuminuriamicroalbuminuria BP < 130/80, (all treated with an ACEi or ARB)BP < 130/80, (all treated with an ACEi or ARB) A1c < 6.5%A1c < 6.5% Total Cholesterol < 175 mg/dlTotal Cholesterol < 175 mg/dl Total Triglyceride 150 mg/dlTotal Triglyceride 150 mg/dl Aspirin 81 mg dailyAspirin 81 mg daily Exercise programExercise program Smoking CessationSmoking Cessation

Gaede et al N.Engl.Med. 3448:383. 2003

Page 37: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Pri

mar

y C

om

po

site

En

d P

oin

t (%

)

10

20

50

60

30

40

00 96842412 4836 7260

P=0.007

Conventional therapy

Intensive therapy

Months of Follow-upNo. at Risk

Intensive therapy

Conventional therapy

80 72 70 63 59 50 44 41 13

80 78 74 71 66 63 61 59 19

Intensive Multi-risk Factor Intensive Multi-risk Factor Intervention Improves Outcomes Intervention Improves Outcomes

in Type 2 Diabetesin Type 2 Diabetes

Gaede et al N.Engl.Med. 3448:383. 2003

Composite outcome: CV death, MI, coronary or peripheral revascularization, CVA, amputation

Page 38: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Risk of Death after AMI is Reduced Risk of Death after AMI is Reduced across all Levels of Kidney Function across all Levels of Kidney Function with Recommended Interventionswith Recommended Interventions

0.520.45

0.40

0.580.620.61

0.440.41

0.52

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.10

1.20

< 1.5 1.5-2.4 2.5-3.9

Serum creatinine (mg/dl)

Hazard

rati

o

Aspirin

Beta Blocker

ACE-I

Shlipak et al., Ann Int Med 2002;137:555-62

Page 39: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Nephropathy: Diabetic Nephropathy: Important MessageImportant Message

Lower blood pressure < 130 / 80 mmHgLower blood pressure < 130 / 80 mmHg Reducing ProteinuriaReducing Proteinuria Inhibition of Renin-Angiotensin SystemInhibition of Renin-Angiotensin System Multiple risk factor interventionMultiple risk factor intervention

GlycemiaGlycemia Dyslipidemia Dyslipidemia Physical activityPhysical activity Aspirin Aspirin Smoking cessationSmoking cessation

Page 40: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Is Combination Therapy Is Combination Therapy With An ACE Inhibitor With An ACE Inhibitor And An ARB Safe And And An ARB Safe And Effective For Patients Effective For Patients With Diabetic Renal With Diabetic Renal

Disease?Disease?

Page 41: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

ACEi- or ARB-Based Regimens ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do for Diabetic Nephropathy Do

Not Go Far Enough!Not Go Far Enough!

ACEi or ARBGFR = - 6 ml/min/yrTime to ESRD 6.6 yrs

Time (yrs)

ESRD

50

2 4 6 8 10

Glo

me

rula

r F

il tr a

t ion

Ra

tem

l/ min

/1.7

3 m

2

No ACEi/ARBor BP control

GFR = - 10 ml/min/yrTime to ESRD 4 yrs

40

30

20

10

ACEi + ARBGFR = - ? ml/min/yr

Time to ESRD ?

RAAS blockade + Other?

Page 42: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Combining an ACEi and an ARB is more Combining an ACEi and an ARB is more Renoprotective than Either Agent alone Renoprotective than Either Agent alone

in in Non-DiabeticNon-Diabetic Nephropathy Nephropathy

TreatmenTreatmentt

NN BaselinBaseline BP e BP

mmHgmmHg

BP from BP from baseline baseline mmHg*mmHg*

Primary Primary EndpoinEndpoin

tt

HazarHazardd

Ratio*Ratio***

P P valuevalue

CombinatCombinationion

8855

130 / 75130 / 75 5.2 / 2.95.2 / 2.9 10 10 (11%)*(11%)*

-- --

TrandolaTrandolaprilpril

8866

130 / 76130 / 76 5.3 / 3.05.3 / 3.0 20 20 (23%)(23%)

0.400.40 0.0160.016

LosartanLosartan 8855

130 / 74130 / 74 5.1 / 2.95.1 / 2.9 20 20 (23%)(23%)

0.380.38 0.0180.018

Nakao et al. Lancet 361:117-124, 2003

*Average number of medications 3.2 per pt, 90% in all groups on dihydropyridine CCB** Hazard Ratio comparing combination with either agent alone

Page 43: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Summary of Studies combining ACEi Summary of Studies combining ACEi and ARB in Diabetic nephropathy: and ARB in Diabetic nephropathy:

Effects on Proteinuria and BPEffects on Proteinuria and BP

DM DM TypeType

DesignDesign NN DuratiDurationon

InterventionIntervention ResultsResults

11Type 2 Type 2 DRBCTDRBCT 44 4 4 weeksweeks

40 mg Lisinopril / 40 mg Lisinopril /

50 Losartan50 LosartanNo effectNo effect

22Type 2 Type 2 DRBCTDRBCT 1818 8 8 weeksweeks

8 mg candesartan8 mg candesartan 25% Prot 25% Prot and BPand BP

33Type 1 Type 1 DBRPCTDBRPCT 2121 8 8 weeksweeks

300 mg irbesartan300 mg irbesartan 43% Prot 43% Prot and BPand BP

44Type 1 Type 1 DBRCTDBRCT 2020 8 8 weeksweeks

20 mg Benazepril/20 mg Benazepril/

ACEi / Valsartan 80 ACEi / Valsartan 80 mgmg

15 % Prot 15 % Prot and BPand BP

55Type 1Type 1 DBRCTDBRCT 2424 8 8 weeksweeks

20 mg Enalapril/300 20 mg Enalapril/300 mg Irbesartanmg Irbesartan

25% Prot 25% Prot and BPand BP

66Type 2Type 2 DBRCTDBRCT 2020 8 8 weeksweeks

ACEi / Candsartan 16 ACEi / Candsartan 16 mgmg

29% Prot29% Prot1 Agarwal et al. Kid Int 59:2282, 2002; 2 Rossing et al. Diab Care. 25:95-100, 2002; 3 Jacobsen et al Neph. Dial. Transplant 17:1019-1024, 2002;4 Jacobsen et al. J. Am. Soc. Neph. 14:992-999, 2003;5 RossingEt al. Kid Int 63:1874-80, 2003 ; 6 Rossing et al. Diab Care 26:2268-2274, 2003.

Page 44: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Nephropathy: Diabetic Nephropathy: Important Message Important Message

Small short-term studies suggest Small short-term studies suggest combinations of ACEi and ARB reduce combinations of ACEi and ARB reduce proteinuria synergisticallyproteinuria synergistically Greater reductions in proteinuria with or Greater reductions in proteinuria with or

without additional lowering in blood without additional lowering in blood pressurepressure

Hyperkalemia and Increased creatinine not Hyperkalemia and Increased creatinine not well documentedwell documented

Safety and Efficacy of combination ACEi and Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well ARB in diabetic with nephropathy not well establishedestablished

Page 45: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Is There a Role for Is There a Role for Spironolactone (or Spironolactone (or

Eplerenone) in Eplerenone) in Combination with Other Combination with Other Drugs in Patients with Drugs in Patients with Diabetic Nephropathy?Diabetic Nephropathy?

Page 46: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Capillary wall injuryInflammation

O2- , TGF-1 / PAI-1

Role of Aldosterone in the Role of Aldosterone in the Pathogenesis Pathogenesis

of Diabetic Nephropathyof Diabetic Nephropathy

Glomerular Hypertension

Angiotensin IIHemodynamic Non-Hemodynamic

Sclerosis andFibrosis

Injury to Glomerular Cells

Proteinuria

Glomerular and Tubular Scarring Progressive Renal Failure

Aldosterone

Page 47: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Adverse Renal and Cardiovascular Adverse Renal and Cardiovascular Effects of AldosteroneEffects of Aldosterone

GlomerulosclerosisInterstitial FibrosisProteinuriaRenal Failure

Ventricular HypertrophyCardiac FibrosisContractile DysfunctionHeart Failure

Endothelial dysfunctionInflammationOxidative Stress

Aldosterone

Page 48: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Mineralocorticoid Receptor Blockade Mineralocorticoid Receptor Blockade Improves Cardiac Outcomes: Placebo Improves Cardiac Outcomes: Placebo

Controlled TrialsControlled Trials

360

10

3

4

5

6

7

8

9

2

1

630 9 30272421181512 33

Placebo

Eplerenone

P=0.03RR=0.79 (95% Cl, 0.64-0.97)

Cu

mu

lati

ve In

cid

ence

of

(%)

Months since Randomization

Eplerenone reduces sudden cardiac deathPost myocardial infarction

1.00

0.00

0.95

0.90

0.85

0.80

0.75

0.70

0.65

0.60

0.55

0.50

0.45P

rob

abili

ty o

f S

urv

ival

Spironolactone

Placebo

36630 9 181512 21 24 27 30 33Months

Spironolactone improves survival in Chronic Heart Failure

P=0.001RR=0.70 (95% Cl, 0.60-0.82

Page 49: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Ang I

Ang II

Progressive Diabetic Nephropathy

ACE

Renal Injury and Proteinuria

ACEi

AT1 Receptor

Non-ACEPathways

Aldosterone

MRA

ARB

Can Dual Blockade of the RAAS Can Dual Blockade of the RAAS Improve Renal Outcomes in Improve Renal Outcomes in

Diabetic Nephropathy?Diabetic Nephropathy?

+

+

Page 50: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Study Design and Study Design and ObjectivesObjectives

Study Design:Study Design: Randomized double-blind placebo Randomized double-blind placebo controlled trialcontrolled trial

Study Population:Study Population: Diabetics with Diabetics with macroalbuminuria despite maximally dosed ACE macroalbuminuria despite maximally dosed ACE inhibitorinhibitor

Intervention:Intervention: Lisinopril 80 mg/d + losartan 100 Lisinopril 80 mg/d + losartan 100 mg/d or + Aldactone 25 mg/d or + placebo mg/d or + Aldactone 25 mg/d or + placebo

Primary Outcome:Primary Outcome: Change in albuminuria Change in albuminuria Secondary Outcomes:Secondary Outcomes: Safety especially serum Safety especially serum

creatinine and hyperkalemiacreatinine and hyperkalemia Follow up:Follow up: 52 weeks 52 weeks

Page 51: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Study Study HypothesisHypothesis

Blockade of the renin-angiotensin system Blockade of the renin-angiotensin system beyond ACE inhibition decreases proteinuria beyond ACE inhibition decreases proteinuria and slows progression of renal disease in and slows progression of renal disease in diabetics with overt nephropathy by diabetics with overt nephropathy by suppressing aldosterone synthesis or suppressing aldosterone synthesis or blocking the aldosterone receptor.blocking the aldosterone receptor.

Page 52: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Time, weeks

Diabetics with SBP > 130 mmHgScr < 3, female, < 4, maleUrine albumin/Cr ratio > 300on ACE inhibitor + CT

Run-inPeriod

Control to SBP < 130 then Randomize

-4 -2 0 24-26 48- 52 56

BP blood pressure, potassium and serum creatinine measurementRF renal function-GFR, RPF, 24 hour urine sodium, creatinine,potassium, protein and urea

Combined Inhibition of the RAAS Pathway: ACEi + ARB vs ACEi + MRA in Diabetic Nephropathy

Lisinopril 80 mg/d

ABPM, aldosteroneKidney Function

Lipids, Inflammation

Lisinopril 80 mg/d +Losartan 100 mg p.o qd

Lisinopril 80 mg/d +Aldactone 25 mg p.o. qd

D/C Study Drug

Lisinopril 80 mg/d + Placebo Maintain SBP 120-129 mmHgWith conventionalantihypertensives

ABPM, aldosteroneKidney Function

Lipids, Inflammation

ABPM, aldosteroneKidney Function

Lipids, Inflammation

Page 53: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Role for spironolactone or eplerenone in Role for spironolactone or eplerenone in diabetics with nephropathy not diabetics with nephropathy not establishedestablished

Small, short-term studies suggest adding Small, short-term studies suggest adding on is efficacious for lowering proteinuriaon is efficacious for lowering proteinuria

Not clear if combinations are safe in Not clear if combinations are safe in larger populationlarger population

No long-term trials with cardiovascular No long-term trials with cardiovascular or renal endpointsor renal endpoints

Diabetic Nephropathy: Diabetic Nephropathy: Important Message Important Message

Page 54: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Beyond RAAS Beyond RAAS BlockadeBlockade

Page 55: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Hypothesis: Anemia is an Hypothesis: Anemia is an Important CV Risk Factor in Important CV Risk Factor in

Chronic Kidney DiseaseChronic Kidney Disease

Chronic Kidney Disease

Cardiovascular disease

Anemia

Page 56: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Hb < 11.3*

Hb > 13.8

Hb 12.5-13.8*

Hb 11.4-12.5*

Time, years

4321

En

d-s

tag

e re

nal

dis

ease

, %

10

20

50

60

30

40

0

Baseline Hemoglobin Predicts Baseline Hemoglobin Predicts ESRD in Type 2 Diabetics with ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial Nephropathy: RENAAL Trial

(N=1513)(N=1513)

Mohanram et al. Kid. Int. Sept 2004

--1.001.00> 13.8> 13.8

0.0020.0021.851.8512.5-13.812.5-13.8

0.020.021.611.6111.3-12.511.3-12.5

0.0010.0011.991.99< 11.3< 11.3

P P valuevalue

AdjusteAdjusted HR*d HR*Hb g/dlHb g/dl

* Age, gender, GFR, Race, Proteinuria,CV disease, A1c, lipids, BP, Ca, P, albumin

Page 57: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Is Anemia Causing Is Anemia Causing Cardiovascular And Cardiovascular And

Renal Disease In Renal Disease In Diabetics, Or is it Just A Diabetics, Or is it Just A

Marker?Marker?

Page 58: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Trial to Reduce Cardiovascular Events Trial to Reduce Cardiovascular Events

with Aranespwith Aranesp (Darbepoietin) Therapy (Darbepoietin) Therapy Patient Population:Patient Population: 4000 Type 2 diabetics with 4000 Type 2 diabetics with

Chronic Kidney Disease (estimated GFR 20-60) and Chronic Kidney Disease (estimated GFR 20-60) and Hb < 11 g/dlHb < 11 g/dl

Study Design:Study Design: R Randomized, double-blind, placebo-andomized, double-blind, placebo-controlled, multicenter international trial controlled, multicenter international trial

Intervention:Intervention: Aranesp Aranesp (darbepoetin alfa) to (darbepoetin alfa) to increase Hb to 11-13 g/dl increase Hb to 11-13 g/dl

Primary OutcomePrimary Outcome: time to all-cause mortality and : time to all-cause mortality and cardiovascular cardiovascular morbidity, including: myocardial morbidity, including: myocardial infarction, acute myocardial ischemia, congestive infarction, acute myocardial ischemia, congestive heart failure and strokeheart failure and stroke

Follow-up:Follow-up: 4 years 4 years

Funded by Amgen

Page 59: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Nephropathy: Some Diabetic Nephropathy: Some Novel Therapies Novel Therapies

Under InvestigationUnder Investigation

Pirfenidone –antifibrotic agentPirfenidone –antifibrotic agent Aliskerin anti-renin agentAliskerin anti-renin agent Robuxistaurin- Protein Kinase C Robuxistaurin- Protein Kinase C

Beta-1 antagonistBeta-1 antagonist Advanced Glycation Endproduct Advanced Glycation Endproduct

antagonistsantagonists OthersOthers

Page 60: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

How Should I How Should I Manage My Patient Manage My Patient

With Diabetic With Diabetic Nephropathy Nephropathy

Today?Today?

Page 61: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Nephropathy Diabetic Nephropathy ManagementManagement

ParameterParameter Lower BP………………………Lower BP……………………… Block RAAS……………………Block RAAS…………………… Improve glycemia Improve glycemia

…………….……………. Lower LDL Lower LDL

cholesterol………..cholesterol……….. Anemia management Anemia management

………...………... Endothelial Endothelial

protection…………protection………… Smoking…………………Smoking…………………

TargetTarget

< 130/80 mmHg< 130/80 mmHg

ACEi or ARB to max ACEi or ARB to max toleratedtolerated

A1c < 6.5% (Insulin/TZD)A1c < 6.5% (Insulin/TZD)

< 100 (70) mg/dl statin + < 100 (70) mg/dl statin + otherother

Hb 11-12 g/dl (Epo + iron)Hb 11-12 g/dl (Epo + iron)

Aspirin dailyAspirin daily

CessationCessation

Page 62: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

Diabetic Nephropathy: Diabetic Nephropathy: What about proteinuria?What about proteinuria?

Lower BP to goal with max dose ACEi or ARBLower BP to goal with max dose ACEi or ARB

Consider Adding: ACEi to ARB, Consider Adding: ACEi to ARB, mineralocorticoid receptor antagonist to ACEi mineralocorticoid receptor antagonist to ACEi or ARBor ARB

Calcium Channel BlockersCalcium Channel Blockers Non-dihydropyridineNon-dihydropyridine DihydropyridineDihydropyridine

Page 63: Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy

LOCKING THE STABLE LOCKING THE STABLE DOORDOOR

…after the horse has bolted…after the horse has bolted

Thank Thank YouYou