Diabetic Nephropathy

Joel Michels Topf, MDClinical Nephrologist

Year Capacity

1926 84,401

1927 85,753

1949 97,239

1956 101,001

1991 102,501

1998 107,501

1999 111,238

2006 111,238

Year Capacity

1926 84,401

1927 85,753

1949 97,239

1956 101,001

1991 102,501

1998 107,501

1999 111,238

2006 111,238

Incident ESRD

0

0

0

0

56,137

87,089

91,523

104,364

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

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

Diabetes has gone from being one of 3

major causes of ESRD to the single most important cause

Incidence Count by Diagnosis

0

10,000

20,000

30,000

40,000

50,000

1980 1985 1990 1995 2000 2005

Hypertension Glomerulonephritis Diabetes

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

Diabetics on Dialysis: 172,938

0

5,000,000

10,000,000

15,000,000

20,000,000

25,000,000

Diabetics Diabetics on Dialysis

Total no of Diabetics: 20,000,000

0.86%0.86%

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

Diabetics on Dialysis: 172,938

0

5,000,000

10,000,000

15,000,000

20,000,000

25,000,000

Diabetics Diabetics on Dialysis

Total no of Diabetics: 20,000,000

0.86%0.86%

Though diabetes is the most important cause of ESRD very few diabetics are on

dialysis

ESRD

CV Mortality

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

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

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

The risk of ESRD is dwarfed by the risk of

death

Diabetic nephropathy

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

Initially patients present with increased GFR (2x normal)

Followed by proteinuria Patients then have progressively

deteriorating GFR

5-10 years

15-20 years

20 years

5-10 years

15-20 years

20 years

Diabetic nephropathy is relatively rare before 10 years,

peaks at 15-20 years and if the patient has not been affected by 20 years, is unlikely to get the disease

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

nodular glomerulosclerosis

Kimmelstiel-Wilson lesions

The Kimmelstiel-Wilson (K-W) lesions are ovoid or spherical, often laminated, hyaline masses situated in the periphery of the glomerulus.

The nodules are composed of lipids and fibrin.

The K-W nodules enlarge until they compress and obliterate the glomerular tuft.

Because of these glomerular and arteriolar lesions, the blood flow to the kidney is compromised and the kidney becomes ischemic. This results in tubular atrophy and interstitial fibrosis and leads to a roughened renal cortical surface.

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.

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

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

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.

Hyperfiltration

Early finding Renal vasodilation

Causes early increases in GFR Later

Nephron loss results in compensatory hyperfiltration

No increase in GFR

Pathology

PathologyTwo biopsies from the same patient, the

patient had unilateral RAS on the left. The

RAS prevented hyper-filtration on the left and protected that

kidney.

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)

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

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

Associated with a reduction in microalbuminuria• Cholesterol• Glycemic control• Blood pressure

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

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

Associated with a reduction in microalbuminuria• Cholesterol• Glycemic control• Blood pressure

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type II

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

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type II

Diagnosis

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

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type I

Diagnosis

Hyperfiltration

Microalbuminuri

a

Macroalbuminuri

a

Renal failure

Type II

Diagnosis

Diagnosis

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

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.

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

When is proteinuria not diabetic nephropathy?

When does a diabetic need a biopsy?

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

Absence of retinopathy or neuropathy

Treatment

1. Blood pressure control

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

Randomized prospective trial of treatment strategies in type two diabetes

ukpds

Protocol written in 1976Recruitment from 1977 - 1991End of study 1997Type 2 diabetic patients 5,102Person years follow-up 53,000

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

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15Years from randomisation

Intensive

Conventional

Risk reduction 25%(95% CI: 7% to 40%)

Microvascular Endpoints

0%

20%

40%

60%

0 3 6 9 12 15Years from randomisation

Intensive (2729)

Conventional (1138)

Risk reduction 12%(95% CI: 1% to 21%)

p=0.029

Any Diabetes Related Endpoint

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15Years from randomisation

Intensive

Conventional

Risk reduction 25%(95% CI: 7% to 40%)

Microvascular Endpoints

0%

20%

40%

60%

0 3 6 9 12 15Years from randomisation

Intensive (2729)

Conventional (1138)

Risk reduction 12%(95% CI: 1% to 21%)

p=0.029

Any Diabetes Related Endpoint

0

10

20

30

40

50

0 3 6 9 12 15

Pro

por

tion

of p

atie

nts

(%)

Years from randomization

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

(%)

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

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

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

0%

5%

10%

15%

20%

0 3 6 9

Years from randomisation

Tight blood pressure control (758)

Less tight blood pressure control (390)

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

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

0%

5%

10%

15%

20%

0 3 6 9

Years from randomisation

Tight blood pressure control (758)

Less tight blood pressure control (390)

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

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

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

Don’t worry about the glucometer get the BP

under control

Microalbumin is the Hemoglobin A1c of blood pressure management.

Dr Whitey routinely

checks A1c to make sure my

diabetes is on track.

Microalbumin is the Hemoglobin A1c of blood pressure management.

Dr Whitey routinely

checks Hgb A1c to

make sure my

diabetes is on track.

Dr Whitey routinely

checks µAlb to verify my

blood pressure is on track.

Treatment

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

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

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

ACEi are goodARB are good

What about both together?

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

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

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.

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

PotassiumPotassium

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.

Any addition of an:ACEiARBAldosterone antagonistDiuretic

Must check electrolytes one week later

High potassiumStop the drugLow potassium

dietLoop diureticThiazide diureticLiberalize sodium

restriction

Treatment

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

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

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…

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

…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

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.

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.

Calcium channel blockers Verapamil does not delay

development of microalbuminuria Verapamil does reduce

proteinuria in diabetics independent of changes in blood pressure

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.

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

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

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.

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 Carvedilol

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

fin