Diabetic NephropathyDinkar Kaw, M.D.,Dinkar Kaw, M.D.,

Division of Nephrology Division of Nephrology

Objectives

Prevalence of diabetic kidney diseasePrevalence of diabetic kidney disease Pathogenesis of diabetic nephropathyPathogenesis of diabetic nephropathy Clinical course of diabetic nephropathyClinical course of diabetic nephropathy Slowing the progression of nephropathySlowing the progression of nephropathy Screening for early nephropathyScreening for early nephropathy

Causes of End Stage Renal DiseaseCauses of End Stage Renal Disease

0%10%20%30%40%50%60%70%80%90%

100%

%

OtherInterstit NCystic KDGNBPDiabetes

USRDS 1993 Annual Data Report

Diabetic Nephropathy The most common cause of ESRD in USA.The most common cause of ESRD in USA. Accounts for nearly 40% of ESRD in USA. This Accounts for nearly 40% of ESRD in USA. This

proportion of ESRD due to DN is less in Europe proportion of ESRD due to DN is less in Europe than in USA.than in USA.

Incidence is increasing, accounted for 10% in Incidence is increasing, accounted for 10% in 1973 but now around 40% of USRD populations.1973 but now around 40% of USRD populations.

However one needs to keep in mind all diabetic However one needs to keep in mind all diabetic patients with ESRD do not have DN as underlying patients with ESRD do not have DN as underlying cause of ESRD. cause of ESRD.

Diabetic Nephropathy Mortality of ESRD patients with Diabetes Mellitus Mortality of ESRD patients with Diabetes Mellitus

is higher than in ESRD patients without Diabetes.is higher than in ESRD patients without Diabetes. This higher mortality is due to increase in This higher mortality is due to increase in

Cardiovascular, cerebro-vascular, peripheral Cardiovascular, cerebro-vascular, peripheral vascular and infection related morbidity.vascular and infection related morbidity.

In USA the health care cost for diabetic ESRD In USA the health care cost for diabetic ESRD patients has approached to $ 2 billion per year.patients has approached to $ 2 billion per year.

Patient Survival on Dialysis by Cause of Renal Failure

Patient Survival on Dialysis by Cause of Renal Failure

From UpToDate v 6.2; Data from USRDS 1995 Annual Report

Diabetic Nephropathy DN occurs in 35-40% of patients with type I DN occurs in 35-40% of patients with type I

diabetes (IDDM) whereas it occurs only in 15-diabetes (IDDM) whereas it occurs only in 15-20% of patients with type II diabetes (NIDDM).20% of patients with type II diabetes (NIDDM).

More frequent in Native Americans, Hispanics More frequent in Native Americans, Hispanics and possibly Asian Indians.and possibly Asian Indians.

Definition or Criteria for diagnosis of DNDefinition or Criteria for diagnosis of DN Presence of persistent proteinuria in sterile urine of Presence of persistent proteinuria in sterile urine of

diabetic patients with concomitant diabetic retinopathy diabetic patients with concomitant diabetic retinopathy and hypertension.and hypertension.

D.N.- Pathogenesis Familial - Genetic Familial - Genetic

Only 35-40% patients with IDDM develop DN.Only 35-40% patients with IDDM develop DN. There is an increased risk of DN in a patient with There is an increased risk of DN in a patient with

family member having DN.family member having DN. Increased predisposition of Native Americans, Hispanic Increased predisposition of Native Americans, Hispanic

to DN.to DN.

D.N.- Pathogenesis Glycemic Control-in both expt & humanGlycemic Control-in both expt & human

DN does not occur in euglycemic patients.DN does not occur in euglycemic patients. In early 80s some controversy but DCCT confirmed In early 80s some controversy but DCCT confirmed

role of hyperglycemia in pathogenesis of DN.role of hyperglycemia in pathogenesis of DN. Renal transplant with early DN showed structural Renal transplant with early DN showed structural

recovery in euglycemic receipient. (Abouna)recovery in euglycemic receipient. (Abouna)

Strict Glycemic Control PreventsMicroalbuminuria in Type 1 Diabetes mellitus

Strict Glycemic Control PreventsMicroalbuminuria in Type 1 Diabetes mellitus

From UpToDate v 6.2; Data from the DCCT Research Group, NEJM(1993) 329:977.

D.N.- Pathogenesis Glomerular HyperfiltrationGlomerular Hyperfiltration Glomerular HypertensionGlomerular Hypertension Glomerular HypertrophyGlomerular Hypertrophy GBM thickeningGBM thickening Mesangial ExpansionMesangial Expansion

D.N.- Pathogenesis

Renal lesions mainly related to Renal lesions mainly related to extracellular matrix accumulationextracellular matrix accumulation

- Occurs in glomerular & tubular basement - Occurs in glomerular & tubular basement

membranemembrane

- Principal cause of mesangial expansion- Principal cause of mesangial expansion

- Contributes to interstitium expansion- Contributes to interstitium expansion

D.N.- Pathogenesis

Extracellular matrix accumulationExtracellular matrix accumulation

- Imbalance between synthesis & degradation of - Imbalance between synthesis & degradation of

ECM componentsECM components

- Linkage between glucose concentration & ECM - Linkage between glucose concentration & ECM

accumulationaccumulation

- Transforming growth factor-Beta associated with- Transforming growth factor-Beta associated with

increased production of ECM molecules increased production of ECM molecules

D.N.- Pathogenesis

Extracellular matrix accumulationExtracellular matrix accumulation

- TGF-B can down regulate synthesis of ECM- TGF-B can down regulate synthesis of ECM

degrading enzymes & upregulate inhibitors ofdegrading enzymes & upregulate inhibitors of

these enzymesthese enzymes

- Angiotensin II can stimulate ECM synthesis - Angiotensin II can stimulate ECM synthesis

through TGF-B activity through TGF-B activity

- Hyperglycemia activates protein kinase C,- Hyperglycemia activates protein kinase C,

stimulating ECM production through cyclic AMPstimulating ECM production through cyclic AMP

PathwayPathway

Diffuse and Nodular Glomerulosclerosis in Diabetic Nephropathy

Diffuse and Nodular Glomerulosclerosis in Diabetic Nephropathy

From UpToDate v 6.2CourtesyH. Rennke, M.D.

Diabetic Nephropathy

Advanced Diabetic GlomerulosclerosisAdvanced Diabetic Glomerulosclerosis

From: UpToDatev 6.2CourtesyH. Rennke, M.D.

Diabetic Nephropathy

Diabetic NephropathyGlomerular Basement Membrane Thickening

Diabetic NephropathyGlomerular Basement Membrane Thickening

From: UpToDatev 6.2CourtesyH. Rennke, M.D.

Natural Course of D.N.

Stage 1: Renal hypertrophy - hyperfunctionStage 1: Renal hypertrophy - hyperfunction Stage 2 : Presence of detectable glomerular Stage 2 : Presence of detectable glomerular

lesion with normal albumin excretion rate lesion with normal albumin excretion rate & normal blood pressure& normal blood pressure

Stage 3 : MicroalbuminuriaStage 3 : Microalbuminuria Stage 4 : Dipstick positive proteinuriaStage 4 : Dipstick positive proteinuria Stage 5 : End stage renal disease Stage 5 : End stage renal disease

Functional changes*

Natural History of IDDM

Proteinuria

End-stage renal disease

Clinical type 1 diabetes

Structural changes†

Proteinuria

Rising serum creatinine levels

Rising blood pressure

Onset of diabetes

2 5 10 20

Years* Kidney size , GFR † GBM thickening , mesangial expansion

Microalbuminuria

30

CV events

Functional changes*

Natural History of NIDDM

Proteinuria

End-stage renal disease

Clinical type 2 diabetes

Structural changes†

Rising blood pressure

Rising serum creatinine levels

Cardiovascular death

Microalbuminuria

Onset of diabetes

2 5 10 20 30

Years* Kidney size , GFR † GBM thickening , mesangial expansion

D.N.- Pathogenesis Hypertension - in both expt & humanHypertension - in both expt & human

Hypertension follows 8-10 years of hyperglycemia Hypertension follows 8-10 years of hyperglycemia in IDDM patients but it is frequently present at the in IDDM patients but it is frequently present at the diagnosis of NIDDM.diagnosis of NIDDM.

Many experimental & human studies have shown Many experimental & human studies have shown HTN accelerating progressive renal injury in DN.HTN accelerating progressive renal injury in DN.

Effect of Angiotensin Blockade

Afferent arteriole

Efferent arteriole

Glomerular pressure AER( GFR)

Glomerulus

Bowman’s Capsule

Angiotensin IIAngiotensin II

ProteinuriaProteinuria

A II blockade:A II blockade:

ACE-I Is More Renoprotective Than Conventional Therapy

in Type 1 Diabetes

% with doubling of

baseline creatinine

100

75

50

25

00 1 2 3 4

Baseline creatinine >1.5 mg/dL

Captopriln=207

Placebon=202

P<.001

Lewis EJ, et al. N Engl J Med. 1993;329(20):1456-1462.

Years of follow-up

RENAAL

Brenner BM et al. N Engl J Med 345:861-869, 2001

Primary Composite End Point: Doubling of Serum Creatinine, ESRD or Death (Kaplan – Meier Curve)

RENAAL

Brenner BM et al. N Engl J Med 345:861-869, 2001

Rate of Progression of Renal Disease (median 1/s Cr slope)

00.010.020.030.040.050.060.070.08

Losartan Placebo

dl/

mg

/yr

Losartan could delay ESRD by 1.5-2 years.

Irbesartan in patients with type 2 diabetes & microalbuminuria study

590 NIDDM patients with HTN and microalbuminuria 590 NIDDM patients with HTN and microalbuminuria with nearly normal GFR.with nearly normal GFR.

Randomly assigned to placebo, 150 mg or 300 mg of Randomly assigned to placebo, 150 mg or 300 mg of irbesartan for 2 years.irbesartan for 2 years.

Primary outcome was time to the onset of diabetic Primary outcome was time to the onset of diabetic nephropathy (urinary albumin excretion rate >200 nephropathy (urinary albumin excretion rate >200 mcg/min and at least 30% greater albuminuria)mcg/min and at least 30% greater albuminuria)

14.9% patients on placebo group, 9.7% of irbesartan 14.9% patients on placebo group, 9.7% of irbesartan 150mg group and 5.2% of irbesartan 300 mg group 150mg group and 5.2% of irbesartan 300 mg group reached the primary point.reached the primary point.

– (Parving et al, NEJM, 2001)(Parving et al, NEJM, 2001)

ARBs in NIDDM,HTN & microalbuminuria-Parving 2001

Lewis et al NEJM 2001

ACE-I + Verapamil: Additive Reduction of Proteinuria in Type 2 Diabetes at 1 Year

Trandolapril (5.5 mg/d)

Verapamil (315 mg/d)

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

-70

-60

-50

-40

-30

-20

-10

0

MAP Proteinuria

*

Bakris GL, et al. Kidney Int. 1998;54:1283-1289. Reprinted by permission, Blackwell Science, Inc.

-33%

-27%

-62%

*p <0.001 combination vs either monotherapy

Perc

en

t re

du

cti

on

n=12 n=11 n=14

D.N.-Management ACEI or AII RB- in both expt & humanACEI or AII RB- in both expt & human

Reduce glomerular hypertensionReduce glomerular hypertension Reduce proteinuria independent of Reduce proteinuria independent of

hemodynamic effectshemodynamic effects Reduce glomerular hypertrophyReduce glomerular hypertrophy well tolerated apart from hyperkalemia & well tolerated apart from hyperkalemia &

worsening of anemia in severe CRFworsening of anemia in severe CRF Cautious use in presence of severe renovascular Cautious use in presence of severe renovascular

diseasedisease

DN: ADA Position Statement

Screening:

Perform an annual test for the presence of microalbuminuria in1) type 1 diabetic patients who have had diabetes > 5 years and2) all type 2 diabetics patients starting at diagnosis.

Treatment:

• In the treatment of albuminuria/nephropathy both ACE inhibitors and ARBs can be used:

• In hypertensive and nonhypertensive type 1 diabetic patients with microalbuminuria or clinical albuminuria, ACE inhibitors are the initial agents of choice

• In hypertensive type 2 diabetic patients with microalbuminuria or clinical albuminuria, ARBs are the initial agents of choice.

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

American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002American Diabetes Association: Position Statement Diabetes Care 25:S85-S89, 2002

UK Prospective Diabetes Study (UKPDS) Major Results: Powerful Risk Reductions

Better blood pressure control reduces…Better blood pressure control reduces… Strokes by Strokes by > > one thirdone third Serious deterioration of vision by Serious deterioration of vision by > > one thirdone third Death related to diabetes by Death related to diabetes by one thirdone third

Better glucose control reduces…Better glucose control reduces… Early kidney damage by Early kidney damage by one thirdone third Major diabetic eye disease by Major diabetic eye disease by one fourthone fourth

Turner RC, et al. BMJ. 1998;317:703-

713.

17% decrease per 10 mmHg decrement in BP

p<0.0001

0.5

1

5

110 120 130 140 150 160 170

UKPDS: Relationship Between BP Control And Diabetes-Related Deaths

Mean systolic blood pressure (mmHg)

Haza

rd r

ati

o

Adler AI, et al. BMJ. 2000;321:412-419.Reprinted by permission, BMJ Publishing Group.

Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS

StrokeAny Diabetic

EndpointDM

DeathsMicrovascularComplications

-50

-40

-30

-20

-10

0

% R

ed

ucti

on

In

Rela

tive R

isk

Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL)

Tight BP Control (Average 144/82 mmHg)

32%

37%

10%

32%

12%

24%

5%

44%

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.Reprinted by permission, Harcourt Inc.

*

*

*

**P <0.05 compared to tight glucose control

National Kidney Foundation Recommendations on Treatment of HTN and Diabetes

Blood pressure goal: 130/80 mmHgBlood pressure goal: 130/80 mmHg Target blood pressure: 125/75 for patients Target blood pressure: 125/75 for patients

with >1 gram/day proteinuriawith >1 gram/day proteinuria Blood pressure lowering medications should Blood pressure lowering medications should

reduce both blood pressure + proteinuriareduce both blood pressure + proteinuria Therapies that reduce both blood pressure Therapies that reduce both blood pressure

and proteinuria have been known to reduce and proteinuria have been known to reduce renal disease progression and incidence of renal disease progression and incidence of ischemic heart diseaseischemic heart disease

Bakris GL, et al. Am J Kidney Dis. 2000;36(3):646-661.

Cholesterol Lowering Therapy and Diabetic Nephropathy

Cholesterol Lowering Therapy and Diabetic Nephropathy

Randomized single-Randomized single-blinded studyblinded study

34 NIDDM patients34 NIDDM patients Lovastatin or PlaceboLovastatin or Placebo Followed for 2 yearsFollowed for 2 years

68

70

72

74

76

78

80

82

84

86

0 12 24

placebolovastatn

GFRml/min

Months

Lam, etal. Diabetologia (1995) 38:604-609

Management of ESRD due to DN

Early planning of Vascular AccessEarly planning of Vascular Access Both HD & PD could be appropriate modalities. Both HD & PD could be appropriate modalities. Early initiation of Dialysis at GFR 18-20 mls/min.Early initiation of Dialysis at GFR 18-20 mls/min. Renal TransplantationRenal Transplantation

CHD very common even in absence of symptoms.CHD very common even in absence of symptoms. Coronary Angiogram in diabetics under 40 years age.Coronary Angiogram in diabetics under 40 years age.

Combined Renal & Pancreatic Transplantation for Combined Renal & Pancreatic Transplantation for IDDM.IDDM.

From UpToDate v 6.2; Data from Nelson, et al JASN(1992)3:1147.

Comparison of Patient Survival on Hemodialysisand CAPD by Cause of Renal Failure

From:UpToDatev 6.2

Simultaneous Pancreas-Kidney TransplantationPatient and Graft Survival

Screening for microalbuminuria in diabetes

Treatment Objectives to Prevent Macrovascular Disease in Diabetic Patients

HypertensionHypertension BP < 130/80 mmHgBP < 130/80 mmHg

HypercholesterolemiaHypercholesterolemia LDL < 100 mg/dLLDL < 100 mg/dL

HyperglycemiaHyperglycemia Hgb AHgb A1C1C < 7.0 % < 7.0 %

American Diabetes Association Clinical Practice Recommendations. Diabetes Care. 2001;24(suppl1):S1-S133.

Management of HTN and Chronic Renal Disease (CRD) in Diabetics

Reduce BP to <130/80 mmHgReduce BP to <130/80 mmHg Use multiple antihypertensive drugs (ACEI, ARB, Use multiple antihypertensive drugs (ACEI, ARB,

diuretic, CCB, beta-blocker)diuretic, CCB, beta-blocker) Maximal reduction of proteinuriaMaximal reduction of proteinuria Treat hyperlipidemia (LDL <100 mg/dL)Treat hyperlipidemia (LDL <100 mg/dL) Control Hgb AControl Hgb A1C1C to <7% to <7%

Low salt diet (<2 gm NaCl/day)Low salt diet (<2 gm NaCl/day) Stop cigarette smokingStop cigarette smoking

Thanks for your attention