Clinical Practice Guidelines Diabetic Nephropathy

Malaysian Society of NephrologyMinistry of Health Malaysia

Clinical Practice Guidelines

Diabetic Nephropathy

Introduction

• Increased prevalence of DM

• Diabetic nephropathy – commonest cause of ESRD

• heavy burden on resources

Adapted from Breyer JA et al. Am J Kid Dis 1992; 20(6): 535.

Time (yrs) 0 5 20 30

Onset ofDiabetes

Onset ofProteinuria

End Stage Renal Disease

STRUCTURAL CHANGES(Increasing glomerular basement

membranethickening and mesangial expansion)

Hypertension

OVERT NEPHROPATHY

Rising Scr,Decreasing GFR

INCIPIENT NEPHROPATHYHyperfiltration,

microalbuminuria,rising blood pressure

PRECLINICAL NEPHROPATHY

Course of Diabetic Nephropathy

Microalbuminuria :

first sign of nephropathy

a strong and independent predictor of cardiovascular disease

Diabetic Nephropathy

Guidelines 1:Screening for proteinuria

Screening for proteinuria should be performed yearly in the following patients*:

(a)Type 1 DM : 5 years after diagnosis of diabetes, or earlier in the presence of other CV risk factors

(b)Type 2 DM: at the time of diagnosis of diabetes

Grade C

*Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria

Guidelines 2:Method of screening for proteinuria

Urine should be screened for proteinuria with

conventional dipstick on an EMU specimen*

Grade C


Guidelines 3:Screening for microalbuminuria

(a) If urine dipstick for proteinuria is -ve, screening for MA should be performed on an EMU specimen

(b) Urine dipstick for MA is an acceptable screening test

(c) If MA is detected, confirmation should be made with 2 further tests within a 3 to 6 month period

Grade C


Increases AER Decreases AER

Strenuous exercise Poorly controlled DM Heart failure UTI Acute febrile illness Uncontrolled HPT Haematuria Menstruation Pregnancy

NSAIDs ACE inhibitors

Factors affecting urinary albumin excretion

Algorithm : Screening for Proteinuria

Urine dipstick for protein(a) Type 1 : 5 years after diagnosis or earlier in the presence of other cardiovascular risk factos(b) Type 2 : at the time of diagnosis

NEGATIVE POSITIVE(urine protein >300mg/l)

on 2 separate occasions (exclude other causes e.g. UTI, CCF etc.)

Overt nephropathyQuantify excretion rate e.g. 24-hr urine protein

POSITIVEScreen for microalbuminuria

on early morning spot urine

Retest twice in 3 –6 months (exclude other causes e.g. UTI, CCF etc.)

NEGATIVE

If 2 of 3 tests are positive, diagnosis of microalbuminuria is established

3-6 monthly follow-up of microalbuminuria

Optimise glycaemic control Strict BP control ACEI/ARB Stop smoking Lifestyle modification Treat hyperlipidaemia Avoid excessive protein intake Monitor renal function Monitor for other diabetic endorgan damage

Yearly test

Definition of abnormal urinary albumin excretion

Albumin Excretion

SPECIMEN COLLECTED

24hr collection (mg/24h)

Timed collection (μg/min)

First voided morning specimen

Urine Albumin concentration

(mg/l)

Urine Albumin:Creatinine ratio* (mg/mmol)

Normoalbuminuria <30 <20 <20 <3.5 (F)

<2.5 (M)

Microalbuminuria 30-300 20-200 20-200 3.5 to 35 (F)

2.5 to 25 (M)

Overt proteinuria >300 >200 >200 >35 (F)

>25 (M)

Glycaemic control should be optimised, with:

FBS 6 mmol/l and/or

HbA1c 7%

Grade A

Guidelines 4:Glycaemic control

Screening methods Microalbuminuria testing

Glycaemic ControlType 1 DM :DCCT

RR = 34% RR = 43%

RR = 56%

1o Prevention cohort 2o Prevention cohort

Risk of micro & macroalbuminuria

-33

-25

-21

-16

-12

-50

-40

-30

-20

-10

0

Microalbuminuria at 12 yrs Microvascular complicationsRetinopathy Myocardial InfarctionAny DM endpoint

% r

ela

tive r

isk r

ed

ucti

on

P=0.03

P<0.01

P<0.01

P=0.05

P=0.02

Over 10 years, HbA1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) vs

HbA1c was7.9% (6.9-8.8) in the conventional group (n=1,138).

Glycaemic ControlType II DM: UKPDS

Target blood pressure in diabetics should be

less than 130/80

Grade B

Guidelines 5:Target blood pressure

Target BP in diabetics

RCT n Target BP Achieved BP Relative risk reduction

HOT 1501 < 80

< 85

< 90

81.1

83.2

85.2

51% major CV events 67% CV mortality

(< 80 cf < 90)

ABCD 470 75

80-89

132/78

138/86

49 % death rate

Clcr, MA, overt proteinuria

UKPDS 1148 < 150/85

< 180/105

144/82

154/87

24% DM related end-points 32% death related to DM 44% stroke

Target BP in Overt NephropathyMDRD

Mean GFR decline and achieved follow-up BP according to baseline proteinuria

Peterson et al, Ann Internal Med 1995

ACEIs or ARBs should be initiated for reduction of

microalbuminuria unless contraindicated

ACEIs in type 1 & type 2 diabetics : Grade A

ARBs in type 2 diabetics : Grade A

Guideline 6:Treatment of microalbuminuria

Evidence for use of ACE Inhibitors

in type 1 and type IIDiabetes mellitus

with microalbuminuria

ACEI in Type I DM with microalbuminuria

StudyStudy BPBP YearYear AHAAHA CommentComment

Mathiesen ER <90 91

(4yr)

Captopril vs placebo

ACE-I postponed nephropathy

European MAStudy Group

DBP <90-95

SBP <140-145

92

(2yr)


Captopril impedes progression to macroalbuminuria

North American MA Study Group

<140/90 95

(2yr)


Less progression of MA,

preserves CrCl

MA Captopril Study Group

DBP <90-95

SBP <140-160

96

(2yr)


Reduces risk of DNindependent of BP lowering

EUCLID DBP 75-90

SBP <155

97

(2yr)

Lisinopril vs placebo

Slows progression of renal disease

Italian MA Study Group

DBP 75-90

SBP 115-140

98

(3yr)

Lisinopril, nifedipine vs placebo

Lisinopril and Nifedipine both delays onset of DN

Authors Dur.

(yrs)

n year BP Treatment Results

Sano T 4 62 1996 <150/90 Enalapril vs no rx

Decrease microalbuminuria

Ravid M 5 93 1993 <140/90 Enalapril vs no treatment

long-term stabilization of creatinine and urinary albumin loss

Micro-HOPE

4.5 3577 2000 142/80 Ramipril vs Placebo

Decreases risk of overt DN

ACEI in normotensive type 2 DM with microalbuminuria

ACEI in hypertensive type 2 DM with microalbuminuria

Authors BP Dur treatment Results

Lacourciere Y

1993

DBP 92-110 3 yrs Captopril vs conservative

Captopril decrease microalbuminuria

Lebovitz H

1994

DBP >90 3 yrs Enalapril vs AHA

Enalapril prevents DN and preserve GFR better

Mosconi L 1992 DBP >90-104 27 mo

Enalapril vs Nitrendipine

Both lowers AER and improves GFR

Velussi M SBP >140 DBP 90-114

3 yrs Cilazapril vs Amlodipine

Both lower AER to similar extent

UKPDS SBP >150 DBP >85

Enalapril vs atenolol

Both equally effectiv

Evidence for use of ARB in

type 1 and type IIDiabetes mellitus with

microalbuminuria

ARB in Type I DM with microalbuminuria

No well conducted studies

ARB in normotensive type 2 DM with microalbuminuria

• Viberti G et al.

MicroAlbuminuria Reduction With VALsartan

(MARVAL) Study Investigators.

Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect.

Circulation 2002;106(6):672-8

ARB in hypertensive type 2 DM with microalbuminuria

• Irbesartan in patients with type 2 diabetes and microalbuminuria study group.(IRMA)

The effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.

N Engl J Med 2001; 345: 870-8

• Lozano J V et al.

Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics.

Nephrol Dial Transplant 2001; 16 (Suppl 6): 1-5

0

5

10

15

20

Inci

denc

e of

Dia

betic

N

ephr

opat

hy (

%)

0 3 6 12 18 22 24

201 201 164 154 139

195 195 167 161 148

194 194 180 172 159

129

142

150

36

45

49

Placebo (n)Irbesartan 150 mg (n)Irbesartan 300 mg

Months of Follow-up

Placebo 150 mg ofirbesartan

300 mg ofirbesartan

P<0.001 for difference between 300 mg irbesartan group and placebo

IRMA II : Incidence of Progression to Diabetic Nephropathy

Are ARBs superior to

ACE inhibitorsin DM with

microalbuminuria?

Authors n Type F-up Medications Results

Lacourciere

KI 2000

92 II 1 yr Lasartan

vs enalapril

Similar GFR decline

Muirhead 122 II 52 wks Valsartan

vs captopril

vs placebo

No difference between 2 active agents and superior to placebo

DETAIL

NEJM 2004

250

81% microalb

II 5 yrs Telmisartan

vs enalapril

Similar rate of GFR decline

ACEI vs ARB in microalbuminuria

-25

-20

-15

-10

-5

0

5

10

0 1 2 3 4 5

DETAIL STUDY: GFR change from baseline

Year

EnalaprilTelmisartan

Number of Enalaprilpatients assessed Telmisartan(carried forward)

113 (39)103 (41)

103 (0)86 (0)

110 (22)99 (23)

113 (23)102 (21)

113 (30)102 (31)

Cha

nge

in G

FR

(ml/m

in/1

.73

m2 )

In patients with proteinuria > 1 g/day, target blood

pressure should be lowered to < 125/75

Grade B

Guidelines 7:Target BP in overt nephropathy

MDRD study.

Mean decline in GFR

Based on severity of proteinuria

— low BP

--- usual BP

In Type 1 diabetics with overt proteinuria, ACEIs should be initiated unless contraindicated

Grade A

In Type 2 diabetics with overt proteinuria, ARBs or ACEIs should be initiated unless contraindicated

ARBs : Grade A

ACEIs : Grade B

Guideline 7:Treatment of overt nephropathy

Evidence for use of ACE Inhibitors

in type II

Diabetes mellitus with overt nephropathy

ACEI in Type II DM with overt nephropathy

1. Nielsen et al

Diabetes 1994;43(9):1108-13

2. Bakris et al

KI 1996;50:1641

3. Leibovitz et al.

KI suppl 1994;45:S150

Evidence for use of ARB in

type IIDiabetes mellitus

with overt nephropathy

ARB in Type II DM with over nephropathy

• RENAAL

Brenner BM, et al.

N Engl J Med. 2001;345(12):861-869

• IDNT

Lewis EJ, et al.

N Engl J Med. 2001;345(12):851-860

0

10

20

30

40

50

Cu

mu

lati

ve %

of

pat

ien

ts w

ith

eve

nt

Months240 12 36 48

554

583

Placebo

Losartan

Risk reduction=16%

P=0.02

762

751

689

692

295

329

36

52

Placebo† (n)

Losartan† (n)

*Composite of a doubling of serum creatinine, end stage renal disease, or death

RENAAL :Patients Reaching the Primary Composite Endpoint*

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

Pro

po

rtio

n w

ith

pri

mar

y en

dp

oin

t

0 6 12 18 24 30 36 42 48 54

579 555 528 496 400 304 216 146 65

565 542 508 474 385 287 187 128 46

568 551 512 471 401 280 190 122 53

Irbesartan

Amlodipine

Placebo

Months of Follow-up

*Composite of a doubling of serum creatinine, end stage renal disease, or death

P=0.02 for irbesartan compared to placebo

IDNT :Proportion of Patients with the Primary Composite Endpoint*

Adapted from Breyer JA et al. Am J Kid Dis 1992; 20(6): 535.

Time (yrs) 0 5 20 30

Onset ofDiabetes Onset of

Proteinuria

End Stage Renal Disease

RENAAL

OVERT NEPHROPATHYINCIPIENT NEPHROPATHYPRECLINICAL NEPHROPATHY

IRMA 2

IDNT

Summary of Clinical Trials in Type II Diabetic Nephropathy

Nielsen. Diabetes 1994

Leibovitz. KI suppl 1994

Bakris. KI 1996

MARVAL

Mosconi L 1992

Lebovitz H 1994

Lacourciere Y1993

Cigarette smoking should be actively discouraged

Grade B

Guideline 9:Cessation of smoking

Guidelines 10: Monitoring of serum lipids

Full lipid profile should be performed at least annually in adult diabetics

Grade C

In diabetics

(a) therapeutic lifestyle changes should be instituted if LDL-cholesterol is > 2.6 mmol/l

(b) drug therapy should be considered if LDL-cholesterol is > 3.4 mmol/l

Grade B

Guideline 11:Correction of dyslipidaemia

Moderate protein restriction of 0.6 – 0.8 g/kg/day* may be considered in patients with overt nephropathy and/or renal impairment

Grade B

* one matchbox sized cooked protein source is equivalent to 7g of protein

Guideline 12:Dietary protein

Hansen HP et al (KI July 2002): Moderate dietary protein restriction improves prognosis in type 1 diabetic patients with progressive diabetic nephropathy in addition to the beneficial effect of antihypertensive treatment.

Dietary protein restriction in type 1 diabetic nephropathy

Sodium intake should be restricted to < 80mmol/day (or 5g sodium chloride)* in patients with hypertension and/or proteinuria

Grade C

* equivalent to 1 teaspoon of salt

Guideline 13:Sodium restriction

Studies on salt restriction essential HPT & diabetic nephropathy

Low sodium diet potentiates antiHPT and antiproteinuric effects of Losartan

Lorsartan80-85Type II DM, HPT, microalbuminuric

RCT2002Houlihan

Albumin excretion was reduced from 2967mg/d to 1294mg/d in diltiazem group on low sodium diet

Diltiazem and Nifedipine

50 vs. 250Diabetic nephro-pathy

Opened label

1996George L Bakris

Additional mean BP reduction of 9%

Captopril83 vs.183Essential HPT

RCT1987Mac Cregor GA

Absolute BP lower for both agents while on a low sodium diet

Enalapril and Isradipine

90 vs. 314Essential HPT

RCT1998Mathew R. Weir

Reduction of 3.5-5.5mmHg SBP and 2-3.5mmHg DBP due to sodium restriction

Nil80 vs. 160Essential HPT

RCT1989Australian National Health

OutcomesAntihypertensives

Sodium restriction

(mmol/day)

Patient group

Trial type

YearStudy

Referral to a nephrologist for pre-dialysis evaluation

should be made if the serum creatinine exceeds 200

umol/L

Grade C

Guideline 14:Referral to nephrologist

Earlier referral to a nephrologist may be indicated if:

Referral to nephrologist

the diagnosis of diabetic nephropathy is in doubt nephrotic syndrome or unexplained haematuria

occurs a sudden worsening of renal function occurs blood pressure is difficult to controlhyperkalaemia arisesrenal artery stenosis is suspected

AV access use at initiation of HD increased with earlier referral time

499ER < 1 moLR > 12 mo

USA1995-1998

CHOICE study

LR > ER78106

ER > 3 moLR < 1 mo

Brazil1992-1995

Sesso et al

LR > ER2264ER > 4 moLR < 4 mo

Texas2002

Stack et al

LR > ER325325

ER > 4 moLR < 4 mo

Edinburgh1987-1992

Eadington et al

LR > ER15365

ER > 6 moLR < 1 mo

Paris1989-1991

Jungers et al

LR > ER3223

ER > 1 moLR < 1 mo

Oxford1981

Ratcliffe et al

Mortality risk

Mean length of hospital stay (days)

No of patients

Timing of referral

Location/year

Source

Studies on Early vs late referral

Healthy individual

Diabetes complications

Diabetes mellitus

Impaired OGTT

Genetic

Environmental

Life style modificationDiabetes Prevention Study

Diabetes Prevention ProgramDa Qing Study Malmo Study

Pharmaceutical agentsSTOP NIDDM study (Acarbose)

DPP (Metformin)TRIPOD study (Troglitazone)

Chinese Diabetes Prevention Study (Acarbose/Metformin)

Prevention of Diabetes

Lifestyle modification

Regular Exercise

HealthyEating

Prevention of Diabetes

Documents

Clinical Practice Guidelines Diabetic Nephropathy