Post on 07-May-2015
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
*Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria
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
*Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria
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 vs placebo
Captopril impedes progression to macroalbuminuria
North American MA Study Group
<140/90 95
(2yr)
Captopril vs placebo
Less progression of MA,
preserves CrCl
MA Captopril Study Group
DBP <90-95
SBP <140-160
96
(2yr)
Captopril vs placebo
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