CPG on HPT

1
Clinical Practice GuidelinesDiabetic Nephropathy
2
Introduction

• Increased prevalence of DM
• Diabetic nephropathy commonest cause of ESRD
• heavy burden on resources

3
Course of Diabetic Nephropathy
Time (yrs)
0
5
20
30
End Stage Renal Disease
Onset of Proteinuria
Onset of Diabetes
PRECLINICAL NEPHROPATHY
OVERT NEPHROPATHY
INCIPIENT NEPHROPATHY Hyperfiltration,
microalbuminuria, rising blood pressure
Rising Scr, Decreasing GFR
Hypertension
STRUCTURAL CHANGES (Increasing glomerular
basement membrane thickening and mesangial
expansion)
Adapted from Breyer JA et al. Am J Kid Dis 1992
20(6) 535.
4
Diabetic Nephropathy

• Microalbuminuria
• first sign of nephropathy
• a strong and independent predictor of
  cardiovascular disease

5
Guidelines 1Screening 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
6
Guidelines 2Method 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
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Guidelines 3Screening for microalbuminuria

• 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
8
Factors affecting urinary albumin excretion
9
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
Overt nephropathy Quantify excretion rate e.g.
24-hr urine protein
NEGATIVE
POSITIVE (urine protein gt300mg/l) on 2 separate
occasions (exclude other causes e.g. UTI, CCF
etc.)
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
Screen for microalbuminuria on early morning
spot urine  
POSITIVE
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
Yearly test
10
Definition of abnormal urinary albumin excretion
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Guidelines 4 Glycaemic control

• Glycaemic control should be optimised, with
• FBS ? 6 mmol/l and/or
• HbA1c ? 7
•  
• Grade A

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Screening methods Microalbuminuria testing
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Glycaemic ControlType 1 DM DCCT
Risk of micro macroalbuminuria
RR 34
RR 43
RR 56
1o Prevention cohort
2o Prevention cohort
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Glycaemic Control Type II DM UKPDS
P0.03
P0.05
relative risk reduction
P0.02
Plt0.01
Plt0.01
Over 10 years, HbA1c was 7.0 (6.2-8.2) in the
intensive group (n2,729) vs HbA1c
was7.9 (6.9-8.8) in the conventional group
(n1,138).
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Guidelines 5 Target blood pressure

• Target blood pressure in diabetics should be less
  than 130/80
• Grade B

16
Target BP in diabetics
17
Target BP in Overt Nephropathy MDRD
Mean GFR decline and achieved follow-up BP
according to baseline proteinuria
Peterson et al, Ann Internal Med 1995
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Guideline 6 Treatment of microalbuminuria

• 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

19
Evidence for use of ACE Inhibitors in type 1
and type II Diabetes mellitus with
microalbuminuria
20
ACEI in Type I DM with microalbuminuria
21
ACEI in normotensive type 2 DM with
microalbuminuria
22
ACEI in hypertensive type 2 DM with
microalbuminuria
23
Evidence for use of ARB in type 1 and type
II Diabetes mellitus with microalbuminuria
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ARB in Type I DM with microalbuminuria

• No well conducted studies

25
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 2002106(6)672-8

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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

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IRMA II Incidence of Progression to Diabetic
Nephropathy
Plt0.001 for difference between 300 mg irbesartan
group and placebo
Placebo
150 mg ofirbesartan
Incidence of Diabetic Nephropathy ()
300 mg ofirbesartan
0
3
6
12
18
22
24
Months of Follow-up
201
201
164
154
139
129
36
Placebo (n)
Irbesartan 150 mg (n)
195
195
167
161
148
142
45
Irbesartan 300 mg
194
180
172
159
150
49
194
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Are ARBs superior to ACE inhibitors in DM with
microalbuminuria?
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ACEI vs ARB in microalbuminuria
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DETAIL STUDY GFR change from baseline
Enalapril
Telmisartan
Change in GFR(ml/min/1.73 m2)
Year
Number of Enalapril patients assessed Telmisartan
(carried forward)
113 (39) 103 (41)
103 (0) 86 (0)
110 (22) 99 (23)
113 (23) 102 (21)
113 (30) 102 (31)
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Guidelines 7 Target BP in overt nephropathy

• In patients with proteinuria gt 1 g/day, target
  blood pressure should be lowered to lt 125/75
•  
• Grade B

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MDRD study.
low BP --- usual BP

• Mean decline in GFR
• Based on severity of proteinuria

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Guideline 7 Treatment of overt nephropathy

• 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

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Evidence for use of ACE Inhibitors in type
II Diabetes mellitus with overt nephropathy
35
ACEI in Type II DM with overt nephropathy

• Nielsen et al
• Diabetes 199443(9)1108-13
• Bakris et al
• KI 1996501641
• Leibovitz et al.
• KI suppl 199445S150

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Evidence for use of ARB in type II Diabetes
mellitus with overt nephropathy
37
ARB in Type II DM with over nephropathy

• RENAAL
• Brenner BM, et al.
• N Engl J Med. 2001345(12)861-869
• IDNT
• Lewis EJ, et al.
• N Engl J Med. 2001345(12)851-860

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RENAAL Patients Reaching the Primary Composite
Endpoint
Placebo
Risk reduction16
Losartan
P0.02
Cumulative ofpatients with event
Composite of a doubling of serum creatinine, end
stage renal disease, or death
24
0
12
36
48
Months
554
762
689
295
36
Placebo (n)
52
583
751
692
329
Losartan (n)
39
IDNT Proportion of Patients with the Primary
Composite Endpoint
P0.02 for irbesartan compared to placebo
Proportion withprimary endpoint
Composite of a doubling of serum creatinine, end
stage renal disease, or death
0
6
12
18
24
30
36
42
48
54
Months of Follow-up
579
555
528
496
400
304
216
146
65
Irbesartan
565
542
508
474
385
287
187
128
46
Amlodipine
568
551
512
471
401
280
190
122
53
Placebo
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Summary of Clinical Trials in Type II Diabetic
Nephropathy
Nielsen. Diabetes 1994
Lacourciere Y 1993
Bakris. KI 1996
Lebovitz H 1994
Leibovitz. KI suppl 1994
Mosconi L 1992
MARVAL
IDNT
RENAAL
IRMA 2
Time (yrs)
0
5
30
20
Onset of Diabetes
End Stage Renal Disease
Onset of Proteinuria
PRECLINICAL NEPHROPATHY
INCIPIENT NEPHROPATHY
OVERT NEPHROPATHY
Adapted from Breyer JA et al. Am J Kid Dis 1992
20(6) 535.
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Guideline 9 Cessation of smoking

• Cigarette smoking should be actively discouraged
• Grade B

42
Guidelines 10 Monitoring of serum lipids

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

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Guideline 11 Correction of dyslipidaemia

• In diabetics
• therapeutic lifestyle changes should be
  instituted if LDL-cholesterol is gt 2.6 mmol/l
• drug therapy should be considered if
  LDL-cholesterol is gt 3.4 mmol/l
• Grade B

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Guideline 12 Dietary protein

• 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
45
Dietary protein restriction in type 1 diabetic
nephropathy
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.
46
Guideline 13 Sodium restriction

• Sodium intake should be restricted to lt
  80mmol/day (or 5g sodium chloride) in patients
  with hypertension and/or proteinuria
•  
• Grade C

equivalent to 1 teaspoon of salt
47
Studies on salt restriction essential HPT
diabetic nephropathy
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Guideline 14 Referral to nephrologist

• Referral to a nephrologist for pre-dialysis
  evaluation should be made if the serum creatinine
  exceeds 200 umol/L
•  
• Grade C

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Referral to nephrologist

• Earlier referral to a nephrologist may be
  indicated if

• 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 control
• hyperkalaemia arises
• renal artery stenosis is suspected

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Studies on Early vs late referral
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Prevention of Diabetes
Life style modification Diabetes Prevention
Study Diabetes Prevention Program Da Qing Study
Malmo Study
Healthy individual
Impaired OGTT
Genetic Environmental
Pharmaceutical agents STOP NIDDM study
(Acarbose) DPP (Metformin) TRIPOD study
(Troglitazone) Chinese Diabetes Prevention Study
(Acarbose/Metformin)
Diabetes mellitus
Diabetes complications
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Prevention of Diabetes
Healthy Eating
Lifestyle modification
Regular Exercise