Diabetes

1. Diabetic Nephropathy
Dr Kamani Wanigasuriya
Senior Lecturer in Medicine
FMS/USJP

2. Magnitude of the problem
• Diabetic nephropathy has become the leading
cause of ESRF in the western world (40% of
patients with ESRF in USA).
• Approximately, 40% of patients with diabetes
develop nephropathy.
• This percentage may be even higher in Asian
countries.

3. Magnitude of the problem
• There will be a considerable increase in
ESRD patients with diabetes as world
diabetic population is expected to double
within the next 10 years.

4. Kumari, 23-years-old female
o DM type 1 since the age of 9 years. On insulin.
o In 2001 (10 years after the onset of DM)
o Oedema&facial swelling
o Nephrotic syndrome was diagnosed.
o No retinopathy
o Renal biopsy – advanced diabetic nephropathy
with nodular sclerosis
o Treatment – blood sugar control, ACEI

5. • 2002 – Hypertension ACEI was increased
• Cr Clearance (Normal 80-120ml/min/1.732
)
2001- 45 ml/min
2002 – 35.6 ml/min
2003- 34.8 ml/min
2004- 32.8 ml/min
2006- 30.0ml/min
• 24 hour urinary Pr 1200mg (Normal <200mg)

6. Diabetic Nephropathy
Is characterized by,
• Persistent albuminuria
• Elevated blood pressure
• Relentless decline in GFR
• High risk of CVS morbidity and
mortality

7. Diabetic nephropathy
A review of
• Risk factors
• Screening
• Evidence based
approach to
management

8. Functional Changes
Elevated GFR (>120 ml1
min1
1.78 m2
)
Clinical Latency
Microalbuminuria (30-300 mg/24 h)
GFR is normal
Macroalbuminuria (>300mg/24 h)
(Overt Nephropathy)
ESRF

9. Microalbuminuria
• Measurement of UAE is now an integral
aspect of routine diabetic care.
• MA is the earliest manifestation of
nephropathy.
• MA is also a marker of increased
cardiovascular mortality and morbidity in
Type 1 and Type 2 DM.

10. Risk Factors for development or
progression of nephropathy
• Development
– Genetic
– Metabolic – hyperglycaemia,duration of diabetes
– Hemodynamic – hypertension
– Other – smoking
• Progression
– Metabolic – hyperglycaemia
– Hemodynamic – Hypertension
– Other - smoking , superimposed renal injury

11. Who should be screened?
 Type 1
Should begin after 5 years duration of
diabetes
And annually thereafter
 Type 2
At the time of diagnosis
And annually thereafter

12. How do you screen?
A routine urinalysis should be
performed first.
If found positive for protein a quantitative
measure should be done.
If negative, proceed to microalbumin
estimation.

13. Screening for microalbuminuria
Three methods.
• Albumin to creatinine ratio in a random
spot collection
• 24 hour urinary albumin excretion
• Timed (eg 4 hr or overnight) urine
collection
Reagent strips may be used if above tests are not available
Should confirm with these tests later

14. Diagnosis of albuminuria
Urine ALB 24 hour
urinary Alb
Spot test
(Adjusted for
U Cr)
Timed
Urine (Alb
excretion rate)
Normal <30mg/24h 30mg/g Cr < 20µg/min
Micro. 30-300mg /
24 h
30-300
mg /g Cr
20-200
µg/min
Macro >300 mg /
24 h
>300mg /g
Cr
> 200
µg/min

15. Screening for MicroAlb (in macroalb –ve)
Microalbumin +ve
Exclude other causes&
Retest
Microalbumin +ve
Repeat over 4-6weeks
No microalbumin
Repeat in 1year
Early morning urine
Microalbumin +veMicroalbumin +ve
Treat with ACEI

16. Transient elevations in urine albumin
can occur in,
• Fever
• Exercise within 24 hours
• Infection
• Marked hypertension
• Marked hyperglycaemia
• Cardiac failure

17. DN or other form of renal disease?
Indications for evaluating other causes of
renal disease:
 Proteinuria in T1 DM for fewer than 10
years or without retinopathy
 Haematuria
 cellular or granular casts in urine
 accelerated renal damage (Decline in GFR
>15ml/min per year)
 Decline in GFR with ACEI therapy

18. Microalbuminuria
• Marker of CVS morbidity & mortality
• Indication for screening for other CVS risk
factors (HT, lipids etc)
• Screen for other complications of diabetes
retinopathy, neuropathy, peripheral vascular
disease, IHD

19. DN in Sri Lankan Type 2 DM
Wanigasuriya & Fernando. Diabetes in Asia 2001
43.10%
27.60%
34.00%
10.30%
retinopathy
P.neuro.
IHD
PVD

20. How should DN be treated?
glycaemic control
Treatment of hypertension
Treatment of proteinuria
Low protein diet
Treatment of hyperlipidaemia
Rx of CVS risk factors

21. Glycaemic control
• Control of blood glucose levels reduces
the development of incipient
nephropathy and to a lesser extent the
progression to overt nephropathy.

22. Glycaemic control
Type 1 DM
 Diabetes Control and Complications Trial (DCCT)
Intensive glycaemic control delays the onset
of DN in Type 1 DM
Type 2 DM
• UK Prospective Diabetes Study (UKPDS) Group
Each 1% reduction in mean HbA1c was
associated with a reduction in risk of 37% for
microvascular complications.

23. Hb A1c < 7%
Pre Prandial plasma glucose 90-130 mg/ dl
(5.0–7.0 mmol/L)
Peak Post Prandial Plasma
glucose
< 180 mg/dl
(< 10 mmol/l)
Recommendations for blood sugar control

24. Treatment of hypertension
UKPDS (Type 2 DM)
 Each 10 mmHg decrease in mean systolic pressure
was associated with reduction of risk of 13% for
micro-vascular complications.
 Anti-hypertensive treatment with either β blocker or
ACEI were effective on preventing the progression
of nephropathy.
UKPDS BMJ 1998:317:703-13

25. Treatment of hypertension
• Life style modifications
– Reduce Na intake, Increase exercise, limit
alcohol
• ACE inhibitors or angiotensin 11 receptor
blockers
• Other antihypertensive agents as needed

27. ACEI in treatment of HT
 Captopril Prevention Trial (The Lancet 1999;353:611-16)
 MICRO-HOPE study ( Heart Outcomes
Prevention Evaluation Study)
 ABCD Trial
 ACEI in HT –Meta analysis (Ann. Int. Med
2001, 134:370-9)

28. MICRO-HOPE Events Per Patient Group
for Primary Endpoint* and Components
0
5
10
15
20
25
Placebo Ramipril
HOPE Study Investigators. Lancet.
2000;355:253-259.
Combined
primary
endpoint*
Myocardial
infarction
Stroke Cardiovascular
death
RR=25%
P<0.001
RR=22
%
P=0.01
RR=33%
P=0.007
RR=37%
P<0.001
Eventsperpatientgroup(%)
RR=Relative risk
reduction
*The occurrence of myocardial infarction, stroke or cardiovascular
death

29. ABCD Trial CV Outcomes and Death in
Hypertensive Subgroup
0
5
10
15
20
25
30
Fatal or
non-fatal
MI
Non-
fatal MI
Congestive
heart
failure
Death from
CV causes
Death from
any cause
MI=myocardial
infarction
CV=cardiovascular
Estacio RO, et al. N Engl J Med. 1998;338:645-
652.
Schrier RW, Estacio RO. N Engl J Med.
2000;343:1969.
P=0.03P=0.03
Numberofevents
P=NS
P=NS
P=NS
Nisoldipine (n=235)
Enalapril (n=235)

30. ACEI in normotensive individuals
• Lisinopril in normotensive Type 1 DM and NA and
MA ( The EUCLID Study)
- A randomized placebo controlled trial
- Little beneficial effect in those started with AER
5µg /min or less
- Those who started with MA benefited from lisinopril
- AER MA/NA 49.7% Vs 12.7%
- ACEI is effective in 2ry prevention in normotensive
individuals with DM

31. Angiotensin type 1 receptor
blockers

32. Angiotensin receptor blockers in DN
Three trials in Type2 DM.
(Microalbuminuria /Overt nephropathy/ renal impairment)
 Ibersartan Diabetic Nephropathy Trial (IDNT)
 The Reduction of Endpoints NIDDM with
Angiotensin 11 antagonist Losartan (RENNAL)
 Ibersartan Microalbuminuriai Type 2 DM
(IRMA2)

33. Angiotensin receptor blockers in DN
ARB conclusion,
 ARBs prevent long-term renal damage in DN
 Beneficial effects of ARBS were independent
of their BP lowering effects.
 Well tolerated, without significant side effects.

34. Recommendations- Rx of HT
In hypertensive and normotensive Type 1
diabetic patients with nephropathy ACEI
are the initial agents of choice.
In Type 2, there is evidence to recommend
ARBs as the drug of first choice
ß blocker, Ca channel blocker, diuretics can
be added in a stepwise fashion

35. Target of Blood Pressure
New guidelines for good blood pressure
control are;
< 130/80 mmHg (American Diabetic
Association)
< 125/ 75 mmHg for patients with renal
insufficiency with greater than 1g/day
proteinuria.

36. ACEIs & ARBs- caution
hyperkalaemia in patients with renal
impairment
deterioration in renal function
severe hypotension in the presence of
bilateral renal artery stenosis
contraindicated in pregnancy

37. Combination theray with ACEI & ARBs.
More effective?
The Candersartan and Lisinopril
microalbuminuria study (CALM Study)
RCT of dual blockage of RA system in patients with HT, MA
& Type 2 DM /24 weeks follow up
Conclusion
Candersartan and lisinopril were effective
monotherapies for reducing MA & HT
Their combined use was well tolerated and more
effective for reducing BP & alb/creat ratio.

38. Issues with dual blockade
• Hyperkalaemia
• Deterioration of renal function
– Low incidence reported in trials
– Only short term studies
– ? Real life situation

39. Protein restriction

40. Protein Restriction
• ?Effectiveness in early stages
• Protein intake of 0.8g kg-1
. Day -1
is
recommended in patients with overt
nephropathy.
• Restriction to 0.6gkg-1
. Day -1
is useful once
the GFR is begin to fall.

41. Rx of Hyperlipidaemia

42. Rx of hyperlipidaemia
• American Association Guidelines
– LDL ≤ 100 mg/dl
– HDL > 45 mg/dl
– TG ≤ 200mg/dl

43. Statins and RAS
• Hpercholesterolaemia induces an
upregulation of vascular AT1 receptors.
• Statins directly down regulate AT1receptor
expression
• Beneficial effect in individuals with normal
cholesterol levels.

44. Modification of CVS risk
factors
• Stop smoking
• Treat hyperlipidaemia
• Correct obesity
• Dietary modifications
• Regular exercise

48. Intensified multifactorial intervention type 2 DM:
The Steno type 2 randomised study
• Intensified multifactorial intervention in
patients with type 2 diabetes and
microalbuminuria slows progression to
nephropathy, retinopathy and autonomic
neuropathy.
Lancet1999:353:617-22

49. Management of ESRD
• Survival of diabetic patients after KT or on
dialysis is inferior to that of non diabetic patients
• KT has a better life expectancy than HD
• Pre-emptive transplantation gives better results
• Additional beneficial effects with SPK
transplantation eg improvement of halting the
process of microangiopathy

50. When to refer?
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
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51. Referal to a nephrologist
• Overt nephropathy
• Elevated serum creatinine >2mg/dl
• Difficulty in controlling hypertension
• Associated hyperkalaemia
– Early referal to nephrologist has been shown to
improve the outcome of RRT
– Are we ready for the challenge ?

52. Conclusion
• Annual screening for MA will allow identification
of DN at a point very early in its course.
• Improving glycaemic control, aggressive anti-HT
treatment and ACEI therapy will slow the
progression of nephropathy.
• Prevention in way of tight glycaemic control and
aggressive antihypertensive therapy should be the
main goal of management.

54. Thank you