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.
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.
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 swellingo Nephrotic syndrome was diagnosed.
o No retinopathyo Renal biopsy – advanced diabetic nephropathy
with nodular sclerosiso Treatment – blood sugar control, ACEI
• 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)
Diabetic Nephropathy
Is characterized by,
• Persistent albuminuria
• Elevated blood pressure
• Relentless decline in GFR
• High risk of CVS morbidity and mortality
Functional ChangesElevated GFR (>120 ml1min1 1.78 m2)
Clinical Latency
Microalbuminuria (30-300 mg/24 h)
GFR is normal
Macroalbuminuria (>300mg/24 h)
(Overt Nephropathy)
ESRF
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.
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
Who should be screened?
Type 1Should begin after 5 years duration of
diabetesAnd annually thereafter
Type 2At the time of diagnosisAnd annually thereafter
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.
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
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
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
Transient elevations in urine albumin can occur in,
• Fever• Exercise within 24 hours
• Infection• Marked hypertension• Marked hyperglycaemia• Cardiac failure
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
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
DN in Sri Lankan Type 2 DMWanigasuriya & Fernando. Diabetes in Asia 2001
43.10%
27.60%
34.00%
10.30%
retinopathyP.neuro.IHDPVD
How should DN be treated?
glycaemic control
Treatment of hypertension
Treatment of proteinuria
Low protein diet
Treatment of hyperlipidaemia
Rx of CVS risk factors
Glycaemic control
• Control of blood glucose levels reduces the development of incipient nephropathy and to a lesser extent the progression to overt nephropathy.
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.
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
Treatment of hypertensionUKPDS (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
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
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)
MICRO-HOPE Events Per Patient Group for Primary Endpoint* and Components
0
5
10
15
20
25Placebo 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
Even
ts p
er
pati
en
t g
rou
p (
%)
RR=Relative risk reduction
*The occurrence of myocardial infarction, stroke or cardiovascular death
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 infarctionCV=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
Nu
mb
er
of
even
ts
P=NS P=NS
P=NS
Nisoldipine (n=235)
Enalapril (n=235)
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
Angiotensin receptor blockers in DNThree 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)
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.
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
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.
ACEIs & ARBs- caution
hyperkalaemia in patients with renal impairment
deterioration in renal functionsevere hypotension in the presence of
bilateral renal artery stenosiscontraindicated in pregnancy
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
ConclusionCandersartan and lisinopril were effective
monotherapies for reducing MA & HTTheir combined use was well tolerated and more
effective for reducing BP & alb/creat ratio.
Issues with dual blockade
• Hyperkalaemia
• Deterioration of renal function– Low incidence reported in trials– Only short term studies– ? Real life situation
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.
Rx of hyperlipidaemia
• American Association Guidelines– LDL ≤ 100 mg/dl– HDL > 45 mg/dl– TG ≤ 200mg/dl
Statins and RAS
• Hpercholesterolaemia induces an upregulation of vascular AT1 receptors.
• Statins directly down regulate AT1 receptor expression
• Beneficial effect in individuals with normal cholesterol levels.
Modification of CVS risk factors
• Stop smoking
• Treat hyperlipidaemia
• Correct obesity
• Dietary modifications
• Regular exercise
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
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
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 ?
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.
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