diabeticnephropathy2009-090910141244-phpapp02.pptx

•Azərbaycan Tibb Universiteti
Patoloji fiziologiya kafedrası
Mövzu-
Tələbə-Telman Rəşidov
Elmi rəhbər – t.ü.f.d.,dos.Əsmət Quliyeva

Diabetik Nefropatiya
 Joel Michels Topf, MD
Clinical Nephrologist

İllər Həcm-Tutum BXSM insidenti
1926 84,401 0
85,753 0
• 97,239 0
• 101,001 0
1991 102,501 56,103
• 107,501 87,179
• 107,501 91,275
2006 107,501 110,854
2009 106,201 117,632

100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Diabet Hipertenziya Qlomerulonefrit
SMBX-nin etiologiyası

Diabet, diabetik nefropatiya və
Amerikada epidemiya həyəcanı

USRDS Atlas 2005
http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7
Diyalizdə olan Diabet :
Şəkərli diabetli xəstələrin ümumi sayı :
183,706
23,600,000
0.78%

Finne, P. JAMA 2005; 294:1782-87.

Diabetik nefropatiya
 I və II tip şəkərli diabetin fonunda
proqressiv böyrək zədələnməsi
 Initially, patients have increased GFR
(2x normal)
 Followed by proteinuria
 Followed by progressively
deteriorating GFR

Diabetic nephropathy
 Progressive renal damage as a result
of diabetis mellitus type I or II
 Initially, patients have increased GFR
(2x normal)
 Followed by progressively
deteriorating GFR
 Followed by proteinuria

15-20 years
5-10 years
20 years

Ritz E, et al. N Engl J Med 1999;341 :1127-33.

220 g 240 g
Ölçü məsələləri
Normal böyrək çəkisi 150 g-dır.
Diseases with large kidneys:
• Multiple Mieloma • Hidronefroz
• Amiloidoz • Böyrək xərçəngi
• ADPKD/ARPKD • Not HIVAN

nodular qlomerulosklerozis
Kimmelstiel-Wilson lezionları

 One in five diabetic patients on
dialysis do not have this “classic”
pathology.
 They have ischemic nephropathy,
with non-specific vascular and
interstitial lesions
Ritz E, Orth SR. N Eng J Med 1999; 341:1127-33.

Diabetik
Nefropatiya
Nephropat
hy yoxdur
Diabetic
Nephropathy
No
Nephropathy
Nefropatiyası olan və olmayanların
arasında qlikemik nəzarətdə fərq
yoxdur.
Ritz E, et al. N Engl J Med 1999;341 :1127-33.
I Tip Diabet II Tip Diabet
Incidence of proteinuria at 25 years after diagnosis

Genetika
 Familial clustering
Diabetic family members of patients with
diabetic nephropathy have an OR of 4.0
 Race
ESRD is 5 times more likely in African
Americans with family members on
dialysis from DN
Pima indians have very high rates of
diabetic nephropathy

Transforming Growth Factor Beta
2407
2000
1500
1000
500
3
0
2500
TGFß
Angiotensin II
Hiperqlikemiya
Extracellular matrix
Fibrosis
TGFß və böyrək xəstəliyi üzrə elmi işlər
Huang Y, Et al. Kidney International 2006; 69: 1713-4.

Hiperfiltrasiya
 Erkən aşkarlanma
 Renal vazodilatasiya
Causes early increases in GFR
 Later
Nephron loss results in compensatory
hyperfiltration
No increase in GFR

Diaqnoz
Hyperfiltration
Microalbuminuria
Macroalbuminuria
Renal failure
Diabet
Mikroalbuminuria nədir?
c.sidikdə bəzi albuminlərin olması
d.Trace protein on dipstick in a
first morning specimen
e.20-200 µg/min on a timed
specimen
f.30-300 mg albumin/g kreatinin
g.30-300 mg/L
What is macroalbuminuria?
c.1+ protein on a dipstick in a
first morning specimen
d.1+ protein on a dipstick at any time
e.>250 mg in 24 hours
f.>3.5 g per 24 hours

Diagnosis
Hyperfiltration
Microalbuminuria
Macroalbuminuria
Renal failure
Diabetes
Microalbuminuria
Dipstick negative
Macroalbuminuria
Dipstick positive
300 mg/d
0 30
Patients with diabetes mellitus (N=3,498)
1.0 0.9
1.4
2.4
0.0
1.0
2.0
3.0
4.0
<2 >14.3
 MI, CVA, CV Death
 All-cause mortality
 CHF hospitalization
Gerstein, H. C. et al. JAMA 2001;286:421-426.
2-5 5-14.3
Albuminuria (mg/d)

Diagnosis
Hyperfiltration
Microalbuminuria
Macroalbuminuria
Renal failure
Type I
Cholesterol < 198
Triglycerides < 145
Glycemic control (hgb a1c <8)
Blood pressure (sbp<115)
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
ACEi

Diagnosis
Hyperfiltration
Microalbuminuria
Macroalbuminuria
Renal failure
Type I
Diagnosis
Hyperfiltration
Microalbuminuria
Type II
Diagnosis
Macroalbuminuria
Diagnosis
Renal failure
Diagnosis
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.

U/A at Diagnosis
(Type 2 patients)
Random spot collection
Albumin:creatinine
Repeat 3x in 3-6 months
Microalbuminuria,
begin treatment
Nephropathy
Quantify µalb:Cr
Consider referral
Modified from the American Diabetes Association. Diabetes Care. 2002; 25 Suppl 1: S85-S89.
No microalbuminuria
Re-screen yearly
Negative
Positive
2 of 3
≥ 30mg/g
creatinine
No Yes
Differential of microalbuminuria
• Early diabetic nephropathy
• Obesity
• Hypertension
• Endothelial dysfunction
• Metabolic syndrome
• Atherosclerosis

When is proteinuria not diabetic nephropathy?
When does a diabetic need a biopsy?

Suspicious for non-diabetic nephropathy
 Onset within 5 years of dx of diabetes
 Acute onset
 Active sediment
 Unusual review of systems
 Serologies
ANA, Hep B, Hep C, HIV
 Absence of retinopathy or neuropathy

Müalicə
1. Qan təziqinə nəzarət
2. Qlikemik nəzarət
3. Angiotenzin 2 nəzarət
4. Proteinuriyaya nəzarət
5. Xolesterola nəzarət

İntensiv terapiya
1. Low fat (<30%) diet
2. 30 minutes exercise 3-5
days/week
3. Smoking cessation
4. ACEi regardless of
blood pressure
5. Vitamin
6.Aspirin 7.
A1c <6.5
8. Qan təziqi kontrol
9. Xolesterol kontrol
Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

Primary end point
1. CV Death
2. Non fatal MI
3. CABG/PCI
4. Nonfatal stroke
5. Amputation
6. Peripheral
revascularization
Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.

Treatment
1. Blood pressure control
2. Glycemic control
3. Angiotensin 2 control
4. Proteinuria control
5. Cholesterol control

Randomized prospective trial of treatment
strategies in type two diabetes
ukpds
• Protocol written in 1976
• Recruitment from 1977-1991
• End of study 1997
• Type 2 diabetic patients 5,102
• Person years follow-up 53,000

Primary Endpoint:
Any Diabetes Related Endpoint
 1401 of 3867 patients (36%)
 First occurrence of any one of:
 diabetes related death
 non fatal myocardial infarction, heart failure or
angina
 non fatal stroke
 amputation
 renal failure
 retinal photocoagulation or vitreous
haemorrhage
 cataract extraction or blind in one eye

Diabetes related deaths
o t li
All cause m r a t y
RR p
Favors
intensive
Relative Risk
Microvascular Endpoints
Any Diabetes Related Endpoint
0
M2y0ocardialinfarction
Stroke
M1ic0rovascular
30
A4
n0
ydiabetes related endpoint
50
0 3 6 9 12 15
Proportion
of
patients
(%)
Years from
randomisation
Hypoglycemia: any episode
0
0.88 0.029
0.90 0.34
0.94 0.44
0.84 0.052
1.11 0.52
0.75 0.0099 1
2
3
4
5
0 3 6
Favors
conventional
9 12 15
0H.5ypoglycemia1:major epis2odes
Proportion
of
patients
(%)

60
80
100
140
160
180
0 8
mmHg
2 4 6
Years from randomisation
154
144
87
82
Blood pressure: Tight vs less tight control
Blood pressure: Bad vs worse control

10%
30%
20%
40%
50%
%
of
patients
with
events
risk reduction
0%
0
Yea
sk reduction
2% p=0.019
Diabetes-related deaths
Stroke
0%
5%
20%
0 9
%
patients
with
event
3 6
15%
risk re
44% p
10%
0%
5%
0 9
%
pati
3 6
24% p=0.0046
ri
3
3 6 9
rs from randomisation
20% Microvascular endp
t
n
e 15%
v
duction e risk reduction
h
=0.013 i 37% p=0.0092
t
w 10%
s
t
n
e
oints
Any diabetes-related endpoints
Less tight blood
pressure control (390)
Tight blood pressure
control (758)

UK Prospective Diabetes Study
An intensive glucose control policy HbA1c 7.0 % vs 7.9 %
reduces risk of
 any diabetes-related endpoints 12% p=0.030
 microvascular endpoints 25% p=0.010
 myocardial infarction 16% p=0.052
A tight blood pressure control policy 144/82 vs 154/87
mmHg reduces risk of
 any diabetes-related endpoint 24% p=0.005
 microvascular endpoint 37% p=0.009
 stroke 44% p=0.013
The benefit from tight
glycemic control is less than
the benefit from lousy blood
pressure control

24.4
18.6
11.9
0
5
10
15
20
25
²90mmHg
(n=501)
²85mmHg
(n=501)
²80mmHg
(n=499)



Hypertension Optimal
Treatment trial (HOT
Trial) randomized 18,790
patients to one of three
diastolic blood pressure
goals
8% of the original cohort
was diabetic
The first line agent was
felodipine
Harrison L, Et al. Lancet 1998; 351: 1755-1762.
HOT Diabetics

Home blood pressure is the hemoglobin
A1c of blood pressure management.
Dr Whitey
routinely
checks Hgb
A1c to make
sure my
diabetes is
on track.
Dr Whitey
asks me
check my
home BP to
verify my BP
is on track.

Treatment


Blood pressure control
Glycemic control
3. Angiotensin 2 control

Lewis, E. J. et al. N Engl J Med 1993;329:1456-1462
Cumulative Incidence of Events in Patients with Diabetic
Nephropathy in the Captopril and Placebo Groups

RENAAL Trial
1513 type II DM with nephropathy
Cr 1.9
Randomized to placebo or losartan
Primary outcome: composite of doubling
serum Cr, ESRD, or death
Brenner BM, Et al. NEJM 2001; 343: 861-9.
50
mg
100
mg

Picture of world with/without electricity

ACEi are good,
ARB are good…
in patients with albuminuria.
What about in normotensive patients
without albuminuria?

Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.

 Multicenter, randomized, double blind
controlled trial
 285 normotensive patients with type I
dm and albuminuria < 20 µg/min
 Randomized to placebo, enalepril
10/20 mg or losartan 50/100 mg
 Primary endpoint was change in
mesangial volume on renal biopsy

Progression of
diabetic
retinopathy ( 2
steps)
Odds ratio vs
placebo
Placebo 38% 1
Enalepril 25% 0.35 (65% reduction)
Losartan 21% 0.30 (70% reduction)

ACEi are good
ARB are good
What about both together?

CALM Study



N= 200
Type II DM with
microalbuminuria
Randomized to:



Lisinopril 20 mg qd
Candesartan 16 mg qd
Combination of
lisinopril 20 mg and
candesartan 16 mg
24
39
50
0
10
20
30
40
0
Candesartan Lisinopril Combinati n
Mogensen CE, Et al. BMJ 2000; 321: 1440-4.

Combination ACEi & ARB:
the Meta analysis
 10 studies of patients with diabetic
nephropathy
 315 patients randomized to ACEi or
ACEi and ARB
Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

Problem: T
woorosnhg
ot
ratrget

 Studies use change in proteinuria as the
primary endpoint
 Most were 8-12 weeks in duration
 Significant reduction in proteinuria compared to
ACEi (p=0.01)
 Reduced GFR (3.9 ml/min, p=0.03)
 Increase in potassium (0.2 mmol/L, p<0.01)
 Reduction in BP (5.2/5.3, p<0.01)
Jennings DL, Kalus JS, et al. Diabetic Medicine. 24(5):486-493, May 2007

What about the data of dual therapy in non-diabetics
STUDIES OF ACEI + ARB IN
NON-DIABETICS

On Target
 Telmisartan + ramipril vs ramipril vs
telmisartan
 Outcome: CV death, MI, CVA,
hospitalization for CHF
 25,620 patients were randomized
 Study population: age >55, coronary,
peripheral or cerebrovascular disease
or diabetes with end-organ damage
ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008

 37% had diabetes
 13% had microalbuminuria
 50% had prior MI
 22%had prior CABG
 68% had history of hypertension
 56 months of follow-up

Primary outcome

Renal outcomes
 Renal impairment:
13.5% with combo tx
10.2% ramipril
10.6% telmisartan
RR 1.33 for combination tx (p=<0.001)
 Initiation of dialysis
0.8% with combination therapy
0.6% with monotherapy
RR 1.37 (p=0.1)

Renal outcomes
 Second publication with data focused
on renal outcomes
Primary outcome for this publication was
dialysis, death or doubling of serum
creatinine
Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008

Mann JFE, Schmieder RE, McQueen M. Lancet. 372: 547-53, 2008
0.037
0.038
0.020

Increased renal outcomes despite
better proteinuria

Cooperate Trial: ACEi+ARB in non-diabetics
263 patients with non-diabetic renal disease
Average GFR 37.5 mL/min
Average protein excretion 2.5 g/day
Randomized to losartan 100mg, trandolapril 3mg, or both
Nakao N, Et al. Lancet 2003; 361: 117-24.
Endpoint: doubling of
serum creatinine or
dialysis

 RESOLVD
 768 patients with heart failure (NYHA II to IV)
 Potassium rose 0.11 mmol/L (p<0.05 vs
Candesartan alone and enalepril alone)
 ValHeFT
 5010 patients with heart failure (NYHA II to IV
and EF<40%)
 Potassium rose 0.12 mmol/L (p<0.001)
 CHARM-Added trial
 2548 patients with heart failure (NYHA II to IV
and EF<40%)
 No significant change in potassium
McKelvie RS, Et al. Circulation 1999; 100: 1056-64.
Cohn JN, Et al. N Eng J Med 2001; 345: 1667-75.
McMurray JJ, Et al. Lancet 2003; 362: 767-71.

 Any addition of
 ACEi
 ARB
 Aldosterone antagonist
 Diuretic
 Must check electrolytes
one week later
 High potassium
 Stop the drug
 Low potassium diet
 Loop diuretic
 Thiazide diuretic
 Liberalize sodium
restriction

Treatment



Glycemic control
Angiotensin 2 control

Theory: reduce proteinuria, reduce
cardiovascular events
High  High | High  Low | Low  High | Low  Low
Ibsen H, Et al. Hypertension 2005; 45: 198-202.
Pre-specified subanalysis of the LIFE trial
8206 men and women ages 55-80 with hypertension and LVH
13% were diabetics
Primary analysis was Atenolol vs Losartan
Composite endpoint (CEP) was CV death, non-fatal stroke, or non-fatal MI
…Reduction in albuminuria during
treatment translates to a reduction in
cardiovascular events…

…Interestingly, suppression of albuminuria was
the strongest predictor of long-term protection
from cardiovascular events…
De Zeeuw D, Et al. Circulation 2004; 110: 921-927.
Theory: reduce proteinuria, reduce
cardiovascular events and renal end-points
Reanalysis of the RENAAL trial.
Instead of the intension to treat analysis, patients were analyzed by baseline proteinuria or
reduction in proteinuria.
The reduction in albuminuria at 6 months predicted outcomes at 42 months

Conclusion: reduction in proteinuria
reduces CV complications and renal
complications
Implications: reduction in proteinuria
can be used as an intermediate end-
point, i.e. interventions which reduce
proteinuria are good.

Calcium channel blockers
Ruggen 1-51.
%
Change
in
Proteinuria
enti P, Et al. N Eng J Med 2004; 351: 194
e
r
ssu
e
r
p
d
o
o
l
B
 Verapamil does not delay
development of microalbuminuria
 Verapamil does reduce proteinuria
in diabetics independent of
changes in blood pressure
Aldosterone antagonists


 Spironolactone reduces
proteinuria in diabetics
 Change in proteinuria is
independent of blood pressure
All patients were treated with
an ACEi or ARB
24-Hr ambulatory BP fell 6/2
Carvedilol
 RCT of metoprolol vs. carvedilol,
improved A1c and albuminuria Schjoedt K
J
,
B
E
a
B
t
k
a
a
r
i
l
k
s
.
r
K
G
i
s
i
L
d
G
,
n
L
E
e
,
y
t
E
a
I
n
t
l
.
t
a
e
K
l
.
r
i
n
d
J
a
n
A
t
e
M
i
o
y
n
A
I
a
n
2
l
t
0
2
1
0
9
4
0
9
;
6
8
2
;9
7
5
2
0
8
:
:2
5
1
2
3
2
6
8
7
-
3
5
-

Aliskiren in addition to losartan in
DM2 and nephropathy
 RCT double blind, multicenter
 N=599
 Placebo vs 150 mg aliskiren for 3
months
 Followed by doubling of the dose of
the placebo and aliskiren (300 mg)
 Study duration 6 months

 Use of aliskiren 150 mg for 3 months
and 300 mg for 3 months lowered
albuminuria 20% compared to placebo
150 mg 300 mg

Treatment




Glycemic control
Angiotensin 2 control
Proteinuria control
0
5,000,000
10,000,000
15,000,000
20,000,000
25,000,000
Diabetics Diabetics on Dialysis

Run-in
ACEi or ARB
ACEi + ARB
Atorvastatin
Group A
Placebo
Group B
20
mg
40
mg
10
mg
Randomization
Bianchi S, Et al. Am J Kidney Dis 2003; 41:565-570.
A Controlled, Prospective Study of the Effects of
Atorvastatin on Proteinuria and Progression of
Kidney Disease
56 men and women with non-diabetic GN
CrCl 53 mL/min and proteinuria = 2.5 g/d

20
mg
40
mg
Atorvastatin Dose
80 10
mg mg
GREACE Study
1541Greek men and women
Age < 75, LDL > 100 and hx CHD
20% DM
3 year follow-up
CHD events:
Study:12% vs control: 24.5%
Athyros VG, Et al. J Clin Pathol 2004; 57: 728-34.

Endothelin antagonists


 Avosentan is an endothelin
A antagonist
Endothelin A receptors
stimulate matrix
production in animal
models of diabetic
nephropathy
Avosentan proof of concept
 286 diabetics with 1.0-1.5 g
proteinuria on ACEi/ARB
 reduced the urinary albumin
excretion rate by about 50%
 No change in BP, HR, CrCl
 Slight decrease in Hct

Ascend trial, Phase III trial of Avosentan


International multi-
center, double-blind,
placebo-controlled trial.
Randomization is 1:1:1
 25 mg avosentan
 50 mg avosentan
 Placebo
End-point is doubling of
serum creatinine,
ESRD or death
  Enrollment criteria
 Type II diabetics age 21-80
 Diabetes at least 3 yrs ago
 Albuminuria > 300 mg/day
 Cr 1.0-1.4 for men
 Cr 1.0-1.3 for women
 All patients must be on
ACEi/ARB or intolerant

Nəticə


 Diabetic nephropathy
is the most common
cause of ESRD in the
world
ESRD is a rare out-
come among diabetics
Just over half of
diabetics will develop
nephropathy




Glycemic control
Angiotensin 2
reduction
Proteinuria reduction
 ACEi + ARB
 Statins
 Aldosterone antagonists
 Dihydropyridine
calcium channel
blockers
 Endothelin antagonists

157 150
625 610
100
0
200
300
400
500
600
700
1980 1985 1990 1995 2000 2005
30-59
60+
under 30
Diyabetik nefropatiya səbəbindən BXSM görülmə sıxlığı
IDNT
RENALL

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