Diabetic Nephropathy Recent advances in management of Diabetic Nephropathy.
Diabetic Nephropathy 2009
-
Upload
joel-topf -
Category
Health & Medicine
-
view
6.312 -
download
6
description
Transcript of Diabetic Nephropathy 2009
Diabetic Nephropathy
Joel Michels Topf, MDClinical Nephrologist
Year Capacity
1926 84,401
1927 85,753
1949 97,239
1956 101,001
1991 102,501
1998 107,501
1999 107,501
2006 107,501
2009 106,201
Incident ESRD
0
0
0
0
56,103
87,179
91,275
110,854
117,632
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004
Diabetes Hypertension Glomerulonephritis
Etiologies of ESRD
Diabetes, diabetic nephropathy and the epidemic raging in the U.S.
USRDS Atlas 2005http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm#7
Diabetics on Dialysis: 183,706Total no of Diabetics: 23,600,000
0.78%0.78%
ESRD
CV Mortality
Finne, P. JAMA 2005; 294:1782-87.
Diabetic nephropathy
Progressive renal damage as a result of diabetis mellitus type I or II
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 proteinuria
Followed by progressively deteriorating GFR
5-10 years
15-20 years
20 years
220 g 240 g
Size MattersNormal kidney weight is 150 g
Diseases with large kidneys:• Multiple Myeloma • Hydronephrosis• Amyloidosis • Renal Cell Cancer• ADPKD/ARPKD • Not HIVAN
nodular glomerulosclerosis
Kimmelstiel-Wilson lesions
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.
Diabetic Nephropathy No
NephropathyDiabetic
Nephropathy
No Nephropathy
Type I Diabetes Type II Diabetes
No difference in glycemic control between people who get
nephropathy and those who don’t
Ritz E, et al. N Engl J Med 1999;341 :1127-33.
Incidence of proteinuria at 25 years after diagnosis
Genetics
Familial clusteringDiabetic family members of patients
with diabetic nephropathy have an OR of 4.0
RaceESRD 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
3
2407
0
500
1000
1500
2000
2500
1990199119921993199419951996199719981999200020012002200320042005
TGFß
Angiotensin II
Hyperglycemia
Extracellular matrix
Fibrosis
Scientific studies on TGFß and renal disease
Huang Y, Et al. Kidney International 2006; 69: 1713-4.
Hyperfiltration
Early finding Renal vasodilation
Causes early increases in GFR Later
Nephron loss results in compensatory hyperfiltration
No increase in GFR
Pathology
A B C
0 years 5 years 10 years
Diagnosis
Hyperfiltration
Microalbuminuri
a
Macroalbuminuri
a
Renal failure
DiabetesWhat is microalbuminuria?
a.Any albumin in the urine
b.Trace protein on dipstick in a first morning specimen
c.20-200 µg/min on a timed specimen
d.30-300 mg albumin/g creatinine
e.30-300 mg/L
What is macroalbuminuria?
a.1+ protein on a dipstick in a first morning specimen
b.1+ protein on a dipstick at any time
c.>250 mg in 24 hours
d.>3.5 g per 24 hours
Diagnosis
Hyperfiltration
Microalbuminuri
a
Macroalbuminuri
a
Renal failure
Diabetes
MicroalbuminuriaDipstick negative
MacroalbuminuriaDipstick positive
30 300 mg/d0
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 2-5 5-14.3 >14.3
Relative Risk
MI, CVA, CV Death
All-cause
mortality
CHF
hospitalization
Gerstein, H. C. et al. JAMA 2001;286:421-426.
Albuminuria (mg/d)
Diagnosis
Hyperfiltration
Microalbuminuri
a
Macroalbuminuri
a
Renal failure
Type I
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
Cholesterol < 198
Triglycerides < 145
Glycemic control (hgb a1c <8)
Blood pressure (sbp<115)
ACEi
Diagnosis
Hyperfiltration
Microalbuminuri
a
Macroalbuminuri
a
Renal failure
Type I
Diagnosis
Hyperfiltration
Microalbuminuri
a
Macroalbuminuri
a
Renal failure
Type II
Diagnosis
Diagnosis
Diagnosis
Perkins BA, Et al. N Engl J Med 2003;348:2285-93.
U/A at Diagnosis(Type 2 patients)
Random spot collectionAlbumin:creatinineRepeat 3x in 3-6 months
2 of 3 ≥ 30mg/g creatinine
Microalbuminuria,begin treatment
NephropathyQuantify µalb:CrConsider referral
Modified from the American Diabetes Association. Diabetes Care. 2002; 25 Suppl 1: S85-S89.
No microalbuminuriaRe-screen yearly
Negative
Positive
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
TREATMENT
1. Blood pressure control
2. Glycemic control3. Angiotensin 2 control4. Proteinuria control5. Cholesterol control
Intensive therapy
1. Low fat (<30%) diet2. 30 minutes exercise
3-5 days/week3. Smoking cessation4. ACEi regardless of
blood pressure5. Vitamin6. Aspirin7. A1c <6.58. Blood pressure control9. Cholesterol control
Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.
Primary end point
1. CV Death2. Non fatal MI3. CABG/PCI4. Nonfatal stroke5. Amputation6. Peripheral
revascularization
Gaerd P, Vedel P, Parving HH. N Engl J Med 2003;348:383-93.
Treatment
1. Blood pressure control
2. Glycemic control3. Angiotensin 2 control4. Proteinuria control5. 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
Favorsconventional
0.5 1 2
0.88
0.90
0.94
0.84
1.11
0.75
0.029
0.34
0.44
0.052
0.52
0.0099
Any diabetes related endpoint
Diabetes related deaths
All cause mortality
Myocardial infarction
Stroke
Microvascular
RR p
Favorsintensive
Relative Risk
Microvascular EndpointsAny Diabetes Related Endpoint
0
10
20
30
40
50
0 3 6 9 12 15
Pro
por
tion
of p
atie
nts
(%)
Years from randomisation
Hypoglycemia: any episode
0
1
2
3
4
5
0 3 6 9 12 15
Hypoglycemia: major episodes
Pro
por
tion
of p
atie
nts
(%)
60
80
100
140
160
180
0 2 4 6 8
mm
Hg
Years from randomisation
144
154
8782
Blood pressure: Tight vs less tight control Blood pressure: Bad vs worse control
0%
10%
20%
30%
40%
50%
0 3 6 9
% o
f pat
ient
s w
ith e
vent
s
Tight blood pressure control (758)
Less tight blood pressure control (390)
risk reduction24% p=0.0046
Years from randomisation
risk reduction32% p=0.019
Diabetes-related deaths
Stroke
0%
5%
10%
15%
20%
0 3 6 9
% p
atie
nts
with
eve
nt
Years from randomisation
risk reduction44% p=0.013
0%
5%
10%
15%
20%
0 3 6 9
% p
atie
nts
with
eve
nt
Years from randomisation
risk reduction37% p=0.0092
Microvascular endpoints
Any diabetes-related endpoints
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 154/87mmHg 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
MI, CVA, CV mortality / 1,000 patient-
years
≤90 mmHg(n=501)
≤85 mmHg(n=501)
≤80 mmHg(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 control3. Angiotensin 2 control4. Proteinuria control5. Cholesterol 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 Trial1513 type II DM with nephropathyCr 1.9Randomized to placebo or losartanPrimary 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
Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
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)
Mauer M, Zinman B, Gardiner R, et al. N Eng J Med 2009; 361: 40-51.
ACEi are goodARB 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
50
Reduction in Albuminuria (%)
Candesartan Lisinopril Combination
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: Too shortWrong target
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
STUDIES OF ACEI + ARB IN NON-DIABETICS
What about the data of dual therapy 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
ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
Primary outcome
ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
Renal outcomes
Renal impairment:13.5% with combo tx10.2% ramipril10.6% telmisartanRR 1.33 for combination tx (p=<0.001)
Initiation of dialysis0.8% with combination therapy0.6% with monotherapyRR 1.37 (p=0.1)
ONTARGET Investigators. N Eng J Med. 358: 1547-59, 2008
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-diabetics263 patients with non-diabetic renal diseaseAverage GFR 37.5 mL/minAverage protein excretion 2.5 g/dayRandomized to losartan 100mg, trandolapril 3mg, or both
Nakao N, Et al. Lancet 2003; 361: 117-24.
Endpoint: doubling of serum creatinine or dialysis
PotassiumPotassium
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 ofACEiARBAldosterone antagonistDiuretic
Must check electrolytes one week later
High potassiumStop the drugLow potassium
dietLoop diureticThiazide diureticLiberalize sodium
restriction
Treatment
Blood pressure control Glycemic control Angiotensin 2 control4. Proteinuria control5. Cholesterol 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 trial8206 men and women ages 55-80 with hypertension and LVH13% were diabeticsPrimary analysis was Atenolol vs LosartanComposite 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-pointsReanalysis 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 Verapamil does not delay
development of microalbuminuria Verapamil does reduce
proteinuria in diabetics independent of changes in blood pressure
Ruggenenti P, Et al. N Eng J Med 2004; 351: 1941-51.
% C
hang
e in
Pro
tein
uria
Blo
od p
ress
ure
Bakris GL, Et al. Kidney Int 1998; 58: 1283-9.
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
Schjoedt KJ, Et al. Kidney International 2006; 70: 536-542.
Carvedilol RCT of metoprolol vs.
carvedilol, improved A1c and albuminuria
Bakris GL, Et al. JAMA 2004; 292: 2227-36.
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
Blood pressure control Glycemic control Angiotensin 2 control Proteinuria control5. Cholesterol control
0
5,000,000
10,000,000
15,000,000
20,000,000
25,000,000
Diabetics Diabetics on Dialysis
Run-inACEi or ARBACEi + ARB
AtorvastatinGroup A
PlaceboGroup 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 Disease56 men and women with non-diabetic GNCrCl 53 mL/min and proteinuria = 2.5 g/d
Atorvastatin Dose80 mg
20 mg
40 mg
10 mg
GREACE Study1541Greek men and womenAge < 75, LDL > 100 and hx CHD20% DM3 year follow-upCHD events:
Study:12% vs control: 24.5%
Athyros VG, Et al. J Clin Pathol 2004; 57: 728-34.
Conclusions
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
Blood pressure control Glycemic control Angiotensin 2
reduction Proteinuria reduction
ACEi + ARB Statins Aldosterone antagonists Dihydropyridine calcium
channel blockers Endothelin antagonists
157 150
625 610
0
100
200
300
400
500
600
700
1980 1985 1990 1995 2000 2005
Incidence per 1,000,000
30-59
60+
under 30
Incidence of ESRD due to diabetic nephropathy
IDNTRENALL
fin