diabetic nephropathy recent advances in management of diabetic nephropathy
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Recent advances in management of
Diabetic Diabetic NephropathyNephropathy
……Tiger by the tailTiger by the tail
Diabetic Kidney
Normal Kidney
Diabetic nephropathyDiabetic nephropathy Diabetic nephropathy is progressive kidney Diabetic nephropathy is progressive kidney
diseasedisease Most common cause of ESRD Most common cause of ESRD More likely to die than progress to ESRDMore likely to die than progress to ESRD Multi-risk factor intervention is criticalMulti-risk factor intervention is critical Lowering blood pressure with RAAS blockade Lowering blood pressure with RAAS blockade
is criticalis critical Combinations of ACEi + ARB or MRA sensibleCombinations of ACEi + ARB or MRA sensible
No long term efficacy or safety dataNo long term efficacy or safety data Prevent cardiovascular morbidity and mortalityPrevent cardiovascular morbidity and mortality
Why is Diabetic Why is Diabetic Nephropathy Nephropathy Important?Important?
Diabetes: The Most Diabetes: The Most Common Cause of ESRDCommon Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes50.1%
Hypertension27%
Glomerulonephritis
13%
Other
10%
United States Renal Data System. Annual data report. 2000.
No. of patientsProjection95% CI
1984 1988 1992 1996 2000 2004 20080
100
200
300
400
500
600
700
r2=99.8%243,524
281,355520,240
No
. o
f d
ialy
sis
pat
ien
ts
(th
ou
san
ds)
Cardiovascular Death is Major Cardiovascular Death is Major
Cause of Mortality in ESRDCause of Mortality in ESRD
0.001
0.01
0.1
1
10
100
25-34 35-44 45-54 55-64 65-74 75-84 > 85
Age (years)
An
nu
al C
ard
iova
scu
lar
Mo
rtal
ity
(%)
GP Male
GP Female
GP Black
GP White
Dialysis Male
Dialysis Female
Dialysis Black
Dialysis White
Sarnak MJ and Levey AS. Am J Kidney Dis. 2000;35(4)(suppl1):S117-S131.Foley RN. Am J Kidney Dis. 1998;32(S3):S112-119.
General Population
ESRD Population
What is the What is the Natural History Natural History
of Diabetic of Diabetic Nephropathy?Nephropathy?
Definition of Diabetic Definition of Diabetic Nephropathy Nephropathy
Clinical diagnosis based on Hx, Exam and Clinical diagnosis based on Hx, Exam and urine albumin/creatinine ratio in most casesurine albumin/creatinine ratio in most cases
Longstanding History of diabetes Longstanding History of diabetes ++ retinopathyretinopathy
Macroalbuminuria (a.k.a “overt Macroalbuminuria (a.k.a “overt nephropathy”) defined as random urine nephropathy”) defined as random urine albumin/creatinine ratio albumin/creatinine ratio >> 300 mg/g 300 mg/g
Hypertension (> 90%)Hypertension (> 90%) Renal Biopsy confirmation is rareRenal Biopsy confirmation is rare
Development of Macroalbuminuria Heralds Rapid Decline in Glomerular Filtration in Type II
Diabetes
-50
-40
-30
-20
-10
0
1 1.5 2 2.5 3 3.5 4
Time yearsC
hang
e in
GFR
ml/m
in
Microalbuminuria
Macroalbuminuria
Nelson RG. et al NEJM, 1996
Diabetics with Nephropathy (DM/CKD) Diabetics with Nephropathy (DM/CKD) are More Likely to Die than to Progress are More Likely to Die than to Progress
to Eto ESRDSRD
Status in the entry period
DM/CKDDM/Non-CKD NDM/CKDNDM/Non-CKD
19,335188,596 33,586N=1,045,263
0.070.31
2.255.85
Per
cen
t o
f P
atie
nts
Event Free
ESRD
All CauseDeath
5% Medicare sample , 1996-1997 cohort, 2 year follow-up
9.40 14.6529.04
85.0473.18
65.12
24.57
90.53
0
20
40
60
80
100
Diabetics with Macroalbuminuria are Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRDMore Likely to Die than Develop ESRD
CV
DEATHElevated Serum Creatinine
19%
No albuminruia1.4%
2.0%
Microalbuminruia3.0%
2.8%
Macroalbuminruia4.6%
2.3%
The United Kingdom Prospective Diabetes Study (approx. 5000 Type 2 Diabetics) Newly diagnosed, predominantly white, medically treated
Adler et al. Kid Int, 2003
What are Diabetics with What are Diabetics with Nephropathy Dying From?Nephropathy Dying From?
Stroke MyocardialInfarction
HeartFailure
SuddenDeath
Improving Outcomes in Diabetic Nephropathy
Prevention of Cardiovascular
Events
Prevention of End-Stage Renal Disease
Diabetic Diabetic NephropathyNephropathy
What is the Proper What is the Proper Therapy of Kidney Therapy of Kidney Disease in patients Disease in patients
with Diabetes?with Diabetes?
The Renal Injury The Renal Injury TriadTriadAngiotensin II
ProteinuriaHypertension
Definition of Abnormal Definition of Abnormal Albuminuria in Diabetes Albuminuria in Diabetes
MellitusMellitusMicroalbuminuriaMicroalbuminuria MacroalbuminurMacroalbuminur
iaia(Nephropathy)(Nephropathy)
Detected by Detected by dipstickdipstick
NoNo YesYes
Urine Albumin / Urine Albumin / CrCr
30 - 299 mg Alb / 30 - 299 mg Alb / g Cr g Cr
>> 300 mg Alb / 300 mg Alb / g Crg Cr
Renal RiskRenal Risk Marker of future Marker of future nephropathy in nephropathy in
somesome
Marker Marker progressive progressive
renal diseaserenal diseaseCardiovascular Cardiovascular RiskRisk
IncreasedIncreased IncreasedIncreased* Random (Spot) urine preferably A.M. recommended
ADA Guidelines: ADA Guidelines: Diabetic NephropathyDiabetic Nephropathy
– To reduce the risk and/or slow the To reduce the risk and/or slow the progression of nephropathy, progression of nephropathy, optimize optimize glucose controlglucose control. .
– To reduce the risk and/or slow the To reduce the risk and/or slow the progression of nephropathy, progression of nephropathy, optimize optimize blood pressure controlblood pressure control..
A-Level Evidence (well done RCTs)
ADA: Screening ADA: Screening GuidelinesGuidelines
– Perform an annual test for the presence of Perform an annual test for the presence of microalbuminuriamicroalbuminuria in (1) type 1 diabetic patients who in (1) type 1 diabetic patients who have had diabetes >5 years and (2) all type 2 have had diabetes >5 years and (2) all type 2 diabetic patients starting at diagnosis.diabetic patients starting at diagnosis.
– Acceptable samples to test for increased urinary Acceptable samples to test for increased urinary albumin excretion are timed (e.g., 12 or 24 h) albumin excretion are timed (e.g., 12 or 24 h) collections for measurement of albumin collections for measurement of albumin concentration and timed or untimed samples for concentration and timed or untimed samples for measurement of the albumin:creatinine ratio. For measurement of the albumin:creatinine ratio. For screening, an untimed sample for albumin screening, an untimed sample for albumin measurement (without creatinine) may be measurement (without creatinine) may be considered if a concentration cutoff is used that considered if a concentration cutoff is used that allows high sensitivity for detection of an increased allows high sensitivity for detection of an increased albumin excretion rate. Level of evidence: Ealbumin excretion rate. Level of evidence: E
Expert Consensus
ADA: Treatment ADA: Treatment GuidelinesGuidelines
— In the treatment of albuminuria/nephropathy both In the treatment of albuminuria/nephropathy both angiotensin-converting enzyme (ACE) inhibitors and angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBsangiotensin receptor blockers (ARBs) can be used: ) can be used:
— In hypertensive and nonhypertensive type 1 diabetic In hypertensive and nonhypertensive type 1 diabetic patients with any degree of albuminuria, ACE inhibitors patients with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. have been shown to delay the progression of nephropathy. (1a)(1a)
— In hypertensive and non hypertensive type 2 diabetic In hypertensive and non hypertensive type 2 diabetic patients with microalbuminuria, ACE inhibitors and ARBs patients with microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to have been shown to delay the progression to macroalbuminuria. (Cochrane 1a DOE)macroalbuminuria. (Cochrane 1a DOE)
— In patients with type 2 diabetes, hypertension, In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have been shown to delay the >1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy.progression of nephropathy.
— If one class is not tolerated, the other should be substituted.If one class is not tolerated, the other should be substituted.
A-Level Evidence (well done trials)
ADA: TreatmentADA: Treatment
— With the onset of overt nephropathy, With the onset of overt nephropathy, initiate initiate protein restriction to <0.8protein restriction to <0.8 g • kg-1 g • kg-1 body weight • day-1 (approximately 10% body weight • day-1 (approximately 10% of daily calories), the current adult of daily calories), the current adult recommended daily allowance for protein. recommended daily allowance for protein. Further restriction may be useful in Further restriction may be useful in slowing the decline of glomerular filtration slowing the decline of glomerular filtration rate in selected patients.rate in selected patients.
B-Level Evidence (well done cohort studies)
ADA: TreatmentADA: Treatment
— If ACE inhibitors or ARBs are used, monitor If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of serum potassium levels for the development of hyperkalemia. hyperkalemia.
— Consider Consider referralreferral to a physician experienced in to a physician experienced in the care of diabetic renal disease when the the care of diabetic renal disease when the glomerular filtration rate has fallen to either <60 glomerular filtration rate has fallen to either <60 mL • min-1 • 173 m-2 or difficulties have mL • min-1 • 173 m-2 or difficulties have occurred in the management of hypertension or occurred in the management of hypertension or hyperkalemia. hyperkalemia.
— Consider the use of non-dihydropyridine calcium Consider the use of non-dihydropyridine calcium channel blockers or beta-blockers in patients channel blockers or beta-blockers in patients unable to tolerate ACE inhibitors or ARBs.unable to tolerate ACE inhibitors or ARBs.
Expert Consensus
ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)
ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)
- 40 –
- 20 –
0 –
- 20 –
- 40 –
- 60 –
% Reduction in
Proteinuria
P <.001
Lewis et al. N Engl J Med. 1993;329:1456-1462.
% with Doubling of
Baseline Creatinine
Baseline creatinine > 1.5 mg/dl
0
25
50
75
100
0 1 2 3 4
Captopril
Conventional therapy
- 2 –
0 –
- 2 –
- 4 –
- 6 –
- 8 –
Decrease in Mean Blood
Pressure (mm Hg)
NS
ARB (losartan) Reduces Risk of ESRD in ARB (losartan) Reduces Risk of ESRD in Diabetic NephropathyDiabetic Nephropathy
ESRD
Months
% w
ith
eve
nt
0 12 24 36 48
0
10
20
30
p=0.002Risk Reduction: 28%
Placebo
Losartan
P (+ CT)
L (+ CT) 751 714 625 375 69762 715 610 347 42
Brenner et al. New Engl J. Med Sept 20 2001
BP 142 / 74
BP 140 / 74
Reduction in Endpoints in NIDDM with Angiotensin Antagonist Losartan (RENAAL) Trial: 1513 type 2 Diabetics with Nephropathy
• Avg: 3.5 BP drugs/pt• 90% in both groups received a CCB
Irbesartan in Diabetic Nephropathy Trial: Irbesartan in Diabetic Nephropathy Trial: Time to Doubling of Serum Creatinine, ESRD, Time to Doubling of Serum Creatinine, ESRD,
or Deathor Death
Lewis EJ, et al. N Engl J Med. 2001;345:851-860.
Su
bje
cts
(%)
0 6 12 18 24 30 36 42 48 54
Follow-up (mo)
60
0
10
20
30
40
50
60
70
RRR 20%P=.02P=NS
RRR 23%P=.006
Irbesartan
Amlodipine
Placebo
1,715 Type 2 Diabetics with Nephropathy
Change in Proteinuria
-35
-30
-25
-20
-15
-10
-5
0
5
Per
cen
t R
edu
ctio
n
IrbesartanAmlodipinePlacebo
BP 141/77
BP 144/80
BP 140/77
% w
ith
ES
RD
en
d p
oin
t
80
100
40
60
20
048362412
Month
≥3.0 g/g
≥1.5<3.0 g/g
<1.5 g/g
HR
8.10
3.23
1.0
0
Albuminuria at Baseline Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial
(N=1513)
Baseline Albuminuria
de Zeeuw et al. Kid. Int. June 2004
Reduction in Proteinuria is Associated Reduction in Proteinuria is Associated with Reduced Risk for End-Stage Renal with Reduced Risk for End-Stage Renal
Disease in Diabetic NephropathyDisease in Diabetic Nephropathy
0.5
1.0
3.5
4.0
2.5
3.0
1.5
2.0
0.0<-40 ≥10 ≥60≥-10≥-40 ≥40
<60<-10 <10 <40
Change in Albuminuria %
Re
lati
ve
Ris
k f
or
ES
RD
de Zeeuw et al. Kid. Int. June 2004
RENAAL; Proteinuria Reduction RENAAL; Proteinuria Reduction (<0% versus >30%) determines the (<0% versus >30%) determines the
cardiovascular outcome cardiovascular outcome CV Endpoint Heart Failure
0 12 24 36 48
Month
0
10
20
30
40
% w
ith C
V e
ndpo
int >30%
<0%
0 12 24 36 48
Month
0
10
20
30
40
% w
ith h
eart
failu
re
<0%
>30%
De Zeeuw et al; Circulation, in press
Continuation of Losartan After Continuation of Losartan After Serum Creatinine Doubles Serum Creatinine Doubles
Reduces Incidence of ESRDReduces Incidence of ESRD
Months
% w
ith E
SR
D e
vent
0 6 12 18 240
20
40
60
80p=0.013
Risk Reduction: 30%
198 111 48 11 4P (+CT)
LP
L (+CT) 162 104 43 19 3
RENAAL; Contribution of Baseline RENAAL; Contribution of Baseline Systolic BP or Proteinuria to ESRD Systolic BP or Proteinuria to ESRD
in diabetic nephropathyin diabetic nephropathy
<140140 - 151151 - 165
>165
<.5
>2.51.25 - 2..5
.5 – 1.2
Proteinuria Quartile at Baseline (g/g)
SBP Quartile atBaseline (mm Hg)
Haz
ard
Rat
io
15.4
5.5
2.4
1.4
13.2
6.7
1.8
1.0
15.7
2.0
1.6
0.9
17.1
3.6
1.1
1.0
0
5
10
15
20
unpublished
Combination Therapy for BP Combination Therapy for BP Control: Control:
Rule Rather Than ExceptionRule Rather Than Exception
1 2 3 4
Number of BP Medications
ALLHAT
IDNT
RENAAL
UKPDS
ABCD
MDRD
HOT
AASK
Trial/Systolic Blood Pressure Achieved (mm Hg)
Adapted from Bakris et al. Am J Kidney Dis. 2000;36:646-661.
138
138
141
144
138
128
132
132
How I do get My Patient’s BP How I do get My Patient’s BP to the Goal of <130 / < 80 to the Goal of <130 / < 80
mmHg?mmHg? ACE Inhibitor / AII Receptor ACE Inhibitor / AII Receptor
Antagonist (maximum dose)Antagonist (maximum dose) Low ( 2 gram ) Sodium DietLow ( 2 gram ) Sodium Diet Diuretic Diuretic
eGFR eGFR >> 50 ml/min, thiazide 50 ml/min, thiazide eGFR < 50 ml/min, loop diureticeGFR < 50 ml/min, loop diuretic
Long-Acting CCB or Long-Acting CCB or -blocker-blocker Long-acting Long-acting -blocker vs clonidine-blocker vs clonidine MinoxidilMinoxidil
Bakris GL et al. Kidney Int. 2004. In press.
NDHP-CCBs show greater reductions in proteinuria in hypertensive adults with proteinuria, with or without diabetes.
DHP-CCB NDHP-CCB
Ch
ang
e (
%)
P=0.01-35
-30
-25
-20
-15
-10
-5
0
5
ProteinuriaN=510
Systolic Blood PressureN=1,338
NS
2%
-30%
-13%
-18.5%
Renal Effects of CCBs: Renal Effects of CCBs: ComparisonComparison
Systematic Review of 28 Studies 17
Combination ACEi and Non-Combination ACEi and Non-Dihydropyridine CCB Reduces Dihydropyridine CCB Reduces Proteinuria Further in Type 2 Proteinuria Further in Type 2 Diabetics With NephropathyDiabetics With Nephropathy
0
-20
-40
-60
Trandolapril5.5 mg/d
Verapamil SR314 mg/d
Trandolapril (2.9 mg/d) +Verapamil SR (219 mg/d)
Per
cent
red
uctio
n fr
om b
asel
ine
Proteinuria
Blood Pressure
Bakris, et al. Kid Int. 1998;54:1283.
NKF Kidney Disease Outcomes NKF Kidney Disease Outcomes Quality Initiative: Quality Initiative:
Pharmacologic TreatmentPharmacologic Treatment
KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004
Type of CKDType of CKD BP GoalBP Goal Preferred Preferred Agents for Agents for CKD, CKD, ++ HTN HTN
Other Agents Other Agents to Reduce to Reduce CVD Risk and CVD Risk and Reach BP Reach BP GoalGoal
DiabeticDiabetic < < 130/80130/80
ACEi or ARBACEi or ARB Diuretic Diuretic Preferred, Preferred, then then --Blocker or Blocker or CCBCCB
Non-Diabetic with Spot Urine Total Non-Diabetic with Spot Urine Total Prot-to-Cr ratio Prot-to-Cr ratio >> 200 mg/g 200 mg/g
< < 130/80130/80
ACEi or ARBACEi or ARB Diuretic Diuretic Preferred, Preferred, then then --Blocker or Blocker or CCBCCB
Non-diabetic with Spot Urine Total Non-diabetic with Spot Urine Total Prot-to-Cr ratio Prot-to-Cr ratio << 200 mg/g 200 mg/g
< < 130/80130/80
None None PreferredPreferred
Diuretic Diuretic Preferred, Preferred, then ACEi, then ACEi, ARB, B-ARB, B-blocker or blocker or CCBCCB
Transplanted Transplanted
CKDCKD< < 130/80130/80
None None PreferredPreferred
CCB, CCB, diuretic, diuretic, --blocker ACEi, blocker ACEi, ARBARB
Steno-2: Multiple Risk Factor Steno-2: Multiple Risk Factor Intervention Improves Outcomes in Intervention Improves Outcomes in
Type 2 diabetics with Microalbuminuria Type 2 diabetics with Microalbuminuria Randomized, open-label, target driven, long-term Randomized, open-label, target driven, long-term
intensified intervention trial aimed at multiple risk intensified intervention trial aimed at multiple risk factors in patients with type 2 diabetes and factors in patients with type 2 diabetes and microalbuminuriamicroalbuminuria BP < 130/80, (all treated with an ACEi or ARB)BP < 130/80, (all treated with an ACEi or ARB) A1c < 6.5%A1c < 6.5% Total Cholesterol < 175 mg/dlTotal Cholesterol < 175 mg/dl Total Triglyceride 150 mg/dlTotal Triglyceride 150 mg/dl Aspirin 81 mg dailyAspirin 81 mg daily Exercise programExercise program Smoking CessationSmoking Cessation
Gaede et al N.Engl.Med. 3448:383. 2003
Pri
mar
y C
om
po
site
En
d P
oin
t (%
)
10
20
50
60
30
40
00 96842412 4836 7260
P=0.007
Conventional therapy
Intensive therapy
Months of Follow-upNo. at Risk
Intensive therapy
Conventional therapy
80 72 70 63 59 50 44 41 13
80 78 74 71 66 63 61 59 19
Intensive Multi-risk Factor Intensive Multi-risk Factor Intervention Improves Outcomes Intervention Improves Outcomes
in Type 2 Diabetesin Type 2 Diabetes
Gaede et al N.Engl.Med. 3448:383. 2003
Composite outcome: CV death, MI, coronary or peripheral revascularization, CVA, amputation
Risk of Death after AMI is Reduced Risk of Death after AMI is Reduced across all Levels of Kidney Function across all Levels of Kidney Function with Recommended Interventionswith Recommended Interventions
0.520.45
0.40
0.580.620.61
0.440.41
0.52
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
< 1.5 1.5-2.4 2.5-3.9
Serum creatinine (mg/dl)
Hazard
rati
o
Aspirin
Beta Blocker
ACE-I
Shlipak et al., Ann Int Med 2002;137:555-62
Diabetic Nephropathy: Diabetic Nephropathy: Important MessageImportant Message
Lower blood pressure < 130 / 80 mmHgLower blood pressure < 130 / 80 mmHg Reducing ProteinuriaReducing Proteinuria Inhibition of Renin-Angiotensin SystemInhibition of Renin-Angiotensin System Multiple risk factor interventionMultiple risk factor intervention
GlycemiaGlycemia Dyslipidemia Dyslipidemia Physical activityPhysical activity Aspirin Aspirin Smoking cessationSmoking cessation
Is Combination Therapy Is Combination Therapy With An ACE Inhibitor With An ACE Inhibitor And An ARB Safe And And An ARB Safe And Effective For Patients Effective For Patients With Diabetic Renal With Diabetic Renal
Disease?Disease?
ACEi- or ARB-Based Regimens ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do for Diabetic Nephropathy Do
Not Go Far Enough!Not Go Far Enough!
ACEi or ARBGFR = - 6 ml/min/yrTime to ESRD 6.6 yrs
Time (yrs)
ESRD
50
2 4 6 8 10
Glo
me
rula
r F
il tr a
t ion
Ra
tem
l/ min
/1.7
3 m
2
No ACEi/ARBor BP control
GFR = - 10 ml/min/yrTime to ESRD 4 yrs
40
30
20
10
ACEi + ARBGFR = - ? ml/min/yr
Time to ESRD ?
RAAS blockade + Other?
Combining an ACEi and an ARB is more Combining an ACEi and an ARB is more Renoprotective than Either Agent alone Renoprotective than Either Agent alone
in in Non-DiabeticNon-Diabetic Nephropathy Nephropathy
TreatmenTreatmentt
NN BaselinBaseline BP e BP
mmHgmmHg
BP from BP from baseline baseline mmHg*mmHg*
Primary Primary EndpoinEndpoin
tt
HazarHazardd
Ratio*Ratio***
P P valuevalue
CombinatCombinationion
8855
130 / 75130 / 75 5.2 / 2.95.2 / 2.9 10 10 (11%)*(11%)*
-- --
TrandolaTrandolaprilpril
8866
130 / 76130 / 76 5.3 / 3.05.3 / 3.0 20 20 (23%)(23%)
0.400.40 0.0160.016
LosartanLosartan 8855
130 / 74130 / 74 5.1 / 2.95.1 / 2.9 20 20 (23%)(23%)
0.380.38 0.0180.018
Nakao et al. Lancet 361:117-124, 2003
*Average number of medications 3.2 per pt, 90% in all groups on dihydropyridine CCB** Hazard Ratio comparing combination with either agent alone
Summary of Studies combining ACEi Summary of Studies combining ACEi and ARB in Diabetic nephropathy: and ARB in Diabetic nephropathy:
Effects on Proteinuria and BPEffects on Proteinuria and BP
DM DM TypeType
DesignDesign NN DuratiDurationon
InterventionIntervention ResultsResults
11Type 2 Type 2 DRBCTDRBCT 44 4 4 weeksweeks
40 mg Lisinopril / 40 mg Lisinopril /
50 Losartan50 LosartanNo effectNo effect
22Type 2 Type 2 DRBCTDRBCT 1818 8 8 weeksweeks
8 mg candesartan8 mg candesartan 25% Prot 25% Prot and BPand BP
33Type 1 Type 1 DBRPCTDBRPCT 2121 8 8 weeksweeks
300 mg irbesartan300 mg irbesartan 43% Prot 43% Prot and BPand BP
44Type 1 Type 1 DBRCTDBRCT 2020 8 8 weeksweeks
20 mg Benazepril/20 mg Benazepril/
ACEi / Valsartan 80 ACEi / Valsartan 80 mgmg
15 % Prot 15 % Prot and BPand BP
55Type 1Type 1 DBRCTDBRCT 2424 8 8 weeksweeks
20 mg Enalapril/300 20 mg Enalapril/300 mg Irbesartanmg Irbesartan
25% Prot 25% Prot and BPand BP
66Type 2Type 2 DBRCTDBRCT 2020 8 8 weeksweeks
ACEi / Candsartan 16 ACEi / Candsartan 16 mgmg
29% Prot29% Prot1 Agarwal et al. Kid Int 59:2282, 2002; 2 Rossing et al. Diab Care. 25:95-100, 2002; 3 Jacobsen et al Neph. Dial. Transplant 17:1019-1024, 2002;4 Jacobsen et al. J. Am. Soc. Neph. 14:992-999, 2003;5 RossingEt al. Kid Int 63:1874-80, 2003 ; 6 Rossing et al. Diab Care 26:2268-2274, 2003.
Diabetic Nephropathy: Diabetic Nephropathy: Important Message Important Message
Small short-term studies suggest Small short-term studies suggest combinations of ACEi and ARB reduce combinations of ACEi and ARB reduce proteinuria synergisticallyproteinuria synergistically Greater reductions in proteinuria with or Greater reductions in proteinuria with or
without additional lowering in blood without additional lowering in blood pressurepressure
Hyperkalemia and Increased creatinine not Hyperkalemia and Increased creatinine not well documentedwell documented
Safety and Efficacy of combination ACEi and Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well ARB in diabetic with nephropathy not well establishedestablished
Is There a Role for Is There a Role for Spironolactone (or Spironolactone (or
Eplerenone) in Eplerenone) in Combination with Other Combination with Other Drugs in Patients with Drugs in Patients with Diabetic Nephropathy?Diabetic Nephropathy?
Capillary wall injuryInflammation
O2- , TGF-1 / PAI-1
Role of Aldosterone in the Role of Aldosterone in the Pathogenesis Pathogenesis
of Diabetic Nephropathyof Diabetic Nephropathy
Glomerular Hypertension
Angiotensin IIHemodynamic Non-Hemodynamic
Sclerosis andFibrosis
Injury to Glomerular Cells
Proteinuria
Glomerular and Tubular Scarring Progressive Renal Failure
Aldosterone
Adverse Renal and Cardiovascular Adverse Renal and Cardiovascular Effects of AldosteroneEffects of Aldosterone
GlomerulosclerosisInterstitial FibrosisProteinuriaRenal Failure
Ventricular HypertrophyCardiac FibrosisContractile DysfunctionHeart Failure
Endothelial dysfunctionInflammationOxidative Stress
Aldosterone
Mineralocorticoid Receptor Blockade Mineralocorticoid Receptor Blockade Improves Cardiac Outcomes: Placebo Improves Cardiac Outcomes: Placebo
Controlled TrialsControlled Trials
360
10
3
4
5
6
7
8
9
2
1
630 9 30272421181512 33
Placebo
Eplerenone
P=0.03RR=0.79 (95% Cl, 0.64-0.97)
Cu
mu
lati
ve In
cid
ence
of
(%)
Months since Randomization
Eplerenone reduces sudden cardiac deathPost myocardial infarction
1.00
0.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45P
rob
abili
ty o
f S
urv
ival
Spironolactone
Placebo
36630 9 181512 21 24 27 30 33Months
Spironolactone improves survival in Chronic Heart Failure
P=0.001RR=0.70 (95% Cl, 0.60-0.82
Ang I
Ang II
Progressive Diabetic Nephropathy
ACE
Renal Injury and Proteinuria
ACEi
AT1 Receptor
Non-ACEPathways
Aldosterone
MRA
ARB
Can Dual Blockade of the RAAS Can Dual Blockade of the RAAS Improve Renal Outcomes in Improve Renal Outcomes in
Diabetic Nephropathy?Diabetic Nephropathy?
+
+
Study Design and Study Design and ObjectivesObjectives
Study Design:Study Design: Randomized double-blind placebo Randomized double-blind placebo controlled trialcontrolled trial
Study Population:Study Population: Diabetics with Diabetics with macroalbuminuria despite maximally dosed ACE macroalbuminuria despite maximally dosed ACE inhibitorinhibitor
Intervention:Intervention: Lisinopril 80 mg/d + losartan 100 Lisinopril 80 mg/d + losartan 100 mg/d or + Aldactone 25 mg/d or + placebo mg/d or + Aldactone 25 mg/d or + placebo
Primary Outcome:Primary Outcome: Change in albuminuria Change in albuminuria Secondary Outcomes:Secondary Outcomes: Safety especially serum Safety especially serum
creatinine and hyperkalemiacreatinine and hyperkalemia Follow up:Follow up: 52 weeks 52 weeks
Study Study HypothesisHypothesis
Blockade of the renin-angiotensin system Blockade of the renin-angiotensin system beyond ACE inhibition decreases proteinuria beyond ACE inhibition decreases proteinuria and slows progression of renal disease in and slows progression of renal disease in diabetics with overt nephropathy by diabetics with overt nephropathy by suppressing aldosterone synthesis or suppressing aldosterone synthesis or blocking the aldosterone receptor.blocking the aldosterone receptor.
Time, weeks
Diabetics with SBP > 130 mmHgScr < 3, female, < 4, maleUrine albumin/Cr ratio > 300on ACE inhibitor + CT
Run-inPeriod
Control to SBP < 130 then Randomize
-4 -2 0 24-26 48- 52 56
BP blood pressure, potassium and serum creatinine measurementRF renal function-GFR, RPF, 24 hour urine sodium, creatinine,potassium, protein and urea
Combined Inhibition of the RAAS Pathway: ACEi + ARB vs ACEi + MRA in Diabetic Nephropathy
Lisinopril 80 mg/d
ABPM, aldosteroneKidney Function
Lipids, Inflammation
Lisinopril 80 mg/d +Losartan 100 mg p.o qd
Lisinopril 80 mg/d +Aldactone 25 mg p.o. qd
D/C Study Drug
Lisinopril 80 mg/d + Placebo Maintain SBP 120-129 mmHgWith conventionalantihypertensives
ABPM, aldosteroneKidney Function
Lipids, Inflammation
ABPM, aldosteroneKidney Function
Lipids, Inflammation
Role for spironolactone or eplerenone in Role for spironolactone or eplerenone in diabetics with nephropathy not diabetics with nephropathy not establishedestablished
Small, short-term studies suggest adding Small, short-term studies suggest adding on is efficacious for lowering proteinuriaon is efficacious for lowering proteinuria
Not clear if combinations are safe in Not clear if combinations are safe in larger populationlarger population
No long-term trials with cardiovascular No long-term trials with cardiovascular or renal endpointsor renal endpoints
Diabetic Nephropathy: Diabetic Nephropathy: Important Message Important Message
Beyond RAAS Beyond RAAS BlockadeBlockade
Hypothesis: Anemia is an Hypothesis: Anemia is an Important CV Risk Factor in Important CV Risk Factor in
Chronic Kidney DiseaseChronic Kidney Disease
Chronic Kidney Disease
Cardiovascular disease
Anemia
Hb < 11.3*
Hb > 13.8
Hb 12.5-13.8*
Hb 11.4-12.5*
Time, years
4321
En
d-s
tag
e re
nal
dis
ease
, %
10
20
50
60
30
40
0
Baseline Hemoglobin Predicts Baseline Hemoglobin Predicts ESRD in Type 2 Diabetics with ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial Nephropathy: RENAAL Trial
(N=1513)(N=1513)
Mohanram et al. Kid. Int. Sept 2004
--1.001.00> 13.8> 13.8
0.0020.0021.851.8512.5-13.812.5-13.8
0.020.021.611.6111.3-12.511.3-12.5
0.0010.0011.991.99< 11.3< 11.3
P P valuevalue
AdjusteAdjusted HR*d HR*Hb g/dlHb g/dl
* Age, gender, GFR, Race, Proteinuria,CV disease, A1c, lipids, BP, Ca, P, albumin
Is Anemia Causing Is Anemia Causing Cardiovascular And Cardiovascular And
Renal Disease In Renal Disease In Diabetics, Or is it Just A Diabetics, Or is it Just A
Marker?Marker?
Trial to Reduce Cardiovascular Events Trial to Reduce Cardiovascular Events
with Aranespwith Aranesp (Darbepoietin) Therapy (Darbepoietin) Therapy Patient Population:Patient Population: 4000 Type 2 diabetics with 4000 Type 2 diabetics with
Chronic Kidney Disease (estimated GFR 20-60) and Chronic Kidney Disease (estimated GFR 20-60) and Hb < 11 g/dlHb < 11 g/dl
Study Design:Study Design: R Randomized, double-blind, placebo-andomized, double-blind, placebo-controlled, multicenter international trial controlled, multicenter international trial
Intervention:Intervention: Aranesp Aranesp (darbepoetin alfa) to (darbepoetin alfa) to increase Hb to 11-13 g/dl increase Hb to 11-13 g/dl
Primary OutcomePrimary Outcome: time to all-cause mortality and : time to all-cause mortality and cardiovascular cardiovascular morbidity, including: myocardial morbidity, including: myocardial infarction, acute myocardial ischemia, congestive infarction, acute myocardial ischemia, congestive heart failure and strokeheart failure and stroke
Follow-up:Follow-up: 4 years 4 years
Funded by Amgen
Diabetic Nephropathy: Some Diabetic Nephropathy: Some Novel Therapies Novel Therapies
Under InvestigationUnder Investigation
Pirfenidone –antifibrotic agentPirfenidone –antifibrotic agent Aliskerin anti-renin agentAliskerin anti-renin agent Robuxistaurin- Protein Kinase C Robuxistaurin- Protein Kinase C
Beta-1 antagonistBeta-1 antagonist Advanced Glycation Endproduct Advanced Glycation Endproduct
antagonistsantagonists OthersOthers
How Should I How Should I Manage My Patient Manage My Patient
With Diabetic With Diabetic Nephropathy Nephropathy
Today?Today?
Diabetic Nephropathy Diabetic Nephropathy ManagementManagement
ParameterParameter Lower BP………………………Lower BP……………………… Block RAAS……………………Block RAAS…………………… Improve glycemia Improve glycemia
…………….……………. Lower LDL Lower LDL
cholesterol………..cholesterol……….. Anemia management Anemia management
………...………... Endothelial Endothelial
protection…………protection………… Smoking…………………Smoking…………………
TargetTarget
< 130/80 mmHg< 130/80 mmHg
ACEi or ARB to max ACEi or ARB to max toleratedtolerated
A1c < 6.5% (Insulin/TZD)A1c < 6.5% (Insulin/TZD)
< 100 (70) mg/dl statin + < 100 (70) mg/dl statin + otherother
Hb 11-12 g/dl (Epo + iron)Hb 11-12 g/dl (Epo + iron)
Aspirin dailyAspirin daily
CessationCessation
Diabetic Nephropathy: Diabetic Nephropathy: What about proteinuria?What about proteinuria?
Lower BP to goal with max dose ACEi or ARBLower BP to goal with max dose ACEi or ARB
Consider Adding: ACEi to ARB, Consider Adding: ACEi to ARB, mineralocorticoid receptor antagonist to ACEi mineralocorticoid receptor antagonist to ACEi or ARBor ARB
Calcium Channel BlockersCalcium Channel Blockers Non-dihydropyridineNon-dihydropyridine DihydropyridineDihydropyridine
LOCKING THE STABLE LOCKING THE STABLE DOORDOOR
…after the horse has bolted…after the horse has bolted
Thank Thank YouYou
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