1. Recent advances in management of Diabetic Nephropathy

2. …Tiger by the tail

3. Normal Kidney
Diabetic Kidney

4. Diabetic nephropathy
Diabetic nephropathy is progressive kidney disease
Most common cause of ESRD
More likely to die than progress to ESRD
Multi-risk factor intervention is critical
Lowering blood pressure with RAAS blockade is critical
Combinations of ACEi + ARB or MRA sensible
No long term efficacy or safety data
Prevent cardiovascular morbidity and mortality

5. Why is Diabetic Nephropathy Important?

6. Diabetes: The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes
50.1%
Hypertension
27%
Glomerulonephritis
13%
Other
10%
No. of patients
Projection
95% CI
700
600
500
No. of dialysis patients (thousands)
400
The pie chart shows that diabetes is currently the most common cause of ESRD.
The lower graph reveals that the number of patients with ESRD maintained on dialysis is predicted to double over present levels by 2010, and the major contributor to this exponential increase is chronic renal failure associated with diabetes.
300
520,240
281,355
200
243,524
100
r2=99.8%
1984
1988
1992
1996
2000
2004
2008
United States Renal Data System. Annual data report
United States Renal Data System. Annual data report Available at: Accessed April 25, 2001.

7. Cardiovascular Death is Major Cause of Mortality in ESRD
100
ESRD Population
GP Male 10
GP Female
GP Black 1
GP White
Annual Cardiovascular Mortality (%)
General Population
Dialysis Male
0.1
Dialysis Female
Dialysis Black
0.01
Key point:
CVD mortality is 10-fold higher in dialysis patients than in the general population, even at extremes in age.
Other information:
Information presented in a logarithmic scale
Cardiovascular mortality was defined as death caused by: arrhythmias, cardiomyopathy, cardiac arrest, MI, artherosclerotic heart disease or pulmonary edema in the general population
Data stratified by age, race, gender
Dialysis White
0.001
25-34
35-44
45-54
55-64
65-74
75-84
> 85
Age (years)
Sarnak MJ and Levey AS. Am J Kidney Dis. 2000;35(4)(suppl1):S117-S131.
Foley RN. Am J Kidney Dis. 1998;32(S3):S

8. What is the Natural History of Diabetic Nephropathy?

9. Definition of Diabetic Nephropathy
Clinical diagnosis based on Hx, Exam and urine albumin/creatinine ratio in most cases
Longstanding History of diabetes + retinopathy
Macroalbuminuria (a.k.a “overt nephropathy”) defined as random urine albumin/creatinine ratio > 300 mg/g
Hypertension (> 90%)
Renal Biopsy confirmation is rare

10. Development of Macroalbuminuria Heralds Rapid Decline in Glomerular Filtration in Type II Diabetes
Nelson RG. et al NEJM, 1996

11. Diabetics with Nephropathy (DM/CKD) are More Likely to Die than to Progress to ESRD
5% Medicare sample , cohort, 2 year follow-up
N=1,045,263
188,596
33,586
19,335
100
Event Free
ESRD 80
All Cause
Death
65.12
73.18 60
Percent of Patients
85.04
90.53 40
5.85
This slide tells us that CKD patients are more likely to die than to survive to ESRD.
So what are the implications?
For the past 25 years we have focused on those patients surviving long enough to enter ESRD when there has been a larger population that perhaps we have not focused on.
2.25
0.31 20
0.07
29.04
24.57
14.65
9.40
NDM/Non-CKD
DM/Non-CKD
NDM/CKD
DM/CKD
Status in the entry period

12. Newly diagnosed, predominantly white, medically treated
Diabetics with Macroalbuminuria are More Likely to Die than Develop ESRD
The United Kingdom Prospective Diabetes Study (approx Type 2 Diabetics)
Newly diagnosed, predominantly white, medically treated
No albuminruia
1.4%
2.0% C V D E A T H
Microalbuminruia
3.0%
2.8%
Macroalbuminruia
4.6%
2.3%
Elevated Serum Creatinine
19%
Adler et al. Kid Int, 2003

13. What are Diabetics with Nephropathy Dying From?
Myocardial
Infarction
Heart
Failure
Stroke
Sudden
Death

14. Diabetic Nephropathy Improving Outcomes in Diabetic Nephropathy
Prevention of
Cardiovascular Events
End-Stage Renal Disease

15. What is the Proper Therapy of Kidney Disease in patients with Diabetes?

16. The Renal Injury Triad
Angiotensin II
Hypertension
Proteinuria

17. Definition of Abnormal Albuminuria in Diabetes Mellitus
Microalbuminuria
Macroalbuminuria
(Nephropathy)
Detected by dipstick No
Yes
Urine Albumin / Cr
mg Alb / g Cr
> 300 mg Alb / g Cr
Renal Risk
Marker of future nephropathy in some
Marker progressive renal disease
Cardiovascular Risk
Increased
* Random (Spot) urine preferably A.M. recommended

18. ADA Guidelines: Diabetic Nephropathy
A-Level Evidence (well done RCTs)
To reduce the risk and/or slow the progression of nephropathy, optimize glucose control.
To reduce the risk and/or slow the progression of nephropathy, optimize blood pressure control.

19. ADA: Screening Guidelines
Expert Consensus
Perform an annual test for the presence of microalbuminuria in (1) type 1 diabetic patients who have had diabetes >5 years and (2) all type 2 diabetic patients starting at diagnosis.
Acceptable samples to test for increased urinary albumin excretion are timed (e.g., 12 or 24 h) collections for measurement of albumin concentration and timed or untimed samples for measurement of the albumin:creatinine ratio. For screening, an untimed sample for albumin measurement (without creatinine) may be considered if a concentration cutoff is used that allows high sensitivity for detection of an increased albumin excretion rate. Level of evidence: E

20. ADA: Treatment Guidelines
A-Level Evidence (well done trials)
In the treatment of albuminuria/nephropathy both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can be used:
In hypertensive and nonhypertensive type 1 diabetic patients with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (1a)
In hypertensive and non hypertensive type 2 diabetic patients with microalbuminuria, ACE inhibitors and ARBs have been shown to delay the progression to macroalbuminuria. (Cochrane 1a DOE)
In patients with type 2 diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dL), ARBs have been shown to delay the progression of nephropathy.
If one class is not tolerated, the other should be substituted.

21. ADA: Treatment B-Level Evidence (well done cohort studies)
With the onset of overt nephropathy, initiate protein restriction to <0.8 g • kg-1 body weight • day-1 (approximately 10% of daily calories), the current adult recommended daily allowance for protein. Further restriction may be useful in slowing the decline of glomerular filtration rate in selected patients.

22. ADA: Treatment Expert Consensus
If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of hyperkalemia.
Consider referral to a physician experienced in the care of diabetic renal disease when the glomerular filtration rate has fallen to either <60 mL • min-1 • 173 m-2 or difficulties have occurred in the management of hypertension or hyperkalemia.
Consider the use of non-dihydropyridine calcium channel blockers or beta-blockers in patients unable to tolerate ACE inhibitors or ARBs.

23. ACE-I is More Renoprotective than Conventional Therapy in Type 1 Diabetes (Total N = 409)
% with
Doubling of
Baseline
Creatinine
Baseline creatinine > 1.5 mg/dl 25 50 75
100 1 2 3 4
Captopril
Conventional therapy
2 –
0 –
- 2 –
- 4 –
6 –
8 –
Decrease in
Mean Blood
Pressure
(mm Hg) NS
40 –
- 20 –
0 –
60 –
% Reduction in
Proteinuria
P <.001
Lewis et al. N Engl J Med. 1993;329:

24. ARB (losartan) Reduces Risk of ESRD in Diabetic Nephropathy
Reduction in Endpoints in NIDDM with Angiotensin Antagonist
Losartan (RENAAL) Trial: 1513 type 2 Diabetics with Nephropathy
Placebo
ESRD 30
BP / 74
BP / 74
Risk Reduction: 28%
Losartan
p=0.002 20
% with event 10
Avg: 3.5 BP drugs/pt
90% in both groups
received a CCB 12 24 36 48
Months
P (+ CT)
762
715
610
347 42
L (+ CT)
751
714
625
375 69
Brenner et al. New Engl J. Med Sept

25. 1,715 Type 2 Diabetics with Nephropathy
Irbesartan in Diabetic Nephropathy Trial: Time to Doubling of Serum Creatinine, ESRD, or Death
1,715 Type 2 Diabetics with Nephropathy 70
Irbesartan
Amlodipine
Placebo
BP 141/77
BP 144/80
BP 140/77
RRR 23% P=.006 60
RRR 20% P=.02
P=NS 50 40
Subjects (%) 30 20
IDNT is a positive study, demonstrating a 20% risk reduction for the primary endpoint vs. the control group, and a 23% risk reduction vs. the amlodipine group, independent of the effects of irbesartan on systemic blood pressure.
The irbesartan group in IDNT demonstrates a 20% RRR vs. the control group (placebo in addition to other nonexcluded antihypertensive therapies) for the primary endpoint of doubling of serum creatinine, development of end-stage renal disease (ESRD), or death from any cause (p=0.02), and a 23% RRR vs. the amlodipine group (p=0.006).1 The Kaplan-Meier curve for irbesartan continues to diverge away from the control and amlodipine curves throughout the course of the study. No significant difference is observed between the control and amlodipine groups.
The better outcomes among patients in the irbesartan group could not be explained by differences in achieved blood pressure. Although the mean arterial blood pressure (MAP) in the irbesartan group was the same as that in the amlodipine group, there was a significant difference in the primary endpoint in favor of irbesartan. Furthermore, correction for achieved MAP at quarterly visits during follow-up in a time-dependent proportional hazards analysis gave results similar to those of the primary analysis. After adjustment for blood pressure, the benefits of irbesartan are still present: RRR of 19% for irbesartan vs. the control group (p=0.03); RRR of 24% for irbesartan vs. the amlodipine group (p=0.005).
1 Lewis et al, 2001. 10 6 12 18 24 30 36 42 48 54 60
Follow-up (mo)
Lewis EJ, et al. N Engl J Med. 2001;345:

26. de Zeeuw et al. Kid. Int. June 2004
Albuminuria at Baseline Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial (N=1513)
100
Baseline Albuminuria HR 80
≥3.0 g/g
8.10 60
% with ESRD end point
≥1.5<3.0 g/g
3.23 40 20
<1.5 g/g
1.0 12 24 36 48
Month
de Zeeuw et al. Kid. Int. June 2004

27. de Zeeuw et al. Kid. Int. June 2004
Reduction in Proteinuria is Associated with Reduced Risk for End-Stage Renal Disease in Diabetic Nephropathy
4.0
3.5
3.0
2.5
Relative Risk for
ESRD
2.0
1.5
1.0
0.5
0.0
<-40
≥-40
≥-10
≥10
≥40
≥60
<40
<-10
<10
<60
Change in Albuminuria %
de Zeeuw et al. Kid. Int. June 2004

28. RENAAL; Proteinuria Reduction (<0% versus >30%) determines the cardiovascular outcome
CV Endpoint
Heart Failure
<0% 40 40
>30% 30 30
% with CV endpoint
% with heart failure 20 20
<0% 10 10
>30% 12 24 36 48 12 24 36 48
Month
Month
De Zeeuw et al; Circulation, in press

29. Continuation of Losartan After Serum Creatinine Doubles Reduces Incidence of ESRD80
Risk Reduction: 30%
p=0.013 60 P 40 L
% with ESRD event 20 6 12 18 24
Months
P (+CT)
198
111 48 11 4
L (+CT)
162
104 43 19 3

30. Proteinuria Quartile at Baseline (g/g)
RENAAL; Contribution of Baseline Systolic BP or Proteinuria to ESRD in diabetic nephropathy
<140
>165
<.5
>2.5
.5 – 1.2
Proteinuria Quartile at Baseline (g/g)
SBP Quartile at
Baseline (mm Hg)
Hazard Ratio
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 5 10 15 20
unpublished

31. Combination Therapy for BP Control: Rule Rather Than Exception
Trial/Systolic Blood Pressure Achieved (mm Hg)
ALLHAT
IDNT
RENAAL
UKPDS
ABCD
MDRD
HOT
AASK
138
138
141
144
132
132
A summary of all clinical trials that randomized to different levels of BP demonstrate the need for multiple antihypertensive medications. An average of 3.2 different antihypertensive meds are required to achieved the recommend BP goal of <130/80 mmHg in those with diabetes and <130/85 mmHg for those with renal insufficiency. The achieved SBPs are shown for the low pressure groups in these trials.
138
128
Number of BP Medications
Adapted from Bakris et al. Am J Kidney Dis. 2000;36:

32. How I do get My Patient’s BP to the Goal of <130 / < 80 mmHg?
ACE Inhibitor / AII Receptor Antagonist (maximum dose)
Low ( 2 gram ) Sodium Diet
Diuretic
eGFR > 50 ml/min, thiazide
eGFR < 50 ml/min, loop diuretic
Long-Acting CCB or b-blocker
Long-acting a-blocker vs clonidine
Minoxidil

33. Renal Effects of CCBs: Comparison
NDHP-CCBs show greater reductions in proteinuria in hypertensive adults with proteinuria, with or without diabetes.
Change (%)
P=0.01
-35
-30
-25
-20
-15
-10 -5 5
Proteinuria
N=510
Systolic Blood Pressure
N=1,338 NS 2%
-30%
-13%
-18.5%
Points of Emphasis / Key Messages
This chart, drawn from a systematic review of 28 independent studies, compares DHPs (eg, amlodipine) and NDHPs (eg, verapamil) in terms of their effects on proteinuria and SBP in hypertensive adults.
In 510 patients participating in these studies, NDHPs had a significant effect on reducing urinary proteins (-30%), whereas DHPs (+2%) showed no effect.
These data also suggest that SBP changes in the 1338 patients were similar with either the NDHP- or DHP-CCBs.
The 28 independent studies used to compile this histogram reviewed data from hypertensive adults with or without diabetes but with clinically evident proteinuria.
Reference
Bakris GT et al. Differential effects of calcium antagonist subclasses on markers of
nephropathy progression. Kidney Int In press.
DHP-CCB
NDHP-CCB
Bakris GL et al. Kidney Int In press.
Systematic Review of 28 Studies 17

34. Percent reduction from baseline
Combination ACEi and Non-Dihydropyridine CCB Reduces Proteinuria Further in Type 2 Diabetics With Nephropathy
Trandolapril
5.5 mg/d
Verapamil SR
314 mg/d
Trandolapril (2.9 mg/d) +
Verapamil SR (219 mg/d)
-20
-40
-60
Percent reduction from baseline
Proteinuria
Blood Pressure
Bakris, et al. Kid Int. 1998;54:1283.

35. NKF Kidney Disease Outcomes Quality Initiative: Pharmacologic Treatment
Type of CKD
BP Goal
Preferred Agents for CKD, + HTN
Other Agents to Reduce CVD Risk and Reach BP Goal
Diabetic
< 130/80
ACEi or ARB
Diuretic Preferred, then b-Blocker or CCB
Non-Diabetic with Spot Urine Total Prot-to-Cr ratio > 200 mg/g
Non-diabetic with Spot Urine Total Prot-to-Cr ratio < 200 mg/g
None Preferred
Diuretic Preferred, then ACEi, ARB, B-blocker or CCB
Transplanted
CKD
CCB, diuretic, b-blocker ACEi, ARB
KDOQI BP guidelines for CKD Am. J. Kid. Dis. Suppl. May 2004

36. BP < 130/80, (all treated with an ACEi or ARB) A1c < 6.5%
Steno-2: Multiple Risk Factor Intervention Improves Outcomes in Type 2 diabetics with Microalbuminuria
Randomized, open-label, target driven, long-term intensified intervention trial aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria
BP < 130/80, (all treated with an ACEi or ARB)
A1c < 6.5%
Total Cholesterol < 175 mg/dl
Total Triglyceride 150 mg/dl
Aspirin 81 mg daily
Exercise program
Smoking Cessation
Gaede et al N.Engl.Med. 3448:

37. Intensive Multi-risk Factor Intervention Improves Outcomes in Type 2 Diabetes
Composite outcome: CV death, MI, coronary or
peripheral revascularization, CVA, amputation 60
P=0.007 50
Conventional therapy 40
Primary Composite End Point (%) 30 20
Intensive therapy 10 12 24 36 48 60 72 84 96
Months of Follow-up
No. at Risk
Conventional
therapy
Intensive
therapy
Gaede et al N.Engl.Med. 3448:

38. Risk of Death after AMI is Reduced across all Levels of Kidney Function with Recommended Interventions
Cooperative cardiovascular project, Medicare patients >=65 yrs, admitted
Patients with higher SCr levels were less likely to receive (<1.5, , ):
Aspirin
Beta Blocker
Ace-I
also less likely to have angiography ( %), PTCA ( %) or thrombolytics ( %)
Shlipak et al., Ann Int Med 2002;137:555-62

39. Diabetic Nephropathy: Important Message
Lower blood pressure < 130 / 80 mmHg
Reducing Proteinuria
Inhibition of Renin-Angiotensin System
Multiple risk factor intervention
Glycemia
Dyslipidemia
Physical activity
Aspirin
Smoking cessation

40. Is Combination Therapy With An ACE Inhibitor And An ARB Safe And Effective For Patients With Diabetic Renal Disease?

41. Glomerular Filtration Rate
ACEi- or ARB-Based Regimens for Diabetic Nephropathy Do Not Go Far Enough!
Time (yrs)
ESRD 50
Glomerular Filtration Rate
ml/min/1.73 m2
No ACEi/ARB
or BP control
DGFR = - 10 ml/min/yr
Time to ESRD 4 yrs 40 30 20 10
RAAS blockade + Other?
ACEi + ARB
DGFR = - ? ml/min/yr
Time to ESRD ?
ACEi or ARB
DGFR = - 6 ml/min/yr
Time to ESRD 6.6 yrs

42. DBP from baseline mmHg*
Combining an ACEi and an ARB is more Renoprotective than Either Agent alone in Non-Diabetic Nephropathy
Treatment N
Baseline BP mmHg
DBP from baseline mmHg*
Primary Endpoint
Hazard
Ratio**
P value
Combination 85
130 / 75
5.2 / 2.9
10 (11%)* -
Trandolapril 86
130 / 76
5.3 / 3.0
20 (23%)
0.40
0.016
Losartan
130 / 74
5.1 / 2.9
0.38
0.018
*Average number of medications 3.2 per pt, 90% in all groups on dihydropyridine CCB
** Hazard Ratio comparing combination with either agent alone
Nakao et al. Lancet 361: , 2003

43. 20 mg Enalapril/300 mg Irbesartan
Summary of Studies combining ACEi and ARB in Diabetic nephropathy: Effects on Proteinuria and BP
DM Type
Design N
Duration
Intervention
Results
1Type 2
DRBCT 4
4 weeks
40 mg Lisinopril /
50 Losartan
No effect
2Type 2 18
8 weeks
8 mg candesartan
25% Prot and BP
3Type 1
DBRPCT 21
300 mg irbesartan
43% Prot and BP
4Type 1
DBRCT 20
20 mg Benazepril/
ACEi / Valsartan 80 mg
15 % Prot and BP
5Type 1 24
20 mg Enalapril/300 mg Irbesartan
6Type 2
ACEi / Candsartan 16 mg
29% Prot
1 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: , 2002;4 Jacobsen et al. J. Am. Soc. Neph. 14: , 2003;5 Rossing
Et al. Kid Int 63: , 2003 ; 6 Rossing et al. Diab Care 26: , 2003.

44. Diabetic Nephropathy: Important Message
Small short-term studies suggest combinations of ACEi and ARB reduce proteinuria synergistically
Greater reductions in proteinuria with or without additional lowering in blood pressure
Hyperkalemia and Increased creatinine not well documented
Safety and Efficacy of combination ACEi and ARB in diabetic with nephropathy not well established

45. Is There a Role for Spironolactone (or Eplerenone) in Combination with Other Drugs in Patients with Diabetic Nephropathy?

46. Role of Aldosterone in the Pathogenesis of Diabetic Nephropathy
Angiotensin II
Hemodynamic
Non-Hemodynamic
Capillary wall injury
Inflammation
O2- , TGF-b1 / PAI-1
Aldosterone
Glomerular Hypertension
Injury to Glomerular Cells
Proteinuria
Sclerosis and
Fibrosis
Glomerular and Tubular Scarring Progressive Renal Failure

47. Adverse Renal and Cardiovascular Effects of Aldosterone
Glomerulosclerosis
Interstitial Fibrosis
Proteinuria
Renal Failure
Ventricular Hypertrophy
Cardiac Fibrosis
Contractile Dysfunction
Heart Failure
Endothelial dysfunction
Inflammation
Oxidative Stress

48. Mineralocorticoid Receptor Blockade Improves Cardiac Outcomes: Placebo Controlled Trials
1.00
0.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
Probability of Survival
Spironolactone
Placebo 36 6 3 9 18 15 12 21 24 27 30 33
Months
Spironolactone improves survival in
Chronic Heart Failure
P=0.001
RR=0.70 (95% Cl, 36 10 3 4 5 6 7 8 9 2 1 30 27 24 21 18 15 12 33
Placebo
Eplerenone
P=0.03
RR=0.79 (95% Cl, )
Cumulative Incidence of (%)
Months since Randomization
Eplerenone reduces sudden cardiac death
Post myocardial infarction

49. Can Dual Blockade of the RAAS Improve Renal Outcomes in Diabetic Nephropathy?
Ang I
Non-ACE
Pathways
ACE
Ang II
ACEi
ARB +
AT1 Receptor
Aldosterone +
MRA
Renal Injury
and Proteinuria
Progressive Diabetic Nephropathy

50. Study Design and Objectives
Study Design: Randomized double-blind placebo controlled trial
Study Population: Diabetics with macroalbuminuria despite maximally dosed ACE inhibitor
Intervention: Lisinopril 80 mg/d + losartan 100 mg/d or + Aldactone 25 mg/d or + placebo
Primary Outcome: Change in albuminuria
Secondary Outcomes: Safety especially serum creatinine and hyperkalemia
Follow up: 52 weeks

51. Study Hypothesis
Blockade of the renin-angiotensin system beyond ACE inhibition decreases proteinuria and slows progression of renal disease in diabetics with overt nephropathy by suppressing aldosterone synthesis or blocking the aldosterone receptor.

52. Lisinopril 80 mg/d + Placebo
Combined Inhibition of the RAAS Pathway: ACEi + ARB
vs ACEi + MRA in Diabetic Nephropathy
Diabetics with SBP > 130 mmHg
Scr < 3, female, < 4, male
Urine albumin/Cr ratio > 300
on ACE inhibitor + CT
Lisinopril 80 mg/d +
Losartan 100 mg p.o qd
Aldactone 25 mg p.o. qd
D/C Study
Drug
Lisinopril 80 mg/d + Placebo
Maintain SBP mmHg
With conventional
antihypertensives
ABPM, aldosterone
Kidney Function
Lipids, Inflammation
Lisinopril 80 mg/d
Control to SBP < 130
then Randomize
Run-in
Period
ABPM, aldosterone
Kidney Function
Lipids, Inflammation
Time, weeks
BP blood pressure, potassium and serum creatinine measurement
RF renal function-GFR, RPF, 24 hour urine sodium, creatinine,potassium, protein and urea

53. Diabetic Nephropathy: Important Message
Role for spironolactone or eplerenone in diabetics with nephropathy not established
Small, short-term studies suggest adding on is efficacious for lowering proteinuria
Not clear if combinations are safe in larger population
No long-term trials with cardiovascular or renal endpoints

54. Beyond RAAS Blockade

55. Chronic Kidney Disease Cardiovascular disease
Hypothesis: Anemia is an Important CV Risk Factor in Chronic Kidney Disease
Chronic Kidney Disease
Anemia
Let us now consider the role of anemia in the CKD and CVD relationship and new data supporting anemia as the “critical link” between CKD and CVD.
Cardiovascular disease

56. Mohanram et al. Kid. Int. Sept 2004
Baseline Hemoglobin Predicts ESRD in Type 2 Diabetics with Nephropathy: RENAAL Trial (N=1513)
Hb < 11.3*
Hb > 13.8
Hb *
Hb *
Time, years 4 3 2 1
End-stage renal disease, % 10 20 50 60 30 40 -
1.00
> 13.8
0.002
1.85
0.02
1.61
0.001
1.99
< 11.3
P value
Adjusted HR*
Hb g/dl
* Age, gender, GFR, Race, Proteinuria,
CV disease, A1c, lipids, BP, Ca, P, albumin
Mohanram et al. Kid. Int. Sept 2004

57. Is Anemia Causing Cardiovascular And Renal Disease In Diabetics, Or is it Just A Marker?

58. Trial to Reduce Cardiovascular Events with Aranesp (Darbepoietin) Therapy
Patient Population: Type 2 diabetics with Chronic Kidney Disease (estimated GFR 20-60) and Hb < 11 g/dl
Study Design: Randomized, double-blind, placebo-controlled, multicenter international trial
Intervention: Aranesp (darbepoetin alfa) to increase Hb to g/dl
Primary Outcome: time to all-cause mortality and cardiovascular morbidity, including: myocardial infarction, acute myocardial ischemia, congestive heart failure and stroke
Follow-up: 4 years
Funded by Amgen

59. Diabetic Nephropathy: Some Novel Therapies Under Investigation
Pirfenidone –antifibrotic agent
Aliskerin anti-renin agent
Robuxistaurin- Protein Kinase C Beta-1 antagonist
Advanced Glycation Endproduct antagonists
Others

60. How Should I Manage My Patient With Diabetic Nephropathy Today?

61. Diabetic Nephropathy Management
Parameter
Lower BP………………………
Block RAAS……………………
Improve glycemia …………….
Lower LDL cholesterol………..
Anemia management ………...
Endothelial protection…………
Smoking…………………
Target
< 130/80 mmHg
ACEi or ARB to max tolerated
A1c < 6.5% (Insulin/TZD)
< 100 (70) mg/dl statin + other
Hb g/dl (Epo + iron)
Aspirin daily
Cessation

62. Diabetic Nephropathy: What about proteinuria?
Lower BP to goal with max dose ACEi or ARB
Consider Adding: ACEi to ARB, mineralocorticoid receptor antagonist to ACEi or ARB
Calcium Channel Blockers
Non-dihydropyridine
Dihydropyridine

63. LOCKING THE STABLE DOOR …after the horse has bolted
Thank You