1. CKD Prevention
?
Thitisak Kitthaweesin MD.
Department of Medicine, Phramongkutklao Hospital
and College of Medicine
Symposium in 24th Annual Meeting
The Royal College of Physicians of Thailand
April 29th, 2008

2. Phyathai Palace

3. Risk Factors for End-Stage Renal Disease
Hyperglycaemia
Dyslipidaemia Proteinuria
End-Stage
Renal Disease
Hypoxia Hypertension
Smoking
Genetic Background
Strippoli et al. J Nephrol 2003;16:487–499

4. Primary
Prevention

5. Hypertension and diabetes are
risk factors for microalbuminuria
Healthy
45
Hypertension (treated)
Prevalence of microalbuminuria (%)
40 Diabetes
Diabetes and hypertension
35
30
25
20
15
10
5
0
Men Women
Hallan et al. Scand J Urol Nephrol 2003;37:151–158

6. Glycemic Control

7. Association of glycaemia with macrovascular and
microvascular complications of type 2 diabetes
UKPDS 35 BMJ

8. The Effect of Intensive Treatment of Diabetes on the
Development and Progression of Long-Term
Complications in Insulin-Dependent Diabetes Mellitus
The Diabetes Control and Complications Trial Research Group
Cumulative Incidence of Urinary Albumin Excretion 300 mg per 24
Hours Dashed Line and 40 mg per 24 Hours Solid Line in Patients
with IDDM Receiving Intensive or Conventional Therapy
N Engl J Med 1993;329:977-986

9. EDIC Study
Prevalence
and
Cumulative Incidence
of
Microalbuminuria
and
Albuminuria
Writing team for DCCT. JAMA ;Vol No.

10. STENO-2
Progression of
Nephropathy, Retinopathy, Aut
onomic and Peripheral
Neuropathy in Intensive-
Therapy Group, as Compared
with Conventional-Therapy
Group after an average of 13.3
years of study and follow-up
Gaede P et al. N Engl J Med

11. Risk of Death from Any Cause
and from Cardiovascular Causes
and the Number of
Cardiovascular Events, According
to Treatment Group
Gaede P et al. N Engl J Med

12. Reversal of DN after Pancreas Tx
DN
5 yrs
10 yrs
Fioretto P et al. N Eng J Med 1998; 339: 69-75

13. Blood Pressure Control

14. HT Linked To Chronic Renal Disease
Among 332,544 Men Screened for MRFIT
250
Age-Adjusted Rate of ESRD
Per 100,000 Person-Years
200
150
100
110
100-109
50 90-99
85-89
80-84
0 <80
180 160-179 140-159 130-139 120-129 <120
Systolic BP (mm Hg)
Klag MJ, et al. N Engl J Med. 1996;334(1):13-18.

15. Risk of Developing Low
Glomerular Filtration
Rate or Elevated Serum
Creatinine in a Screened
Cohort in Okinawa, Japan
Iseki et al. Hypertens Res 2007;30:164-174

16. BP and Incidence of High Scr
Iseki et al. Hypertens Res 2007;30:164-174

17. Blood Pressure Predicts Risk of
Developing End-Stage Renal Disease
Tozawa M et al. Hypertension 2003

18. Treatment algorithm (JNC 7)
Hypertension without Hypertension with
compelling indications compelling indications
Stage 1 hypertension Stage 2 hypertension Drug(s) for the
compelling
Thiazide-type diuretic Two-drug
indications
for most combination for most
Other antihypertensive
May consider ACE-I, Usually thiazide-type
drugs (thiazide-type
ARB, b-blocker, CCB diuretic and ACE-I,
diuretic and ACE-I,
or combination ARB, b-blocker or CCB
ARB, b-blocker, CCB)
as needed
JNC 7. JAMA 2003;289:2560–2572

19. Non-Pharmacological Treatment
• Lifestyle modification
• Smoking cessation
• Regular aerobic exercise
• Reduction in alcohol consumption
• Weight for overweight individuals
• Lowering dietary sodium intake
• DASH diet : high fiber, low fat

20. Obesity and
Metabolic Syndrome

21. Changes in the Demographics and Prevalence of
Chronic Kidney Disease in Okinawa, Japan -
Odds Ratio (95% CI)
1.4
1.2
1
0.8
0.6
0.4
0.2
0
NoMS MS
No MS MS
N=87018 N=20490
Odds ratio and 95% CI of low GFR according to metabolic syndrome
among screening subjects in 2003
Iseki et al. Hypertens Res 2007;30:164-174

22. BMI and Incidence of ESRD
8
Cumulative 7
Incidence of
6
ESRD
per 1000 5 T tl
oa
screenees 4 Mn
e
3 Wm
oe
n
2
1
0
BMI, kg/m2
<1
2.0 2. - 3
1 2.
0 1 2. - 5
3 2.
2 4 2. +
55
Iseki et al. Kidney International, 2004;65:1870-1876

23. Secondary
Prevention

24. Glycemic Control

25. Progression of diabetic nephropathy
(Type 2 DM)
Rossing et al. Kidney International, ; :

26. Progression of diabetic nephropathy
(Type 1 DM)
Decline in GFR, mL/min/year Decline in GFR, mL/min/year
6
5
7
6
4
5
< .2
9
4
> .2
9
3 Q inile o H A c%
ut sf b1
3
2 > .2
9
2
1
< .2
9 HbA1c %
0
1 >0
12 <0
12
MABP, mmHg
0
7.8 8.8 9.2 9.8 1 .9
0
HbA1c %
Hovind et al. Kidney International ; :

27. Blood Pressure Control

28. Reducing blood pressure slows rate of
decline in GFR in DM and non-DM
Mean arterial pressure (mmHg)
95 98 101 104 107 110 113 116 119
0
Decline in GFR (mL/min/year)
-2
r = 0.69; P < 0.05
-4
-6
-8 Untreated
hypertension
-10
-12
130/85 140/90
-14
Bakris et al. Am J Kidney Dis 2000;36:646–661

29. K DOQI Clinical Practice Guidelines on
Hypertension and Antihypertensive
Agents in Chronic Kidney Disease
Am J Kidney Dis 2004; 43:S65-S223 (suppl 1

30. Choice of antihypertensive in chronic
kidney disease – simplified algorithm
Does the patient have diabetic kidney disease?
OR
Does the patients have nondiabetic kidney disease with
spot urine total protein:creatinine ratio 200 mg/g?
YES NO
Can an ACE inhibitor or
Is blood pressure
ARB be introduced or
<130/80 mmHg?
increased?
YES NO
Introduce or increase Introduce or increase
ACE inhibitor or ARB diuretic or other agent
National Kidney Foundation. Am J Kidney Dis 2004; 43(5 Suppl 1):S65–S230

31. ACEI and ARB

32. Benefits of RAAS Blockade for Renal
Protection
• Hemodynamic effects
– Reduction in systemic BP
– Reduction in glomerular capillary pressure
– Reduction in proteinuria
Angiotensin II
• Non-hemodynamic effects
– Stimulation of extracellular matrix degradation
– Inhibition of macrophage/monocyte infiltration

33. Comparison of ACEI and ARB in Renal
Diseases
• Similarities • Differences
– Lower BP and glomerular ARB:
pressure – Do not inhibit kinin
– Reduce proteinuria breakdown
– Renal protective in – Less cough
animal model – Less angioedema
– Renal protection proven – Less hyperkalemia
in patients esp. diabetic
nephropathy type 2

34. ACEI in Non-DM CKD
Study Duration Patients N Comparison Risk
reduction
AIPRI 3 yrs Non DM 583 Benacepril 53%
(1996) Chronic Vs
nephropathy placebo
REIN 2.5 yrs Non DM 117 Ramipril 52%
stratum 2 Chronic Vs
(1997) nephropathy placebo
REIN 1.4 yrs Non DM 186 Ramipril 56%
stratum 1 Chronic Vs
(1999) nephropathy placebo
Uprot 1-3 g/d
AASK 3 yrs African American 653 Ramipril 48%
(2001) HT Vs
Nephrosclerosis Amlodipine

35. ACEI in DM-CKD
Study Duration Patients N Comparison Risk
reduction
Captopril 3 yrs Type 1 DM 409 Captopril 45%
study proteinuria Vs
(1993) placebo
UKPDS 15 yrs Type 2 DM 758 Captopril NS
(1998) HT Vs
Atenolol

36. A Meta-Analysis of Individual Patient Data
The ACE Inhibitors in Diabetic Nephropathy Trialist Group*
Risk for progression to macroalbuminuria and regression to normoalbuminuria
Type 1 DM
Ann Intern Med -

37. Preventing Microalbuminuria in Type 2 DM
(BENEDICT)
Ruggenenti P et al. N Engl J Med

38. Kaplan–Meier
No ACEI
Curves for the
Percentages of
ACEI Subjects with
Microalbuminuria
during Treatment
CCB
No CCB
Ruggenenti P et al. N Engl J Med

39. ACEI Trials in Sample Reduction of Reduction of Reduction in
Type 2 DM proteinuria GFR fall ESRD
Ravid et al. 94
Ann Int Med 1993
Lebovitz et al. 121
KI 1994
Bakris et al. 52
KI 1996
Ahmed et al. 103
Diabetes Care 1996
Nielsen et al. 43
Diabetes 1997
UKPDS 758
BMJ 1998
Fogari et al. 107
J Hum HT 1999
ABCD 470
Diabetes Care 2000
MICRO-HOPE 3577
Lancet 2000

40. Morbidity and Mortality Along the
Renal Continuum
IRMA-2 AMADEO IDNT
INNOVATION VIVALDI RENAAL
DETAIL
MARVAL
CALM Macro-
proteinuria
Micro- Nephrotic
albuminuria Proteinuria
Endothelial End-Stage
Dysfunction Renal Disease
Risk factors
Diabetes ARB Trial Death
Hypertension

41. Evidence for ARBs and Renoprotection
in Diabetes
Trial Number BP goal Rx comparator Major Findings
T2DM with microalbuminuria
MARVAL 332 < 135/85 Valsartan vs  baseline albuminuria, 56% vs 92%
<2002> 0.5 yr Amlodipine
IRMA-2 590 < 135/85 Irbesartan vs  incidence of progression to macroal-
<2001> 2.0 Placebo buminuria (hazard ratio = 0.30, 0.14-0.61)
yrs
INNOVATION 675 < 130/80 Telmisartan vs ↓ transition to overt nephropathy, 55%,
<2007> 1.0 yr Placebo 66% in 40, 80 mg
DETAIL 250 Telmisartan vs No inferiority in the change in GFR
<2004> 5 yrs Enalapril from baseline
CALM 199 Candesartan vs  24% of proteinuria with mono Rx
<2000> 0.5 yr lisinopril + both  50% with combined Rx

42. ARBs prevent diabetic renal disease progression
Albumin excretion in patients with microalbuminuria
MARVAL
p<0.001
100
Urinary albumin excretion rate
90
80
70
(% of baseline)
60
50
40
30
20
10
0
Valsartan Amlodipine
Viberti et al. Circulation 2002;106:672–678

43. Benefit of Angiotensin II Blockade on Disease
Progression with Type 2 Diabetes (IRMA 2)
20 Placebo
150 mg of irbesartan
300 mg of irbesartan
Incidence of Diabetic
15
Nephropathy (%)
44%
Risk
10 reduction
68% *
5 Risk
reduction
0
0 3 6 12 18 22 24
Months of Follow-up
*P<0.001 vs. placebo
Parving, HH et al. NEJM 2001;345: 870-878

44. Ang II Blockade Reduced the Development of
Overt Nephropathy
(IRMA 2)
16
14
12  39%
Of Patients
P=NS
Percent
10
8  70%
6 P<0.001
4
2
0
Placebo Irbesartan Irbesartan
150 mg/d 300 mg/d
NNT: 10 patients over 2 years to prevent 1 case of overt nephropathy
Parving, HH et al. NEJM 2001;345:870.

45. Telmisartan renoprotection in type 2 diabetic
nephropathy
Reduced transition to overt nephropathy (INNOVATION)
0.8
Patients with and without hypertension
0.6
Transition rate
49.9%
Placebo
Telmisartan 40mg p<0.0001
0.4 Telmisartan 80 mg RRR: 55%
p<0.0001
NNT: 3.7
RRR: 66%
22.6% NNT: 3.0
0.2
16.7%
0
0 3 6 9 12 15 18 21 24 27 30
Month
RRR: relative risk reduction
NNT: number needed to treat to prevent 1 transition Makino et al. Diabetes Care 2007

46. Telmisartan renoprotection in type 2 DM
Reduces long-term decline in GFR (DETAIL)
Total GFR Change in GFR
Telmisartan Enalapril
p= NS† 0
100
90
80 -5
ml/min/1.73m2
ml/min/1.73m2
70
60 -10
50
40 -15
-15.0
30
20 -20 -17.5
10
0 -25
p = NS†
Telmisartan Enalapril
Baseline After 5 years
Barnett et al. N Engl J Med 2004;351:1952–1961. Erratum in: N Engl J Med 2005;352:1731
†p = NS, telmisartan vs enalapril Barnett. Acta Diabetol 2005; 42 Suppl 1:S42–S49

47. Combination therapy provides
additive benefit – CALM study
Candesartan
60
Candesartan Lisinopril
18
Lisinopril Combination
50
Reduction from baseline (%)
16 Combination
Reduction from baseline (mmHg)
14
40
12
10 30
8
6 20
4
10
2
0 0
SBP Albumin/creatinine ratio
Mogensen et al. BMJ 2000;321:1440–1444

48. Evidence for ARBs and Renoprotection
in Diabetes
Trial Number BP Rx comparator Major Findings
goal
T2DM with overt nephropathy
VIVALDI 800 < 130/80 Telmisartan vs ↓ proteinuria , comparable
<2003> 1 yr Valsartan
AMADEO 800 < 130/80 Telmisartan vs ↓ proteinuria 29% vs 19%
<2003> 1 yr Losartan
RENAAL 1513 < 140/90 Losartan vs  16% risk of composite end point
<2001> 3.4 yrs Placebo (doubling SCr/ESRD/death)
 25% risk of doubling SCr, 28% ESRD
IDNT 1715 < 135/85 Irbesartan vs  20-23% risk of composite end point
<2001> 2.6 yrs Amlodipine vs (doubling SCr/ESRD/death)
Placebo  29-39% risk of doubling SCr

49. ARBs prevent diabetic renal disease progression
Serum creatinine in patients with macroproteinuria
RENAAL IDNT
30 30
p=0.003
concentration (% of patients)
Doubling of serum creatinine
p=0.006
p<0.001
25 25
20 20
15 15
10 10
5 5
0 0
Losartan Placebo Irbesartan Amlodipine Placebo
Brenner et al. N Engl J Med 2001;345:861–869. , Lewis et al. N Engl J Med 2001;345:851–860

50. Telmisartan reduces proteinuria in patients
with hypertension and type 2 diabetic
nephropathy (VIVALDI)
Valsartan Telmisartan
0
Change in proteinuria (%)
-5
-10
-15
-20
-25
-30
-35 -33 -33
Galle et al. Diabetologia 2006; 49 (Suppl 1):638–639

51. Reduction of proteinuria after one year of treatment
:29% with Telmisartan 80 mg vs.19% with losartan 100
mg, p<0.05 (AMADEO)
Proteinuria reduction of 1 year
Telmisartan Losartan
0
-5
-10
-15
-20
-25
-30
-35
Weber. J Hypertens 2003;21 (Suppl 6):S37–S46

52. ARB renoprotection in type 2 diabetes
GFR decline with ARB treatment
RENAAL* IRMA2† IDNT† DETAIL†
Treatment
3.4 years 2.6 years 2 years 5 years
duration:
Losartan 100 mg Irbesartan 300 mg Irbesartan 300 mg Telmisartan 80 mg
0
-1
(mL/min/1.73m2/year)
GFR decline
-2
-3
-4 -3.7
-4.4
-5
-4.9
-6 -5.5
*Median; †Mean
Completers

53. Treatment of
Primary Renal Disease
• Immunosuppressive agents
• Non-immunosuppression

54. • Proteinuria
• Low protein diet
• Smoking cessation
• Avoid nephrotoxic agents
• Other modalities

55. Thank You