1. Management of hypertension in CKD

2. Hypertension is an important cause of ESRD
Hypertension is common in patients with CKD and accelerate the progression of renal failure
Key Question
Can effective antihypertensive therapy prevent the development of ESRD and retard the progression of CKD ?

3. Age and change of renal function
Prevalence of low GFR
<60 ml/mkn/1.73㎡,%>
Prevalence of decreased kidney function (GFR < 60 mL/min/1.73 m2 ) in the overall noninstitutionalized US population, as well as by history of diabetes and presence of hypertension: NHANES III, 1988 to 1994.
overall diabetes
hypertension no DM and no HT

4. Three major causes of ESRD

5. loss of nephrons Renal disease Progressive decline in GFR Systemic
hypertension
Proteinuria

6. CKD: Common pathway in disease progression
RENAL INJURY
Nephron mass
Glomerular capillary hypertension
Glomerular permeability to macromolecules
Filtration of plasma proteins  Proteinuria
Excessive tubular protein reabsorbtion
Tubulo-interstitial inflammation
SYSTEMIC
HYPERTENSION
RENAL SCARRING

7. MAJOR RISK FACTORS FOR CARDIOVASCULAR DISEASE
OBESITY
DIABETES
CHRONIC KIDNEY DISEASE
PHYSICAL INACTIVITY
AGE > 55 IN MEN, > 65 IN WOMEN
HYPERTENSION
HYPERLIPIDEMIA
SMOKING
FAMILY HISTORY

8. Why are CKD/ESRD Patients Predisposed to CV Disease?
ANEMIA
LVH/CHF
LIPIDS
HTN
INFLAMMATION plus CaP deposition
CV DISEASE AND DEATH
CAD and PVD

9. Why are CKD/ESRD Patients Predisposed to CV Disease?
30-50% of ESRD patients have INFLAMMATION (increased CRP, increased IL-6, decreased albumin)
Increased CRP is a primary marker for inflammation predicting cardiovascular disease in normal adults
Increased CRP is the primary marker for increased cardiovascular mortality on dialysis
CKD/ESRD patients have metastatic calcification (coronary arteries) because of secondary hyperparathyroidism and elevated PO4 levels.

10. Miettinen H et al, Stroke 27:2033, 1996
Microalbuminuria and proteinuria as a risk factor for CAD and CVA – marker of endovascular health
Miettinen H et al, Stroke 27:2033, 1996

11. Prevalence of HTN in CKD
80% of patients with glomerulonephritis and 30% of patients with chronic interstitial disease are hypertensive.

12. Hypertension and renal function% 90 80
normal 70
hypertension 60 50 40 30 20 10
stage 1
stage 2
stage 3
stage 4 1
0.9
0.8
0.7
0.6
Probability of HT
0.5
0.4
0.3
0.2
0.1
stage 1
stage 2
stage 3
stage 4

13. How important is systemic blood pressure control?
Relative risk of ESRD according to quintile BP
MRFIT study
N= 332,544 men

14. Hypertension in CKD
Pathophysiology thought to be both pressor- and volume-related, thus CKD patients respond to both vasodilators as well as diuretics/sodium restriction.
As kidney function declines closer to ESRD, volume-dependent hypertension becomes more important. Often on dialysis, we can remove antihypertensive agents as we bring the patient down to their dry weight with ultrafiltration.

15. Concept of Glomerular Hypertension
Normally, increased glomerular capillary pressure (PGC) is good, as it results in increased GFR.
Increased PGC is not good in a kidney that is already damaged = GLOMERULAR HYPERTENSION.
Increased PGC occurs with:
Increased systemic blood pressure
Increased efferent artery vasoconstriction (angiotensin II)
Increased afferent artery dilation (protein loads, calcium channel blockers)

16. A II Angiotensin II plays a central role in organ damage
Atherosclerosis*
Vasoconstriction
Vascular hypertrophy
Endothelial dysfunction
Stroke
Hypertension
A II
LV hypertrophy
Fibrosis
Remodeling
Apoptosis
Heart Failure MI
Death
GFR
Proteinuria
Aldosterone release
Glomerular sclerosis
Renal Failure
*Preclinical data.
LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate.

17. Non-ACE pathways (eg, chymase)
Renin Angiotensin Aldosterone System
Non-ACE pathways (eg, chymase)
Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activation
Angiotensinogen
AT1
Renin
Angiotensin I
Angiotensin II
ACE
Aldosterone
AT2
Cough, angioedema
Benefits?
Vasodilation
Antiproliferation (kinins)
Inactive fragments
 Bradykinin

18. Angiotensin II Effects on Glomerular Capillary Pressure
PGC AA EA
A II

19. Angiotensin II Causes Glomerular Hypertension
PGC AA EA
A II

20. How does blood pressure relate to progression of CKD?
PGC AA EA BP
In a sick kidney, increased glomerular capillary pressure (GLOMERULAR HYPERTENSION) causes progression of the CKD (increased fibrosis)

21. PGC  Injury to Glomerular cells  Proteinuria
Angiotensin II and CKD
Angiotensin II
PGC  Injury to Glomerular cells  Proteinuria
O2. and TGF- 
Scarring/Fibrosis

22. Angiotensin II
One of the most potent vasoconstrictors – critical in maintenance of blood pressure
Renal actions
Increased sodium reabsorption
Increased GFR by increasing glomerular capillary pressure

23. A II Blockade – Experimental data with diabetic rats at 70 weeks
ACE Inh/ARB  AII  BP  Proteinuria/Renal Disease
Anderson S et al, Kidney Int 36:526, 1989
Glomerular Pressure 40s

24. Goals of Treatment of HTN in CKD
To preserve renal function: maintain GFR and reduce proteinuria
To reduce CV morbidity and mortality
:most clinical trials in past have excluded patients with CKD

25. What should be the treatment goal?
Treatment goal for hypertension in the general population has remained relatively the same for the last decade.
Guidelines
BP target
British Hypertension Society (2004)
< 140/85
JNC VII (2003)
<140/90

26. (JNC 7, K/DOQI) <125/75 mmHg
Target Blood Pressure
For Individuals With:
BP Goal:
Hypertension (no diabetes or renal disease)
<140/90 mmHg
(JNC 7)
<130/80 mmHg
(ADA, JNC 7)
Diabetes Mellitus
Renal Disease
with proteinuria >1 gram/24 hours or diabetic kidney disease
<130/80 mmHg
(JNC 7, K/DOQI) <125/75 mmHg
(NKF)
Clinical trials have convincingly demonstrated that aggressive treatment of hypertension can reduce the risk of cardiovascular disease and associated morbidity and mortality. BP goals are set lower as renal impairment becomes increasingly more severe.
It is recommended in JNC 7 that hypertension be managed by achieving and maintaining SBP below 140 mmHg and DBP below 90 mmHg and lower if tolerated.1 For diabetes mellitus, the American Diabetes Association and JNC 7 recommends goals of <130 mmHg for SBP and <80 mmHg for DBP.2 For chronic kidney disease without proteinuria, the National Kidney Foundation recommends maintaining SBP below 135 mmHg and DBP below 85 mmHg. With proteinuria or diabetic kidney disease, their recommendation drops to <125 mmHg for SBP and <75 mmHg for DBP.3
1. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003;289:2560–2571.
2. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002;25:199–201.
3. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.
Chobanian AV et al. JAMA. 2003;289:2560–2571.
American Diabetes Association. Diabetes Care. 2002;25:134–147.
National Kidney Foundatrion. Am J Kid Dis. 2002;39(suppl 1):S1–S266.

27. What should be the treatment goal
for renal disease?
Should be lower than the general population
Should be tailored according to :
the severity of renal failure
the severity of the proteinuria

28. Klahr S et al, N Engl J Med 330:877, 1994
Aggressive BP Control, Proteinuria and CKD Progression – what is the optimal BP for CKD? * *
Klahr S et al, N Engl J Med 330:877, 1994
GOAL BP<125/75 if >1 gm proteinuria

29. Steps to Reduce Renal Disease
Steps every clinician should take to reduce the incidence and/or progression of CKD
Aggressive BP reduction
Use of agents that interfere with the RAAS
Hypertension not only plays an important role in the development and progression of renal damage, as seen in diabetes, but is a major risk factor for the increased cardiovascular morbidity and mortality seen in these patients.1
Inhibiting the RAAS plays an essential role in the treatment of hypertension and diabetes-related complications.1 For this reason, the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) acknowledges that hypertension with chronic kidney disease is a high-risk condition with a compelling indication for the use of an ACEI or an ARB.2  
1. Deferrari G, Ravera M, Deferrari L, Vettoretti S, Ratto E, Parodi D. Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers. J Am Soc Nephrol. 2002;13(suppl 3):S224–S229.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003;289:2560–2571.

30. BP control, GFR decline and proteinuria
Intense BP control
An initial reduction in proteinuria of 1.0 g/d  slower mean decrease in GFR
by 0.92 ± 0.31 mL/min·y, GFR 25-55
by 1.32 ± 0.46 mL/min·y, GFR 15-24

31. Progression of CKD and BP

32. REIN follow-up trial chronic nephropathy and proteinuria>3g/day45
Continued ramipril
Switched to ramipril
-0.44ml/min per month 2 40
-0.10ml/min per month
GFR decline (mL/min/1.73m /month) 35
-0.81ml/min per month 30
-0.14ml/min per month 25
Core study Follow-up trial
Ruggenenti et al. Lancet 1998;352:

33. AASK: ACEI vs CCB in Hypertensive Renal Disease
CCB arm terminated prematurely because ACEI and beta blocker demonstrated clear superiority
GFR Event, ESRD, or Death 25
P = 0.005 20 15
Amlodipine
Cumulative Incidence, % 10
Ramipril 5 3 12 24 36
Months
Agodoa LY et al. JAMA. 2001;285:2719–2728.

34. End-organ damage and mortality in general population
Cardiovascular mortality
Non-cardiovascular mortality
Adjusted effect of UAC on hazard function. Solid line shows estimated relation when logarithmic hazard is modeled as linear function of log(UAC). Dotted lines are 95% confidence limits for more general functional relation, as estimated by P-splines. Hatched area represents upper and lower limit of current definition of microalbuminuria (20 to 200 mg/L).
Hans L. Hillege, et al., Circulation, 2002, 106:1777

35. Lewis EJ et al , New Engl J Med 329:1456-62, 1993
The Effect of Angiotensin-Converting Enzyme Inhibition on Diabetic Nephropathy
409 Type I diabetics ages with nephropathy (U protein>500 mg and S Cr <2.5)
Prospective, double-blinded multicenter (30) trial randomized to captopril vs. placebo for 3 years
Lewis EJ et al , New Engl J Med 329: , 1993

36. ACE Inhibition and Type I DM Nephropathy
If S Cr > 1.5 mg/dl:
Captopril reduced doubling of S Cr by 48% over 4 years.
Captopril reduced ESRD(dialysis or transplant) or death by 50% over 4 years.
3) These effects were independent of effects on blood pressure.
Lewis EJ et al, New Engl J Med 329:1456, 1993

37. Brenner BM et al, New Engl J Med 345:861-869, 2001
Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan – RENAAL
1513 Type II diabetics with nephropathy
(U alb/Cr ratio >300 or U prot >500 mg and S Cr mg/dl)
Prospective, randomized, double-blinded multicenter (250) trial
Two arms – Losartan ( mg) to keep BP<140/90 vs. placebo for 3.4 years
Brenner BM et al, New Engl J Med 345: , 2001

38. RENAAL – ARB Reduction of Renal Failure
16%
25%
28%
20%
Brenner BM et al, N Eng J Med 345:861, 2001

39. Irbesarten Diabetic Nephropathy Trial (IDNT)
1715 Type II diabetics with hypertension (BP >135/85) and nephropathy (proteinuria >900 mg, S Cr mg/dl)
Prospective, randomized, double-blinded, multicenter (210) trial
Three arms: Irbesarten, amlodipine, and placebo
Lewis EJ et al, New Engl J Med 345:851, 2001

40. IDNT – ARB Reduction of Renal Failure
23%
20%
33%
Lewis EJ et al, N Eng J Med 345:851, 2001

41. ARB Effects of Type II DM Nephropathy - RENAAL and IDNT
Endpoints RENAAL IDNT
Composite 16% %
S Cr Doubling 25% %
ESRD 28% %

42. ACE Inhibitors and CKD Progression Meta-analysis -Jafar T, Ann Intern Med 135:73-87, 2001
11 randomized controlled trials comparing ACE inhibitors vs. other medications in treatment of hypertension in 1860 nondiabetic patients with CKD (S Cr=2.3).
Results: ACE Inhibitors lowered BP and proteinuria.
Results: ACE inhibitors decreased risk of ESRD by 31%, combined risk of progression of renal insufficiency and development of ESRD by 30% independent of BP lowering effects.

43. Proportion of Patients With First Event, %
LIFE: Primary Composite Endpoint 2 4 6 8 10 12 14 16
Intent-to-Treat
There was no significant difference in BP between groups at all time points
Atenolol
Losartan
Proportion of Patients With First Event, %
Adjusted Risk Reduction 13.0%, P = 0.021
Unadjusted Risk Reduction 14.6%, P = 0.009 6 12 18 24 30 36 42 48 54 60 66
Months
Dahlöf B et al. Lancet. 2002;359:995–1003.

44. Patients; non-diabetic patients affected by proteinuric renal disease
MAP > 98 mmHg
Treatment; telmisartan 80mg, once daily
Systolic BP change ± 11 to 122 ± 13 mmHg
Diastolic BP change ± 8.1 to 75.9 ± 8.5 mmHg
mean BP 101 ± 8 to 91 ± 9 mmHg
Proteinuria ± 0.90 to 1.06 ± 0.63 g/24 h
Cupisti A et al., Biomed Pharmacother, 2003, 57:169

45. What is the evidence that combining an ACEI and an ARB will have additive benefits?

46. COOPERATE: Study Design
Design: Randomized, double-blind trial in patients with non-diabetic renal disease
Primary Composite of time to doubling of sCr/ESRD
Endpoint:
Randomization: Losartan 100 mg/day + AHT* as needed
Trandolapril 3 mg/day + AHT* as needed
Duration: 3 yrs
Target BP: SBP <130 mmHg
DBP <80 mmHg
*Antihypertensive therapy (excluding other ACEIs or other ARBs).
Nakao N et al. Lancet. 2003;361:117–124.

47. Proportion Reaching Endpoint, %
Doubling of Serum Creatinine or Progression to ESRD 30
Trandolapril
Losartan
Combination 25 20
Proportion Reaching Endpoint, % 15 10 5
P = 0.02 5 12 18 24 30 36
Months after Randomization
Number at Risk
Losartan 89 88 84 79 65 59 47
Trandolapril 86 85 83 75 72 63 58
Combination 88 87 86 83 76 73 67
Nakao N et al. Lancet. 2003;361:117–124.

48. Additive antiproteinuric effect of ACEI and ARB in patients with IgA nephropathy
Russo, et al., Am J Kid Dis, 1999, 33

49. Hypertension and CKD: summary
Most patients with CKD have hypertension
Lowering BP (<130/80) important for reducing CV and renal risk: Lower targets for proteinuric patients
Angiotensin blockade slows progression of CKD independent from BP effects. ACEI/ARBs first line therapy
Diuretics/Na restriction often necessary
> 2 drugs are often needed
Blood pressure response as well as proteinuria should be monitored

50. Thank You