1. Department of Medicine
고혈압
General view and
Focus on CKD
Department of Medicine
임 천 규

2. 증례  55세 남자 혈압 170/100 mmHg 단백뇨 1일 2g 혈청 크레아티닌 2.5 mg/dL
양측 신장 길이 8.8cm 
치 료: 이뇨제, ARB, CCB,
베타차단제, Statin, Aspirin
1년 후: 혈압 125/75 mmHg
혈청 크레아티닌 2.2 mg/dL
단백뇨 1일 0.6g
신장 질환 환자들은 이 환자에서처럼
신기능 저하시 혈압 조절이 완강하여 두 세가지 이상의 혈압 약제를 투여해야하며
병태생리를 모두 target으로 하는 multifactorial 치료가 필요하다.

3. 신질환 - 고혈압 본태성 고혈압 - 고혈압성 신경화증 당뇨병성 신증 만성 사구체신염 신혈관성 고혈압 다낭신
IgA nephropathy
Hypertension 19-53%
Malignant hypertension 7-15%

4. Primary renal mechanisms of hypertension
Renal ischemia Vasoconstriction due to afferent arteriolar disease Oxidative stress & inflammation
Reduction in GFR Reduction in filtered sodium load
Tubule transport mechanisms Stimulation of Na reabsorption in the collecting duct

5. GFR 감소에 따른 고혈압 유병률
MDRD 연구

6. 수축기 혈압과 말기 신질환 발생 위험 MRFIT 연구: n=332,544
P<.001
P<.001
A further analysis of MRFIT screenees examined the relation of systolic BP to the risk of ESRD during an average 16 years of follow-up. Excluded from the original 361,662 men screened were 3 men already being treated for ESRD at the time of entry in the study and 29,115 for whom information about systolic BP or income was not available; the analysis included 332,544 men. The definition of ESRD included treated cases of ESRD from the Health Care Financing Administration National Registry and deaths from ESRD. The risk of ESRD was analyzed in relation to quintiles of systolic BP and diastolic BP.11
As shown here, the adjusted relative risk (RR) of ESRD was not significantly increased in the next-to-lowest quintile of systolic BP compared with the lowest quintile, but the risk of ESRD was significantly increased for the third, fourth, and highest quintiles. The RR was adjusted for age, race, serum cholesterol concentration, number of cigarettes smoked per day, use of medications for diabetes mellitus, and previous myocardial infarction (MI). For example, those in the highest systolic BP quintile (>140 mm Hg) had 5 times the RR of developing ESRD compared with those in the lowest systolic BP quintile (<117 mm Hg).11
When systolic and diastolic BP were considered together in the same proportional hazards model with adjustment for the other variables, a baseline systolic BP higher by 1 standard deviation had more predictive power than a similar increase in diastolic BP.11
P =.009
Adjusted Relative Risk
Systolic BP (mm Hg)
Klag MJ et al. N Engl J Med. 1996;334:13-18.
11. Klag MJ, Whelton PK, Randall BL, et al. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996;334:13-18.
SLIDE 6

7. 단백뇨: 제 2형 당뇨병 뇌졸중과 관상동맥 심질환의 발병과 사망을 예측
A: U-Prot <150 mg/L
B: U-Prot 150–300 mg/L
C: U-Prot >300 mg/L 40 1
p<0.001
0.9 A 30
Survival curves for CV mortality
0.8 B
Incidence (%) 20
0.7
0.6 C 10
Overall: p<0.001
0.5
Slide 73.
Proteinuria Predicts Stroke and CHD Events in Type 2 Diabetes
핀란드에서 제2형 당뇨병 환자 1,056명을 대상으로 7년간 추적조사한 결과 임상적인 단백뇨는 고혈압과 다른 심혈관계 위험인자를 조절한 후에 있어서도 뇌졸중이나 기타 동맥경화성 혈관 질환에 대한 사망률과 유병률을 예측하는 인자임이 밝혀졌다. 치료전 아침 점적뇨를 기준으로 요중 단백질의 농도를 크게 3가지로 분류하였다 : 무 단백뇨(<150mg/L), 경계역 단백뇨(150–300mg/L), 임상적 단백뇨(>300mg/L). 모든 원인으로 인한 사망률과 심혈관계 질환으로 인한 사망률은 모두 단백뇨가 없는 환자에 비해 임상적 단백뇨가 있는 환자에서 훨씬 더 높았다. 뇌졸중이나 관상동맥질환의 위험률은 단백뇨의 정도와 비례했다 (p<0.001 for trend) [Miettinen et al, 1996].
따라서 미소알부민뇨증과 임상적 단백뇨는 고혈압과 다른 심혈관계 위험인자를 조절한 후에 있어서도 심혈관계 질환의 유병률과 사망률의 주요 예측인자이다 [Wang et al, 1996; Miettinen et al, 1996; Dinneen et al, 1997].
Stroke
CHD events 10 20 30 40 50 60 70 80 90
Months
Miettinen H et al. Stroke. 1996;27:

8. Predictor of CV Outcomes and the Impact of Ramipril
신기능 저하 [HOPE 연구]
Predictor of CV Outcomes and the Impact of Ramipril
Mann JF, Ann Intern Med. 2001,134:629

9. 철저한 혈압 조절

10. 적극적 혈압 강하의 신 보호 효과 [MDRD 연구]
125/75 mmHg
vs 140/85 mmHg
3년간 GFR 감소 완만
단백뇨 심할수록 효과적
Peterson JC, Ann Intern Med 1995;123:754

11. Tight control of systolic BP (Cardio-Sis 연구)
Non-diabetic patients  55 yrs
Systolic BP  150 mm Hg with antihypertensive Tx
Additional risk factor
BP at 2-year visit
135.6/78.7 mm Hg in the usual-control group
131.9/77.4 mm Hg in the tight-control group
Additional risk factor, as described in the guidelines of
the European Society of Hypertension3 (cigarette
smoking, total cholesterol ≥5・2 mmol/L, HDL cholesterol
<1・0 mmol/L, LDL cholesterol ≥3・4 mmol/L, family
history of premature cardiovascular disease in fi rst
degree relative [<65 years in women and <55 years in
men], previous transient ischaemic attack or stroke, or
established coronary or peripheral arterial disease).
Lancet 2009; 374: 525–33

12. General principles-1 Drug dosing Drug frequency Younger vs Elderly
Low doses with few side effects
Drug frequency
Giving one-half the dose twice a day
Non-dipper  
Younger vs Elderly
Volume vs Renin
a greater daily BP load and early morning abrupt elevations in BP can increase cardiovascular risk.

13. 철저한 혈압 조절 고혈압 약제의 선택 Beyond BP control
이처럼 철저한 혈압 조절이 신질환 및 심혈관계 합병증 예방에 가장 중요하며 그 다음으로 선택약제에 따른 효과의 차이가 있을 수 있다.
고혈압 약제의 선택
Beyond BP control

14. ACE inhibitor & ARB Spironolactone Aliskiren
Cardiovascular - 심부전, LV dysfunction
- 심근경색증
- 동맥경화증
- 내피 이상
신보호효과: Proteinuric chronic kidney disease
Spironolactone
Aliskiren
ACEI나 ARB제제는 사구체 압력을 감소시키고 사구체 장벽 기능 이상을 개선시켜 단백뇨가 감소되고, 항염작용과 함께 신경화증을 억제시킨다.
사구체압력 감소
단백뇨 감소
항염증 작용
항산화 작용
신경화증 예방

15. Diuretics Volume control in HF or chronic kidney disease
Nephrotic syndrome: loop diuretic
Aldosterone antagonist:
Advanced HF
Prevention or treatment of hypokalemia
  Chlorthalidone (ALLHAT 연구) vs
Hydrochlorothiazide: less potent and shorter acting
Shortcomings: Metabolic complications
hypokalemia, glucose intolerance, hyperuricemia

16. CCB Cardiovascular 탁월한 수축기 혈압 조절 뇌졸중 협심증 동맥경화증
Atrial fibrillation (non-DHP CCB)
Obstructive airways disease
신보호효과
ACEI나 ARB제제는 사구체 압력을 감소시키고 사구체 장벽 기능 이상을 개선시켜 단백뇨가 감소되고, 항염작용과 함께 신경화증을 억제시킨다.
사구체 Afferent arteriole의 혈관 확장
Efferent arteriole의 확장: T-CCB, N-CCB
허혈성 신손상 (Ang II, ET-1)의 혈관수축 회복
보상성 신비대 감소

17. Beta blocker Indications Angina Prior myocardial infarction
Stable patients with heart failure
Asymptomatic left ventricular dysfunction
Atrial fibrillation
Shortcomings
Should NOT be used for initial antihypertensive therapy, particularly in patients over age 60.
Associated with impaired glucose tolerance and an increased risk of new onset diabetes

18. Indications for antihypertensive drugs
Compelling indication (major improvement in outcome independent of BP)
Systolic heart failure
ACE inhibitor, ARB, b blocker, Diuretic,
Aldo antagonist
Proteinuric chronic kidney dis.
ACE inhibitor / ARB
DM (no proteinuria)
Diuretic, ACE inhibitor
Angina pectoris
b blocker, CCB
Post-myocardial infarction
ACEi, b blocker, Aldo antagonist
High coronary disease risk
Diuretic, ? ACE inhibitor (HOPE)
Atrial fibrillation
b blocker, Nondihydropyridine CCB

19. Contraindications for antihypertensive drugs
Angioedema
ACE inhibitor
Bronchospastic disease
b blocker
Depression
Reserpine
Liver disease
Methyldopa
Pregnancy
ACE inhibitor, ARB
2nd or 3rd degree heart block
b blocker, non-DHP CCB
* May have adverse effect on comorbid conditions
Depression
b blocker, central alpha agonist
Gout
Diuretic
Hyperkalemia
Aldo antagonist, ACE inhibitor, ARB
Hyponatremia
Thiazide diuretic
Renovascular disease
ACE inhibitor or ARB

20. Ramipril Efficacy in Nephropathy
REIN 연구
대상: 비당뇨 만성 단백뇨성 신질환

21. Valsartan in IgA nephropathy [Hong Kong study]
Double-Blind, Randomized; 109명, 2년
Proteinuria > 1 g/d & SCr < 2.8 mg/dL or SCr mg/dL
BP: Valsartan 9210 mmHg
Placebo 100 9 mmHg
(P < 0.001)
Proteinuria reduction
Valsartan -33% vs Placebo (-)
GFR decrease
Valsartan 5.6  6.7 mL/min/y
Placebo 6.9  6.1mL/min/y
Time to 2x SCr level or
the development of ESRD
Valsartan decreases proteinuria and slows renal deterioration in patients with IgAN.
Li PK et al, Am J Kidney Dis 47:751, 2006

22. Renal and Retinal Effects of Enalapril and Losartan in Type 1 Diabetes
Anti-
Renal and Retinal Effects of Enalapril
and Losartan in Type 1 Diabetes
285 normotensive patients with type 1 DM and normoalbuminuria
Early blockade of RAS in patients with type 1 diabetes did not slow
nephropathy progression but slowed the progression of retinopathy
Mauer M, N Engl J Med 2009;361:40-51

23. Progression to death, dialysis or transplant
제1형 당뇨병-신증 ACE억제제의 효과 40
Captopril
Placebo 30
Progression to death, dialysis or transplant
(%) 20 * 10
Slide 82.
Effect of ACE Inhibition on Diabetic Nephropathy in Patients With Type 1 Diabetes
제1형 당뇨병, 당뇨병성 신증, 단백뇨 500mg/d 이상 및 혈중 크레아티닌치가 2.5mg/dL 이하인 환자 409명을 대상으로 ACE 저해제 captopril과 placebo를 비교하기 위해 무작위 대조시험이 실시되었다. 추적기간의 중앙값은 3년이었다. 1차 종말점은 치료전 혈중 크레아티닌치가 2배가 되는 것으로 하였다. Captopril은 당뇨병성 신증의 진행을 지연시키고, 혈중 크레아티닌이 2배가 되는 위험성도 48% 감소시켰다(p=0.007). 또한 captopril은 사망, 투석 및 이식 필요성과 같은 복합적인 종말점의 위험성을 50% 감소시켰다. Captopril은 혈압만을 감소시켰을 때 예측했던 것보다 더 큰 정도로 제1형 당뇨병성 신증에서의 신기능 악화를 예방했다 [Lewis et al, 1993]. 1 2 3 4
Follow-up (y)
Collaborative Study Group
*p=0.006 vs placebo.
Lewis EJ et al. N Engl J Med. 1993;329:

24. 제2형 당뇨병–신증: ARB 효과 Microalbuminuria  Proteinuria
Irbesartan in Microalbuminuria Trial
Microalbuminuria reduction with valsartan
IRMA-2
MARVAL
(%)
IRMA-2

25. 제2형 당뇨병–신증: ARB 효과 Clinical Proteinuria
Reduction of Endpoints in NIDDM with AII
Antagonist Losartan
Irbesartan Diabetic Nephropathy Trial
* 제 2형 당뇨병성 신증의 진행 예방
23-37% 감소
심부전에 의한 입원 감소
심혈관계 사망률 감소 효과 없음
RENAAL
IDNT

26. No. of antihypertensive agents
목표혈압 달성을 위한 치료 약물 수
Bakris GL et al. Am J Kidney Dis. 2000;36:
Lewis EJ et al. N Engl J Med. 2001;345:
No. of antihypertensive agents
Trial
Target BP (mm Hg) 1 2 3 4
UKPDS DBP <85
ABCD DBP <75
MDRD MAP <92
HOT DBP <80
목표혈압에 도달하기 위해서 여러 고혈압 약제가 필요하다는 것을 입증하는 6가지 study를 보시겠습니다.
이 6가지 study는 double-blind, placebo-controlled study로 목표혈압에 도달하기 위해서는 2가지 이상의 약제가 사용되었음을 보여주고 있습니다.
예를 들어 HOT study에서는 68%가 한가지 이상의 약제를 복용했고 41%가 felodipine과 ACEI를 복용했고 28%는 felodipine과 beta-blocker를 복용했습니다.
그리고 UKPDS (United Kingdom Prospective Diabetes Study)에서는 대상자의 29%가 150/85 이하의 혈압에 도달하기 위해 3개 혹은 그 이상의 약물을 복용했습니다.
이 6가지 study에 의하면 target BP에 도달하기 위해 2가지 이상, 최대 4가지의 약제가 사용되었음을 알 수 있습니다.
UKPDS (United Kingdom Prospective Diabetes Study)
ABCD (Appropriate Blood Pressure Control in Diabetes)
MDRD(Modification of Diet in Renal Disease)
HOT (Hypertension Optima Treatment)
AASK ( African American Study of Kidney Disease)
IDNT (Irbesartan Diabetic Nephropathy Trial )
AASK MAP <92
IDNT SBP <135/DBP <85
DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.

27. General principles-2 First-line combination therapy
BP > 20/10 mmHg above goal (JNC 7)
Combination of a long-acting ACE inhibitor/ARB plus a long-acting DHP-CCB
(ACCOMPLISH trial)

28. 최상의 장기보호 효과 ACE 억제제 / ARB + 이뇨제 ACE 억제제 / ARB + CCB High-dose ARB
ACE 억제제 / ARB + Spironolactone
ACE 억제제/ARB + Aliskiren
2007 ESH-ESC
신질환 환자에서 병합요법으로 JNC-7의 경우 ACEI / ARB + 이뇨제를 추천하지만 이것만으로는 부족해서 ACEI / ARB에 CCB를 추가하여 보다 철저한 혈압을 조절해야 하는 경우가 많습니다. 또 최근에는 신장분야에서는 aldosterone receptor blocker가 의미있는 약제라는 주장이 나오고 있어 향후 연구가 더 필요할 것으로 생각됩니다
Aldosterone breakthrough

29. ACE inhibitor and CCB [ACCOMPLISH Study]
Hypertension, ≥ 55 years
Evidence of cardiovascular, renal disease or target organ damage
20% Risk Reduction
CV morbidity / mortality
p =
Single tablet combination therapy was initiated in 11,462 high risk hypertensive patients
After mean follow-up of 39 months,
The combination of ACEI / CCB was superior to ACEI / diuretic
CV morbidity / mortality was reduced by 20% (p=0.0002)
Hard CV Endpoint (CV death, stroke and MI) was reduced by 20% (p=0.007)
Prior to study entry, 97% of patients were on antihypertensive medication, 74% receiving > 2 therapies
After mean follow up of 30 months,
Overall BP control rates increased from 37% to 80%
Mean SBP decreased from 145 to <130 mmHg
50% of participants required only one tablet
N Engl J Med 2008;359:
* proteinuria?

30. ACEi / ARB와 CCB의 병용 요법 ACEi / ARB: AngII 생산 또는 수용체 차단 SNS reflex 억제
부종 조절 (정맥확장)
CCB: AngII에 의한 신동맥의 수축 억제
(postreceptor antagonist)
RAA axis와 SNS 활성화
부종 (동맥확장)
CCB
ACEi
/ARB
CCB + ACEi /ARB:
RAS 차단제의 신보호효과를 감소시키지 않고
혈압을 더 강하시킨다.
(REIN, Nephros, RENAAL 연구)

31. Albuminuria response to very high-dose valsartan in type 2 DM
391 patients with type 2 DM, hypertension, and albuminuria for 30 week
High doses of valsartan reduced albuminuria more than 160mg dose, independent of BP.
Hollenberg NK, Journal of Hypertension 2007, 25:1921–1926

32. Antiproteinuric Response to Dual Blockade of RAS
in Primary Glomerulonephritis: Meta-analysis
The antiproteinuric response to ACE-inhibitor plus ARB therapy versus either monotherapy
is consistently greater and strictly related to baseline proteinuria, associated with only moderate
increase in serum potassium levels
Catapano F, Am J Kidney Dis 52: , 2008

33. ONTARGET 연구 No advanced CKD Anti-
대상: 25,620 patients aged 55 years or older with
atherosclerotic vascular disease or DM with end-organ damage
Death from CV causes, myocardial infarction, stroke, or hospitalization for heart failure: similar
No advanced CKD
a value between 3・4 mg/mmol
and below 33・9 mg/mmol was defined as microalbuminuria.
A value of 33・9 mg/mmol or more (roughly
300 mg/g creatinine) was defi ned as macroalbuminuria.
This trial does not answer the question about
progression of chronic kidney disease in patients with
advanced nephro pathy, because few patients with
advanced nephro pathy were included. Moreover, the
interpretation that the group receiving a combination
regimen (ramipril and telmisartan) to block the reninangiotensin
system group had more renal events is
troubling. Loss of estimated glomerular fi ltration rate in
the combination group was 6 mL/min for 56 months,
a decline of 1・29 mL min–1 year–1 (the normal range6,7
is between 0・6 and 1・1 mL min–1 year–1). Thus, while
slightly above the normal range, this would not be
considered a major loss of kidney function
Patients without proteinuria, dual RAS blockade no benefits
Dialysis, doubling of serum creatinine,
And death
Lancet 2008; 372: 547– N Engl J Med 2008;358:

34. Addition of ARB or Mineralocorticoid Antagonism
To Maximal ACE Inhibition in Diabetic Nephropathy
Serum
potassium level was significantly higher with the addition of either spironolactone or losartan. In
conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE
inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP.
UACR % change:
Spironolactone vs placebo 34.0% P=0.007
Losartan vs placebo 16.8% P=0.2
Mehdi UF, JASN 20: 2641–2650, 2009

35. Aliskiren Combined with Losartan
in Type 2 DM and Nephropathy: AVOID study
Placebo
Aliskiren
The baseline characteristics of the two groups were similar. Treatment with 300 mg
of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-tocreatinine
ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction
of 50% or more in 24.7% of the patients who received aliskiren as compared with
12.5% of those who received placebo (P<0.001). A small difference in blood pressure
was seen between the treatment groups by the end of the study period (systolic,
2 mm Hg lower [P = 0.07] and diastolic, 1 mm Hg lower [P = 0.08] in the aliskiren
group). The total numbers of adverse and serious adverse events were similar in the
groups.
Conclusions
Aliskiren may have renoprotective effects that are independent of its bloodpressure−
lowering effect in patients with hypertension, type 2 diabetes, and nephropathy
who are receiving the recommended renoprotective treatment
Parving HH, N Engl J Med 2008;358:

36. Unlike ACEIs and ARBs, DRIs reduces Ang I, Ang II and PRA
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
PRA
ACE
Non ACE pathways
Feedback Loop
ACEIs
Ang II
ARBs
Blockade of the Renin System (RS) at any point leads to a compensatory increase in renin release. Angiotensin converting enzyme (ACE) inhibitors or ACEIs and aliskiren cause angiotensin II (Ang II) levels to drop and angiotensin receptor blockers (ARBs) block the action of Ang II on type 1 Ang II (AT1) receptors – both these effects reduce the level of stimulation of AT1 receptors on juxtaglomerular cells in the kidney, leading to increased renin release.
Aliskiren is unique in counteracting the resultant increase in circulating renin concentration by inhibiting its action as an enzyme, i.e. reducing plasma renin activity (PRA). Other classes of drugs acting on the RS, ACEIs and ARBs, are associated with elevation of PRA in parallel with increased renin release. As PRA reflects the capacity of circulating renin to cleave angiotensinogen and form angiotensin I (Ang I), levels of Ang I also increase in the presence of these agents.
ACEIs reduce subsequent conversion of Ang I to Ang II, leading to an overall reduction in Ang II levels, although some Ang II generation continues, mediated by non-ACE pathways, for which substrate (Ang I) is increased. With ARBs, elevated Ang I leads to increased Ang II production. The whole RS is therefore upregulated, although AT1 receptor-mediated effects of the effector molecule Ang II are blocked.
As aliskiren reduces PRA, generation of Ang I decreases. Less substrate is therefore available for conversion to Ang II by ACE or other enzymes. Direct renin inhibition therefore produces effective overall RS suppression.
Abbreviations
Ang I = angiotensin I
Ang II = angiotensin II
ACE = angiotensin converting enzyme
ACEI = angiotensin converting enzyme inhibitor
ARB = angiotensin receptor blocker
AT1 = type 1 angiotensin II receptor
PRA = plasma renin activity
RS = Renin System
Reference
Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens 2006;24(2):
Müller DN, Luft FC. Direct renin inhibition with aliskiren in hypertension and target organ damage. Clin J Am Soc Nephrol 2006;1:221–8.
AT1 Receptor
Ang I
Ang II
Renin
PRA ↑ ↓ ↑ ↑
ACEI ↑ ↑ ↑ ↑
ARB
Aliskiren ↓ ↓ ↑ ↓
Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006

37. Hypertension in dialysis patients
Pathogenesis
Volume and sodium overload 
Increased RAAS
Increased sympathetic activity 
Altered endothelial cell function 
Erythropoietin administration
Treatment
Self-measured BP at home
Attainment of BP targets vs cardiomyopathy
Salt restriction & Stable dry weight
Prolonged and/or more frequent hemodialysis 
Reduced dialysate sodium concentration
Cardioprotective anti-HT medications 
RAAS inhibitors, CCB, b-blockers
Sodium restriction + drugs

38. Take Home Message  Remission Clinic 치료의 목적: 신장 질환 진행 예방 심혈관계 합병증의 예방
치료의 목적: 신장 질환 진행 예방
심혈관계 합병증의 예방
미국신장학회와 신장재단, JNC VII, ESH
철저한 혈압조절: 130/80 (125/75) mmHg
+ 일차 선택약: ACE 억제제 /ARB 권고
병용요법: >160/100, target organ damage
Conclusions
Hypertension and the Cardio-Renal Cascade: Importance of Goal BP Reduction
In summary, hypertension exacts a high toll in the form of debilitating target-organ manifestations, including a cardio-renal cascade of dysfunction. Groups with a higher prevalence of hypertension, including older individuals, African Americans, and patients with diabetes, also have a higher risk of poor cardiac and renal outcomes.
The JNC VI guidelines emphasize that achieving goal BP is critical for cardio-renal health—to preserve renal function, including GFR, and to reduce risk of poor CVD outcomes.
 Remission Clinic