Hypertension and Chronic Kidney Disease

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Hypertension and Chronic Kidney Disease

• Paul S. Kellerman, M.D., FACP
• Associate Professor
• University of Wisconsin School of Medicine and
  Public Health

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Hypertension and CKD

• Definitions and epidemiology of CKD
• What do these patients die from?
• Prevalence of HTN with CKD
• HTN as a risk factor for progression of CKD
• Therapy of HTN with CKD and role of angiotensin
  blockade.

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Question 1 - What proportion of the adult
population has CKD?

• A. one in fifty
• B. one in twenty
• C. one in eight
• D. one in four

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Question 1 - What proportion of the adult
population has CKD?

• A. one in fifty
• B. one in twenty
• C. one in eight
• D. one in four

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Definition and Prevalence of CKD

• Definition of CKD
• Kidney damage (abnormalities in blood, urine or
  imaging studies)
• or
• eGFR lt 60 mL/min/m2
• for gt 3 months

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Stages of Chronic Kidney Disease
300,000
Stage V GFRlt15 mL/min/m2 DIALYSIS
NHANES 2004
700,000
Stage IV GFR 15-29 ml/min/m2
15.5 Million
Stage III GFR 30-59 ml/min/m2
6.5 Million
Stage II - pathology GFR 60-89 ml/min/m2
3.6 Million
Stage I pathology gt90 ml/min/m2
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Question 2 - The primary cause of death in
patients with CKD is

• A. Infections
• B. Cardiovascular disease
• C. Kidney failure
• D. Malignancies

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Question 2 - The primary cause of death in
patients with CKD is

• A. Infections
• B. Cardiovascular disease
• C. Kidney failure
• D. Malignancies

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MAJOR RISK FACTORS FOR CARDIOVASCULAR DISEASE
OBESITY DIABETES CHRONIC KIDNEY DISEASE PHYSICAL
INACTIVITY AGE gt 55 IN MEN, gt 65 IN WOMEN
HYPERTENSION HYPERLIPIDEMIA SMOKING FAMILY
HISTORY
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Why are CKD/ESRD Patients Predisposed to CV
Disease?
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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.

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Microalbuminuria and proteinuria as a risk factor
for CAD and CVA marker of endovascular health
Miettinen H et al, Stroke 272033, 1996
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Prevalence of HTN in CKD
80 of patients with glomerulonephritis and 30
of patients with chronic interstitial disease are
hypertensive.
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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.
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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)

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How does blood pressure relate to progression of
CKD?
PGC
AA
EA
In a sick kidney, increased glomerular capillary
pressure (GLOMERULAR HYPERTENSION) causes
progression of the CKD (increased fibrosis)
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Question 3 Goal BP when treating a patient
with CKD with proteinuria is

• A. lt 160/100
• B. lt 140/90
• C. lt 125/75
• D. lt 115/70

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Question 3 Goal BP when treating a patient
with CKD with proteinuria is

• A. lt 160/100
• B. lt 140/90
• C. lt 125/75
• D. lt 115/70

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Progression of CKD and BP
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Aggressive BP Control, Proteinuria and CKD
Progression what is the optimal BP for CKD?


Klahr S et al, N Engl J Med 330877, 1994
GOAL BPlt125/75 if gt1 gm proteinuria
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Question 4 Treatment goals when using
angiotensin II blockade (ACE-inh or ARBs) in
patients with CKD include

• A. BP lt 125/75
• B. Reduction of proteinuria by 60
• C. Frequent daily dosing to enhance effect.
• D. A and B
• E. A and C

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Question 4 Treatment goals when using
angiotensin II blockade (ACE-inh or ARBs) in
patients with CKD include

• A. BP lt 125/75
• B. Reduction of proteinuria by 60
• C. Frequent daily dosing to enhance effect.
• D. A and B
• E. A and C

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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

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Angiotensin II Effects on Glomerular Capillary
Pressure
PGC
AA
EA
A II
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Angiotensin II Causes Glomerular Hypertension
PGC
AA
EA
A II
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Angiotensin II and CKD
Angiotensin II
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A II Blockade Experimental datawith diabetic
rats at 70 weeks
ACE Inh/ARB ? AII ? BP ?
Proteinuria/Renal Disease
Anderson S et al, Kidney Int 36526, 1989
Glomerular Pressure 40s 64 46 56
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The Effect of Angiotensin-Converting Enzyme
Inhibition on Diabetic Nephropathy

• 409 Type I diabetics ages 18-49 with nephropathy
  (U proteingt500 mg and S Cr lt2.5)
• Prospective, double-blinded multicenter (30)
  trial randomized to captopril vs. placebo for 3
  years

Lewis EJ et al , New Engl J Med 3291456-62, 1993
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ACE Inhibition and Type I DM Nephropathy
3) These effects were

independent of effects on
blood pressure.
Lewis EJ et al, New Engl J Med 3291456, 1993
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Reduction of Endpoints in NIDDM with the
Angiotensin II Antagonist Losartan RENAAL

• 1513 Type II diabetics with nephropathy
• (U alb/Cr ratio gt300 or U prot gt500 mg and S
  Cr 1.3-3.0 mg/dl)
• Prospective, randomized, double-blinded
  multicenter (250) trial
• Two arms Losartan (50-100 mg) to keep BPlt140/90
  vs. placebo for 3.4 years

Brenner BM et al, New Engl J Med 345861-869, 2001
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RENAAL ARB Reduction of Renal Failure
16
25
28
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Brenner BM et al, N Eng J Med 345861, 2001
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Irbesarten Diabetic Nephropathy Trial (IDNT)

• 1715 Type II diabetics with hypertension (BP
  gt135/85) and nephropathy (proteinuria gt900 mg, S
  Cr 1.0-3.0 mg/dl)
• Prospective, randomized, double-blinded,
  multicenter (210) trial
• Three arms Irbesarten, amlodipine, and placebo

Lewis EJ et al, New Engl J Med 345851, 2001
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IDNT ARB Reduction of Renal Failure
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20
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Lewis EJ et al, N Eng J Med 345851, 2001
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ARB Effects of Type II DM Nephropathy - RENAAL
and IDNT
Endpoints RENAAL IDNT
Composite 16 20
S Cr Doubling 25 33
ESRD 28 23
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ACE Inhibitors and CKD ProgressionMeta-analysis
-Jafar T, Ann Intern Med 13573-87, 2001

• 11 randomized controlled trials comparing ACE
  inhibitors vs. other medications in treatment of
  hypertension in 1860 nondiabetic patients with
  CKD (S Cr2.3).
• 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.

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Question 5 ACE inhibitors/ARBs should be
stopped when

• Serum creatinine has risen by 20 as an
  outpatient.
• Potassium is more than 5.4 mg/dL
• In the face of acute kidney injury in the
  hospital.
• D. A and B
• E. A and C

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Question 5 ACE inhibitors/ARBs should be
stopped when

• Serum creatinine has risen by 20 as an
  outpatient.
• Potassium is more than 5.4 mg/dL
• In the face of acute kidney injury in the
  hospital.
• A and B
• A and C

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Take Home Points

• CKD is very common patients have endothelial
  dysfunction, and die from cardiovascular disease.
• Hypertension occurs in a large proportion of CKD
  patients.
• Hypertension causes progression of CKD, and
  reduction in BP to lt 125/75 slows progression
  optimally.
• Angiotensin blockade slows progression of CKD
  independent from BP effects. Moderate
  hyperkalemia or mild increases in creatinine
  should not stop use of the medications.

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