Aldosterone and MR Activation Revisited - PowerPoint PPT Presentation


Title: Aldosterone and MR Activation Revisited


1
Aldosterone and MR Activation Revisited
  • Philip J. Klemmer, MD
  • UNC Kidney Center
  • Chapel Hill NC USA

2
Case 1
  • A 39 y.o. white female with a 20-yr history of
    neuromuscular symptoms, orthostatic syncope, salt
    craving, and nocturia. No GI symptoms.BP 96
    / 62
  • Serum 138 96 Cr 0.8 Aldo 39
  • 2.7 28 Mg 1.2 PRA
    19


3
Case 1
  • Spot urinalysis Na 77, Cl 81, K 59, Ca
    1.4, Mg 1.2 (FE mg 13)
  • EKG revealed U waves
  • Diuretic screen negative
  • Family history significant for 2/3 siblings with
    hypokalemia and similar symptoms. Parents
    normal.
  • Physical exam normal

4
Gitelmans Syndrome
5
Case 2
  • 37 yo white male with refractory hypertension
    (185/102 mm Hg) on 4 medications
  • Labs Cr 1.1, K 3.7-4.1
  • Aldo 20.5 ARR 200
  • PRA .1
  • 2 D Echo- 4 LVH No retinopathy


6
Case 2
  • FST Aldo
  • Baseline 20.5
  • Day 4 6.1
  • CT revealed normal adrenals hybrid gene (FH-1)
    negative
  • AVS Aldo
  • Right 83
  • Left 2190

7
Primary Aldosteronism (APA)
8
Aldosterone-Producing Adenoma Missed by
Computer-Aided Tomography
Stowasser, M and Gordon RD. Trends Endocrinol
Metab 200314(7) 310-317
9
Increased rate of CV events in PA patients
Milliez 2005 J Am Coll Card
10
When to Consider for Primary Aldosteronism
Young WF Jr. Endocrinology 2003 144(6)2208-2213
11
Range of Supine PAC and 18-OH-B in APA and BAH
Phillips J.L. et al. J Clin Endo Metab 2000
85(12)4526-4533
12
Prevalence of Unrecognized PA in Patients with
Hypertension
Young WF Jr. Endocrinology 2003 144(6)2208-2213
13
Primary Aldosteronism Management
14
Case 3
  • 40 yo asymptomatic outdoorsman
  • Physical exam weight 52 kg, BP 95/61 mm Hg
  • Lytes normal Cr - .7
  • 24-hour urine Na 1.3 mEq, K 200
  • Labs Aldo 74
  • PRA 13

15
Yanomami
Culture Chapter 3 Sociology, Schaefer, 2003 and
2003.
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
Carvalho J et al. Hypertension 1989 14238-246
20
Br Med J 1988 297319-328
21
NHANES II 1982
22
(No Transcript)
23
(No Transcript)
24
Angiotensin ll Dependent Normotension
  • BP 95/61
  • Aldo 74 ng / ml
  • PRA 13

25
Brazil Viper(Bothrops jararaca)
26
Aldosterone Issues
  • Sodium Cofactor
  • Aldosterone Escape
  • Non- Epithelial effects
  • What activates the MR ?
  • Why was Aldo upstaged by the RAS?

27
Aldosterone X High Salt Effects
  • HBP PA , EH
  • Renal fibrosis, proteinuria
  • CV CHF, cardiac fibrosis

28
Sodium Cofactor
  • High aldo / low salt
  • Normal physiologic response to
  • Low dietary sodium
  • Renal salt wasting
  • High aldo / high salt
  • High blood pressure
  • Heart fibrosis / inflammation
  • Kidney proteinuria / fibrosis

29
Aldosterone and Serum Cofactor
  • PA

Normals
Aldosterone
Aldo PRA Suggests PA
ARR
gt 20
PRA
30
Aldosterone and Serum Cofactor
Normals
31
Aldosterone and Serum Cofactor
Normals
32
Aldosterone and Serum Cofactor
Normals
33
Aldosterone and Serum Cofactor
Normals
34
Aldosterone and Serum Cofactor
PA, fibrosis
Normals
35
Aldosterone and the Sodium Cofactor
  • No HBP or vascular damage in high aldosterone
    states associated with low dietary sodium or
    renal sodium wasting
  • Myocardial, vascular, and renal fibrosis in
    animals treated with DOCA require high sodium
    intake for effect
  • MR activation may occur in the absence of
    elevated serum aldosterone levels

36
Key Question
  • How does high sodium cofactor convert the effect
    of aldosterone ( MR receptor activation) from
    physiological to pathological?

37
Physiologic and pathophysiologic effects of
aldosterone on the kidney and heart in relation
to dietary salt
Dluhy RG et al. N Engl J Med 2004 3518-10
38
Aldosterone Escape
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
Counterregulatory Stimulation
43
Aldosterone Escape
  • CHF treated with ACE-I for 36 months (Pitt 95)
  • HBP (Linjen 82)
  • DM nephropathy (Sato 03)
  • Exercise (Huang 93)

44
Aldosterone Escape
  • Occurs in 40 of patients with diabetic
    nephropathy who are treated with ACEIs ( Sato,
    Hypertension , 03)
  • A secondary increase in proteinuria parallels the
    escape and responds to spironolactone ( no
    change in BP)

45
Classical Epithelial Effects of Aldosterone
46
Cross-section of a distal tubule
McMurray JJV et al. N Engl J Med 2004
351(6)526-528
47
Classic Genomic Action of Aldosterone on
Epithelial Tissue
Connell JMC et al. J Endocrinol 2005 1861-20
48
Non Epithelial Effects of Aldosterone Fibrosis
49
Nonepithelial Effects of Aldosterone
  • Selye 1947 general adaptation theory
  • Webber, Pitt 1993 CV remodeling/vasculitis
    caused by aldosterone in face of RAAS suppression
  • Hostetter 1995 ditto for kidney (REM)
  • Rocha 1998 ditto for brain (SHR, REM)
  • Napoli 1999 end organ effects PA gt EH
  • MR antagonists (spironolactone, eplerenone)
    prevent / reduce tissue effects
  • Rales 1999

50
Non-Epithelial Effects of Aldosterone Excess
Rocha R, Funder JW. Ann NY Acad Sci 2002
97089-100
51
Aldosterone-Mediated Vascular Injury
Joffe HV et al. Heart Fail Rev 2005 1031-37
52
L-NAME AII High Salt
Joffe HV et al. Heart Fail Rev 2005 1031-37
53
L-NAME AII High Salt Adrenalectomy
Joffe HV et al. Heart Fail Rev 2005 1031-37
54
(No Transcript)
55
Epstein M. Nephrol Dial Transplant 2003
1819884-1992
56
Aldosterone and the Heart
57
(No Transcript)
58
Williams JS et al. 2005 Clin Endocrin Metab
882364-2372
59
Aldosterone and the Kidney
60
Non-Hemodynamic Non- Epithelial Renal Effects of
Aldosterone
  • Increase in type IV collagen production in
    cultured mesangial cells
  • MR receptors Glomeruli (mesangia and podocytes
    )
  • Renal vasculature

61
Aldosterone and the Development and Progression
of Renal Injury
  • 1946 Selye DOCA/salt rats malignant
    hypertension
  • 1964 Conn 145 PA cases, 85 had proteinuria
  • 1992 Walser Adrenalectomy improved renal
    histology in rats (REM)
  • 1993 Webber Aldo in REM causes cardiac fibrosis
  • 1996 Hostetter Renal fibrosis (REM)
    independently associated with aldosterone

62
Aldosterone and the Development and Progression
of Renal Injury
  • 1999 Rocha Malignant hypertension histology in
    SHR improved with ACE-I but effect lost if
    treated with ACE-I IV aldo (same degree of HBP)
  • 2001 Shiiga Late escape of antiproteinuric
    effect of ACE-I (50 of patients)
  • 2005 Quinkler Increased MR in human renal
    biopsies (mesangium) in patients with proteinuria

63
Aldosterone and Renal Disease
  • Animal models
  • REM DOCA 1 saline
  • SHR 1 saline
  • Radiation nephritis
  • L NAME SHR
  • All studies showed improved renal, cardiac, and
    CNS pathology with addition of spironolactone,
    eplerenone, or adrenalectomy.
  • No differences in level of HBP

Stier CTet al. Heart Fail Prev 2005 1053-62
64
Aldosterone and ProteinuriaHuman Studies
65
Aldosterone in CKD
  • Aldosterone levels are elevated 4 x baseline in
    CKD (Berl 78)
  • Aldosterone level correlates with rate of renal
    function decay (Walker 93)
  • Aldosterone blockade or adrenalectomy attenuates
    rate of GFR decline, proteinuria and GS (remnant
    kidney model) (Quan 92)
  • Aldosterone escape occurs with ACE-I and/or ARB
    in CKD Aldo 266 ? 105 ? 234 pg/ml after 12
    months treatment (Pitt 95)

66
Aldosterone Escape Correlates with Rate of GFR
Decline
  • 63 type I diabetes mellitus with proteinuria and
    high blood pressure
  • Treated with ARB (losartan 100 mg qd) for 35
    months
  • Aldo escape group (n26) of 41 patients
  • Rate of GFR decline in aldo escape group was 2 x
    that of non-aldo escape group (5 ml min/yr vs
    2.4 ml min/yr)

Parving 2004. Diabetoligia
67
Beneficial effect of SARA in diabetic nephropathy
  • 20 type I diabetics double-blind crossover study
    treated for 2 months with spironolactone (25
    mg/d) vs. placebo
  • Spironolactone added to ACE-I, ARB, diuretic
  • 30 ? albuminuria with spironolactone (831 mg/d ?
    584)
  • Proteinuric reduction was independent of BP and
    GFR reduction

Parving KJ 2005 Kidney Int 2005 682829-2836
68
Effect of spironolactone 25 mg to conventional
antihypertensive medication
Parving KJ 2005 Kidney Int 2005 682829-2836
69
Diabetic Nephropathy 24 week study Epstein 2002
No BP differences K ? 2/266
Hollenberg NK. Kidney Int 2004 661-9
70
SUMMARY
  • 1) The Aldosterone component of the RAAS has been
    conserved as an adaptation to the hunter-gatherer
    diet (low Na ,high K) of our forbearers.
  • 2) Essential HBP in post agricultural age man
    (high dietary Na) has little to do with
    Aldosterone

71
SUMMARY
  • 3) MR activation in the setting of high Na
    cofactor results in inflammation and fibrosis in
    the heart and kidney
  • 4) Aldosterone Escape attenuates the effects of
    ACEIs and ARBs.
  • 5) There may be a role for use of aldosterone
    receptor antagonists (spironolactone ,
    epleronone) in early CKD and CVD.

72
Nothing in biology makes sense except in light
of evolution T.Dobzhansky
Introduction to Cultural Anthropology Course
Syllabus. Christopher Fennell Fall 2003
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Aldosterone and MR Activation Revisited

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Title: Aldosterone and MR Activation Revisited


1
Aldosterone and MR Activation Revisited
  • Philip J. Klemmer, MD
  • UNC Kidney Center
  • Chapel Hill NC USA

2
Case 1
  • A 39 y.o. white female with a 20-yr history of
    neuromuscular symptoms, orthostatic syncope, salt
    craving, and nocturia. No GI symptoms.BP 96
    / 62
  • Serum 138 96 Cr 0.8 Aldo 39
  • 2.7 28 Mg 1.2 PRA
    19


3
Case 1
  • Spot urinalysis Na 77, Cl 81, K 59, Ca
    1.4, Mg 1.2 (FE mg 13)
  • EKG revealed U waves
  • Diuretic screen negative
  • Family history significant for 2/3 siblings with
    hypokalemia and similar symptoms. Parents
    normal.
  • Physical exam normal

4
Gitelmans Syndrome
5
Case 2
  • 37 yo white male with refractory hypertension
    (185/102 mm Hg) on 4 medications
  • Labs Cr 1.1, K 3.7-4.1
  • Aldo 20.5 ARR 200
  • PRA .1
  • 2 D Echo- 4 LVH No retinopathy


6
Case 2
  • FST Aldo
  • Baseline 20.5
  • Day 4 6.1
  • CT revealed normal adrenals hybrid gene (FH-1)
    negative
  • AVS Aldo
  • Right 83
  • Left 2190

7
Primary Aldosteronism (APA)
8
Aldosterone-Producing Adenoma Missed by
Computer-Aided Tomography
Stowasser, M and Gordon RD. Trends Endocrinol
Metab 200314(7) 310-317
9
Increased rate of CV events in PA patients
Milliez 2005 J Am Coll Card
10
When to Consider for Primary Aldosteronism
Young WF Jr. Endocrinology 2003 144(6)2208-2213
11
Range of Supine PAC and 18-OH-B in APA and BAH
Phillips J.L. et al. J Clin Endo Metab 2000
85(12)4526-4533
12
Prevalence of Unrecognized PA in Patients with
Hypertension
Young WF Jr. Endocrinology 2003 144(6)2208-2213
13
Primary Aldosteronism Management
14
Case 3
  • 40 yo asymptomatic outdoorsman
  • Physical exam weight 52 kg, BP 95/61 mm Hg
  • Lytes normal Cr - .7
  • 24-hour urine Na 1.3 mEq, K 200
  • Labs Aldo 74
  • PRA 13

15
Yanomami
Culture Chapter 3 Sociology, Schaefer, 2003 and
2003.
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
Carvalho J et al. Hypertension 1989 14238-246
20
Br Med J 1988 297319-328
21
NHANES II 1982
22
(No Transcript)
23
(No Transcript)
24
Angiotensin ll Dependent Normotension
  • BP 95/61
  • Aldo 74 ng / ml
  • PRA 13

25
Brazil Viper(Bothrops jararaca)
26
Aldosterone Issues
  • Sodium Cofactor
  • Aldosterone Escape
  • Non- Epithelial effects
  • What activates the MR ?
  • Why was Aldo upstaged by the RAS?

27
Aldosterone X High Salt Effects
  • HBP PA , EH
  • Renal fibrosis, proteinuria
  • CV CHF, cardiac fibrosis

28
Sodium Cofactor
  • High aldo / low salt
  • Normal physiologic response to
  • Low dietary sodium
  • Renal salt wasting
  • High aldo / high salt
  • High blood pressure
  • Heart fibrosis / inflammation
  • Kidney proteinuria / fibrosis

29
Aldosterone and Serum Cofactor
  • PA

Normals
Aldosterone
Aldo PRA Suggests PA
ARR
gt 20
PRA
30
Aldosterone and Serum Cofactor
Normals
31
Aldosterone and Serum Cofactor
Normals
32
Aldosterone and Serum Cofactor
Normals
33
Aldosterone and Serum Cofactor
Normals
34
Aldosterone and Serum Cofactor
PA, fibrosis
Normals
35
Aldosterone and the Sodium Cofactor
  • No HBP or vascular damage in high aldosterone
    states associated with low dietary sodium or
    renal sodium wasting
  • Myocardial, vascular, and renal fibrosis in
    animals treated with DOCA require high sodium
    intake for effect
  • MR activation may occur in the absence of
    elevated serum aldosterone levels

36
Key Question
  • How does high sodium cofactor convert the effect
    of aldosterone ( MR receptor activation) from
    physiological to pathological?

37
Physiologic and pathophysiologic effects of
aldosterone on the kidney and heart in relation
to dietary salt
Dluhy RG et al. N Engl J Med 2004 3518-10
38
Aldosterone Escape
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
Counterregulatory Stimulation
43
Aldosterone Escape
  • CHF treated with ACE-I for 36 months (Pitt 95)
  • HBP (Linjen 82)
  • DM nephropathy (Sato 03)
  • Exercise (Huang 93)

44
Aldosterone Escape
  • Occurs in 40 of patients with diabetic
    nephropathy who are treated with ACEIs ( Sato,
    Hypertension , 03)
  • A secondary increase in proteinuria parallels the
    escape and responds to spironolactone ( no
    change in BP)

45
Classical Epithelial Effects of Aldosterone
46
Cross-section of a distal tubule
McMurray JJV et al. N Engl J Med 2004
351(6)526-528
47
Classic Genomic Action of Aldosterone on
Epithelial Tissue
Connell JMC et al. J Endocrinol 2005 1861-20
48
Non Epithelial Effects of Aldosterone Fibrosis
49
Nonepithelial Effects of Aldosterone
  • Selye 1947 general adaptation theory
  • Webber, Pitt 1993 CV remodeling/vasculitis
    caused by aldosterone in face of RAAS suppression
  • Hostetter 1995 ditto for kidney (REM)
  • Rocha 1998 ditto for brain (SHR, REM)
  • Napoli 1999 end organ effects PA gt EH
  • MR antagonists (spironolactone, eplerenone)
    prevent / reduce tissue effects
  • Rales 1999

50
Non-Epithelial Effects of Aldosterone Excess
Rocha R, Funder JW. Ann NY Acad Sci 2002
97089-100
51
Aldosterone-Mediated Vascular Injury
Joffe HV et al. Heart Fail Rev 2005 1031-37
52
L-NAME AII High Salt
Joffe HV et al. Heart Fail Rev 2005 1031-37
53
L-NAME AII High Salt Adrenalectomy
Joffe HV et al. Heart Fail Rev 2005 1031-37
54
(No Transcript)
55
Epstein M. Nephrol Dial Transplant 2003
1819884-1992
56
Aldosterone and the Heart
57
(No Transcript)
58
Williams JS et al. 2005 Clin Endocrin Metab
882364-2372
59
Aldosterone and the Kidney
60
Non-Hemodynamic Non- Epithelial Renal Effects of
Aldosterone
  • Increase in type IV collagen production in
    cultured mesangial cells
  • MR receptors Glomeruli (mesangia and podocytes
    )
  • Renal vasculature

61
Aldosterone and the Development and Progression
of Renal Injury
  • 1946 Selye DOCA/salt rats malignant
    hypertension
  • 1964 Conn 145 PA cases, 85 had proteinuria
  • 1992 Walser Adrenalectomy improved renal
    histology in rats (REM)
  • 1993 Webber Aldo in REM causes cardiac fibrosis
  • 1996 Hostetter Renal fibrosis (REM)
    independently associated with aldosterone

62
Aldosterone and the Development and Progression
of Renal Injury
  • 1999 Rocha Malignant hypertension histology in
    SHR improved with ACE-I but effect lost if
    treated with ACE-I IV aldo (same degree of HBP)
  • 2001 Shiiga Late escape of antiproteinuric
    effect of ACE-I (50 of patients)
  • 2005 Quinkler Increased MR in human renal
    biopsies (mesangium) in patients with proteinuria

63
Aldosterone and Renal Disease
  • Animal models
  • REM DOCA 1 saline
  • SHR 1 saline
  • Radiation nephritis
  • L NAME SHR
  • All studies showed improved renal, cardiac, and
    CNS pathology with addition of spironolactone,
    eplerenone, or adrenalectomy.
  • No differences in level of HBP

Stier CTet al. Heart Fail Prev 2005 1053-62
64
Aldosterone and ProteinuriaHuman Studies
65
Aldosterone in CKD
  • Aldosterone levels are elevated 4 x baseline in
    CKD (Berl 78)
  • Aldosterone level correlates with rate of renal
    function decay (Walker 93)
  • Aldosterone blockade or adrenalectomy attenuates
    rate of GFR decline, proteinuria and GS (remnant
    kidney model) (Quan 92)
  • Aldosterone escape occurs with ACE-I and/or ARB
    in CKD Aldo 266 ? 105 ? 234 pg/ml after 12
    months treatment (Pitt 95)

66
Aldosterone Escape Correlates with Rate of GFR
Decline
  • 63 type I diabetes mellitus with proteinuria and
    high blood pressure
  • Treated with ARB (losartan 100 mg qd) for 35
    months
  • Aldo escape group (n26) of 41 patients
  • Rate of GFR decline in aldo escape group was 2 x
    that of non-aldo escape group (5 ml min/yr vs
    2.4 ml min/yr)

Parving 2004. Diabetoligia
67
Beneficial effect of SARA in diabetic nephropathy
  • 20 type I diabetics double-blind crossover study
    treated for 2 months with spironolactone (25
    mg/d) vs. placebo
  • Spironolactone added to ACE-I, ARB, diuretic
  • 30 ? albuminuria with spironolactone (831 mg/d ?
    584)
  • Proteinuric reduction was independent of BP and
    GFR reduction

Parving KJ 2005 Kidney Int 2005 682829-2836
68
Effect of spironolactone 25 mg to conventional
antihypertensive medication
Parving KJ 2005 Kidney Int 2005 682829-2836
69
Diabetic Nephropathy 24 week study Epstein 2002
No BP differences K ? 2/266
Hollenberg NK. Kidney Int 2004 661-9
70
SUMMARY
  • 1) The Aldosterone component of the RAAS has been
    conserved as an adaptation to the hunter-gatherer
    diet (low Na ,high K) of our forbearers.
  • 2) Essential HBP in post agricultural age man
    (high dietary Na) has little to do with
    Aldosterone

71
SUMMARY
  • 3) MR activation in the setting of high Na
    cofactor results in inflammation and fibrosis in
    the heart and kidney
  • 4) Aldosterone Escape attenuates the effects of
    ACEIs and ARBs.
  • 5) There may be a role for use of aldosterone
    receptor antagonists (spironolactone ,
    epleronone) in early CKD and CVD.

72
Nothing in biology makes sense except in light
of evolution T.Dobzhansky
Introduction to Cultural Anthropology Course
Syllabus. Christopher Fennell Fall 2003
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