Aldosterone and MR Activation Revisited

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Aldosterone and MR Activation Revisited

• Philip J. Klemmer, MD
• UNC Kidney Center
• Chapel Hill NC USA

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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

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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

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Gitelmans Syndrome
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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

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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

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Primary Aldosteronism (APA)
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Aldosterone-Producing Adenoma Missed by
Computer-Aided Tomography
Stowasser, M and Gordon RD. Trends Endocrinol
Metab 200314(7) 310-317
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Increased rate of CV events in PA patients
Milliez 2005 J Am Coll Card
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When to Consider for Primary Aldosteronism
Young WF Jr. Endocrinology 2003 144(6)2208-2213
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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
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Prevalence of Unrecognized PA in Patients with
Hypertension
Young WF Jr. Endocrinology 2003 144(6)2208-2213
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Primary Aldosteronism Management
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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

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Yanomami
Culture Chapter 3 Sociology, Schaefer, 2003 and
2003.
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Carvalho J et al. Hypertension 1989 14238-246
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Br Med J 1988 297319-328
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NHANES II 1982
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Angiotensin ll Dependent Normotension

• BP 95/61
• Aldo 74 ng / ml
• PRA 13

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Brazil Viper(Bothrops jararaca)
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Aldosterone Issues

• Sodium Cofactor
• Aldosterone Escape
• Non- Epithelial effects
• What activates the MR ?
• Why was Aldo upstaged by the RAS?

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Aldosterone X High Salt Effects

• HBP PA , EH
• Renal fibrosis, proteinuria
• CV CHF, cardiac fibrosis

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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

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Aldosterone and Serum Cofactor

• PA

Normals
Aldosterone
Aldo PRA Suggests PA
ARR
gt 20
PRA
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Aldosterone and Serum Cofactor
Normals
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Aldosterone and Serum Cofactor
Normals
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Aldosterone and Serum Cofactor
Normals
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Aldosterone and Serum Cofactor
Normals
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Aldosterone and Serum Cofactor
PA, fibrosis
Normals
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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

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Key Question

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

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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
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Aldosterone Escape
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Counterregulatory Stimulation
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Aldosterone Escape

• CHF treated with ACE-I for 36 months (Pitt 95)
• HBP (Linjen 82)
• DM nephropathy (Sato 03)
• Exercise (Huang 93)

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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)

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Classical Epithelial Effects of Aldosterone
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Cross-section of a distal tubule
McMurray JJV et al. N Engl J Med 2004
351(6)526-528
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Classic Genomic Action of Aldosterone on
Epithelial Tissue
Connell JMC et al. J Endocrinol 2005 1861-20
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Non Epithelial Effects of Aldosterone Fibrosis
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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

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Non-Epithelial Effects of Aldosterone Excess
Rocha R, Funder JW. Ann NY Acad Sci 2002
97089-100
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Aldosterone-Mediated Vascular Injury
Joffe HV et al. Heart Fail Rev 2005 1031-37
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L-NAME AII High Salt
Joffe HV et al. Heart Fail Rev 2005 1031-37
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L-NAME AII High Salt Adrenalectomy
Joffe HV et al. Heart Fail Rev 2005 1031-37
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Epstein M. Nephrol Dial Transplant 2003
1819884-1992
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Aldosterone and the Heart
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Williams JS et al. 2005 Clin Endocrin Metab
882364-2372
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Aldosterone and the Kidney
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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

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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

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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

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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
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Aldosterone and ProteinuriaHuman Studies
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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)

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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
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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
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Effect of spironolactone 25 mg to conventional
antihypertensive medication
Parving KJ 2005 Kidney Int 2005 682829-2836
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Diabetic Nephropathy 24 week study Epstein 2002
No BP differences K ? 2/266
Hollenberg NK. Kidney Int 2004 661-9
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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

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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.

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