aldosterone and mr activation revisited

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

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. Gitelman�s 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

9. Increased rate of CV events in PA patients

10. When to Consider for Primary Aldosteronism

11. Range of Supine PAC and 18-OH-B in APA and BAH

12. Prevalence of Unrecognized PA in Patients with Hypertension

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

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

30. Aldosterone and Serum Cofactor

31. Aldosterone and Serum Cofactor

32. Aldosterone and Serum Cofactor

33. Aldosterone and Serum Cofactor

34. Aldosterone and Serum Cofactor

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

38. Aldosterone Escape

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

47. Classic Genomic Action of Aldosterone on Epithelial Tissue

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 > EH MR antagonists (spironolactone, eplerenone) prevent / reduce tissue effects Rales 1999

50. Non-Epithelial Effects of Aldosterone Excess

51. Aldosterone-Mediated Vascular Injury

52. L-NAME + AII + High Salt

53. L-NAME + AII + High Salt + Adrenalectomy

56. Aldosterone and the Heart

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

64. Aldosterone and Proteinuria:Human 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 (n=26) 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)

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

68. Effect of spironolactone 25 mg to conventional antihypertensive medication

69. Diabetic Nephropathy 24 week study : Epstein 2002

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