Giornate Nefrologiche Pisane 2009 Bianchi uso antialdosteronici

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Giornate Nefrologiche Pisane 2009 Bianchi uso antialdosteronici

  1. 1. Gli Anti-Aldostenonici in Nefrologia: istruzioni per l’uso Stefano Bianchi Unita’ Operativa Nefrologia Ospedale San Donato, Arezzo stefano.bianchi@usl8.toscana.it
  2. 2. Angiotensinogen Angiotensin I Angiotensin II ACE Renin Bradykinin Inactive peptides Nonrenin Non-ACE Vaso- constriction Aldosterone secretion Sodium and fluid retention AT1 receptor Cell growth Sympathetic activation Renin-Angiotensin-Aldosterone System Renin inhibitors ARBs Aldosterone Antagonists
  3. 3. Primary aldosteronism, a new clinical syndrome Jerome W Conn J Lab Clin Med 1955; 45:3-17 Konstitution des aldosterons, des neuen mineralocorticoids Simpson SA, Tait JF, Wettstein A, Neher R, vonEuw J, Schindler O, Reichstein T Experientia 1954; 10:132-3 Jerome W Conn 1907-1981
  4. 4. Aldosterone MR Epithelial Cells (Kidney, Colon, Salivary glands etc) “Slow” (hours) > Sodium and water reabsorption > Potassium excretion > Intravascular volume > Blood pressure
  5. 5. Aldosterone MR Fibroblasts, Myocytes Endothelial Cells etc Epithelial Cells (Kidney, Colon, Salivary glands etc) “Slow” (hours) MR “Slow” (hours) Enhanced cardiac remodelling LV hypertrophy LV dysfunction Heart failure ↑Endothelial dysfunction ↑PAI – 1 ↑Vascular inflammation ↑Oxidative stress ↑Endothelin and Angio II receptors ↑Proliferation of myocytes and fibroblasts ↑Perivascular and interstitial fibrosis > Sodium and water reabsorption > Potassium excretion > Intravascular volume > Blood pressure
  6. 6. Aldosterone induces a vascular inflammatory phenotype in the rat heart Rocha R et al. Am J Physiol Heart Circ Physiol, 2002 A) Coronary and myocardial lesions induced by 4 wk of aldosterone/ salt treatment B) Vascular inflammatory lesions and fibrinoid necrosis of small coronary arteries (arrows) accompanied by a severe perivascular inflammatory response C) Coronary lesion in the heart of a rat that received aldosterone/salt treatment for 4 wk. The majority of cells infiltrating the lesions were identified as macrophages. D) Myocardium of an animal receiving aldosterone/salt treatment for 4 wk, in the presence of the selective aldosterone blocker eplerenone, showing no lesions.
  7. 7. Immunohistochemistry Representative photomicrographs of sections from uninephrectomized, saline-drinking rats receiving either vehicle, aldosterone infusion, or aldosterone infusion plus eplerenone for 4 wk. Sections were immunostained with specific antibodies against each molecule ED1: monocyte/macrophage CD3: T cell OPN: osteopontin VCAM-1: vascular cell adhesion molecule-1 ICAM-1: intracellular adhesion molecule-1 Aldosterone induces a vascular inflammatory phenotype in the rat heart Rocha R et al. Am J Physiol Heart Circ Physiol, 2002
  8. 8. Aldosterone blockade: Trials in HF and post-MI-LV dysfunction Pitt B et al. N Eng J Med. 1999 Pitt B et al. N Eng J Med. 2003 RALES 0.75 0.60 1.00 0 Placebo Spironolactone Months Probability of survival 24 366 30% Risk reduction RR 0.70 (0.60–0.82) P < 0.001 30 0.00 12 18 0.90 0.45 22 10 2 6 24 300 Eplerenone Months 18 14 6 3612 EPHESUS 15% Risk reduction RR 0.85 (0.75–0.96) P = 0.008 Cumulative Incidence of CV events(%) Placebo 0 18
  9. 9. Aldosterone MR Fibroblasts, Myocytes Endothelial Cells etc Epithelial Cells (Kidney, Colon, Salivary glands etc) “Slow” (hours) MR MMR Epithelial and non-Epithelial Cells Increased systemic resistance and heart rate Vasoconstriction of pre- glomerular afferent and (mostly) post-glomerular efferent arterioles Increased endothelial cell volume Others….. “Slow” (hours) “Fast” (minutes) ↑Endothelial dysfunction ↑PAI – 1 ↑Vascular inflammation ↑Oxidative stress ↑Endothelin and Angio II receptors ↑Proliferation of myocytes and fibroblasts ↑Perivascular and interstitial fibrosis > Sodium and water reabsorption > Potassium excretion > Intravascular volume > Blood pressure
  10. 10. Non genomic actions of aldosterone MMR Epithelial and non-Epithelial cells Increased systemic resistance and heart rate Vasoconstriction of pre-glomerular afferent and (mostly) post- glomerular efferent arterioles Increased endothelial cell volume Others “Fast” (seconds-minutes) M M R Aldosterone Intracellular signals cAMP DAG IP3 etc >Ca++ MAK phosphorylation Spiro and Eple do not block Aldosterone
  11. 11. Aldosterone-induced Vasoconstriction in Afferent and Efferent Arterioles of Rabbits Arima S et al. J Am Soc Nephrol, 2003
  12. 12. Jerome W Conn 1907-1981 Clinical Characteristics of Primary Aldosteronism from an Analysis of 145 Cases Jerome W Conn, M.D., Ralph F Knopf, M.D. and Reed M Nesbit, M.D. Ann Arbor, Michigan Ann J Surg 1964:107:159-72 Table VII RENAL STUDIES IN 113 CASES OF PRIMARY ALDOSTERONISM Renal Function Normal Impaired Proteinuria •Absent 12 … •Present … 69 Concentrating ability 16 69 Pitressin response 9 33 PSP excretion 12 6 Other indices of renal function: BUN, Cl urea, Cl creat, Cl inul, Cl pah 46 27 →85% →36%
  13. 13. Nephrologists overlooked the role of aldosterone in chronic kidney disease (?) 1. Chronic renal disease is characterized by high aldosterone levels
  14. 14. 0,5 1 1,5 2 2,5 3 3,5 4 0 50 100 150 200 250 300 Basal aldosterone pg/ml Basalproteinuria g/gcreatinine Regression line between plasma aldosterone levels and proteinuria in 165 subjects with chronic kidney disease Bianchi S et al. Kidney Int, 2006
  15. 15. 0 50 100 150 200 250 300BasalAldosteronepg/ml 30 40 50 60 70 80 90 100 110 120 Basal GFR, mL/min Relationship between plasma aldosterone and GFR levels in 165 subjects with chronic kidney disease Bianchi S et al. Kidney Int, 2006 R=.482 p<.0001
  16. 16. 1. Chronic renal disease is characterized by high aldosterone levels 2. Many of the deleterious effects of AII are mediated by aldosterone Nephrologists overlooked the role of aldosterone in chronic kidney disease (?)
  17. 17. 1. Chronic renal disease is characterized by high aldosterone levels 2. Many of the deleterious effects of AII are mediated by aldosterone 3. “Aldosterone escape” is common in the majority of patients treated with drugs inhibiting the RAAS Nephrologists overlooked the role of aldosterone in chronic kidney disease (?)
  18. 18. Plasma ACE (nmol/mL/min) Plasma Aldosterone (ng/dl) 100- 80- 60- 40- 20- 0 0 4hr 24hr 1 2 3 4 5 6 * * * * * * * * Hospital Months 100- 80- 60- 40- 20- 0 * Aldosterone is Not Adequately Suppressed by ACE inhibitors Biollaz J et al. J Cardiovasc Pharmacol, 1982 Enalapril 20 mg bid p<.001 p<.01
  19. 19. 60 40 20 0 -20 -40 Change in Aldosterone from baseline (%) 17 weeks 43 weeks Candesartan 4 mg Candesartan 8 mg Candesartan 16 mg Candesartan 4 mg +Enalapril 20 mg Candesartan 8 mg +Enalapril 20 mg Enalapril 20 mg RESOLVD Investigators ACC, 1998 Aldosterone “Escape” Despite Ace inhibition and Angiotensin II Blockade
  20. 20. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney ↑Endothelial dysfunction ↑PAI – 1 ↑Vascular inflammation ↑Oxidative stress, Podocyte dysfunction ↑Endothelin and Angio II receptors. Mesangial proliferation, interstitialinflamation, and renal fibrosis MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone
  21. 21. 8 weeks after 5/6 nephrectomy (biopsy) After 4 weeks of treatment (autopsy) CONTROLS progression SPIRO regression SPIRO+AT1RA regression Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone Jean Claude Aldigier, Talerngsak Kanjanbuch, Li-Jun Ma, Nancy J. Brown, and Agnes B. Fogo Departments of Pathology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
  22. 22. The Janus Effect: Two Faces of aldosterone Physiological effects (acute): Maintenance of body fluid Composition Sodium reabsorption Potassium secretion Hydrogen ion secretion Pathophysiological effects (chronic): Hypokalemic alkalosis Hypertension Inflammation Fibrosis
  23. 23. The Renin-Angiotensin-Aldosterone System (RAAS) Progression of renal and cardiovascular disease Angiotensinogen Angiotensin I Angiotensin II Aldosterone Inflammation and interstitial fibrosis Cardiac Hypertrophy Endothelial dysfunction Inflammation Glomerular sclerosis Tubular damage HR variability ↓ Baroreceptor sensitivity ↓ > Sodium and water reabsorption > Potassium excretion > Intravascular volume > Blood pressure
  24. 24. Aldosterone Antagonists and Chronic Kidney Disease • Proteinuria • Renal function • Potential side effects
  25. 25. Aldosterone Antagonists and Chronic Kidney Disease Do aldosterone antagonists reduce proteinuria?
  26. 26. 0,5 1 1,5 2 2,5 3 3,5 4 0 50 100 150 200 250 300 Basal aldosterone (pg/ml) Basalproteinuria (g/gcreatinine) Regression line between baseline plasma aldosterone levels and proteinuria in 165 subjects with chronic kidney disease r=0.766 P<0.0001 Long-Term Effects of Spironolactone on Proteinuria and Kidney Function in Patients with Chronic Kidney Disease Bianchi S et al. Kidney Int, 2006
  27. 27. Spironolactone in Chronic Renal Disease Background therapy NS50%ACEis and/or ARBs 8Non-DN (n=32)Bianchi S. et al (2005) Bianchi S. et al (2006) NS38%ACEis12DN and non-DN (n=32)Sato A. et al (2005) NS42%ACEis12Dn and Non-DN (n=22) Chrysostomou A (2006) NS25%ACEis24T2 DM with micro- or macro-albuminuria (n=15) Sato A. et al (2003) NS54%ACEis4DN and Non-DN (n=8)Chrysostomou A. et al. (2001) Reduction of BP (mm Hg) Reduction of Proteinuria Duration (weeks) Study PopulationAuthor (year) Spironolactone 25 mg added on top of previous antiproteinuric treatment DN=Diabetic Nephropathy; Non-DN=Non Diabetic Nephropathy Non DM (n=83) 52 Aceis and/or 54% 6/3 ARBs
  28. 28. Spironolactone Reduces Proteinuria in Patients with non Diabetic Chronic Kidney Disease 1.32 1.15 1.05 1.57 2.09 0 0.5 1 1.5 2 2.5 Basal 2 wks 4 wks 8 wks 12 wks Optimal Care + Spiro Optimal Care STOP SPIRO * * * ** δ * p <.001 vs 8 wks ** p<.0001 vs basal δ p< .05 vs basal Bianchi S et al. Am J Kidney Dis, 2005 Urinaryproteinexcretion gr/24hours
  29. 29. 5 - 4 - 3 - 2 - 1 - 0 - Basal 2 wks 4 wks 8 wks 12 wks Proteinuria,gr/24hrs Spironolactone Reduces Proteinuria in Patients with Chronic Kidney Disease Stop spiro Bianchi S et al. Am J Kidney Dis, 2005
  30. 30. Effect of Spironolactone on Proteinuria 0 0.5 1 1.5 2 2.5 Basal 1 3 6 9 12 Months Conventional therapy Conventional therapy plus Spironolactone *p<0.001 vs. CT **p<0.01 vs. CT ** * * * * Bianchi S et al. Kidney Int, 2006 Proteinuria gr/gr creat
  31. 31. • Proteinuria • Renal function • Potential side effects Aldosterone Antagonists and Chronic Kidney Disease
  32. 32. Effect of spironolactone on GFR in patients with chronic kidney disease *p<0.01 2,4,8 weeks of treatment with Spiro Post: 4 weeks after discontinuation of Spiro ReductionofGFR vsbasalvalues(%) 2- 4- 6- 8- 2wks 4wks 8wks Post -4.6% -6% -6.2% -1.8% * * * Bianchi S et al. Am J Kidney Dis, 2005
  33. 33. * * * * * * * ** Conventional therapy Conventional therapy +Spironolactone *p<0.001 vs basal GFR **p<0.0001 vs basal GFR %reductionofGFR vsbasalvalues Bianchi S et al. Kidney Int, 2006 Long-Term Effects of Spironolactone on GFR in Patients with Chronic Kidney Disease -2 -4 -6 -8 -10 -12 1 3 6 9 12 Months
  34. 34. Monthly rate of decrease in GFR in patients with CKD treated with spironolactone and in controls Spironolactone -0.323±0.044 ml/min Controls -0.474±0.037 ml/min* * p<0.01 Bianchi S et al. Kidney Int, 2006
  35. 35. • Proteinuria • Renal function • Potential side effects - Endocrine disorders - Hyperkalemia Aldosterone Antagonists and Chronic Kidney Disease
  36. 36. <000160Gynecomastia in men Endocrine disorders ns4*2*Hyperkalemia (K+>6 mEq/L) p Conventional Therapy + Spiro (n=83) Conventional therapy (n=82) Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease (Adverse effects) *All patients developing hyperkalemia had eGFR<60 ml/min 5 out of 6 patients did not discontinue the study Bianchi S et al. Kidney Int, 2006
  37. 37. Rates of Hyperkalemia and Death After Publication of RALES 500% ↑ in spironolactone Rx (p<0.001) 275% ↑ in hosp for Hyperkalemia (p<0.001) 285% ↑ in death due to Hyperkalemia (p<0.001) Juurlink, et al. NEJM 2004
  38. 38. Aldosterone Blockade: limiting hypekalemia (Relative) contraindications eGFR<30 mL/min Serum potassium >5 mEq/L Potassium monitoring Before starting therapy then 1 week, 1 month, and every 3 months If serum potassium >6 mEq/L without a precipitating factor,(e.g., NSAID) discontinue aldosterone blockade
  39. 39. Reducing the Risk of Hyperkalemia During Aldosterone Blockade Withdraw potassium supplements and discontinue other meds that interfere in K+ excretion Low K+ diet (<70 mEq/d) Use low doses – spironolactone 25 mg /eplerenone 50 mg and start diuretic therapy when K>5 mEq/L Monitor potassium regularly Pause (or decrease) RAAS blocking agents during dehydration Particular caution when GFR is severely reduced
  40. 40. Back-up slides
  41. 41. • Dual ( or triple) block is like driving a Ferrari: exciting, powerfull, but risky. If you do not know how to do it, you could soon find yourself in deep trouble
  42. 42. RAAS not RAS (aldosterone is included in the system) Do not forget!
  43. 43. Summary (1) • Aldosterone plays a significant role in the pathogenesis of renal disease • Initial studies designed to evaluate the efficacy of aldosterone blockade in animals and humans are encouraging
  44. 44. Summary (2) • Because of the potential serious toxicity, and lack of more definitive studies, at present these agents should not be used routinely as a means of treating people with CKD or ESRD • Clinical studies are warranted to address more definitively the safety and the efficacy of aldosterone antagonism in CKD and ESRD
  45. 45. Antiproteinuric Effects of Mineralocorticoid Receptor Blockade in Patients With Chronic Renal Disease Sato A et al. AJH, 2005 Spiro 25 mg/day Thirty-two outpatients with diabetic (17 patients) and non diabetic (15 patients) renal disease with persistent proteinuria (> 0.5 g/d), after medical treatment for 10 to 14 months, including an ACE inhibitor (trandolapril) were treated with Spiro for 12 weeks BP during spiro treatment did not significantly change when compared with the basal values
  46. 46. 160- 120- 90- 60- 30- 0 * Conventional Therapy 2 1.5 1 0.5 0 δ Conventional Therapy * p<.001 δ p<.01 PAS/PAD (mmHg) Albuminuria (mg/24h) 20 type 2 diabetic pts Age (yrs) 58±10 Duration diabetes (yrs) 12±6 BMI (kg/m2 ) 35±7 A1C (%) 7.9 UAE (mg/24/h) >300 GFR (ml/min/1.73 m2) >30 RAAS blocking agents ACE inhibitors 4/20 ARBs 11/21 Both ACEis and ARBs 5/20 Diuretics 16/20 Dihydropyridines 16/20 Β-Blockers 13/20 Statins 18/20 Low-dose aspirin 20/20 Beneficial Effects of Adding Spironolactone to Raccomended Antihypertensive Treatment in Diabetic Nephropathy Rossing P et al. Diabetes Care, 2005 Conventional Therapy + Spiro 25 mg/day Conventional Therapy + Spiro 25 mg/day *
  47. 47. 160- 120- 90- 60- 30- 0 * Conventional Therapy 2 1.5 1 0.5 0 δ Conventional Therapy * p<.001 δ p<.01 PAS/PAD (mmHg) Albuminuria (mg/24h) 20 type 2 diabetic pts Age (yrs) 58±10 Duration diabetes (yrs) 12±6 BMI (kg/m2 ) 35±7 A1C (%) 7.9 UAE (mg/24/h) >300 GFR (ml/min/1.73 m2) >30 RAAS blocking agents ACE inhibitors 4/20 ARBs 11/21 Both ACEis and ARBs 5/20 Diuretics 16/20 Dihydropyridines 16/20 Β-Blockers 13/20 Statins 18/20 Low-dose aspirin 20/20 Beneficial Effects of Adding Spironolactone to Raccomended Antihypertensive Treatment in Diabetic Nephropathy Rossing P et al. Diabetes Care, 2005 Conventional Therapy + Spiro 25 mg/day Conventional Therapy + Spiro 25 mg/day *
  48. 48. 0 -5 -10 -15 -20 -25 0 3 6 9 12 Months ChangeineGFR (mL/min/1.73m2) * * * * P<.0001 Placebo Spiro Effect of Spironolactone in type II Diabetic Nephropathy van den Meiracker et al. J Hyperten, 2006
  49. 49. Effect of aldosterone in different tissue Extra adrenal glands sites of aldosterone’synthesis
  50. 50. 0 100 200 300 400 500 600 700 800 900 Normal Adrenalectomy 0 5 10 15 20 25 Normal Adrenalectomy 0 5 10 15 20 25 Normal Adrenalectomy Undetectable * * * A Plasma Aldosterone Levels B Renal Interstitial Fluid C Kidney Tissue Xue C et al. Hypertension 2005 A B C Aldosterone in Normal and Adrenalectomized Rats pg/ml pg/mlpg/mgkidneyweight
  51. 51. 0 20 40 60 80 100 120 0 50 100 150 200 250 300 350 0 100 200 300 400 500 600 700 800 Xue C et al. Hypertension 2005 Renal Aldosterone Synthesis (expressed as % total renal CYP11B2mRNA) Renal Cortex Medulla Normal salt High salt Low salt ┬ * ┬ * ┬ ┬ * ** Control Ang II Ang II+ Valsartan %totalrenalCYP11B2mRNA) %totalrenalCYP11B2mRNA) %totalrenalCYP11B2mRNA) ┬ ┬┬ ┬
  52. 52. Lumen Interstitial fluid (blood) CortisolCortisone 11β-HSD2 Aldosterone HRE Gene Endoplasmic reticulum Sgk1 CHIF, KI-ras, PI3K, etc Na+ Na+ H2O H2O K+ K+ Na+ K+ ATP ADP ENa+channel α,β,γ subunits Na+/k+ ATPase ••• • • • • • •• • • • • Spironolactone Eplerenone MR The classical genomic action of aldosterone on epithelial cell. Nedd4-2
  53. 53. CortisolCortisone 11β-HSD2 Aldosterone HRE Gene Endoplasmic reticulum Sgk1 CHIF, KI-ras, PI3K, etc Na+ Na+ H2O H2O K+ K+ Na+ K+ ATP ADP ENa+channel α,β,γ subunits Na+/k+ ATPase ••• • • • • • •• • • • • Spironolactone Eplerenone MR P P Nedd4-2 Lumen Interstitial fluid (blood) The classical genomic action of aldosterone on epithelial cell.
  54. 54. Nongenomic Vascular Action of Aldosterone in the Glomerular Microcirculation SHUJI ARIMA,* KENTARO KOHAGURA,* HONG-LAN XU,* AKIRA SUGAWARA,*TAKAAKI ABE,* FUMITOSHI SATOH,* KAZUHISA TAKEUCHI,* and SADAYOSHI ITO* Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University School of Medicine, Sendai, 980-8574, Japan Abstract. Aldosterone (Aldo) accelerates hypertension, proteinuria, and glomerulosclerosis in animal models of malignant hypertension or chronic renal failure. Aldo may exert these deleterious renal effects by elevating renal vascular resistanceand glomerular capillary pressure. To test this possibility, directly examined were the action of Aldo on the afferent (Af) and efferent (Ef) arterioles (Arts). Examined were the effect of Aldo added to both the bath and lumen on the intraluminal diameter (measured at the most responsive point) of rabbits. Aldo caused dose-dependent constriction in both arterioles with a higher sensitivity in Ef-Arts. Vasoconstrictor action of Aldo was not affected by a mineralocorticoid receptor antagonist spironolactone and was reproduced by membrane-impermeable albumin-conjugated Aldo, suggesting that the vasoconstrictor actions are nongenomic. Pretreatment with neomycin (a specific inhibitor of phospholipase C) abolished the vasoconstrictor action of Aldo in both arterioles. In addition, the vasoconstrictor action of Aldo on Af-Arts was inhibited by both nifedipine and efonidipine, whereas that on Ef-Arts was inhibited by efonidipine but not nifedipine. The results demonstrate that Aldo causes nongenomic vasoconstriction by activating phospholipase C with a subsequent calcium mobilization thorough L- or T-type voltage-dependent calcium channels in Af- or Ef-Arts, respectively. These vasoconstrictor actions on the glomerular microcirculation may play an important role in the pathophysiology and progression of renal diseases by elevating renal vascular resistance and glomerular capillary pressure. Arima S et al. J Am Soc Nephrol, 2003
  55. 55. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney Reduced availability of endothelial NO Endothelial dysfunction MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone
  56. 56. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney Stimulation of PAI-1 synthesis MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone
  57. 57. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney vascular NADPH oxidase activity and plasma markers of oxidative stress MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone
  58. 58. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney Renal hemodynamic effect ↑ RVR ↑↑ FF Glomerular hypertension MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone
  59. 59. Role of Aldosterone in the Remnant Kidney Model in the Rat E.L. Greene, S. Kren, and T.H. Hostetter Department of Medicine, Renal Division, University of Minnesota, Minneapolis, Minnesota 55455 UPE(mg/24h) Control REM REM+ REM+AII+ AIIA Aldo § * Green et al. J Clin Invest, 1996 PlasmaAldosterone(pg/ml) Control REM REM+ REM+AII+ AIIA Aldo *p<0.01 vs REM **p<0.05 vs REM+AIIA §p<0.01 vs REM+AIIA * 160 140 120 100 80 60 40 20 0 600 500 400 300 200 100 0
  60. 60. Podocyte Injury and Proteinuria in aldosterone- infused rats with partially nephrectomy Nephrin Staining Electron microscopy Ctrl Aldo0 0.2 0.4 0.6 0.8 1 1.2 1.4 Ctrl Aldo /βactin Nephrin gene expression Ctrl 2W 0 100 200 300 400 500 Urinary Protein Excretion mg/day Ctrl 2W Ctrl 4W Ctrl 6W Aldo 2W Aldo 4W Aldo 6W Aldo 2W Aldo 4W Aldo 6W ** ** ** ** ** ** Shibata S, Fujita T et al. Hypertension 49;355-464, 2007
  61. 61. 600- 400- 200- 0- тPlasmaAldo(pg/ml) Control Remnant REM Control Systolic BP 185±26 124±18 (mmHg) UPE 121±54* 11±2 (mg/24h) Glom.sclerosis 37.2±26.5* 1.9±1.2 (%) P Aldosterone 526±50* 50±12 (pg/ml) Adrenal weight 63±4* 51±4 (mg) * *p<.0001 Green et al. J Clin Invest, 1996 Role of Aldosterone in the Remnant Kidney Model in the Rat E.L. Greene, S. Kren, and T.H. Hostetter Department of Medicine, Renal Division, University of Minnesota, Minneapolis, Minnesota 55455
  62. 62. Regression of Existing Glomerulosclerosis by Inhibition of Aldosterone Jean Claude Aldigier, Talerngsak Kanjanbuch, Li-Jun Ma, Nancy J. Brown, and Agnes B. Fogo Departments of Pathology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee In this study, the effects of inhibition of aldosterone on regression of existing hypertension-related glomerulosclerosis were investigated. Adult male Sprague Dawley rats (220 to 250 g) underwent 5/6 nephrectomy (Nx). Severity of glomerulosclerosis was assessed by renal biopsy 8 wk later, and rats were divided into four groups with equal biopsy sclerosis and then randomized by group to 4-wk treatments as follows: Control with no further treatment (CONT; n 6); spironolactone (SP) alone (200 mg/kg per d, by gavage, n 6); or SP combined with nonspecific triple antihypertensive drugs (TRX; reserpine,hydralazine, and hydrochlorothiazide in drinking water; SPTRX, n 7) or with angiotensin type 1 receptor antagonist (AT1RA; losartan in drinking water; SPAT1RA, n 8). When the rats were killed 12 wk after Nx, autopsy glomerulosclerosis index (SI; 0 to 4 scale) was compared with biopsy SI in the same rats. Systolic BP was increased at 8 wk after Nx and continued to increase at 12 wk after Nx in the CONT and SP groups but not in SPTRX- or SPAT1RA-treated rats. Serum creatinine at 12 wk was significantly decreased in all SP-treated groups versus CONT. CONT rats had on average a 157% increase in SI from biopsy to killing at 12 wk, compared with only 84% increase in SP rats, with regression of SI in some rats. The effects on glomerulosclerosis by SP were further enhanced (when systolic BP was controlled by TRX or by AT1RA). It is concluded that inhibition of aldosterone by SP not only slows development of glomerulosclerosis but also induces regression in some rats of existing glomerulosclerosis. J Am Soc Nephrol 16: 3306–3314, 2005.
  63. 63. 1 3 6 9 12 All patients Patients with GFR<60 mL/min Patients with GFR>60 mL/min * * * * ** * * * * * * # * * * * * *p<0.001 vs. basal proteinuria #p<0.05 vs. patients with eGFR <60 mL/min **p< 0.01 vs. patients with eGFR <60 mL/min %reductionofproteinuria vsbasalvalues Long-Term Effects of Spironolactone on Proteinuria and Kidney Function in Patients with Chronic Kidney Disease Months of treatment 0- 20- 40- 60- 80- Bianchi S et al. Kidney Int, 2006
  64. 64. Five endothelial cells (numbered 1–5) of bovine aorta imaged at 37°C using the atomic force microscope. Image recorded during aldosterone incubation (5 min aldosterone) Image representing the corresponding subtraction image (volume difference). Atomic Force Microscopy on Living Cells: Aldosterone-Induced Localized Cell Swelling Kidney Blood Press Res 1998;21:256–258 S.W. Schneidera, P. Pagela, J. Storcka, Y. Yanob, B.E. Sumpioc, J.P. Geibeld, H. Oberleithner
  65. 65. Aldosterone Aldosterone+Amiloride
  66. 66. Incomplete Blockade of Aldosterone by ACE-Is & ARBs Angiotensinogen Ang I Ang II Renin ACEACE-I Chymase ARB Aldosterone Incomplete Receptor Blockade [K+], ACTH (acutely) Adipose tissue factors, NO, Endothelin, Norepinephrine, Serotonin., ANP, others) Non RAAS stimulators of aldosterone secretion
  67. 67. Aldosterone MR Podocytes In rats treated with aldosterone and high-salt diet: - MR is present in cultured podocytes - Nephrin and podocin, components of the slit diaphragms are markedly suppressed while desmin expression, a marker for podocyte injury is enhanced - Transmission electron microscopy analysis shows severe degeneration changes of podocytes and foot processes retraction - The infusion of aldosterone antagonists nullified almost completely the podocyte damage Non-epithelial Actions of Aldosterone
  68. 68. Type 2 diabetic rats at 52 wk of age Type 2 diabetic rats at 52 wk of age treated with spiro at 20 mg/kg per d for 8 mo. Sang-Youb H et al. J Am Soc Nephrol, 2006
  69. 69. Type II diabetics rats at 52 wk of age ED-1 MIF TGF-1 Type 2 diabetic rats at 52 wk of age treated with spiro at 20 mg/kg per d for 8 mo Spironolactone Prevents Diabetic Nephropathy through an Anti-Inflammatory Mechanism in Type 2 Diabetic Rats J Am Soc Nephrol, 2006
  70. 70. 0,5 1 1,5 2 2,5 3 3,5 4 0 50 100 150 200 250 300 Basal aldosterone pg/ml Basalproteinuria g/gcreatinine Regression line between plasma aldosterone levels and proteinuria in 165 subjects with chronic kidney disease Bianchi S et al. Kidney Int, 2006
  71. 71. Aldosterone-induced Renal Injury Progression of renal diseaseProgression of renal disease Systemic hypertensionSystemic hypertension MR Fibroblasts, Myocytes Endothelial cells Kidney MR Epithelial Cells (Kidney, Colon, Salivary glands etc) SodiumSodium retentionretention PotassiumPotassium lossloss Electrolyte transportElectrolyte transport Aldosterone Aldosterone ↑Endothelial dysfunction ↑PAI – 1 ↑Vascular inflammation ↑Oxidative stress ↑Endothelin and Angio II receptors ↑Proliferation of and fibroblasts ↑Perivascular and interstitial fibrosis
  72. 72. Quantitative analysis of nephrin gene expressions in the glomeruli of control and aldosterone infused rats Nephrin/β-actin 1.2 1 0.8 0.6 0.4 0.2 0 Ctrl Aldo Aldo Aldo+ 2 wks 2wks 4wks Eplerenone ** ** Modified from: Shibata S et al. Hypertension, 2007 Control rat Aldosterone- infused rat Aldosterone- infused rat+ Eplerenone Micrographs of immunostaining for nephrin in the glomeruli of control, aldosterone-infused animals, and aldosterone-infused rats receiving eplerenone P<.0001
  73. 73. Transmission electron micrographs of control and aldosterone-infused rats at 2 weeks Control rats show normal structure of podocytes. In aldosterone-infused rats, podocytes exhibit degeneration of the cell body and retraction of the foot processes. Shibata S et al. Hypertension. 2007

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