(J Exper Med 59: , 1934)

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Aldous Owens
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1 (J Exper Med 59: , 1934)

2 Goldblatt experiments Allowed the discovery of the renin-angiotensinaldosterone system -- Braun-Menendez: 'hypertensin' -- Bumpus: 'angiotonin' Angiotensin Led to surgical/interventional treatment of secondary, ischemic hypertension Were not gratified with the Nobel prize

3 Angiotensin pathways Angiotensinogen Renin Angiotensin I Atrial Natriuretic Peptides (-) Endopeptidase Converting Enzyme Bradykinin Inactive Fragments Angiotensin-(1 (1-7) Angiotensin II Inactive Fragments AT (1-7) AT 2 7) Vasodilation AT Natriuresis Anti-Trophic Factor Anti-Proliferative Responses AT 1 Vasoconstriction Sodium Retention Vascular Growth Proliferative Responses

6 E CL A

7 Determinants of the Glomerular Filtration Rate GFR = K f x net filtration pressure Af-art MD Mesangial cells A II receptors NaCl Ef-art Renal nerves Hydrostatic pressure 60 mm Hg Bowman's capsule pressure Colloid osmotic pressure 30 mm Hg 18 mm Hg Glomerulus

8 Consequences of renal artery stenosis

9 Renal artery stenosis Aldosterone Renin Renin Reduced Compensation of sodium excretion sodium excretion Renovascular Hypertension

Two variants of renovascular hypertension Côté de la One sténose clip Two kidneys - Natriuresis Sodium Retention Diuresis Water Blood volume

10 Two variants of renovascular hypertension Côté de la One sténose clip Two kidneys - Natriuresis Sodium Retention Diuresis Water Blood volume remains normal, or even diminishes ('Pressure natriuresis') Blood volume increases Renin tends to normalize Sodium Retention Water One kidney - One clip

11 HTA rénovasculaire maligne par sténose de

12 UIV 3 minutes Retard de secrétion à gauche

13 UIV 7 minutes

14 13 minutes

15 18 minutes Hyperconcentration retardée du côté de la sténose

16 Consequences of Critical Renal Artery Stenosis Functional Morphologic Preglomerular pressure and flow + Efferent arteriole vasoconstriction Glomerulotubular balance tipped toward inappropriate Na reabsorption Renal atrophy Vascular sclerosis Tubular atrophy Interstitial fibrosis Interstitial inflammation Glomerulosclerosis Cholesterol crystals

17 Consequences of Critical Renal Artery Stenosis Functional Preglomerular pressure and flow + Efferent arteriole vasoconstriction CEI induced drop of GFR Critical perfusion pressure Glomerulotubular balance tipped toward inappropriate Na reabsorption Flash pulmonary edema Refractory hypertension

18 Renovascular hypertension frequently assumes a severe or even malignant course High systolic/diastolic recordings Headache, thirst, loss of weight Rapid onset of LVH Funduscopic changes Microangiopathic anemia Hypokalemia and kaliuria >>> 20 mmol/d High renin-aldosterone when two kidneys-one clip model Hypervolemia and flash pulmonary edema when two kidneys-two clips or solitary kidney + clip model

19 Malignant hypertension Exsudates, hemorrhages, papillary edema

20 Microangiopathic anemia : schistocytes

21 Malignant nephrosclerosis

22 Contrary to an old concept The stenotic kidney is not 'protected ' It loses size and volume CT scan discloses cortical thinning Tubular cells undergo atrophy and apoptosis *

23 Anti-human renin antibody (Courtesy Dominique Nochy MD)

24 Tubulointerstitial lesions induced by slow, almost non-pressive Ang 2 infusion

25 ED1 Osteopontin Giacchelli & al, Kidney Int, 45:515-24, 1994

26 Causes of renovascular hypertension Atherosclerotic renal artery stenosis Fibromuscular renal artery dysplasia Renal infarct Renal cancer Renal trauma -- Renal artery dissection -- Perirenal hematoma leading to "Page kidney" Percutaneous renal biopsy -- AV fistula (blood flow steal) -- Perirenal hematoma leading to "Page kidney"

27 Atherosclerotic renovascular hypertension covers all models of Goldblatt hypertension

28 Renal Ischemia Two decades of nephrological blindness Gifford RW, Mc Cormack LJ, Poutasse EF: The atrophic kidney: its role in hypertension. Mayo Clin.Proc. 40: , 1965 Hricik DE & al: Captopril-induced functional renal insufficiency in patients with bilateral renal-artery stenosis or renal-artery stenosis in a solitary kidney. N.Engl.J.Med. 308: , 1983

29 Stenosis of left renal artery Bilateral Fork branching Extensive aortic plaques Risk of CCE Polar artery almost occluded

30 MRI Selective angiography * Left nephrectomy for cancer (*). History of coronary bypass. Serum creatinine 210 µmol/l. Systematic search for renal artery stenosis on solitary kidney. MRI ( ) exaggerates the degree of stenosis (50% on angiography and reassuring Doppler indices). No angioplasty done. Renal function remained stable

31 RENAL ARTERY INVOLVEMENT WITH ATHEROSCLEROTIC PLAQUES IS: Common Bilateral Developing

32 Source: Conlon PJ & al, AJKD, 35:573-87, 2000

33 Renal artery stenoses are developing 30 to 50% involve both sides within months In case of renal atrophy, the opposite artery is involved in 35% of patients Stenosis is developing in 42 to 71% of patients The renal artery diameter diminishes by 4.5% per year Zierler, 1994 Sources: Greco & Breyer: Semin Nephrol, 1996 Tollefson, 1991

34 Probability of showing 50% or more progression in degree of RAS in pts undergoing serial aortography Source: Conlon PJ & al, AJKD, 35:573-87, 2000

35 Occlusion in 11 to 16% of pts within a month follow up Stenosis = 50%: Thrombosis in 5% within 56 months Stenosis = 50-75%: Thrombosis in 10% within 24 months Stenosis > 75%: Thrombosis in 39% within 13 months Source: Schreiber, 1984 Caps, 1998

36 Atherosclerotic stenoses and two-year renal survival Unilateral Stenosis : 97% Bilateral Stenoses : 82% Unilateral Stenosis + Contralateral Occlusion : 45% Source: Conolly JO, QJM, 87:413-21, 1994

37 Survival Probability 1.0 Unadjusted Survival Survival Probability No RAS p = % RAS PJ Conlon & al, J Am Soc Nephrol 9: , 256, 1998

38 SUSPICION OF ISCHEMIC RENAL DISEASE FROM ARAS Atherosclerotic background, coronary disease Renal insufficiency without evidence of other cause Aggravation by antihypertensive treatment Flash pulmonary edema Asymmetry of renal size Evidence of cholesterol crystal embolism Proteinuria > 1 g/d does not rule out the diagnosis

39 Diagnostic work up Ultrasound examination: one kidney smaller Peripheral blood renin activity Comparative renal vein renin assays Pulsed Doppler Captopril test Selective angiography

40 Atherosclerotic renal artery stenoses Revascularize or not? Novick 1984, Scoble 1990: Definitely YES New developments: IN FACT, NOT SO OFTEN - Three recent randomized studies: Webster 1998, Plouin 1998, van Jaarsfeld Angioplasty vs drug treatment in pts with moderate renal insufficiency - No significant difference in terms of renal function and of hypertension control, except for cases with bilateral stenoses in whom the HBP score diminished

41 ANGIOPLASTY Sos, 1991 Improvement in pts with serum creat < 132 µmol/l Jensen, KI, 1995: 107 patients Hypertension substantially improved Renal function: 74% improved, 26% worsened In 44 patients whose serum creatinine was < 270 µmol/l Mayo Clinic, 1995: 253 pts Improved: 27% Stabilized: 52% Worsened: 21%

42 Before angioplasty After angioplasty

43 * Abdominal aorta with severe atherosclerosis. Ulcerated plaques, covered with blood clots Ulcerated aortic plaque covered with clot *. Cholesterol crystals Renal interlobular artery obstructed by cholesterol crystals and by the inflammatory reaction to foreign bodies CUTANEOUS SIGNS OF CHOLESTEROL CRYSTAL EMBOLIS M

44 Angioplasty for atheromatous renal artery stenosis: current knowledge and trial results awaited Srivastava S & Beevers DG J Human Hypert 21:507-8, 2007 Does it lead to an improvement in BP control? Does it lead to an improvement in renal function? >> Possibly a small effect in some patients >> Sometimes Does it delay the deterioration of renal function? Does it delay the onset of ESRD? >> Sometimes >> We don't know Does it save lives by preventing heart attacks and strokes? >> We don't know Wait for the results of the CORAL AND ASTRAL trials

45 Other causes of renovascular hypertension Fibromuscular hyperplasia: the best indication and the best results of angioplasty Renal infarct: renin secretion progressively diminishes and disappears when fibrosis sets in. Treatment mostly medical Renal cancer: Up to 40 % of renal cancers are accompanied by new onset hypertension Thomas MC & al. Nephrol Dial Transplant. 1998; 13: Handler J J Clin Hypert 7:249-51, 2005

46 Fibromuscular hyperplasia

47 CT MRI

48 Multiple arteriovenous shunts lead to renal ischemia. >Twenty percent of renal cancers elicit renovascular hypertension. Hypertension may reveal renal cancer

49 Posttraumatic Renal infarct Complicated by malignant high-renin hypertension Cured by polar nephrectomy

50 Summary and conclusions Renovascular hypertension represents % of cases of hypertension and (aside from ESRD) the first cause of secondary hypertension The most common etiology is atherosclerotic renal artery disease It's diagnosis is easy, but treatment is disappointing. The results of the CORAL and ASTRAL trials are eagerly awaited Fibromuscular hyperplasia in a young female is the best indication for angioplasty Renal cancer is a common and curiously overlooked cause of renovascular hypertension

51 Similarities and Differences Component β-blockers ACE Inhibitors AII-A Renin Activity Angiotensin I Converting Enzyme Angiotensin II Angiotensin-(1 (1-7) Kinin (-) (+++) (++) (- / +) (+++) (+) (- / +) (-) (- / +) (-) Acutely (-) Chronically (- / +) Not determined (+++) (+) (+++) (++) (- / +) (+++) (-) Keys: : (-/+),( no change; (+), increase; ; (-),( inhibits

Functional vascular disorders

Functional vascular disorders Raynaud s phenomenon Raynaud s phenomenon Refers to Intermittent,bilateral attacks of ischemia of the fingers or toes, and sometimes ears or nose. It clinically manifests