Kidney, Sodium, Renin-Angiotensin SystemRenovascular Hypertension

Andreas Pittaras MD

Anatomy and Physiology

The juxtaglomerular apparatus

5' flanking region of the renin gene

Pathway of active renin in the juxtaglomerular cell

Renin mRNA accumulation in the juxtaglomerular cells

Renin protein in the juxtaglomerular cells of the afferent arteriole

Major mechanisms governing renin release

Individual nephron signals•  Low macula densa sodium chloride (stimulates)•  Decreased afferent arteriolar pressure (stimulates)Whole kidney modulating signals• Angiotensin II negative feedback (inhibits)•  β-1 receptor stimulation (stimulates)•   Other humoral factors        Vasopressin (inhibits)         Atrial natriuretic peptide (inhibits)         Dopamine DA-1 receptor (stimulates)Local effectors•   Prostaglandins (stimulate)•   Nitric oxide (inhibits)•   Adenosine (inhibits)•   Kinins (stimulate)

Physiologic stimulation of renin release

PHYSIOLOGY PHARMACOLOGY

Blood pressure Antihypertensive agents

Fluid volume Stimulators

     Sodium intake Renin-angiotensin blockade

     Hydration Diuretics

     Diuretics Vasodilators

     Menstrual cycle Suppressors

     Diurnal changes β-Adrenergic blockers

Posture Central α2-adrenergic agonists

Potassium intake Neutral

Protein intake Calcium antagonists

In situ hybridization histochemistry of rat kidney

Immunohistochemistry of a section of rat kidney

Plasma renin activity in human subjects

Analysis of human genomic DNA

The renin-angiotensin system

Angiotensinogen in the proximal tubular cells

The human angiotensin-converting enzyme gene

Angiotensin-converting enzyme (ACE)

Actions of ACE

Metabolism of the angiotensin peptides

Half-life of renin and angiotensin

Metabolism of the renin-angiotensin system

COMPONENT HALF-LIFE IN CIRCULATION DEGRADING ENZYME(S)

Renin 15 -20 min -

Angiotensinogen 4 -16 H Renin

Angiotensin I 1 -2 min Angiotensin-converting enzyme

Angiotensin II Seconds Aminopeptidase A,

Εndopeptidase, Ρrolylcarboxypeptidase

Angiotensin peptides and receptor subtypes that interact with each peptide

RECEPTOR ANGIOTENSINNone Angiotensinogen Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Asn-Glu ReninNone Angiotensin I NH2-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-COOH Angiotensin-converting enzymeAT1, AT2 Angiotensin II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe AngiotensinasesAT1, AT2 Angiotensin III

Arg-Val-Tyr-Ile-His-Pro-Phe AngiotensinasesUnknown Angiotensin (1-7) Asp-Arg-Val-Tyr-Ile-His-Pro AngiotensinasesAT4 Angiotensin (3-7)

Val-Tyr-Ile-His-Pro

Heterogeneity in the angiotensin II receptor population

Classification criteria of angiotensin receptor subtypes AT1 AT2

Potency order Angiotensin II > angiotensin III Angiotensin II =angiotensin IIISelective antagonistsI Losartan PD 123177 (Parke-Davis, NJ) PD 123319 (Parke-Davis) Valsartan CGP 42112A (Novartis) Eprosartan Zorsartan Irbesartan Candesartan Telmisartan TasosartanEffector pathways Phospholipase CGuanylate cyclase Phospholipase D Adenylate cyclaseSensitivity to dithiothreitol (sulfhydryl-reducing agents) Binding Binding Affinity No changeEffect of GppNHp Hill coefficient to no Change ~1

The AT1 receptor

mRNA for the angiotensin AT1 receptor

The angiotensin subtype-2 (AT2) receptor

Signal transduction mechanisms for the AT2 receptor

Renal effects of angiotensin subtype-2 receptor

•Release of bradykinin, nitric oxide, and cGMP

•Cell differentiation

•Antiproliferation

•Apoptosis

•Vasodilation

Blocking the AT1 receptor with valsartan

Combining benazepril and valsartan

Renal tissue localization of angiotensin II receptors

Cellular action of angiotensin II

Effects of angiotensin II

Renal effects of angiotensin II

•Decreased renal blood flow

•Proportionately increased efferent arteriolar resistance

increased glomerular capillary hydrostatic pressure

increased filtration

•Glomerular mesangial cell contraction decreased

glomerular capillary surface area available for filtration

decreased filtration (offsets above effect)

•Decreased medullary blood flow

•Increased tubular sodium reabsorption sodium retention

Paracrine effects of angiotensin II

Pathophysiology

Circulating components of the renin-angiotensin system

Mechanisms involved in renovascular hypertension

Animal models of renovascular hypertension

Administration of an angiotensin II inhibitor

Sodium dependency in the animal model

Renovascular Hypertension

Clinical clues suggesting renovascular hypertension•Systolic/diastolic epigastric, subcostal, or flank bruit

•Accelerated or malignant hypertension (HTN)

•Unilateral small kidney discovered by any clinical study

•Severe HTN in child or young adult, or after age 50 y

•Sudden development or worsening of HTN at any age

•HTN and unexplained impairment of renal function

•Sudden worsening of renal function in hypertensive patient

•Hypertension refractory to appropriate three-drug regimen

•Impairment in renal function in response to ACE inhibitor

•Extensive occlusive disease in coronary, cerebral, and

peripheral circulation

Causes of renal artery stenosis

Work-up for renovascular hypertension

SENSITIVITY, % SPECIFICITY, %•Rapid sequence IVP 74 86•Isotope renography 93 95 with ACE inhibition test•Peripheral vein PRA with 74 89 ACE inhibition test (captopril test)•Renal vein ratio of PRA test (stenotic/contralateral):    >1.3 85 40    >1.9 78 60•Peripheral vein PRA 92 96•Intravenous digital 88 89 subtraction angiography•Doppler ultrasonography 86 93•MRI 97 95•Renal artery angiography 100 100

Diagnostic indicators for renovascular hypertension

Diagnostic studies for renovascular hypertension

The captopril test

Criteria for renovascular hypertension

•Stimulated PRA of 12 ng/mL/h

•Absolute increase in PRA of 10 ng/mL/h

•Increase in plasma renin activity PRA of 150% or

400% if baseline PRA is <3 ng/mL/h

Plasma renin response to captopril

Objectives in the management of renovascular hypertension

Outcome after angioplasty or surgery for renal artery stenosis

ETIOLOGY ATHEROMA FIBROMUSCULAR DYSPLASIA

Treatment Angioplasty Surgery Angioplasty Surgery

Patients 391 1310 175 486

BP response

     Cured 19 45 50 64 ( 56- 81)

     Improved 52 29 42 23 ( 5 -40)

     Failed 30 24 9 11 ( 0 -25)

Selective renal arteriogram of a 43-year-old nonsmoking male

Selective renal arteriogram of a 31-year-old female

Renal arteriogram of a 31-year-old female

Renal causes of hypertension RENAL PARENCHYMAL RENOVASCULAR

•Acute and chronic

glomerulonephritis;

pyelonephritis;

nephrocalcinosis; neoplasms;

glomerulosclerosis; interstitial,

hereditary, or radiation

nephritis

•Obstructive uropathies and

hydronephrosis

•Renin-secreting renal tumors

•Renal trauma

•Renal arterial lesions;

occlusions; stenosis;

aneurysms; thrombosis;

Vasculitis•Connective tissue or

autoimmune disease with

renal vasculitis or

glomerulitis•Coarctation of the aorta with

renal ischemia•Aortitis with renal ischemia

Mechanisms that can influence the kidney

Sequence of events demonstrating the role of sodium retention

References