Curs 02 Renal Vascular Diseases

RENAL VASCULAR DISEASES

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DEFINITION (K/DOQI)

• Renal artery disease (RAD) is defined as a stenosis of the main renal artery or its proximal branches.

• Significant RAD– anatomically if there is a >50% stenosis of the lumen – hemodynamically if the stenosis exceeds 75%.

“clinically significant stenosis”

• RVHT - systemic hypertension due to hemodynamically significant RAD.

• Ischemic nephropathy – decreased GFR due to hemodynamically significant

RAD (K/DOQI) – impairment of renal function beyond occlusive disease

of the main renal arteries (Textor).

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SIGNIFICANCE

• The prevalence and incidence of chronic kidney disease (CKD) are increasing.

• ESRD incidente patients rates are 168 in Canada, 1 250 in the USA and 85.7 in Romania.

• It is of importance to search for reversible causes of CKD.

• Renal artery stenosis (RAS) may account for 5–22% of patients with ESRD who are older than 50 years;

• Correction of ischemic lesions can reverse decrease in renal function and improve CV outcomes.

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PREVALENCE

• RAS due to:– Atherosclerotic renovascular disease (ARVD >90%)– Fibromuscular disease (FMD). – Takayashu’s arteritis up to 60% (Indian subcontinent

and the Far East)

autopsy studies - 4–50% of subjects, (16.4 vs. 5.5% > 60 vs < 60 years)aortic angiography - 38% of patients with aortic aneurysm, - 33% in those with aortic occlusive disease - 39% lower limb occlusive disease. cardiac catheterization - 14–29% prevalence in coronary disease - < 10% in normal coronary arteries .

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PATHOGENY (1)

• ARVD is associated with three major clinical syndromes:– ischemic renal disease – hypertension.– Renal failure (acute and chronic)

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PATHOGENY (2)

Interrelation among Renal-Artery Stenosis, Hypertension, and Chronic Renal FailureRobert D. Safian, M.D., and Stephen C. Textor, M.D NEJM, Nr 6, vol 344:431-442, 2001

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RAS AND KIDNEY FUNCTION (1) 27% of those with RAS develop chronic renal failure within 6 years.

Nephrol Dial Transplant (2007) 22: 1002–1006; Atherosclerotic renovascular disease: beyond the renal artery stenosis; Pascal Meier, Jerome Rossert, Pierre-Francois Plouin ,Michel Burnier

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ISCHAEMIC NEPHROPATHY (1)

• Interstitial fibrosis, • tubular atrophy, • glomerulosclerosis (including focal segmental

glomerulosclerosis), • periglomerular fibrosis • arteriolar abnormalities (hialinosclerosis,

atheroembolism).

atherosclerotic nephropathy

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Histologic studies of interstitial fibrosis (Trichrome stain, left two (a) low magnification and high magnification (b) and immunohistochemistry for NF-kappa-B (NFkB, right) in swine. The presence of renal artery stenosis (RAS) induces both interstitial fibrosis and NFkB), which is accelerated by the presence of high cholesterol levels (HC). (Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, Napoli C, Lerman LO: Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106: 1165–1171, 2002)

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• Acute renal failure– bilateral renal arterial occlusion (RAO)– intra-renal cholesterol atheroembolization– damage from radiocontrast agents during intra-

arterial angiography– hypovolaemia, often with concurrent diuretic use– concurrent use of angiotensin-converting enzyme

inhibitors (ACE-I) or angiotensin II receptor blockers (AII-RBs).

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ARVD AND ITS ASSOCIATION WITH HEART AND OTHER VASCULAR

DISEASES (1)

Coronary artery disease

• RAS is associated with more severe and extensive coronary artery disease

• ? effects of renal ischemia or is a marker for advanced atherosclerosis and cardiovascular risk?

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DISEASES (2)Cardiac dysfunction including ‘flash’ pulmonary oedema • presenting clinical syndrome in 41% of patients with

bilateral ARAS and in 12% of patients with unilateral ARAS.• angiotensin II promoted sodium retention and increase in

pulmonary microcirculation permeability • ARVD patients were found to have significantly higher

prevalence– left ventricular hypertrophy (78.5% compared with

46.0%) – left ventricular diastolic dysfunction (40.5% compared

with 12.0%),– greater left ventricular mass index (183 ± 74 g/m2

compared with 116 ± 33 g/m2).

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DISEASES (3)

Aortic aneurysm and peripheral vascular disease– Prevalence of ARVD in patients undergoing aortography

for intermittent claudication varying from 33%, 39%, 44.9%;

Cerebrovascular disease– The coexistence of ARVD in patients who have stroke

and/or carotid stenoses In an autopsy series of 346 cases of brain infarcts >75% RAS was found in 10.4% of subjects and carotid artery stenosis in 33.6%.

– Patients with carotid stenosis were more likely to have ARVD than those without carotid disease.

– Conversely, ARVD patients are more likely to have carotid disease.

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DISEASES (4)

ARVD and hypertension• ARVD is found in 2–5% of all cases of hypertension 90% of patients with ARVD are hypertensive. • hypertension precedes ARVD development in many

cases.

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DIAGNOSIS OF ARVD (1)Clinical features suggestive of renovascular disease

Hypertension• Abrupt onset of hypertension in patients aged <30 years (suggestive of

FMD) or >50 years (suggestive of ARVD)• Absent family history of hypertension• Accelerated or malignant hypertension• Resistance to therapy (≥3 drugs)• Hypertension may be absent, particularly in patients with chronic

cardiac disfunction.

Renal abnormalities• Unexplained renal failure in patients aged >50 years• Elevation in plasma creatinine level after the initiation of ACE-I or AII-

RB therapy (> 30% increase in serum creatinine)• Asymmetrical kidneys on imaging

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DIAGNOSIS OF ARVD (2)

Other• Unexplained acute pulmonary oedema or

congestive cardiac failure• Femoral, renal, aortic or carotid bruits• Severe retinopathy• History of extra-renal vascular disease• Hypokalaemia

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DRASTIC

The most powerful predictors for detecting lesions of at least 50%:– age, – symptomatic vascular disease, – elevated cholesterol – the presence of an abdominal bruit.

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Investigation of ARVDDuplex ultrasonography

– widely available, noninvasive, and inexpensive.

– First line screening test

– sensitivity of 85% and specificity of 92%. – peak systolic velocity, has the highest

performance characteristics;

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DIAGNOSIS OF ARVD (6)Magnetic resonance imaging• the favoured imaging method for the proximal renal vasculature• The sensitivity ranges from 83% to 100% and specificity from 92% to

97%.• Gadolinium is non-nephrotoxic at low doses;

MR renal angiogram showing tight stenosis of the right renal artery and occlusion of the left renal artery

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Computed tomography angiography • Sensitivity and specificity of 95%• Best for aortorenal calcification (utility in stent

placement);• Visualise main and accesory renal arteries.• Limitations

– risk of contrast nephropathy– poor visualization of the distal main renal

artery and segmental branches.

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Renal scintigraphy and measurement of individual kidney function

• the captopril test unravel the degree of renin activation• Asymmetric result of a functional test RAS• Sensitivity and specificity variable: 43% - 93%• Insufficient sensitivity in:

– Renal failure;– Renin independent hypertension

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Renal Arteriography• the gold standard diagnostic test. • risks of contrast nephropathy and

atheroembolic renal disease

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TREATMENT OPTIONS IN ARVD (1)

Few topics provoke more controversy between nephrologists and interventional cardiologists than management of atherosclerotic renovascular disease

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Medical treatmentLimiting the progression of atheromatous disease and chronic kidney disease– vigorous control of hypertension and hyperlipidemia,– diabetes control– use of antiplatelet agents, – cessation of smoking – lifestyle modification (including reduced dietary intake

of salt and increased exercise).– attention to the complications of renal insufficiency

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CORAL study (Cardiovascular Outcomes in Renal Atherosclerotic Lesions)

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Antihypertensive therapy• Is there an ideal blood pressure target that confers

maximal cardiovascular protection?• In CORAL, the target blood pressure is ≤140/ 90 mm

Hg ; ≤130/80 mm Hg is recommended for patients with hypertension and diabetes or renal disease.

• Is there a specific antihypertensive regimen that provides cardiovascular benefits beyond just lowering blood pressure?

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TREATMENT OPTIONS IN ARVD (5)First-line agent

– Angiotensin receptor antagonist – First-line agent if ARB not tolerated - ACE inhibitor – especially for those

• with proteinuric chronic parenchymal disease, • and those with coexisting coronary artery disease and

cardiac dysfunction. Second-line agent • Thiazide diuretic • Combinations with ARB/ACE may be available• Use loop diuretics for patients with serum creatinine 2 mg/dLThird-line agents (function of comorbidities)• Calcium channel blocker • Beta Blocker • Alfa Blocker• Vasodilator

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Dyslipidemia Treatment• in terms of cardiovascular risk RAS is considered a

coronary artery disease equivalent. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)

• Goal of therapy – low-density lipoprotein cholesterol <100 mg/dL – some suggesting a target of < 70 mg/dL

Statins• effects independent of lipid-lowering• stabilize, slow progression or even induce regression of

atherosclerotic plaque • reduction of proteinuria

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Diabetes Mellitus• HbA1c of <7 % with oral agents and/or insulin • medical nutrition therapy;• physical activity;• multidisciplinary foot and eye care;Chronic Renal Insufficiency• Tight control of blood pressure, dyslipidemia, diabetes;

manage anemia; hyperparathyroidism. (Guidelines) Antiplatelet Agents• Although there are no direct data in patients with RAS,

administration of an antiplatelet agent is required in CORAL and recommended for all patients with RAS.

• Aspirin, Clopidogrel or Ticlopidin.

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Effect of the Medical Therapy Intervention• reduce cardiovascular risk • progression to end-stage renal disease actually

does not respond very well to medical therapy

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Surgical treatment• revascularization • nephrectomy of small kidneys with relatively complete

arterial occlusion.

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Evidence for renal revascularizationRandomized Trials in Renal Artery Stenosis Intervention

Year n Medical Balloon Stent End Points

Weibull 1993 58 X X BP/renal functionPlouin 1998 49 X X BPWebster 1998 55 X X BP/renal functionvan de Ven 1999 84 X X Patency/BP/renal function

van Jaarsveld 2000 106 X X BP/renal function

Benefits: • A modest improvement in blood pressure control • no improvement in renal function.

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Definite indications for renal revascularization

• Recurrent ‘flash’ pulmonary oedema • Severe hypertension resistant to all medical therapy.• When a patient who requires ACE-I or AII-RB

therapy (e.g. for cardiac failure) presents with significant ACE-I-related uraemia.

• RAO in a reasonably sized kidney

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CONTROVERSIES

Effect of Revascularization on Blood Pressure

Revascularization may fail to cure hypertension

In long-standing hypertension, secondary processes that sustain hypertension– Vascular remodeling, – atherosclerosis, – ischemic damage to the poststenotic kidney, – hypertensive injury to the nonstenotic kidney

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PROGNOSIS OF PATIENTS WITH ARVD

• Major mortality from cardiovascular complications; risk of death is almost six times that of developing ESRD

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NEPHROSCLEROSIS

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Definition

• clinical syndrome characterized by long-term essential hypertension, hypertensive retinopathy, left ventricular hypertrophy, minimal proteinuria, and progressive renal insufficiency

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Pathophysiology

• Glomerular ischemia:chronic hypertension result in narrowing of preglomerular arteries and arterioles, with a consequent reduction in glomerular blood flow

• Glomerulosclerosis induce by glomerular hypertension and glomerular hyperfiltration

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Genetics

• a significant loss in kidney function was observed in black people despite similar levels of BP control

• polymorphism in the angiotensin-converting enzyme (ACE) gene, the DD genotype

• increased angiotensinogen mutations

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Frequency

• USA: 1985-2005, adjusted rates of ESRD caused by hypertension increased 140%

• Hypertensive nephrosclerosis accounts for more than one third of patients on hemodialysis.

• Europe: 12% of new patients starting renal replacement therapy

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Race

• In black people, hypertensive nephrosclerosis occurs earlier, is more severe, and more often causes ESRD (36.8% in black patients vs 26% in white patients).

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Age

• The diagnosis of hypertensive nephrosclerosis increases with advancing age.

• The peak age for the development of ESRD in white patients is 65 years and older, while the peak age is 45-65 years in black people

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DIAGNOSIS

• Long-standing or very severe hypertension• Black race • Hypertension preceding renal dysfunction • Hypertension diagnosed prior to the onset of

proteinuria • No evidence of another renal disease • Biopsy findings compatible with the diagnosis • Proteinuria less than 0.5 g/d • Hypertensive retinal changes • Left ventricular hypertrophy

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Lab Studies(I)

• Baseline complete blood cell count

• Creatinine level

• Electrolyte status

• Urinalysis

• Either a spot urine test for albumin or creatinine ratio or a 24-hour urine collection - To determine total protein excretion

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Lab Studies(II)

• urine protein excretion of lower than 1 g/d;• in some patients a 24-hour urinary protein

excretion greater than 1 g/d has been described.

• When secondary changes of focal segmental glomerulosclerosis (FSGS) related to hyperfiltration develop, proteinuria can increase to the nephrotic range.

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Imaging Studies

• echocardiogram to assess left ventricular size. • Renal imaging with either an ultrasound or an

intravenous pyelogram reveals that kidney size is usually symmetric and may be normal or modestly reduced.

• The renal calices and pelves are normal. • Renal asymmetry or irregularities in the contour raise the

possibility that hypertension could be secondary to renal artery stenosis or reflux nephropathy

• ECG typically shows left ventricular hypertrophy; the sensitivity of ECG in helping to detect left ventricular hypertrophy may be as low as 22%.

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Histologic Findings (I)

• medial and intimal thickening with intimal fibrosis of preglomerular arterioles

• hyalinosis of afferent arterioles

• secondary tubular atrophy

• interstitial fibrosis

• malignant hypertension – Fibrinoid necrosis– microinfarcts

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Histologic Findings (II)

• GLOMERULAR CHANGES– Obsolescent glomeruli were defined as glomeruli in

which Bowman's space was occupied by collagenous, PAS positive material, and the tuft was retracted

– Solidified glomeruli were defined as glomeruli in which the entire tuft was solidified, in the absence of the collagenous change in the capsular space

– Disappearing glomeruli were identified as globally sclerotic glomeruli where there was an absence or partial disappearance of Bowman's capsule

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TREATMENT (I)• BP goal of less than 130/80 mm Hg to preserve renal function and to reduce

cardiovascular events in patients with hypertension and diabetes.• Lower BPs are recommended for patients with proteinuria greater than 1 g/d and

renal insufficiency, regardless of etiology

• ACE inhibitors

• Effects and indications – Reduce proteinuria – Specific renal protective effect both in diabetic and nondiabetic renal impairment – Reduce morbidity and mortality rates in congestive heart failure – Monotherapy less effective in older patients (>50 y) – Larger doses required in black patients – Inhibit or blunt all adverse metabolic effects of thiazides – Dose reduction required in renal failure – Reduce left ventricular hypertrophy and thirst

• Adverse effects – Cough (approximately 10%) – Angioedema (rare) – Hyperkalemia (especially in renal tubular acidosis type IV) – GFR reduction in patients with impaired renal function – May precipitate acute renal failure in patients with renal artery stenosis – Interfere with breakdown of bradykinin – Contraindicated in pregnancy

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TREATMENT (II)• Angiotensin II receptor antagonists • Effects and indications

– Reduce proteinuria – Indicated in patients intolerant of ACE inhibitors – Can be used in combination with an ACE inhibitor – Do not cause cough – Reduce left ventricular hypertrophy and thirst similarly to ACE

inhibitors – Do not interfere with breakdown of bradykinin

• Adverse effects – Hyperkalemia – May reduce GFR in patients with impaired renal function – May precipitate acute renal failure in patient with renal artery

stenosis – Angioedema (rare) – Contraindicated in pregnancy – Data in black patients limited

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TREATMENT (III)

• Calcium channel blockers• Effects and indications • Effective as monotherapy in black patients and elderly patients • Potentiate ACE inhibitor effects • Renal protection not proven • Reduce morbidity and mortality rates in congestive heart failure • Indicated in patients with diastolic dysfunction • No change in dose with renal failure• Adverse effects • Possible increase in cardiovascular mortality rate with short-acting

dihydropyridines • Edema • Constipation (verapamil) • Profound bradycardia possible when verapamil and diltiazem used

in combination with a beta-blocker

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Malignant hypertension (1)

• 1% of patients with hypertension;• It may occur in patients with preexisting hypertension or

in a previously normotensive patient • Systolic BP can range from 150-290 mm Hg while

diastolic BP can vary from 100-180 mm Hg. • Keith-Wagener grade III (hemorrhages and exudates)

and grade IV retinal changes (papilledema) are the hallmarks of malignant hypertension.

• Acute heart failure: pulmonary edema can be the presenting signs in approximately 10% of patients.

• Left ventricular hypertrophy is present in as many as 75% of patients at presentation

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• 60% of patients complain of headaches • 5-10% cerebrovascular event (eg, focal

cerebral ischemia, cerebral/subarachnoid hemorrhage)

• hypertensive encephalopathy is characterized by headache, nausea, vomiting, and visual blurring, together with impaired cognitive function, generalized seizures, or cortical blindness.

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• Microangiopathic hemolytic anemia (schistocytes, thrombocytopenia, increased fibrin degradation products, and increased fibrinogen) is frequently present

• Renal involvement is common, but the degree of severity varies

• Proteinuria is common, but overt nephrotic syndrome is unusual

• 30% of patients will have an elevated serum creatinine level at presentation

• Other symptoms include weakness, malaise, fatigue, and weight loss

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TREATMENT OF MALIGNANT HYPERTENSION

• Malignant hypertension complicated by organ failure is a medical emergency and requires rapid reduction in BP

• In uncomplicated malignant hypertension, rapid BP reduction is not as critical as in the previous group with BP reduction by up to 20% of the presenting values, or a systolic BP of greater than 170 mm Hg in the first 24 hours has been an acceptable target.

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Curs 02 Renal Vascular Diseases