RENAL VASCULAR DISEASES

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). Takayashus arteritis up to 60% (Indian subcontinent and the Far East)
autopsy studies - 450% 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 - 1429% 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)

PATHOGENY (2)

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

RAS AND KIDNEY FUNCTION (1)

27% of those with RAS develop chronic renal failure within 6 years.

Nephrol Dial Transplant (2007) 22: 10021006; Atherosclerotic renovascular disease: beyond the renal artery stenosis; Pascal Meier, Jerome Rossert, Pierre-Francois Plouin ,Michel Burnier

ISCHAEMIC NEPHROPATHY

(1)

Interstitial fibrosis, tubular atrophy, glomerulosclerosis (including focal segmental glomerulosclerosis), periglomerular fibrosis arteriolar abnormalities (hialinosclerosis, atheroembolism). atherosclerotic nephropathy

ISCHAEMIC NEPHROPATHY (2)

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 9 atherosclerosis and renovascular disease. Circulation 106: 11651171, 2002)

ISCHAEMIC NEPHROPATHY

(3)

Acute renal failure bilateral renal arterial occlusion (RAO) intra-renal cholesterol atheroembolization damage from radiocontrast agents during intraarterial 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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ARVD AND ITS ASSOCIATION WITH HEART AND OTHER VASCULAR 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 12 compared with 116 33 g/m2).

ARVD AND ITS ASSOCIATION WITH HEART AND OTHER VASCULAR 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 13 carotid disease.

ARVD AND ITS ASSOCIATION WITH HEART AND OTHER VASCULAR DISEASES (4)
ARVD and hypertension ARVD is found in 25% 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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DIAGNOSIS OF ARVD (3)

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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DIAGNOSIS OF ARVD (4)

Investigation of ARVD Duplex 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 19 renal artery

DIAGNOSIS OF ARVD (7)

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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DIAGNOSIS OF ARVD (8)

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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DIAGNOSIS OF ARVD (9)

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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TREATMENT OPTIONS IN ARVD (2)

Medical treatment Limiting 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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TREATMENT OPTIONS IN ARVD (3)

CORAL study (Cardiovascular Outcomes in Renal Atherosclerotic Lesions)

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TREATMENT OPTIONS IN ARVD (4)

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/dL

Third-line agents (function of comorbidities)

Calcium channel blocker Beta Blocker Alfa Blocker Vasodilator

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TREATMENT OPTIONS IN ARVD (6)

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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TREATMENT OPTIONS IN ARVD (7)

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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TREATMENT OPTIONS IN ARVD (8)

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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TREATMENT OPTIONS IN ARVD (9)

Surgical treatment revascularization nephrectomy of small kidneys with relatively complete arterial occlusion.

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TREATMENT OPTIONS IN ARVD (9)

Evidence for renal revascularization Randomized Trials in Renal Artery Stenosis Intervention
Year Weibull 1993 Plouin 1998 Webster 1998 van de Ven 1999 van Jaarsveld 2000 n Medical Balloon 58 X 49 X 55 X 84 X 106 X Stent End Points X BP/renal function X BP X BP/renal function X Patency/BP/renal function X BP/renal function

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

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TREATMENT OPTIONS IN ARVD (10)

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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TREATMENT OPTIONS IN ARVD (11)

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 longterm 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 angiotensinconverting 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 50 Interfere with breakdown of bradykinin Contraindicated in pregnancy

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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Malignant hypertension (2)

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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Malignant hypertension (3)

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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