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the impact of genetic modulation of vein grafts on the development of intimal hyperplasia, and hold some promise in reducing or
minimizing this significant cause of vein graft failure.
126
Late graft
failures occurring beyond 2 years are typically due to progression
of atherosclerotic occlusive disease within the inflow or outflow
arteries.
Given the known incidence of graft failure and the potentially
dire consequence in terms of limb salvage or preservation of limb
function in a patient with limited options for secondary or tertiary
bypass, the ability to maintain graft patency through early identification and prompt correction of graft stenoses is of paramount
importance.
127
Serial postoperative surveillance scanning with a
duplex ultrasound has proved an excellent means of accurately
identifying hemodynamically significant stenoses within the vein
graft that threaten the graft patency.
128
Subsequent confirmation by
angiography and prophylactic treatment by percutaneous cutting
balloon angioplasty, surgical patch angioplasty, or interposition
grafting of significant lesions minimizes the risk of graft thrombosis and ensures optimal long-term graft patency.
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PA RT V
RENAL ARTERY DISEASE
CHAPTER
22 Pathophysiology of Renal
Artery Disease
Stephen C. Textor
Vascular disease affecting the renal arteries presents complex
challenges to clinicians. Thanks to recent advances in vascular
imaging, more patients than ever before are being identified with
some degree of atherosclerotic or fibromuscular renovascular
disease. Many of these lesions are of minor hemodynamic
importance at the time of detection. Some reach a degree at
which perfusion pressures and intrarenal hemodynamics are
altered, leading to changes in blood pressure regulation and
renal function. These can produce a variety of recognizable clinical syndromes illustrated in Figure 22-1. These range from modest
changes in systemic arterial pressure to impaired volume control
associated with congestive heart failure (CHF) to threatened viability of the kidney, sometimes designated
Understanding the pathways by which renovascular disease affects
cardiovascular and renal disease is important for both diagnosis
and for defining optimal management using tools both to block
the renin-angiotensin system and to restore the circulation.
Most renovascular lesions are the result of atherosclerosis. With
the aging of the U.S. and other Western populations and reduced
mortality from stroke and coronary disease, the prevalence of
vascular disease in other vascular beds reaching clinically critical levels appears to be increasing.
clinical manifestations of these lesions, the potential for disease
progression, and the benefits and limitations of vascular repair
are essential for vascular medicine specialists. This chapter will
examine the pathophysiology of renovascular lesions regarding
blood pressure control, ischemic nephropathy, and clinical syndromes such as flash pulmonary edema. Specific issues regarding
diagnostic evaluation and management are addressed elsewhere
(see Chapter 23).
A wide range of lesions can affect the renal blood supply,
some of which are summarized in
ognition of renovascular disease resulted from searching for
underlying causes of hypertension. This followed the seminal
observations of Goldblatt more than 70 years ago2 that renal artery
constriction produced a rise in arterial pressure in the dog. These
studies were among the first to establish a primary role of the
kidney in overall blood pressure regulation. Renovascular hypertension produced by a “clipped” renal artery remains among the
most widely studied experimental forms of angiotensin-dependent hypertension.
3,4
1
Epidemiology of Renal Artery Disease
Fibromuscular disease may be identified in 1% to 3% of normal
kidney donors subjected to angiography before donor nephrec-
5
tomy.
Of those developing clinical hypertension and referred for
revascularization, more than 85% are females with a predilection
for disease in the right renal artery.
most commonly in the midportion and distal segments of the renal
6
The location of these lesions is
ischemic nephropathy.
Understanding the variety of
Box 22-1. Historically, rec-
artery. A variety of fibromuscular lesions have been described,
but the most common is medial fibroplasia. Occasionally, such
lesions may be found in the carotid and other vascular beds, but
most commonly they are limited to the renal arteries. Most do not
progress to impair renal function, although some lead to arterial
dissection and/or thrombosis with loss of the kidney.
Atherosclerosis is the most common cause of renal artery
disease. Its presence and severity are related to age and the presence of other atherosclerotic disease of the descending aorta and
lower extremities. Population-based series, such as one from North
Carolina, indicate that among 834 subjects older than 65 years,
significant renal artery stenosis (RAS; defined as Doppler peak systolic velocity (PSV) above 1.8 m/s) can be identified in 6.8% of the
general population, regardless of race.7 Recent series of carotid,
coronary, and peripheral angiography indicate that the prevalence
of renovascular disease corresponds to overall atherosclerotic burden. Incidental renal artery occlusive disease (>
been reported in 11% to 18% of patients with coronary artery disease (CAD), particularly when significant hypertension is present.
Peripheral vascular and aortic disease is associated with higher
prevalence (25%-33%). As expected, risk factors predicting the presence of RAS include smoking, hyperlipidemia, hypertension, and
diabetes. A corollary observation is that renovascular hypertension
resulting from these lesions is now most commonly superimposed
gradually upon preexisting essential hypertension. Hence, the
blood pressure response and “cure” rates after successful restoration
of blood flows to the kidney are limited by preexisting conditions.
50% stenosis) has
8
Pathophysiological Consequences
of Renovascular Disease
Under basal conditions, renal blood flow is among the highest of
all organs. This feature reflects the kidney's filtration function, and
less than 10% of delivered oxygen is sufficient to maintain renal
metabolic needs. Importantly, a fall in renal blood flow is accompanied by decreased oxygen consumption, partly due to reduced
metabolic demands of filtration and tubular solute reabsorption.
Reduced renal blood flow can be sustained without measurable
change in total kidney oxygen levels (as assessed by renal vein oxygen tension),
medullary and cortical tissue oxygenation as measured in human
subjects using blood oxygen level–dependent (BOLD) magnetic
resonance (MR).
of oxygen as a primary stimulus for either hypertension or renal
tissue injury and cast some doubt on the term ischemic nephrop-
athy. Alternative terms proposed included
disease and hypoperfusion injury.12 Nonetheless, severe vascular
stenosis leading to diminished renal perfusion eventually does
lead to renal tissue injury and interstitial fibrosis.
9
stimulation of erythropoietin release,10 or reduced
11
These observations argue against an overall lack
azotemic renovascular
c0110
285
286
500
Syndromes of Renovascular Disease
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Asymptomatic
"Incidental RAS"
Renovascular hypertension
CH
22
FIGURE 221 Renal artery stenosis (RAS) produces a broad range of
manifestations, ranging from “incidental” disease with no hemodynamic
effect to deteriorating kidney function and accelerating cardiovascular
morbidity. CHF, congestive heart failure; CV, cardiovascular. (Modified with permission
from Garovic V, Textor SC: Renovascular hypertension and ischemic nephropathy. Circulation
112:1362–1374, 2005.)
RAS
89
Accelerated CV disease
CHF
Stroke
Secondary aldosteronism
Ischemic nephropathy
Box 22-1 Vascular Lesions That Produce Renal
Hypoperfusion and Renovascular
Hypertension Syndrome
Unilateral Disease (Analogous to Two-Kidney,
One-Clip [2K1C] Hypertension)
Unilateral atherosclerotic renal artery stenosis (RAS)
Unilateral fibromuscular dysplasia (FMD)
Medial fibroplasia
Perimedial fibroplasia
Intimal fibroplasia
Medial hyperplasia
Renal artery aneurysm
Arterial embolus
Arteriovenous fistula (AVF)(congenital/traumatic)
Segmental arterial occlusion (posttraumatic)
Extrinsic compression of renal artery (e.g., pheochromocytoma)
Renal compression (e.g., metastatic tumor)
Bilateral Disease or Solitary Functioning Kidney
(Analogous to One-Kidney, One-Clip [1K1C] Model)
Stenosis to a solitary functioning kidney
Bilateral RAS
Aortic coarctation
Systemic vasculitis (e.g., Takayasu's arteritis, polyarteritis)
Atheroembolic disease
Vascular occlusion due to endovascular aortic stent graft
400
300
200
Increase in renin (%)
100
0
1 (BL1)1 (BL2) 0.9 0.8 0.7 0.6 0.5 1 (end)
Degree of Stenosis (Pd/Pa)
FIGURE 222 Relationship between developed pressure gradient
between aorta (Pa) and distal renal artery (Pd) and activation of reninangiotensin system in humans. Progressive gradients were developed by
expanding a catheter balloon. Data indicate that activation of renal venous renin
activity from stenotic kidney (closed circles), nonstenotic kidney (open circles), and
aorta (closed squares) occurred only after a translesional gradient between 10
and 20 mmHg was created. Such a gradient usually requires advanced occlusive
disease, usually more than 70% lumen occlusion. (Reproduced with permission
from De Bruyne B, Manoharan G, Pijls NH, et al: Assessment of renal artery stenosis
severity by pressure gradient measurements. J Am Coll Cardiol 48:1851–1855, 2006.)
16
translesional pressure gradients, but the relationship is not linear.
In some instances, an abrupt fall in poststenotic pressure develops
beyond a subcritical range of stenosis.
17
Even moderate stenosis,
especially when superimposed on intrarenal microvascular disease, may contribute to adverse renal outcomes. Kidneys with a
baseline renal artery disease classification of less than 60% stenosis
have 11.7% 2-year cumulative incidence of renal atrophy (defined
radiologically as a loss of kidney size)
dence of renal artery disease progression, although progression to
total renal artery occlusion is uncommon.
18
and 28% cumulative inci-
19
Increased severity of
RAS in patients undergoing cardiac catheterization has an adverse
effect on survival, with the 4-year adjusted survival for patients with
a 50% stenosis decreasing to 70%, compared to 89% in patients
without RAS.
20
Therefore, even relatively minor stenosis in the renal
artery might have long-term functional implications, especially in
the presence of additional risk factors or coexisting renal disease.
Subcritical Levels of Stenosis
The majority of renal artery lesions that compromise renal function are caused by gradually developing atherosclerosis of the renal
vascular bed. As noted earlier, some patients undergoing cardiac
catheterization have “incidental” renal lesions producing more than
50% cross-sectional stenosis,
strong independent predictor of mortality. Moreover, nonobstructive
RAS (20%-50% decrease in renal arterial luminal diameter) can be
found in an additional 28% of patients undergoing cardiac catheter-
13
ization
eral vascular disease.
including more than 15,000 subjects confirmed this overall range
of disease prevalence and the rise with increasing atherosclerotic
burden.
nal diameter are not considered hemodynamically significant, the
relationships between resting pressure gradients and angiographic
degree of stenosis are curvilinear and only approximate at best. As a
predictor of mortality, even low-grade atherosclerotic lesions denote
a hazard nearly equal to more advanced disease.
ity of vascular occlusion from angiographic images is notoriously
unreliable. It should be emphasized that activation of pressor mechanisms depends upon the presence of a pressure gradient between
the aorta and distal renal vasculature
eral relationship between estimated diameter stenosis and peak
and 48% of patients undergoing aortography for periph-
8
Although lesions producing less than 50% in arterial lumi-
14
13
for whom the presence of RAS is a
A recent systematic analysis of these reports
15
Estimating sever-
16
(Fig. 22-2). There is a gen-
RENAL MICROVASCULAR DISEASE
Lesions in the main renal artery may be superimposed upon or confused with other causes for ischemic renal injury. Intrarenal vascular
lesions are commonly observed in the course of various nephropathies, many of which have an ischemic component.
including diabetes, hypertension, atherosclerosis, and aging elicit
vasoconstriction or structural changes leading to intrarenal smallvessel disease and ischemic injury similar to that observed in largevessel disease. Loss of microvessels and impaired capillary repair
correlate with development of glomerular and tubulointerstitial
scarring,
22,23
and may lead to end-stage renal failure. Renal microvascular disease distal to a stenosis in the renal artery may perpetuate and exacerbate renal parenchymal injury and may blunt renal
recovery. The presence of small microvessel injury is difficult to
verify but may account for changes in diastolic blood flow such as
that producing changes in renal resistance index. Elevations of renal
resistance index have been proposed to predict poor outcomes in
many renal diseases, including renovascular disease.
Critical Renal Artery Stenosis
High-grade vascular stenosis eventually leads to a decrease in renal
perfusion pressure. Critical stenosis is identified when it produces
a fall in renal blood flow and glomerular filtration rate (GFR).
21
Risk factors
24
During experimental renal artery occlusion, the kidney sustains
autoregulation of blood flow through a range of perfusion pressures
from 200 mmHg to approximately 80 mmHg. Mechanisms underlying autoregulation include myogenic responses to changes in wall
tension, release of vasoactive substances, and the tubuloglomerular feedback. The latter responds to decreased renal perfusion pressure and salt delivery by decreasing vascular resistance distal to the
obstruction. In addition, during a fall in renal perfusion pressure,
the kidney activates multiple pathways that elevate systemic blood
pressure, an effect that tends to restore renal perfusion pressure
and sustain renal blood flow at the expense of arterial hypertension (
Fig. 22-3). Consequently, as long as systemic arterial pressure is
allowed to rise, a fall in renal blood flow does not occur until renal
arterial diameter is reduced by 65% to 75%. Recent clinical studies suggest that noninvasive radiological imaging commonly overstates the degree of stenosis. Measurement of physiological stimuli,
such as the release of renin, indicate that a translesion gradient of
at least 10% to 20% reduction is necessary for biological responses
to occur in humans.
16
To achieve such a gradient, luminal occlusion may need to exceed 80% stenosis. Under some conditions, gradients above 20 mmHg that develop during intrarenal hyperemic
challenge with dopamine may disclose hemodynamic significance
of lesions under 60% in severity.
25
When renal perfusion pressure falls gradually, additional mechanisms are recruited that protect the kidney from the functional
and morphological consequences observed after acute ischemic
injury. These include development of collateral vessels and redistribution of intrarenal blood flow from the cortex to the medulla.
Renal cortical blood flow autoregulates more efficiently than
the outer medulla, which is continuously on the verge of anoxia.
During chronic reduction of renal blood flow, medullary perfusion
and oxygenation are relatively maintained by adaptive mechanisms at the expense of cortical blood flow.
26
When poststenotic
renal artery pressures eventually fall further, either due to progressive vascular occlusion or reduction of systemic blood pressures
by drug therapy, renal volume decreases.
In clinical terms, renal atrophy can be defined as a loss of renal
length by at least 1 centimeter, and a difference in size between
the two kidneys is suggestive of unilateral RAS (or a higher grade of
stenosis in one of the kidneys). A decrease in renal volume results
from a decrease in filling pressure, filtrate, and blood content of
the kidney, as well as structural atrophy of the renal tubules due
to apoptosis and necrosis. Apoptosis is an active, pre-programmed
**
Carotid (n=5)
**
**
Iliac (n=6)
(n=9)
(n=9)
180
160
140
120
100
80
mmHg
60
40
20
FIGURE 223 Development of arterial hypertension after placement of
renal artery clip lesion in conscious rat aortic coarctation model. Poststenotic
pressures (iliac artery) rise to near-baseline levels at the expense of systemic
arterial pressures (carotid). Despite significant pressure gradient, renal perfusion
is maintained. Reduction of systemic pressures, however, lowers renal perfusion
and activates pressor systems, including renin-angiotensin system (see text).
(Reproduced with permission from Textor SC, Smith-Powell L: Post-stenotic arterial
pressure, renal haemodynamics and sodium excretion during graded pressure reduction
in conscious rats with one- and two-kidney coarctation hypertension. J Hypertens
6:311–319, 1988.)
**P<0.01
0
90
Aortic coarctation
**
−5 −3 −1 0 +1 +3 +5 4−6
Time relative to coarctation (days) Weeks
form of cell death that is intricately regulated and distinct from
cellular necrosis and likely serves as a protective mechanism to
allow renal “hibernation.” These changes may be reversible, since
tubular cells show vigorous potential for regeneration. Loss of intrarenal microvessels that accompanies the ongoing scarring process
may also contribute to renal shrinkage
partly reversible upon enhancement of angiogenic signaling.
27
(Fig. 22-4), but might be
28
However, if a blood flow deficit persists, permanent damage to the
kidney may occur. As mentioned, decreased renal blood flow is
often accompanied by a decline in GFR and inhibition of tubular epithelial transport that limit renal oxygen consumption and
maintain oxygen saturation. Hence, the kidney does not actually
develop “ischemia” until an extreme decrease in renal blood flow
develops.
RENOVASCULAR HYPERTENSION
Goldblatt et al and Loesch were the first to show in the 1930s
that obstruction of the renal artery is followed by an increase
in systemic blood pressure.
2,29
The characteristics of renovascular hypertension depend to a large extent on the status of the
kidneys. Unilateral RAS may be present with an intact contralateral renal artery (the experimental form is termed two-kidney, one-
clip, or 2K1C). This model is characterized by counterregulatory
processes in the contralateral kidney leading to sodium excretion
in response to elevated arterial pressure (pressure natriuresis;
Fig. 22-5A-B). Alternatively, RAS may affect a solitary kidney (one-
kidney, one-clip, or 1K1C;
Fig. 22-6A-B). Bilateral RAS and 1K1C lead
to more severe renovascular hypertension, although bilateral RAS
may behave similarly to 2K1C if one kidney is significantly less
ischemic than the other. Patients with this constellation of findings
have higher mortality, are more prone to circulatory congestion,
and are more likely to experience deterioration of kidney function
during administration of antihypertensive agents, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II)
receptor blockers (ARBs).
The exact mechanisms responsible for renovascular hypertension have long been debated. The immediate increase in blood
pressure in RAS results from release of renin from the stenotic
kidney. This leads to increased formation of Ang II, which
increases peripheral vascular resistance, plasma aldosterone,
sodium retention, extracellular volume, and cardiac output
(
Fig. 22-7). Early studies using ACE inhibitors30 and more recent
studies in an AT1A receptor knockout mouse model of 2K1C
confirm the essential role of Ang II in mediating Goldblatt
hypertension during its initial phase.
31
Experiments with kidney transplantation in these knockout strains indicate that both
renal and extrarenal angiotensin receptors participate in regulation of blood pressure.
4
Blockade of angiotensin action in
experimental models prevents the initial series of events and
delays the development of renovascular hypertension indefinitely. Activation of the sympathetic nervous system also plays
an important role in the pathogenesis of renovascular hyperten-
32
sion
primarily via the renal afferent nerves. Both the peripheral
and central aspects of the autonomic system are also under the
influence of Ang II. If the increase in pressure restores renal
perfusion pressure distal to the stenosis, most of these alterations return to baseline levels, with the exception of peripheral
vascular resistance.
After the initial rise in activity from the renin-angiotensin system, maintenance of renovascular hypertension in 1K1C models depends mainly on volume expansion. In 2K1C, the interplay
between plasma renin activity and extracellular volume is more
complex. The contralateral kidney responds to the elevated
systemic pressure by increasing sodium excretion (pressure
natriuresis), an effect that tends to drive blood pressure down
and decrease perfusion pressure of the stenotic kidney. This effect
again leads to an increase in renin release, which in turn elevates
systemic blood pressure, and so forth. In high-grade RAS, this cycle
of events may induce extracellular volume depletion and renal
failure. Although these features are consistently demonstrated in
287
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288
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CH
Medulla
22
Cortex
NormalABCMV proliferation
(early atherosclerosis)
FIGURE 224 Microcomputed tomography imaging of vascular structures in kidney cortex and medulla in a swine model. A, Normal vascular density.
B, Microvascular (MV) proliferation observed after cholesterol feeding. C, MV rarefaction and interstitial fibrosis observed beyond a high-grade renal artery stenosis
(RAS). (Reproduced with permission from Lerman LO, Chade AR: Angiogenesis in the kidney: a new therapeutic target? Curr Opin Nephrol Hypertens 18:160–165, 2009.)
MV rarefaction
(chronic renal ischemia)
91
experimental models, human renovascular hypertension frequently has elements of both 1 K and 2 K pathophysiology, particularly
when the function of the contralateral kidney is compromised.
It is important to recognize that activation of the systemic
renin-angiotensin system is temporary in renovascular hypertension. After a period of time, circulating levels of plasma
renin activity and angiotensin fall despite sustained elevation
of peripheral vascular resistance. This may be the result of both
(1) a slow response to Ang II, through which low levels of angiotensin have pressor actions, and (2) recruitment of additional
mechanisms of vasoconstriction. The latter include activation
of vasoconstrictor lipoxygenase products, oxidative stress, and
endothelin. Additional rise in pressure results from an imbalance
between vasoconstrictors and vasodilators, such as that derived
from decreased bioavailability of nitric oxide (NO). An important role is ascribed to dissociation between systemic blood pressure, extracellular volume, and inappropriate levels of Ang II.33
The complexity of these relationships partly explains the failure of measuring any single pathway to predict blood pressure
responses to renal revascularization.
34
ACCELERATED HYPERTENSION
AND PULMONARY EDEMA
Series of patients referred for renal revascularization in the last
decade have included older patients with more widespread
atherosclerotic disease than ever before.
35,36
This reflects both
improved medical care leading to better blood pressure control and reduced mortality from coronary and cerebrovascular
disease. Patient demographics commonly include more women
than men and a high prevalence of coronary disease, CHF, and
known cerebrovascular disease. In some cases, suspicion
arises regarding RAS because of rapid acceleration of these processes, particularly the rapid rise in arterial pressure in a previously
stable patient. When untreated, a cycle of malignant-phase hypertension and hyponatremia (attributed to the dipsogenic action of
Ang II) may ensue. In other cases, presenting symptoms include
recent progression of hypertension followed by neurological
symptoms of an acute stroke.
Some patients develop cycles of worsening CHF out of proportion to left ventricular (LV) dysfunction. This sometimes
has been designated flash pulmonary edema.
37
Many of these
patients have bilateral disease or stenosis to a solitary functioning kidney. When volume expanded, renal function may improve
slightly at the price of hypertension and circulatory congestion.
Sudden pulmonary edema partly reflects diastolic dysfunction
precipitated by a rapid rise in afterload
38
in addition to impaired
sodium excretion as a result of renal hypoperfusion. During
volume depletion, serum creatinine commonly rises with evidence of prerenal azotemia. This condition warrants recognition
because several series indicate that cycles of symptomatic exacerbation and hospitalization can be improved with successful
renal revascularization.
39,40
RENAL HYPOPERFUSION INJURY: ISCHEMIC
NEPHROPATHY
The precise mechanisms responsible for irreversible renal scarring in so-called ischemic nephropathy in the absence of true
ischemia have not been fully elucidated. They are likely related
to interaction among several systems activated in the kidney,
the most prominent of which is the renin-angiotensin system.
289
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PATHOPHYSIOLOGY OF RENAL ARTERY DISEASE
A
Unilateral Renal Artery Stenosis
Reduced renal perfusion
↑ Renin-angiotensin system (RAS)
↑ Renin
Suppressed RAS Increased Na
Increased renal perfusion
(pressure natriuresis)
+
excretion
↑ Ang II
↑ Aldosterone
Ang II-dependent hypertension
Effect of blockade of RAS
Reduced arterial pressure
Enhanced lateralization of diagnostic tests
GFR in stenotic kidney may fall
Diagnostic tests
Plasma renin activity elevated
Lateralized features (e.g., renin levels in renal veins, captopril-enhanced renography)
B
FIGURE 225 A, Angiogram of unilateral renal arterial stenosis with well-preserved vascular supply to contralateral kidney. B, Schematic illustrating pathophysiology
of unilateral renovascular hypertension (two-kidney, one-clip [2K1C]). Stenotic kidney responds to reduced perfusion with activation of renin-angiotensin system,
producing widespread effects that include rise in arterial pressure. Elevated pressures subject nonstenotic kidney to so-called pressure natriuresis, leading to
asymmetrical sodium excretion, fall in blood pressure, and continued stimuli to stenotic kidney. Such asymmetry is the basis for diagnostic testing such as captopril
renography and renal vein renin measurements. Ang, angiotension; GFR, glomerular filtration rate.
Renal Vasoactive Hormonal Systems
ANGIOTENSIN II
Renal hypoperfusion is accompanied by activation of the reninangiotensin system, a mechanism normally designed to regulate volume homeostasis and maintain GFR during a transient
decrease in renal perfusion pressure. Angiotensin II maintains glomerular capillary pressure and GFR by way of its predominant
vasoconstrictor effect on the efferent arteriole. The importance
of Ang II for preserving GFR is most evident under conditions of
reduced preglomerular arterial pressures, particularly under conditions of volume depletion.
41
This feature underlies the fall in
290
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22
A
Bilateral Renal Artery Stenosis
Bilateral
Stenosis of solitary kidney
Reduced renal perfusion
+
↑ Renin-angiotensin system (RAS)
↑ Renin
Impaired Na
and water
excretion
↑ Ang II
↑ Aldosterone
Inhibit RAS
Volume expansion
Normal or low Ang II
Increased arterial pressure
Effect of blockade of RAS
Reduced arterial pressure only after volume depletion
May lower GFR
Diagnostic tests
Plasma renin activity normal or low
Lateralized features: None
B
FIGURE 226 A, Angiogram illustrating renal artery stenosis affecting entire renal mass, in this case a solitary functioning kidney. Contralateral kidney is occluded.
B, Schematic illustrating pathophysiology of renovascular hypertension in which stenosis affects entire renal mass. In the absence of a normal contralateral kidney,
sodium retention occurs, and hypertension is heavily dependent upon volume mechanisms. Ang, angiotension; GFR, glomerular filtration rate.
GFR sometimes observed following administration of ACE inhibitors to patients with RAS, particularly when the entire renal mass
is affected.
Angiotensin II effects in the kidney include induction of
cell hypertrophy and hyperplasia, and stimulation of hormone
synthesis and ion transport. It also seems to contribute to the
pathogenesis of renal fibrosis by recruiting bone marrow–derived
fibrocytes, circulating cells that contribute to the pathogenesis of
fibrotic diseases.42 Its renal actions are mediated primarily through
AT1 receptors expressed on endothelial, epithelial, and vascular
smooth muscle cells (VSMCs). Chronic activation of AT1 receptors in renal ischemic injury may elicit local inflammatory and
fibrogenic responses. Angiotensin II has been implicated in stimulation of vascular smooth muscle and mesangial cell growth, platelet aggregation, generation of superoxide, activation of adhesion
molecules and macrophages, infiltration of inflammatory cells,
Stenosis
291
Angiotensinogen
Ang I
Renin
ACE
Ang II
Vaso-
constriction
FIGURE 227 Actions of angiotensin II (Ang II) in generation of renovascular hypertension. In addition to direct effects on vascular tone and sodium
homeostasis, Ang II modulates and induces vasoconstriction by several independent mechanisms, including oxidative stress. Induction of “slow pressor” responses
are associated with reduction of circulating levels of plasma renin activity and loss of demonstrable pressure dependence upon Ang II (see text). ACE, angiotensinconverting enzyme; Ang, angiotensin; LV, left ventricular; PF, prostaglandin.
Renal
sodium
retention
increased expression of extracellular matrix (ECM) proteins, and
induction of proto-oncogenes.
The intrarenal effects of Ang II during renal ischemia are modulated by interactions with other humoral systems (
Vasodilator prostaglandins (PGs) attenuate vasoconstriction
caused by Ang II and may limit ischemia due to elevated levels
of this hormone.
43
Nitric oxide negates many actions of Ang II,
modulates the effects of Ang II on the afferent arteriole and the
proximal tubule, and down-regulates ACE and AT1 gene expres-
44
sion.
On the other hand, endothelin-1 (ET-1) regulates renal ACE
expression, mediates some of the vascular effects of Ang II and
amplifies its pressor effects, and activates a similar signal transduction pathway for growth- and differentiation-related genes.
Thromboxane A
donic acid, is also released within the kidney by Ang II and mediates much of the pressor and renal hemodynamic responses to
45
Ang II.
, TxA2, a vasoconstrictor metabolite of arachi-
2
Therefore, Ang II is involved in short-term renal adaptive
response to ischemia, but long-term activation of the reninangiotensin system and its interaction with other humoral systems
can lead to progressive destruction of renal tissue.
NITRIC OXIDE
Nitric oxide is synthesized from l-arginine within the kidney by
a family of nitric oxide synthases (NOS) and plays a crucial role
in the regulation of renal hemodynamics and excretory function.
Differential expression, localization, and regulation of three isoforms of NOS expressed in the kidney—neuronal (nNOS), inducible (iNOS), and endothelial (eNOS)—contribute to diverse
intrarenal actions.
46
Consequently, NO reduces vascular tone,
increases sodium excretion, modulates tubuloglomerular feedback, has antithrombotic protection, inhibits growth-related
responses to injury, and modulates the aforementioned renal
actions of Ang II. Nitric oxide further buffers many processes
implicated in the pathogenesis of tissue injury in renovascular
disease, including growth of (VSMCs), mesangial cell hypertrophy and hyperplasia, and synthesis of ECM. However, regulation
of renal blood flow becomes less dependent on eNOS-derived
NO and more dependent on PGs as RAS progresses
Aldosterone
secretion
47
Vascular effects
• Hypertrophy
• Remodeling
• Endothelin release
• PGs
• Oxidative stress
Fig. 22-8) .
because of
Sympathetic
nerve system
activation
Myocardial effects
• LV hypertrophy
• Myocyte growth
• LV remodeling
a decrease in renal perfusion pressure and vascular shear stress
distal to the stenosis, which are primary stimuli to eNOS. On the
other hand, the contralateral kidney continues to rely on NO to
negate the actions of Ang II.
The role of NO in renal tissue ischemia is complex, however.
The iNOS isoform is up-regulated during renal ischemia
48
49
and
generates NO that can be cytotoxic to renal epithelial cells and
contributes to tubular injury, both by decreasing activity of the
eNOS isoform and by formation of the oxidant peroxynitrite.
ENDOTHELINS
The endothelin peptides comprise a family of peptides produced
and released from endothelial cells (ECs), which have potent and
long-lasting vasoconstrictor effects on the renal microcirculation
and modify tubular function. Endothelin release can be stimulated by Ang II, thrombin, transforming growth factor (TGF)-β, and
other cytokines (e.g., tumor necrosis factor [TNF]-α, interleukin
[IL]-1β). Tissue levels of ET-1 are increased in the stenotic kid-
50
ney,
and in fact in most forms of renal failure, and may persist
for days after resolution of the initial injury. Its involvement in
renal ischemic injury is underscored by the observation that ET-1
blockade is more efficient in improving the early course of postischemic renal injury than inhibition of Ang II.
51
Chronic blockade of the endothelin-A receptor directly inhibits cellular growth
and gene expression, and in ischemic acute renal failure provides
long-term functional and morphological benefits. These effects
are greater than those observed during simultaneous blockade
of both the A and B receptor,
52
likely because of the role of the
latter in eliminating salt, although the endothelin-B receptor has
also been implicated in inflammation and fibrosis in progressive
renal injury.
53
PROSTAGLANDINS
Prostaglandins are cyclooxygenase (COX) derivatives of arachidonic acid that have important roles in maintaining renal blood
flow and glomerular filtration. Biosynthesis of vasodilator PGs
like prostacyclin (PGI
ney against the effects of prolonged ischemia and Ang II
) and prostaglandin E2 protects the kid-
2
43
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"Critical" RAS
CH
22
Recurrent local ischemia Hypoperfusion
ATP↓ Ang II↑
Tubulointerstitial
injury
Necrosis
Tubular
transport
dysfunction
Microvascular
Vasoconstriction
Thrombosis
Immune
response
damage
Fibrosis
Scarring
Increased free
oxygen radicals
Vasoconstriction
Altered Cytoskeleton
Interstitial Fibrosis
Tissue
injury
Reduced Shear Stress
Altered endothelial
and epithelial factors
Cytokines and
inflammatory
mediators↑
Apoptosis
Shrinkage
Necrosis
Atrophy
Fibrosis
NO
Endothelin
PG
NFkB
TNF
TGF-β
PAI-1
IL-1
Decreased
tubular
transport
FIGURE 228 Proposed pathways by which renal hypoperfusion activates fibrogenic mechanisms within kidney and ultimately produce irreversible
parenchymal injury and interstitial fibrosis. Both intermittent local ischemia (left) and vasoconstrictor-mediated cytokine-mediated pathways (right) participate in
this process. Ang, angiotensin; ATP, adenosine triphosphate; IL-1, interleukin 1; NO, nitric oxide; NF-κB, nuclear factor kappa B; PAI-1, plasminogen activator inhibitor 1; PG,
prostaglandin; RAS, renal artery stenosis; TGF-b, transforming growth factor beta; TNF, tumor necrosis factor. (Modified with permission from Lerman L, Textor SC: Pathophysiology
of ischemic nephropathy. Urol Clin North Am 28:793–803, 2001.)
and prevents hypoxic tissue injury. In RAS, they selectively prevent preglomerular constriction and thus limit a fall in GFR in the
stenotic kidney,
NO. Conversely, TxA
PG that is up-regulated in kidneys with renovascular disease.
54
potentially through regulatory interactions with
is an endothelium-derived vasoconstrictor
2
is released within the kidney by reactive oxygen species (ROS)
or Ang II, modulates some of the deleterious effects of Ang II and
ET-1, and contributes to kidney disease. Blockade of TxA2 receptors thus improves urine volume, GFR, and renal plasma flow in
ischemic kidneys and exerts a variety of beneficial effects that
reduce the severity of ischemic damage. Furthermore, vascular
expression of COX-2 is up-regulated in kidneys with arterial steno-
56
sis,
and COX-2-derived prostaglandin I2 regulates renin release
and renovascular hypertension in severe and moderate RAS.
92
have been implicated in decreasing stenotic kidney blood flow
and sustaining renovascular hypertension.
58,59
Furthermore, oxidative stress contributes to progressive tissue
55
damage in the stenotic kidney. In mesangial cells, superoxide promotes hypertrophy and ECM production by both interaction with
It
NO and by acting as an intracellular signal for growth-related
responses, which may lead to microvascular and tissue remodel-
60
ing.
In addition, ROS are implicated in the pathogenesis of ischemic renal injury by causing lipid peroxidation of cell and organelle
membranes and disrupting the structural integrity and capacity for
cell transport and energy production, especially in the proximal
tubule. Activation of growth factors and cytokines like nuclear factor (NF)-κB
61
may also play an important role in the mechanism of
action of Ang II and ROS. Studies in humans confirm that oxidative
stress contributes to the impairment in endothelium-dependent
Oxidative Stress
A growing body of evidence implicates increased generation
of reactive radical species in the mechanisms of renal injury in
renovascular disease.
superoxide production via the membrane NADH/NADPH oxidase system, and xanthine oxidase is an important source of
oxygen free radicals during renal ischemia. Increased oxidative
stress can promote formation of a variety of vasoactive mediators including ET-1, leukotrienes, and prostaglandin F
tanes, endogenous products of lipid peroxidation. In addition, a
chemical reaction between superoxide anion and NO not only
decreases bioavailability of NO but also leads to production of
toxic species (e.g., peroxynitrite [ONOO−]). Functionally, ROS
3,57
Angiotensin II is a potent stimulus for
isopros-
2α
vasodilation observed in patients with renovascular hypertension,
which can be reversed with successful renal revascularization.
62
The fibrogenic factors TGF-β, tissue inhibitor of matrix metallo-
proteinases (TIMP)-1, and plasminogen activator inhibitor (PAI)-1,
which are up-regulated in stenotic kidneys,
61
are important medi-
ators of ECM synthesis that characterizes progression of renal tissue injury. Early induction of TGF-β via the AT1 receptor plays a
major role in tissue fibrosis
63
by increasing type IV collagen deposition and may play a role in interstitial scarring observed in
chronic renal injury characterized by increased activity of intrarenal Ang II.
64
It interacts with endothelin and several growth factors and cytokines in promoting progressive interstitial fibrosis,
primarily via its downstream effectors from the Smad family, but
also participates in postischemic renal healing.
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