Hypertensive nephrosclerosis

Gary S. Hill

European Hospital Georges

Pompidou, Paris, France
Correspondence to Gary S.
Hill, 26 rue Edouard
Jacques, 75014 Paris, France
Tel: +331 43 20 46 86; e-mail:
garyhillparis@aol.com
Current Opinion in
Nephrology and
Hypertension 2008, 17:266-
270
Purpose of review
Hypertensive
nephrosclerosis is the
second most common
cause of end-stage
renal disease,
however morphologic
evidence on the
subject is poorly
understood. A
perennial and vexing
problem in
understanding kidney
hypertension is that
correlations between
hypertension and
vascular and
glomerular lesions are
only moderate, in part
because all of these
lesions are present to
a greater or lesser degree in the normotensive,
aging kidney, with racial differences in severity
further compounding the problem. This review
looks at newer data on this topic. Recent
findings
Recent data suggest that there are two
different processes leading to
glomerulosclerosis, and the combination of the
two begins to explain why global correlations
between hypertension and morphologic lesions
are destined to remain poor. Arterial stiffening
with increased pulse pressure down as far as
the afferent arteriolar level likely plays an
important role in the progression of glomerular
lesions. Loss of renal autoregulation with
glomerular hypertrophy, hyperfiltration, and
focal segmental glomerulosclerosis is now
recognized to contribute significantly to
nephrosclerosis, particularly in the black
population. Ischemic glomerulosclerosis,
however, may ultimately be the most important
lesion, with consequent hypoxia in the
parenchyma beyond, leading to tubular atrophy
and interstitial fibrosis. Summary
Hypertensive nephrosclerosis should be seen
as a process with two principal modes of
glomerular sclerosis, ischemic and
hypertrophic, with consequent focal segmental
glomerulosclerosis, contributing variably to
renal failure according to race and level of
hypertension.

Keywords
arterial stiffening, hypertension, hypertrophic glomerulosclerosis,
ischemic glomerulosclerosis, nephrosclerosis, renal autoregulation,
renal hypoxia

CurrOpin Nephrol Hypertens 17:266-270

© 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1062-4821

Introduction actually go on to develop

This review concentrates on end-stage renal disease
the morphologic aspects of (ESRD), because of the
hypertensive nephrosclerosis. sheer numbers of patients
It should be pointed out at the with the condition,
outset, however, that hypertensive
although only a small percen- nephrosclerosis constitutes
tage of patients with the second largest cause of
hypertensive nephrosclerosis ESRD. Hypertensive

Copyright © Lippincott Williams & Wilkins.

Unauthorized reproduction of this article is
prohibited.
nephro- sclerosis is also
strongly associated with
other forms of cardiovascular
disease, points laid out in a
recent review by Rosario and
Wesson [1]. These authors
stress that, among patients
reaching ESRD, proteinuria
of some degree is universal,
and that even
microalbuminuria is
associated with substantially
increased mortality.
Despite the obvious links
between hypertension and the
kidney, our understanding of
the morphologic evidence
remains less than clear even
now. Correlations between

1062-4821 © 2008 Wolters Kluwer Health |

Lippincott Williams & Wilkins
hypertension on the one hand and
arterial, arteriolar, and glomerular
lesions on the other are only
moderate [2-4], certainly not
enough to convict on
circumstantial evidence. One
reason for this is that all of the
primary lesions described can be
found in normotensive, aging
kidneys as well, and indeed begin
early in life [2,5]. In addition, as
will be discussed below, it is
becoming apparent that there are
two separate populations of
arterioles and glomeruli leading to
two separate types of glomerulo-
sclerosis; the mixture of the two
types blurs and weakens any
potential correlation with
hypertension. There are also
pronounced racial differences in
the distribution of lesions [2],
leading to the hypothesis a decade
ago that many of the differences
could be attributed to low birth
weight, which is more frequent
among blacks than whites. A
simple concept with much
evidence to support it [6], but as
discussed elsewhere in this issue
[7], it is clear that the issue is
much more complex than that
presumed by the initial
hypothesis.

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Unauthorized reproduction of this article is
prohibited.
 Hypertensive nephrosclerosis Hill
267

Contribution of preglomerular vascular Glomerular lesions

lesions In uncomplicated hypertensive nephrosclerosis there are basically
This section examines arterial stiffening and afferent arteriolar three types of glomeruli [12,13]: normal; ischemic glomeruli with
hyalinosis. varying degrees of capillary collapse and retraction of the tuft,
with filling of Bowman's space with collagen as the glomerulus
Arterial stiffening becomes sclerotic leading to glomeruli termed obsolescent [14];
In all aging individuals there is a progressive breakdown in elastic and hypertrophic glomeruli with enlarged tufts and dilated
fibers in the aorta and large elastic arteries, with the result that the capillaries, eventually manifesting the lesions typical of FSGS
pulse wave velocity increases, the pulse pressure rises and flow with capsular adhesions, segmental scars and hyalinosis lesions.
becomes pulsatile further down into the ramifications of the arterial Such glomeruli, when they become sclerotic, show a pattern
tree [8,9**]. In the kidney parenchyma, supplied by muscular arteries deemed glomerular solidification, with the former tuft adherent to
and arterioles, there is an accompanying progressive intimal Bowman's capsule circumferentially, leaving little or no evidence
thickening, as a part of the normal aging process. This thickening is of the former Bowman's space [14]. A point of importance is that
greater on average among blacks than whites and has a strong in normotensive individuals [12] 75% of ischemic glomeruli are
correlation with hypertension [2,10]. The intimal thickening is served by 'normal' arterioles, without deposits. The reverse is true
composed of several elements, including collagen and elastic fibers for hypertrophic/FSGS glomeruli, with 90% of such glomeruli
and myofibroblasts that have migrated in from the media, often with being served by afferent arterioles with evident hyaline deposits.
resulting thinning of the underlying media. Importantly, these This distinction becomes blurred in advanced hypertension when
myofibroblasts are aligned in the long axis of the lumen (as opposed 80% of afferent arterioles show hyaline deposits [13]. The
to the circumferential arrangement of medial myocytes). Hence, their combination of dilated hyaline afferent arter- ioles serving
contraction would have little effect on lumen caliber (as opposed to glomeruli with enlarged tufts and increased size of the individual
the medial myocytes), and would actually tend to render the wall as a capillary loops points to possible loss of autoregulation in these
whole stiffer. Thus, even in normal aging, the arcuate and interlobular glomeruli.
arteries and afferent arterioles are exposed to increasingly pulsatile
flow at ever widening pressures, changes that are only accentuated in
hypertension. In confirmation, isolated systolic hypertension, with Loss of autoregulation of renal blood flow in
increased pulse pressure, has been associated with microalbuminuria animal models
[11], strongly implying that the increased pressure reaches down to Alterations in autoregulation of renal blood flow are at work in a
the glomerular level, and is a factor in the progression of variety of models of renal disease, most or all associated with
glomerulosclerosis. hypertension. The most extensive studies have been in the renal
ablation (5/6 nephrectomy) model [15-17]. However, loss of
Afferent arteriolar hyalinosis autoregulation is also seen in streptozotocin-induced diabetes [18]
Afferent arteriolosclerosis, or afferent arteriolar hyalinosis, once and desoxycorticosterone-induced hypertension [19]. In addition,
considered a hallmark of the hypertensive kidney, is now recognized in spontaneously hypertensive (SH) rats, the autoregulation curve
to be present universally in aging kidneys, regardless of blood is shifted to the right, that is to say that autoregulation comes into
pressure [5,12,13]. Arteriolosclerosis is actually a misnomer because play at higher pressures [20]. Several species of rats show
the hyaline deposits occur at points where the smooth muscle is spontaneous impairment of renal autoregulation, including fawn-
deficient/atrophic, such that circumferential luminal tension and thus hooded rats [21,22], Brown Norway rats [23] and Dahl salt-
endothelial permeability increase, permitting insudation of plasma sensitive rats [24]. In all of these strains, under the appropriate
proteins [12,13]. In a sense the condition is not one of stimulus, there is a propensity to hyperfiltration-type glomerular
arteriolosclerosis but of arteriolomalacia, since the wall is more lesions and resulting renal damage.
expansible than before the advent of deposits. In fact, although
This loss of autoregulation is manifest by dilatation of afferent
arteriolar hyalinosis is associated with hypertension, the association is
arterioles [25,26] and hyperperfusion of glomeruli [17,27,28]
actually less strong than with lesions in the terminal renal arteries
from the very outset. It follows, and indeed has been confirmed,
[2,10].
that interruption of autoregulation by drugs such as nifedipine in
rat remnant kidneys will lead to accelerated and worsened FSGS-
Our studies [12,13] have demonstrated two important points about
type lesions [17,29].
afferent arteriolar hyalinosis that run counter to traditional notions of
the pathogenesis of benign nephrosclerosis. First, hyaline deposits are
first recognized in dilated rather than constricted hyaline arterioles
Loss of autoregulation of renal blood flow in
(likely because of underlying smooth muscle atrophy). The lumens
humans
are substantially larger than those in arter- ioles without hyalinosis.
A Danish group [30] demonstrated loss of glomerular
Second, the glomeruli they serve are not ischemic, but rather
autoregulation in patients with diabetes and proteinuria by
hypertrophic, with enlarged tufts and individual capillary diameters,
measuring the drop in glomerular filtration rate when the blood
with lesions of focal segmental glomerulosclerosis (FSGS) eventually
pressure was abruptly lowered by the vasodilator clonidine. This
ensuing. Ischemic glomeruli are almost invariably served by arterioles
same group [31] subsequently found that patients with proteinuria
with small lumens and no hyalinosis lesions [12].
due to a variety of causes also showed a loss of autoregulation.

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268 Renal immunology and pathology

Loss of autoregulation has also been identified in black but not white obvious that relative hypoxia must play a role in this process, but
patients with hypertension [32], and in another study in severe but not it was not until 1998 that Fine et al. [40] elaborated the chronic
moderate hypertension [33]. hypoxia hypothesis, postulating that chronic ischemic damage in
the tubulointerstitium constitutes a final common pathway in
Further support for the notion that glomerular lesions in man are renal injury, a concept that has held up extremely well,
related to loss of autoregulation comes from our studies [12,13]. For summarized nicely in two recent reviews [41,42**].
normal glomeruli no relationship was found between the diameters of
the afferent arter- ioles and the mean area of individual capillaries in Three principal mechanisms for progressive renal par- enchymal
the glomeruli they serve. For hypertrophic and FSGS-type glomeruli, disease have been proposed: hypoxic cellular damage related to
however, an excellent correlation was found between increasing damage to, or reduced flow in peri- tubular capillaries; damage to
diameter of the afferent arteriole and the mean area of individual tubular epithelium, with interstitial consequences, induced by
glomerular capillaries, exactly what one would expect if there were massive proteinuria (summarized by Zoja et al. [43]); and
loss of autoregulation in these glomeruli [13]. diversion of urinary filtrate in FSGS-type lesions to the
periglomerular and peritubular interstititum, as proposed by Kriz
The next logical question, then, is could loss of autoregulation be [44]. Here it is clear that the initiating mechanism in hypertensive
responsible for most or all of the progression in hypertensive nephrosclerosis must be predominantly the first, hypoxic damage,
nephrosclerosis? Our studies [13] have shown that in kidneys of although in the later proteinuric stages as the patient approaches
advanced hypertension, glomer- uli in the hypertensive/FSGS end stage, the other two mechanisms likely come into play as
spectrum constitute 75.0% of the viable glomeruli, whereas ischemic well.
glomeruli account for only 11.2%. However, since we do not know
the time course of glomerulosclerosis, perhaps a better idea of the Under hypoxic conditions tubular cells undergo trans-
relative importance of hypertrophic glomeruli in disease progression differentiation into myofibroblasts, and hypoxia also promotes
may be gained from looking at totally sclerotic glomeruli in the same fibrogenesis in fibroblasts [41], a process that can only exacerbate
specimens. There, 58.8% were found to be solidified, the type of the process as the residual peritub- ular capillaries become further
glomerular sclerosis associated with hypertrophic glomeruli [13], but separated from the tubular cells they nourish. Tubular cell
42.2% appeared to have died an ischemic death, leaving behind apoptosis may be prominent. Hypoxia induces a family of
obsolescent glomeruli. The disparity between the number of viable mediators known as hypoxia-inducible factors that mediate many
ischemic glomeruli (11.2%) and obsolescent glomeruli (42.2%) of these processes, including recruitment of macrophages to the
suggests that the ischemic glomeruli die at a faster rate than the sites of injury [45]. A notable advance has been the development
hypertrophic glomeruli. Marcantoni et al. [14] found a similar of techniques using pimonidazole to give a measure of tissue
percentage of solidified glomeruli among blacks, but among whites a oxygenation [46].
much larger proportion of the sclerotic glomeruli were of the
obsolescent type (79.5%), the type associated with ischemic One study using this technique has particular relevance to
glomerular sclerosis. hypertensive nephrosclerosis with its progressive ischemic and
FSGS-type glomerulosclerosis. Matsumoto et al. [46] used the
So it becomes apparent that loss of autoregulation accounts for only a Thy-1 model of glomerulonephritis leading to progressive
portion of the progression of hypertensive nephrosclerosis, and that glomerular sclerosis, largely complete by 2 weeks. Using
any model for progression of hypertensive nephrosclerosis must take pimidazole they were able to demonstrate hypoxia in the cortex at
into account both ischemic and hypertrophic/FSGS types of 2 weeks before recognizable tubulointerstitial injury and further
glomerulosclerosis. demonstrated by lectin binding to endothelium that the circulation
was diminished before demonstrable histologic damage,
confirming by intravital microscopy that circulation was
Postglomerular changes and mechanisms decreased by 40% during this time period. Studies at 11 weeks
Ischemic glomeruli show an increase in periglomerular extracellular confirmed the loss of peritubular capillaries and interstitial
matrix and atrophic tubules long before there is complete glomerular fibrosis.
capillary collapse, and as noted above they appear to die at a faster
rate than hypertrophic/FSGS glomeruli. FSGS glomeruli do not show
such changes until lesions are visible, indicating partial blockage to Interstitial inflammation
glomerular circulation. For many years it was casually thought that the generally sparse
interstitial inflammatory infiltrate in hypertensive nephrosclerosis
was a response to tubular atrophy. It has been found, however,
Tubulointerstitial hypoxia with ensuing that both monocyte chemoattrac- tant protein-1 (MCP-1) [47,48]
tubular atrophy and interstitial fibrosis and osteopontin [49,50] are upregulated in angiotensin II-
The observation that the functional impairment of the kidney is more dependent models of experimental hypertension, and further,
closely associated with the degree of tubulointerstitial damage than of correspond temporally with an influx of macrophages into the
apparent glomerular damage is practically antediluvian [34-36]. Later, parenchyma in these models. The importance of their active
Bohle et al. [37] were the first to associate this tubular atrophy and involvement was shown by treatment with angiotensin II receptor
interstitial fibrosis to loss of peritubular capillaries, an observation blockers which attenuated the proteinuria and renal injury. Partial
since confirmed and expanded [38,39]. It would seem intuitively confirmation of these findings in humans has come with the

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

demonstration that in renal biopsies in patients with hypertensive
nephrosclerosis, there are lower levels of glomerular macrophages
and MCP-1 in those treated with angiotensin blockers [51*]. Another
group [52] found that in proteinuric glo- merular diseases,
pentoxifylline, an anti-inflammatory and immunomodulatory agent,
reduces both proteinuria and urinary excretion of MCP-1.
Role for transforming growth factor b
Transforming growth factor b (TGF-b), one of the main cytokines
driving progression of renal parenchymal disease, must play a role in
hypertensive nephroscler- osis. TGF-b is capable of stimulating
epithelial-to- mesenchymal transformation [53], potentiating renal
epithelial cell death [54], and augmenting net extracellular matrix
synthesis [55]. As with monocyte/macrophage accumulation,
angiotensin II stimulates TGF-b expression, and treating with
angiotensin inhibitors mitigates the process [56], an observation more
recently extended to a model of L-NAME-exacerbated nephrosclerosis
in SH rats [57].
Conclusion
Hypertensive nephrosclerosis is a potent cause of ESRD, particularly
in the black population. Low nephron numbers appear to predispose
to and, once under way, accelerate the progress of nephron sclerosis.
Age and hypertension-related arterial stiffening mean that blood is
delivered to afferent arterioles at increased pressure. Those arterioles
with hyaline deposits are dilated, perhaps because of smooth muscle
atrophy, leading to glomerular hyperperfusion and hypertrophy. This
in turn results in microalbuminuria and frank proteinuria. Such
glomeruli have the features of loss of autoregulation. However, this
process is likely to account for only about half of the total
glomerulosclerosis cases, the remainder being due to ischemic
glomerulosclerosis. Glomerular ischemia leads to hypoxia in the
postglomerular vasculature at an early stage with resulting
predominantly moncytic/macrophagic inflammation, increase in
extracellular matrix and tubular atrophy. These changes appear
delayed in the (presumably well perfused) hypertrophic glomeruli
until the onset of changes of FSGS and then appear to follow the
same course of ischemia, inflammation and tubular atrophy.
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• of special interest
• • of outstanding interest
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269
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