New Developments in Renal Disease
Moderators: Jan A. Bruijn and J. Charles Jennette
Section 5 -
Pathology and Pathogenesis of Thrombotic Microangiopathies with an Emphasis on Malignant Hypertension
Praveen N. Chander
New York Medical College
The term thrombotic microangiopathy (TMA)
was first coined by Symmers in 1952 . As the
name implies, pathology is primarily seen in the microvessels, i.e. arterioles and capillaries, and
consists of a wide spectrum of histologic findings initiated by endothelial injury culminating in
microvascular thickening. The vessels show variable obliteration of lumina due to any or a combination
of the following: mucoid or edematous intimal thickening; concentric myointimal hyperplasia ("onion
skinning"); endothelial swelling, detachment or loss; accumulation of intraluminal platelets or fibrin
thrombi, and of fibrin degradation products (floccular material) in the subendothelial space;
extravasation of fragmented erythrocytes and fibrinoid necrosis. Glomerular lesions of TMA consist of
ischemic retraction of the capillary tufts secondary to arteriolar obliteration or thrombo- necrosis
similar to, and frequently as an extension of the arteriolar lesions. There is frequent accumulation of
subendothelial floccular material on electron microscopy. A spectrum of the following glomerular changes
may be also be present: focal to global loss of mesangium (mesangiolysis), endocapillary and
extracapillary cellular swelling, increase in mesangial matrix and cell numbers, frequent double
contouring of peripheral capillary walls and rarely small crescents. Immunofluorescence findings are
specific only for microvascular staining for fibrin-related antigens.
TMA is seen in a wide variety of clinical conditions with variegated pathogenetic agents,
all of which are uniformly toxic to the microvascular endothelium . Pathogenesis of TMA has been
reviewed in several articles
but with none to very limited emphasis towards TMA seen in malignant
hypertension. The discussion here primarily focuses on the pathogenesis of TMA in
Hypertension is a leading cause of end stage renal disease and of cardiovascular
mortality. In the majority of patients, renal pathology is chronic and termed "benign nephrosclerosis".
A subgroup of patients develop severe or "malignant hypertension", characterized by markedly elevated
blood pressure, stimulation of the renin-angiotensin-aldosterone system (RAAS), papilledema and acute
multiorgan dysfunction associated with TMA in the target organs. Microvascular injury is
indistinguishable from other causes of TMA . Endothelial injury is believed to be the inciting event
in the pathogenesis of TMA of any etiology
Pathogenesis of Endothelial Injury In Malignant Hypertension:
There are 2 major pathways proposed in the pathogenesis of endothelial injury in malignant
hypertension: 1) markedly elevated blood pressure with shear stress damage or mechanical injury, and 2)
over-stimulated RAAS. Primacy of one pathway over the other has been a controversial issue. Amongst the
hormonal mediators, while both the hormones in the activated RAAS namely, angiotensin (Ang) II and
aldosterone are considered key players in the pathogenesis of hypertension, only over-stimulation of Ang
II, historically, has been implicated in the pathogenesis of TMA in malignant hypertension
Aldosterone has received very little attention as a major player in this arena until recently.
Stroke-prone spontaneously hypertensive rat (SHRSP), a sub-strain of spontaneously
hypertensive rat (SHR), is frequently utilized as a genetic experimental model of malignant hypertension
. SHRSP on a high-salt intake rapidly develop severe hypertension and TMA consistent with malignant
nephrosclerosis, and die of strokes. These animals display a paradoxical increase in plasma renin
activity with time, despite continued salt-loading
an evidence of the participation of
stimulated RAAS. Interference with Ang II synthesis or actions in this model, with a variety of
angiotensin converting enzyme inhibitors (ACE-I)
and Ang II receptor blockers
respectively, prevents the development of TMA, but interestingly in the absence of a blood pressure
lowering effect. Blood pressure in the animals thus protected remains extremely high, in the range of
200 – 240 systolic. These studies; 1) identified hormonal mediators including, Ang II or others down
stream, as major factors in the pathogenesis of acute hypertensive injury (TMA), and 2) demonstrated for
the first time that, hemodyanamic stress of elevated blood pressure alone is insufficient to induce
endothelial injury and TMA in malignant hypertension.
Although Ang II has been conventionally implicated as the primary hormonal mediator of
hypertensive damage, more recent studies have raised the possibility of an emerging role of aldosterone
in the pathogenesis of renal vascular damage in malignant hypertension
It is difficult to
determine the relative contributions of aldosterone versus Ang II in the pathogenesis of TMA, as Ang II
is a major stimulator of aldosterone synthesis and normally these two hormones are concomitantly elevated
during activation of the RAAS in malignant hypertension. None-the-less, the role of mineralocorticoids
in the pathogenesis of malignant nephrosclerosis is apparent in deoxycorticosterone acetate (DOCA)- salt,
a well known experimental model of hypertension. . In clinical studies too, aldosterone has been
recognized as an independent risk factor for heart attack and stroke (21) and is certainly incriminated
in chronic vascular disease and malignant hypertension in primary hyperaldosteronism
studies in SHRSP also suggested aldosterone, as a mediator of TMA in malignant hypertension, independent and down stream from Ang II. The evidence is as follows: 1)
treatment with spironolactone, a nonselective ,
and eplerenone, a selective
receptor blocker, both effectively prevent the development of TMA in this animal model; 2) infusion of
aldosterone in SHRSP, that were completely protected by treatment with Captopril, resulted in the
reappearance of TMA, even as Ang II was suppressed by the ACE-I ; bilateral adrenalectomy with
undetectable plasma aldosterone levels, completely abolished TMA, despite persistent severe hypertension
. Vasoprotectitive effects of spironolactone and eplerenone, were also unrelated to an
anti-hypertensive response, natriuresis or a change in volume status. These findings suggest the primacy
of direct aldosterone induced endothelial injury rather than aldosterone mediated hemodynamic factors in
the pathogenesis of malignant nephrosclerosis. This was further confirmed by reappearance of TMA upon
restoration of plasma aldosterone levels in animals otherwise protected with bilateral adrenalectomy,
despite the presence of comparable and severe hypertension in both groups . An additional surprising
finding was the virtual lack of TMA in bilaterally adrenalectomized rats upon restoration of plasma Ang
II levels . The studies in SHRSP therefore, suggest that contrary to the conventional belief,
aldosterone is of primary importance in the pathogenesis of TMA in malignant hypertension.
Aldosterone mediates the hemodyanamic effects primarily by stimulating epithelial sodium
channels(ENaC) via classical mineralocorticoid receptor binding resulting
in increased sodium entry in the distal nephron. It is now known that ENaC
like sodium channels 
and mineralocorticoid receptors  are both expressed on the endothelial
cells as well. In SHRSP, blocking the sodium channel function with amiloride and benzamil markedly
attenuates TMA, in the absence of significant changes in arterial blood pressure, or water and
raising the possibility of interference with sodium channels at
non-epithelial sites, in particular, the vascular endothelium. There is indeed evidence for a direct
aldosterone interaction with the endothelial cell .
The mechanism for aldosterone-induced endothelial injury is not well established. There
is some evidence that oxidative injury plays a role in the pathogenesis of TMA in SHRSP . Other
possible mediators include alterations in nitric oxide synthesis
stimulation of thrombogenic
plasminogen inhibitor- 1 activity ,
increased expression of chemoattractant osteopontin  and
reduced neuronal uptake of norepinephrine , amongst others.
In conclusion, there is now a large body of literature, indicating that aldosterone plays a unique and
pivotal role, independent of severe hypertension and Ang II, in the pathogenesis of TMA in malignant
nephrosclerosis. Presence of inappropriately high salt  and perhaps hypertension play a salutary
role in its pathogenesis. The interplay between elevated blood pressure and Ang II in the aldosterone
induced vascular injury requires further investigations.
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