—  SYMPOSIUM #11  —

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
Vallhalla, NY


The term thrombotic microangiopathy (TMA) was first coined by Symmers in 1952 [1]. 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 [2]. Pathogenesis of TMA has been reviewed in several articles [2, 3, 4, 5, 6], but with none to very limited emphasis towards TMA seen in malignant hypertension. The discussion here primarily focuses on the pathogenesis of TMA in malignant hypertension.

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 [7]. Endothelial injury is believed to be the inciting event in the pathogenesis of TMA of any etiology [2, 3].

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 [8, 9]. 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 [10]. 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 [10, 11, 12], 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) [12-14] and Ang II receptor blockers [15, 16] 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 [17, 18, 19]. 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. [20]. 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 [22, 23]. Recent 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 [24], and eplerenone, a selective [25, 26] mineralocorticoid 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 [27]; bilateral adrenalectomy with undetectable plasma aldosterone levels, completely abolished TMA, despite persistent severe hypertension [28]. 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 [28]. An additional surprising finding was the virtual lack of TMA in bilaterally adrenalectomized rats upon restoration of plasma Ang II levels [28]. 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 [29] and mineralocorticoid receptors [30] 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 electrolyte balance [31, 32], 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 [33].

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 [34]. Other possible mediators include alterations in nitric oxide synthesis [35, 36], stimulation of thrombogenic plasminogen inhibitor- 1 activity [37], increased expression of chemoattractant osteopontin [38] and reduced neuronal uptake of norepinephrine [39], amongst others.

Conclusion:
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 [40] 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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