Current approaches to atherosclerotic obstructive renal artery stenosis

Abstract

Increased lifespan in the last few decades has substantially changed the scenario for renal artery stenosis. Indeed, because older populations show a higher prevalence of atherosclerotic disease, the incidence of atheromatous renal artery stenosis has also increased. Intuitively, one could surmise that stenosis removal should void both the hypertension and the kidney damage resulting from the obstructive stenosis. Surprisingly, a number of important clinical trials have failed to show the reversion seen in experimental models. The reasons for these differences may be linked to chronicity and inflammation associated with the atherosclerotic lesion. However, the failure to obtain a favorable response may also be related to abnormalities in the contralateral kidney. Indeed, this apparently normal kidney should work to compensate the hemodynamic effects of the ipsilateral stenosed kidney. Instead, structure and function in the contralateral kidney can be altered in renal artery stenosis to the point that this nonstenotic kidney may sustain both, hypertension and progressive kidney disease. Certainly, comparing the effects of clip removal in the Goldblatt model to angioplasty in clinical settings with atherosclerotic lesions may be totally inappropriate. Nevertheless, there remain certain clinical situations such as bilateral renal arterial disease, congestive heart failure, and progressive renal failure, where angioplasty may be an alternative. These approaches however are yet to be tested.

Background

In 1934, Harry Goldblatt opened up a large chapter in medicine linking the kidney to blood-pressure regulation by partially constricting renal arteries in dogs. Indeed, using an adjustable silver clamp, he reduced blood flow to the kidney and reasoned that renal ischemia was triggering the resultant blood-pressure elevation [Goldblatt et al. 1934]. Translated to clinical practice, these observations implied that correcting a stenotic lesion, as when removing the clip in the dog model, should restore renal blood flow, thereby normalizing blood pressure. Many years of experimental work identified components of the renin-angiotensin-aldosterone system that initiate systemic hypertension in this disorder.

In fact, significant renal artery stenosis not only can increase blood pressure but may also lead to progressive kidney disease and ultimately affect survival. As vascular surgery methods improved in the 1960s, restoring renal blood flow with bypass grafts or endarterectomy sometimes produced normalization of blood pressures and/or recovery of kidney function [Juncos et al. 1974; Libertino et al. 1992]. For these reasons, removing or bypassing a stenotic lesion was traditionally viewed as a reasonable approach, although the results were often unpredictable. Renal revascularization was appealing, because for decades medical-pharmacologic management was limited to relatively inefficient drugs (e.g. thiazides, alpha methyldopa, reserpine, etc.), or to poorly tolerated agents (e.g. hydralazine, hexamethonium, pentolinium, etc.). Hence, the search for a ‘curable’ form of secondary hypertension that could be treated with surgery was the prevailing approach. Considerable effort was directed to studies to develop criteria that could predict the response to surgery, specifically the improvement or the cure of hypertension [Juncos et al. 1974]. Renal disease progression and survival had yet to become major targets.

Renal angioplasty and stents became available in the 1980s. These boosted enthusiasm for the detection of obstructive renal artery stenosis, as the new methods were safer than surgery. However, at about the same time, newer antihypertensive agents became available, including those that allowed blockade of the renin-angiotensin system, for example, angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and better tolerated sympathetic blockers. As a result, hypertension control based on medical therapy became easier and more efficient. These developments led to several studies to test the efficacy of angioplasty against medical therapy [Isles et al. 1999; Dorros et al. 1998; Novick, 2001]. Three small prospective, randomized clinical trials were carried out in Europe: the Dutch Renal Artery Stenosis Intervention Cooperative Study Group (DRASTIC) in the Netherlands [van Jaarsveld et al. 2000], the Essai Multicentrique Medicaments vs Angioplastie (EMMA) in France [Plouin et al. 1998], and the Scottish and Newcastle Renal Artery Stenosis Collaborative Group (SNRASCG) in Scotland [Webster et al. 1998]. None of these studies showed angioplasty to be superior to medical treatment regarding hypertension control or slowing renal disease progression. Unfortunately, the three studies received vehement criticism, partly because of numerous treatment crossovers (from medical therapy to revascularization due to poorly controlled hypertension). Results were analyzed based upon ‘intention to treat’ despite these crossovers. Since 2009, three prospective, randomized studies also reported no additional benefit from renal artery angioplasty with stent placement compared with medical therapy. These were the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) (Wheatley et al. 2009), the STent placement in patients with Atherosclerotic Renal artery stenosis and impaired renal function (STAR) [Bax et al. 2009], and the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) [Cooper et al. 2014]. Again, none of these trials showed higher efficacy, neither in hypertension control, nor in kidney disease progression, or survival. The rates of progression to ‘renal endpoints’ ranged between 16% and 22% in both the medical and revascularization arms of these trials. Indeed, in the CORAL trial, primary endpoints were reached in 161/459 patients treated with stenting (31.5%), and in 169/472 patients treated only with medication (31.8%); 95% confidence interval (CI) 0.94 (0.76–1.17), a not significant difference. Similarly, in the STAR trial, primary endpoints were reached in 16/76 patients (2.2%) treated by stenting plus medication, while these endpoints were reached in 10/64 patients (16%) of the patients treated only with medication (hazard ratio 0.73; CI 0.33–1.61). Finally, in the ASTRAL trial, there were no significant differences in the primary outcome in protocol-specified subgroups (as defined by severity of stenosis, serum creatinine, estimated glomerular filtration rate, and rate of progression of renal dysfunction). Although criticisms have been made regarding design, enrolment, and evaluation in these three studies, the notion remains, angioplasty with or without stent has yet to show added benefits over current medical treatment.

Why does renal revascularization fail to reduce blood pressure?

The stenotic kidney

Until recently, our pathophysiologic explanations were based primarily from studies performed on the Goldblatt model. However, the clip used in this acute model has little resemblance to clinically diagnosed renal artery stenosis, particularly, when the obstruction is caused by atherosclerosis. Indeed, it can safely be assumed that patients with renal artery obstruction are usually diagnosed after carrying the lesion for months or years. Progressive vascular occlusion causes chronic changes in the ipsilateral stenotic kidney, including inflammation and fibrosis that could perpetuate the hypertension and increase renal injury progression despite successful revascularization [Kotliar et al. 2012; Chade et al. 2002; Lerman et al. 2009; Zhu et al. 2009; Eirin et al. 2011]. Moreover, increased blood flow through capsular collateral arterioles in the ipsilateral stenotic kidney may contribute to glomerulosclerosis [Eirin et al. 2012]. All of these changes could explain the failure of renal artery angioplasty to control long-established hypertension, or to modify renal disease progression despite successful restoration of the renal blood flow. The best clinical predictor of improved blood-pressure control after revascularization remains a short duration of hypertension.

The contralateral kidney

High blood pressure from obstructive renal artery stenosis reflects the failure of the contralateral kidney to correct abnormalities initiated by the stenotic kidney, including increased renin production and sodium retention. By the time the clinical diagnosis is made, the contralateral kidney often has suffered neuro-humoral and structural changes that limit its ability to counteract the prohypertensive effects of the stenotic kidney (Table 1). Indeed, in the two kidney-one clip Goldblatt hypertension model, the contralateral kidney shows changes in renal blood flow and renal renin production that are inappropriately high for the blood-pressure levels and urinary sodium excretion that is insufficient to lower blood pressure. Moreover, a recent report shows that glomerular filtration in the contralateral kidney falls after revascularization of the stenotic kidney [Herrmann et al. 2014a]. Hence, long-term changes in the contralateral kidney likely play a role in maintaining the hypertensive status. In this regard, the sympathetic nervous system may play an important role. Indeed, the contralateral kidney suffers a reversal of the inhibitory central nervous system stimuli [Kopp et al. 1989] (Figure 1). This leads to sodium retention by the contralateral kidney and may be responsible for the increased renal renin-angiotensin expression [Navar et al. 2003]. These changes in renal nerve activity were tested in patients with renal artery stenosis, by applying renal denervation techniques in isolated cases, with very variable results. Thus, this approach needs validation through an adequate clinical trial. Elevated renal angiotensin II levels and prolonged exposure to high blood pressure generate a microvascular injury in the contralateral kidney [Eirin et al. 2011]. The susceptability of the contralateral kidney to ischemia in the opposite kidney has been shown even in acute models [Kato et al. 2014].

Table 1.

Changes in RBF, intrarenal angiotensin II, and urinary sodium excretion (UxVNa) in the stenotic and contralateral (non-stenotic kidney) during the acute and chronic phases in the one clip Goldblatt hypertension model.

Phase	Kidney	RBF	Intrarenal Ang. II	UxV Na	Role in increasing BP	BP after angioplasty
Acute	Stenotic	↓	↓		↑↑	↓
	Contralateral	↑/↓	NC	NC	NS
Chronic	Stenotic	↓	↑	↓	↑	NC
	Contralateral	NC/↓	↑ *	↑ #	↑↑

RBF, renal blood flow; Ang. II, angiotensin II; BP, blood pressure; NC, no change; NS, not significant.

*

Inappropriately high for BP levels. # Inadequate to lower BP.

Figure 1.

Reno-renal reflex in normal kidneys and in unilateral renal artery stenosis.

Summary

Atherosclerotic renal artery stenosis is usually diagnosed a long time after a long progression to significant obstruction. By then, the stenosed kidney may have undergone important structural and functional changes that no longer may be responsive to a successful dilatation. There were no significant differences in the primary outcome in any of the protocol-specified subgroups, which were defined according to serum creatinine level, estimated glomerular filtration rate, severity of renal-artery stenosis, kidney length, and previous rate of progression of renal impairment. In addition, the contralateral kidney, having suffered the long-term effects of high blood pressure, increased renin production, and chronic sympathetic stimulation, may play a part in maintaining the elevated blood pressure, through inappropriate renin secretion and insufficient sodium excretion. This may explain the failure of prospective trials to show that restoring the renal blood flow in obstructive renal artery stenosis improves or cures hypertension and prevents renal disease progression more effectively than current antihypertensive drug therapy and statins.

It seems reasonable then, not to submit to revascularization in those patients whose hypertension is well controlled with tolerable medication. Based on clinical experience, it seems logical to attempt these procedures only in patients whose hypertension is uncontrolled despite the use of three (or more) medications at full-recommended doses, although not proven by randomized controlled trials. From a clinical perspective, it is an important alternative if the renal artery in the contralateral kidney also becomes stenotic, leaving the entire renal mass subject to reduced blood flow. Other potential indications are the development of congestive heart failure of unknown cause, particularly if accompanied by unexplained episodes of acute pulmonary edema and rapid worsening of renal failure [Herrmann et al. 2014b]. For most patients, particularly those with atherosclerotic lesions, effective antihypertensive drug treatment (particularly with inhibitors of the renin-angiotensin system), and lipid lowering may produce a healthy regression of the atherosclerotic stenosis [Textor et al. 2014, Basta et al. 1976]. Most cases benefit from a low salt diet, renin-angiotensin inhibitors, and lipid-lowering agents [Khong et al. 2001].