Renovascular Hypertension and Ischemic Nephropathy

Advances and Major Points of Emphasis

• 1.

  Definition of the spectrum of progressive clinical manifestations attributable to renovascular disease

• 2.

  Recognition that moderate reductions in renal blood flow do not induce tissue hypoxia or damage, thereby allowing ongoing medical therapy of renovascular hypertension.

• 3.

  Integration of limited prospective trial results into clinical practice in favor of optimized medical therapy using agents that block the renin-angiotensin system.

• 4.

  Identification of high-risk subsets that have mortality benefits associated with renal revascularization

• 5.

  Establishing the limits of kidney adaptation to reduced blood, beyond which tissue hypoxia and activation of inflammatory pathways ensue

More than 80 years have passed since the original observations indicating that constriction of the renal arteries produces a rise in systemic arterial pressures. These studies established the primal role of the kidney in regulating the circulation and blood pressure. Since then, occlusive renovascular lesions have been recognized as a major form of “secondary hypertension” and have been a widely applied model for understanding the role of the renin-angiotensin-aldosterone system (RAAS). In clinical terms, this has produced an odyssey of surgical and endovascular attempts to restore the kidney circulation, and eventually led to pharmacologic blockade of the RAAS. The range of clinical manifestations particularly associated with atherosclerotic renovascular disease (RVD) is highly variable and continues to challenge clinicians. Despite the intuitive benefits of restoring kidney blood flow, results of several prospective, randomized clinical trials attempting to clarify the modern role of adding renal revascularization to optimized medical therapy have been ambiguous. Enrollment for these studies has been hampered by the history of major clinical benefits after successful revascularization for cases of severe disease that limited physicians’ willingness to randomize patients. As a result, the clinical decision regarding when to move forward with renal revascularization most commonly falls to experienced clinicians after failure of medical therapy. It behooves those caring for complex vascular and renal disease to be familiar with the pathophysiology and management of these disorders.

Disease Definition

Renovascular hypertension (RVH) and ischemic nephropathy both refer to clinical conditions related to occlusive renovascular disease. RVH identifies a variety of disorders in which a rise in arterial pressure is induced by reduction in renal perfusion pressure. Experiments in the 1930s linked reduced renal perfusion to a rise in systemic pressure. It should be emphasized that this can occur at levels of renal pressure above those that impair kidney function, although further reduction in renal blood flow ultimately leads to additional sequelae, including impaired volume control, circulatory congestion, and ultimately irreversible kidney injury. Hence, occlusive renovascular disease (RVD) comprises a spectrum of clinical disorders ranging from incidental, minor disease to incipient occlusion with tissue ischemia as illustrated in Fig. 13.1 for atherosclerotic disease. Ischemic nephropathy refers to advanced hemodynamic impairment of glomerular filtration that ultimately threatens kidney survival. Recognizing this spectrum and its specific manifestations within an individual patient is an important responsibility of the cardiovascular clinician or nephrologist.

Epidemiology

Within western countries the dominant (at least 85%) cause of RVD is atherosclerotic renal artery stenosis (ARAS). This develops invariably as part of systemic atherosclerotic disease affecting various vascular beds, including coronary, cerebral, and peripheral vascular territories. Risk factors for ARAS include advancing age, smoking, dyslipidemia, preexisting essential hypertension, and diabetes. Community-based studies suggest that up to 6.8% of individuals older than 65 have ARAS producing more than 60% occlusion. Screening studies indicate rising prevalence of detectable ARAS in hypertensive subjects from 3% (ages 50 to 59 years) to 25% (above age 70 years) with older ages. Imaging studies of patients with symptomatic coronary or peripheral vascular disease indicate that more than 50% lumen occlusion of the renal arteries may be detected in 14% to 33% of such individuals. It must be emphasized that many such cases are incidental in nature and have minimal hemodynamic or clinical importance. Clinically significant atherosclerotic RVD most often appears as worsening or accelerating blood pressure elevation in older individuals with preexisting hypertension. Establishing the clinical significance of incidentally detected atherosclerotic RVD remains challenging but should be considered carefully before embarking on vascular interventional procedures.

Alternative causes of RVH derive from other flow-limiting lesions affecting the renal circulation. These can arise from various fibromuscular dysplasias (FMD), such as medial fibroplasia that typically presents an appearance of “string-of-beads” ( Fig. 13.2 ). Some form of FMD may be detected incidentally in up to 3% of normotensive men or women presenting as potential kidney donors. Those that progress to develop renovascular hypertension are predominantly females, some of whom are smokers. This gender predominance suggests that hormonal factors modulate the progression of this disorder and its clinical phenotype. Other disorders that produce RVH include renal trauma, arterial occlusion from dissection or thrombosis, and embolic occlusion of the renal artery ( Table 13.1 ). Particularly in Southeast Asia, inflammatory vascular disorders such as Takayasu arteritis commonly impinge upon the renal circulation. An emerging iatrogenic form of RVD includes occlusion of the renal arteries from endovascular aortic stent grafts, for which landing zones may migrate or be deliberately placed across the origins of the renal arteries. Loss of renal function from vascular compromise limits the clinical success of endovascular aortic repair.

Pathophysiology

RVH is triggered initially by activation of release of pressor hormones, primarily renin from the juxtaglomerular apparatus within the kidney. Circulating renin acts upon its substrate, angiotensinogen, to release angiotensin I, which is converted to angiotensin II (Ang II) in many sites, particularly the lung. Studies over several decades have identified numerous actions of Ang II, including direct vasoconstriction, stimulation of adrenal release of aldosterone, and induction of sodium retention. Ang II also mobilizes additional pressor mechanisms, such as sympathetic adrenergic pathways, vascular remodeling, and modification of prostaglandin dependent vasodilation. Experimental studies demonstrate that blockade of the renin-angiotensin system or genetic knockout of AT-1 receptors prevents the development of RVH. Ang II is recognized to induce T-cell activation leading to accelerating hypertension and end-organ inflammatory injury. After initial activation of the RAAS, the secondary vasoconstrictor pathways can become dominant with the result that pharmacologic RAAS blockade and/or renal revascularization may no longer completely reverse RVH.

Two classic models of RVH have been proposed, depending upon the functional role of the remaining kidney (the nonstenotic or “contralateral” kidney) ( Fig. 13.3A and B ). When the contralateral kidney is normal, it responds to rising systemic pressure with suppression of its own renin release and enhanced sodium excretion, termed pressure natriuresis. This 2-kidney-1-clip condition is characterized by unilateral release of renin into the renal veins, elevated levels of plasma renin activity and arterial pressure demonstrably dependent upon the pressor effects of Ang II. These features have been used as diagnostic tests to establish the diagnosis of RVH and the likely response of arterial hypertension to revascularization of the stenotic kidney. Such testing was undertaken routinely in the era of surgical renal revascularization aimed specifically for the treatment of renovascular hypertension. The second model has been designated 1-kidney-1-clip RVD in which no functional contralateral kidney is present or capable of ongoing pressure natriuresis (see Fig. 13.3B ). This occurs typically in the setting of a solitary functioning kidney or severe RVD affecting both kidneys. As a result, the rise in systemic pressure no longer is offset by increased sodium excretion, leading to volume expansion and secondary reduction in renin release from the stenotic kidney. These events lead to lower values for circulating plasma renin activity, loss of renal vein renin lateralization, and loss of detectable angiotensin dependence of systemic hypertension, unless or until diuresis and volume contraction are accomplished. In reality, the contralateral kidney in 2-kidney-1-clip renovascular hypertension is rarely entirely normal, possibly as a result of tissue injury from direct effects of angiotensin II and/or other pathways. As a result, impaired contralateral kidney function commonly impairs sodium excretion and renal function in many patients with longstanding RVH. Hence, clinical laboratory manifestations in human subjects vary widely between the extremes predicted by 1-kidney and 2-kidney experimental models.

“Ischemic nephropathy” is used to designate parenchymal kidney injury that develops beyond vascular occlusive lesions. Remarkably, clinical studies using blood oxygen level dependent (BOLD) magnetic resonance (MR) indicate that substantial reductions in blood flow (up to 35% to 40%) can occur without demonstrable tissue hypoxia or evident long-term kidney fibrosis ( Fig. 13.4 ). This is partly because of the abundant perfusion of the kidney cortex as part of its filtration function, reflected by the fact that less than 10% of oxygen is required for fulfilling the energy requirements of the kidney. The medulla, by contrast, is supplied by postglomerular arterioles with lower blood flow and has greater oxygen extraction because of energy-dependent active solute transport. Thus, the kidney normally has a large cortical-medullary oxygen gradient with areas of reduced oxygen tension in deep medullary areas. Moderate reductions in blood flow therefore exert only minor effects on oxygen delivery to the cortex and the reductions in glomerular filtration that result also reduce net solute transport and thereby reduce oxygen requirements in medullary regions. Taken together, the kidney normally adapts to heterogeneous blood flows and regional hypoxia. An important corollary of these observations is that medical therapy of renovascular hypertension (albeit necessarily reducing perfusion pressure and blood flow to the poststenotic kidney) can be tolerated, sometimes for many years, without necessarily inducing parenchymal kidney damage.

Renal tolerance to reduced blood flow has limits, of course. More severe and prolonged reductions in blood flow eventually threaten both tissue oxygenation and viability of the poststenotic kidney. Studies of both experimental and human RVD indicate that cortical hypoxia eventually is associated with activation of inflammatory pathways. These are characterized by abundant renal vein levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α, monocyte chemoattractant protein 1 [MCP-1]), biomarkers of injury (e.g., neutrophil gelatinase-associated lipocalin (NGAL) in addition to the appearance of t-lymphocytes and macrophages within the tissue parenchyma (see Fig. 13.4 ). Inflammatory changes associated with severe ischemia lead to obliteration of tubules with failure to regenerate intratubular epithelial cells with resulting atubular glomeruli. At some point, these processes become refractory to restoring vessel patency with revascularization, despite partial restoration of renal blood flow and reversal of tissue hypoxia.

Diagnosis