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.
| Unilateral Disease (Analogous to 1-Clip-2-Kidney Hypertension) |
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| Bilateral Disease or Solitary Functioning Kidney (Analogous to 1-Clip-1-Kidney Model) |
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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
Clinical Manifestations
RVH and ischemic nephropathy are diagnosed primarily by recognition of a clinical syndrome consistent with these disorders, particularly progressive or secondary hypertension with or without unexplained chronic kidney disease (CKD). Occlusive RVD is expressed across a range of manifestations generally related to the severity and/or duration of vascular occlusion, as illustrated in Fig. 13.1 . Many incidental lesions are now identified during imaging procedures for other indications, including computed tomography (CT) and/or MR angiography. It should be emphasized that hemodynamic effects of lumen occlusion such as changes in either translesional pressure or flow are barely detectable until lumen occlusion reaches a “critical level” in the vicinity of 70% to 80% lumen occlusion. Studies in humans subjected to stepwise partial balloon obstruction of the renal artery indicate that gradients of at least 10% to 20% reductions in postobstruction pressures are required to detect measurable renin release. An important corollary is that failure to identify a pressure gradient across such a vascular lesion makes it unlikely that renal revascularization will have detectable hemodynamic benefits.
Clinical characteristics of atherosclerotic RVH include rapid changes in arterial pressure, often in subjects with preexisting hypertension ( Table 13.2 ). The average age of recent interventional reports for RVH is above 70 years. Arterial pressure rises with age in Western societies, so the majority of these individuals will have previously identified hypertension. Recognizing recent progression and rising antihypertensive drug requirements should raise the question of a superimposed secondary process such as atherosclerotic RVH. As compared with essential hypertension, patients with RVH have more evident activation of the renin-angiotensin system and increased sympathetic nerve activation, sometimes associated with wide pressure fluctuations and variability. Clinical findings suggestive of RVH as opposed to essential hypertension are listed in Table 13.3 . Target organ manifestations including vascular injury, left ventricular hypertrophy, and renal dysfunction are more common with RVH as compared with age-matched subjects with essential hypertension of similar levels.
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Based on clinical features alone, some authors indicate that a scoring system based on age, gender, smoking history, recent onset of hypertension, and elevated serum creatinine allows excellent estimates of pretest probability of identifying renovascular lesions.
The presence of occlusive RVD and RVH can accelerate manifestations of other vascular disease. Impaired volume control related to RVD worsens circulatory congestion associated with left-ventricular dysfunction. When RVD triggers additional rises in arterial pressure, the resulting left-ventricular outflow resistance can precipitate congestive heart failure, sometimes designated “flash” pulmonary edema. This is a recognizable clinical syndrome and is often associated with rapid worsening of renal function as arterial pressure is lowered and/or diuresis is achieved. Observational series report higher rates of mortality and rehospitalization for patients with combined congestive heart failure and RVD.
Ultimately, progressive atherosclerotic RVD leads to loss of kidney function in the affected kidney(s). Prospective trials including ASTRAL (Angioplasty and Stenting for Renal Artery Lesions) and CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) indicate that 15% to 22% of subjects with RVD progress to a renal “endpoint” over a follow-up period between 3 and 4 years. As a practical matter, establishing whether this progression poses a clinical problem in a specific individual is often the central element in management of atherosclerotic RVD.
Physical Examination
Detailed review of blood pressure measurement is beyond the scope of this chapter (for more information, see American Heart Association recommendations). Ambulatory blood pressure monitoring with RVH commonly identifies disturbed day-night circadian rhythms with loss of the normal nocturnal fall. Retinal examination may reveal vascular changes of long-term hypertension, although grading these is notoriously variable between physicians. Peripheral pulses may be diminished and/or asymmetric as a result of vascular occlusive disease in other vascular beds. Audible bruits are sometimes heard over the abdomen and/or other vascular sites, such as carotid or aortic regions, but are nonspecific and relatively insensitive. Other evidence of peripheral arterial occlusive disease, including claudication, temperature differences, loss of limb perfusion with elevation, hair loss over the extremities, and peripheral atheroembolic lesions may provide clues to underlying peripheral arterial disease.
Laboratory Studies
General values for hematologic and electrolyte levels are normal or consistent with the degree of glomerular filtration rate (GFR) reduction (stage of CKD). Unexplained elevations of serum creatinine merit further evaluation with at least ultrasound duplex imaging. Urinalyses are typically “bland” with few cellular elements or proteinuria. The presence of significant albuminuria (or elevation of urinary albumin/creatinine ratio) should raise consideration of other parenchymal renal disorders, including diabetic nephropathy.
Measurement of circulating plasma renin activity warrants consideration. As noted previously, elevated levels are consistent with RVH, although sodium retention, drug effects, and transitions to alternative pressor pathways sometimes leave these levels normal or low. Examination of the aldosterone/renin ratio typically is consistent with secondary aldosterone excess, and may account for hypokalemia observed either spontaneously or during diuretic therapy. These hormonal and electrolyte levels are affected by many other factors, making their diagnostic value limited. They are most useful when positive and identify distinctly abnormal patterns.
Measurement of renal vein renin levels was commonly performed during planning for surgical renal artery procedures when this was the primary therapy for RVH. Identification of overt lateralization to the poststenotic kidney along with suppression of renin release from the contralateral kidney has been associated with substantial pressure reduction in more than 90% of subjects. Once again, the utility of this procedure is limited by variable conditions under which the measurements are made, which are often associated with saline administration during the imaging procedure that suppresses renin. Hence, failure to identify lateralization was associated with improved blood pressure in at least 50% of cases, rendering it of limited sensitivity and specificity. Repeated measurement after sodium depletion has been shown to “unmask” renal vein lateralization and identify RVH. As a clinical measure, identifying a specific kidney as a “pressor kidney” with unilateral renin release is most useful when contemplating therapeutic nephrectomy for blood pressure control.
Imaging Studies
Establishing the diagnosis of occlusive RVD intrinsically requires demonstrating renal arterial obstruction. Hence, imaging studies are a sine qua non for this diagnosis. Before embarking on detailed imaging procedures, some of which are expensive and potentially hazardous, clinicians would do well to establish exactly what goals of the imaging study should be. Is the purpose simply to identify if one or both arteries have evident occlusive disease? Is it to establish the viability and functional characteristics of the poststenotic kidney? Is it to identify the specific location and severity of RVD for revascularization? Is it to identify translesional gradient information and/or response to revascularization? Perhaps most importantly, to what degree do the clinical conditions of the specific patient warrant acting on the imaging data, specifically regarding either renal revascularization or nephrectomy? As a result, the choice and pace of diagnostic imaging depend partly on the response to medical therapy and the clinical status of the specific patient.
Duplex Ultrasonography
Duplex Doppler renal ultrasonography is an excellent initial imaging tool and provides both some degree of functional and structural assessment. Because it is relatively inexpensive, ultrasound can be used to follow patients serially and to evaluate vascular patency after revascularization. The peak systolic velocity (PSV) has the highest performance characteristics and reaches a sensitivity of 85% and a specificity of 92% for the diagnosis of atherosclerotic RVD in experienced laboratories. An example of extremely high PSV is illustrated in Fig. 13.5 . The limitations of this technique hinge upon its dependence upon operator skills and patient body habitus, leading to reported accuracy estimates that range from 60% to more than 90%. The resistive index (RI) is determined from segmental arterial flow characteristics. The RI is defined as height of the peak systolic velocity minus height of the end-diastolic velocity (EDV) divided by the peak systolic velocity (RI= (PSV − EDV) ÷ PSV) and thus reflects the status of the flow characteristics in the renal microcirculation beyond the main renal arteries. An elevated RI indicates limited diastolic flow and may reflect intrinsic parenchymal or small vessel disease. In conjunction with clinical findings, RI has been promoted as a useful parameter to predict benefit after revascularization. Initial reports indicate that patients with RI below 0.8 before angioplasty have better outcomes regarding both blood pressure and renal function as compared with those with RI above 0.8, as we have reviewed. Other authors find less consistent separation based on segmental artery resistance, although the general condition of the poststenotic kidney and likely recovery after revascularization are better with a low RI. Hence, reliance upon RI as a predictive parameter for ARAS management remains ambiguous. Our interpretation of these studies is that lower RI is likely associated with more preserved renal flow characteristics and better kidney function overall, but should not be the final determinant regarding the decision for revascularization.
