Predicting blood pressure response in hypertensive patients with renal artery stenosis: The search continues

Goldblatt’s observation that experimentally induced renal artery stenosis leads directly to renin-dependent hypertension stands as a classic experiment in the physiology of the renin-angiotensin system and its relationship to chronic elevation of blood pressure (BP).1 By reducing renal artery perfusion pressure, renin release is stimulated, angiotensin II and aldosterone levels increase, and the resulting vasoconstriction and sodium retention produce hypertension in a seemingly simple demonstration of the pathophysiology of the renin-angiotensin system. Recognition that the same sequence of events occurs in man held out the possibility that cure of hypertension might be possible in afflicted patients, and generated a great deal of early enthusiasm among clinicians for identifying and treating patients with this condition.

Renal artery stenosis is, in fact, the most common etiology of secondary hypertension other than renal insufficiency. In the general population of patients with hypertension, 1% to 6% have some element of renal artery stenosis.2 Among older, high-risk hyperten-

sive patients who undergo cardiac catheterization for screening of coronary artery disease, the prevalence of significant renal artery stenosis varies from 19.2% to 28%.3,4 In the relatively small number of patients with renal artery stenosis owing to fibromuscular hyperplasia, the early promise of renal artery revascularization has generally been fulfilled; dramatic improvement in hypertension is ob-

served in more than 60% of patients following either surgical or catheter-based revascularization. Clinical trials in patients with hypertension and atherosclerotic renal artery disease—which accounts for 90% of all renal artery stenosis—have been disappointing, however. Cure rates for hypertension have averaged less than 10%, and most studies demonstrate only modest decreases in BP, accompanied by reduction in the number of required antihypertensive medications.5 In 20% to 40% of treated patients, no improvement in BP occurs. What accounts for this apparent contradiction?

Essential hypertension is a common condition, and its prevalence exceeds 50% in elderly patients. Coexistence of atherosclerotic renal artery disease in elderly patients with hypertension, therefore, is often coincidental rather than etiologic. Attempts at identifying the subgroup of patients in whom hypertension is the result of renin-angiotensin system activation secondary to renovascular obstruction has proved difficult. Quantification of stenosis severity, assessment of renal vein renin concentrations, measurement of renin concentrations before and after captopril (Capoten) administration, and the use of captopril renography to assess differential renal perfusion have all proved unreliable in predicting which patients will exhibit a favorable antihypertensive response to renal artery revascularization.

In animal models, angiotensin II induced by clipping a renal artery leads to immediate upregulation of brain natriuretic peptide (BNP) mRNA.6 Based on this observation, Silva and White (page 32) utilized BNP levels to identify responders to renal artery stenting in a group of hypertensive patients with renal artery stenosis that was 70% or greater. After excluding patients in whom coexistent heart failure or an acute coronary syndrome could produce BNP elevation independent of renal artery stenosis, the authors noted that significant BP reduction occurred only in patients with baseline BNP elevation greater than 80 pg/mL and in none of those with a normal BNP. Presumably, renal artery stenosis is incidental in these latter patients, and BP elevation is due to unrelated physiology. In patients in whom an elevated BNP decreased by at least 30%, 94% exhibited significant improvement in hypertension, the fall in BNP level apparently serving as a marker of reduced angiotensin II production following relief of renal artery obstruction. The absolute level of BNP at baseline and its decline after stenting were both independent predictors of significant BP reduction using a multivariate analysis.

The authors’ novel approach, if confirmed, may help to solve the conundrum presented by hypertensive patients with demonstrated atherosclerotic renal artery obstruction. Because these results are based on a study of only 27 patients, confirmation must await larger series in which criteria found useful in this study are prospectively evaluated. Given the modest overall benefit of this therapy, renal stenting as a treatment for BP elevation should currently be reserved for patients in whom hypertension is truly refractory after treatment with at least three antihypertensive medications—and whose BNP level exceeds 80 pg/mL.