Brain natriuretic peptide and blood pressure response in patients with renal artery stenosis

Endoluminal stent placement is considered the revascularization treatment of choice for patients with refractory hypertension and hemodynamically significant renal artery stenosis. However, about one third of patients fail to have improved blood pressure following successful renal stent placement.1

In conditions of cell stretching, ventricular myocytes release brain natriuretic peptide (BNP), a neurohormone that antagonizes the renin-angiotensin system and angiotensin II and promotes arterial vasodilation, natriuresis, and diuresis.2 In animal studies, it has been shown that BNP mRNA is markedly upregulated 6 hours after clipping the renal artery and that angiotensin II may stimulate the synthesis and release of BNP.3,4 We hypothesized that, in patients with renovascular hypertension, which is known to stimulate the renin-angiotensin system and release of angiotensin II,5 the BNP level may be elevated.

We investigated whether BNP levels are increased in patients with renal artery stenosis, and whether they would be influenced by successful renal artery revascularization. We also evaluated whether the increased levels would foretell which patients would have a reduction in blood pressure following renal stent implantation.

Patients and methods

This prospective study included 27 patients with significant atherosclerotic renal artery stenosis (≥ 70% diameter stenosis), as shown on angiographic evaluation. There were seven patients who were excluded from the study because of chronic renal insufficiency, recent myocardial infarction (MI), acute coronary syndrome, or congestive heart failure exacerbation with left ventricular dysfunction.

BNP levels were taken 2 to 7 days before the procedure in 23 patients, 1 day before the procedure in 27 patients, 1 day after the procedure in 27 patients, and 7 days to 2 months after the procedure in 25 patients. Twenty-four to 48 hours before the procedure and within 1 week after the procedure, serum creatinine levels were measured. The Cockroft-Gault equation was used to determine the estimated glomerular filtration rate (eGFR). Levels of BNP were obtained using the Biosite assay (Biosite Diagnostics, San Diego, CA). Similar to previous studies, a BNP level of 80 pg/mL or less was considered normal.6

A patient with a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher was considered to have hypertension. If a patient’s blood pressure could not be decreased to below 140/90 mm Hg with three drugs, he or she was considered to have refractory hypertension. Patients with a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 90 mm Hg on the same or a lesser number of drugs or who had a decrease in diastolic blood pressure of at least 15 mm Hg were considered to have improved hypertension and to be blood pressure responders.7

Patients who had a residual diameter stenosis of less than 30% after the procedure were considered to have angiographic success. Those who had no major complications (defined as the need for hemodialysis or surgery; MI; bleeding requiring a transfusion, stroke, or death) while in the hospital, along with angiographic success, were considered to have procedural success. For those patients who had a BNP above 80 pg/mL at the start of the study, a reduction in BNP of greater than 30% from baseline was considered a decline in BNP.

The comparison between BNP levels at baseline and after the procedure was the primary end point of the study. Determining whether the baseline BNP level was associated with the improvement in blood pressure at follow-up was the secondary end point.

Pearson’s or phi coefficients were used to perform bivariate correlation analysis. After adjusting for preprocedural diastolic blood pressure, creatinine levels, eGFR (a continuous variable), and eGFR below 60 mL/min/1.73 m2 (a categorical variable), the association of BNP with hypertension improvement at follow-up was evaluated independently with multivariate analysis. A

P value of .05 or less (two-tailed) was accepted as statistical significance.

Results

The mean age of patients was 74 ± 3 years, and 70% were women. The angiographic and procedural success was 100%. As shown in Figure 1, BNP levels decreased to 96 pg/mL (25th—75th percentiles, 61–182 pg/mL) from 187 pg/mL (25th–75th percentiles, 89–306 pg/mL) and continued to stay low during follow-up. After the procedure, blood pressures fell to 144 ± 24 over 72 ± 12 mm Hg at a mean of 3.5 ± 1.3 months (range, 2–7 months) from the baseline levels of 172 ± 18 over 89 ± 13 mm Hg (P < .001 for systolic and diastolic blood pressure). At the time of discharge, hypertension had improved in 19 of the 27 patients (70%), and at 3.5 ± 1.3 months of follow-up, 17 of 27 patients (63%) had continued improvement.

Eighty-one percent of patients (n = 22) with renal artery stenosis had a BNP level over 80 pg/mL at the start of the study. Seventeen of these patients (77%) had improved blood pressure compared with none of the five patients with a baseline BNP of 80 pg/mL or lower (P = .001). For 63% of patients (n = 17), BNP was reduced more than 30% from baseline following the procedure, and 94% of these patients (n = 16) had improved blood pressure. As shown in Figure 2, only 10% (n = 1) of the patients whose BNP levels fell by less than 30% had improved blood pressure (P < .001). Twelve patients had an eGFR below 60 (49 ± 7) mL/min/1.73 m2, and 15 had an eGFR of 60 mL/min/1.73 m2 or higher. Following the procedure, the eGFR remained the same (61 ± 13 mL/min/1.73 m2 before the procedure and 63 ± 13 mL/min/1.73 m2 after the procedure). No improvement in eGFR was seen in patients with unilateral renal artery stenosis (61.7 ± 14 mL/

min/1.73 m2 before the procedure and 62 ± 12 mL/min/1.73 m2 after the procedure), and nine patients with bilateral renal artery stenosis had improvement in eGFR (61 ± 13 before the procedure and 63 ± 13 mL/

min/1.73 m2 after the procedure). There were no significant differences in the levels of BNP before or after stent placement among patients with eGFRs below 60 and above 60 mL/

min/1.73 m2.

Differences between blood pressure responders and blood pressure nonresponders are shown in the Table. After adjustment for pre-

procedural diastolic blood pres-

sure, serum creatinine, preprocedural eGFR, and eGFR below 60 mL/

min/1.73 m2, preprocedural BNP (coefficient of correlation: 0.62; P = .023) and postprocedural decrease (coefficient of correlation: 0.82; P = .001) were independently associated with improvement in hypertension on multivariate correlation analysis.

Discussion

It is important to improve patient selection before percutaneous transluminal stent placement in patients with significant renal artery stenosis because 20% to 40% fail to have

improved blood pressure postpro-cedure.2 Other studies have tried

to identify predictors of blood pressure response after revascularization of renal artery stenosis.8 In the present study, we showed that BNP is

increased in patients with refractory hypertension and renal artery stenosis and that this peptide may be useful in predicting which patients will have clinically improved blood pressure after successful renal revascularization. The results of our study showed a significant association between BNP and improvement in blood pressure apart from baseline blood pressure, serum creatinine, and eGFR. After 3.5 months of follow-up, hypertension improvement was significantly associated with a BNP level above 80 pg/mL.

The significant decline of BNP after stent placement strongly suggests a cause-and-effect relationship between renal artery stenosis and BNP elevation. Furthermore, patients with known causes of BNP elevation, such as congestive heart failure or an acute coronary syndrome, were excluded so that the baseline elevation of BNP in the patients in our study cannot be attributed to these conditions.6,9,10 In patients with an eGFR below 60 mL/min/1.73 m2, BNP has also been shown to be increased.11 Our study showed that BNP is a helpful assay for the prediction of blood pressure response no matter what the eGFR is at baseline, as shown by the fact that there were no marked differences for increased BNP (> 80 pg/mL) or BNP decrease following stent placement stratified for an eGFR below 60 or above 60 mL/min/1.73 m2.

It has been shown that BNP can

be synthesized and released from glomerular mesangial and epithelial cells, although the chief source of

circulating BNP is ventricular myocytes.12 Hemodynamically significant renal artery stenosis is known to promote activation of the renin-angiotensin system, leading to elevated angiotensin II levels.5 Experimental studies have shown that BNP mRNA is upregulated in the two-kidney, one-clip renal artery stenosis model4 and that, independent of cell stretching, angiotensin II directly instigates the synthesis and release of BNP.3 The finding that 81% of our hypertensive patients with renal artery stenosis had an increased BNP level (> 80 pg/mL) concurs with the results of these experimental studies. BNP levels may be a useful marker to identify activation of the renin-angiotensin system and therefore may identify those patients who will benefit from revascularization because the severity of the stenosis has no correlation with blood pressure response.

Conclusions

We have shown in the present investigation that, in patients with renal artery stenosis and refractory hypertension, BNP is increased and that it decreases following renal artery revascularization with a stent. An increased BNP level prior to stent placement is significantly associated with improvement in hypertension following revascularization. Assessing BNP levels may be useful in selecting patients for renal artery revascularization procedures and therefore may improve clinical outcomes.