Elevated Brain Natriuretic Peptide Predicts Blood Pressure Response After Stent Revascularization in Patients With Renal Artery Stenosis
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循环学杂志 2005年第1期
the Department of Cardiology, Ochsner Clinic Foundation, New Orleans, La.
Abstract
Background— A significant number (20% to 40%) of hypertensive patients with renal artery stenosis will not have blood pressure improvement after successful percutaneous revascularization. Identifying a group of patients with refractory hypertension and renal artery stenosis who are likely to respond to renal stent placement would be beneficial.
Methods and Results— Brain natriuretic peptide (BNP) was measured in 27 patients with refractory hypertension and significant renal artery stenosis before and after successful renal artery stent placement. This neuropeptide was elevated (median, 187 pg/mL; 25th to 75th percentiles, 89 to 306 pg/mL) before stent placement and fell within 24 hours of the successful stent procedure (96 pg/mL; 25th to 75th percentiles, 61 to 182 pg/mL; P=0.002), remaining low (85 pg/mL; 25th to 75th percentiles, 43 to 171 pg/mL) at follow-up. Clinical improvement in hypertension was observed in the patients with a baseline BNP >80 pg/mL (n=22) in 17 patients (77%) compared with 0% of the patients with a baseline BNP 80 pg/mL (n=5) (P=0.001). After correction for glomerular filtration rate, BNP was strongly correlated with improvement in hypertension.
Conclusions— BNP is increased in patients with severe renal artery stenosis and decreases after successful stent revascularization. In addition, an elevated baseline BNP level of >80 pg/mL appears to be a good predictor of a blood pressure response after successful stent revascularization.
Key Words: hypertension, renal ; natriuretic peptides ; stents
Introduction
Use of percutaneous transluminal renal angioplasty and stenting to treat refractory hypertension secondary to renal artery stenosis has increased dramatically. In Medicare beneficiaries, between 1996 and 2000, the number of renal interventions increased from 7660 to 18 520; half of these were performed by cardiologists.1 Approximately one third of the treated patients failed to show improvement in hypertension after the procedure.2 Biomarkers that would identify patients likely to respond to revascularization would enhance patient selection and improve cost effectiveness.
Brain natriuretic peptide (BNP) is a neurohormone released from the ventricular myocardium in conditions that cause myocardial cell stretching such as congestive heart failure and pulmonary embolism.3–5 This neurohormone, which has a serum half-life of 20 minutes, has been shown to directly correlate with pulmonary capillary wedge pressure.6,7 BNP is also considered a good predictor of major cardiovascular events and sudden death in patients with unstable angina, myocardial infarction, and ischemic cardiomyopathy.8–10
Although most of the circulating BNP is synthesized and released from ventricular myocytes, its most important physiological actions occur at the kidney level not only during conditions of health but also in pathological states.11,12 BNP promotes diuresis, natriuresis, and arterial vasodilation and antagonizes renin activity.3 In vitro data have also shown that angiotensin II may directly induce the synthesis and release of BNP, and an animal study has suggested that BNP mRNA is significantly upregulated 6 hours after clipping of the renal artery.13,14 Theoretically, BNP may be increased in patients with renovascular hypertension, a condition known to promote activation of the renal angiotensin system and the release of angiotensin II.15–17
The aims of the present investigation were to determine whether BNP may be increased in patients with renal artery stenosis, whether successful renal artery revascularization would affect BNP levels, and whether elevated BNP levels might predict which patients would have a blood pressure response after successful renal artery revascularization with a stent.
Methods
Patient Selection
Thirty-four consecutive patients with significant renal artery stenosis (70% diameter stenosis) by angiography were prospectively included in the study. Seven initially screened patients were excluded from the protocol because of (1) congestive heart failure exacerbation and left ventricular dysfunction (ejection fraction <40%; n=3), (2) recent (within 6 months) myocardial infarction and/or acute coronary syndromes (n=2), and (3) chronic renal insufficiency (creatinine 2 mg/dL; n=2).
All renal artery stenoses were atherosclerotic ostial stenoses (within 5 mm of the origin of the vessel). Eighteen patients had unilateral renal artery stenosis; 9 patients had bilateral renal artery stenosis. The investigators enrolled all patients in the protocol without knowledge of the patients’ BNP levels. The study was approved by the Investigational Review Board of the Ochsner Clinic Foundation. All patients enrolled in the protocol signed informed consent.
Procedure
All patients were pretreated with aspirin for 24 hours before the procedure, and aspirin was continued indefinitely. The renal stent placement procedure has been described previously.18 All patients had BNP measured on 4 occasions: 2 to 7 days before the procedure (n=23), within 24 hours of the intervention (n=27), 1 day after the intervention (n=27), and 7 days to 2 months after the intervention (n=25). Serum creatinine was measured 24 to 48 hours before and within 1 week after the renal artery intervention. Blood pressures were measured according to the guidelines proposed by the AHA,19 and the number of antihypertensive medications before the procedure, at hospital discharge, and at follow-up was recorded.
The operator performing the procedure visually estimated diameter stenosis. Kidney length was calculated by measuring the pole-to-pole kidney shadow during the parenchymal phase of renal angiography with computerized quantitative angiography (Image Comm Systems Inc). The estimated glomerular filtration rate (eGFR) was calculated with the Cockroft-Gault equation20 and standardized in each patient to 1.73 m2 body surface. The investigators obtained these measurements without knowledge of the patients’ BNP levels or blood pressures.
For determination of BNP, all blood samples were collected by venipuncture into EDTA tubes. The blood samples were kept at room temperature and analyzed within 4 hours with the Biosite assay (Biosite Diagnostics). For the present investigation and similar to previous studies, BNP levels were dichotomized through the use of published criteria for BNP normality at 80 pg/mL.9,21
Definitions
Hypertension was defined as systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg. Refractory hypertension was defined as a blood pressure that could not be reduced to <140/90 mm Hg with a 3-drug regimen. Improvement in hypertension (blood pressure responders) was defined as diastolic blood pressure <90 mm Hg and systolic blood pressure <140 mm Hg on the same or reduced number of antihypertensive medications or a reduction in diastolic blood pressure of 15 mm Hg on the same or reduced number of antihypertensive medications. These definitions follow the guidelines for reporting clinical trials in renal artery revascularization.22
Angiographic success was defined as a residual diameter stenosis of <30% after stent placement. Procedural success was defined as angiographic success and the absence of a major complication during hospitalization. Major complications included death, myocardial infarction, stroke, bleeding requiring transfusion, and need for hemodialysis or surgery. A significant decrease in BNP was defined as a decline in this peptide of >30% from baseline in patients with an elevated baseline BNP of >80 pg/mL.
Study End Points
The primary end point of this study was to compare the baseline and posttreatment BNP levels. The secondary end point was to determine whether the baseline BNP level correlated with clinical improvement in hypertension at follow-up.
Statistical Analysis
Categorical variables are reported as frequencies and percentages; continuous variables, as mean±SD. However, when the variable was significantly skewed or had extreme values, the median (25th to 75th percentiles) was reported. Student’s t tests or Wilcoxon’s 2-sample tests were used to compare continuous variables; 2 tests were used to compare categorical variables.
Bivariate correlation analysis was performed with Pearson’s or coefficients to investigate whether percent diameter stenosis was correlated with BNP and with hypertension improvement and whether BNP and eGFR were correlated with hypertension improvement. The correlation of BNP with hypertension improvement at follow-up was then assessed independently with multivariate analysis (partial correlation analysis), with correction for eGFR (a continuous variable), eGFR <60 mL · min–1 · m–2 (a categorical variable), creatinine, and preprocedural diastolic blood pressure (SPSS version 11.0, SPSS Inc). Differences at the level of P<0.05 (2 tailed) were considered statistically significant.
Results
Twenty-two patients (81%) with renal artery stenosis had a baseline BNP >80 pg/mL. In this group, hypertension improvement occurred in 77% of the patients (n=17) compared with 0% of the 5 patients with a baseline BNP 80 pg/mL (P=0.001) (Figure 2). The sensitivities, specificities, and positive and negative predictive values of using a baseline BNP >80 pg/mL to predict hypertension improvement at 3.5±1.3 months of follow-up were 100%, 50%, 77%, and 100%, respectively. After renal stent placement, BNP decreased by >30% of the baseline value in 17 patients (63%). In those patients whose posttreatment BNP fell by >30%, blood pressure improved at follow-up in 94% (16 of 17 patients). In patients whose BNP fell by 30%, only 1 patient (10%) had improved blood pressure (P<0.001) (Figure 2). After renal stent placement, there was a significantly greater decrease in BNP in blood pressure responders compared with blood pressure nonresponders (Figure 3).
Influence of GFR and Severity of Renal Artery Stenosis
We found no correlation between the severity of the renal artery stenosis and preprocedural BNP levels (as a continuous variable) (P=0.51), BNP >80 pg/mL (as a categorical variable) (P=0.30), or blood pressure response (P=0.24).
Blood Pressure Responders Versus Nonresponders
There was a good correlation between baseline BNP >80 pg/mL, postprocedural BNP drop, and GFR with blood pressure response to treatment (Table 4). Using a multivariate correlation analysis, we found that preprocedural BNP (r=0.62, P=0.023) and postprocedural BNP drop (r=0.82, P=0.001) independently correlated with hypertension improvement after correction for preprocedural eGFR and eGFR <60 mL · min–1 · 1.73 m–2, serum creatinine, and preprocedural diastolic blood pressure.
Discussion
We have demonstrated that BNP is increased in patients with refractory hypertension and renal artery stenosis and that this peptide may be useful for predicting which patients will have clinically improved blood pressure after successful renal revascularization. Patients with clinical evidence of congestive heart failure or an acute coronary syndrome were excluded, so the baseline elevation of BNP in our study patients cannot be attributed to these conditions. The significant decline in BNP after renal artery revascularization strongly suggests a cause-and-effect relationship for renal artery stenosis and BNP elevation. Identifying patients who are likely to have blood pressure improvement after renal revascularization is important for clinicians, because 20% to 40% of patients with refractory hypertension and renal artery stenosis do not have a blood pressure reduction after renal revascularization.2
BNP plays an important role in renal physiology. It increases the GFR, promotes natriuresis, and antagonizes the renin-angiotensin-aldosterone system.3 The main source of circulating BNP is the ventricular myocardium. However, BNP has also been shown to be synthesized and released from glomerular mesangial and epithelial cells.23 Renal artery stenosis induces the activation of the renin-angiotensin system with increased levels of angiotensin II.15–17 Recent animal data have shown that angiotensin II directly stimulates the synthesis and release of BNP independently of cell stretching13 and that the mRNA for both atrial natriuretic peptide (ANP) and BNP is upregulated in the 2-kidney, 1-clip renal artery stenosis model.14 Our data support the results of these experimental studies in that we found an elevated BNP (>80 pg/mL) in 81% (22 of 27) of our hypertensive patients with renal artery stenosis. BNP may represent a biochemical marker for activation of the renin-angiotensin system and thus may be a useful clinical assay to help identify patients who will benefit from revascularization.
In agreement with previous studies, eGFR increased only in patients with bilateral renal artery stenosis after stent revascularization. In unilateral renal artery stenosis, the unobstructed kidney is capable of compensating for the contralateral stenotic kidney by increasing its GFR.24,25 After revascularization, however, the compensatory increase in GFR of the nonobstructed kidney returns to baseline, and the overall GFR remains unaltered. Although BNP has been reported to be elevated in patients with a GFR <60 mL · min–1 · 1.73 m–2,26 our data demonstrated no statistical significant difference for elevated BNP (>80 pg/mL) stratified for an eGFR <60 or >60 mL · min–1 · 1.73 m–2 (92% versus 67%; P=0.14). We also showed that BNP declines in both groups after revascularization, implying that BNP is a useful assay to predict blood pressure response regardless of the baseline GFR.
Previous investigations have attempted to identify predictors of blood pressure response after revascularization of renal artery stenosis.27–29 We have demonstrated a strong correlation between BNP and hypertension improvement that is independent of eGFR, serum creatinine, and baseline blood pressure. An elevated baseline BNP of >80 pg/mL was a strong predictor of hypertension improvement at follow-up (100% sensitivity, 77% positive predictive value, and 100% negative predictive value), with a specificity of 50%. There was no correlation between severity of the renal artery stenosis on angiography and blood pressure improvement or elevated BNP. Angiography suffers from limited precision when trying to image aorto-ostial renal artery lesions. These vessels arise at unpredictable angles from the aorta and may not be seen well with 2D angiographic imaging. Previous reports have also failed to show this correlation,27,29 and 1 study found that a reduction in renal cortical perfusion was not directly related to the severity of renal artery stenosis.30
Study Limitations
Our study is limited by the relatively small number of patients; the likelihood of a type I statistical error is increased. Because we do not have a control group of refractory hypertensive patients without renal artery stenosis, it remains speculative whether other potential factors such as older age or the presence of coronary artery disease may have contributed to the elevated BNP in this group of patients with renal artery stenosis.31–33
Conclusions
We report that BNP is increased in patients with medically refractory hypertension and significant renal artery stenosis and that the elevated BNP level falls after revascularization. An elevated preprocedural BNP level correlates strongly with clinical improvement in blood pressure after successful percutaneous renal revascularization. A BNP-guided strategy may improve patient selection for the revascularization procedure and clinical outcomes.
References
Murphy TP, Soares G, Kim M. Increased utilization of percutaneous renal artery interventions by Medicare beneficiaries, 1996–2000. AJR Am J Roentgenol. 2004; 183: 561–568.
Safian DR, Textor SC. Renal-artery stenosis. N Engl J Med. 2001; 344: 431–442.
Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, Shrirakami G, Jougasaki M, Obata K, Yasue H, Kambayashi Y, Inoue K, Imura I. Brain natriuretic peptide as a novel cardiac hormone in humans: evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 1991; 87: 1402–1412.
Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea. J Am Coll Cardiol. 2002; 39: 202–209.
ten Wolde M, Tulevski II, Mulder JWM, Sohne M, Mulder BJ, Buller HR. Brain natriuretic peptide as a predictor of adverse outcome in patients with pulmonary embolism. Circulation. 2003; 107: 2082–2084.
Pedersen EB, Pedersen HB, Jensen KT. Pulsatile secretion of atrial natriuretic peptide and brain natriuretic peptide in healthy humans. Clin Sci. 1999; 97: 201–206.
Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000; 355: 1126–1130.
Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin-converting-enzyme inhibition after myocardial infarction. Lancet. 1993; 341: 1109–1113.
De Lemos JA, Morrow D, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001; 345: 1014–1021.
Berger R, Huelsman M, Strecter K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with congestive heart failure. Circulation. 2002; 105: 2392–2397.
Suganami T, Mukoyama M, Sugawara A, Mori K, Nagae T, Kasahara M, Yahata K, Makino H, Fujinaga Y, Ogawa Y, Tanaka I, Nakao K. Overexpression of brain natriuretic peptide in mice ameliorates immune-mediated renal injury. J Am Soc Nephrol. 2001; 12: 2652–2663.
Kasahara M, Mukoyama M, Sugawara A, Makino H, Suganami T, Ogawa Y, Nakagawa M, Yahata K, Goto M, Ishibashi R, Tamura N, Tanaka I, Nakao K. Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol. 2000; 11: 1691–1701.
Wiese S, Breyer T, Dragu A, Wakili R, Burkard T, Schmidt-Schweda S, Fuchtbauer EM, Dohrmann U, Beyersdorf F, Radicke D, Holubarsch CJF. Gene expression of brain natriuretic peptide in isolated atrial and ventricular myocardium: influence of angiotensin II and diastolic fiber length. Circulation. 2000; 102: 3074–3079.
Kurtz WK, Pfeifer M, Hochel K, Riegger GA, Kramer BK. Different regulation of left ventricular ANP, BNP, and adrenomodullin mRNA in the two-kidney, one-clip model of renovascular hypertension. Pflugers Arch. 2001; 442: 212–217.
DeForrest JM, Knappenberger RC, Antonaccio MJ, Ferrone RA, Creekmore JS. Angiotensin II is a necessary component for the development of hypertension in the two kidney, one clip rat. Am J Cardiol. 1982; 49: 151–1517.
Martinez-Maldonado M. Pathophysiology of renovascular hypertension. Hypertension. 1991; 17: 707–719.
Nishimura M, Milsted A, Bloch CH, Brosnihan KB, Ferrario CM. Tissue renin-angiotensin systems in renal hypertension. Hypertension. 1992; 20: 158–167.
White CJ, Ramee SR, Collins TJ, Jenkins JS, Escobar A, Shaw D. Renal artery stent placement: utility in lesions difficult to treat with balloon angioplasty. J Am Coll Cardiol. 1997; 30: 1445–1450.
Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157: 2413–2446.
Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41.
Morrow DA, de Lemos JA, Sabatine MS, Murphy SA, Demoupoulus LA, DiBattiste PM, McCabe CH, Gibson CM, Cannon CP, Braunwald E. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide for prognosis in TACTICS-TIMI 18. J Am Coll Cardiol. 2003; 41: 1264–1272.
Rundback JH, Sacks D, Kent C, Cooper C, Jones D, Murphy T, Rosenfield K, White CJ, Bettmann M, Cortell S, Puschett J, Clair D, Cole P, for the AHA Councils on Cardiovascular Radiology, High Blood Pressure Research, Kidney in Cardiovascular Disease, Cardio-Thoracic and Vascular Surgery, and Clinical Cardiology, and the Society of Interventional Radiology FDA Device Forum Committee, American Heart Association. Guidelines for reporting renal artery revascularization in clinical trials. Circulation. 2002; 106: 1572–1585.
Lai KN, Leung JC, Yandle TG, Fisher S, Nicholls MG. Gene expression and synthesis of natriuretic peptides by cultured human glomerular cells. J Hypertens. 1999; 17: 575–583.
La Batide-Alanore A, Azizi M, Froissart M, Raygnaud A, Plouin PF. Split renal function outcome after renal angioplasty in patients with unilateral renal artery stenosis. J Am Soc Nephrol. 2001; 12: 1235–1241.
Leertouwer TC, Derkx FHM, Pattynama PMT, Deinum J, van Dijk LC, Schalekamp MADH. Functional effects of renal artery stent placement on treated and contralateral kidneys. Kidney Int. 2002; 62: 574–579.
McCullough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, Herrmann HC, Steg PG, Westheim A, Knudsen CW, Storrow AB, Abraham WT, Lamba S, Wu ALH, Perez A, Clopton P, Krishnaswamy P, Kazanegra R, Maisel A, for the Breathing Non Properly Multinational Study Investigators. B-type natriuretic peptide in the diagnosis of heart failure: an analysis from the Breathing Non Properly Multinational Study. Am J Kidney Dis. 2003; 41: 571–579.
Rocha-Singh, KJ, Mishkel GJ, Katholi RE, Ligon RA, Armbruster JA, McShane KJ, Zeck KJ. Clinical predictors of improved long-term blood pressure control after successful stenting of hypertensive patients with obstructive renal artery stenosis. Cathet Cardiovasc Intervent. 1999; 47: 167–172.
Radermacher J, Chavan A, Bleck J, Vitzthum A, Stoess B, Gebel MJ, Galanski M, Koch KM, Haller H. Use of Doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis. N Engl J Med. 2001; 344: 410–417.
Lederman RJ, Mendelsohn FO, Santos R, Phillips HR, Stack RS, Crowley JJ. Primary renal artery stenting: characteristics and outcomes after 363 procedures. Am Heart J. 2001; 42: 314–323.
Lerman LO, Taler SJ, Textor SC, Sheedy PF 2nd, Stanson AW, Romero JC. Computed tomography-derived intrarenal blood flow in renovascular and essential hypertension. Kidney Int. 1996; 49: 846–854.
McCullough PA, Kuncheria J, Mathur VS. Diagnostic and therapeutic utility of B-type natriuretic peptide in patients with renal insufficiency and decompensated heart failure. Rev Cardiovasc Med. 2003; 4 (suppl 7): S3–S12.
Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002; 40: 976–982.
Bibbins-Domingo K, Ansari M, Schiller NB, Massie B, Whooley MA. B-type natriuretic peptide and ischemia in patients with stable coronary disease: data from the Heart and Soul Study. Circulation. 2003; 108: 2987–2992.(Jose A. Silva, MD; Albert)
Abstract
Background— A significant number (20% to 40%) of hypertensive patients with renal artery stenosis will not have blood pressure improvement after successful percutaneous revascularization. Identifying a group of patients with refractory hypertension and renal artery stenosis who are likely to respond to renal stent placement would be beneficial.
Methods and Results— Brain natriuretic peptide (BNP) was measured in 27 patients with refractory hypertension and significant renal artery stenosis before and after successful renal artery stent placement. This neuropeptide was elevated (median, 187 pg/mL; 25th to 75th percentiles, 89 to 306 pg/mL) before stent placement and fell within 24 hours of the successful stent procedure (96 pg/mL; 25th to 75th percentiles, 61 to 182 pg/mL; P=0.002), remaining low (85 pg/mL; 25th to 75th percentiles, 43 to 171 pg/mL) at follow-up. Clinical improvement in hypertension was observed in the patients with a baseline BNP >80 pg/mL (n=22) in 17 patients (77%) compared with 0% of the patients with a baseline BNP 80 pg/mL (n=5) (P=0.001). After correction for glomerular filtration rate, BNP was strongly correlated with improvement in hypertension.
Conclusions— BNP is increased in patients with severe renal artery stenosis and decreases after successful stent revascularization. In addition, an elevated baseline BNP level of >80 pg/mL appears to be a good predictor of a blood pressure response after successful stent revascularization.
Key Words: hypertension, renal ; natriuretic peptides ; stents
Introduction
Use of percutaneous transluminal renal angioplasty and stenting to treat refractory hypertension secondary to renal artery stenosis has increased dramatically. In Medicare beneficiaries, between 1996 and 2000, the number of renal interventions increased from 7660 to 18 520; half of these were performed by cardiologists.1 Approximately one third of the treated patients failed to show improvement in hypertension after the procedure.2 Biomarkers that would identify patients likely to respond to revascularization would enhance patient selection and improve cost effectiveness.
Brain natriuretic peptide (BNP) is a neurohormone released from the ventricular myocardium in conditions that cause myocardial cell stretching such as congestive heart failure and pulmonary embolism.3–5 This neurohormone, which has a serum half-life of 20 minutes, has been shown to directly correlate with pulmonary capillary wedge pressure.6,7 BNP is also considered a good predictor of major cardiovascular events and sudden death in patients with unstable angina, myocardial infarction, and ischemic cardiomyopathy.8–10
Although most of the circulating BNP is synthesized and released from ventricular myocytes, its most important physiological actions occur at the kidney level not only during conditions of health but also in pathological states.11,12 BNP promotes diuresis, natriuresis, and arterial vasodilation and antagonizes renin activity.3 In vitro data have also shown that angiotensin II may directly induce the synthesis and release of BNP, and an animal study has suggested that BNP mRNA is significantly upregulated 6 hours after clipping of the renal artery.13,14 Theoretically, BNP may be increased in patients with renovascular hypertension, a condition known to promote activation of the renal angiotensin system and the release of angiotensin II.15–17
The aims of the present investigation were to determine whether BNP may be increased in patients with renal artery stenosis, whether successful renal artery revascularization would affect BNP levels, and whether elevated BNP levels might predict which patients would have a blood pressure response after successful renal artery revascularization with a stent.
Methods
Patient Selection
Thirty-four consecutive patients with significant renal artery stenosis (70% diameter stenosis) by angiography were prospectively included in the study. Seven initially screened patients were excluded from the protocol because of (1) congestive heart failure exacerbation and left ventricular dysfunction (ejection fraction <40%; n=3), (2) recent (within 6 months) myocardial infarction and/or acute coronary syndromes (n=2), and (3) chronic renal insufficiency (creatinine 2 mg/dL; n=2).
All renal artery stenoses were atherosclerotic ostial stenoses (within 5 mm of the origin of the vessel). Eighteen patients had unilateral renal artery stenosis; 9 patients had bilateral renal artery stenosis. The investigators enrolled all patients in the protocol without knowledge of the patients’ BNP levels. The study was approved by the Investigational Review Board of the Ochsner Clinic Foundation. All patients enrolled in the protocol signed informed consent.
Procedure
All patients were pretreated with aspirin for 24 hours before the procedure, and aspirin was continued indefinitely. The renal stent placement procedure has been described previously.18 All patients had BNP measured on 4 occasions: 2 to 7 days before the procedure (n=23), within 24 hours of the intervention (n=27), 1 day after the intervention (n=27), and 7 days to 2 months after the intervention (n=25). Serum creatinine was measured 24 to 48 hours before and within 1 week after the renal artery intervention. Blood pressures were measured according to the guidelines proposed by the AHA,19 and the number of antihypertensive medications before the procedure, at hospital discharge, and at follow-up was recorded.
The operator performing the procedure visually estimated diameter stenosis. Kidney length was calculated by measuring the pole-to-pole kidney shadow during the parenchymal phase of renal angiography with computerized quantitative angiography (Image Comm Systems Inc). The estimated glomerular filtration rate (eGFR) was calculated with the Cockroft-Gault equation20 and standardized in each patient to 1.73 m2 body surface. The investigators obtained these measurements without knowledge of the patients’ BNP levels or blood pressures.
For determination of BNP, all blood samples were collected by venipuncture into EDTA tubes. The blood samples were kept at room temperature and analyzed within 4 hours with the Biosite assay (Biosite Diagnostics). For the present investigation and similar to previous studies, BNP levels were dichotomized through the use of published criteria for BNP normality at 80 pg/mL.9,21
Definitions
Hypertension was defined as systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg. Refractory hypertension was defined as a blood pressure that could not be reduced to <140/90 mm Hg with a 3-drug regimen. Improvement in hypertension (blood pressure responders) was defined as diastolic blood pressure <90 mm Hg and systolic blood pressure <140 mm Hg on the same or reduced number of antihypertensive medications or a reduction in diastolic blood pressure of 15 mm Hg on the same or reduced number of antihypertensive medications. These definitions follow the guidelines for reporting clinical trials in renal artery revascularization.22
Angiographic success was defined as a residual diameter stenosis of <30% after stent placement. Procedural success was defined as angiographic success and the absence of a major complication during hospitalization. Major complications included death, myocardial infarction, stroke, bleeding requiring transfusion, and need for hemodialysis or surgery. A significant decrease in BNP was defined as a decline in this peptide of >30% from baseline in patients with an elevated baseline BNP of >80 pg/mL.
Study End Points
The primary end point of this study was to compare the baseline and posttreatment BNP levels. The secondary end point was to determine whether the baseline BNP level correlated with clinical improvement in hypertension at follow-up.
Statistical Analysis
Categorical variables are reported as frequencies and percentages; continuous variables, as mean±SD. However, when the variable was significantly skewed or had extreme values, the median (25th to 75th percentiles) was reported. Student’s t tests or Wilcoxon’s 2-sample tests were used to compare continuous variables; 2 tests were used to compare categorical variables.
Bivariate correlation analysis was performed with Pearson’s or coefficients to investigate whether percent diameter stenosis was correlated with BNP and with hypertension improvement and whether BNP and eGFR were correlated with hypertension improvement. The correlation of BNP with hypertension improvement at follow-up was then assessed independently with multivariate analysis (partial correlation analysis), with correction for eGFR (a continuous variable), eGFR <60 mL · min–1 · m–2 (a categorical variable), creatinine, and preprocedural diastolic blood pressure (SPSS version 11.0, SPSS Inc). Differences at the level of P<0.05 (2 tailed) were considered statistically significant.
Results
Twenty-two patients (81%) with renal artery stenosis had a baseline BNP >80 pg/mL. In this group, hypertension improvement occurred in 77% of the patients (n=17) compared with 0% of the 5 patients with a baseline BNP 80 pg/mL (P=0.001) (Figure 2). The sensitivities, specificities, and positive and negative predictive values of using a baseline BNP >80 pg/mL to predict hypertension improvement at 3.5±1.3 months of follow-up were 100%, 50%, 77%, and 100%, respectively. After renal stent placement, BNP decreased by >30% of the baseline value in 17 patients (63%). In those patients whose posttreatment BNP fell by >30%, blood pressure improved at follow-up in 94% (16 of 17 patients). In patients whose BNP fell by 30%, only 1 patient (10%) had improved blood pressure (P<0.001) (Figure 2). After renal stent placement, there was a significantly greater decrease in BNP in blood pressure responders compared with blood pressure nonresponders (Figure 3).
Influence of GFR and Severity of Renal Artery Stenosis
We found no correlation between the severity of the renal artery stenosis and preprocedural BNP levels (as a continuous variable) (P=0.51), BNP >80 pg/mL (as a categorical variable) (P=0.30), or blood pressure response (P=0.24).
Blood Pressure Responders Versus Nonresponders
There was a good correlation between baseline BNP >80 pg/mL, postprocedural BNP drop, and GFR with blood pressure response to treatment (Table 4). Using a multivariate correlation analysis, we found that preprocedural BNP (r=0.62, P=0.023) and postprocedural BNP drop (r=0.82, P=0.001) independently correlated with hypertension improvement after correction for preprocedural eGFR and eGFR <60 mL · min–1 · 1.73 m–2, serum creatinine, and preprocedural diastolic blood pressure.
Discussion
We have demonstrated that BNP is increased in patients with refractory hypertension and renal artery stenosis and that this peptide may be useful for predicting which patients will have clinically improved blood pressure after successful renal revascularization. Patients with clinical evidence of congestive heart failure or an acute coronary syndrome were excluded, so the baseline elevation of BNP in our study patients cannot be attributed to these conditions. The significant decline in BNP after renal artery revascularization strongly suggests a cause-and-effect relationship for renal artery stenosis and BNP elevation. Identifying patients who are likely to have blood pressure improvement after renal revascularization is important for clinicians, because 20% to 40% of patients with refractory hypertension and renal artery stenosis do not have a blood pressure reduction after renal revascularization.2
BNP plays an important role in renal physiology. It increases the GFR, promotes natriuresis, and antagonizes the renin-angiotensin-aldosterone system.3 The main source of circulating BNP is the ventricular myocardium. However, BNP has also been shown to be synthesized and released from glomerular mesangial and epithelial cells.23 Renal artery stenosis induces the activation of the renin-angiotensin system with increased levels of angiotensin II.15–17 Recent animal data have shown that angiotensin II directly stimulates the synthesis and release of BNP independently of cell stretching13 and that the mRNA for both atrial natriuretic peptide (ANP) and BNP is upregulated in the 2-kidney, 1-clip renal artery stenosis model.14 Our data support the results of these experimental studies in that we found an elevated BNP (>80 pg/mL) in 81% (22 of 27) of our hypertensive patients with renal artery stenosis. BNP may represent a biochemical marker for activation of the renin-angiotensin system and thus may be a useful clinical assay to help identify patients who will benefit from revascularization.
In agreement with previous studies, eGFR increased only in patients with bilateral renal artery stenosis after stent revascularization. In unilateral renal artery stenosis, the unobstructed kidney is capable of compensating for the contralateral stenotic kidney by increasing its GFR.24,25 After revascularization, however, the compensatory increase in GFR of the nonobstructed kidney returns to baseline, and the overall GFR remains unaltered. Although BNP has been reported to be elevated in patients with a GFR <60 mL · min–1 · 1.73 m–2,26 our data demonstrated no statistical significant difference for elevated BNP (>80 pg/mL) stratified for an eGFR <60 or >60 mL · min–1 · 1.73 m–2 (92% versus 67%; P=0.14). We also showed that BNP declines in both groups after revascularization, implying that BNP is a useful assay to predict blood pressure response regardless of the baseline GFR.
Previous investigations have attempted to identify predictors of blood pressure response after revascularization of renal artery stenosis.27–29 We have demonstrated a strong correlation between BNP and hypertension improvement that is independent of eGFR, serum creatinine, and baseline blood pressure. An elevated baseline BNP of >80 pg/mL was a strong predictor of hypertension improvement at follow-up (100% sensitivity, 77% positive predictive value, and 100% negative predictive value), with a specificity of 50%. There was no correlation between severity of the renal artery stenosis on angiography and blood pressure improvement or elevated BNP. Angiography suffers from limited precision when trying to image aorto-ostial renal artery lesions. These vessels arise at unpredictable angles from the aorta and may not be seen well with 2D angiographic imaging. Previous reports have also failed to show this correlation,27,29 and 1 study found that a reduction in renal cortical perfusion was not directly related to the severity of renal artery stenosis.30
Study Limitations
Our study is limited by the relatively small number of patients; the likelihood of a type I statistical error is increased. Because we do not have a control group of refractory hypertensive patients without renal artery stenosis, it remains speculative whether other potential factors such as older age or the presence of coronary artery disease may have contributed to the elevated BNP in this group of patients with renal artery stenosis.31–33
Conclusions
We report that BNP is increased in patients with medically refractory hypertension and significant renal artery stenosis and that the elevated BNP level falls after revascularization. An elevated preprocedural BNP level correlates strongly with clinical improvement in blood pressure after successful percutaneous renal revascularization. A BNP-guided strategy may improve patient selection for the revascularization procedure and clinical outcomes.
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