Nephrol Dial Transplant (2016) 31: 1437–1443 doi: 10.1093/ndt/gfv448 Advance Access publication 29 January 2016
Original Articles Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis Wei Wang1,2, Ahmed Saad1, Sandra M. Herrmann1, Alfonso Eirin Massat1, Michael A. McKusick3, Sanjay Misra3, Lilach O. Lerman1 and Stephen C. Textor1 1
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA, 2Department of Nephrology, Dalian Municipal Central Hospital
Affiliated of Dalian Medical University, Dalian, Liaoning, China and 3Department of Radiology, Mayo Clinic, Rochester, MN, USA
Correspondence and offprint requests to: Stephen C. Textor; E-mail: [email protected]
A B S T R AC T
INTRODUCTION
Background. Atherosclerotic renal artery stenosis (ARAS) activates oxidative stress and chronic inflammatory injury. Contrast imaging and endovascular stenting pose potential hazards for acute kidney injury, particularly when superimposed upon reduced kidney perfusion. Methods. We measured sequential early and long-term changes in circulating inflammatory and injury biomarkers in 12 ARAS subjects subjected to computed tomography imaging and stent revascularization compared with essential hypertensive (EH) subjects of similar age under fixed sodium intake and medication regimens in a clinical research unit. Results. NGAL, TIMP-2, IGFBP7, MCP-1 and TNF-α all were elevated before intervention. Post-stenotic kidney volume, perfusion, blood flow and glomerular filtration rate (GFR) were lower in ARAS than in EH subjects. TIMP-2 and IGFBP7 fell briefly, then rose over 18 h after contrast imaging and stent deployment. Circulating NGAL decreased and remained lower for 27 h. These biomarkers in ARAS returned to baseline after 3 months, while kidney volume, perfusion, blood flow and GFR increased, but remained lower than EH. Conclusions. These divergent patterns of inflammatory signals are consistent with cell cycle arrest (TIMP-2, IGFBP7) and relative protection from acute kidney injury after imaging and stenting. Sustained basal elevation of circulating and renal venous inflammatory biomarkers support ongoing, possibly episodic, renal stress in ARAS that limits toxicity from stent revascularization.
Atherosclerotic renal artery stenosis (ARAS) reduces blood flow and perfusion pressures to the post-stenotic kidney, produces renovascular hypertension and threatens glomerular filtration rate (GFR). For selected cases, restoring vessel patency with stent revascularization can lower arterial pressure and prevent the loss of renal function [1]. The procedures of endovascular stenting may be associated with contrast-induced nephropathy, atheroembolism, renal artery or aortic dissection, or renal artery rupture [1]. ARAS is associated with activation of the renal-angiotensinaldosterone system, oxidative stress and chronic inflammatory injury [2]. Although endovascular stenting can provide major benefits for high-risk patients with severe hypertension, rapidly progressive renal failure and/or pulmonary edema [3], prospective treatment trials [4–6] fail to show consistent additional benefit of renal artery revascularization in improving renal function as compared with optimal medical therapy. The role and immediate changes of inflammatory biomarkers in this condition remain poorly defined. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) have been proposed as signaling biomarkers of acute kidney injury (AKI) [7]. Recent studies using urinary insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) validate these biomarkers for risk stratification of moderate and severe AKI in the Discovery and Sapphire studies [8]. Urinary IGFBP7*TIMP-2 has been approved by the US Food and Drug Administration as a biomarker to predict early AKI and prognosis in postoperative AKI [9, 10] and critically ill patients [11]. Both IGFBP7 and TIMP-2 participate in
Keywords: acute kidney injury, atherosclerotic renal artery stenosis (ARAS), biomarkers, endovascular stenting, ischemic preconditioning (IPC) © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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G1 cell cycle division during the early phase of cell injury and prevent cells with damaged DNA from dividing [9]. Hence, they are sensitive to and potentially protective for early tubular injury. Studies of remote ischemic preconditioning suggest that individuals with a rise in TIMP-2 and IGFBP7 are those most likely to be protected from AKI after surgery [12]. The aim of our present study was to examine changes in renal injury and inflammatory biomarkers in peripheral blood during the first 27 h after contrast imaging and stent revascularization and to compare them to levels achieved 3 months later. We further sought to examine renal venous levels of these biomarkers before and after restoring blood flow 3 months later.
ORIGINAL ARTICLE
METHODS Patient selection ARAS patients (n = 12) with clinical indications for renal revascularization (including treatment-resistant hypertension, circulatory congestion or rapidly progressive renal failure) and essential hypertension (EH) (n = 12) were prospectively enrolled for inpatient studies in the clinical research unit of Saint Mary’s Hospital (Rochester, MN, USA) [13] from 2008 to 2014. Written informed consent was obtained from all patients at the time of enrollment, as approved by the Institutional Review Board of the Mayo Clinic. ARAS was quantified using entry criteria analogous to enrollment in Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL) [14] with magnetic resonance/computed tomography (CT) angiography showing at least 60% luminal occlusion in the affected artery estimated by Doppler ultrasound, with the additional requirement for serum creatinine
Original Articles Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis Wei Wang1,2, Ahmed Saad1, Sandra M. Herrmann1, Alfonso Eirin Massat1, Michael A. McKusick3, Sanjay Misra3, Lilach O. Lerman1 and Stephen C. Textor1 1
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA, 2Department of Nephrology, Dalian Municipal Central Hospital
Affiliated of Dalian Medical University, Dalian, Liaoning, China and 3Department of Radiology, Mayo Clinic, Rochester, MN, USA
Correspondence and offprint requests to: Stephen C. Textor; E-mail: [email protected]
A B S T R AC T
INTRODUCTION
Background. Atherosclerotic renal artery stenosis (ARAS) activates oxidative stress and chronic inflammatory injury. Contrast imaging and endovascular stenting pose potential hazards for acute kidney injury, particularly when superimposed upon reduced kidney perfusion. Methods. We measured sequential early and long-term changes in circulating inflammatory and injury biomarkers in 12 ARAS subjects subjected to computed tomography imaging and stent revascularization compared with essential hypertensive (EH) subjects of similar age under fixed sodium intake and medication regimens in a clinical research unit. Results. NGAL, TIMP-2, IGFBP7, MCP-1 and TNF-α all were elevated before intervention. Post-stenotic kidney volume, perfusion, blood flow and glomerular filtration rate (GFR) were lower in ARAS than in EH subjects. TIMP-2 and IGFBP7 fell briefly, then rose over 18 h after contrast imaging and stent deployment. Circulating NGAL decreased and remained lower for 27 h. These biomarkers in ARAS returned to baseline after 3 months, while kidney volume, perfusion, blood flow and GFR increased, but remained lower than EH. Conclusions. These divergent patterns of inflammatory signals are consistent with cell cycle arrest (TIMP-2, IGFBP7) and relative protection from acute kidney injury after imaging and stenting. Sustained basal elevation of circulating and renal venous inflammatory biomarkers support ongoing, possibly episodic, renal stress in ARAS that limits toxicity from stent revascularization.
Atherosclerotic renal artery stenosis (ARAS) reduces blood flow and perfusion pressures to the post-stenotic kidney, produces renovascular hypertension and threatens glomerular filtration rate (GFR). For selected cases, restoring vessel patency with stent revascularization can lower arterial pressure and prevent the loss of renal function [1]. The procedures of endovascular stenting may be associated with contrast-induced nephropathy, atheroembolism, renal artery or aortic dissection, or renal artery rupture [1]. ARAS is associated with activation of the renal-angiotensinaldosterone system, oxidative stress and chronic inflammatory injury [2]. Although endovascular stenting can provide major benefits for high-risk patients with severe hypertension, rapidly progressive renal failure and/or pulmonary edema [3], prospective treatment trials [4–6] fail to show consistent additional benefit of renal artery revascularization in improving renal function as compared with optimal medical therapy. The role and immediate changes of inflammatory biomarkers in this condition remain poorly defined. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) have been proposed as signaling biomarkers of acute kidney injury (AKI) [7]. Recent studies using urinary insulin-like growth factor binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) validate these biomarkers for risk stratification of moderate and severe AKI in the Discovery and Sapphire studies [8]. Urinary IGFBP7*TIMP-2 has been approved by the US Food and Drug Administration as a biomarker to predict early AKI and prognosis in postoperative AKI [9, 10] and critically ill patients [11]. Both IGFBP7 and TIMP-2 participate in
Keywords: acute kidney injury, atherosclerotic renal artery stenosis (ARAS), biomarkers, endovascular stenting, ischemic preconditioning (IPC) © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
1437
G1 cell cycle division during the early phase of cell injury and prevent cells with damaged DNA from dividing [9]. Hence, they are sensitive to and potentially protective for early tubular injury. Studies of remote ischemic preconditioning suggest that individuals with a rise in TIMP-2 and IGFBP7 are those most likely to be protected from AKI after surgery [12]. The aim of our present study was to examine changes in renal injury and inflammatory biomarkers in peripheral blood during the first 27 h after contrast imaging and stent revascularization and to compare them to levels achieved 3 months later. We further sought to examine renal venous levels of these biomarkers before and after restoring blood flow 3 months later.
ORIGINAL ARTICLE
METHODS Patient selection ARAS patients (n = 12) with clinical indications for renal revascularization (including treatment-resistant hypertension, circulatory congestion or rapidly progressive renal failure) and essential hypertension (EH) (n = 12) were prospectively enrolled for inpatient studies in the clinical research unit of Saint Mary’s Hospital (Rochester, MN, USA) [13] from 2008 to 2014. Written informed consent was obtained from all patients at the time of enrollment, as approved by the Institutional Review Board of the Mayo Clinic. ARAS was quantified using entry criteria analogous to enrollment in Cardiovascular Outcomes for Renal Atherosclerotic Lesions (CORAL) [14] with magnetic resonance/computed tomography (CT) angiography showing at least 60% luminal occlusion in the affected artery estimated by Doppler ultrasound, with the additional requirement for serum creatinine
