commentary
http://www.kidney-international.org & 2015 International Society of Nephrology
see basic research on page 719
Coronary artery stenosis: a new risk factor for chronic kidney injury? Lars Christian Rump1 and Johannes Stegbauer1 Coronary artery stenosis induces renal inflammation and kidney injury in pigs even in the absence of myocardial infarction or clinically significant heart failure. This effect is aggravated by experimentally induced renovascular hypertension. Interestingly, oxidative stress originating from the ischemic myocardium was identified as a possible mediator of this new pathophysiological link between heart and kidney. Renin–angiotensin or sympathetic nervous system activation did not appear to play a role in the observed cardio-renal link. Kidney International (2015) 87, 676–677. doi:10.1038/ki.2014.431
It is well known that acute or chronic kidney injury is an important independent risk factor for developing heart failure as well as other cardiovascular diseases and vice versa. This bidirectional heart–kidney interaction concept has been termed cardiorenal syndrome (CRS) and has gained a lot of attention due to its high clinical relevance. The mechanisms by which injured kidneys accelerate cardiovascular diseases in CRS types 3 and 4 are versatile and include increased sympathetic nervous system activity, accumulation of uremic toxins, activated renin–angiotensin system, hypertension, calcium–phosphate disturbances, and systemic inflammation. On the other hand, acute heart failure frequently leads to kidney injury in CRS type 1 by arterial underfilling or venous congestion.1 The mechanisms by which chronic heart failure causes kidney injury in CRS type 2 are less 1
Department of Nephrology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany Correspondence: Lars Christian Rump, Department of Nephrology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany. E-mail: [email protected] 676
clear but involve hemodynamic and non-hemodynamic effects mediated by the renin–angiotensin and the sympathetic nervous system. In addition, there is some evidence that chronic heart failure is a proinflammatory state characterized by marked increases in the serum levels of several interleukins, adhesion molecules, and tumor necrosis factor-a that may also lead to kidney injury.1 Sun et al.2 now add a new, unexpected pathophysiological link between heart and kidney. They show in pigs that an experimental coronary artery stenosis (CAS) without myocardial infarction causes systemic oxidative stress and thereby mediates kidney damage. This CAS-associated damage is further aggravated by experimentally induced renovascular hypertension (Figure 1). However, it is necessary to take a closer look at how CAS and hypertension were induced. Sun et al.2 placed local irritant coils in the left circumflex coronary and/or right renal artery to obtain cardiac ischemia and renovascular hypertension. In animals with right renal artery stenosis but without CAS, microvascular remodeling and
tubular injury were observed in the contralateral left kidney. Such a deleterious effect on the uninstrumented kidney has been previously described by Hilgers et al.3 in rats with twokidney, one-clip hypertension, which in their model apparently was mediated by non-hemodynamic, inflammatory effects of angiotensin II. Sun et al. did not find a significantly increased plasma renin activity in their model of renovascular hypertension as compared with the sham and CAS groups. It appears that in pigs unilateral renal artery stenosis induces only a transient increase of plasma renin activity, which disappears by 10 weeks after induction of renal artery stenosis.4 Nevertheless, transient and/or local angiotensin II effects in the non-stenotic kidney cannot be ruled out entirely, since renal tissue renin–angiotensin activity was not measured by Sun et al.2 In line with this, there is substantial evidence for an increased sympathetic nervous system activity in renovascular hypertension5 as well as in myocardial ischemia. Moreover, our group has reported an enhancement of kidney disease progression by increased sympathetic neurotransmitter release from the renal nerves.6 This mechanism seems an unlikely explanation for the findings of Sun et al. since plasma norepinephrine levels did not differ between groups. However, it is well known that plasma norepinephrine concentration is only a poor marker of sympathetic nervous system activity, and therefore efferent renal sympathetic nerves of the contralateral kidney may still be selectively activated—for instance, by afferent signals arising from the stenotic kidney to the brain, or even by direct reno-renal reflexes.7 Strikingly, the combination of CAS and renovascular hypertension markedly exaggerated renal fibrosis and proteinuria, impaired endothelial function, and reduced renal blood flow in the non-stenotic kidneys of pigs to a larger extent than hypertension alone. This is a fascinating finding since this was due to CAS with only mild myocardial ischemia producing a systemic Kidney International (2015) 87
commentary
Experimental coronary artery stenosis
Stenotic kidney
Left coronary artery Circumflex artery Left anterior descending artery
Aorta
Myocardial perfusion ↓ Slightly decreased ejection fraction
Right coronary artery Systemic oxidative stress ↑↑ (PGF2-isoprostane)
Renal artery stenosis
Hypertension Transient increase of the renin–angiotensin system inflammatory response
+
Mechanisms: • Renal endothelial dysfunction • Renal inflammation ↑ (MCP-1, TNF-α) • Renal oxidative stress ↑ (DHE, nitrotyrosine, gp91-phox) • Renal hypoxia ↑ (HIF-1α) • Renal microvascular injury (microvascular wall thickening ↑, capillary density ↓)
Non-stenotic kidney
initiates systemic and renal oxidative stress remain unresolved. So far, no particular clinical benefit of arterial revascularization was shown in patients with stable CAS or in patients with renal artery stenosis and presumed renovascular hypertension as compared with optimal medical treatment alone.8 There is a substantial number of patients who have both CAS and significant renal artery stenosis with a reported prevalence of up to 17.8%.9 The present experimental study2 showed that coexisting stable CAS and renovascular hypertension exaggerated renal injury in pigs. Thus, in the future one may have to look in more detail at whether, in patients with stable CAS and renovascular hypertension, interventional therapy provides additional benefit at least for long-term kidney function.
Kidney damage:
DISCLOSURE
• • • •
The authors declared no competing interests.
Glomerular sclerosis Tubular injury Renal fibrosis Proteinuria
Figure 1 | Schematic pathway by which coronary artery stenosis and renal artery stenosis exaggerates kidney injury in the non-stenotic kidney.
REFERENCES 1.
2.
3.
oxidative stress and a renal inflammatory response. It is conceivable that the creation of CAS and renal artery stenosis by irritant coils led to a coil-induced inflammatory state and oxidative stress. However, this possibility was ruled out by elegant experiments in which similar coils were placed into a femoral artery and did not induce renal ischemia or fibrosis. Nevertheless, the question remains how CAS induces renal oxidative stress and hypoxia leading to exaggerated kidney injury in the absence of atherosclerosis or myocardial infarction. The authors believe that mild myocardial ischemia without symptoms of significant heart failure is sufficient to stimulate oxidative stress. However, it must be noted that the pigs in the CAS and CAS
Kidney International (2015) 87
with hypertension groups had slightly decreased ejection fractions. It can therefore not be totally excluded that some minor heart failure contributed to the findings of Sun et al.2 The observation that CAS alone induces renal damage is further supported by experiments with the mitochondriatargeted antioxidant Bendavia, which led to improved renal endothelial function and decreased tubular injury. This may fuel again ideas of antioxidant therapeutic strategies in chronic kidney and cardiovascular disease. Taken together, the authors have provided substantial evidence in favor of new pathways leading to kidney damage in CAS and renovascular hypertension; however, the mechanisms by which mild myocardial ischemia in CAS
4.
5.
6.
7.
8.
9.
House AA. Cardiorenal syndrome: new developments in the understanding and pharmacologic management. Clin J Am Soc Nephrol 2013; 8: 1808–1815. Sun D, Eirin A, Zhu X-Y et al. Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine. Kidney Int 2015; 87: 719–727. Hilgers KF, Hartner A, Porst M et al. Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int 2000; 58: 2408–2419. Lerman LO, Nath KA, Rodriguez-Porcel M et al. Increased oxidative stress in experimental renovascular hypertension. Hypertension 2001; 37: 541–546. Johansson M, Elam M, Rundqvist B et al. Increased sympathetic nerve activity in renovascular hypertension. Circulation 1999; 99: 2537–2542. Amann K, Rump LC, Simonaviciene A et al. Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats. J Am Soc Nephrol 2000; 11: 1469–1478. Johns EJ, Kopp UC, DiBona GF. Neural control of renal function. Compr Physiol 2011; 1: 731–767. Cooper CJ, Murphy TP, Cutlip DE et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med 2014; 370: 13–22. De Mast Q, Beutler JJ. The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review. J Hypertens 2009; 27: 1333–1340.
677
http://www.kidney-international.org & 2015 International Society of Nephrology
see basic research on page 719
Coronary artery stenosis: a new risk factor for chronic kidney injury? Lars Christian Rump1 and Johannes Stegbauer1 Coronary artery stenosis induces renal inflammation and kidney injury in pigs even in the absence of myocardial infarction or clinically significant heart failure. This effect is aggravated by experimentally induced renovascular hypertension. Interestingly, oxidative stress originating from the ischemic myocardium was identified as a possible mediator of this new pathophysiological link between heart and kidney. Renin–angiotensin or sympathetic nervous system activation did not appear to play a role in the observed cardio-renal link. Kidney International (2015) 87, 676–677. doi:10.1038/ki.2014.431
It is well known that acute or chronic kidney injury is an important independent risk factor for developing heart failure as well as other cardiovascular diseases and vice versa. This bidirectional heart–kidney interaction concept has been termed cardiorenal syndrome (CRS) and has gained a lot of attention due to its high clinical relevance. The mechanisms by which injured kidneys accelerate cardiovascular diseases in CRS types 3 and 4 are versatile and include increased sympathetic nervous system activity, accumulation of uremic toxins, activated renin–angiotensin system, hypertension, calcium–phosphate disturbances, and systemic inflammation. On the other hand, acute heart failure frequently leads to kidney injury in CRS type 1 by arterial underfilling or venous congestion.1 The mechanisms by which chronic heart failure causes kidney injury in CRS type 2 are less 1
Department of Nephrology, Medical Faculty, Heinrich Heine University, Du¨sseldorf, Germany Correspondence: Lars Christian Rump, Department of Nephrology, Medical Faculty, Heinrich Heine University, Moorenstrasse 5, 40225 Du¨sseldorf, Germany. E-mail: [email protected] 676
clear but involve hemodynamic and non-hemodynamic effects mediated by the renin–angiotensin and the sympathetic nervous system. In addition, there is some evidence that chronic heart failure is a proinflammatory state characterized by marked increases in the serum levels of several interleukins, adhesion molecules, and tumor necrosis factor-a that may also lead to kidney injury.1 Sun et al.2 now add a new, unexpected pathophysiological link between heart and kidney. They show in pigs that an experimental coronary artery stenosis (CAS) without myocardial infarction causes systemic oxidative stress and thereby mediates kidney damage. This CAS-associated damage is further aggravated by experimentally induced renovascular hypertension (Figure 1). However, it is necessary to take a closer look at how CAS and hypertension were induced. Sun et al.2 placed local irritant coils in the left circumflex coronary and/or right renal artery to obtain cardiac ischemia and renovascular hypertension. In animals with right renal artery stenosis but without CAS, microvascular remodeling and
tubular injury were observed in the contralateral left kidney. Such a deleterious effect on the uninstrumented kidney has been previously described by Hilgers et al.3 in rats with twokidney, one-clip hypertension, which in their model apparently was mediated by non-hemodynamic, inflammatory effects of angiotensin II. Sun et al. did not find a significantly increased plasma renin activity in their model of renovascular hypertension as compared with the sham and CAS groups. It appears that in pigs unilateral renal artery stenosis induces only a transient increase of plasma renin activity, which disappears by 10 weeks after induction of renal artery stenosis.4 Nevertheless, transient and/or local angiotensin II effects in the non-stenotic kidney cannot be ruled out entirely, since renal tissue renin–angiotensin activity was not measured by Sun et al.2 In line with this, there is substantial evidence for an increased sympathetic nervous system activity in renovascular hypertension5 as well as in myocardial ischemia. Moreover, our group has reported an enhancement of kidney disease progression by increased sympathetic neurotransmitter release from the renal nerves.6 This mechanism seems an unlikely explanation for the findings of Sun et al. since plasma norepinephrine levels did not differ between groups. However, it is well known that plasma norepinephrine concentration is only a poor marker of sympathetic nervous system activity, and therefore efferent renal sympathetic nerves of the contralateral kidney may still be selectively activated—for instance, by afferent signals arising from the stenotic kidney to the brain, or even by direct reno-renal reflexes.7 Strikingly, the combination of CAS and renovascular hypertension markedly exaggerated renal fibrosis and proteinuria, impaired endothelial function, and reduced renal blood flow in the non-stenotic kidneys of pigs to a larger extent than hypertension alone. This is a fascinating finding since this was due to CAS with only mild myocardial ischemia producing a systemic Kidney International (2015) 87
commentary
Experimental coronary artery stenosis
Stenotic kidney
Left coronary artery Circumflex artery Left anterior descending artery
Aorta
Myocardial perfusion ↓ Slightly decreased ejection fraction
Right coronary artery Systemic oxidative stress ↑↑ (PGF2-isoprostane)
Renal artery stenosis
Hypertension Transient increase of the renin–angiotensin system inflammatory response
+
Mechanisms: • Renal endothelial dysfunction • Renal inflammation ↑ (MCP-1, TNF-α) • Renal oxidative stress ↑ (DHE, nitrotyrosine, gp91-phox) • Renal hypoxia ↑ (HIF-1α) • Renal microvascular injury (microvascular wall thickening ↑, capillary density ↓)
Non-stenotic kidney
initiates systemic and renal oxidative stress remain unresolved. So far, no particular clinical benefit of arterial revascularization was shown in patients with stable CAS or in patients with renal artery stenosis and presumed renovascular hypertension as compared with optimal medical treatment alone.8 There is a substantial number of patients who have both CAS and significant renal artery stenosis with a reported prevalence of up to 17.8%.9 The present experimental study2 showed that coexisting stable CAS and renovascular hypertension exaggerated renal injury in pigs. Thus, in the future one may have to look in more detail at whether, in patients with stable CAS and renovascular hypertension, interventional therapy provides additional benefit at least for long-term kidney function.
Kidney damage:
DISCLOSURE
• • • •
The authors declared no competing interests.
Glomerular sclerosis Tubular injury Renal fibrosis Proteinuria
Figure 1 | Schematic pathway by which coronary artery stenosis and renal artery stenosis exaggerates kidney injury in the non-stenotic kidney.
REFERENCES 1.
2.
3.
oxidative stress and a renal inflammatory response. It is conceivable that the creation of CAS and renal artery stenosis by irritant coils led to a coil-induced inflammatory state and oxidative stress. However, this possibility was ruled out by elegant experiments in which similar coils were placed into a femoral artery and did not induce renal ischemia or fibrosis. Nevertheless, the question remains how CAS induces renal oxidative stress and hypoxia leading to exaggerated kidney injury in the absence of atherosclerosis or myocardial infarction. The authors believe that mild myocardial ischemia without symptoms of significant heart failure is sufficient to stimulate oxidative stress. However, it must be noted that the pigs in the CAS and CAS
Kidney International (2015) 87
with hypertension groups had slightly decreased ejection fractions. It can therefore not be totally excluded that some minor heart failure contributed to the findings of Sun et al.2 The observation that CAS alone induces renal damage is further supported by experiments with the mitochondriatargeted antioxidant Bendavia, which led to improved renal endothelial function and decreased tubular injury. This may fuel again ideas of antioxidant therapeutic strategies in chronic kidney and cardiovascular disease. Taken together, the authors have provided substantial evidence in favor of new pathways leading to kidney damage in CAS and renovascular hypertension; however, the mechanisms by which mild myocardial ischemia in CAS
4.
5.
6.
7.
8.
9.
House AA. Cardiorenal syndrome: new developments in the understanding and pharmacologic management. Clin J Am Soc Nephrol 2013; 8: 1808–1815. Sun D, Eirin A, Zhu X-Y et al. Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine. Kidney Int 2015; 87: 719–727. Hilgers KF, Hartner A, Porst M et al. Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Kidney Int 2000; 58: 2408–2419. Lerman LO, Nath KA, Rodriguez-Porcel M et al. Increased oxidative stress in experimental renovascular hypertension. Hypertension 2001; 37: 541–546. Johansson M, Elam M, Rundqvist B et al. Increased sympathetic nerve activity in renovascular hypertension. Circulation 1999; 99: 2537–2542. Amann K, Rump LC, Simonaviciene A et al. Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats. J Am Soc Nephrol 2000; 11: 1469–1478. Johns EJ, Kopp UC, DiBona GF. Neural control of renal function. Compr Physiol 2011; 1: 731–767. Cooper CJ, Murphy TP, Cutlip DE et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med 2014; 370: 13–22. De Mast Q, Beutler JJ. The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review. J Hypertens 2009; 27: 1333–1340.
677
