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Lipids, inflammation, and chronic kidney disease: a SHARP perspective
commentary
Lipids, inflammation, and chronic kidney disease: a SHARP perspective David D. Waters1 and Liffert Vogt2 Accumulating evidence indicates that inflammation plays a role in the initiation and progression of chronic kidney disease. In the Study of Heart and Renal Protection (SHARP) trial, higher baseline C-reactive protein and higher baseline low-density lipoprotein cholesterol levels were both associated with a higher risk of cardiovascular events, but higher baseline C-reactive protein levels were also associated with a higher risk of nonvascular events. Simvastatin/ezetimibe reduced cardiovascular events independent of baseline C-reactive protein levels. However, this observation does not exclude inflammation as a causal factor for cardiovascular disease development in chronic kidney disease patients. Kidney International (2018) 93, 784–786; https://doi.org/10.1016/j.kint.2017.11.031 Copyright ª 2018, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical trial on page 1000
C
hronic kidney disease (CKD) and coronary heart disease (CHD) share common pathologic features and often coexist in the same patient. Risk factors for the development and the progression of CHD and CKD overlap and include diabetes, hypertension, and inflammation. Our understanding of the role of inflammation in both CHD and CKD has grown substantially in recent years.
Inflammation in CHD
Markers of inflammation have been shown to predict future cardiovascular (CV) events in subjects with established CHD, in those with risk factors for CHD, and in unselected populations. High-sensitivity C-reactive protein (CRP) is the inflammatory marker with the most evidence because it can be 1 Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, California, USA; and 2Department of Internal Medicine, Section Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Correspondence: David D. Waters, Zuckerberg San Francisco General Hospital, 1001 Potrero Avenue, 5G1, San Francisco, California 94110, USA. E-mail: [email protected] 784
targeting interleukin-1b, given subcutaneously every 3 months at 3 different doses.1 Canakinumab reduced CRP levels in a dose-dependent fashion. After a median follow-up of 3.7 years, the composite primary endpoint was reduced at the 2 higher doses of canakinumab (hazard ratio 0.85, 95% confidence interval 0.74–0.98, and P ¼ 0.021 at the 150-mg dose; and hazard ratio 0.86, 95% confidence interval 0.75–0.99, P ¼ 0.031 at the 300-mg dose). Deaths due to infection or sepsis were statistically significantly more common in the pooled canakinumab groups compared with the placebo groups. This, combined with the high cost of canakinumab, means that this treatment is unlikely to ever be widely used for CV event prevention; however, it has opened the door for other anti-inflammatory drugs and has established the concept that this form of treatment has the potential to reduce CV events. Inflammation in CKD
easily measured in stored frozen blood samples. CRP has major limitations: it is nonspecific, suffers from measurement variability, and is a downstream marker of the pathophysiologic effects of inflammation upon atherosclerosis. Inflammation accelerates the progression of atherosclerosis in chronic inflammatory conditions such as HIV infection and rheumatoid arthritis. Statins reduce not only low-density lipoprotein cholesterol (LDL-C) levels but also levels of CRP and other inflammatory markers. Statins reduce CV events by reducing both LDL-C and inflammation within the arterial wall. In acute coronary syndromes, where inflammation plays a major pathophysiologic role, the anti-inflammatory effects of statins are thought to be particularly important. Whether anti-inflammatory therapy reduces CV events in patients already treated with statins is currently under investigation in clinical trials. In the first of these trials to be completed, 10,061 patients with previous myocardial infarction and CRP levels $2 mg/dl were randomized to placebo or to canakinumab, a monoclonal antibody
Accumulating evidence indicates that inflammation plays a role in the initiation and progression of many forms of CKD, and accounts for at least part of the increased risk of CV events in CKD patients. Higher CRP levels are associated with a higher risk of CV events in CKD patients,2 and with a decline in estimated glomerular filtration rate (eGFR).3 Local inflammatory activity of the arterial wall can be assessed by measuring 18 F-fluorodeoxyglucose (18F-FDG) uptake with positron emission computed tomography, as illustrated in Figure 1. Representing increased metabolic activity, 18 F-FDG uptake has been linked to plaque macrophage content and is an independent predictor for future CV events. In a recent study, CKD patients with no other inflammatory conditions or evidence of atherosclerosis had increased 18 F-FDG uptake in the aorta and carotid arteries compared with controls.4 Plasma urea levels and eGFR were independent predictors of arterial inflammation. Stains reduce CV events in patients with CKD.5 The relative risk reduction is greatest among patients with mild CKD, and decreases progressively in Kidney International (2018) 93, 771–786
commentary
Figure 1 | Example of arterial wall inflammation assessed with 18F-fluorodeoxyglucose positron emission tomography and computed tomography imaging. (a) Cross-sectional low-dose computed tomography image showing the thoracic cavity. Analyses of fluorodeoxyglucose uptake (zoom of the aortic arch) reveal increased uptake in (b) a patient with chronic kidney disease compared with (c) a healthy control. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org.
more advanced categories of CKD, almost disappearing in stage 5 patients who require dialysis.5,6 Because CV risk increases in higher stages of CKD, the number needed to treat with statins to prevent an event is relatively equal across CKD stages. Whether the antiinflammatory effects of statins contribute to the CV event reduction in CKD is uncertain. The SHARP trial
The Study of Heart and Renal Protection (SHARP) trial provides the largest and most comprehensive data on the effect of lipid-lowering therapy in CKD. A total of 9270 CKD patients were enrolled in SHARP, of whom 3023 were on maintenance hemodialysis.7 Participants were randomized to simvastatin 20 mg plus ezetimibe 10 mg/d or to placebo, and median follow-up was 4.9 years. The primary outcome was a composite of first nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure. This outcome occurred in 11.3% of drugtreated and 13.4% of placebo-treated patients (relative risk 0.83, 95% confidence interval 0.74–0.94, P ¼ 0.0021). The 17% event reduction in the primary outcome was accompanied by Kidney International (2018) 93, 771–786
a 0.85 mmol/l difference in LDL-C between the treatment groups. This relationship is in line with the effects of statins in other patient populations, where on average, a 1 mmol/l difference in LDL-C is associated with a 22% reduction in CV events. In this issue, Storey et al.8 (2018) describe the relationships between CRP and CV events and LDL-C and CV events in the SHARP trial. Higher baseline CRP and higher baseline LDL-C levels were both associated with a higher risk of CV events, but higher baseline CRP levels were also associated with a higher risk of a broad spectrum of nonvascular events. In contrast, there was a weak inverse correlation between baseline LDL-C levels and a composite of all nonvascular outcomes. Importantly, the efficacy of simvastatin/ezetimibe in reducing CV events was similar irrespective of baseline CRP concentration. This finding, plus the finding that higher CRP levels were associated with both CV and non-CV events and were thus nonspecific, leads the authors to conclude that SHARP provides no evidence that the benefit of lipid-lowering treatment in patients with CKD is related to a reduction in inflammation.
As the authors acknowledge, a limitation of this study is the absence of ontreatment CRP measurements in all study participants. In 2 trials of statins in patients without CKD, patients with the greatest reductions in CRP experienced the greatest reductions in CV events, implying that inflammation is an important component of atherosclerosis progression. In patients with CKD, elevated CRP levels are driven not just by vascular inflammation but also by the accumulation of uremic toxins and dialysisrelated inflammation. These latter CKD-specific contributors to elevated CRP levels may not be modified by statins. Indeed, in SHARP simvastatin/ ezetimibe lowered CRP levels much less than LDL-C levels, 21% versus 35% of baseline, or 0.2 compared with 1.1 SDs, respectively.8 Lipid-lowering may thus address only part of the inflammatory stimulus in CKD. It seems therefore too early to exclude inflammation as a causal factor for CV disease development in CKD patients. Clinical implications and future directions
Part of the authors’ conclusion is that the decision to offer statins to patients with CKD should continue to be guided by their absolute CV risk. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends a statin, with or without ezetimibe, for adults aged $50 years with an eGFR <60 ml/min per 1.73 m2, and for those aged 18 to 49 years with a 10-year CV risk greater than 10%.9 Notably, the KDIGO guideline makes the point that LDL-C is not an accurate predictor of CV risk in CKD patients and should not be used to determine who should receive lipid-lowering treatment. The role of inflammation in CKD remains unresolved. A large, properly conducted clinical trial testing an antiinflammatory drug in CKD patients with CV events as the primary endpoint would be most welcome. Subjects in the early stages of CKD are more likely to die from heart disease than to progress to end-stage renal disease. Given the high prevalence of CKD worldwide and 785
commentary
the high CV event rate in CKD, finding additional treatments to reduce CV risk in CKD deserves high priority. DISCLOSURE
All the authors declared no competing interests. REFERENCES 1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. 2. Knight EL, Rimm EB, Pai JK, et al. Kidney dysfunction, inflammation, and coronary events: a prospective study. J Am Soc Nephrol. 2004;15:1897–1903.
786
3. Stuveling EM, Hillege HL, Bakker SJL, et al. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int. 2003;63:654–661. 4. Bernelot Moens SJ, Verweij SL, van der Valk FM, et al. Arterial and cellular inflammation in patients with CKD. J Am Soc Nephrol. 2017;28:1278–1285. 5. Waters DD. LDL-cholesterol lowering and renal outcomes. Curr Opin Lipidol. 2015;26: 195–199. 6. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systemic review and meta-analysis. Eur Heart J. 2013;34:1807–1817. 7. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with
simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial. Lancet. 2011;377: 2182–2192. 8. Storey BC, Staplin N, Haynes R, et al, on behalf of The SHARP Collaborative Group. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 2018;93:1000–1007. 9. Tonelli M, Wanner C, Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Int Med. 2014;160:182–189.
Kidney International (2018) 93, 771–786
Lipids, inflammation, and chronic kidney disease: a SHARP perspective David D. Waters1 and Liffert Vogt2 Accumulating evidence indicates that inflammation plays a role in the initiation and progression of chronic kidney disease. In the Study of Heart and Renal Protection (SHARP) trial, higher baseline C-reactive protein and higher baseline low-density lipoprotein cholesterol levels were both associated with a higher risk of cardiovascular events, but higher baseline C-reactive protein levels were also associated with a higher risk of nonvascular events. Simvastatin/ezetimibe reduced cardiovascular events independent of baseline C-reactive protein levels. However, this observation does not exclude inflammation as a causal factor for cardiovascular disease development in chronic kidney disease patients. Kidney International (2018) 93, 784–786; https://doi.org/10.1016/j.kint.2017.11.031 Copyright ª 2018, International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
see clinical trial on page 1000
C
hronic kidney disease (CKD) and coronary heart disease (CHD) share common pathologic features and often coexist in the same patient. Risk factors for the development and the progression of CHD and CKD overlap and include diabetes, hypertension, and inflammation. Our understanding of the role of inflammation in both CHD and CKD has grown substantially in recent years.
Inflammation in CHD
Markers of inflammation have been shown to predict future cardiovascular (CV) events in subjects with established CHD, in those with risk factors for CHD, and in unselected populations. High-sensitivity C-reactive protein (CRP) is the inflammatory marker with the most evidence because it can be 1 Division of Cardiology, Zuckerberg San Francisco General Hospital, San Francisco, California, USA; and 2Department of Internal Medicine, Section Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
Correspondence: David D. Waters, Zuckerberg San Francisco General Hospital, 1001 Potrero Avenue, 5G1, San Francisco, California 94110, USA. E-mail: [email protected] 784
targeting interleukin-1b, given subcutaneously every 3 months at 3 different doses.1 Canakinumab reduced CRP levels in a dose-dependent fashion. After a median follow-up of 3.7 years, the composite primary endpoint was reduced at the 2 higher doses of canakinumab (hazard ratio 0.85, 95% confidence interval 0.74–0.98, and P ¼ 0.021 at the 150-mg dose; and hazard ratio 0.86, 95% confidence interval 0.75–0.99, P ¼ 0.031 at the 300-mg dose). Deaths due to infection or sepsis were statistically significantly more common in the pooled canakinumab groups compared with the placebo groups. This, combined with the high cost of canakinumab, means that this treatment is unlikely to ever be widely used for CV event prevention; however, it has opened the door for other anti-inflammatory drugs and has established the concept that this form of treatment has the potential to reduce CV events. Inflammation in CKD
easily measured in stored frozen blood samples. CRP has major limitations: it is nonspecific, suffers from measurement variability, and is a downstream marker of the pathophysiologic effects of inflammation upon atherosclerosis. Inflammation accelerates the progression of atherosclerosis in chronic inflammatory conditions such as HIV infection and rheumatoid arthritis. Statins reduce not only low-density lipoprotein cholesterol (LDL-C) levels but also levels of CRP and other inflammatory markers. Statins reduce CV events by reducing both LDL-C and inflammation within the arterial wall. In acute coronary syndromes, where inflammation plays a major pathophysiologic role, the anti-inflammatory effects of statins are thought to be particularly important. Whether anti-inflammatory therapy reduces CV events in patients already treated with statins is currently under investigation in clinical trials. In the first of these trials to be completed, 10,061 patients with previous myocardial infarction and CRP levels $2 mg/dl were randomized to placebo or to canakinumab, a monoclonal antibody
Accumulating evidence indicates that inflammation plays a role in the initiation and progression of many forms of CKD, and accounts for at least part of the increased risk of CV events in CKD patients. Higher CRP levels are associated with a higher risk of CV events in CKD patients,2 and with a decline in estimated glomerular filtration rate (eGFR).3 Local inflammatory activity of the arterial wall can be assessed by measuring 18 F-fluorodeoxyglucose (18F-FDG) uptake with positron emission computed tomography, as illustrated in Figure 1. Representing increased metabolic activity, 18 F-FDG uptake has been linked to plaque macrophage content and is an independent predictor for future CV events. In a recent study, CKD patients with no other inflammatory conditions or evidence of atherosclerosis had increased 18 F-FDG uptake in the aorta and carotid arteries compared with controls.4 Plasma urea levels and eGFR were independent predictors of arterial inflammation. Stains reduce CV events in patients with CKD.5 The relative risk reduction is greatest among patients with mild CKD, and decreases progressively in Kidney International (2018) 93, 771–786
commentary
Figure 1 | Example of arterial wall inflammation assessed with 18F-fluorodeoxyglucose positron emission tomography and computed tomography imaging. (a) Cross-sectional low-dose computed tomography image showing the thoracic cavity. Analyses of fluorodeoxyglucose uptake (zoom of the aortic arch) reveal increased uptake in (b) a patient with chronic kidney disease compared with (c) a healthy control. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org.
more advanced categories of CKD, almost disappearing in stage 5 patients who require dialysis.5,6 Because CV risk increases in higher stages of CKD, the number needed to treat with statins to prevent an event is relatively equal across CKD stages. Whether the antiinflammatory effects of statins contribute to the CV event reduction in CKD is uncertain. The SHARP trial
The Study of Heart and Renal Protection (SHARP) trial provides the largest and most comprehensive data on the effect of lipid-lowering therapy in CKD. A total of 9270 CKD patients were enrolled in SHARP, of whom 3023 were on maintenance hemodialysis.7 Participants were randomized to simvastatin 20 mg plus ezetimibe 10 mg/d or to placebo, and median follow-up was 4.9 years. The primary outcome was a composite of first nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure. This outcome occurred in 11.3% of drugtreated and 13.4% of placebo-treated patients (relative risk 0.83, 95% confidence interval 0.74–0.94, P ¼ 0.0021). The 17% event reduction in the primary outcome was accompanied by Kidney International (2018) 93, 771–786
a 0.85 mmol/l difference in LDL-C between the treatment groups. This relationship is in line with the effects of statins in other patient populations, where on average, a 1 mmol/l difference in LDL-C is associated with a 22% reduction in CV events. In this issue, Storey et al.8 (2018) describe the relationships between CRP and CV events and LDL-C and CV events in the SHARP trial. Higher baseline CRP and higher baseline LDL-C levels were both associated with a higher risk of CV events, but higher baseline CRP levels were also associated with a higher risk of a broad spectrum of nonvascular events. In contrast, there was a weak inverse correlation between baseline LDL-C levels and a composite of all nonvascular outcomes. Importantly, the efficacy of simvastatin/ezetimibe in reducing CV events was similar irrespective of baseline CRP concentration. This finding, plus the finding that higher CRP levels were associated with both CV and non-CV events and were thus nonspecific, leads the authors to conclude that SHARP provides no evidence that the benefit of lipid-lowering treatment in patients with CKD is related to a reduction in inflammation.
As the authors acknowledge, a limitation of this study is the absence of ontreatment CRP measurements in all study participants. In 2 trials of statins in patients without CKD, patients with the greatest reductions in CRP experienced the greatest reductions in CV events, implying that inflammation is an important component of atherosclerosis progression. In patients with CKD, elevated CRP levels are driven not just by vascular inflammation but also by the accumulation of uremic toxins and dialysisrelated inflammation. These latter CKD-specific contributors to elevated CRP levels may not be modified by statins. Indeed, in SHARP simvastatin/ ezetimibe lowered CRP levels much less than LDL-C levels, 21% versus 35% of baseline, or 0.2 compared with 1.1 SDs, respectively.8 Lipid-lowering may thus address only part of the inflammatory stimulus in CKD. It seems therefore too early to exclude inflammation as a causal factor for CV disease development in CKD patients. Clinical implications and future directions
Part of the authors’ conclusion is that the decision to offer statins to patients with CKD should continue to be guided by their absolute CV risk. The Kidney Disease: Improving Global Outcomes (KDIGO) guideline recommends a statin, with or without ezetimibe, for adults aged $50 years with an eGFR <60 ml/min per 1.73 m2, and for those aged 18 to 49 years with a 10-year CV risk greater than 10%.9 Notably, the KDIGO guideline makes the point that LDL-C is not an accurate predictor of CV risk in CKD patients and should not be used to determine who should receive lipid-lowering treatment. The role of inflammation in CKD remains unresolved. A large, properly conducted clinical trial testing an antiinflammatory drug in CKD patients with CV events as the primary endpoint would be most welcome. Subjects in the early stages of CKD are more likely to die from heart disease than to progress to end-stage renal disease. Given the high prevalence of CKD worldwide and 785
commentary
the high CV event rate in CKD, finding additional treatments to reduce CV risk in CKD deserves high priority. DISCLOSURE
All the authors declared no competing interests. REFERENCES 1. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. 2. Knight EL, Rimm EB, Pai JK, et al. Kidney dysfunction, inflammation, and coronary events: a prospective study. J Am Soc Nephrol. 2004;15:1897–1903.
786
3. Stuveling EM, Hillege HL, Bakker SJL, et al. C-reactive protein is associated with renal function abnormalities in a non-diabetic population. Kidney Int. 2003;63:654–661. 4. Bernelot Moens SJ, Verweij SL, van der Valk FM, et al. Arterial and cellular inflammation in patients with CKD. J Am Soc Nephrol. 2017;28:1278–1285. 5. Waters DD. LDL-cholesterol lowering and renal outcomes. Curr Opin Lipidol. 2015;26: 195–199. 6. Hou W, Lv J, Perkovic V, et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systemic review and meta-analysis. Eur Heart J. 2013;34:1807–1817. 7. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with
simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomized placebo-controlled trial. Lancet. 2011;377: 2182–2192. 8. Storey BC, Staplin N, Haynes R, et al, on behalf of The SHARP Collaborative Group. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney Int. 2018;93:1000–1007. 9. Tonelli M, Wanner C, Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. Lipid management in chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Int Med. 2014;160:182–189.
Kidney International (2018) 93, 771–786