Reducing the excess vascular risk associated with chronic kidney disease





Vlado PERKOVIC, MBBS, PhD
Muh Geot WONG, MBBS, PhD
George Institute for Global Health, University of Sydney, Sydney, AUSTRALIA

Reducing the excess vascular risk associated with chronic kidney disease


by M. G. Wong and V. Perkovic, Australia



Chronic kidney disease (CKD) is common, affecting more than 10% of the adult population, and has been clearly demonstrated to be a strong risk factor for cardiovascular events. Developing effective treatment strategies for this population is therefore important. A range of processes are likely to be key in mediating this excess cardiovascular risk, including atherosclerosis, arteriosclerosis, left ventricular hypertrophy, atrial fibrillation, and others. Different of approaches are therefore likely to be required to abrogate the excess cardiovascular risk in CKD. Blood pressure elevations are common in CKD, and are likely to be important in most or all of the mechanisms causing elevated cardiovascular risk in CKD. The available data suggest that blood pressure lowering substantially reduces the risk of cardiovascular events in CKD, and that agents acting via the renin-angiotensin system are preferred due to their coexistent renoprotective benefits. Lipid lowering prevents atherosclerotic cardiovascular events in early CKD, but other mechanisms may be more important as kidney function declines. Recent studies suggest that strategies targeting metabolic bone disease may modulate the risk of cardiovascular events, but more studies are required to define the optimal approach. Other approaches have been disappointing to date, highlighting the need for continued effort and innovation in this area.

Medicographia. 2015;37:461-466 (see French abstract on page 466)



Chronic kidney disease (CKD), usually defined by an estimated glomerular filtration rate (eGFr) below 60 ml/min/1.73 m2 or the presence of albuminuria or other markers of kidney damage, causes significant morbidity, premature death, and decreased quality of life.1,2 CKD is now also well recognized as a potent risk factor for cardiovascular disease. The risk of cardiovascular events and mortality progressively increases with declining renal function. The presence of reduced eGFr and albuminuria are each independently associated with an increased risk of cardiovascular events and death, and are additive so that the highest risk is seen in people with both conditions. CKD has been reported to be a stronger risk factor for myocardial infarction and death than diabetes,3 although the two are additive; individuals who have both conditions are at particularly high risk, with an almost 10-fold increase in cardiovascular disease risk compared to unaffected individuals.4 the highest risk of almost any group is observed in people with end stage kidney disease (ESKD), where the risk of cardiovascular events and death increases more than twentyfold.5

Despite the well-documented increase in cardiovascular risk with kidney disease, current risk prediction tools do not currently incorporate kidney disease markers in risk estimation equations, leading to underestimation of risk and suboptimal prevention measures in patients with CKD.6 Cardiovascular disease is frequently underdiagnosed and undertreated in patients with CKD. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that needs particular attention at an individual level.

A growing number of studies and clinical trials, either conducted specifically in CKD populations or through analyses of CKD subgroups, and systematic reviews have shed light on the processes involved in elevating cardiovascular risk in CKD and on strategies for the prevention of cardiovascular events in people with CKD.

Pathophysiological mechanisms

Increased cardiovascular risk in individuals with CKD is due partly to the high prevalence of traditional risk factors, such as hypertension and diabetes, which increase the risk of the development and progression of atherosclerosis. The associations of kidney function with cardiovascular risk and albuminuria with cardiovascular risk are, however, independent of these traditional cardiovascular risk factors.7 thus, nontraditional kidney-specific mechanisms make notable contributions to cardiovascular risk, and a number of recent studies have highlighted the role of factors such as arteriosclerosis and vascular calcification in the risk of adverse cardiovascular outcomes in CKD. Evidence currently available suggests that both probably play a role.

A broad range of risk factors are likely to be important in this regard. Hypertension, a well-known and strong risk factor for development and progression of CKD,8 is also a strong risk factor for the development of cardiovascular disease. Even in the early phases of CKD, both average blood pressure (BP) levels and the prevalence of hypertension are elevated and increase further progressively as kidney function declines.





When eGFR is lower than 30 ml/min/1.73 m2, around 50% of patients develop left ventricular hypertrophy,9 which is predominantly caused by hypertension, with additional contributions from renal anemia and increased vascular stiffness due to arteriosclerosis. Hypertension is also a contributor to the risk of atherosclerosis, arteriosclerosis, and left ventricular hypertrophy, each of which leads to reduced coronary reserve.10

Dyslipidemia and low-grade inflammation are also more common in the presence of CKD.11 In patients with impaired kidney function and severe albuminuria, lipid profiles become atherogenic owing partly to the defective function of high-density– lipoprotein cholesterol and excessive oxidation of low-density– lipoprotein cholesterol.12 the mechanisms of increased systemic inflammation in CKD are unclear, but increased production of inflammatory mediators has been attributed to raised oxidative stress and accumulation of posttranslation modified proteins and toxins that are ordinarily cleared with normal renal function.11

Additionally, CKD is associated with a range of metabolic abnormalities, the so-called milieu of uremic toxicity,13 and involvement of the neurohormonal axis, including the renin-angiotensin system,14 vitamin D receptors,15 and altered bone metabolism (eg, phosphate, parathyroid hormone, fibroblast growth factor 23,16 and others), all of which may contribute to accelerated damage to the heart and vasculature. Finally, the dialysis procedure itself may have a direct toxic effect on the myocardium.17

Reducing cardiovascular risk in kidney disease

Lifestyle modification
Lifestyle modification is the cornerstone of prevention strategies for cardiovascular disease in the general population. Although the effects of lifestyle modifications, such as smoking cessation,18 a low-sodium diet, exercise, and weight loss, have not been greatly studied in the CKD population, it appears reasonable to extrapolate the results from non-CKD populations and recommend similar approaches in the CKD population. Detailed discussion of these approaches is beyond the scope of this review.

Blood pressure lowering
There is no question regarding the benefit of BP lowering in reducing cardiovascular events in both the general and CKD populations. the Blood Pressure lowering treatment trialists’ Collaboration19 assessed over 30 randomized trials involving approximately 30 000 people with early stage CKD (mostly stage 3a) out of 160 000 participants in total. these showed that treatment with angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers produced almost identical 17% reductions in the risk of cardiovascular events in participants with or without CKD with a 5 mm Hg reduction in systolic BP. the effects were consistent across a range of cardiovascular outcomes, and no overall differences were identified between different classes of agents (ACE inhibitors vs calcium channel blockers vs diuretics or β-blockers).

The evidence in people with advanced kidney failure receiving dialysis is much more limited. However, a systematic review pooling several small trials of limited quality showed a significantly reduced risk of cardiovascular events and death in people receiving BP-lowering therapy compared to controls.

BP lowering is therefore a key element of strategies to prevent cardiovascular events in people with CKD. While evidence available from trials suggests that different classes of agents have similar effects on cardiovascular events, ACE inhibitors and angiotensin receptor blockers (ARBs) are recommended by guidelines as the preferred BP-lowering agents for people with CKD due to their proven benefits in preventing kidney failure more effectively than other classes of agents in this population.20 An additional consideration is the role of β-blockers in the presence of cardiac failure in people with CKD. these agents are routinely recommended in people with cardiac failure in the general population, and the limited data available in people with CKD suggest they have similar benefits in this population.21

Optimal BP target has been a matter of controversy in both the general population and in people with CKD. Observational analyses have raised concerns about the possibility of a J-curve, with an increased risk of cardiovascular events at lower BP levels, but these analyses have a high risk of confounding with incorrect conclusions being the result. A number of randomized trials have assessed the impact of different BP targets in both these groups, and they have effectively excluded the likelihood of a J-curve at commonly observed BP levels. A systematic review of a number of trials found that intensive BP lowering in people with CKD was no more beneficial than standard BP lowering in terms of cardiovascular event reduction.22 In participants with CKD and proteinuria, however, intensive BP lowering may be of benefit.

The KDIGO (Kidney Disease Improving Global Outcomes) BP guidelines20 therefore recommend BP lowering in people with CKD, with a regimen incorporating ACE inhibitors or ARBs, and a systolic BP target below 140 mm Hg (or below 130 mm Hg for people with CKD and proteinuria).

Lipid-lowering therapy
The lack of a clear relationship between cholesterol levels and the risk of cardiovascular events and death in advanced kidney disease has led to substantial debate about the efficacy and safety of lipid lowering in CKD. the largest individual study in the area is the SHARP (Study of Heart And renal Protection) trial involving approximately 9500 participants with CKD. this trial showed that participants randomized to combined simvastatin and ezetimibe had a 17% reduction in the risk of major atherosclerotic events (coronary death, myocardial infarction, nonhemorrhagic stroke, or any revascularization) compared to those randomized to placebo.23 the results of the SHARP trial are supported by post hoc analyses of CKD subgroups of randomized trials of statin versus placebo in the general population, which reported that statins reduce the relative risk of cardiovascular events to a similar degree in patients with or without CKD.24 the use of statins in CKD, particularly early on, is therefore now widely recommended by guidelines.

The role of statins in ESKD is less certain, with meta-analyses of results of randomized trials clearly demonstrating that there is less reduction in relative risk compared with people with preserved kidney function, although absolute risk reduction is likely to be similar.25,26 this may well be due to a similar effect on atherosclerotic events being drowned out by a larger number of nonatherosclerotic cardiovascular events. While BP lowering, especially using ACE inhibitors or ARBs, is likely to reduce the incidence and progression of atherosclerosis, arteriosclerosis, and left ventricular hypertrophy, lipid lowering is only likely to substantially impact atherosclerotic events.

Concerns that the well-documented side effects (rhabdomyolysis, myalgia, and abnormal liver function test) with statin use may be more frequent in patients with CKD, especially when high doses are used, have proven unfounded. recent evidence has confirmed there is no difference in side effect profiles between statins and placebo even in patients with reduced kidney function.23,26

Fewer data exist for other lipid-lowering agents. Fibrates have been shown to prevent cardiovascular events in the general population, with particular benefit in preventing coronary events.27 Secondary analyses of trial subsets with CKD suggest similar benefits may exist in the CKD population, but the total amount of data available is limited.28 Fibrates transiently and reversibly increase serum creatinine levels, which has limited their use in CKD. Nevertheless, trial data suggest that this does not translate into renal harm, and that there may in fact be protection of kidney function.28,29

Recently, a number of novel agents for the treatment of dyslipidemia, including alirocumab30 and evolocumab31 (proprotein convertase subtilisin/kexin type 9 inhibitors), have been developed and are being studied in large clinical trials. In a large, long-term study (n=4465) comparing monthly subcutaneous evolocumab injection plus standard therapy versus standard therapy alone, the addition of evolocumab to standard therapy reduced low-density–lipoprotein levels by 61% (P<0.001) and lowered the incidence of cardiovascular events (hazard ratio, 0.47; 95% confidence interval [CI], 0.28–0.78; P=0.003). However, neither this study or the alirocumab study has to date published data on subgroup analyses according to kidney function.30,31

Antiplatelet agents
People with CKD appear to have a thrombogenic profile, with an increased risk of venous thromboembolism identified in large observational studies.32 the risk of atrial fibrillation has also been shown to increase in the presence of reduced kidney function,33 and the risk of thromboembolic complications in people with atrial fibrillation is also increased in people with CKD compared to those with normal kidney function.34 Conversely, the risk of bleeding has also been shown to increase in CKD, particularly when antiplatelet35 or anticoagulant36 therapy is used. Data are sparse regarding the efficacy of aspirin in advanced CKD.

A recent Cochrane systematic review of antiplatelet agents for chronic kidney disease included 44 studies (21 460 participants) comparing an antiplatelet agent with placebo or no treatment and 6 studies (5679 participants) directly comparing one antiplatelet agent with another. the authors showed antiplatelet agents reduced the risk of myocardial infarction compared with placebo (relative risk, 0.87; 95% CI, 0.76-0.99), but not the risks of all-cause mortality, cardiovascular mortality, or stroke.

Post hoc subgroup analyses of randomized trials suggested that the protective effect of daily aspirin may be increased in individuals with an eGFr <45 ml/min/1.73 m2,35 but these studies also showed a higher incidence of bleeding (major and minor) in CKD patients. these data suggest that antiplatelet agents should be used in a similar fashion in CKD patients as they are in the general population, but with greater caution as CKD patients are at increased risk of bleeding. Additional studies in this area are urgently required.

There are no randomized controlled trial data regarding the safety and efficacy of warfarin therapy in people with CKD, causing much uncertainty regarding the balance of risks versus benefits of this therapy in the CKD population. More recent studies of the novel anticoagulants in people with CKD and atrial fibrillation suggest that these agents might reduce thromboembolic complications and have a better risk profile than warfarin.38

Arteriosclerosis
Arteriosclerosis progressively and substantially increases in people with CKD.39 this has been demonstrated from both an anatomical perspective, with a rapid increase in the risk of vascular thickening and calcification in the presence of reduced kidney function, as well as a functional perspective, with an increase in markers of arterial stiffness (eg, pulse wave velocity, augmentation index, pulse pressure, and others). These factors are likely to be important contributors to the increased risk of left ventricular hypertension and heart failure in CKD.

While some BP-lowering agents (ACE inhibitors, ARBs, calcium channel blockers) appear to reduce vascular stiffness, other BP-lowering agents appear to have no effect on markers such as pulse wave velocity, suggesting a potential additional rationale for considering the use of these drug classes ahead of others.

Given the central role of calcification in these processes and the documented relationship between vascular calcification and bone metabolism in people with CKD, there has been much interest in the effects on the risk of cardiovascular events of agents that modulate mineral metabolism.

Phosphate levels increase ubiquitously in people with ESKD, and also commonly in those with advanced CKD. Phosphate levels predict the risk of cardiovascular events and death in CKD,40 leading to interest in the use of oral phosphate binders to reduce serum phosphate levels in blood along with the risk of cardiovascular events and death. The most commonly used phosphate binders were originally aluminium-based. These, however, have been effectively abandoned due to the risks of aluminium absorption and brain, blood, and bone toxicity. Calcium-based phosphate binders subsequently became the standard of care. Again, there were safety concerns; this time relating to the potential for these agents to increase the risk of vascular calcification due to calcium absorption from the gut. this led to a drive to develop alternative agents.

The most commonly used noncalcium-based phosphate binder is sevelamer, a nonabsorbed phosphate binder that appears to be associated with lower calcium levels and a lower risk of vascular calcification compared to calcium-based phosphate binders.

The largest trial comparing sevelamer to calcium-based phosphate binders was the Dialysis Clinical Outcomes revisited (DCOr) trial, which enrolled over 2000 people with ESKD.41 this trial failed to show any difference overall, but was limited in its ability to do so by the large proportion of participants who discontinued randomized therapy and also by the number lost to follow-up. Subgroup analyses suggested mortality benefits for individuals over the age of 65 years and those receiving treatment for 2 years or more, but these analyses were not conclusive in the presence of a negative overall result. Other studies have suggested mortality benefits for noncalcium- based phosphate binders compared to calcium based phosphate binders,42 but the optimal strategy has yet to be defined. Nonetheless, phosphate management appears to be useful, and further studies in this area are required.

An additional factor highly relevant to metabolic bone disease in CKD is parathyroid hormone. Parathyroid hormone levels are commonly and substantially elevated in CKD and have been associated with an increased risk of cardiovascular events in some, but not all, observational studies.40 While surgical parathyroidectomy has traditionally been the treatment of choice for hyperparathyroidism, the introduction of calci- mimetic hormones that lower parathyroid hormone levels led to optimism that the widespread use of these agents might help prevent cardiovascular events in advanced CKD. the EVOlVE (EValuation Of cinacalcet hydrochloride therapy to lower cardiovascular eVEnts) trial compared the effect of cinecalcet versus placebo on cardiovascular events and death in people with ESKD requiring dialysis and increased parathyroid hormone levels.43 the primary results of the study revealed a small and nonsignificant reduction in the risk of cardiovascular events, but baseline risk imbalances and high drop-out and drop-in rates appear likely to have contributed to a false negative result for this study.44 Overall, the available data suggest that interventions to lower parathyroid hormone may have an important role in preventing cardiovascular events in advanced CKD, but more data are clearly required.

Other strategies
A range of other strategies have been studied for the prevention of cardiovascular events in CKD. Normalizing hemoglobin levels using erythropoietin has clearly been shown to be harmful, and this has been abandoned as a therapeutic strategy in CKD.45 Homocysteine lowering is ineffective and is similarly no longer recommended for cardiovascular protection in CKD.46

New CKD-specific strategies, along with a better understanding of the effects of therapies that are effective in the general population, are urgently required.

Conclusion

People with kidney disease have been clearly and unequivocally proven to be at increased risk of cardiovascular events, and effective preventive strategies are urgently required. BP lowering and lipid lowering clearly have an important protective role in this population, and antiplatelet therapy is also likely to be useful for some people with CKD. Available data suggest that strategies targeting mineral metabolism and metabolic bone disease may also have a role in cardiovascular prevention in CKD. More effective strategies are urgently required. ■


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Keywords: cardiovascular risk; chronic kidney disease; end-stage kidney disease; risk reduction; risk factor