Nephrology Hypertension

Chronic Kidney Disease: Cardiovascular Disease and Dyslipidemia

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Does this patient with chronic kidney disease have underlying cardiovascular disease?

Cardiovascular disease (CVD) remains the leading cause of death among adults in both developed and developing countries. In the United States, more than 92 million adults have at least one type of CVD, which accounted for 30.8% of all deaths in 2014. Every year approximately 635,000 Americans will experience a new heart attack, and 300,000 will experience a recurrent event. Chronic Kidney Disease (CKD) is also a major public health problem, affecting 14.8% of the US population per the National Health and Nutrition Examination Survey (NHANES) of 2015 (CKD defined as an eGFR<60 ml/min/1.73m2 or albumin/creatinine ratio (ACR) >=30 mg/g). Furthermore, the coexistence of both CVD and CKD is highly prevalent. It is estimated that 17% of adults with stable coronary heart disease (CHD) also have concomitant CKD. Moreover, CVD affects 68.8% of individuals with CKD aged 66 and older, which is two-fold greater than those of a similar age without CKD.

CKD is a recognized and accepted major independent risk factor for CVD, encompassing coronary disease, heart failure (HF), stroke, peripheral vascular disease, and arrhythmia/sudden death. CKD is associated with a higher incidence of CVD and a worse prognosis after a cardiovascular (CV) event, including a greater risk of recurrent events and CV mortality. These associations increase exponentially with decreasing eGFR, and patients with CKD are more likely to die from CV causes than to receive renal replacement therapy (RRT).

The symptoms and signs of coronary heart disease in the setting of CKD are similar to patients with preserved renal function, and may include exertional chest discomfort, shortness of breath, palpitations, nausea, diaphoresis, and lightheadedness. In dialysis patients, coronary disease is often under-diagnosed, due to the atypical or silent nature of symptoms.

A retrospective cohort study involving more than one million patients revealed that dialysis patients with acute myocardial infarction were 35% and 47% less likely to have chest pain or characteristic ST segment elevation on EKG respectively, and twice as likely to have been misdiagnosed on presentation, when compared to matched patients not on renal replacement therapy. Furthermore, among eligible patients, dialysis patients were 37% less likely to undergo reperfusion therapy, and their odds of dying during the hospitalization was 1.5- fold greater when compared to patients not on dialysis.

A number of factors may contribute to the under-diagnosis of CHD in end-stage renal disease (ESRD) patients. Independent of the presence of diabetes, myocardial ischemia may be clinically silent in this population. The high prevalence of baseline ECG abnormalities may limit sensitivity for identifying acute coronary syndrome (ACS). Shortness of breath may mistakenly be attributed to extracellular volume overload and need for more aggressive ultrafiltration. In the hemodialysis patient, symptoms of nausea, dizziness, and fatigue may often be overlooked as part of the post-dialysis syndrome commonly experienced by patients following their treatment session.

Beyond ACS, sudden cardiac death is a major source of morbidity and mortality in patients with CKD. Structural and functional abnormalities of the heart predispose to arrhythmias and may be responsible for up to 50% of cardiovascular-related deaths in patients with ESRD. The prevalence of left ventricular hypertrophy is estimated to be as high as 80% among patients receiving renal replacement therapy. Additionally, dilated cardiomyopathy with systolic dysfunction is also a prevalent finding, affecting up to a third of patients with advanced kidney failure.

Why are patients with chronic kidney disease at increased risk of cardiovascular disease?

CVD accounts for half of all deaths in patients with CKD (defined as an eGFR <60 mL/min/1.73m2). In fact, patients with CKD are more likely to die from CVD-related complications than progress to ESRD, with an age-adjusted CVD mortality rate that is 30 times greater than the general population for those with ESRD. Increased CV risk in CKD is driven by multiple mechanisms, including the clustering of co-morbid conditions traditionally viewed as risk factors for CVD. Diabetes remains the leading cause of CKD in the western world. While hypertension is highly prevalent amongst the CKD population, greater than 90% by CKD stage 4, the majority of patients have not achieved recommended target blood pressure goals. Yet, traditional Framingham Risk factors alone do not account for the substantially increased CV risk and a number of non-traditional risk factors have also been postulated.

  • Chronic Inflammation: The chronic inflammatory state of CKD is notable for activation of key mediators including C-reactive protein (CRP), TNF-alpha, and IL-6. As limited antioxidant defense mechanisms become overwhelmed, oxidative modification of lipoprotein and other macromolecules promote atherogenesis.

  • Endothelial dysfunction: Decreased bioavailability of nitric oxide leads to endothelial dysfunction while disturbance in the relative balance of inducers and inhibitors promotes vascular calcification and increases vascular stiffness.

  • Accelerated vascular calcification: Vascular calcification in CKD is multifactorial owing to systemic inflammation, smooth muscle cell transformation to chondrocyte- and osteoblast-like cells, accelerated mineralization derived from abnormal calcium and phosphorus metabolism and low levels of systemic and local inhibitors of mineral formation, such as matrix G1a protein (MGP) and fetuin-A.

  • Anemia: A reduction in red blood cell mass is implicated in structural heart disease and subsequent cardiovascular mortality in advanced CKD. The resultant physiologic increase in cardiac output not only leads to left ventricular hypertrophy and subsequent dilation, but also vascular remodeling with intimal-medial thickening. Anemia has also been highlighted as a strong predictor of high on-clopidogrel platelet reactivity (a predictor of adverse CV events) in patients with stable coronary artery disease (CAD).

  • Uric acid: While hyperuricemia is commonly associated with both CKD and CVD, whether it plays a causal role in disease pathogenesis remains a controversial debate. For example, experimental studies have demonstrated a role for uric acid in smooth muscle proliferation and activation of pro-inflammatory pathways and epidemiologic studies have demonstrated an association with the carotid artery intimal thickening and the development of atherosclerosis in the general population. However, others argue that higher uric acid levels are not pathogenic and simply a consequence of reduced renal clearance.

  • High on-treatment platelet reactivity: High platelet reactivity is associated with recurrent and incident cardiovascular events, such as myocardial infarction (MI) and stent thrombosis. An inverse relationship between eGFR and on-treatment platelet reactivity with various antiplatelet agents has been described. Increased thrombin generation, higher concentration of procoagulant factors, augmented non-purinergic pathways of platelet aggregation and nitric oxide synthesis abnormalities have been thought to contribute to this phenomenon; however, whether this association is causal is also unclear.

  • Underuse of evidence-based therapies: Despite a greater risk of short- and long-term cardiovascular events and death, patients with CKD are less likely to receive effective cardiovascular medications and to undergo diagnostic and therapeutic coronary procedures.

What tests to perform?

What laboratory tests should I order to evaluate cardiovascular risk in my patient with chronic kidney disease?

A number of lab tests are germane to the assessment of cardiovascular risk in the setting of CKD.

Basic metabolic panel

This should include an estimated glomerular filtration rate (GFR; provided the patient is in steady state with stable serum creatinine), as cardiovascular risk increases with advancing stage of CKD. Given the risk of arrhythmia and sudden cardiac death, monitoring of serum electrolytes, in particular potassium, should be performed on a routine basis.

By stage 4 CKD, it is recommended that the patient should be referred to a nephrologist, as further delay is associated with increased morbidity and mortality. Some recommend earlier referral at stage 3. Monitoring of renal function is recommended every 1 to 3 months, though frequency should be tailored to the individual patient based on degree of kidney dysfunction, rate of disease progression, and change in medications which may affect K+ homeostasis (including renin-angiotensin-aldosterone system [RAAS] antagonists and diuretics).

Hemoglobin

Anemia (defined by the World Health Organization as hemoglobin <13.0 g/dL in males and <12.0 g/dL in females) is a common finding in patients with advanced CKD, affecting more than 50% of patients with stage IV disease. While iron deficiency is often a contributing factor, the anemia of CKD is mostly due to a relative deficiency of erythropoietin and reduced red blood cell half-life. Anemia in patients with CKD is associated with cardiovascular dysfunction, including left ventricular hypertrophy, worsening anginal symptoms, and greater all-cause mortality. Erythropoietin levels are not routinely checked and the diagnosis of CKD-associated anemia is generally made on empiric grounds after other common causes have been excluded.

The frequency of measuring hemoglobin should be tailored to the individual patient. According to KDIGO guidelines, monitoring of patients without anemia should be performed by measuring Hb concentration once a year in stage 3, twice per year in stages 4 and 5, and every 3 months in patients with CKD stage 5. For patients with diagnosed anemia not treated with an erythropoietin stimulating agent, follow-up with Hb concentration should take place every 3 months in stages 3 to 5 and at least monthly in patients with stage 5. At the time of diagnosis, the following tests should be considered:

  • Complete blood count (CBC)

  • Absolute reticulocyte count

  • Serum ferritin level

  • Serum transferrin saturation (TSAT)

  • Serum vitamin B12 and folate levels

  • TSH

Serum phosphate

Regulation of phosphate balance within the body requires renal clearance of the absorbed dietary phosphate load. As GFR declines, the fractional excretion of phosphate per nephron increases. While traditionally considered to be mediated by upregulation of intact parathyroid hormone (PTH), mounting evidence suggests that increased levels of the phosphaturic hormone FGF23 may be an earlier and more sensitive marker of abnormal phosphate homeostasis. As GFR falls below 30 ml/min, the compensatory mechanisms become overwhelmed, leading to hyperphosphatemia. Recently, alpha klotho was identified as a co-receptor for FGF23, and has a protective role against oxidative stress in the endothelium while safeguarding against osteogenic transformation of smooth muscle cells. Progressive kidney disease is associated with a deficiency of alpha klotho, which may predispose to vascular calcification.

Elevated phosphate levels are associated with increased all-cause mortality in the dialysis population. Observational studies of patients with moderate CKD revealed that even modest increases in serum phosphate within the accepted normal range are associated with increased risk of CV event in a graded fashion. While FGF23 levels have been shown to be highly predictive of left ventricular hypertrophy (LVH), CVD, including MI and stroke, and cardiovascular death, monitoring FGF23 levels has not yet been implemented into routine clinical practice.

Serum calcium and intact PTH

Intact PTH and serum calcium have been suggested as an independent risk factor for development of CVD in the CKD population, although the data have been conflicting. A meta-analysis of more than 300,000 patients failed to show a consistent independent association of iPTH or serum calcium with risk of CV events. Recently, in the MESA study, a longitudinal study of over 6000 patients without clinically evident CVD at baseline, elevated iPTH levels were associated with a significant increase in left ventricular mass and incident HF. Despite the widespread use of clinical practice guidelines in nephrology for the management of mineral metabolism, several limitations are identified including the relative interdependence of iPTH, phosphorus, and calcium levels, diurnal fluctuation of iPTH levels, and poor correlation between serum levels and total body mineral stores.

Lipid panel

Screening for dyslipidemia with a fasting lipid profile in patients with CKD is routinely recommended. However, the typical lipid profile in CKD differs markedly from the general population, due largely to defective clearance pathways from circulation.

Hypertriglyceridemia is a common finding, affecting up to half of all patients with CKD, and is particularly common in diabetics. Serum HDL is often low due to impaired maturation, leading to an increased LDL:HDL ratio. While serum LDL is often seemingly in a normal range, subtype analysis reveals a number of abnormalities including increased levels of chylomicron remnants, lipoprotein (a) and oxidized LDL particles, all of which have been associated with increased atherogenic potential.

Proteinuria

The magnitude of proteinuria correlates with both progression of CKD and risk of experiencing a CV event. A recent meta-analysis involving more than 5-million person-years revealed that urinary albumin excretion was strongly associated with cardiovascular-related death in a graded and linear fashion.

Specifically, for patients with early stage III CKD (eGFR 45 – 59 ml/min/1.73m2), when compared to patients with absence of increased urinary albumin, the risk of CV death was increased 3.1 fold in the presence of microalbuminuria (albumin to creatinine ratio (ACR) of 30 to 299 mg/g) and 5.0-fold in the setting of overt albuminuria (ACR>300). Measurement of albumin excretion by spot urine albumin:creatinine ratio is preferable to a semi-quantitative urine dipstick.

Uric acid

While hyperuricemia is often associated with CKD and CVD, whether therapies to reduce uric acid levels have a protective role on disease progression has been the source of debate. A recent study found that high dose allopurinol (600 mg daily) resulted in regression of left ventricular hypertrophy in diabetic patients with preserved kidney function and in patients with stage 3 CKD (NCT00688480). The role of uric acid reduction on slowing progression of renal disease and reducing cardiovascular events remains unclear, though the PERL trial (Preventing Early Renal Loss in Diabetes) may help to address this question in the future (NCT02017171).

Homocysteine

Hyperhomocysteinemia has been causally associated with CVD in the general population, possibly through oxidative injury, smooth muscle cell proliferation, and platelet aggregation. However, its significance in patients with underlying renal impairment is unclear as up to 85% of dialysis patients have mild to moderate increased levels of homocysteine, possibly reflective of decreased clearance. Furthermore, randomized controlled trials have not shown any benefit of lowering homocysteine levels on CVD end points, thus its routine measurement in assessing the CVD risk profile in CKD patients does not appear to be clinically warranted.

Cardiac troponins

Cardiac troponins (cTn) have been at the cornerstone for the evaluation and diagnosis of ACS in the general population, however, the utility of this enzyme test in the setting of renal disease has been challenging. Stably elevated cTn levels are a common finding in patients with underlying CKD and may be reflective of processes other than acute ischemic injury, including underlying structural heart disease, chronic ischemia and possibly impaired clearance mechanisms. Therefore, in the setting of an ACS, the use of repeated measures of cTn is encouraged instead, of single measurements at presentation. A specific threshold for this acute increase in baseline cTn has not been validated to date and, although some authors advocate for the use of cTnI instead of cTnT (claiming greater specificity for the former), a preference for either assay is not reflected in clinical practice guidelines. High-sensitivity (hsT) assays are promising and recent studies suggest that they may improve the diagnostic accuracy of ACS in CKD when considering a change from baseline. For instance, among patients on dialysis (compared with a single admission measure), repeating hsTnT at 3 hours improved the discrimination C-statistic for MI from 0.68 to 0.9 and 0.88 when using a relative change of 24% and an absolute change of 32.6 ng/L.

In addition to being sensitive markers of myocardial injury, cTn and hsTn have prognostic features when measured at baseline after ACS and in patients with stable atherosclerotic disease with and without CKD. Baseline troponin was associated with an increased risk of cardiac death and the composite of death or reinfarction at 30 days and long-term in a pooled analysis involving almost 19,000 post-ACS patients, including patients with eGFR <60 mL/min/1.73m2. In a recent secondary analysis from the TRA-2P TIMI-50 trial, a strong graded relationship between hsTnI and the incidence of CV death, MI or stroke that was independent of renal function in patients with history of MI, peripheral artery disease (PAD) or stroke. Finally, a recent meta-analysis commission by the Agency for Healthcare Research and Quality (AHRQ) found that among dialysis patients without clinical evidence of an ACS, elevation in either troponin T or troponin I was associated with a 2.0- to 4.0-fold increase in cardiovascular-related mortality or major adverse cardiac event. Similar patterns were also seen in patients with less advanced stages of CKD. Despite the worse prognosis of asymptomatic CKD patients with elevated troponin levels, the clinical significance in terms of treatment strategies remains unclear.

What imaging tests should I order to evaluate cardiovascular risk in my patient with chronic kidney disease?

CAD artery disease in advanced CKD is substantial, affecting one third of incipient dialysis patients. Similarly, structural and functional abnormalities are common, including up to 80% of patients with ESRD presenting with left ventricle (LV) abnormalities, mostly LVH. However, dedicated evidence-based guidelines regarding non-invasive assessment or risk stratification of cardiac disease in the CKD population are lacking. Evaluation should be individualized based on patient’s functional status, co-morbid conditions, and availability of local expertise.

Echocardiogram

While a baseline echocardiogram and electrocardiogram are generally recommended as part of the initial assessment when initiating maintenance dialysis, they should also be considered in the evaluation of any CKD patient with unexplained symptoms of dyspnea on exertion, orthopnea, or hypotension. Sudden cardiac death accounts for 25% of dialysis-related mortality and is ascribed to structural and functional abnormalities including left ventricular hypertrophy, systolic dysfunction, and metabolic derangements. Further, among the almost three fourths of patients receiving dialysis who have left ventricle hypertrophy, two thirds of deaths are attributable to HF or sudden cardiac death. In addition to LVH, lower LV ejection fraction, LV diastolic function, an enlarged left atrium and mitral and aortic valve calcification are prognostically important measures associated with an increased risk of death.

Exercise stress tests

While of potential use in certain patients with moderate to late CKD, the National Kidney Foundation K/DOQI guidelines cautions against the routine use of exercise-based stress tests in the ESRD population. In patients with advancing CKD, the high prevalence of ECG abnormalities at baseline, in addition to an increasing burden of co-morbid conditions (e.g., deconditioning, arthritis, peripheral vascular disease), may limit the practical and diagnostic utility of these tools.

Pharmacologic stress test

Dobutamine echocardiography appears superior to other forms of non-invasive stress tests, achieving a reported specificity and sensitivity of 75%. For CKD patients undergoing transplant evaluation, dobutamine stress echocardiography remains the standard for CAD screening. Limitations include development of atrial arrhythmias in up to 4% of patients and inability to detect regional wall motion abnormalities in the setting of severe LVH. While dipyrodine or adenosine may be an alternate option, they are less sensitive than dobutamine echocardiography. False negative results may occur in the setting of endothelial dysfunction with blunted vasodilatory response or diffuse three-vessel disease.

Myocardial perfusion-based studies

Nuclear scintigraphic imaging is a valuable adjunct to functional assessment and improves sensitivity for the detection of inducible ischemia. Prognostic value has been validated across the spectrum of patients with CKD including ESRD patients. A meta-analysis of myocardial perfusion single photon emission computed tomography (MSPECT)-based stress tests revealed that that the presence of scintigraphic evidence of inducible ischemia was associated with a four-fold increase in cardiac death and six-fold increase in MI.

Coronary artery calcification score (CACS)

Electron beam or multi-slice computed tomography (CT) scan may be employed to detect intimal calcification of the coronary arteries. The burden of coronary calcification is a highly sensitive predictor for the presence of significant (>50%) luminal stenosis in the general population. However, CKD is additionally associated with medial calcification of the coronaries, which contributes to CACS without necessarily increasing likelihood of atherosclerotic disease.

Due to poor sensitivity, applicability of this tool in renal disease has been questioned. Recent studies of patients with moderate to advanced CKD have shown that progression of coronary artery calcification may occur independent of GFR and a CACS greater than 750 Agatston Units correlates with increased likelihood of subsequent cardiac event or all-cause mortality. While assessment of CACS may prove to be a valuable tool for non-invasive cardiac risk assessment and primary prevention in the future, further study is warranted prior to routine use in the clinical management of CKD.

Cardiac catheterization

While angiography remains the gold standard for the diagnosis of CAD, the risk to benefit analysis must be carefully weighed in the setting of CKD. By the time patients progress to ESRD, atheromatous disease is highly prevalent, ranging from 25% to greater than 80% among diabetic patients on long-term renal replacement therapy. Up to 40% of asymptomatic patients may have significant coronary artery stenosis detected on coronary angiogram as part of the routine pre-transplant evaluation. In the absence of functional assessment of cardiac function, interpretation of clinical relevance of coronary disease and how best to manage (medical therapy versus intervention versus surgery) can be a challenge.

Meanwhile, the obligatory exposure to contrast load can have significant sequelae. In the patient with advanced CKD, development of contrast-associated nephropathy may, on occasion, lead to a progressive and irreversible decline in renal function necessitating the initiation of renal replacement therapy.

Even among patients on dialysis, contrast exposure may have significant adverse effects, including accelerated loss of residual renal function (which may impact adequacy of clearance), particularly for patients on peritoneal dialysis who are often dependent on residual kidney function. In non-oliguric patients, decline in urine output may lead to volume management issues and predispose to extracellular volume excess.

Controversies in risk assessment for cardiovascular disease in chronic kidney disease patients

Despite the high prevalence of CAD amongst patients with CKD, evidence-based guidelines as when to perform risk stratification are lacking. A few scientific societies have provided suggestions about when to perform non-invasive testing, while most societies recommend against routine coronary angiography.

Recommendations for non-invasive risk assessment per the National Kidney Foundation for the patient with ESRD awaiting renal transplantation are as follows:

  • All patients with diabetes, and repeat every 12 months

  • Prior CAD if not revascularized, repeat every 12 months

  • Prior PCI, repeat every 12 months

  • Prior CABG, repeat after first 3 years and then every 12 months

  • Repeat every 24 months in ‘high-risk” non-diabetics (>=2 risk factors, history of CAD, LVEF <=40%, PAD)

ACC/AHA recommend non-invasive testing in the following scenario:

  • Presence of multiple (>=3) CAD risk factors regardless of functional status (risk factors include: diabetes mellitus, prior CVD, >1 year on dialysis, LVH, age >60 years, smoking, hypertension, dyslipidemia)

How should patients with chronic kidney disease and underlying cardiovascular disease be managed?

How can I minimize the risk of contrast-induced nephropathy (CIN) in my patient undergoing cardiac catheterization?

CKD is a major risk factor for CIN, and its incidence increases with decreasing GFR. Administration of intravenous radiocontrast may result in acute kidney injury due to tubular dysfunction. The risk of CIN is quite variable in the literature and ranges from essentially less than 1% to greater than 50%, depending on presence of comorbid conditions and the threshold change in serum creatinine used to define index cases of CIN. The major risk factors include pre-existing CKD at baseline, diabetes, older age, intravascular volume depletion, concurrent use of NSAIDs, use of non-iso-osmotic agents, volume of dye load, multiple dye loads (within 48-72 hours of one another), and multiple myeloma. Serum creatinine should be measured pre-procedure and then at 48 to 72 hours following the application of contrast in all patients determined at risk of CIN.

While spontaneous recovery is often the case, high-risk patients with advanced CKD at baseline should be forewarned of the distinct possibility of acute-on-chronic kidney injury and progression to ESRD.

While avoidance of contrast exposure is the most definitive preventive measure, when a contrast dye load must be given, the following are general guidelines for at-risk patients (GFR<60 ml/min and/or concomitant diabetes):

Ensure that the patient is adequately volume expanded. Normal saline is the crystalloid most commonly used (1–1.5 mL/kg/h for 12 h pre-procedure and up to 24 h post procedure, although longer infusion periods may be cautiously considered in the setting of more severe renal dysfunction, cognizant of the risk of inducing hypervolemia). There is evidence that sodium bicarbonate may also have a beneficial effect on preventing CIN, perhaps by mitigating free radical-induced injury. For example, two meta-analyses have reported a 43-48% reduction in the odds of CIN with the use of sodium bicarbonate based solutions. However, these results should be interpreted carefully given the quality of some studies included.

Concurrent use of diuretics or osmotic agents such as mannitol to augment urine flow is not beneficial and may in fact worsen renal injury.

While the data are inconclusive, use of the anti-oxidant n-acetyl cysteine may have a beneficial role in reducing the incidence of CIN. Various dosing regimens have been suggested, the most common being 600mg orally twice daily for 2 days, beginning the day prior to the contrast study.

The use of dialysis in pre-ESRD patients for removal of dye load is not routinely recommended for all patients. While pre-emptive dialysis may be considered in a subset of patients considered high-risk who have a dialysis access already in place, there is no definitive evidence that this approach reduces the likelihood of developing contrast-induced nephropathy. In ESRD patients already receiving renal replacement therapy, urgent dialysis is not routinely performed following dye exposure, especially if iso-osmotic contrast is used.

One recent meta-analysis has suggested that high-dose statin therapy may be effective preventing CIN in in patients with and without ACS undergoing coronary angiography and percutaneous coronary intervention. However, this has not been widely adopted in clinical practice.

The European Society of Cardiology (ESC) recommends adopting a single invasive approach with cardiac angiography followed by ad hoc PCI and minimising contrast volumes to <4 mL/kg or V/CrCl <3.7:1.

Nephrotoxic drugs, including non-steroidal anti-inflammatory (NSAIDs) and certain antimicrobial agents, should be discontinued 24 hours prior to and avoided 48 hours after any procedure requiring contrast.

To minimize the risk of lactic acidosis, metformin should be stopped 48 prior to contrast exposure and restarted no earlier than 48 hours in patients receiving intravenous or intra-arterial contrast with an eGFR of <45 mL/min/1.73 m2 and <60 mL/min/1.73 m2, respectively Measure serum creatinine 48-72 hours following contrast exposure and, if diagnosed, manage CIN accordingly.

Management of cardiovascular disease risk

The management of CV risk in patients with CKD is based largely on extrapolation of evidence-based guidelines for the general population. However, CVD in the setting of CKD differs from the general population in many respects including association with non-traditional risk factors, disease pathogenesis, and outcomes.

In addition, the most widely used CVD risk assessment tools, including the Framingham Risk Score and the ACC/AHA ASCVD risk estimator, do not consider renal dysfunction, thereby likely underestimating the rate of CV events in patients with CKD. Consequently, no specific recommendations for CKD patients based on these risk stratification scores are available to guide therapy. The clinical management of CV risk requires pharmacotherapy interventions, management of co-morbid conditions, and comprehensive lifestyle changes.

Antiplatelet therapy

In addition to lifestyle modifications and blood pressure control, antiplatelet and lipid lowering therapy are the cornerstone for primary and secondary prevention of cardiovascular events in the general population and in patients with CKD. However, limited data exist regarding the efficacy of oral antiplatelet in patients with renal dysfunction due to systematic exclusion from RCTs especially in ESRD. Also, concerns about bleeding have limited the use of antiplatelets in this population despite the benefits observed mainly in secondary analyses from randomized clinical trials (RCT).

Acetylsalicylic acid (ASA)

While the use of aspirin for prevention of cardiovascular endpoints is well established in the general population, there is limited data in patients with underlying renal insufficiency. In an observation from the Hypertension Optimal Treatment (HOT) trial involving 18,597 primary prevention patients followed for a median of 3.8 years, aspirin use was associated with greater absolute reductions in major cardiovascular events (MI, stroke or cardiovascular death) among patients with poorer renal function (9%, 15% and 66% risk reductions for patients with baseline eGFR of ≥ 60, 45 to 59, and < 45 ml/min/1.73 m2, respectively). Similar to these results, aspirin is effective at reducing cardiovascular endpoints in patients with stable CHD and after a MI. However, aspirin use may be associated with an increase in minor and major bleeding complications, but, its risk may be outweighed by a reduction in major cardiovascular events, particularly as a secondary prevention strategy amongst patients with GFR<45 ml/min. In the absence of obvious contraindication, the use of 81 mg ASA in CKD patients considered to be at high CV risk is recommended.

P2Y12 inhibitors

P2Y12 inhibitors are commonly used in secondary prevention in addition to aspirin for 12-30 months after an index MI. Similar to aspirin, data supporting the use of P2Y12 inhibitors in CKD stem from observational studies, mostly secondary analyses from RCTs.

Clopidogrel, the most widely used P2Y12 inhibitor reduces the risk of recurrent cardiovascular events in the general population. However, a limited benefit from this drug has been described for patients with CKD. In patients undergoing elective PCI with renal dysfunction clopidogrel failed to reduce MI, stroke or death after one year compared to placebo in a secondary analysis from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, moreover, treatment was associated with an increased risk of major and minor bleeding. However, there may be some benefit in CKD patients with unstable CAD according to an observation from the CURE trial in patients randomized after an ACS without ST-segment elevation.

Prasugrel, a more potent thienopyridine, reduced the risk of death from cardiovascular causes, non-fatal MI or non-fatal stroke by 19% when compared to clopidogrel in patients after an ACS in the TRITON-TIMI 38. In subgroup analysis, the signal for benefit was consistent among patients with creatinine clearance <60 mL/min with a 14% risk reduction in the primary endpoint although not statistically significant, and perhaps attributable to the smaller subset of patients with impaired kidney function (<12% of the total 13,608 randomized subjects).

Another potent P2Y12 inhibitor, ticagrelor, was compared to clopidogrel in patients after an acute MI in the Study of Platelet Inhibition and Patient Outcomes (PLATO trial) demonstrating a significant 16% reduction in major adverse cardiovascular events (cardiovascular death, MI or stroke) in the overall trial population after a median follow-up of 277 days, at the expense of increased minor bleeding without differences in major bleeding rates. In a pre-specified analysis, the absolute and relative risk reduction of cardiovascular events was greater among patients with chronic kidney disease, defined as creatinine clearance <60 mL/min by the Cockroft Gault equation, than in those with normal renal function. Ticagrelor reduced the primary endpoint by 23% (ticagrelor 17.3% vs. clopidogrel 22.0%, HR, 0.77; 95% CI, 0.65 to 0.90) in the subgroup with CKD, and by 10% in those without CKD (ticagrelor 7.9% vs. clopidogrel 8.9%, HR, 0.90; 95% CI, 79 to 1.02).

Extending dual antiplatelet therapy beyond one year after an ACS in patients with CKD may be beneficial. A secondary analysis from the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial stratified by CKD (defined as eGFR <60 mL/min/1.73m2 by the MDRD formula) described a similar relative risk reduction in the risk of major adverse cardiovascular events in subjects with normal renal function (HR 0.88, 95% CI 0.77 to 1.00) and in those with CKD (HR 0.81, 95% CI 0.68 to 0.96) with a greater absolute risk reduction among those with impaired kidney function (2.7% vs. 0.63%) and similar rates of Thrombolysis In Myocardial Infarction (TIMI) major bleeding (1.19 vs. 1.43%).

Hypertension

The pathogenesis of hypertension in renal failure is multi-factorial, including possible contributions from vascular calcification, the uremic milieu, extracellular volume excess, and activation of the renin angiotensin system. Elevated blood pressure contributes to the pathogenesis and progression of both of CKD and CVD, and as such should be aggressively managed. In addition to lifestyle modifications (see below), KDIGO guidelines recommend that anti-hypertensive therapy be initiated for all patients with CKD to achieve a blood pressure of <140/90. For patients with diabetes and/or proteinuric kidney disease (including microalbuminuria), a blood pressure of <130/80 mmHg is recommended. While more aggressive blood pressure control (to systolic blood pressure of 115 mmHg) may further lower risk of CV event, the data is conflicting. The KDIGO guidelines must be reconciled with the more recently released JNC 8 recommendations for a blood pressure goal of <140/90 (same goal recommended by the European Society of Hypertension/European Society of Cardiology) for all patients with CKD regardless of underlying etiology or presence of proteinuria.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD), a subset of patients was randomly assigned in a 2x2 factorial design to either an intensive or standard blood-pressure control and to intensive glucose lowering therapy (glycated hemoglobin target below 6.0%) or standard therapy (glycated hemoglobin target between 7.0 to 7.9%). Stricter goals of systolic blood pressure (120 mmHg vs. 140 mmHg) showed a lower rate of stroke without modifying the risk for other CV endpoints. However, these results deserve careful interpretation as concerns for this trial included a relatively low event rate.

Furthermore, in adults at higher CV risk, with SBP between 130 to 180 mmHg, without diabetes or prior stroke, the Systolic Blood Pressure Intervention Trial (SPRINT) trial also demonstrated that lower goals, 120 mmHg vs 140 mmHg, were associated with a 27% reduction in the risk of death (HR 0.73, 95% CI 0.60 to 0.90, p=0.003) and with a 25% reduction in the primary composite endpoint of MI, other ACS, stroke, HF and cardiovascular death (HR 0.75, 95% 0.64 to 0.89, p<0.001) after a median follow-up of 3.26 years when the trial was stopped early due to excess benefit in the intensive-treatment group. Importantly there was not significant effect modification by CKD (p interaction = 0.36). However, such low goals were associated with a higher risk of hypotension, syncope, electrolyte abnormalities and acute kidney injury in the overall trial population (patients with and without CKD). Further, among patients without CKD at baseline, an intended goal of less than 120 mmHg of SBP increased the risk of the renal endpoint of a decrease in the eGFR of 30% or more to a value of less than<60 ml/min/1.73m2. Among participants with CKD there were no significant differences in any of the renal endpoints between the two interventions.

Several randomized control trials have repeatedly demonstrated the need for multiple agents, often three or more, to achieve target blood pressure in the CKD population, an important message to reinforce with patients. First-line therapy should be either an ACE inhibitor or angiotensin receptor blocker (ARB), especially if the patient is diabetic or has proteinuria. An early drop in GFR may occur, due to a direct hemodynamic effect of lowering intraglomerular capillary pressure.

Underlying CKD is not a contraindication to initiation of an ACE-I or ARB, though development of hyperkalemia should be monitored closely, and may be a limitation in patients with more advanced CKD. Addition of a loop diuretic is generally considered second-line therapy. In addition to having a synergistic effect with RAAS blockade, the kaliuretic effect may offset any tendency towards hyperkalemia.

While helpful in managing patients with essential hypertension and preserved renal function, thiazides are of limited utility in patients with moderate to advanced CKD or clinical evidence of edema, and should be avoided. A calcium channel blocker or beta-blocker, particularly if known history of coronary disease, should be used as adjunct therapy to achieve blood pressure target. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial demonstrated that amlodipine was superior to hydrochlorothiazide when combined with benazepril in reducing the incidence of primary CV events and slowing progression of CKD. This trial randomized more than 11,000 hypertensive patients with high cardiovascular risk or a history of MI, stroke or revascularization to either benazepril plus amlodipine or benazepril plus hydrochlorothiazide, and suggested a role for dihydropyridines as second-line therapy.

Anemia management

Recombinant erythropoietin has been the cornerstone of managing anemia of chronic kidney disease for the past two decades. A number of benefits have been offered including a reduction in need for blood transfusion and improvement in patient reported quality of life. Furthermore, use of erythropoiesis stimulating agents is associated with a regression in ventricular mass among patients with left ventricular hypertrophy.

However, several trials have highlighted an increased risk of adverse CV outcomes with the use of recombinant erythropoietin, leading to major changes in clinical guidelines and surveillance programs. The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) is the largest and only double-blinded placebo controlled trial to date. More than 4000 patients with CKD were randomized to receive either darbepoetin to target a hemoglobin of 13.0 g/dl versus placebo. Patients in the later group could receive darbepoetin as ‘rescue therapy’ if hemoglobin fell below 9.0 g/dL.

After mean follow-up of 29 months, no difference was noted between the two groups with respect to the composite primary endpoint of nonfatal CV event or death. Treatment with darbepoetin was associated with a near two-fold increase risk of stroke, as well as increased likelihood of thromboembolic events and deaths from cancer, although the event rate for the latter was relatively low. No differences were noted with regards to progression to end-stage renal disease. Benefits with regards to quality of life measures were modest.

Accordingly, the appropriateness of ESA should be carefully weighed on a case-by-case basis. Reducing transfusion dependency has significant implications on immunologic risks and sensitization in the pre-transplant setting. A target hemoglobin <=11.5 g/dl is recommended by KDIGO based on results from RCTs that suggest more harm than benefit at higher concentrations. It is recommended that ESA should be initiated in adults with CKD stage 5D when the hemoglobin concentration is between 9.0 to 10.0 g/dl. Prior to initiating ESA therapy, iron stores should be verified and supplemented parentally if necessary. In the setting of systemic inflammation, use of ESA is questionable as inflammation may limit the clinical responsiveness. Dose escalation in this setting may worsen hypertension and increase risk of potential cardiovascular complications.

Proteinuria

Numerous studies have reported an independent association of proteinuria with the development of CVD as well as the progression of CKD. The association is not limited to patients with overt nephropathy (albumin to creatinine ratio, ACR >300 mg/g or protein to creatinine ratio, PCR>500 mg/g), as patients with microalbuminuria are also at increased risk.

Whether proteinuria plays a causal role in this regard is unclear. In patients with CKD, high levels of proteinuria may simply reflect more extensive underlying injury, which carries an inherently greater risk of progressive deterioration in renal function. Similar to CVD, proteinuria may be a potential cofounder due to overlap with such comorbid conditions as hypertension, diabetes or systemic inflammation known to promote CVD.

While many studies have shown a beneficial role of lowering proteinuria on reducing CVD endpoints as well as slowing progression of CKD, a causal role cannot be definitively established due to the observational nature of these studies. Based on the evidence to date, it is generally recommended that strategies be employed to reduce proteinuria, particularly in the setting of overt nephropathy (ACR>300mg/g or PCR>500 mg/g). ACE-I or ARB are at the cornerstone of managing proteinuria, through a reduction in intra-glomerular capillary pressure. The benefits of RAAS blockade in this regard are independent of anti-hypertensive effects.

While combination therapy with ACE-I and ARB may have a synergistic effect in further reducing proteinuria, a role of dual therapy in slowing kidney disease progression has not been established. The ONTARGET trial, a randomized controlled trial of more than 25,000 patients comparing the impact of single RAAS blockade with lisinopril or telmisartan versus dual blockade with both agents not only failed to show any difference in combined cardiovascular endpoints after 56 months of follow-up, but was associated with a significant increase in renal outcomes (doubling of serum creatinine, need for dialysis, or death) in the combination therapy group. Lastly, in the ALTITUDE trial, more than 8,500 patients were randomized to receive either aliskiren 300 mg or placebo on an angiotensin-converting–enzyme inhibitor or an angiotensin-receptor blocker background therapy. The primary efficacy endpoint of time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal MI; nonfatal stroke; unplanned hospitalization for HF; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level, did not differ between the two randomized groups. Similar to the primary endpoint, neither the composite of cardiovascular endpoints, nor the composite renal endpoints, nor the individual components were significantly different between the two groups after a median follow-up of 32.9 months.

The goal should be at least a 30% reduction in proteinuria, ideally to less than 0.5 grams daily if possible. Diltiazem may be used as adjunct therapy to further reduce proteinuria. The importance of adhering to a low sodium diet and moderating protein intake (0.8 grams/kg of body weight daily) must be reinforced, as both factors directly impact urinary protein excretion.

Patients with diabetes and CKD may derive cardiovascular benefits from the initiation of sodium-glucose co-transporter 2 (SGLT2) inhibitors. Located in the S1 segment of the proximal tubule, SGLT2 reabsorbs 90% of the filtered plasma glucose; therefore, its blockade increases urinary glucose excretion, especially in hyperglycemic conditions. Two recent phase 3 RCTs, EMPAREG and CANVAS, evaluated two drugs in this class, empagliflozin and canagliflozin. In EMPAREG more than 7,000 patients were randomized to empagliflozin or placebo on background standard therapy, including more than 15% patients with eGFR between 30-60 mL/min/1.73 m2 (patients with CKD stage 4 or 5 were excluded). After a median follow-up of 3.1 years, randomization to active treatment reduced the composite of cardiovascular death, MI or stroke by 14%, death by 32% and cardiovascular death by 38%, with consistent signals for those with eGFR <60 mL/min/1.73 m2. Consequently, emplagliflozin was the first anti-diabetic drug approved for the reduction of cardiovascular death in patients with type 2 diabetes and concomitant cardiovascular disease. Also, a significant 35% reduction in hospitalization for HF was described. However, the use of empagliflozin increased the rate of genital infections but not that of urinary infections.

More recently, in patients with type 2 diabetes and established CVD or multiple CV risk factors, canagliflozin achieved 14% reduction in the primary composite endpoint of death from cardiovascular causes, nonfatal MI, or nonfatal stroke (HR 0.86; 95% CI 0.75 to 0.97; p<0.001 for noninferiority; p=0.02 for superiority) and a significant 33% reduction in hospitalization due to HF in the CANVAS program. In the subset of subjects with eGFR between 30 and 60 mL/min/1.73 m2 the reduction in the primary endpoint was even more pronounced (HR 0.70; 95% CI 0.55 to 0.90). In terms of renal endpoints, the CANVAS program noted that active treatment resulted in a decrease in: 1) the progression to albuminuria; 2) the composite of 40% reduction in eGFR, renal replacement therapy, or renal death; and 3) regression of albuminuria.

Lastly, a third ongoing CV outcome trial, DECLARE TIMI-58, will aim to evaluate the CV and renal effects of dapagliflozin in mixed primary and secondary prevention population, and is estimated to be completed in 2019.

Dyslipidemia

The evidence between serum cholesterol and development of atherosclerotic disease in the general population is compelling. Statins are at the cornerstone of primary and secondary CVD prevention strategies and have proven superior to any other intervention in reducing CV risk and over-all mortality.

In contrast to the general population, where several randomized control trials have been performed, to date there has not been a clinical trial evaluating the efficacy of statins in the CKD population. Observational studies and post hoc subgroup analysis of the early statin trials of patients with moderate (stage III) CKD suggest a beneficial role.

While retrospective studies reported an association between statin use and reduced cardiovascular mortality in dialysis patients, two large scale randomized control trials have cast serious doubt on this issue. The 4D trial randomized more than 1200 diabetic patients with ESRD to atorvastatin versus placebo, while the AURORA study compared rosuvastatin with placebo in a largely non-diabetic population of almost 3000 patients. While effective reduction of LDL levels was achieved in both trials, neither study demonstrated a significant benefit in reducing CV events.

Many explanations have been offered to account for the surprisingly negative findings of these studies, including death due to non-atheromatous CVD such as arrhythmias, cross-over between the two groups which would dilute any potential benefits, study size being underpowered, and biologic paradigm that patients were simply too far advanced in their disease spectrum to realize any benefit of statin therapy.

SHARP, the largest trial to date, recruited more than 9000 total patients with advanced CKD (GFR<60ml/min) and ESRD. Individuals were randomized to receive daily simvastatin plus ezetimibe versus placebo. After a median follow-up period of 4.9 years, the treatment group experienced a 17% reduction in the risk of a primary atherosclerotic event compared with the placebo group. Importantly, the benefits of lipid lowering therapy were evident across the continuum of advanced CKD, including patients receiving dialysis. Furthermore, treatment was not associated with an increased risk of major side effects including myopathy, hepatic injury, or malignancy.

In the IMPROVE-IT trial (enrolled patients with baseline CrCl >=30 mL/min), adding ezetimibe to a background of simvastatin, compared to placebo and simvastatin reduced the risk of cardiovascular death, major coronary events (nonfatal MI, unstable angina requiring rehospitalization, or coronary revascularization ≥30 days after randomization), or nonfatal stroke by almost 7% and the risk of cardiovascular death, MI or stroke by 10%, after a median follow-up of 6 years in patients after ACS. In a subgroup analysis, patients with eGFR <=60 mL/min/1.73 m2 and <=45 mL/min/1.73 m2 obtained the greatest benefit with relative risk reductions of 12% (HR 0.88, 95% CI 0.82 to 0.95) and 13% (HR 0.87, 95% CI 0.78-0.98) in the primary composite, respectively.

The Kidney Disease Improving Global Outcome (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease recommends that all patients with identified CKD have a baseline lipid panel (total cholesterol, HDL, LDL, and triglycerides). Once remedial secondary causes of dyslipidemia have been excluded, the decision to initiate lipid lowering therapy should be based on age and stage of kidney disease. In adults over the age of 50 with CKD (although not yet requiring dialysis), statin therapy is recommended, whereas for adults less than 50, therapy is reserved for those patients with known coronary/cerebrovascular disease, diabetes mellitus, or a 10-year risk of >10% for a cardiac event. In patients who have progressed to ESRD and are requiring dialysis, initiation of a statin or statin/ezetimibe combination is not recommended, although therapy may be continued if the patient is already on this agent. Given the high risk of CVD in renal allograft recipients, a statin or statin/ezetimibe combination is recommended for all transplant recipients. Per KDIGO, in adults aged 18 to 49 years with CKD but not on dialysis, statin therapy is recommended if one of the following is met: diabetes, history of CAD (prior MI or coronary revascularization), prior stroke or an Framingham risk score >=10%.

In contrast to the past “treat to target” approach for cholesterol-lowering, a “fire and forget” approach is recommended for the CKD population as well as the general population, obviating the need for serial lipid monitoring and dose titration based on cholesterol levels. This is the approach of the latest KDIGO guidelines, as well as that of the AHA/ACC.

Management of hypertriglyceridemia in CKD has also been an evolving area. While there is some evidence in the literature that the use of fibrates may reduce the risk of a major cardiovascular event, the over-all impact is modest and supporting evidence is of questionable validity. Furthermore, any potential benefit to be gained from fibrate therapy must be weighed against possible side effects, particularly in the transplant setting, given the increased risk of myopathy when fibrates are concurrently used with statins and calcineurin inhibitors. The current KDIGO recommendation is that hypertriglyceridemia (>500 mg/dl) in CKD patients (including those who have progressed to ESRD or have received a renal transplant) should be managed with therapeutic lifestyle changes only. Treatment with fibrates is only suggested in those with levels > 1000 mg/dL, adjusted by renal function and concomitant statin therapy with a fibric acid derivate and a statin is not recommended due to potential toxicity.

Bone/mineral metabolism

Vascular calcification, known to correlate with CV events and all-cause mortality, is highly prevalent amongst patients with CKD, affecting more than 60% of patients with stage V CKD. Phosphate burden is considered to be key to the pathogenesis of vascular calcification. While there are no randomized control trials demonstrating that lowering serum PO4 decreases the rate of cardiovascular events, observational evidence suggests that strategies to manage hyperphosphatemia are prudent.

Adhering to a low phosphate diet is recommended and may be sufficient in early stages of CKD to maintain normophosphatemia. However, pharmacotherapy is usually indicated with advanced stages of renal disease. While calcium-based phosphate binders taken with meals (calcium carbonate, calcium acetate) are efficacious in controlling serum phosphate levels, there are growing concerns that this may occur at the expense of increasing total calcium burden and promotion of vascular calcification.

Sevelamer, a non-calcium-based binder, has proven efficacious in managing serum phosphate levels while also favorably impacting coronary artery calcification in some, though not all, studies. While aluminum hydroxide historically was used to manage hyperphosphatemia, complications including neurotoxicity and adynamic bone disease in advanced CKD have precluded its use as chronic therapy.

Studies on the impact of iPTH-lowering therapy have been inconclusive. Most recently, the EVOLVE trial, which randomized almost 4000 hemodialysis patients with secondary hyperparathyroidism to receive either cinacalcet or placebo failed to demonstrate a significant reduction in the risk of death or major cardiovascular events when compared to placebo. Post hoc analysis, however, suggest that cinacalcet may have had a benefit on reducing non-atherosclerotic related cardiovascular events.

Lifestyle

In addition to pharmacotherapy interventions, comprehensive lifestyle changes similar to recommendations for the general population are promoted to optimally manage cardiovascular risk profile in the setting of CKD. Smoking cessation is warranted for all patients. Beyond being an established risk factor for CV disease, active smoking may be a relative contraindication to kidney transplantation in certain programs.

In patients who are able to exercise, 30 to 60 minutes of moderate intensity aerobic exercise should be encouraged at least four times per week. Studies in the dialysis population have demonstrated a myriad of benefits from exercise, including better blood pressure control, improved cardiac function with increased ejection fraction and fewer arrhythmias, better glycemic control in diabetic patients, favorable changes to dyslipidemia profiles, and improvement in quality of life measures.

While exercise in patients with CKD was not associated with increased risk of medical complications, CV risk assessment in the high-risk patient is advised prior to implementing a moderate intensity exercise program. Weight loss in the obese patient through exercise and diet (see below) has further benefits in terms of decreasing insulin resistance and also lowering degree of proteinuria through its favorable effects on reducing intra-glomerular capillary pressure.

What dietary interventions should be employed to reduce cardiovascular disease risk?

Population-based studies from the 1960s first demonstrated the association between diet and CV risk. The Seven Countries Study found the lowest death rates, located in Crete, were almost 50% below the rate for the highest cohort. The decreased incidence of CVD was ascribed, at least in part, to dietary factors unique to the Mediterranean Basin.

Clinical studies have confirmed superiority of the Mediterranean-style diet versus western diet on primary and secondary prevention of CV events and related deaths. These findings have led the American Heart Association and other professional organizations to recommend a “heart healthy” diet as follows:

Consume a diet rich in vegetables and fruits

  • Choose whole-grain, high-fiber foods

  • Consume fish, especially oily fish, twice a week

  • Limit intake of saturated fat (<7% of energy), trans fat (<1% of energy), and cholesterol (<300 mg) per day by choosing lean meats and vegetable alternatives, and selecting fat-free (skim), 1%-fat, and low-fat dairy products

  • minimizing intake of partially hydrogenated fats

  • Minimize intake of beverages and foods with added sugars

  • Choose and prepare foods with little or no salt (<2400 mg/day)

  • Consume alcohol in moderation only (<2 drinks/day in men and <1 drink/day in women)

It is important to recognize that these guidelines are intended for the general population. Despite being among the highest risk group for developing CVD, dietary guidelines for reducing CV risk in the CKD population are scant and evidence-based recommendations are lacking. Furthermore, recommendations regarding specific nutritional interventions in the general population may in fact be potentially harmful in the patient with reduced GFR as follows:

Protein intake: Though the Institute of Medicine and World Health Organization both recommend a daily allowance for protein of 0.8 grams per kg of ideal body weight, the typical western diet is higher in protein content. Recent weight loss trials have shown a beneficial role of increased protein intake (up to 25% of daily caloric target) with reduced total calorie load as an effective approach for sustained weight loss with improvement in CV risk factors including more favorable lipid profile and better blood pressure control.

While well-tolerated in the setting of a normal GFR, such a protein load (up to 1.8 grams/kg of body weight) could have deleterious consequences for the patient with limited renal reserve. Increased protein intake, particularly of animal origin, increases intra-glomerular capillary pressure. Ensuing hyperfiltration promotes glomerular scarring and irreversible renal fibrosis resulting in a more rapid decline in GFR.

The Nurses’ Health Study, a prospective cohort study, investigated the impact of protein intake on change in renal function over an 11-year period. Amongst subjects with eGFR 55 ml/min to 80 ml/min/1.73 m2, the odds ratio of having at least a 15% reduction in GFR was 3.51 (95% CI 1.36 to 9.07) for the quintile with the highest protein consumption (>90 grams per day) when compared to their counterparts in the lowest quintile (<60 grams per day).

Early clinical trials in patients with diabetes demonstrated a benefit of protein restriction on ameliorating the rate of decline in GFR. However, the Modified Diet in Renal Disease (MDRD) trial, the largest randomized control trial to date, failed to establish a clear protective role. Including 840 patients with stage 3 to 4 CKD, subjects were randomized in a 2x2 factorial design to either standard versus low protein diet and standard versus low blood pressure target.

While the overall rate of decline in GFR did not differ significantly between the diet groups at three-year follow-up, significant limitations may have masked a beneficial role for protein moderation. Only 3% of the patients enrolled were diabetic, the subset of patients most likely to benefit from a reduction in dietary protein intake.

When a 2-slope model is applied to the results, a biphasic response is noted. Following a significant decline in GFR over the first 4 months in the low protein group, which may represent an acute hemodynamic response due to precipitous drop in intra-glomerular capillary pressure, the slope of the rate of loss of GFR was lower over the remainder of the study. Long-term analysis of the low protein subgroup revealed a trend towards decreased kidney failure and mortality.

A meta-analysis of randomized trials compared different levels of protein intake for at least 1 year on progression of known renal disease. Encompassing 10 studies and 2000 patients in the analysis, reduction of protein intake (0.6 - 0.8 g/kg body weight per day) led to a statistically significant 31% reduction in the occurrence of renal death when compared to unrestricted dietary protein intake. Beyond beneficial effects on slowing progression of renal disease, moderating protein intake may have beneficial effects on over-all CVD risk by ameliorating many of the downstream metabolic complications including metabolic acidosis, hyperphosphatemia, and hyperkalemia.

High fruit/fiber diet

Diets rich in plant and fruit content are associated with reduced incidence of CVD, the benefit being ascribed to increased fiber intake as well as potassium. The AHA recommendation for a daily intake of 4700 mg, or 120 mEq of elemental K+, represents a three-fold increase over the daily recommended allowance for patients with underlying renal disease. As GFR declines, the ability of the kidneys to handle a K+ load is compromised. While aldosterone is normally a key regulator of renal K+ excretion, this compensatory mechanism is often blunted by the concomitant use of RAAS antagonists.

Fatty food consumption

Observational studies have provided compelling evidence for the association between dietary fat intake and CVD. The Nurses’ Health Study demonstrated that for every 5% increase in energy intake originating from saturated fat, the relative risk of a coronary event increased by 17%, whereas, a 5% increase in energy intake originating from monounsaturated or polyunsaturated fats was associated with a reduced relative risk (0.81 and 0.62 respectively).

Dietary saturated fat intake and increased LDL cholesterol are recognized as a driving force in the development of atherosclerotic disease. While interventional studies have shown a benefit of replacing saturated fat on intermediary markers of CVD, the more prominent randomized interventional dietary trials either did not provide information regarding renal function or excluded patients with underlying kidney disease entirely. Nonetheless, even though mechanisms underlying accelerated atherosclerosis in CKD likely differ from the general population, given the overwhelming epidemiologic evidence available, emphasizing a diet that avoids trans fats and replaces saturated fats with poly- and mono-unsaturated fatty acids seems prudent.

Caution must be exercised, however, with interpretation of guidelines and distribution of macronutrient content. If total fat intake is restricted, at times to less than 25% of total caloric intake, the most likely source for meeting the caloric requirements is carbohydrate. However, increasing CHO intake, especially with high glycemic index foods, poses a number of potential concerns with regards to CV risk, including increased insulin secretion, triglyceride levels and small dense LDL cholesterol all of which may further create an environment which promotes atherogenesis, and possibly fuel progression of CVD.

Observational studies have suggested an inverse relationship between fish and coronary heart disease. Subsequent randomized control trials have convincingly shown a protective effect of fish oils and/or omega-3 fatty acids on secondary prevention of CVD. Though data on CV events is not yet available in the setting of renal disease, a randomized double blinded placebo controlled trial of 85 patients with stage 3 to 4 CKD, demonstrated that daily supplementation with omega 3 fatty acids favorably impacted blood pressure and reduced triglyceride levels. Because oily fish may potentially harbor higher amounts of mercury and other heavy metals, caution must be exercised in the CKD population, as impaired excretory capacity may result in accumulation to toxic levels.

Phosphate intake

There are many aspects of the heart healthy diet that may predispose to increased phosphate consumption. Oily fish such as salmon, which are emphasized in the heart healthy diet, have a much higher phosphate to protein ratio relative to other lean meats such as chicken. Other elements of the heart healthy diet also represent significant potential sources of phosphate, including nuts and legumes (a particular emphasis of the Mediterranean Diet), certain leafy vegetables, and whole grain fiber-rich foods such as bran. Unlike healthy volunteers who are able to dramatically increase the fractional excretion of phosphate post-prandially by as much as 75%, this compensatory response is markedly blunted in the patients with stage 3 CKD.

DASH diet

Dietary interventions are an essential component to the successful management of hypertension in CKD. The landmark DASH diet clinical trial randomized hypertensive patients to a diet which featured 8 - 10 fruit and vegetable servings, 2 to 3 dairy servings daily, and less than 25% total fat, achieving a reduction of 11.4 mmHg and 5.5 mmHg in systolic and diastolic blood pressures respectively at 8 weeks.

Although the DASH diet has been readily embraced and championed in most published dietary guidelines, caution must be exercised before implementation in the CKD population, due to potential metabolic complications that may arise. The DASH diet was associated with a 2.6 fold increase in potassium intake, which could predispose to hyperkalemia in patients with diminished renal excretory capacity. Additionally, implementation of the higher protein content in conjunction with dairy and legumes is associated with a 20% increase in 24-hour urinary phosphate excretion, indicative of a significant increase in over-all phosphate burden.

An integrated dietary approach to reduce CV risk specifically in the CKD population

Protein recommendation based solely as a percentage of daily caloric requirements is potentially dangerous and may accelerate decline in renal function and fuel metabolic complications. Plant and egg-based protein sources may be preferable in this regard.

Moderating protein intake to 0.6 to 0.8 grams per kg of ideal body weight per day, in concordance with recommendations of the WHO and IOM, is the preferred approach. Moderation of protein intake is usually well-tolerated and may be performed safely, though ongoing monitoring and involvement of a registered dietician experienced in CKD should occur to ensure caloric and other nutritional needs are met.

Replacing saturated and trans fats with unsaturated fats is recommended. Omega-3 fatty acids appear to be safe and may have benefits in reducing CVD risk profile beyond blood pressure-lowering effects alone. Oily fish as a source of omega-3 must be ingested in moderation, due to potential risks of mercury and other heavy metal exposure.

If intake from protein and fat is restricted, careful attention must be paid to ensuring that caloric needs are not being met solely through high glycemic index CHO.

While a high fruit and vegetable diet confers cardioprotective effects, the resulting K+ load may increase risk of developing hyperkalemia. Dietary K+ intake levels suggested by the DASH diet may be impractical in the patient with advanced CKD, especially if concomitant medications which predispose to hyperkalemia such as ACE-inhibitors, ARB, or calcineurin inhibitors are used.

Serum phosphate is an insensitive and late manifestation of total phosphate burden. Dietary interventions to limit daily phosphate load employed in the early stages of CKD seem prudent and may lower risk of vascular calcification and CVD in this high-risk population. While a daily phosphate intake of ~800 mg seems reasonable, careful attention must be paid to hidden sources of phosphate in highly processed foods.

Lastly, K/DOQI recommends nutritional status monitoring at 1-3 month intervals in patients with GFR <20 mL/min. However, this may be generalizable to patients with eGFR <30 mL/min/1.73 m2, with less frequent monitoring, e.g., every 6-12 months, for CKD stage 3 (30 to 60 mL/min/1.73 m2).

Residual Inflammatory Risk

In the general population, despite intensive LDL lowering with statins, ezetimibe, PCSK9 inhibitors and other lipid lowering therapies, many patients continue to experience secondary cardiovascular events. This issue, commonly described as ‘residual risk’, has been ascribed in part to a ‘residual inflammatory risk’.

For instance, in the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22) and in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT-TIMI 40) trials, patients who achieved an LDL goal <70 mg/dL but did not achieve a high-sensitivity CRP goal of <2 mg/L were at a higher risk of recurrent vascular events compared to those who achieved both goals. This issue is relevant for CKD patients, who experience a pro-inflammatory milieu as evidenced by elevated CRP and pro-inflammatory cytokines levels.

Although not targeted specifically to the CKD population, recent results from the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) indicate that anti-inflammatory therapy targeting interleukin-1β, thereby interfering with the interleukin-6 pathway, reduces recurrent vascular events in patients with persistent proinflammatory response (defined as a high-sensitivity CRP >= 2 mg/L). Three doses were compared to placebo (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months). Patients receiving canakinumab 150 mg every 3 months experienced a 15% reduction in nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death after a median follow-up of 3.7 years. The Cardiovascular Inflammation Reduction (CIRT) trial will provide further insights into whether modulating chronic inflammation with low-dose methotrexate reduces the risk of major cardiovascular events.

What happens to patients with chronic kidney disease and underlying cardiovascular disease?

What will be the natural progression of cardiovascular disease in my patient with chronic kidney disease?

Despite the epidemic of CKD in the United States, numbering greater than 25 million adults, it is estimated that only 2% may live long enough to progress to requiring renal replacement therapy. However, caution must be exercised when interpreting these data as 10 million were either stage 1 or 2, including a significant number of elderly patients who may have physiologic decline in GFR associated with aging. The critical question to address is whether these patients are truly at risk of experiencing clinical complications of declining renal function and progressing to ESRD or are at increased cardiovascular risk.

Nonetheless, long-term observational studies indicate that patients with moderate (stage 2 to 4) CKD are eight times more likely to die than progress to requiring renal replacement therapy, due largely to cardiovascular complications. A prospective observational study of more than one million patients revealed that a progressive reduction in estimated GFR below 45 ml/min strongly correlated in a graded fashion with risk of CVD and over-all mortality, reaching a respective event rate of 2.8-fold and 3.2-fold by stage 4 CKD.

However, the spectrum of cardiovascular disease differs, as deaths due to arrhythmia and HF are more common in patients with advanced kidney disease when compared to the general population. Amongst ESRD population, the mortality rate in the United States remains amongst the highest worldwide, exceeding 20% annually for patients on dialysis.

How to utilize team care?

How should I use a multi-disciplinary team approach?

Approaching CVD risk in patients with CKD is not straightforward. Lack of evidence-based guidelines, heterogeneity in terms of underlying pathogenesis and attendant CVD risk, and complex co-morbidities with at times divergent management approaches all contribute to the uncertainty in management. The engagement of a multi-disciplinary team can be extremely helpful in this regard and is supported by at least a few studies.

A four-year comparison to referral to an outside nephrologist showed that a multi-disciplinary team consisting of a nephrologist, a nephrology nurse, a pharmacy specialist, a diabetes educator, a dietitian and a social worker was associated with a slower decline in GFR and a smaller proportion of patients initiating dialysis.

Specialty consultations

The National Kidney Foundation KDOQI guidelines recommend that all patients with stage 4 CKD (GFR 15 - 30 ml/min) be referred to a nephrologist, as a delay in referral is associated with increased morbidity and mortality. While referral to a cardiologist is not routine practice for all patients with CKD, it is prudent in certain situations including management of all high-risk patients for primary and secondary prevention, guide work up for risk stratification assessment, and evaluation of patient with new or unexplained symptoms of possible cardiac etiology.

Nurses

Partnering with a nurse specialist in the advanced stages of CKD is recommended and provides an invaluable resource for the patient in terms of ensuring ongoing monitoring, communication, and troubleshooting problems or patient concerns as they arise.

Pharmacists

Involvement of a pharmacist can be especially valuable in specific situations including monitoring of drug interactions which may increase the risk of serious arrhythmias, particularly in the setting of electrolyte derangements as occur in advanced CKD or metabolic shifts following dialysis. Additionally, monitoring of patients on systemic anticoagulation may help reduce major bleeding complications that may be compounded by use of anti-platelet agents or the dysfunctional platelets of uremia.

Dieticians

Effective dietary management in the CKD setting mandates a multi-disciplinary team approach which includes ongoing assessment by a dedicated registered dietician experienced in CKD to ensure delivery of a consistent message to the patient and regular monitoring of metabolic parameters including electrolytes and nutritional metrics. Essential to this team structure are open lines of communication with ongoing education and empowerment of the patient to make healthy dietary choices.

Are there clinical practice guidelines to inform decision making?

All evidence-based clinical guidelines for managing cardiovascular risk are derived from the general population, often based on studies that excluded patients with significant kidney disease. The reasons for exclusion of patients with advanced kidney disease from cardiovascular outcome clinical trials include the potential for diminished treatment effects, issues with recruitment, retention and safety, competing risks, and the intricate pathophysiology including non-atherosclerotic mechanisms for CVD such as arrhythmia, and as consequence the potential loss of signal for benefit. In the absence of randomized control trials involving patients with CKD, clinical guidelines from regulatory bodies such as the National Kidney Foundation or the United Kingdom Clinical Practice Guidelines for the management of cardiovascular risk in CKD patients are derived largely from the literature and extrapolated from the general population. Below is an integrated approach to modifying CVD risk in patients with underlying CKD.

(see Table I).

Table I.

Integrated Approach to Modifying CVD Risk in Patients with Underlying CKD
Risk factor Management approach
hypertension low sodium diet generally recommended for all patients (2400 mg Na daily)CKD: target BP <140/90 mmHg; some recommend <130/80 mmHg in proteinuric CKD and diabetics*1st line therapy: ACE-inhibitor or ARB2nd line therapy: diuretic Beta blocker (especially if known CAD and less than 60 yrs of age) or CCB as adjunctive therapy to achieve goal
dyslipidemia CKD: lipid-lowering therapy guidelines as extrapolated from the general population (stages 1 - 4 CKD)ESRD: efficacy of statins unproven; reasonable to continue statins, ezetimibe or statin/ezetimibe combination therapy if previously had been taking
proteinuria goal is < 500-1,000 mg/24 hours if possibleACE-i or ARB as first-line therapymoderate protein intake (0.6 - 0.8 grams/kg daily)preference for egg or plant-based protein sources instead of meat
anemia use of ESA no longer routinely recommended; consider on case-by-case basistarget Hb concentration = 10 - 11.5 mg/dlInitiate ESA when Hb concentration below 10.0 g/dlensure iron stores are adequate
phosphate management low PO4 diet and use of PO4 binders as warrantednon-calcium-containing salts may be preferable in setting of significant vascular calcification
lifestyle changes smoking cessationencourage regular aerobic exercise of moderate intensity (30 - 60 minutes, at least 4 times weekly)weight loss to achieve ideal body weightdietary interventions to promote healthy lifestyle (see Table I)
other if no contraindication present, consider low-dose ASA especially as secondary preventionAdd further antiplatelets as needed while balancing the risk of bleeding (i.e., after ACS)

What is the evidence?

"K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification". Am J Kidney Dis. vol. 39. 2002. pp. S1-266.

Abboud, H,, Henrich, WL. "Stage IV Chronic Kidney Disease". N Engl J Med. vol. 362. 2010. pp. 56-65.

Rucker, D,, Tonelli, M. "Cardiovascular risk and management in chronic kidney disease". Nature Reviews, Nephrology. vol. 5. 2009. pp. 287-296.

Hakeem, A,, Hatti, S,, Trevino, AR,, Samad, Z,, Chang, SM. "Non-invasive risk assessment in patients with chronic kidney disease". J Nucl Cardiol. vol. 18. 2011. pp. 472-485.

Foley, RN,, Parfrey, PS,, Sarnak, MJ.. "Epidemiology of cardiovascular disease in chronic renal disease". J Am Soc Nephrol.

"Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis". The Lancet. vol. 375. 2010. pp. 2073-2081.

Berns, JS. "Are there implications from the Trial to Reduce Cardiovascular Events with Aranesp Therapy study for anemia management in dialysis patients?". Current Opinions in Nephrology and Hypertension. vol. 19. 2010. pp. 567-572.

Keith, DS,, Nichols, GA,, Gullion, CM,, Brown, JB,, Smith, DH. "Longitudinal follow-up and outcomes amongst a population with chronic kidney disease in a large managed care organization". Arch Intern Med. vol. 164. 2004. pp. 659-663.

Bakris, G,, Vassalotti, J,, Ritz, E,, Wanner, C,, Stergiou, G,, Molitch, M,, Nesto, R,, Kaysen, GA,, Sowers, JR. "National Kidney Foundation consensus conference on cardiovascular and kidney diseases and diabetes risk: an integrated therapeutic approach to reduce events". Kidney International. vol. 78. 2010. pp. 726-736.

Toussaint,, ND,, Kerr, PG. "Vascular calcification and arterial stiffness in chronic kidney disease: Implications and management". Nephrology. vol. 12. 2007. pp. 500-509.

Palmer, SC,, Hayen, A,, Macaskill, P,, Pellegrini, F,, Craig, JC,, Elder, GJ,, Strippoli, GF. "Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis". JAMA. vol. 305. 2011. pp. 1119-1127.

Cheung, AK. "Is lipid control necessary in hemodialysis patients?". Clin J Am Soc Nephrol. vol. 4. 2009. pp. S95-S101.

Prakash, S,, O'Hare, AM. "Interaction of aging and chronic kidney disease". Semin Nephrol. vol. 29. 2009. pp. 497-503.

Buckalew, VM,, Berg, RL,, Wang, SR,, Porush, JG,, Rauch, S,, Schulman, G. "Prevalence of hypertension in 1,795 subjects with chronic renal disease: the modification of diet in renal disease study baseline cohort. Modification of Diet in Renal Disease Study Group". Am J Kidney Dis. vol. 28. 1996. pp. 811-821.

Levey, AS,, Greene, T,, Sarnak, MJ,, Wang, X,, Beck, GJ,, Kusek, JW,. "Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study". Am J Kidney Dis. vol. 48. 2006. pp. 879-888.

Mandayam, S,, Mitch, WE.. "Dietary protein restriction benefits patients with chronic kidney disease". Nephrology. vol. 11. 2006. pp. 53-57.

Go, AS,, Chertow, GM,, Fan, D,, McCulloch, CE,, Hsu, CY.. "Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization". N Engl J Med. vol. 351. 2004. pp. 1296-1305.

Wanner, C,, Krane, V,, März, W,, Olschewski, M,, Mann, JF,, Ruf, G. "Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis". N Engl J Dis. vol. 353. 2005. pp. 238-248.

Hage, FG,, Venkataraman, R,, Zoghbi, GJ,, Perry, GJ,, DeMattos, AM,, Iskandrian, AE.. "The scope of coronary heart disease in patients with chronic kidney disease". J Am Coll Cardiol. vol. 53. 2009. pp. 2129-2140.

Ix, JH,, Shlipak, MG,, Liu, HH,, Schiller, NB,, Whooley, MA.. "Association between renal insufficiency and inducible ischemia in patients with coronary artery disease: the heart and soul study". J Am Soc Nephrol. vol. 14. 2003. pp. 3233-3238.

Sarnak, MJ,, Levey, AS,, Schoolwerth, AC,, Coresh, J,, Culleton, B,, Hamm, LL,. "Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention". Hypertension. vol. 42. 2003. pp. 1050-1065.

de Lorgeril, M,, Salen, P,, Martin, JL,, Monjaud, I,, Delaye, J,, Mamelle, N.. "Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study". Circulation. vol. 99. 1999. pp. 779-785.

Kestenbaum, B,, Sampson, JN,, Rudser, KD,, Patterson, DJ,, Seliger, SL,, Young, B.. "Serum phosphate levels and mortality risk among people with chronic kidney disease". J Am Soc Nephrol. vol. 16. 2005. pp. 520-528.

London, GM,, Guérin, AP,, Marchais, SJ,, Métivier, F,, Pannier, B,, Adda, H.. "Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality". Nephrol Dial Transplant. vol. 18. 2003. pp. 1731-1740.

Goodman, WG,, Goldin, J,, Kuizon, BD,, Yoon, C,, Gales, B,, Sider, D.. "Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis". N Engl J Med. vol. 18. 2000. pp. 1478-1483.

Wanner, C,, Ritz, E.. "Reducing lipids for CV protection in CKD patients-current evidence". Kidney Int Suppl. vol. 111. 2008. pp. S24-8.

Berl, T.. "Review: renal protection by inhibition of the renin-angiotensin-aldosterone system". J Renin Angiotensin Aldosterone Syst. vol. 10. 2009. pp. 1-8.

Lichtenstein, AH,, Appel, LJ,, Brands, M,, Carnethon, M,, Daniels, S.. "Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee". Circulation. vol. 114. 2006. pp. 82-96.

Sacks, FM,, Bray, GA,, Carey, VJ,, Smith, SR,, Ryan, DH,, Anton, SD.. "Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates". N Engl J Med. vol. 360. 2009. pp. 859-873.

Estruch, R,, Martínez-González, MA,, Corella, D,, Salas-Salvadó, J,, Ruiz-Gutiérrez, V,, Covas, MI,. "Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial". Ann Intern Med. vol. 145. 2006. pp. 1-11.

Appel, LJ,, Moore, TJ,, Obarzanek, E,, Vollmer, WM,, Svetkey, LP,, Sacks, FM,. "A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group". N Engl J Med. vol. 336. 1997. pp. 1117-1124.

Thoms, E.. "The DASH diet--is it a realistic option for people with kidney disease?". CANNT. vol. 5. 2005. pp. 58-59.

Fellström, BC,, Jardine, AG,, Schmieder, RE,, Holdaas, H,, Bannister, K,, Beutler, J.. "Rosuvastatin and cardiovascular events in patients undergoing hemodialysis". J Med. vol. 360. 2009. pp. 1395-1407.

Coresh, J,, Astor, BC,, Greene, T,, Eknoyan, G,, Levey, AS.. "Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey". Am J Kidney Dis. vol. 41. 2003. pp. 1-12.

Keith, DS,, Nichols, GA,, Gullion, CM,, Brown, JB,, Smith, DH.. "Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization". Arch Intern Med. vol. 164. 2004. pp. 659-663.

Baigent, C,, Landray, MJ. "on behalf of the SHARP investigators. The effect of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial". Lancet. vol. 377. 2011. pp. 2181-2192.

Sarnak, MJ,, Astor, BC.. "Implications of proteinuria: CKD progression and cardiovascular outcomes". Advances in Chronic Kidney Disease. vol. 18. 2011. pp. 258-266.

Bakris, GL,, Sarafidis, PA. "on behalf of the ACCOMPLISH Trial investigators. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial". Lancet. vol. 375. 2010. pp. 1173-1181.

"KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease". Kidney inter., Suppl. vol. 3. 2013. pp. 259-305.

Kestenbaum, B,, Sachs, MC,, Hoofnagle, AN,, Siscovick, DS,, Ix, JH,, Robinson-Cohen, C,, Lima, JA,, Polak, JF,, Blondon, M,, Ruzinski, J,, Rock, D,, de Boer, IH.. "Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-Ethnic Study of Atherosclerosis". Circ Heart Fail. vol. 7. 2014. pp. 409-17.

Fenech, G,, Rajzbaum, G,, Mazighi, M,, Blacher, J.. "Serum uric acid and cardiovascular risk: state of the art and perspectives". Joint Bone Spine. vol. 81. 2014. pp. 392-7.

Hu, MC,, Kuro-o, M,, Moe, OW.. "Klotho and vascular calcification: An evolving paradigm". Curr Opin Nephrol Hypertens. vol. 23. 2014. pp. 331-9.

Szwejkowski, BR,, Gandy, SJ,, Rekhraj, S,, Houston, JG,, Lang, CC,, Morris, AD,, George, J,, Struthers, AD.. "Allopurinol reduces left ventricular mass in patients with type 2 diabetes and left ventricular hypertrophy". J Am Coll Cardiol. vol. 62. 2013. pp. 2284-93.

Bansal, N,, Zelnick, L,, Robinson-Cohen, C,, Hoofnagle, AN,, Ix, JH,, Lima, JA,, Shoben, AB,, Peralta, CA,, Siscovick, DS,, Kestenbaum, B,, de Boer, IH.. "Serum parathyroid hormone and 25-hydroxyvitamin D concentrations and risk of incident heart failure: the multi-ethnic study of atherosclerosis". J Am Heart Assoc. 2014.

Chertow, GM,, Block, GA,, Correa-Rotter, R,, Drüeke, TB,, Floege, J,, Goodman, WG,, Herzog, CA,, Kubo, Y,, London, GM,, Mahaffey, KW,, Mix, TC,, Moe, SM,, Trotman, ML,, Wheeler, DC,, Parfrey, PS.. "Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. EVOLVE Trial Investigators". N Engl J Med. vol. 367. 2012. pp. 2482-94.

Wheeler, DC,, London, GM,, Parfrey, PS,, Block, GA,, Correa-Rotter, R,, Dehmel, B,, Drüeke, TB,, Floege, J,, Kubo, Y,, Mahaffey, KW,, Goodman, WG,, Moe, SM,, Trotman, ML,, Abdalla, S,, Chertow, GM,, Herzog, CA.. "Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial Investigators". J Am Heart Assoc. vol. 3. 2014.

Mann, JF,, Schmieder, RE,, McQueen, M,. "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial". Lancet. vol. 372. 2008. pp. 547-553.

Updated KDIGO guidelines 2017:

"Improving Global Outcomes (KDIGO) CKD Work Group KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease". Kidney Int Suppl. 2013. pp. 31-150.

Ketteler, M,, Block, GA,, Evenepoel, P,, Fukagawa, M4,, Herzog, CA,. "Executive summary of the 2017 KDIGO Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guideline Update: what's changed and why it matters". Kidney Int. vol. 92. 2017. pp. 26-36.

The following references address the key issue of ‘residual inflammatory risk’ in CHD as proposed by Dr. Paul Ridker. The first reference explains the concept of ‘residual risk’ and inflammation, a pathophysiologic feature of CHD in CKD, and the two other references pertain to the rationale and design of two awaited ongoing clinical trials targeting inflammatory modulation towards preventing recurrent cardiovascular events. Although not dedicated to patients with CKD, secondary analysis in such population may be expected:

Ridker, PM,, Thuren, T,, Zalewski, A,, Libby, P.. "Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the CanakinumabAnti-inflammatory Thrombosis Outcomes Study (CANTOS)". Am Heart J. vol. 162. 2011. pp. 597-605.

Everett, BM,, Pradhan, AD,, Solomon, DH,. "Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis". Am Heart J. vol. 166. 2013. pp. 199-207.e15.

"addressing the obverse side of the atherosclerosis prevention coin". Eur Heart J. vol. 37. 2016. pp. 1720-2.

The following references provide a ‘deeper dive’ into the pathophysiology of CHD in CKD, and underuse of evidence-based cardiovascular therapies in CKD. These two aspects are determinant to understand the burden of CHD in CKD and to guide therapeutics and future research:

Moe, SM1,, Chen, NX.. "Mechanisms of vascular calcification in chronic kidney disease". J Am Soc Nephrol. vol. 19. 2008. pp. 213-6.

Kahn, MR,, Robbins, MJ,, Kim, MC,, Fuster, V.. "Management of cardiovascular disease in patients with kidney disease". Nat Rev Cardiol. vol. 10. 2013. pp. 261-73.

Leng, WX,, Ren, JW,, Cao, J,. "Chronic kidney disease--is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease?". Thromb Res. vol. 131. 2013. pp. 218-24.

Franchi, F,, Rollini, F,, Angiolillo, DJ.. "Defining the link between chronic kidney disease, high platelet reactivity, and clinical outcomes in clopidogrel-treated patients undergoing percutaneous coronary intervention". Circ Cardiovasc Interv. vol. 8. 2015. pp. e002760.

Coca, SG,, Krumholz, HM,, Garg, AX,, Parikh, CR.. "Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease". JAMA. vol. 296. 2006. pp. 1377-84.

Santolucito, PA1,, Tighe, DA,, McManus, DD,. "Management and outcomes of renal disease and acute myocardial infarction". Am J Med. vol. 123. 2010. pp. 847-55.

These references pertain to the updated epidemiology of CKD and CHD, a new paragraph on this topic has ben added to the beginning of the chapter. The most recent reports from Europe (2017) and the US (2016) have been included:

Atlas o Chronic Kidney Disease and End-Stage Renal Disease. National Institutes o Health, National Institute of Diabetes and Digestive and Kidney Diseases. 2017.

Wagner, M,, Wanner, C,, Kotseva, K,. "Prevalence of chronic kidney disease and its determinants in coronary heart disease patients in 24 European countries: Insights from the EUROASPIRE IV survey of the European Society of Cardiology". Eur J Prev Cardiol. vol. 24. 2017. pp. 1168-1180.

Nichols, M,, Townsend, N,, Scarborough, P,, Rayner, M.. "Cardiovascular disease in Europe 2014: epidemiological update". Eur Heart J. vol. 35. 2014. pp. 2950-9.

Lopez, AD,, Mathers, CD,, Ezzati, M,, Jamison, DT,, Murray, CJ.. "Global and regional burden of disease and risk factors". systematic analysis of population health data. Lancet. vol. 367. 2006. pp. 1747-57.

Mozaffarian, D,, Benjamin, EJ,, Go, AS,, Arnett, DK,, Blaha, MJ,, Cushman, M,. "Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association". Circulation. vol. 133. 2016. pp. e38-360.

Sarnak, MJ,, Levey, AS,, Schoolwerth, AC,. "Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention". Circulation. vol. 108. 2003. pp. 2154-69.

This reference presents update information on monitoring of anemia in CKD:

Kliger, AS1,, Foley, RN,, Goldfarb, DS.. "KDOQI US commentary on the 2012 KDIGO Clinical Practice Guideline for Anemia in CKD". Am J Kidney Dis. vol. 62. 2013. pp. 849-59.

This reference pertains to a recent study from some of our colleagues on FGF-23, a biomarker that has gained a lot of interest recently:

Udell, JA,, Morrow, DA,, Jarolim, P,. "Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease". J Am Coll Cardiol. vol. 63. 2014. pp. 2421-8.

The references below update the section on cardiac troponins. This is very relevant for two reasons. Cardiac troponins are the cornerstone for diagnosis of acute coronary syndromes in patients with and without CKD, and second, troponin exhibit great predictive ability for adverse cardiovascular outcomes in patients with stable and unstable CAD. Lastly, important comments on high-sensitivity assays have been added:

Fridén, V,, Starnberg, K,, Muslimovic, A,. "Clearance of cardiac troponin T with and without kidney function". Clin Biochem. vol. 50. 2017. pp. 468-474.

Parikh, RH,, Seliger, SL,, deFilippi, CR.. "Use and interpretation of high sensitivity cardiac troponins in patients with chronic kidney disease with and without acute myocardial infarction". Clin Biochem. vol. 48. 2015. pp. 247-53.

Huang, HL,, Zhu, S,, Wang, WQ,. "Diagnosis of Acute Myocardial Infarction in Hemodialysis Patients With High-Sensitivity Cardiac Troponin T Assay". Arch Pathol Lab Med. vol. 140. 2016. pp. 75-80.

Aviles, RJ,, Askari, AT,, Lindahl, B,. "Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction". N Engl J Med. vol. 346. 2002. pp. 2047.

The reference below advocates for the inclusion of patients with advanced renal disease in cardiovascular clinical trials, an unmet need:

Zannad, F,, Rossignol, P.. "Cardiovascular Outcome Trials in Patients With Advanced Kidney Disease: Time for Action". Circulation. vol. 135. 2017. pp. 1769-1771.

This reference adds evidence with regards to MDT approaches in CKD:

Bayliss, EA,, Bhardwaja, B,, Ross, C,, Beck, A,, Lanese, DM.. "Multidisciplinary team care may slow the rate of decline in renal function". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 704-10.

The following references reveal the prognostic value of several imaging modalities:

Patel, RK,, Mark, PB,, Johnston, N,. "Prognostic value of cardiovascular screening in potential renal transplant recipients: a single-center prospective observational study". Am J Transplant. vol. 8. 2008. pp. 1673-83.

Paoletti, E,, Zoccali, C.. "A look at the upper heart chamber: the left atrium in chronic kidney disease". Nephrol Dial Transplant. vol. 29. 2014. pp. 1847-53.

Raggi, P,, Bellasi, A,, Gamboa, C.. "All-cause mortality in hemodialysis patients with heart valve calcification". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 1990-5.

Rakhit, DJ,, Zhang, XH,, Leano, R,, Armstrong, KA,, Isbel, NM,, Marwick, TH.. "Prognostic role of subclinical left ventricular abnormalities and impact of transplantation in chronic kidney disease". Am Heart J. vol. 153. 2007. pp. 656-64.

Chiu, DY,, Green, D,, Abidin, N,, Sinha, S,, Kalra, PA.. "Cardiac imaging in patients with chronic kidney disease". Nat Rev Nephrol. vol. 11. 2015. pp. 207-20.

Raggi, P,, Alexopoulos, N.. "Cardiac Imaging in Chronic Kidney Disease Patients". Semin Dial. vol. 30. 2017. pp. 353-360.

The following references represent advances in management of CVD in CKD and prevention of CIN:

Trivedi, H1,, Nadella, R,, Szabo, A.. "Hydration with sodium bicarbonate for the prevention of contrast-induced nephropathy: a meta-analysis of randomized controlled trials". Clin Nephrol. vol. 74. 2010. pp. 288-96.

Meier, P,, Ko, DT,, Tamura, A,, Tamhane, U,, Gurm, HS.. "Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis". BMC Med. vol. 7. 2009. pp. 23.

Rear, R,, Bell, RM,, Hausenloy, DJ.. "Contrast-induced nephropathy following angiography and cardiac interventions". Heart. vol. 102. 2016. pp. 638-48.

In addition to lifestyle modifications and blood pressure control, antiplatelet and lipid lowering therapy are the cornerstone for primary and secondary prevention of cardiovascular events in the general population and in patients with CKD. We added a dedicated section to antiplatelet therapy including the following references:

Jardine, MJ,, Ninomiya, T,, Perkovic, V,. "Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial". J Am Coll Cardiol. vol. 56. 2010. pp. 956-65.

Best, PJ,, Steinhubl, SR,, Berger, PB,. "The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial". Am Heart J. vol. 155. 2008. pp. 687-93.

Keltai, M,, Tonelli, M,, Mann, JF,. "Renal function and outcomes in acute coronary syndrome: impact of clopidogrel". Eur J Cardiovasc Prev Rehabil. vol. 14. 2007. pp. 312-8.

Franchi, F,, Rollini, F,, Angiolillo, DJ.. "Defining the link between chronic kidney disease, high platelet reactivity, and clinical outcomes in clopidogrel-treated patients undergoing percutaneous coronary intervention". Circ Cardiovasc Interv. vol. 8. 2015. pp. e002760.

Baber, U,, Mehran, R,, Kirtane, AJ.. "Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry". Circ Cardiovasc Interv. vol. 8. 2015. pp. e001683.

Leng, WX,, Ren, JW,, Cao, J,. "Chronic kidney disease--is it a true risk factor of reduced clopidogrel efficacy in elderly patients with stable coronary artery disease?". Thromb Res. vol. 131. 2013. pp. 218-24.

Barbieri, L,, Pergolini, P,, Verdoia, M,. "Platelet reactivity in patients with impaired renal function receiving dual antiplatelet therapy with clopidogrel or ticagrelor". Vascul Pharmacol. vol. 79. 2016. pp. 11-5.

Wiviott, SD,, Braunwald, E,, McCabe, CH,. "Prasugrel versus clopidogrel in patients with acute coronary syndromes". N Engl J Med. vol. 357. 2007. pp. 2001-15.

Wallentin, L,, Becker, RC,, Budaj, A,. "Ticagrelor versus clopidogrel in patients with acute coronary syndromes". N Engl J Med. vol. 361. 2009. pp. 1045-57.

James, S,, Budaj, A,, Aylward, P,. "Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial". Circulation. vol. 122. 2010. pp. 1056-67.

Bonaca, MP,, Bhatt, DL,, Cohen, M,. "Long-term use of ticagrelor in patients with prior myocardial infarction". N Engl J Med. vol. 372. 2015. pp. 1791-800.

Magnani, G,, Storey, RF,, Steg, G,. "Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial". Eur Heart J. vol. 37. 2016. pp. 400-8.

Morrow, DA,, Braunwald, E,, Bonaca, MP,, Ameriso, SF,, Dalby, AJ,, Fish, MP,. "Vorapaxar in the secondary prevention of atherothrombotic events". The New England journal of medicine. vol. 366. 2012. pp. 1404-13.

These references below pertain to SGLT2 inhibitors, the first antidiabetic drug class demonstrating superiority for cardiovascular outcomes, including patients with CKD and improvement in renal outcomes as well. This represents an extremely relevant advance in the diabetes space with repercussions on the management of diabetic kidney disease:

Neal, B,, Perkovic, V,, Mahaffey, KW,. "Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes". N Engl J Med. 2017.

Zinman, B,, Wanner, C,, Lachin, JM,. "Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes". N Engl J Med. vol. 373. 2015. pp. 2117-28.

This reference updates the section on risk stratification:

Hakeem, A,, Bhatti, S,, Chang, SM.. "Screening and risk stratification of coronary artery disease in end-stage renal disease". JACC Cardiovasc Imaging. vol. 7. 2014. pp. 715-28.

This reference adds to the evidence of ezetimibe in CKD:

Stanifer, JW1,, Charytan, DM,, White, J,. "Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function". J Am Soc Nephrol. 2017.

This reference pertains to the latest guidelines on lifestyle management to reduce CV risk:

Eckel, RH,, Jakicic, JM,, Ard, JD,. "2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. vol. 129. 2014. pp. S76-99.

This reference is added for the protein intake and worsening eGFR paragraph:

Knight, EL1,, Stampfer, MJ,, Hankinson, SE,, Spiegelman, D,, Curhan, GC.. "The impact of protein intake on renal function decline in women with normal renal function or mild renal insufficiency". Ann Intern Med. vol. 138. 2003. pp. 460-7.

**The original author(s) for this chapter was Dr. Raghu Durvasula. The chapter was revised by Drs. Simon C. Gaviria and Finnian R. Mc Causland.
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