Nephrology Hypertension

Chronic Kidney Disease: Cardiovascular Disease and Dyslipidemia

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

Chronic kidney disease (CKD) is a recognized and accepted major independent risk factor for cardiovascular disease (CVD), encompassing coronary disease, heart failure, stroke, peripheral vascular disease, and arrhythmia/sudden death. Both the National Kidney Foundation and American Heart Association have suggested that moderate CKD be considered a CHD risk equivalent.

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, and their odds ratio of dying during the hospitalization was 1.5 when compared to patients not on dialysis.

A number of factors may contribute to the underdiagnosis 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 disease. 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 acute coronary syndrome, 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 renal insufficiency. 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. 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 ESRD disease in the western world. While hypertension is highly prevalent amongst the CKD population, greater than 90% by stage 4, the majority of patients have not achieved target blood pressure goal. 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 implicated.

  • Chronic Inflammation: The chronic inflammatory state of CKD is notable for activation of key mediators including C-reactive protein, 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.

  • Anemia: a reduction in red blood cell mass is implicated in the structural heart disease and subsequent cardiovascular mortality in renal failure. 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.

  • Uric acid: While hyperuricemia is commonly associated with both chronic kidney disease and cardiovascular disease, whether it plays a causal role in disease pathogenesis is controversial. 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.

What tests to perform?

What lab 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 stage of CKD in a graded fashion. Given the risk of arrhythmia and sudden cardiac death, monitoring of serum electrolytes, in particular potassium, should be performed on as 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. 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 RAAS anatgonists and diuretics).

Hemoglobin

Anemia is a common finding with advancing CKD, affecting more than 50% of patients with stage IV disease. While iron deficiency is often a contributing factor, the anemia of CKD is due to deficiency of erythropoietin and reduced red blood cell half-life. Anemia of CKD is associated with cardiovascular dysfunction including left ventricular hypertrophy, worsening anginal symptoms, and over-all mortality.

Erythropoietin levels are not routinely checked and the diagnosis is made on empiric grounds after other causes of anemia have been excluded. There are not consensus guidelines regarding ongoing Hb monitoring in CKD, and the frequency should be tailored to the individual patient. In the setting of ESRD, monthly monitoring is performed per Medicare guidelines.

Serum phosphate

Regulation of PO4 balance within the body requires renal clearance of the absorbed dietary PO4 load. As GFR declines, the fractional excretion of PO4 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 PO4 homeostasis. When GFR falls to 30 ml/min, the compensatory mechanisms are 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 PO4 levels correlate with increased all-cause mortality in the dialysis population. Observational studies of patients with moderate CKD revealed that even modest increases in serum PO4 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) and cardiovascular death in clinical studies, monitoring FGF23 levels has not yet been implemented into routine clinical practice.

Serum calcium and intact PTH

Intact PTH and serum Ca++ 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 Ca++ with risk of CV events. Recently, in the MESA study, a longitudinal study of over 6000 patients without clinically evident cardiovascular disease at baseline, elevated iPTH levels was associated with a significant increase in left ventricular mass and incident heart failure. 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, PO4, and Ca++ levels, diurnal fluctuation of PTH 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 and affects up to half of all patients with CKD. 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

Degree 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 (GFR 45 – 59 ml/min), when compared to patients with absence of 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 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) causes regression of left ventricular hypertrophy in diabetic patients with preserved kidney function. 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 address this question.

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 seem to be clinically warranted.

Cardiac troponins

Cardiac troponins have been at the cornerstone for the evaluation and diagnosis of acute coronary syndrome in the general population, however, the utility of this enzyme test in the setting of renal disease has been challenging. Elevated troponin levels are a common finding in patients with underlying CKD and may be reflective of processes other than ischemic injury, including underlying structural heart disease or possibly impaired clearance mechanisms. A recent meta-analysis commission by the Agency for Healthcare Research and Quality (AHRQ) found that among dialysis patients without clinical evidence of an acute coronary syndrome, 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 further risk stratification or treatment strategies remains unclear. Recent studies suggest that high sensitivity cardiac troponin may improve the diagnostic accuracy of acute coronary syndrome in patients with CKD, particularly if the acute change from baseline levels is considered.

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

Prevalence of coronary artery disease in advanced CKD is substantial, affecting one third of incipient dialysis patients. However, 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

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. 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.

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. Beyond the high prevalence of ECG abnormalities at baseline, a number of non-cardiac factors may limit the utility of this modality, including deconditioning and such co-morbidities as arthritis or peripheral vascular disease.

Pharmacologic stress test

Dobutamine echo 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 echo remains the gold standard for coronary artery disease 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 echo. 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 myocardial infarction.

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 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 coronary artery disease (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 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 native 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 coronary artery disease (CAD) amongst patients with CKD, evidence-based guidelines as when to perform risk stratification are lacking. Recommendations for non-invasive risk assessment per the National Kidney Foundation are as follows:

  • pre-transplant evaluation if DM or high risk or known CAD

  • non-transplant candidates if high risk history of revascularization procedure > 3 years ago

  • ejection fraction < 40%

  • unexplained change in symptoms or clinical status

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

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

Administration of intravenous radiocontrast may result in acute kidney injury due to tubular dysfunction. The risk of contrast-induced nephropathy (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 biggest risk factors include pre-existing CKD at baseline, diabetes, elderly patients, intravascular volume depletion, concurrent use of NSAIDs, use of non-iso-osmotic agents, volume of dye load, multiple dye loads (within 48 to 72 hours of one another), and multiple myeloma.

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

Ensure that the patient is adequately volume expanded. Normosaline is the crystalloid most commonly used (1 ml/kg/hr for 6 -12 hours before and after the procedure, although longer infusion periods may be considered in the setting of more severe renal dysfunction). There is evidence that sodium bicarbonate may have further beneficial effect, perhaps by mitigating free radical-induced injury.

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 study.

The use of dialysis in pre-ESRD patients for removal of dye load is not routinely recommended for all patients. While preemptive dialysis may be considered in a subset of patients considered high-risk who have 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.

Management of cardovascular 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 nontraditional risk factors, disease pathogenesis, and outcomes.

The most widely utilized CV risk assessment, the Framingham Risk Model, does not take into account renal dysfunction. Consequently, its performance in the CKD population is suboptimal, significantly underestimating the rate of CV events at 5 and 10 years of follow-up. The clinical management of CV risk requires pharmacotherapy interventions, management of co-morbid conditions, and comprehensive lifestyle changes.

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. Aspirin use may be associated with an increase in minor and major bleeding complications, however, its risk may be outweighed by the benefits in reducing 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.

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 for all patients with CKD regardless of underlying etiology or presence of proteinuria.

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. An early drop in GFR of 20% is anticipated, 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. 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 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 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, suggesting 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 patients’ reported quality of life. Furthermore, use of erythrocyte stimulating agents is associated with a regression in ventricular mass amongst patients with left ventricular hypertrophy.

However, recent trials have cast serious doubt on the utility of recombinant erythropoietin and led to sweeping 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 achieve a hemoglobin of 13.0 g/dl versus placebo.

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. No differences were noted with regards to progression to end-stage renal disease, and 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 concentration of 10.0 to 12.0 g/dl is recommended. Prior to initiating ESA therapy, iron stores should be verified and repleted parentally if necessary. In the setting of systemic inflammation, use of ESA is questionable as inflammatory block will limit the clinical responsiveness. Dose escalation in this setting may worsen hypertension and increase risk of potential cardiovascular complications.

Proteinuria

Numerous studies have implicated proteinuria as an independent risk factor for both development of CVD as well as 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. Similarly with CVD, proteinuria may be a potential cofounder due to overlap with such comorbid conditions as hypertension or systemic inflammation known to promote CVD.

While a number of 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 intraglomerular 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. 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.

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.

A number of 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 trail to date, has provided some needed clarity to this issue.

Involving more than 9000 total patients with advanced CKD (GFR<60ml/min) and ESRD, subjects 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 versus 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.

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 indicated, 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. 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.

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. Current KDIGO recommendations is for hypertriglyceridemia (>500 mg/dl) in CKD patients (including those who have progressed to ESRD or have received a renal transplant) to be managed with therapeutic lifestyle changes only.

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, strategies to manage hyperphosphatemia seems prudent.

Adhering to a low PO4 diet is recommended and may be sufficient in early stages of CKD. However, pharmacotherapy is usually indicated with advanced stages of renal disease. While calcium-based PO4 binders taken with meals (calcium carbonate, calcium acetate) are efficacious in controlling serum PO4 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 PO4 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 preclude 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, suggests 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 needed 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 profile including reduced TG levels, and improvement in quality of life measures.

While exercise in this population 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 intraglomerular 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 intraglomerular 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 early CKD (GFR range of 55 ml/min to 90 ml/min), the odds ratio of having at least a 15% reduction in GFR was 3.51 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 diabetic patients demonstrated a benefit of protein moderation 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 intraglomerular capillary pressure, the slope of the rate of loss of GFR is actually significantly 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 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 mechanisms 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 reduction in relative risk of 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 per se 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 PO4 consumption. Oily fish such as salmon, which are emphasized in the heart healthy diet, have a much higher PO4 to protein ratio relative to other lean meats such as chicken. Other elements of the heart healthy diet also represent significant potential sources of PO4, 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 PO4 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 which 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 PO4 excretion, indicative of a significant increase in over-all PO4 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 PO4 is an insensitive and late manifestation of total PO4 burden. Dietary interventions to limit daily PO4 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 PO4 intake of ~800 mg seems reasonable, careful attention must be paid to hidden sources of PO4 in highly processed foods.

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 heart failure 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.

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 which 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 which excluded patients with significant kidney disease. 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

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