	Despite the rising incidence of chronic kidney disease (CKD), this condition remains underrecognized and is costly to treat. Care of CKD accounts for a substantial portion of US Medicare spending, with major costs primarily associated with hospitalization and drug therapy. The leading cause of death and hospitalization in patients with CKD is cardiovascular disease (CVD). Strategies to improve identification of CKD have proved to be cost-effective in the highest risk patients (eg, those with diabetes), but determining the most appropriate way to identify high-risk patients remains a significant challenge. There is also evidence to suggest that referral to a specialist once the estimated glomerular filtration rate reaches approximately 60 mL/min/1.73 m2 is cost-effective, especially when patients are greater than 50 years of age and/or have diabetes. Individualized patient care has shown to be cost-effective (or even cost saving), and associated with improved outcomes, such as reduced incidence of CVD events and mortality. Individualized care centers treat numerous comorbidities (eg, hypertension, diabetes, albuminuria, dyslipidemia) in a given patient to prevent the downstream consequences of worsening CVD. Ensuring access to specialist care and effective therapies, along with adherence to such therapies, appears to be a cost-effective, or even cost-saving, strategy based on current available evidence.

An increasing public health concern, chronic kidney disease (CKD) is rising in incidence, from 10% of the US population between 1988 and 1994 to 13% 10 years later.

 CKD is associated with substantial morbidity and mortality. The leading cause of death in patients with CKD is cardiovascular disease (CVD), accounting for approximately 100 deaths per 1000 patient-years.

 CVD occurs as a direct effect of CKD and the contribution of commonly experienced CVD risk factors, such as diabetes, hypertension, dyslipidemia, and proteinuria. The contribution of numerous underlying comorbid conditions and high rates of hospitalization and CVD events (eg, stroke, myocardial infarction [MI], heart failure, hospitalization) result in a tremendous economic impact to the patient with CKD and the healthcare system.

 In one study, patients with CKD had 65% higher 10-year healthcare costs than non-CKD patients.

 Inpatient treatment and drug costs, but not outpatient costs, primarily accounted for these differences. Angina, MI, diabetes, and anemia also strongly influenced costs.

From a managed care perspective, the CKD population must be accurately identified. Patients should be assessed for needed treatment, and treatment should be delivered in an evidence-based, cost-effective way. Use of inappropriate or ineffective therapies should be minimized or eliminated when possible.

 Correct identification and early treatment of CKD is important because it is a progressive disease. Evidence from predictive modeling studies suggests that 11% of patients with a creatinine clearance less than 60 mL/min (stage 3 CKD) will eventually reach a creatinine clearance less than 15 mL/min (stage 5), and overall, 3.7% of patients will develop end-stage renal disease (ESRD) requiring dialysis or transplantation.

 This article will evaluate the importance of appropriately identifying patients with CKD and managing CVD risk to enhance quality and cost-efficiency of care in the CKD population.

Although patients with CKD comprise 6.8% of the US Medicare population, these individuals consume over 14% of overall Medicare expenditures.

 The overall Medicare cost per person per year for CKD was $19,752 in 2008. Costs in the subset of Caucasian patients with CKD and diabetes were $21,740, $25,352 for African American patients with CKD and diabetes, and $28,809 and $35,009 in respective heart failure cohorts with CKD.

 A review article examining costs of glomerular filtration rate (GFR) monitoring determined the annual medical costs in patients with and without CKD 65 years and older. In that paper, the average annual costs were $20,784 for all patients with CKD, $11,760 for patients with a creatinine clearance greater than 60 mL/min, and $68,808 for those with ESRD, indicating that the costs increase as kidney disease progresses.

 The review also determined that death was an important cost to consider in patients with CKD, and estimated the onetime cost of death at $37,611.

Chronic conditions (eg, obesity, hypertension, MI, angina, diabetes, dyslipidemia, anemia, and hyperuricemia) are also associated with an increase in cost of care in patients with CKD.

 The leading reason for hospitalization in patients with CKD is CVD.

 In addition to chronic costs associated with CKD and incident CVD, costs of dialysis initiation and maintenance are also major cost factors.

 To address the issue of the importance of comprehensive care in patients with CKD at risk for requiring dialysis, one study randomized 69 patients to nephrologist care and 71 patients to a CKD care program which included a nephrologist, trained nurses, and a dietitian with specific goals for patient education.

 The comprehensive program to improve pre-ESRD care was associated with lower total medical costs at dialysis initiation ($942 vs $2674; 

 <.001) due to early preparation for vascular access and avoidance of hospitalization at dialysis initiation.

 Providing specialized comprehensive care to patients with CKD is important because, in the US healthcare system, inappropriate care leads to unnecessary costs. A recent review noted that in managed care populations, unneeded or inappropriate care is delivered as much as 30% of the time, resulting in unnecessary costs. If resources were added to improve the frequency of appropriate care to more than the current value of approximately 50%, it would be possible to improve outcomes and reduce overall costs.

 Recognizing that care of the CKD population is often inappropriate, and that the costs of managing CKD are high, early identification and specialized management of CKD is likely to significantly reduce cost of care to the patient and the healthcare system.

As mentioned in the first article in this supplement,

 elevated serum creatinine is an indicator of reduced kidney function, but it is not a sensitive measure. GFR, a more accurate reflection of kidney function, is dependent on other factors (eg, sex, body weight/body mass, and ethnic background). Unfortunately, it is impractical to routinely measure GFR because of the complexity, expense, and time involved, so clinicians routinely estimate GFR in order to stage CKD and make treatment decisions. The Modification of Diet in Renal Disease and the CKD-Epi equations are most commonly used to estimate GFR by incorporating serum creatinine, age, sex, and race.

 Recent data have suggested that addition of other factors (eg, cystatin C, urinary albumin-to-creatinine ratio) improves estimation of kidney function and the consequent CVD risk.

 The value of these tests in practice remains to be determined, especially in settings where the incidence of CKD is unappreciated. Current clinical practice guidelines recommend recognition of CKD and appropriate treatment as early as possible, but there are a number of barriers.

 The remainder of this section will address attempts to improve recognition of CKD, and later sections will review the delivery of appropriate treatment.

One current barrier to appropriate CKD care is that CKD is underrecognized by primary care physicians and specialists.

 In one recent study of managed care patients with an estimated GFR of 10 to 60 mL/min/1.73 m

, only 14.4% had a documented CKD diagnosis.

 In a multivariate analysis, physicians were more likely to document CKD among patients of older age and lower estimated GFR (

 <.001 for each 10 mL/min incremental decline below 50 mL/min), but the presence of CVD, cerebrovascular disease, peripheral arterial disease, and heart failure did not improve recognition of CKD. CKD was also documented to a lower degree in women compared with men.

One intervention to improve CKD recognition was the implementation of mandatory reporting in certain states. In 2007, laboratories in Connecticut, Louisiana, Michigan, New Jersey, Pennsylvania, and Tennessee were mandated to automatically provide estimated GFR when a serum creatinine test was requested. In a study examining the cost and benefit of this approach, reporting estimated GFR was associated with a cost-effectiveness ratio (CER) of $16,751 per quality-adjusted life-year (QALY), while reporting serum creatinine alone had a CER of $16,779 per QALY.

 Simulations for a hypothetical cohort of 10,000 patients over 10 years estimated 13 fewer deaths,

 fewer ESRD events, and 11,348 more false positive CKD cases. The potential cost benefit of automatic estimated GFR was negated by the impact of a false positive test on QALYs.

 Because a spuriously low GFR could lead to unnecessary tests and treatments, and associated decline in QALYs, this practice of automatic reporting must be carefully considered by clinicians and policy makers with regard to how the test is interpreted. It is likely that action should be taken based on a trend over time, rather than based on an isolated value.

Another way to evaluate patients for CKD is to target screening in at-risk populations. A study determined the impact of population-based screening for CKD, as compared with screening of patients with diabetes or hypertension. The cost per QALY (2009 Canadian dollars) for population screening (vs no screening) was $104,900, with an expected decline in the number of patients developing ESRD from 675 to 657 per 100,000 patients. By comparison, the cost per QALY was $22,600 for diabetics and $572,000 for nondiabetics, $334,000 for patients with hypertension, and $411,100 for those without hypertension.

 These results suggest that screening of patients with diabetes for CKD is a cost-effective intervention.

Another study that evaluated annual microalbuminuria screening (beginning at 50 years of age) found a CER per QALY of $73,000 relative to nonscreening, and $145,000 relative to usual care. Usual care was defined as annual screening for 22% of diabetics, 2% of hypertensives, and 23% of patients with diabetes and hypertension. Relative to no screening, the CERs per QALY were $21,000 for diabetics, $55,000 for hypertension, and $155,000 for patients without diabetes or hypertension.

 These results indicate that strategies to improve identification of patients with CKD may be cost-effective (<$50,000 CERs per QALY), particularly in patients with diabetes.

When patients with CKD have been identified, care may be improved by referral to a specialist. The goal of identification of patients with CKD is to deliver the most appropriate treatment to prevent or treat comorbid conditions (eg, CVD) and to slow the progression of kidney disease. A systematic review summarized the cost-effectiveness (2006- 2007 pounds) of early referral strategies to a nephrologist to provide better kidney and cardiovascular care.

 In that review, the incremental CER per QALY relative to standard care ranged from £4091 (approximately $6750) for referral at CKD stage 3a to £5923 (approximately $9770) for referral at stage 4.

 A large part of the improvement in QALYs was attributed to improvements in CVD care. Based upon these findings, authors of the study recommended referral to a nephrology specialist as warranted under several circumstances including: (1) patients with stage 4 or 5 CKD; (2) when the albumin-creatinine ratio (ACR) is at least 70 mg/mmol and not due to diabetes; (3) when ACR is 30 mg/mmol with hematuria and rapidly declining GFR is observed; (4) poorly controlled hypertension despite 4 antihypertensive drugs; (5) suspected genetic cause of CKD; and (6) renal artery stenosis.

 It is also recommended that patients with renal outflow obstruction be seen by a urologist.

Articles on the managed care perspective of a disease often focus on prevention rather than treatment. In the case of CKD, many of the comorbid conditions are already present at baseline and remain prevalent throughout the disease.

 The goal of therapy is to limit the risk of hospitalization for acute events and delay disease progression. Recognition of CKD and assessment of CVD risk factors is critical to the prevention of ESRD, and delivery of the most appropriate treatments. In a previously mentioned managed care study,

 subjects documented by their caregiver to have CKD compared with those without documented CKD were more likely to receive appropriate care; 61% were more likely to use an angiotensin-converting enzyme inhibitor (ACEI) (

 <.0001), 67% were more likely to use an angiotensin receptor blocker (ARB) (

 = .008), 27% were more likely to use an HMG-CoA reductase inhibitor (statin) (

 = .0014), and 37% were less likely to use a nonsteroidal anti-inflammatory drug (

 <.0001). This indicates that the first step in delivery of appropriate management of CKD is the identification of the presence of CKD.

Recent evidence highlights that management of multiple risk factors may simultaneously increase quality of care and reduce cost of care. For example, random care for blood pressure (BP) will increase costs to prevent MI and stroke. Isolated treatment of BP according to Joint National Committee hypertension guidelines without regard to other risk factors may also lead to slightly higher costs to prevent MI and stroke. However, treating multiple CVD risk factors using patient-individualized guidelines can decrease overall costs with improved outcomes.

 These facts suggest that a comprehensive approach to the patient, rather than isolating treatment to a specific indication, or focusing on a single guideline, can be a more economically feasible approach to care. It is interesting to speculate that this concept may be applied directly to patients with CKD, but since study populations had very low risk of CKD, any related assumptions could not be determined.

 It stands to reason, however, that holistic evaluation and treatment of the patient and all associated problems will improve care, especially when treatment modalities can be used to treat multiple targets. Unfortunately, there are few formal cost-effectiveness studies of interventions to improve CVD outcomes in patients with CKD.

Despite a lack of formal intervention studies prospectively designed to evaluate the outcomes associated with treatment of CVD risk factors in patients with CKD, much has been learned from studying the relationship between treatment and outcomes based on CKD markers, such as GFR and albuminuria. In hypertension associated with CKD, treatment of albuminuria should be considered an integral part of care. In one study lasting approximately 5 years in 8206 patients with left ventricular hypertrophy, use of the ARB losartan to lower BP and albuminuria reduced the composite end point of cardiovascular mortality, stroke, and MI (independent of BP reduction).

 Evidence suggests that the goal BP in patients with CKD should be less than 130/80 mm Hg unless proteinuria exceeds 1g/L, in which case it should be less than 125/75 mm Hg.

 In another study which sought to determine the effect of trandolopril on survival where BP reduction was studied in the absence of documented albuminuria, the ACEI trandolopril did not improve survival in the overall cohort with relatively normal GFR.

 In a subgroup analysis of patients with GFRs less than 60 mL/min/1.73 m

, reduction of BP with trandolopril decreased cardiovascular and all-cause mortality (

 Finally, in a formal, 7-year economic analysis conducted on the ACEI benazepril for blood pressure control,

 the CER per QALY demonstrated reduced cost ($10,000-$13,000) over the course of the study, due to improvements in outcomes (

). These results suggest that ACEI therapy in CKD (GFR <60 mL/min/1.73 m

) may improve cardiovascular outcomes and result in cost savings.

It should be noted, however, that despite nearly universal awareness of hypertension, adequate control of BP in accordance with current consensus standards remains highly suboptimal. 24 A recent study was conducted to determine community-based factors associated with awareness of hypertension, treatment patterns, and control rates using multivariable statistical adjustment. The study evaluated factors associated with BP control and lack of BP control in patients with a GFR of 20 to 70 mL/min/1.73 m

, and found that ACEIs and ARBs were associated with enhanced BP control. Older patients, African Americans, and those with higher urinary albumin excretion were less likely to achieve BP control after multivariable adjustment.

 In light of these findings, it is interesting to speculate that the lack of BP control in patients with CKD, or lack of ACEI and ARB therapy, may potentially be due to concerns among clinicians that ARBs and ACEIs are associated with GFR reductions and the risk of acute kidney injury.

 Because of the documented benefits of ACEIs and ARBs in hypertension, diabetic nephropathy, heart failure, and coronary artery disease (CAD), these agents should be used with caution rather than avoided in patients with CKD.

The impact of ACEIs and ARBs on reduction of GFR is also commonly considered a therapeutic tool for management of proteinuria associated with diabetes. ACEIs and ARBs are the most well-studied agents for prevention of progression of CKD in diabetes, and they have also been studied extensively for their effects in CVD.

 In 2 large diabetic nephropathy studies, despite slowing progression to ESRD, losartan and irbesartan failed to improve cardiovascular outcomes or death, suggesting a potential inadequate followup period to assess effects (or lack of effects) on CVD.

 Clearly, patients with CKD and diabetes should be managed with a patient-specific, customized approach (rather than given a specific agent) due to the frequent presence of concomitant hyperglycemia, dyslipidemia, and hypertension.

 In an economic evaluation examining the cost-effectiveness of a multifactorial approach to reducing CVD in diabetes, patients were randomized to the Diabetes Care Protocol (DCP) or usual care.

 The DCP consisted of a 1-hour consultation by a practice nurse and computerized decision support software assessment that provided patient-specific advice (on targets for glycosylated hemoglobin, blood pressure, body weight, cholesterol, and smoking) and feedback to the practice and patient every 3 months. The incremental CER was €38,243 ($55,307) per QALY in the overall population. In patients with CVD, the CER was €14,814 ($21,424) per QALY, and the CVD costs were reduced by €587 ($849) (

 <.05). In contrast, the CER per QALY for diabetic patients without CVD was €121,285 ($175,402). It should be noted that this study did not specifically address patients with CKD, but did demonstrate that diabetic patients with CVD could be treated in a cost-effective, and potentially cost-saving, manner using a comprehensive intervention.

A Cochrane review evaluated the effects of statins in patients with CKD who did not require dialysis.

 The evaluation consisted of 25,017 patients from 26 studies, and demonstrated a statin-induced reduction in low-density lipoprotein cholesterol (-42.38 mg/dL), total cholesterol (-41.48 mg/dL), all-cause death (19% reduction), cardiovascular death (20% reduction), and 24-hour urinary protein excretion (-0.73 g/24 hours). Statins appeared to be well tolerated, with associated adverse effects similar to those in controls.

 The therapeutic benefits observed in the Cochrane review are consistent with recent trials.

 In the absence of well-designed cost-effectiveness studies, it may be inferred that statins, with their established benefits and tolerability, appear to be a worthwhile intervention for patients with CKD and dyslipidemia or CVD.

To a similar extent, evidence on the cost-effectiveness of interventions for CAD, MI, and heart failure in patients with CKD is lacking.

 However, similar trends are noted— standard therapies are effective, but they are underutilized.

), standard therapies for MI (eg, ACEIs, ARBs, beta-blockers, aspirin, statins) are underutilized in patients with CKD, despite current evidence supporting their use in the presence of CAD or heart failure.

Efforts to improve adherence are another important consideration in the treatment of CVD in CKD. In a 2007 survey of patients with Medicare Part D prescription drug plans, 23% to 31% of patients with ESRD reported cost-related nonadherence to prescription medication in the preceding 6 months, and patients with ESRD (vs those without ESRD) were 2.34-fold more likely to report cost-related nonadherence.

 African Americans and patients with Medicare Part D Low-Income Subsidy assistance had higher rates of cost-related nonadherence in the multivariate analysis.

 Any treatment decisions should include an assessment of the patient’s ability to pay, as well as the availability of well-tested, less costly generic options, especially when the regimen may be complicated and involve multiple medications.

In another study evaluating a privately insured population, patients taking medication for hypertension, dyslipidemia, and/or diabetes between 2004 and 2008 were evaluated for adherence (days per year covered by filled prescription).

 In that study, adherence (defined as a medication possession ratio of 80% or more) was highest with medications for diabetes, followed by agents for hypertension and dyslipidemia. Interestingly, adherence was highest among patients taking the most medications (ie, those treated for all 3 conditions).

 Enhanced compliance when multiple conditions are treated supports the theory that recognition of disease improves delivery of treatment. This is especially important for patients with CKD because they tend to have multiple comorbidities and consequently require numerous medications. The suggestion that taking more medications results in better compliance is encouraging, because it may mean that if patients with CKD can be identified, they can be partners in their care with more adequately followed therapeutic regimens.

In patients with CKD, the key factor associated with delivering the most effective therapy is correctly identifying patients. However, in practice, identification of patients with CKD has proved to be a challenge for clinicians. Strategies to improve identification of CKD, such as mandatory GFR reporting and promotion of annual screening, are increasing awareness and have proved to be cost-effective in at least a subset of those at greatest risk for complications (eg, those with diabetes). Based on limited formal economic analyses in the CKD population, it appears that interventions which target CVD risk factors, such as hypertension, albuminuria, dyslipidemia, and diabetes, are effective in lowering CVD events and mortality. These therapies may be cost-effective or even cost saving, due primarily to the high costs associated with CVD hospitalization and death, and the cost savings associated with avoiding these events. Additional considerations to improve care include ensuring appropriate access to affordable medications, and eliminating inappropriate or ineffective therapies which may negatively impact therapeutic outcomes and lead to higher overall healthcare costs.

 The author would like to thank A. Scott Mathis, BS, PharmD, for editorial assistance in the preparation of the manuscript. A. Scott Mathis, BS, PharmD, has no relevant affiliations or financial relationships to disclose related to this activity.

 Northeastern University Bouvé College of Pharmacy and Allied Health Sciences, Boston, MA, and MedMetrics Health Partners, an SXC company, Worcester, MA.

 This activity is supported by an educational grant from Merck & Co, Inc.

 Mr Calabrese has no relevant financial relationships to disclose related to this activity.

 Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

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Articles

ARTICLES

Management of Cardiovascular Disease in Chronic Kidney Disease: Implications for Managed Care

	The prevalence of chronic kidney disease (CKD) is rising in the United States, and cardiovascular disease (CVD) is increasingly recognized to occur at elevated rates in patients with CKD compared with the general population. The impact of CVD in patients with CKD is significant, inversely related to the level of kidney function, and exaggerated when compared with matched patients without CKD. CKD is associated with an increased risk of CVD, CVD events, and death, but the prevalence of traditional CVD risk factors is also increased compared with the general population. Proteinuria, hypertension, dyslipidemia, and diabetes are common in patients with CKD and contribute directly to CVD events. CKD-related factors (eg, disorders of electrolyte and mineral metabolism, anemia, and vascular calcification) also contribute to mortality associated with CKD.

Chronic kidney disease (CKD) is characterized by decreased kidney function, as determined by the glomerular filtration rate (GFR), or kidney damage (with or without proteinuria). CKD is staged according to the level of GFR, with stage 1 representing the highest level of kidney function (GFR >90 ml/min/1.73 m

) and stage 5 representing the lowest level of kidney function (GFR <15 ml/ min/1.73 m

). Recent evidence indicates that the prevalence of CKD is increasing in the United States.

 Coresh and colleagues evaluated the National Health and Nutrition Examination Surveys data and were able to demonstrate that the prevalence of albuminuria and decreased GFR increased from 1988 to 1994 and from 1999 to 2004.

 Furthermore, the prevalence of CKD (stages 1 to 4) increased from 10% (95% confidence interval [CI], 9.2%-10.9%) in 1988-1994 to 13.1% (95% CI, 12%-14.1%) in 1999-2004. The mean serum creatinine was also higher in the second cohort.

 Although increased serum creatinine is an indicator of reduced kidney function, it is not a sensitive measure, since GFR (which directly impacts serum creatinine) is dependent on other factors, such as age, sex, body weight/body mass index, and race. Since routine measurement of GFR is impractical (due to complexity, expense, and involved time), clinicians routinely estimate GFR, using equations such as the Modification of Diet in Renal Disease (MDRD) and more recently, the CKD-Epi formula, to stage CKD.

 These equations include serum creatinine, age, sex, and race to estimate GFR with very good precision.

 It is important to note that many cardiovascular trials have excluded patients with known CKD, usually by establishing a serum creatinine level cutoff. As such, data on CKD have been inferred from these trials, usually by post hoc analysis based on GFR estimates among patients who were included in the trial.

End-stage renal disease (ESRD) is loosely defined by signs and symptoms of kidney failure, a GFR less than 15 mL/min/1.73 m

, and the requirement for renal replacement therapy (usually dialysis).

 The leading cause of death in patients with ESRD has long been recognized as cardiovascular disease (CVD), which occurs in more than 50% of patients.

 CVD is also the leading cause of hospitalization among patients with ESRD.

 Evidence also suggests that other stages of CKD are associated with increased cardiovascular risk, and this article will examine the relationship between CVD and CKD.

 This supplement will describe the link between CKD and CVD, the treatment of CVD in CKD, and the impact on managed care.

A recent publication correlated the stages of CKD to the approximate odds ratios (ORs) of CVD based on a thorough literature review (

 As shown in Table 1, compared with a population without CKD, a graded inverse relationship between CKD and CVD was identified, where the lower the degree of kidney function, the higher was the risk of CVD. This relationship was noted to be approximate and affected by patient age.

 A review of results from several of these studies is warranted, since the relationship between CVD and CKD is varied across populations, and CVD is a broad term with multiple potential contributing factors.

One landmark study evaluated 1,120,295 subjects (from a database owned by Kaiser Permanente) for age-standardized death, cardiovascular events, and hospitalization per 100 person-years relative to various levels of GFR over approximately 3 years.

 Cardiovascular events were defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, and peripheral arterial disease; results appear in 

. For all studied events, a clear association between the age-standardized rate of outcome and degree of kidney function was noted. As GFR fell below 60 mL/min/1.73 m

, the rate of death, cardiovascular events, and hospitalization increased in graded fashion.

 Another study compared pooled data from community-based trials (including the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study) among patients with a GFR of 15 to 59 mL/min/1.73 m

 to those with a GFR of at least 60 mL/min/1.73 m

 The composite outcome (myocardial infarction [MI]/fatal coronary heart disease [CHD], stroke, or all-cause mortality) occurred in 30.1% of patients in the lower GFR group and in 13.2% of those in the higher GFR group. Moreover, all components of the combined end point were more frequently experienced in the lower GFR group (MI/fatal CHD, 10.1% vs 5.3%; stroke, 7.5% vs 2.8%; all-cause mortality, 23% vs 8.1%). The risk of MI/fatal CHD or all-cause mortality, but not stroke, was higher in African Americans than in Caucasians.

In a secondary analysis of a 15-year follow-up of the Framingham Heart Study, CVD and mortality was evaluated in male patients with baseline serum creatinine value of 1.5 to 3 mg/dL, and in female patients with baseline serum creatinine value of 1.4 to 3 mg/dL (reduced GFR), and compared with patients with lower (“normal”) serum creatinine levels.

 The rates of CVD events and mortality were higher in men than women, but the rate of CVD (adjusted for body mass index, systolic blood pressure, hypertension treatment, diabetes, smoking, total cholesterol, prevalent CVD, cardiac medications, and left ventricular hypertrophy on electrocardiogram) did not differ between men and women relative to the “normal” serum creatinine groups. Adjusted all-cause mortality was higher in men with reduced GFRs versus “normal” serum creatinine values, but this effect was not demonstrated in women. Interestingly, the prevalence of hypertension, diabetes, elevated total cholesterol, low high-density lipoprotein (HDL) cholesterol, and body mass index at or above 27.8 were statistically higher in women with reduced GFRs versus those with “normal” serum creatinine values. Only the prevalence of diabetes, low HDL cholesterol, and body mass index at or above 27.

 were statistically higher in men with reduced GFRs versus those with “normal” serum creatinine values. Smoking was less prevalent in women and men with reduced GFRs, as compared with those with “normal” serum creatinine values.

 The results of this study suggest a high prevalence of CVD risk factors among patients with CKD, but also point out the potential pitfalls of using serum creatinine values as a marker for kidney function.

Disease Factors Contributing to CVD in CKD

Urinary albumin excretion, an indicator of kidney damage and a risk factor for progression of kidney disease, is known to be associated with an increased risk of CVD events in the general population,

 and established atherosclerotic disease.

 A prospective, population-based cohort study of 16,958 patients conducted in Iceland compared patients with estimated GFRs of at least 90, 75 to 89, and 60 to 74 mL/min/1.73 m

 without proteinuria (no CKD) to patients with proteinuria and GFRs of at least 90 (stage 1 CKD) and 60 to 89 (stage 2 CKD), and patients with CKD and GFRs of 45 to 59 (stage 3a), 30 to 44 (stage 3b), or 15 to 29 mL/min/1.73 m

 The primary end point of CHD or nonvascular mortality was adjusted for age, sex, smoking status, diabetes, total cholesterol, triglycerides, systolic blood pressure, and body mass index. The risk/hazard ratios were compared with the reference group (GFR 75-89 mL/min/1.73 m

 without proteinuria). Although the highest risk of CHD was present in patients with stage 3b and 4 CKD, there was a significant 1.55-fold increase in the risk of CHD in those with a GFR of at least 90 mL/min/1.73 m

 with proteinuria (stage 1 CKD), and a significant 1.72-fold increase in risk of CHD in those with a GFR of 60 to 89 mL/min/1.73 m

 with proteinuria (stage 2 CKD), relative to the reference group without proteinuria. Nonvascular mortality increased significantly only in those with stage 3b or 4 CKD.

 An evaluation of the Third Copenhagen City Heart Study linked CHD or death at 7 to 9 years follow-up to a baseline overnight urinary albumin excretion rate. Urinary albumin excretion of greater than 4.8 μg/min during the overnight sample (or about 6.4 μg/ min during daytime) was a strong predictor of CHD or death independent of renal function, hypertension, or diabetes.

 Taken together, these results further highlight the important role of CVD in patients with CKD, and the direct impact of albuminuria/proteinuria. Proteinuria is usually assessed in practice by urine albumin to creatinine ratio or urine protein to creatinine ratio.

The Joint National Committee 7 report on blood pressure regards microalbuminuria or an estimated GFR less than 60 mL/min/1.73 m

 as risk factors for CVD, and CKD as a target-organ consequence of hypertension.

 Fluid retention and other factors may contribute to hypertension in CKD, and hypertension contributes to development of left ventricular hypertrophy, MI, angina, heart failure, stroke, and peripheral arterial disease.

 Assessment of the baseline incidence of risk factors for CVD, such as hypertension, in community-based studies is an important way to determine their frequencies in the population (

 According to 2008 data from the US Renal Data System (USRDS), hypertension was present in 91.4% of patients with advanced CKD, and was more common in African Americans (96%) than in Caucasians (90.7%).

 Elevated serum creatinine levels in patients with hypertension have long been recognized as a significant risk factor for death.

 A post hoc analysis of the Heart Outcomes and Prevention Evaluation (HOPE) trial also evaluated cardiovascular outcomes according to baseline serum creatinine value and presence or absence of hypertension.

 In the placebo group, the primary outcome (cardiovascular death, MI, or stroke) was affected by serum creatinine concentration at study entry. Compared with hypertensive individuals having a serum creatinine value less than 1.4 mg/dL, hypertensive patients with a serum creatinine value of at least 1.4 mg/dL had higher primary cardiovascular end point rates (approximately 45 events per 1000 person-years vs 65 events per 1000 person-years). The respective rates in normotensive subjects were approximately 35 events and 60 events per 1000 person-years. Interestingly, the rates of CVD events were similar in the higher serum creatinine level group regardless of the presence of hypertension at baseline.

 A post hoc analysis of the Hypertension Optimal Treatment study evaluated cardiovascular events in hypertensive patients according to baseline serum creatinine value and GFR.

 Major cardiovascular events (defined as nonfatal MI, nonfatal stroke, and all cardiovascular deaths) were evaluated according to serum creatinine value (≤1.5 mg/dL or >1.5 mg/dL) and creatinine clearance (>60 mL/min or ≤60 mL/min). Major cardiovascular events, cardiovascular mortality, and total mortality were predicted by serum creatinine values greater than 1.5 mg/ dL (vs ≤1.5 mg/dL). However, major cardiovascular events, cardiovascular mortality, total mortality, and stroke were seen with lower GFRs. These results highlight the differences in outcomes when assessing kidney function through GFR estimation versus serum creatinine level.

According to USRDS 2008 data, diabetes mellitus is prevalent in patients with CKD, occurring in 48.2% of patients with stage 1 or 2 disease and in 49.4% of those with stage 3 to 5 disease.

 A post hoc analysis of the previously mentioned HOPE trial also evaluated cardiovascular outcomes according to baseline serum creatinine level and presence or absence of diabetes.

 In the placebo group, the primary outcome (cardiovascular death, MI, or stroke) was affected by serum creatinine concentration at study entry. Compared with diabetic individuals having a serum creatinine less than 1.4 mg/dL, those with a serum creatinine of at least 1.4 mg/dL had higher primary end point rates (approximately 45 events per 1000 person-years vs 85 events per 1000 person-years, respectively). The respective rates in nondiabetic subjects were approximately 35 events and 50 events per 1000 person-years.

 When compared with the outcomes based on the presence or absence of hypertension noted in the section above, patients with diabetes and a higher serum creatinine level tended to have worse outcomes than those with hypertension and a higher serum creatinine level. However, among patients with lower serum creatinine values, those without diabetes and hypertension appeared to have similar risk.

Improving Outcomes in Chronic Kidney Disease: Optimizing Management of Cardiovascular Diseases [CME/

Management of Cardiovascular Disease in Chronic Kidney Disease: Implications for Managed Care

Recognizing the Link Between Chronic Kidney Disease and Cardiovascular Disease

Optimizing Outcomes in Patients With Cardiovascular Disease and Chronic Kidney Disease

Participating Faculty: Improving Outcomes in Chronic Kidney Disease: Optimizing Management of Cardiovascular Diseases

Improving Outcomes in Chronic Kidney Disease: Optimizing Management of Cardiovascular Diseases