Abstract
Chronic kidney disease (CKD) is a public health dilemma contributing to increasing global morbidity and mortality. In the USA, CKD has increased from 12.7 %, noted in the National Health and Nutrition Examination Survey (NHANES) III (1988–1994), to 15.1 % in 2009 as reported in the United States Renal Data System (USRDS) annual report based on NHANES (2003–2006) data. CKD has also been found to be an independent risk factor for cardiovascular disease (CVD). The coexistence of risk factors such as diabetes mellitus, hypertension, and dyslipidemia illustrates this relationship and is associated with a wide range of metabolic and nutritional deficiencies that directly, or indirectly, lead to CVD (Chmielewski et al., Curr Opin Lipidol 20:3–9, 2009). Our understanding of the underlying pathophysiology of CKD has evolved in the past few decades and includes common pathways for CVD. Emerging evidence supports a complex interplay of traditional and nontraditional risk factors such as metabolic abnormalities and immune mechanisms in CKD that contribute to a higher incidence of CVD. This chapter will focus on the concepts of the pathophysiology of CVD in CKD and provide up-to-date recommendations of early identification of CKD and methods to decrease CVD mortality in high-risk subjects.
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Keywords
- Chronic Kidney Disease
- Glomerular Filtration Rate
- Chronic Kidney Disease Patient
- ESRD Patient
- National Kidney Foundation
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
4.1 Introduction
There is a strong relationship between chronic kidney disease (CKD) and cardiovascular disease (CVD) risk [1–3]. The increased risk for CVD in those with CKD is heightened in the presence of traditional Framingham CVD risk factors such as type 2 diabetes, hypertension, and dyslipidemia, and the ensuing CVD contributes to a more rapid progression to end-stage renal disease (ESRD), defined as glomerular filtration rate (GFR) <15 mL/min/1.73 m2 [4]. It should also be noted that the relationship between CKD and CVD events is a graded one, wherein there exists a strong linear relationship between diminishing GFR and increasing CVD events. In this context, there is an alarming trend wherein younger ESRD patients have an equivalent CVD risk equivalent to those above 65 years of age in the general population. Thereby, there is growing interest in CVD risk reduction strategies in earlier stages of CKD not only to reduce the CVD burden but also to reduce progression of CKD [5].
The mounting evidence of the kidney cardiovascular relationship prompted the National Kidney Foundation (NKF) task force on CVD in chronic renal disease to consider CKD as a coronary artery disease equivalent for the purposes of risk stratification [6]. Moreover, the work group also recommended considering patients with CKD in the “highest-risk group” for subsequent CVD events [6]. This recommendation was largely based on findings suggesting that, even after adjusting for most traditional Framingham risk factors for CVD, the higher mortality noted in CKD subjects from CVD suggests the possible contribution of uremia-related, nontraditional risk factors [7]. This has led to an understanding of a complex association of both traditional- and nontraditional-related CVD risk factors in CKD patients. To better delineate this dynamic disease process, this chapter will focus on the pathophysiology of CVD in CKD subjects along with early identification of CKD to prevent disease progression.
4.2 Epidemiology
CKD is an ongoing public health dilemma affecting approximately 24–28 million, with an estimated 20 million yet unidentified, with more than one million of them receiving some form of renal replacement therapy [8, 9]. According to the United States Renal Data System 2010 annual report (USRDS), the incidence of Medicare CKD in patients aged 65 or older was 4.3 % in 2008, an increase from 1.2 % seen in 1995. The prevalence of CKD patients among Medicare patients aged 65 and older is noted to be 7.6 %, a 4.6 times increase from the rate of 1.7 % seen in 1995. The rising incident and prevalent rates for CKD are paralleled by an increasing annual cost of Medicare ESRD program in the USA approaching approximately 20.8 billion dollars. The estimated annual Medicare cost to treat patients with CKD is 57.5 billion US dollars, thus contributing to 28 % of the total Medicare expenditure [10].
4.3 Definition and Classification of CKD
The Kidney Disease Outcomes Quality Initiative (NKF KDOQI) established clinical guidelines in 2002 for the definition of CKD for staging purposes that continue to be adapted. The diagnosis of CKD is based on the presence or absence of structural damage to the kidney and the level of kidney function, irrespective of the cause [11]. CKD is defined as either (a) kidney damage ≥3 months, as confirmed by kidney biopsy or markers of kidney damage as noted by the presence of structural or functional abnormalities such as abnormal blood, urine, or imaging studies, with or without decrease in GFR, or (b) GFR < 60 mL/min/1.73 m2 for ≥3 months with or without kidney damage [11]. Staging of CKD is based on the level of GFR; stage 1 = 90–120 mL/min/1.73 m2 and stage 2 = 60–90 mL/min/1.73 m2 both require the presence of abnormal urine or imaging studies, wherein stages 3–5 do not; stage 3 = 30–60 mL/min/1.73 m2; stage 4 = 15–30 mL/min/1.73 m2, and stage 5 < 15 mL/min/1.73 m2 is roughly equivalent to ESRD.
4.4 Pathophysiology of CKD
There are multiple risk factors that place individuals at risk for the development and more rapid progression of CKD, the most common of which are long-standing diabetes and hypertension. The pathophysiology of CKD involves a sequence of initiating events specific to the underlying etiology, leading to a set of common consequent mechanisms ultimately resulting in the reduction of renal mass and function. In those with diabetes, and to a lesser extent hypertension, there is an initial adaptive hyperfiltration mediated by elevation of glomerular capillary pressure and flow along with functional hypertrophy of the remaining nephrons. These initial adaptive responses eventually become maladaptive over a course of time and predispose to atrophy, fibrosis, and sclerosis of the remaining functional nephrons. There are numerous mechanisms that elicit the initial adaptive hyperfiltration and subsequent maladaptive tissue remodeling of nephrons such as inappropriate activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS) [12].
4.5 CKD as Risk Factor for CVD
As compared to age-matched control subjects without kidney disease, patients with CKD have increased CVD mortality even after adjusting for traditional CVD risk factors [10–14]. The strength of this association is driven by CKD patients with GFR < 60 mL/min/1.73 m2 who are at increased risk for CVD compared to those with an eGFR > 60 [13]. Further, approximately half of the mortality in ESRD patients has been attributed to heart disease [10]. However, it is important to note this is a graded, linear relationship that begins in the earliest stages of CKD with GFR approaching 120 mL/min/1.73 m2 and with proteinuria. The observation the majority of individuals do not reach the requirement of renal replacement therapy (e.g., dialysis or transplantation) due to the high CVD mortality has led to an increase in scientific exploration in prevention and detection strategies [15, 16]. It is known that individuals with CKD have a high prevalence of other disorders that independently are associated with poor CVD outcomes, such as the presence of diabetes and hypertension; reduced physical activity; and the presence of high concentration of inflammatory or oxidative biomarkers and deranged lipid parameters.
4.6 Traditional and Nontraditional CVD Risk Factors in CKD
The relationship between CKD and CVD is largely considered to be due to the occurrence of many common traditional Framingham risk factors such as hypertension, diabetes, dyslipidemia, and advancing age [17, 18]. However, there has been little information on successful CVD risk prediction with established equations in subjects with CKD, suggesting the presence of other risk factors that confer additional CVD risk in CKD. Uremia-related risk factors, the term first used by Sahart et al., refers to the risk factors that accumulate in CKD patients as a result of impaired renal clearance [19].
4.6.1 CKD and the Cardiorenal Metabolic Syndrome
Metabolic syndrome (e.g., cardiorenal metabolic syndrome) is a constellation of metabolic abnormalities including the presence of 3 or more clinical abnormalities such as hypertension, diabetes, atherogenic dyslipidemia, abdominal obesity, and albuminuria and/or diminished renal function that are associated with a pro-inflammatory and pro-thrombotic state. This constellation of metabolic and renal disorders is a risk factor for developing both CKD and CVD. Central to the metabolic dysregulation is inappropriate activation of RAAS [20, 21] and insulin resistance with the compensatory hyperinsulinemia that contribute to inflammation and oxidative stress and the development of endothelial dysfunction [17, 22–24]. Multiple cross-sectional [25, 26] and prospective studies [27] support the association between the cardiorenal metabolic syndrome and CKD. Furthermore, the risk for CVD-related outcomes in individuals with CKD increases incrementally with each component of the syndrome (e.g., hypertension, diabetes, obesity, and dyslipidemia) [28].
4.6.2 Role of Common Uremia-Related Comorbidities in the Pathogenesis of CKD-Related CVD
In addition to traditional Framingham CVD risk factors individuals with CKD possess intrinsic uremia-related risk factors such as mineral metabolism disorders, anemia, and increased levels of inflammatory and oxidative markers; abnormal apolipoprotein levels; elevated plasma homocysteine [6]; and enhanced coagulability that independently contribute to the development of endothelial dysfunction as a precursor to CVD risk [25–31].
4.6.2.1 Mineral Metabolism Disorders: Calcium and Phosphorus Metabolism
During the early stages of CKD, a diminution of 1,25-vitamin D3 formation and gut calcium absorption occurs leading to compensatory increase in parathyroid hormone (PTH). A compensated state of increased phosphorus concentration, normal serum calcium concentration, and low normal vitamin D3, along with mild to moderate increases in PTH, exists until GFR declines to <30 mL/min. As kidney disease progresses to end stage, increases in phosphorus concentration and decrease in vitamin D3 ultimately result in overt secondary hyperparathyroidism (2HPT) in the majority of individuals of CKD. Recent epidemiologic data has shown a strong clinical correlation between hyperphosphatemia and CVD mortality in ESRD patients, manifesting as vascular calcification [32]. A 41 % increase in relative risk of death from coronary artery disease has been noted with serum phosphate concentration greater than 6.5 mg/dL, as has 20 % increase in mortality from sudden death [33]. Further, increased serum phosphate concentration has been noted as an independent predictor for mortality in ESRD patients [34].
The sequential effects of disturbed mineral homeostasis are mediated by promotion of vascular calcification, bone resorption, and direct PTH toxicity [29, 32]. Hyperphosphatemia is considered a potent stimulant of intimal and medial calcification of blood vessels [35]. Intimal calcification involves formation of atherosclerotic plaque, which upon destabilization leads to an adverse cardiovascular event. On the other hand, medial calcification increases arterial stiffness, thus decreasing vascular compliance without compromising arterial lumen [36]. Numerous indices of arterial stiffness such as aortic pulse wave velocity and elastic modulus are noted to be strong independent predictors of CVD in ESRD patients [31]. This association between abnormal bone-mineral metabolism and increased vascular calcification has been suggested as the major uremia-related risk factor contributing to increased risk of CVD in CKD population.
4.6.2.2 Anemia
Anemia is thought to be a contributing risk factor for cardiac remodeling leading to the development of left ventricular hypertrophy (LVH), congestive heart failure (CHF), and CVD mortality [30]. The development of anemia starts early in CKD and is multifactorial. Indeed, decreased levels of erythropoietin, iron depletion, chronic inflammation, bone marrow fibrosis, and impaired erythropoietin response are a few common causes of anemia in individuals with CKD [37]. Two different studies conducted using the National Health and Nutrition Examination Survey (NHANES) III suggest the prevalence of anemia increases from 1 % at an eGFR of 60 mL/min/1.73 m2 to 9 % at an eGFR of 30 mL/min/1.73 m2 and to 33–67 % at an eGFR of 15 mL/min/1.73 m2 [38–40]. Data from NHANES and the NKF’s Kidney Early Evaluation Program (KEEP) support anemia in those 61 years and older with stage 3 or higher CKD [41].
Treatment of anemia with erythropoiesis-stimulating agents (ESAs) has shown to decrease LVH in CKD as well as ESRD patients on dialysis [42]. However, the use of ESAs remains controversial due to two randomized control trials, Correction of Hemoglobin and Outcomes in Renal Disease (CHOIR) [43] and Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) [44], studies which do not support improved outcomes among patients’ subgroups randomized to higher hemoglobin level. Further, treatment of anemia in hemodialysis patients with severe cardiac disease was associated with increased risk of death in the Normalization of Hemoglobin trial [45]. However, in another Canadian study, normalization of LV dilatation did not show any increased risk of mortality [46]. Further randomized control studies are needed to delineate whether correction of anemia, and to what level, has with CVD morbidity and mortality.
4.6.2.3 Hyperhomocysteinemia
An elevated plasma homocysteine level is considered an independent CVD risk factor in the general population [6]. There are numerous conflicting studies indicating a potential role for homocysteine in CKD and CVD mortality and morbidity. Homocysteine levels are persistently elevated in ESRD patients and also in patients with cardiac diseases. Another study suggests that the antioxidant drug acetylcysteine reduces plasma homocysteine level to normal range and is associated with improvements in endothelial dysfunction and CVD events when administered long term in patients undergoing hemodialysis [47]. However, it is unclear the role the diminished kidney function and clearance has to elicit this relationship. A recent study would suggest that elevations in plasma homocysteine levels may simply be a function of reductions in GFR [48]. Thereby, further long-term interventional studies are needed to better understand the role of homocysteine for CVD risk in CKD.
4.6.2.4 Inflammatory and Oxidative Stress
C-reactive protein (CRP) has been observed to be elevated in patients with kidney disease [49] and has been shown to be an independent predictor of CVD events in the general population [50]. Recent data would suggest CRP may be a marker for CVD in individuals with CKD undergoing renal replacement therapy with peritoneal dialysis, hemodialysis, or post-kidney transplant [51–54]. In earlier stages, CRP was also noted to be an independent predictor of CVD events in women with creatinine clearance <74 mL/min and with no underlying CVD [54], thereby suggesting a potential role for inflammation in the development of CVD in CKD. To further substantiate the role of inflammation in CVD, the use of aspirin is associated with CVD risk reduction directly related to CRP levels [50].
Oxidative stress has also been noted as an underlying mechanism for CVD in CKD potentially due to ongoing low-grade inflammation and impaired antioxidant mechanisms [55]. The strength of the association between the cardiorenal metabolic syndrome and CKD underscores the significance of oxidative stress due to metabolic dysregulation in the pathogenesis of CVD in CKD due to excess reactive oxygen species [56].
The evidence derived from numerous cross-sectional, population-based, and prospective studies supports the role of uremia-related risk factors in CVD in CKD. However, a direct relationship between intervention focusing on uremic, nontraditional risk factors and CVD risk reduction has yet to be established, and further large-scale randomized controlled trials are needed to verify these associations.
4.7 Screening and Detection
It is not known whether population-based screening of CKD is cost-effective. In a recent study, population-based screening for CKD with assessment of estimated GFR was found to be not cost-effective in subgroups with hypertension or older people. However, targeted screening of patients with diabetes was associated with cost-effectiveness [57]. Current practice guidelines promote early screening and detection of CKD patients in order to prevent the progression of kidney disease. Several initiatives like NKF-sponsored KEEP, National Institutes of Health (NIH) Healthy People 2010, and the National Kidney Disease Education Program (NKDEP) have emphasized educating patients as well as healthcare professionals about the positive impact of early screening and diagnosis. At this point, it is conventional wisdom that a concerted team effort by primary care physicians and subspecialists is necessary to tackle this public health dilemma [58].
The NKF Kidney Disease Outcomes Quality Initiative (KDOQI) recommends screening at-risk individuals for CKD using blood pressure, GFR estimation, urine albumin to creatinine ratio, urine analysis, and imaging studies of kidneys (in select at-risk individuals) [59]. Those identified as highest risk are individuals with diabetes, hypertension, autoimmune diseases, and patients recovering from an episode of acute renal failure or with family history of kidney diseases.
The most common indices used in clinical practice for evaluation of CKD are serum creatinine (sCr) as a marker for clearance and then estimating GFR as well as determination of proteinuria. Even though sCr is the most commonly used test in clinical practice to assess renal function, sCR may not be the most accurate in early stages of kidney disease when screening and detection are critical. There are multiple reasons including biologic, pharmacologic, and estimation misclassification. In this context, rises in sCr appear only after significant loss of functioning nephrons. Moreover, the generation of sCr is based on muscle mass and diet, and the excretion or secretion of sCr is influenced by drugs such as cephalosporins, aminoglycosides, cisplatin, cimetidine, and trimethoprim. However, estimating GFR may be the best available index for kidney function. The National Kidney Disease Educational Program (NKDEP) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and American Society of Nephrology (ASN) recommend estimating GFR from serum Cr by using either Modification of Diet in Renal Disease (MDRD) study equation or Cockcroft-Gault equation [60, 61]. Both equations take into account sCr along with age, sex, and weight variables thus minimizing the limitations of using sCr alone. However, there are limitations of the MDRD equation for estimation of GFR due to imprecision and systematic underestimation of GFR at higher levels [62]. Thereby, in 2009 a recent adaption for estimating GFR, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) [63], may overcome the limitations of MDRD in earlier stages for screening, detection, and classification of CKD.
Proteinuria is another accepted marker for kidney damage and serves as a guide for screening and detection for CKD especially in earlier stages. However, the presence of increasing levels of proteinuria in CKD is associated with a poor prognosis for both progression of CKD and the development of CVD [64, 65]. Thereby accuracy is important and measurement of albumin to creatinine ratio or total protein to creatinine ratio in untimed spot urine samples is widely accepted for assessment of proteinuria [4]. One of the earliest markers of kidney disease is microalbuminuria, defined as urinary albumin excretion between 30 and 299 mg/24 h. Annual screening allows early identification of CKD in those at highest risk and also serves as a prognostic tool [66].
4.8 Treatment
The treatment options for CKD patients are focused on risk factor reduction and interventions to prevent or slow the progression of CKD and importantly decrease risk for CVD-related outcomes. Treatment guidelines for risk factor reduction focus on blood pressure and glycemic control in CKD. Evidence supports that reduction in systolic blood pressure without decreasing albuminuria is insufficient in preventing the progression of CKD. Thereby, optimization of blood pressure with therapies targeting proteinuria should be a primary goal [67]. The reduction of proteinuria has shown protective effects in CVD risk in those with diabetic kidney disease [67]. Both the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) support the decreased risk of development of microalbuminuria and overt nephropathy with intensive glycemic and blood pressure control [68, 69]. However, the UKPDS further supports that blood pressure reduction may take precedence.
There is sufficient evidence to support utilizing interventions that target RAS that have shown to improve CVD-related outcomes and kidney-related outcomes in patients with or without diabetes [70]. The African American Study of Kidney Disease and Hypertension (AASK) addressed the optimal drug regimen for African Americans with hypertensive renal disease supported by the rationale that ACE inhibitors that improved renal outcomes [71, 72]. Moreover, the Lotrel and Enalapril in African Americans with Diabetes (LEAAD) study, conducted in African American patients with both hypertension and diabetes, concluded that combination therapy with ACE inhibitor/CCB (calcium channel blocker) was much better in achieving RAS blockade and BP reduction compared to monotherapy with ACE inhibitors [73].
4.9 Conclusion
Recent work has clearly established a strong relationship between CKD and an increased CVD risk. In this context, the relationship is a graded linear relationship beginning at the earliest stages of CKD, thereby highlighting the importance for detection of CKD early to improve kidney-related outcomes. Current recommendations by NKF and other societies classify individuals with CKD in the highest-risk group for CVD. Recent studies in CKD population have noted the concurrent presence of uremia-related risk factors along with traditional CVD risk factors leading to the development of CVD. However this association of uremia-related risk factors is yet to be conclusively proven to establish a causal relationship. In the clinical practice, CKD is a compelling indication for aggressive blood pressure control. However, additional risk factor reduction strategies in CKD patients should be pursued by clinicians.
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Buddenini, J.P., Chaudhary, K., Sowers, J.R., Whaley-Connell, A. (2014). Chronic Kidney Disease and Cardiovascular Risk. In: Obrosova, I., Stevens, M., Yorek, M. (eds) Studies in Diabetes. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4899-8035-9_4
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