Authoritative Review

Epidemiology and Mechanisms of Uremia-Related

Cardiovascular Disease
Marcello Tonelli, MD, SM; S. Ananth Karumanchi, MD; Ravi Thadhani, MD, MPH

Abstract—Patients with chronic kidney disease and end-stage renal disease are at 5- to 10-fold higher risk for developing
cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery
disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and
hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD.
In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus
on postulated mechanisms of the latter. In the context of current and emerging diagnostics and therapies for CVD, we
highlight what we interpret as major gaps in the medical management of this growing population that need to be addressed
with targeted epidemiological and translational research. Finally, we describe the global challenges associated with the
recognition and management of uremia-related CVD in developed and developing nations. (Circulation. 2016;133:518-536.
DOI: 10.1161/CIRCULATIONAHA.115.018713.)

Key Words: dialysis ◼ heart diseases ◼ kidney diseases ◼ stroke

We must call attention to the cardiac symptoms…. of CVD among people with CKD, noting the limitations of
Almost always death comes from uraemic accidents, available research. We then discuss common risk factors for
which may assume two principal forms, pulmonary CVD (traditional and nontraditional) and key shared aspects
and cerebral. In the pulmonary form the patient is of its pathophysiology with CKD. Next we describe emerging
seized by paroxysmal dyspnoea, which comes espe- diagnostic tools and novel therapies that may help to delay
cially at night, and which may be accompanied by pul- or prevent end-stage renal disease (ESRD) and to curtail the
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monary congestion, with expectoration of rust-­colored escalating burden of cardiorenal disease. In the final section,
sputum. This dyspnoea may lead to the death of the we discuss the health services and health policy challenges
patient. The cerebral form is much more frequent. A that CKD and its inextricably linked CVD morbidities pose
number of patients show symptoms of cerebral apo- worldwide, particularly for low- and middle-income countries
plexy, together with hemiplegia, and die comatose. (LMICs).
P. Jousset, MD,1 describing common causes of death
among patients with Bright disease
Phenotypes and Epidemiology of
CVD in Patients With CKD
C hronic kidney disease (CKD) is an increasingly urgent
public health concern that is projected to grow worldwide
at a rate of 8% annually, with the fastest growth expected in
Patients with CKD and some forms of CVD share a number
of risk factors and underlying pathophysiological mecha-
nisms that, by virtue of their similarities, offer opportunities
developing nations.2,3 It has long been known that patients to improve their management. The epidemiology of 4 of the
with kidney failure are predisposed to cardiovascular disease commonest clinical phenotypes of CVD associated with CKD
(CVD) that manifests clinically in various forms, including is discussed below.
coronary artery disease, atrial or ventricular arrhythmias,
myocardial infarction, stroke, or congestive heart failure. Over Coronary Artery Disease
the last 30 years, it has become clear that the risk of CVD Coronary artery disease (CAD) is a leading cause of death
increases early in the course of progressive kidney disease and among people with advanced CKD. Clinical syndromes
that the epidemiology, pathophysiology, prevention, and treat- compatible with CAD (including angina and myocardial
ment of CVD and CKD are closely related and interdepen- infarction) are exceedingly common in patients with non–
dent.4 In this review, we initially describe the epidemiology dialysis-dependent CKD, and the incidence of myocardial

From Department of Medicine, University of Calgary, AB, Canada (M.T.); Department of Medicine and Obstetrics and Gynecology, Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston, MA, and Howard Hughes Medical Institute, Chevy Chase, MD (S.A.K..); and Division of
Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston (R.T.).
Correspondence to Marcello Tonelli, MD, SM, University of Calgary, 7th Floor, TRW Bldg, 3280 Hospital Dr NW, Calgary, AB T2N 4Z6, Canada.
E-mail [email protected]
© 2016 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.115.018713

518
 Tonelli et al   Uremia-related CVD   519

infarction increases at lower levels of estimated glomeru- 68.3% in otherwise similar patients without a history of kidney
lar filtration rate (eGFR) and more severe albuminuria5,6 failure.12 Cardiac troponin levels are more likely to be chroni-
(Figure 1). Interpretation of the epidemiology of CAD is cally elevated in people with kidney failure than in the general
complicated by the frequent coexistence of CKD and diabe- population,13 emphasizing the importance of searching for a
tes mellitus because the latter is also a predisposing factor for temporally appropriate rise and fall of these biomarkers when
cardiac events. However, even modest impairment of eGFR considering the possibility of acute coronary syndrome.14
(without diabetes mellitus) is associated with an increased Existing epidemiological data related to CAD are limited
risk of myocardial infarction that is similar to or exceeds that by the considerations above and by the relatively poor predic-
associated with diabetes mellitus alone.7 Among people with tive performance of exercise stress testing, radionuclide per-
both albuminuria and eGFR<45 mL·min−1·1.73 m−2, the rate fusion imaging, and stress echocardiography in people with
of coronary events is substantially higher than that associ- advanced CKD.15–17 At least in the relatively healthier subset
ated with diabetes mellitus alone (12.4 per 1000 person-years of patients with advanced CKD who are potential candidates
[95% confidence interval (CI), 9.7–15.9] versus 6.6 per 1000 for kidney transplantation, stress echocardiography appears to
person-years [95% CI, 6.4–6.9] respectively.)8 The risk among be associated with higher sensitivity and specificity for critical
people with both CKD and diabetes mellitus is comparable to coronary disease than radionuclide perfusion imaging.15
that among people with prior coronary disease.8 Such findings Because of the known limitations of death certificate infor-
have led to the suggestion that individuals with CKD (with or mation,18 the true incidence and prevalence of CAD are uncer-
without diabetes mellitus) should be considered at very high tain, especially among patients with ESRD. Clearly, the case
risk of future coronary events.9 fatality rate after myocardial infarction is markedly elevated for
Unfortunately, acute coronary syndromes can be challeng- both dialysis-dependent19 and non–dialysis-dependent8 CKD
ing to diagnose in people with severe CKD because chest pain patients compared with people with normal kidney function.
and diagnostic electrocardiographic changes are less common
than in the general population10 and because the prevalence Ventricular and Atrial Arrhythmias
of these clinical clues among people with acute coronary Sudden cardiac death (SCD) is defined as any sudden, unex-
syndromes decreases in parallel with eGFR decline.11 For pected death of cardiac cause, generally occurring without much
example, one study found that chest pain accompanied acute (if any) warning. As others have noted,20 whether death is unex-
coronary syndrome among 44.4% of dialysis patients versus pected in dialysis patients given their very high burden of illness
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A B

C D

Figure 1. Relationships between cardiac events and loss of life expectancy resulting from cardiovascular disease (CVD) by stage of
chronic kidney disease (CKD). A and B, The adjusted relative rate of all-cause mortality (ACM) and acute myocardial infarction as a func-
tion of glomerular filtration rate (eGFR; mL·min−1·1.73 m−2) and severity of albuminuria as assessed by albumin-to-creatinine ratio (ACR;
normal, ACR <30 mg/g; mild, ACR 30–300 mg/g; or heavy, ACR >300 mg/g). C and D, Adjusted loss of life expectancy resulting from
CVD by CKD stage. Loss is compared with life expectancy in people with normal or mildly impaired kidney function (stage 1–2, eGFR ≥60
mL·min−1·1.73 m−2) and normal or mildly increased albuminuria (stage 1, ACR< 30 mg/g). RRT indicates renal replacement therapy. C and
D are reproduced from The Lancet, Gansevoort et al7 with permission from the publisher. Copyright © 2013, Elsevier.
 520  Circulation  February 2, 2016

can be difficult to ascertain. In clinical practice, determination hypertension and CVD), excessive inflammation, atrial and
of SCD requires either a witnessed collapse (with or without ventricular hypertrophy, activation of the renin-angiotensin
electrocardiographic evidence of serious ventricular arrhythmia) pathway, and disorders of mineral metabolism. Reported
in an individual who subsequently dies or, after an unwitnessed estimates of the prevalence of atrial fibrillation in cohorts of
death with no other obvious explanation, recent (ie, within 24 non–dialysis-dependent CKD patients range from 8% to 18%
hours) observation of the decedent in his or her usual state of compared with 0.4% to 1.0% in the population as a whole and
health.21 Anecdotally, because dialysis patients are known to be ≈8% among those >80 years of age.34
at high risk of heart disease, many unwitnessed deaths are attrib- Atrial fibrillation can cause symptoms and increase the
uted to SCD even though their true cause is unknown. risk of iatrogenic complications, as described below. As in
With recognition of these limitations, the proportion of the general population, atrial fibrillation is a leading cause of
deaths caused by SCD have been estimated at ≈20% to 25% stroke in patients with CKD. Thus, atrial fibrillation appears
among both hemodialysis and peritoneal dialysis patients.22 to make a substantial contribution to the high rate of CVD
Some evidence of regional/ethnic variation exists. For exam- morbidity in CKD populations, although the magnitude of its
ple, the estimated proportion of SCD deaths among Japanese contribution has yet to be precisely quantified.
dialysis patients appears lower than in Western dialysis
patients.23 SCD causes a substantial proportion of deaths even Stroke
among adolescents and young adults with kidney failure, sug- Stroke risk is elevated in those with non–dialysis-dependent
gesting that nonischemic mechanisms may be responsible,24 CKD and is markedly increased in the presence of ESRD.35
as further described below. Accurately identifying SCD is less The magnitude of this excess risk appears to be greater than
challenging in non–dialysis-dependent CKD patients, given that for CAD. For example, compared with those with nor-
their generally lower burden of comorbidity. mal kidney function, the relative risk of stroke in ESRD is
Multiple studies suggest that the likelihood of SCD is 5- to 10-fold,36 whereas the relative risk of myocardial infarc-
inversely proportional to eGFR,21,25 and one study in older tion in ESRD patients is 2.5- to 3-fold.35,37 Risk appears to be
patients found that even very mild impairment of kidney func- proportionately increased for both ischemic and hemorrhagic
tion (ie, eGFR <60 mL·min−1·1.73 m−2 [estimated with cystatin strokes, although there is some ethnic and racial variation.38
C but not creatinine]) was associated with an approximate Cardioembolic strokes account for a relatively large propor-
doubling in the adjusted risk of SCD compared with those tion of ischemic strokes within the dialysis population,37 per-
with normal eGFR.26 More information on the true incidence haps because of the increased prevalence of atrial fibrillation,
of unexpected deaths of cardiac origin would be extremely as discussed above.
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useful, as would precise electrocardiographic data on the type Risk factors for stroke in CKD patients largely mirror those
of cardiac rhythm responsible for death. in the general population: Diabetes mellitus, hypertension, and
In patients with ESRD, episodes of supraventricular increasing age are all associated with higher-than-average risk,
tachycardia (including atrial fibrillation) are common in the and black race is associated with lower risk.36,39 Available data
postdialysis period, although they are often self-limiting.27 In in patients with ESRD do not convincingly support a temporal
addition to transient episodes, persistent atrial fibrillation and association between strokes and hemodialysis treatments.
paroxysmal atrial fibrillation are highly prevalent in hemodi- Stroke severity also tends to be higher among people with
alysis populations (7%–27%, depending on the definition and CKD compared with the general population, especially among
cohort studied).28–32 Kidney failure is a major risk factor for those with kidney failure.40,41 At 30 days after stroke, mortal-
atrial fibrillation, even after adjustment for age and comor- ity among dialysis patients in the United States approaches
bidity.33 As recently reviewed,33 the mechanisms underlying 30% compared with 10% to 13% in the general population.
the elevated risk of atrial fibrillation in CKD patients include Furthermore, only 56% of US dialysis patients who suffer a
older age (with age-accompanying comorbidities such as stroke will be discharged home (or to acute rehabilitation)37

Figure 2. Histology of left ventricular wall from a normal heart (A) and from a patient with chronic kidney disease (CKD; B, lumen at top of
pictures). The normal heart has no significant interstitial fibrosis, and myocytes appear healthy and uniform. In CKD, there is patchy inter-
stitial fibrosis (blue) and chronic myocyte injury throughout the wall, sparing the subendocardial zone. Masson trichrome stain, original
magnification ×10. Pictures courtesy of Isaac Stillman, MD, Beth Israel Deaconess Medical Center, Boston MA.
 Tonelli et al   Uremia-related CVD   521

Table 1.  Five Subtypes of Cardiorenal Syndrome those without CKD.43,44 In the setting of severe kidney dys-
Cardiorenal
function, the signs and symptoms of heart failure can result
Syndrome from impaired renal excretion of salt and water, primary car-
Type Diagnosis Description diac dysfunction (systolic or diastolic), or both. Thus, among
I Acute cardiorenal Abrupt worsening of cardiac function (eg,
patients with advanced CKD, a diagnosis of heart failure
syndrome acutely decompensated congestive heart identifies a very heterogeneous group, and a functional clas-
failure) leading to acute kidney injury sification system was recently proposed for use in this popula-
II Chronic cardiorenal Chronic abnormalities in cardiac function tion.45 As for the other forms of CVD discussed in this review,
syndrome (eg, chronic congestive heart failure) the prevalence of heart failure in CKD populations increases
causing progressive and permanent with age, is inversely proportional to eGFR,46 is markedly
chronic kidney disease more common in dialysis patients (prevalence, 31%–36%)47,48
III Acute renocardiac Abrupt worsening of renal function (eg, than in those with normal kidney function (prevalence, 1.8%–
syndrome acute kidney injury) causing acute cardiac 4.4%),46,49–51 and is associated with poor prognosis. The pres-
disorder (acute heart failure)
ence of interstitial and perivascular fibrosis (Figure 2) in the
IV Chronic renocardiac Chronic kidney disease (diabetic heart is a major determinant of diastolic dysfunction among
syndrome nephropathy) contributing to decreased
patients with CKD and hypertension.52 The simultaneous pres-
cardiac function, cardiac hypertrophy,
fibrosis, or increased risk of adverse ence of heart and kidney failure has been called the cardiorenal
cardiovascular events syndrome. A detailed classification based on pathophysiology
V Secondary Systemic condition (eg, sepsis) causing and clinical context has been proposed (Table 1).53–55
cardiorenal both acute cardiac and renal injury and
syndrome dysfunction Risk Factors and Pathophysiology
These cardiorenal syndrome types have been proposed by the Acute Dialysis of CVD in CKD
Quality Initiative, as recently reported by McCullough et al.55 Reproduced with There is little doubt that the elevated risk of CVD in patients
permission from the publisher. Copyright © 2013, S. Kargel AG.
with CKD is attributable in large part to shared risk factors.
These well-known and overlapping risk factors are summa-
compared with 72% to 76% for the general population.42
rized, along with key epidemiological and outcomes evidence,
Potential explanations for these poor outcomes include the
in Table 2. However, large epidemiological studies suggest that
older average age of dialysis patients, frequent presence of CKD incidence and progression and CVD in CKD patients
comorbidities, delayed presentation to medical services, and
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cannot be entirely explained by traditional CVD risk factors.76

possibly underuse of cardioprotective medications. Complex, redundant, and bidirectional feedback loops (Figure
3), some of which have yet to be precisely defined, set up a
Congestive Heart Failure vicious cycle for progressive organ damage77; for example,
The prevalence of left ventricular hypertrophy and conges- CKD is both a cause and a consequence of hypertension. The
tive heart failure is higher among patients with CKD than in state of uremia undoubtedly conveys additional risk for CVD

Table 2.  Traditional Risk Factors for CVD in Patients With CKD and Key Supporting Evidence
Risk Factor Epidemiological Evidence Outcomes Evidence
Diabetes mellitus Accounts for 45% of incident ESRD and is the most common Presence of CKD is strongly correlated with adverse outcomes, including all-
cause of CKD.56 cause mortality, acute myocardial infarction, stroke, and need for coronary
Approximately 42% of US adults with undiagnosed diabetes revascularization.60
mellitus also have CKD.57 Approximately 30% of the projected $1.1 trillion cost of dialysis treatments
The prevalence of stage 3 or worse CKD in the US diabetes during 2010–2020 will result from diabetic kidney disease.56,61
population exceeds 15%.58,59
Hypertension The prevalence of hypertension is significantly higher (50%–60%) Kidney dysfunction is a major cause of hypertension, and hypertension in
in people with CKD than in the general population and rises to turn aggravates CKD and accelerates its progression.63
90% in CKD patients age >65 y of age.58 Hypertension is the major risk factor for the development and progression of
Approximately 8% of US adults with diagnosed hypertension have diabetic and nondiabetic CKD.64,65
eGFR <60 mL·min−1·1.73 m−2.62 CKD is a common and often underappreciated cause of resistant
hypertension.66
Albuminuria Albuminuria is present in ≈9.5% of US adults.67 Albuminuria is strongly and independently associated with multiple adverse
outcomes, including death, cardiovascular events, and kidney failure.5
Dyslipidemia Dyslipidemia is common among people with CKD (especially Dyslipidemia appears to correlate with the rate of kidney function loss in CKD
those with the nephrotic syndrome or treated with peritoneal populations; however, it is unclear whether this association is causal.70
dialysis).68,69
Smoking Smokers are 1.5–3 times as likely to have CKD as Tobacco use accelerates kidney function loss once CKD is established.71,72,73
nonsmokers.71–74 Some studies have shown a correlation between tobacco use and the
risk and severity of albuminuria, but this has not been confirmed in all
studies.72,75
CKD indicates chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; and ESRD, end-stage renal disease.
 522  Circulation  February 2, 2016

Figure 3. Proposed feedback loops in cardiorenal syndrome. Cardiac dysfunction leads to renal dysfunction (green arrows) and vice versa
(orange arrows). GFR indicates glomerular filtration rate. Adapted with permission of the publisher from Bock and Gottlieb.77 Copyright ©
2010, Wolters Kluwer Health.

above and beyond the traditional risk factors. Below, we focus lipoprotein has also been shown to markedly accelerate ath-
our discussion on some novel factors that likely contribute to erosclerosis and to reduce myocardial function in mice.80
the pathogenesis of CVD. Levels of carbamylated proteins provide a time-averaged indi-
cator of urea concentration (analogous to the widespread use
Protein Carbamylation of hemoglobin A1c to indicate glycemic control in individu-
Recent evidence suggests that chronically elevated blood urea als with diabetes mellitus). Berg et al78 and Drechsler et al81
may contribute directly to cardiovascular morbidity and mor- reported that higher levels of carbamylated albumin (C-Alb)
tality risk in CKD patients.78,79 As kidney function declines, are associated with a higher risk of all-cause mortality and
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accumulating urea spontaneously dissociates to form cyanate, uremic heart failure in both incident and prevalent ESRD
which reacts irreversibly with proteins and free amino groups populations. Koeth et al82 also demonstrated that increased
in a reaction known as carbamylation (Figure 4). Impaired concentrations for serum protein-bound homocitrulline (an
acetylcholine-induced vasorelaxation has been observed in alternative index of total protein carbamylation) was associ-
mice with urea levels comparable to those in uremic patients, ated with cardiovascular risk in ESRD patients. Importantly,
suggesting that protein carbamylation may lead to uremia- animal and human studies have suggested that protein carba-
related endothelial dysfunction. Carbamylated low-density mylation can be reversed by amino acid scavenger therapy.83

Figure 4. Carbamylation chemistry in uremia and

the hypothesized pathogenic pathways.
 Tonelli et al   Uremia-related CVD   523

Intensification of hemodialysis therapy also reduces protein but not by nutritional vitamin D95 and that cardiac-specific
carbamylation and may in part explain the benefits seen when vitamin D receptor knockout mice develop cardiac hyper-
dialysis dose (ie, frequency) is increased.84 Protein carba- trophy.96 Small clinical studies in hemodialysis patients have
mylation has thus emerged as a major pathogenic nontradi- demonstrated a role of vitamin D agonists in reducing left
tional risk factor among patients with CKD and ESRD and ventricular wall thickness and improving diastolic function
accordingly may be a promising target for intervention. parameters, although larger randomized trials in CKD have
not.97,98 These larger trials have suggested that activated forms
Fibroblast Growth Factor-23–Klotho Signaling Axis of vitamin D reduce left atrial size and potentially episodes
Fibroblast growth factor (FGF)-23 is a protein secreted primar- of heart failure,97 which are interesting findings that warrant
ily by bone tissue that regulates phosphate excretion via inter- confirmation.
action with classic FGF receptors. FGF23 signaling requires
the presence of a coreceptor (Klotho).85 Human studies suggest Oxidative Stress
that Klotho deficiency and increased FGF23 are hallmarks of Several animal and human studies have suggested that indi-
CKD that are independently associated with cardiovascu- cators of oxidative stress are markedly elevated in CKD.
lar mortality.86 Klotho-deficient mice develop an accelerated Because the kidney is the one of the most important sources of
aging syndrome with vascular calcification that resembles antioxidant enzymes such as glutathione peroxidases, levels
features of uremia.87 In Klotho-deficient mice, Faul et al88 of pro-oxidants increase with worsening renal function. Urea
demonstrated that high levels of FGF23 directly contributed itself has been demonstrated to induce reactive oxygen spe-
to left ventricular hypertrophy by acting on noncanonical FGF cies in cell culture studies. Uremic mice have responded to
receptors in the heart. FGF23 has also been shown to directly treatment with antioxidants, showing improvements in both
impair endothelium-dependent vasorelaxation by increasing insulin resistance and vascular function.99 Iron therapy, fre-
vascular superoxide levels.89 Moreover, FGF23 regulates renal quently used to correct anemia in patients with CKD, may
sodium absorption and may contribute to the hypertension that also induce oxidative stress. Iron is normally sequestered by
accompanies CKD. Neutralization of FGF23 in mouse models proteins such as transferrin and ferritin. Because administra-
of CKD leads to decreases in secondary hyperparathyroidism tion of intravenous iron may overwhelm the ability of these
but also to increases in serum phosphate and vascular calcifi- proteins to sequester iron, free (not protein bound) iron can
cation.90 Secondary analysis of the Evaluation of Cinacalcet be distributed in excess into tissues where its oxidative prop-
HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial erties can be injurious.100 Free iron can react with hydrogen
in hemodialysis patients with secondary hyperparathyroidism peroxide via the Fenton reaction to generate hydroxyl radi-
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(intact parathyroid hormone >300 pg/mL) demonstrated that cals.54 However, not all studies implicate iron as responsible
FGF23 concentrations were reduced by ≥30% in 68% ver- for inducing oxidative stress of uremia, and perhaps differ-
sus 28% of patients randomized to receive cinacalcet plus ences in the way iron is measured (ie, total versus catalytic)
phosphate binders/vitamin D versus placebo plus phosphate explain the discrepancies.101 Whether the oxidative stress of
binders/vitamin D, respectively. FGF23 concentrations were uremia is a primary driver of CVD or a secondary phenome-
reduced by ≥50% in 50% versus 15% in patients random- non is unclear. Small randomized trials in ESRD patients have
ized to cinacalcet versus placebo, respectively.91 By week 20, not shown any significant benefit of antioxidant treatment,102
neutralization of FGF23 was associated with a significantly suggesting that oxidative stress may not be a primary media-
reduced risk of cardiovascular mortality, SCD, and heart fail- tor of cardiovascular risk. Alternatively, targets and interven-
ure and in the primary composite end point (ie, time to death tions that are more specific for uremia related oxidative stress
or a first nonfatal cardiovascular event [myocardial infarction, should be studied.
hospitalization for angina, heart failure, or a peripheral vascu-
lar event]). Reductions in the risk of all-cause mortality, myo- Cardiac Glycosides
cardial infarction, unstable angina, peripheral vascular event, Endogenous cardiotonic steroids are another major class of
stroke, fracture, and parathyroidectomy were not statistically metabolites that have been shown in small clinical studies to
significant. be significantly elevated (2- to 3-fold) in patients with CKD.103
These metabolities block Na/K-ATPase and include endoge-
Vitamin D nous ouabain, marinobufagenin, and telocinobufagin. In ani-
A number of observational studies in hemodialysis patients mal models of CKD, cardiotonic steroids appear to induce
have suggested a survival advantage associated with activated myocardial dysfunction and fibrosis. Interestingly, monoclo-
vitamin D therapy.92,93 In various animal models, vitamin D nal antibodies against marinobufagenin has also been shown
supplementation has been shown to block the development of to reverse cardiac fibrosis in rats with chronic renal failure.104
cardiac hypertrophy and heart failure. In the Dahl salt-sen- However, the exact role of cardiotonic steroids in mediat-
sitive rat model of heart failure, treatment with paricalcitol ing cardiovascular risk in CKD patients is unknown because
attenuated the development of cardiac hypertrophy and dys- no high-throughput, reliable assays are available to measure
function as measured by functional, biochemical, and molecu- these metabolites in large cohorts of patients.
lar measures of cardiac stress.94 These findings appear to be
related directly to inhibition of renin production by calcitriol. Other Pathways
Other groups have demonstrated that cardiac hypertrophy in The gut microbiome is emerging as an attractive candidate for
1α-hydroxylase–deficient mice can be reversed by calcitriol investigation as a potential source of uremic toxins.105 Patients
 524  Circulation  February 2, 2016

with CKD have altered gut microbiome patterns, and colonic individual's risk of progressive kidney function loss. Limited
bacteria are the main sources of several well-known toxins high-quality data are currently available to guide the treatment
such as p-cresol sulfate, indoxyl sulfate, and trimethylamine- of hypertension in patients with ESRD.114
N-oxide. Recent studies have suggested that trimethylamine- Statins reduce the risk of coronary events in people with
N-oxide levels are elevated in patients with CKD and confer non–dialysis-dependent CKD, but there is no evidence that
a nearly 3-fold excess risk for 5-year mortality.106 Circulating they are beneficial in the presence of ESRD.115–117 Because
levels of asymmetrical dimethylarginine, an endogenous low-density lipoprotein cholesterol levels are poorly correlated
inhibitor of nitric oxide synthase, have also been implicated with the risk of adverse clinical outcomes in CKD patients,118
as an independent risk factor for CVD among patients with overall cardiovascular risk, not the serum lipid profile, is now
CKD.107 Some have speculated that the asymmetrical dimeth- the primary basis for prescribing statins in this population.119
ylarginine pathway contributes to endothelial dysfunction and International guidelines recommend that statins be prescribed
progression of atherosclerosis; however, treatment with silde- to all patients with non–dialysis-dependent CKD who are ≥50
nafil or l-arginine to restore impaired nitric oxide signaling years of age and to patients whose estimated 10-year risk of
has failed to reverse CVD.108,109 Finally, increased circulating cardiovascular events exceeds 10%. The guidelines do not
levels of uremic solutes such as p-cresol sulfate and phenyl- recommend initiating statins in dialysis patients, although
acetylglutamine have been associated with higher cardiovas- patients who initiate dialysis while on a statin might reason-
cular morbidity and mortality in patient with ESRD,110 but it ably continue such treatment.119
is not known whether removal or blocking these uremic toxins No trial data support the cardiovascular benefits of exer-
will lead to improved cardiovascular outcomes. cise, dietary sodium restriction, avoiding overweight/obesity,
or smoking cessation in CKD populations. However, dietary
Current Management and Therapeutic Gaps sodium restriction120,121 is useful (perhaps essential) for good
blood pressure control in the setting of CKD. Tobacco use71,72
Coronary Artery Disease and overweight/obesity122,123 may accelerate kidney function
Medical management of acute coronary events in patients loss. It is therefore appropriate, as with the general popula-
with CKD has recently been reviewed by Washam et al.14 tion, to recommend lifestyle changes to patients with CKD.
Supporting data in patients with CKD are extremely limited However, important questions remain as to what extent such
because randomized, clinical trials (RCTs) have not been changes can be achieved.
conducted specifically to evaluate the benefit of β-blockers, Markedly worse outcomes after percutaneous124 or sur-
angiotensin-converting enzyme inhibitors/angiotensin recep- gical coronary revascularization125–128 have been observed in
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tor blockers, heparin, thrombolytics, or immediate reperfu- patients with ESRD compared with individuals with normal
sion strategies in this specific group. One systematic review kidney function. As a consequence of these studies, dialysis
using pooled RCT data to compare antiplatelet agents with patients are less likely to receive coronary revascularization
placebo in patients with CKD reported that the point estimate than those with normal kidney function.129,130 Recent studies
for the relative risk of myocardial infarction was consistent are more optimistic and suggest a small net survival benefit of
with a clinically relevant benefit of active treatment (relative both surgical and percutaneous revascularization among dial-
risk=0.89; 95% CI, 0.76–1.05). However, the risk of major ysis patients and that surgical procedures are associated with
bleeding was significantly increased (relative risk=1.4; 95% better long-term survival than percutaneous revascularization,
CI, 1.07–1.86).111 The different pathophysiology of CVD in although at the expense of increased short-term morbidity and
patients with renal disease, the increased risk of bleeding a higher risk of periprocedural death.131 Similar considerations
among people with advanced CKD, the need to dose adjust or apply to patients with non–dialysis-dependent CKD.132
to avoid low-molecular-weight heparins at lower eGFR, and Indications for coronary revascularization in CKD patients
the high case fatality rate after myocardial infarction among have yet to be evaluated in well-controlled studies, although a
those with CKD all suggest the need for more trials compar- large RCT with a target enrollment of 1000 patients with coro-
ing different approaches to treat acute myocardial infarction in nary disease and eGFR <30 mL·min−1·1.73 m−2 or on dialysis
this vulnerable population.112 is underway and will compare a routine invasive strategy with
Slightly more data are available to guide long-term medi- conservative management.133 No RCTs have specifically com-
cal treatment of coronary disease in CKD patients. Antiplatelet pared percutaneous and surgical methods for revascularization
agents appeared to reduce the risk of myocardial infarction in in people with CKD. A secondary analysis of data from a trial
11 701 people with CKD (4398 with stage 5 CKD), some of comparing percutaneous coronary angioplasty with surgi-
whom had no history of coronary events (relative risk=0.66; cal revascularization suggested that patency after the former
95% CI, 0.51–0.87), perhaps at the expense of excess major might be less durable that with the latter among the subgroup
bleeding (relative risk=1.29; 95% CI, 0.69–2.42).111 Although with eGFR<60 mL·min−1·1.73 m−2.128,134 However, because
treatment of hypertension reduces the risk of cardiovascular this trial studied bare metal stents, its applicability to the cur-
events in people with non-dialysis-dependent CKD, there is rent era is unclear.
no specific cardiovascular benefit for more aggressive (eg, Although the risk of postprocedural acute kidney injury
<130/80 mm Hg) compared with conventional (eg, <140/90 (with the risk of permanent kidney failure) is a valid concern,
mm Hg) blood pressure targets and no evidence that any spe- observational studies of people with non–dialysis-dependent
cific class of agent is preferred.113 Therefore, management of CKD suggest that there is net clinical benefit of revascular-
hypertension in non-dialysis-dependent CKD is tailored to the ization because the risk of permanent dialysis is relatively
 Tonelli et al   Uremia-related CVD   525

uncommon.135 It is less clear whether this apparently favor- Which equation performs best for estimating stroke risk in
able risk-to-benefit ratio applies to dialysis patients or would CKD populations has been the subject of some debate. Most
persist if revascularization were more liberally used in CKD such equations do not incorporate eGFR (known to correlate
patients. On the other hand, even among patients undergoing with stroke risk), and none incorporate albuminuria (known
coronary revascularization, postprocedural use of potentially to correlate with stroke risk in the general CKD population
cardioprotective medications is lower in CKD patients than in but not necessarily in the subset with atrial fibrillation).151–153
those with normal kidney function,136 suggesting that closer Although all 3 major equations for estimating bleeding risk
attention to medical regimens may improve outcomes. incorporate information on kidney function, the relative per-
formance of each within CKD populations is unknown.154–156
Sudden Cardiac Death More research is needed to identify how best to predict stroke
β-Blockers and mineralocorticoid receptor blockers (eg, risk in people with atrial fibrillation and CKD, especially
eplerenone and spironolactone) reduced the risk of SCD in because the prevalence of both are expected to rise over the
randomized trials of patients with heart failure.137–140 Whether coming decades.
these benefits also apply to the subset who also have advanced Aspirin appears to modestly reduce the risk of stroke
CKD is unknown. A small (n=114) RCT in hemodialy- among people with atrial fibrillation (general population), but
sis patients with cardiomyopathy suggested that carvedilol to a lesser extent than warfarin.157,158 RCTs have yet to assess
reduced mortality141 but this requires confirmation in a larger the benefits and harms of aspirin for stroke prevention in peo-
study. A small (n=201) placebo-controlled RCT in hemodi- ple with advanced CKD and atrial fibrillation, although RCTs
alysis patients suggested that n-3 polyunsaturated fatty acids have been recommended.159,160
reduced the rate of cardiovascular events.142 However, much Warfarin has long been the standard of care for most indi-
larger RCTs of n-3 polyunsaturated fatty acid supplemen- viduals (general population) with atrial fibrillation. This sta-
tation have shown no benefit in the general population.143 tus has recently been challenged by the emergence of novel
Accordingly, given the potentially different mechanisms for oral anticoagulants such as rivaroxaban, dabigatran, apixaban,
SCD (and the strong rationale for n-3 polyunsaturated fatty and edoxaban. Warfarin use among patients with atrial fibril-
acid supplementation in severe CKD considering its higher lation and advanced CKD currently enjoys less enthusiasm
likelihood of deficiency), a larger study is ongoing in hemo- because of the relatively high bleeding risk in this popula-
dialysis patients.144 tion20 and the concern that warfarin might precipitate calci-
Implantable cardiac defibrillators (ICDs) are currently rec- phylaxis, a devastating condition that affects a small number
ommended for the primary prevention of SCD in people with of patients on dialysis.161 Such concerns are particularly rel-
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severe heart failure.145 However, available data in non–dialy- evant because observational studies have shown no associa-
sis-dependent CKD patients indicate that the clinical benefit tion between warfarin use and averted stroke in patients with
of ICDs is reduced at lower eGFR (30–60 mL·min−1·1.73 severe CKD.160,162–164
m−2).146 No RCT data support the use of ICDs in dialy- Available data suggest that the efficacy of rivaroxaban,
sis patients, and some evidence suggests that ICDs may be dabigatran, apixaban, and edoxaban is comparable to that of
less effective in this population (ie, poorer outcomes despite warfarin and that they can be safely used in people with stage
more frequent shocks) and may be more likely to cause life- 3 CKD. Rivaroxaban, dabigatran, and apixaban are approved
threatening infection than in those with normal kidney func- for use in the United States in people with stage 4 CKD, and
tion.147 Limited data suggest that ICDs reduce the risk of death apixaban is approved for use in dialysis patients, all on the
among dialysis patients with a history of cardiac arrest.148 A basis of pharmacokinetic data without any evidence of clinical
small trial (planned enrollment, n=200) is ongoing in dialysis efficacy or safety.165–169 A recent systematic review did not find
patients who do not meet current criteria for ICD use but who that the newer agents were superior, but the point estimate for
appear to be at high risk of SCD,149 and a larger trial in patients the risk of stroke was compatible with a substantial clinical
undergoing incident dialysis (target enrollment, n=2600) that benefit compared with warfarin despite a similar risk of bleed-
is powered for clinically relevant outcomes began recruitment ing (Figure 5).170,171 Additional trials are ongoing, and more
in mid-2015.150 information will soon be available.

Atrial Fibrillation Congestive Heart Failure

Medical management of atrial fibrillation is divided into In general, CKD patients with heart failure and eGFR ≥30
control of ventricular rate and rhythm (not discussed further mL·min−1·1.73 m−2 are treated the same as those with normal
except to note the well-known potential for digoxin toxicity kidney function except that hyperkalemia may be more likely
in people with CKD) and prevention of cardioembolic events, to limit doses of medications such as angiotensin-converting
including stroke. The usual approach to the latter among the enzyme inhibitors or aldosterone antagonists.172,173 Reductions
general population is to estimate the risks of stroke or iatro- in eGFR reported in patients with heart failure treated with
genic bleeding with validated equations151–156 and then use renin-angiotensin-aldosterone system inhibitors pose an addi-
these estimates to select the appropriate treatment (ie, aspirin, tional concern that decline in renal function could be acceler-
warfarin, or other oral anticoagulants). Unfortunately, neither ated by these agents (by blocking renal autoregulation)174 and
the performance of the validated equations nor the risk-to- therefore limit their utility in this population. Patients with a
benefit ratio of available treatments is completely understood eGFR of 15 to 30 mL·min−1·1.73 m−2 or with severe albumin-
in people with advanced CKD. uria may have increased diuretic requirements compared with
 526  Circulation  February 2, 2016

strategies are needed for coupling the rate and schedule of

intradialytic fluid removal to each individual patient’s volume
status and hemodynamic tolerance. Although moderation of
dietary sodium intake and avoidance of excessive intradialytic
fluid gains can effectively manage ECF volume overload,
these objectives are often difficult for patients to achieve.

Optimizing Cardiac Function

Medications that antagonize the renin-angiotensin-aldosterone
system such as angiotensin-converting enzyme inhibitors,
angiotensin receptor blockers, spironolactone, and eplere-
none are all relatively unstudied in the presence of advanced
CKD and heart failure. A single, small RCT suggested that
telmisartan improved mortality in 332 hemodialysis patients
(compared with placebo), but this result requires confirma-
Figure 5. Efficacy and safety of novel anticoagulants. Relative tion.187 A recently published subanalysis188 of the Prospective
risk reductions in stroke, systemic embolism, and major hem- Comparison of ARNI With ARB on Management of Heart
orrhage for novel anticoagulants vs warfarin in patients with
non–dialysis-dependent chronic kidney disease (CKD). Patients Failure With Preserved Ejection Fraction (PARAMOUNT)
with CKD had estimated creatinine clearances of 30 to 49 mL/ trial189 showed that the first-in-class angiotensin receptor
min, except for those treated with apixaban (25–50 mL/min). Risk neprilysin inhibitor (LCZ696) induced less eGFR decline
reductions were statistically significant for dabigatran 150 mg on than valsartan in patients with eGFR ≥30 mL·min−1·1.73 m−2.
stroke and for apixaban on major hemorrhage. Reproduced with
permission from Hart et al171 with permission from the publisher. Provided that the LCZ696 data are reproduced in an RCT and
Copyright © 2012, Macmillan Publishers Ltd. further evaluated in patients with worse renal function, this
agent might prove superior to other renin-angiotensin-aldo-
those with less severe CKD or with normal kidney function.175 sterone system inhibitors in CKD patients. Although in theory
Management of heart failure in the setting of advanced CKD treating anemia in patients with CKD should improve cardiac
can be broadly divided into 4 non–mutually exclusive objec- function, epoetin therapy in this population has not improved
tives: preventing/controlling extracellular fluid (ECF) volume cardiac outcomes or has caused harm.190–192 Randomized tri-
overload, optimizing cardiac function, preventing complica- als of cardiac resynchronization have not been carried out in
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tions of heart failure (eg, CD) and treating the underlying people with advanced CKD, although subgroup analyses of
disease. The last 2 objectives are not discussed further, and CKD patients in larger trials suggest a mortality benefit with
significant questions remain about how to achieve the first 2 resynchronization.193
objectives, especially in people with kidney failure.
Stroke
Preventing/Controlling ECF Volume Overload The treatment of acute stroke in the general population con-
Management of heart failure in advanced CKD would be tinues to evolve, with increasing interest in catheter-based
facilitated by better methods for routinely assessing ECF therapies.194–196 Data supporting the use of these newer treat-
volume status. Current assessment of ECF volume status in ments in patients with CKD or ESRD are scant. In theory,
this population is surprisingly crude. Promising techniques an increased likelihood of diffuse small-vessel disease and a
such as online blood volume monitoring,176 routine measure- higher prevalence of stiff, calcified cerebral blood vessels in
ment of inferior vena cava diameter,177 noninvasive lung water CKD patients (especially in advanced CKD) may tip the risk-
measurement,178 lung ultrasound,179 and routine bioimped- to-benefit balance to be less favorable, although this is specu-
ance assessment180 remain understudied or can actually cause lative.20 The risk-to-benefit ratio of intravenous thrombolysis
harm. Blood levels of brain natriuretic peptide correlate with for acute stroke in CKD patients is similarly unknown com-
left ventricular filling pressures in the general population and pared with that in individuals with normal kidney function.197
in people with non–dialysis-dependent CKD. A recent study Evidence for medical treatments aimed at preventing forms
suggests that amino-terminal pro-brain natriuretic peptide of ischemic stroke is broadly similar to the evidence base for
levels are useful for diagnosing heart failure, regardless of prevention of acute coronary disease, although numerous gaps
baseline eGFR.181 However, because brain natriuretic peptide remain. Even fewer data are available on strategies to prevent
appears to accumulate in the setting of kidney failure,182–184 hemorrhagic stroke. Gaps of particular importance related to
further studies are required to clarify the role of brain natri- ischemic and hemorrhagic stroke include the risk-to-benefit
uretic peptide assays to assess ECF volume status in CKD. ratio of antiplatelet agents, the optimal blood pressure target
Even when ECF volume overload is correctly identified, (and how to achieve it, especially for dialysis patients), and
how to best manage this condition poses unresolved chal- how to mitigate the bleeding risk associated with anticoagu-
lenges. Ultrafiltration to treat heart failure in patients with lants either during dialysis or when administered to treat other
moderate CKD who lack a traditional indication for dialysis medical conditions.
could exacerbate kidney dysfunction compared with diuretic Percutaneous and surgical approaches for stroke preven-
treatment.185 For patients with kidney failure, quotidian hemo- tion, as noted earlier in the discussion on atrial fibrillation, are
dialysis appears effective186 but is not widely available. Better also poorly studied in CKD patients. Calcified vessels may
 Tonelli et al   Uremia-related CVD   527

increase the risk of procedural complications,198 and clinical semiquantitative measures such as urine dipstick assessment
benefit has not been demonstrated for CKD populations.199 of albuminuria are also useful for risk stratification at all lev-
els of baseline eGFR.5,208–210 A population-based study of >1
Emerging Diagnostic Tools and Therapies million people from Alberta, Canada, demonstrated that albu-
Vascular Calcification minuria was associated with marked increases in the risks of
Vascular calcification (Figure 6) is a strong risk factor for kidney failure, cardiovascular events, and all-cause mortality
future CVD-related events in the general population and, nota- independently of eGFR (Figure 1).5 Other studies have shown
bly, is an independent risk factor for CVD in CKD.200,201 Data that albuminuria is independently associated with the risk of
from a post hoc analysis of 8 studies evaluating individuals in stroke, myocardial infarction, and coronary revascularization
the general population receiving high-intensity statin therapy procedures.209,211 These findings have been shown to apply to
have recently suggested that statins may actually increase a broad range of populations, regardless of age, sex, ethnicity,
vascular calcification and in so doing may stabilize otherwise and underlying risk factor profile,212 and extend to very low
unstable plaques.202 Statins have not been conclusively shown
levels of albuminuria that were previously considered innocu-
to reduce CVD events in patients with ESRD; however, medial
ous (15–29 mg/d).205,213 Collectively, these studies confirm
rather than intimal calcification predominates in patients with
kidney disease.119,203 Medial calcification results from altera- that albuminuria is a powerful predictor of future cardiovas-
tions in a number of factors unique to patients with kidney dis- cular events independently of eGFR, hypertension, diabetes
ease, namely changes in mineral metabolism and alterations mellitus, and traditional cardiovascular risk factors.205,214–219
in pathways linked to bone metabolism (see above). Routine Although albuminuria is an unequivocal risk factor for CVD
clinical measures of vascular calcification cannot distinguish in CKD, it may not be an appropriate surrogate for CKD-
intimal from medial calcification. However, because patients related outcomes,220 and it is even possible certain therapies
with CKD and ESRD are at particularly high risk for medial that improve CKD-related outcomes may in fact increase
calcification, calcification in general remains a potentially albuminuria.221
strong surrogate and an important potential therapeutic target
to modify CVD in those with kidney disease.
Carbamylated Albumin
C-Alb responds to changes in dialysis dose, and unlike stan-
Albuminuria
Although reduced eGFR is strongly associated with adverse dard clinical measures of uremia (ie, blood urea, creatinine,
urea reduction ratio, or Kt/V), C-Alb is strongly associated
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outcomes, the risk of future cardiovascular events and

mortality is better correlated with albuminuria than with with mortality.78,81 As rapid assays for measurement of C-Alb
eGFR.204–207 Most of these studies have assessed the severity become available, C-Alb may emerge as a useful marker to
of albuminuria using quantitative measures (eg, urinary albu- assess the efficacy of dialysis and adequacy of nutrition. C-Alb
min-to-creatinine or protein-to-creatinine ratio). However, may also be considered when making treatment decisions
on which patients are best treated with standard intermittent
hemodialysis, ascertaining which patients require extended
duration or increased frequency hemodialysis, and identifying
patients with residual renal function who may be able to be
adequately maintained on less frequent twice-weekly hemo-
dialysis. Analogous to hemoglobin A1c, C-Alb measurement
may also play a central role in testing the pharmacodynamic
efficacy of these combined treatments and the need for supple-
mentary nutritional measures.

Frequent Hemodialysis
Home hemodialysis use has increased, resulting in more
patients with ESRD receiving nocturnal dialysis 6 times a
week instead of intermittent hemodialysis 3 times a week. In
small studies, intensification of dialysis frequency has been
associated with a reduction in hypertension and an improve-
ment in left ventricular mass.222–225 Interestingly, however, a
follow-up study of patients originally assigned to frequent
nocturnal hemodialysis does not support lower future mortal-
Figure 6. Vascular calcification. Three-dimensional reconstruc- ity rates.226 Additional studies with specific markers that moni-
tion image of 64-slice gated cardiac computed tomography scan tor uremic burden (eg, C-Alb) may be needed to better assess
demonstrating heavy calcification of the left anterior descend-
ing coronary artery. Image courtesy of Rajeev Malhotra, MD, which ESRD patients may benefit from intensification of their
Massachusetts General Hospital. dialysis regimen.
 528  Circulation  February 2, 2016

Health Services and Health Policy Changes interruption of the renin-angiotensin system, control of blood
sugar, consideration of statin and aspirin, and advice on
Health Policy Priorities for LMICs
healthy weight, exercise, and smoking cessation. Arguably,
Available data clearly show that the most rapid increases in only those with nephrotic-range proteinuria, very low eGFR
noncommunicable chronic disease (NCD) prevalence will (eg, <30 mL·min−1·1.73 m−2), and evidence of collagen vas-
occur in LMICs.64,227,228 For example, during the last 3 decades, cular disease or vasculitis would require involvement of a
the prevalence of type 2 diabetes mellitus has increased nearly nephrologist per se, whereas only those with severe heart fail-
5-fold in East Asia and South Asia compared with a doubling ure or valvular heart disease, symptoms suggesting the need
in the United States.56,61 Given that diabetes mellitus and for revascularization, or evidence of serious arrhythmia would
hypertension cause both CKD and CVD, it seems clear that require that a cardiologist be involved. In short, most patients
the prevalence of these 4 conditions will increase in parallel. with both CKD and CVD in developed countries might need to
This is especially the case in LMICs, where CKD and CVD see just a single specialist. This approach would require agree-
may be more likely to remain undetected until later stages of ment on the common elements of care and possibly changes
illness. to physician reimbursement structures. However, if success-
Not surprisingly, awareness, treatment, and adequate fully implemented, this strategy would increase the capacity
control of CKD (alone or in combination with CVD) are to streamline care by eliminating unnecessary specialist visits.
low in LMICs, with the biggest gaps observed in the poor- Second, even 1 visit to a specialist may be unnecessary for
est patients.229 Lessons learned from the battle against tuber- many patients with NCDs. Strengthening the capacity for pri-
culosis, for which complex treatment regimens have been mary care practices to manage CKD, CVD, and other NCDs
delivered in fixed-dose combinations by successful adoption will be critical. Nonphysicians such as specially trained nurses
of care pathways, can perhaps be used to tackle the growing could play an important role, using care pathways and other
burden of NCDs. Care pathways are structured protocols in protocols230,234 that identify patients with “red flag” symptoms
which criteria-based medication prescription adjustment is (eg, ongoing angina), signs (eg, severe edema), or labora-
the default approach to clinical encounters rather than the sta- tory results (eg, nephrotic range albuminuria, very low ejec-
tus quo, in which medication adjustments require deliberate tion fraction) who require prompt physician assessment. The
action by the clinician. Although incompletely studied, care majority of patients without such red flags could be cared for
pathways may help to address quality gaps in NCD care.230 by the nurses, with or without input from allied health profes-
Data from RCTs indicate that prescribing fixed-dose com- sionals such as dieticians or pharmacists.4,235,236 These models
binations of cardioprotective medications (otherwise known could allow teams led by a single physician to care for hun-
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as the polypill) can improve adherence rates compared with dreds of patients with NCDs.
prescriptions for multiple tablets.231 Such combination treat- Other prerequisites for improving the care of people with
ments appear highly cost-effective232 and are potentially cost CKD, CVD, and other NCDs in wealthy countries include
saving.233 Moreover, because the decision to prescribe the comprehensively addressing the social determinants of health;
polypill is binary (rather than multifaceted, as when mul- engaging, educating, and empowering patients and the general
tiple medications are prescribed), wider use of the polypill public about the significance of effective self-management;
may increase the likelihood that patients with NCDs would and implementing a robust public health response to combat
receive all recommended treatments, although this remains to obesity, diabetes mellitus, and hypertension.
be shown.
These collective observations suggest that care pathways Summary
and the polypill will be important tools for NCD control in CVD is a leading cause of death among patients with CKD.
LMICs. Besides the traditional risk factors that contribute to both
conditions, uremic toxins may be directly responsible for the
Health Services and Health Policy Challenges for pathogenesis of CVD in CKD. Both clinical and benchtop
Developed Countries researchers will need to actively collaborate to characterize
Two interrelated challenges confront developed countries novel pathways and to identify new therapeutic targets to con-
seeking to improve the quality of NCD care generally and trol this growing epidemic. There is an urgent need to con-
the care of people with CKD and CVD specifically. First, tinue performing well-designed clinical trials in the CKD and
the prevalence of people who have both CKD and CVD is ESRD populations that target both traditional and nontradi-
not compatible with a specialist-based care model. Second, tional risk factors and not to assume that results of trials (posi-
the health systems of wealthy countries are best equipped to tive or negative) done in the general population are applicable
deal with 1 disease at a time, but coexistent CKD and CVD to individuals with kidney disease.
can interact with each other (and with other comorbid condi-
tions) to affect prognosis, function, communication between Acknowledgments
physicians, and the likelihood that treatment will be helpful We thank Dr Brian Nadler for assistance with literature searching and
or harmful. These 2 challenges imply the need to restructure Dr Kathryn Lucchesi for assistance with manuscript editing.
health services for NCD care in most developed countries.
First, a more integrated approach to management is Sources of Funding
needed. Most patients with both CKD and CVD require rela- Dr Tonelli was supported by a Population Health Scholar award from
tively generic treatment that includes blood pressure control, Alberta Innovates Health Solutions. This work was partially funded
 Tonelli et al   Uremia-related CVD   529

by an Collaborative Research and Innovation Opportunity award to Kidney in Cardiovascular Disease, and Council on Quality of Care and
the Interdisciplinary Collaborative Disease Collaboration (www.icdc. Outcomes Research. Pharmacotherapy in chronic kidney disease patients
ca). Dr Thadhani is supported by National Institutes of Health grants presenting with acute coronary syndrome: a scientific statement from
K24 DK094872 and R01 DK094486. the American Heart Association. Circulation. 2015;131:1123–1149. doi:
10.1161/CIR.0000000000000183.
15. Wang LW, Fahim MA, Hayen A, Mitchell RL, Baines L, Lord S, Craig JC,
Disclosures Webster AC. Cardiac testing for coronary artery disease in potential kid-
Drs Karumanchi and Thadhani are coinventors on a provisional pat- ney transplant recipients. Cochrane Database Syst Rev. 2011:CD008691
ents filed by Harvard Hospitals for the use of carbamylated albumin 16. Dahan M, Viron BM, Faraggi M, Himbert DL, Lagallicier BJ, Kolta AM,
as biomarker for uremia. Dr Thadhani reports serving as a consul- Pessione F, Le Guludec D, Gourgon R, Mignon FE. Diagnostic accu-
tant to Fresenius Medical Care North America. Dr Tonelli reports no racy and prognostic value of combined dipyridamole-exercise thallium
conflicts. imaging in hemodialysis patients. Kidney Int. 1998;54:255–262. doi:
10.1046/j.1523-1755.1998.00988.x.
17. De Lima JJ, Sabbaga E, Vieira ML, de Paula FJ, Ianhez LE, Krieger EM,
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