American Journal of Kidney Diseases, Vol 56, No 2 (August), 2010: pp 399-417 399
400 Shastri and Sarnak
Table 1. Selected Randomized Clinical Trials in Dialysis Patients With Focus on Clinical CVD Outcomes/Mortality
Completed Trials
High vs standard dose; high- HEMO HD 1,846 All-cause mortality
vs low-flux membrane
High- vs low-flux membrane MPO Incident HD 738 All-cause mortality Benefit in those with
albumin 4 g/dL
Carvedilol vs placebo HD & dilated 114 Change in LVEDV, LVESV, EF, Decreased morbidity &
cardiomyopathy clinical status mortality
Amlodipine vs placebo HD & hypertension 251 All-cause mortality Beneficial effect on CVD
outcomes
Epoetin to target Hct of 42% HD & HF or IHD 1,233 Composite CVD Trend toward worse
vs 30% outcomes in higher
HCT group
Ongoing Trials
Cinacalcet vs placebo EVOLVE HD & PTH 300 pg/mL 3,883 Composite CVD NA
Abbreviations: AURORA, Assessment of Survival and Cardiovascular Events; CVD, cardiovascular disease; 4D, Die
Deutsche Diabetes Dialyse Studie; DCOR, Dialysis Clinical Outcomes Revisited; EF, ejection fraction; EVOLVE, Evaluation
of Cinacalcet HCl Therapy to Lower Cardiovascular Events; FOSIDIAL, Fosinopril in Dialysis Study; Hct, hematocrit; HD,
hemodialysis; HEMO, Hemodialysis Study; HF, heart failure; HOST, Homocysteinemia in Kidney and Endstage Renal
Disease; IHD, ischemic heart disease; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic
volume; LVH, left ventricular hypertrophy; MPO, Membrane Permeability Outcome; NA, not available; PD, peritoneal
dialysis; PTH, parathyroid hormone; SHARP, Study of Heart and Renal Protection; SPACE, Secondary Prevention With
Antioxidants of Cardiovascular Disease in Endstage Renal Disease.
References not included in other portions of the Core Curriculum:
Eknoyan G, Beck GJ, Cheung AK, et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl
J Med. 2002;347(25):2010-2019.
Kopple JD, Cheung AK, Christiansen JS, et al. OPPORTUNITY: a randomized clinical trial of growth hormone on outcome
in hemodialysis patients. Clin J Am Soc Nephrol. 2008;3(6):1741-1751.
Locatelli F, Martin-Malo A, Hannedouche T, et al. Effect of membrane permeability on survival of hemodialysis patients.
J Am Soc Nephrol. 2009;20(3):645-654.
a
Composite CVD outcome may include all-cause mortality, and each trial may have different cardiovascular events.
b
Results reported are for primary outcome of the study: indicates benefit of intervention, indicates no significant
benefit.
Core Curriculum in Nephrology 401
Table 2. Selected Randomized Clinical Trials in Patients with CKD Stages 1-4 With Focus on Clinical CVD
Outcomes/Mortality
Trial Primary
Intervention Name Population N Outcomea Resultb Comment
Completed Trials
Fosinopril vs PREVEND Microalbuminuria 864 Composite CVD Trend to decrease in
placebo; IT CVD events in
pravastatin fosinopril group
vs placebo
Epoetin alfa to CHOIR CKD, GFR of 15-50 mL/ 1,432 Composite CVD Increased risk
target Hb of min/1.73 m2, Hb 11 of primary
13.5 vs g/dL outcome in
11.3 g/dL higher Hb
group
Darbepoetin TREAT DM, CKD, & anemia 4,038 Composite CVD Increased risk of
alfa vs stroke in higher
placebo Hb group
Ongoing Trials
Simvastatin SHARP CKD component of 3,000 Composite CVD NA
ezetimibe SHARP
vs placebo
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CHOIR, Correction of
Hemoglobin Outcomes in Renal Insufficiency; CKD, chronic kidney disease; CREATE, Cardiovascular Risk Reduction by
Early Anemia Treatment With Epoetin Beta; CVD, cardiovascular disease; DM, diabetes mellitus; GFR, glomerular filtration
rate; Hb, hemoglobin; HOST, Homocysteinemia in Kidney and Endstage Renal Disease; LIRICO, Long-term Impact of RAS
Inhibition on Cardiorenal Outcomes; NA, not available; PREVEND IT, Prevention of Renal and Vascular Endstage Disease
Intervention Trial; SBP, systolic blood pressure; SHARP, Study of Heart and Renal Protection; SPRINT, Systolic Blood
Pressure Intervention Trial; TREAT, Trial to Reduce Cardiovascular Events With Aranesp Therapy.
Reference not included in other parts of this article:
Maione A, Nicolucci A, Craig JC, et al. Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes
(LIRICO) randomized trial. J Nephrol. 2007;20(6):646-655.
a
Composite CVD outcome may include all-cause mortality, and each trial may have different cardiovascular events.
b
Results reported are for primary outcome of the study. indicates benefit of intervention, indicates no significant
benefit.
Risk factors include volume overload and Higher LDL cholesterol Volume overload
Family history of
Lipoprotein(a) and Apo(a)
Increased systolic blood pressure and pulse isoforms & lipoprotein
coronary disease
pressure Left ventricular remnants
Homocysteine
hypertrophy
Oxidative stress/inflammation
White race
Cardiomyopathy Malnutrition
Thrombogenic factors
Greater severity of traditional CVD risk Box 2. Evidence Grades for KDOQI Guideline
factors Recommendations
Role of nontraditional risk factors Grade A
In dialysis patients, goal predialysis and tensive haemodialysis patients. Nephrol Dial Transplant.
postdialysis blood pressures are 140/90 2008;23(11):3605-3612.
Zager PG, Nikolic J, Brown RH, et al. U Curve
and 130/80 mm Hg, respectively (level C association of blood pressure and mortality in hemodialysis
evidence) patients. Medical Directors of Dialysis Clinic, Inc. Kidney
ACE inhibitors or angiotensin II receptor Int. 1998;54(2):561-569.
blockers (ARBs) should be preferred in
patients on dialysis (level C evidence) CVD RISK FACTORS: DYSLIPIDEMIA
In patients with CKD stages 1-4, goal blood
pressure is 130/80 mm Hg for prevention Although the nature of dyslipidemia can be highly
of CVD and kidney disease progression variable, it is common in all stages of CKD.
(level B evidence)
Dietary sodium intake 2.4 g/d should be Dialysis
recommended in most adults with CKD and In hemodialysis patients, high-density li-
on the composite primary end point of apply to dialysis patients, given results of
death from CVD causes, nonfatal myocar- the 4D Study and AURORA, particularly in
dial infarction, or nonfatal stroke com- individuals with an expected remaining life-
pared with placebo span less than 5 years
SHARP (Study of Heart and Renal Protec-
CKD Stages 3-4 tion), a randomized trial of a combination of
Higher prevalence of increased LDL choles- simvastatin and ezetimibe, will offer addi-
terol and triglyceride and low HDL choles- tional guidance in individuals with CKD
terol levels compared with the general popu- stages 4-5
lation
Nephrotic-range proteinuria can exacerbate SUGGESTED READING
dyslipidemia Baigent C, Landry M. Study of Heart and Renal Protec-
Post hoc analyses of secondary prevention tion (SHARP). Kidney Int Suppl. 2003(84):S207-210.
trials of statins in the general population Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosu-
show similar benefits in patients with and vastatin and cardiovascular events in patients undergoing
hemodialysis. N Engl J Med. 2009;360(14):1395-1407.
without CKD Liu Y, Coresh J, Eustace JA, et al. Association between
In the CARE (Cholesterol and Recurrent
cholesterol level and mortality in dialysis patients: role of
Events) Study, participants with decreased inflammation and malnutrition. JAMA. 2004;291(4):451-
GFR (creatinine clearance 75 mL/min 459.
[1.25 mL/s]) receiving pravastatin had a National Kidney Foundation. K/DOQI Clinical Practice
Guidelines for Managing Dyslipidemias in Chronic Kidney
lower incidence of death from coronary Disease. Am J Kidney Dis. 2003;41(suppl 3):S1-S92.
disease or symptomatic nonfatal myocar- Strippoli GF, Navaneethan SD, Johnson DW, et al.
dial infarction than those receiving pla- Effects of statins in patients with chronic kidney disease:
cebo meta-analysis and meta-regression of randomised controlled
In a pooled analysis using data from 3 trials. BMJ. 2008;336(7645):645-651.
Tonelli M, Keech A, Shepherd J, et al. Effect of pravasta-
randomized trials, pravastatin decreased tin in people with diabetes and chronic kidney disease. J Am
CVD events compared with placebo in Soc Nephrol. 2005;16(12):3748-3754.
patients with CKD Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G.
In a meta-analysis of secondary prevention Pravastatin for secondary prevention of cardiovascular events
of CVD, statins significantly decreased lipid in persons with mild chronic renal insufficiency. Ann Intern
Med. 2003;138(2):98-104.
concentrations and CVD end points in pa- Wanner C, Krane V, Marz W, et al. Atorvastatin in
tients with CKD, but had no benefit on patients with type 2 diabetes mellitus undergoing hemodialy-
all-cause mortality sis. N Engl J Med. 2005;353(3):238-248.
In a primary prevention study, atorvastatin Weiner DE, Sarnak MJ. Managing dyslipidemia in
decreased CVD events, but not all-cause chronic kidney disease. J Gen Intern Med. 2004;19(10):1045-
1052.
mortality, in a post hoc analysis of the CKD
subgroup of CARDS (Collaborative Atorva- CVD RISK FACTORS: DIABETES MELLITUS
statin Diabetes Study)
Diabetes is the leading cause of kidney failure in
KDOQI Guideline Recommendations the United States. Approximately 53% of inci-
All patients with CKD, even in the absence dent dialysis patients in the United States have
of known CVD, should be considered at diabetes.
high risk of CVD outcomes
Goal lipid levels are LDL cholesterol 100
Dialysis
mg/dL (2.59 mmol/L) and non-HDL cho- Diabetes is an independent risk factor for
lesterol 130 mg/dL (3.36 mmol/L) (level ischemic heart disease, heart failure, and
B evidence) all-cause mortality
Worse long-term outcomes after coronary
Additional Considerations interventions than nondiabetic patients
The KDOQI guidelines potentially are still Lack of studies of the relationship between
valid for CKD stage 3, but likely do not glycemic control and CVD outcomes
Core Curriculum in Nephrology 407
tive for assessing left ventricular mass, but CVD RISK FACTORS: SMOKING
is not yet widely available and is more Few studies have examined specific effects
expensive of smoking in dialysis patients
Magnetic resonance imaging with gadolin- Evaluation of US Renal Data System
ium is contraindicated in patients with (USRDS) data showed that smoking was a
estimated GFR 30 mL/min/1.73 m2 strong independent risk factor for incident
(0.50 mL/s/1.73 m2), including patients heart failure, incident peripheral vascular
on dialysis therapy, given the risk of disease, and all-cause mortality
nephrogenic systemic fibrosis Given marked benefits of smoking cessation
in the general population, the general consen-
Treatment sus is to recommend smoking cessation
Goal is afterload reduction, blood pressure
Three large randomized trials have been with cardiac disease who are receiving hemodialysis and
published on the effect of anemia treatment epoetin. N Engl J Med. 1998;339(9):584-590.
Drueke TB, Locatelli F, Clyne N, et al. Normalization of
on CVD events hemoglobin level in patients with chronic kidney disease
In the CREATE (Cardiovascular Risk Re-
and anemia. N Engl J Med. 2006;355(20):2071-2084.
duction by Early Anemia Treatment with Mehdi U, Toto RD. Anemia, diabetes, and chronic
Epoetin Beta) Study, correction of anemia kidney disease. Diabetes Care. 2009;32(7):1320-1326.
to a hemoglobin target of 13-15 g/dL National Kidney Foundation. KDOQI Clinical Practice
Guidelines and Clinical Practice Recommendations for Ane-
(130-150 g/L) compared with correction mia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5
to 10.5-11.5 g/dL (105-115 g/L) did not suppl 3):S11-145.
reduce the risk of the primary CVD com- National Kidney Foundation. KDOQI Clinical Practice
posite Guideline and Clinical Practice Recommendations for Ane-
In the CHOIR (Correction of Hemoglobin mia in Chronic Kidney Disease: 2007 update of hemoglobin
target. Am J Kidney Dis. 2007;50(3):471-530.
Outcomes in Renal Insufficiency) Study,
Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of
targeting a hemoglobin level of 13.5 g/dL darbepoetin alfa in type 2 diabetes and chronic kidney
(135 g/L) compared with 11.3 g/dL (113 disease. N Engl J Med. 2009;361(21):2019-2032.
g/L) was associated with increased risk of Singh AK, Szczech L, Tang KL, et al. Correction of
death and CVD hospitalizations and no anemia with epoetin alfa in chronic kidney disease. N Engl
J Med. 2006;355(20):2085-2098.
incremental improvement in quality of
Vlagopoulos PT, Tighiouart H, Weiner DE, et al. Anemia
life as a risk factor for cardiovascular disease and all-cause
In TREAT (Trial to Reduce Cardiovascu- mortality in diabetes: the impact of chronic kidney disease.
lar Events With Aranesp Therapy), target- J Am Soc Nephrol. 2005;16(11):3403-3410.
ing a hemoglobin level of 13 g/dL (130 Unger EF, Thompson AM, Blank MJ, Temple R. Eryth-
ropoiesis-stimulating agentstime for a reevaluation. N Engl
g/L) compared with rescue therapy with
J Med. 362(3):189-192.
darbepoetin alfa when hemoglobin level
was 9 g/dL (90 g/L) did not reduce the
risk of the 2 primary composite outcomes CVD RISK FACTORS: OXIDANT STRESS AND
(either death or CVD event or death or INFLAMMATION
kidney event) and was associated with Background
increased risk of stroke
Proposed as a unifying concept linking both
Besarab A, Bolton WK, Browne JK, et al. The effects of patients suggest that decreasing oxidative
normal as compared with low hematocrit values in patients stress may improve outcomes
410 Shastri and Sarnak
Vitamin E administration in patients with advanced chronic kidney disease and end-stage renal dis-
prevalent CVD was associated with lower ease: a randomized controlled trial. JAMA. 2007;298(10):
1163-1170.
incidence of primary composite CVD end Wrone EM, Hornberger JM, Zehnder JL, McCann LM,
point compared with placebo Coplon NS, Fortmann SP. Randomized trial of folic acid for
Acetylcysteine administration was associ- prevention of cardiovascular events in end-stage renal dis-
ated with a decrease in composite CVD ease. J Am Soc Nephrol. 2004;15(2):420-426.
end points
CVD RISK FACTORS: NITRIC OXIDE,
Because the trials were small, there cur-
rently is insufficient evidence to recommend ASYMMETRIC DIMETHYLARGININE (ADMA),
screening or treatment of inflammation and AND ENDOTHELIAL FUNCTION
oxidative stress In patients with CKD, decreased nitric oxide
Until recently, homocysteine was impli- tabolism with vascular calcification and arte-
cated in the general population as a risk riosclerosis are complex and not fully under-
factor for myocardial infarction and stroke stood
Reflects interrelationship among hyper-
Levels increase as GFR decreases
Trials have shown that treatment with high phosphatemia, secondary hyperparathy-
doses of B vitamins decreases homocysteine roidism, vitamin D deficiency, and other
levels, but do not decrease CVD outcomes promoters or inhibitors of calcification
Active cellular process in which vascular
in patients with CKD
smooth muscle cells differentiate into os-
SUGGESTED READING teoblast-like cells, which are able to syn-
Jamison RL, Hartigan P, Kaufman JS, et al. Effect of thesize proteins that favor vascular calcifi-
homocysteine lowering on mortality and vascular disease in cation
Core Curriculum in Nephrology 411
rosis and medial calcification that is com- Patients with ST-segment elevation myocar-
mon in CKD dial infarction should receive acute reperfu-
sion therapy
Cardiac Catheterization In dialysis patients, the potential for in-
creased hemorrhagic risk is associated with
Anatomic description and possible repair of
thrombolytic therapy, and percutaneous cor-
the coronary anatomy
onary intervention is the preferred treatment
In dialysis patients who are at high risk of
if it is available (level C evidence)
CAD, coronary angiography may be appro- Specific attention should be given to medica-
priate, even when stress imaging test results
tions that have altered clearance in patients
are negative due to lower diagnostic accu- with CKD (eg, low-molecular-weight
racy of noninvasive stress imaging tests heparin)
(level C evidence)
Conversely, patients may have ischemic Chronic Ischemic Heart Disease
heart disease in the absence of large-vessel Few trial data for secondary prevention
coronary disease strategies that have focused on patients with
Higher risk population for complications, CKD
including bleeding and re-stenosis with or Medical management of chronic CAD simi-
without stent placement lar to that in the general population and
Recent study showed that approximately
should include aspirin, -blockers, nitroglyc-
22% of dialysis patients who underwent erin, ACE inhibitors or ARBs, statins, and
percutaneous coronary intervention re- calcium channel blockers (level C evidence
ceived a contraindicated antithrombotic in dialysis)
(low-molecular-weight heparin and eptifi- Challenges specific to the CKD population
batide), which in turn was associated with include
increased risk of in-hospital major bleed- More frequent hyperkalemia with block-
ing and mortality ade of the renin-angiotensin-aldosterone
Preservation of existing kidney function is system
an important consideration in all stages of Increased risk of rhabdomyolysis with
in CKD
Diagnosis
Use extremely judiciously, with careful
Nonspecific symptoms, such as chest pain,
attention to dosage, drug levels, and potas-
sium balance fever, chills, malaise, dyspnea, and cough
Pericardial friction rub on physical examina-
Edwards FH, Peterson ED, Coombs LP, et al. Prediction CVD SYNDROMES: VENTRICULAR
of operative mortality after valve replacement surgery. J Am
Coll Cardiol. 2001;37(3):885-892. ARRHYTHMIAS AND SUDDEN DEATH
Herzog CA, Ma JZ, Collins AJ. Long-term survival of Epidemiologic Characteristics
dialysis patients in the United States with prosthetic heart
valves: should ACC/AHA practice guidelines on valve selec- Ventricular arrhythmias and ectopy com-
tion be modified? Circulation. 2002;105(11):1336-1341. mon in patients with CKD
London GM, Pannier B, Marchais SJ, Guerin AP. Calci- During the first year of dialysis therapy,
fication of the aortic valve in the dialyzed patient. J Am Soc
cardiac arrest rate is 93 events/1,000 patient-
Nephrol. 2000;11(4):778-783.
Perkovic V, Hunt D, Griffin SV, du Plessis M, Becker GJ. years
Accelerated progression of calcific aortic stenosis in dialysis Sudden cardiac death accounts for about
patients. Nephron Clin Pract. 2003;94(2):c40-45. 60% of all cardiac deaths in dialysis patients
Core Curriculum in Nephrology 417