Acute Coronary Syndrome in Chronic Kidney Disease

Author : Zainuddin
Senin, 27 Juli 2009 11:56:26

dipresentasikan : Jum'at, 24 Juli 2009

Introduction
Chronic kidney disease (CKD), defined by a glomerular filtration rate (GFR) under 60 mL/ min/ 1.73 m2 or evidence
of kidney damage (for example, proteinuria) for at least three months, is a major public health problem. It is one
of the most potent risk factors for cardiovascular disease, and patients with CKD who also have cardiovascular
disease are more likely to progress to renal failure than those without cardiovascular disease.1
Tens of millions of persons worldwide have combined cardiovascular disease and CKD. In the USA alone, over 300
000 individuals are on renal replacement therapy (RRT) which confers a five- to 40- fold increased risk of fatal
cardiovascular events.2
Patients with renal impairment experience a disproportionate burden of cardiovascular morbidity and mortality,
largely the result of accelerated atherogenesis, a hallmark characteristic of significant renal dysfunction.3 Patients
with CKD have shown higher rates of silent ischemia, which cluster with serious arrhythmias and other cardiac
events.4 It progresses at a more rapid rate than in people without chronic kidney disease and is often
undertreated.5 Patients with end-stage renal disease (ESRD) have a 20 to 40 fold higher cardiovascular mortality
than patients without renal disease.6
The traditional risk factors consist of older age, male, hypertension, dyslipidemia (high LDL and low HDL
cholesterol), diabetes mellitus, smoking, physical inactivity, family history (premature onset ) cardiovascular
disease and left ventricular hypertrophy, are independent predictors of cardiovascular disease in chronic kidney
disease. Meanwhile, non-traditional cardiovascular risk factors which play a potentially important role in chronic
kidney disease are albuminuria, elevated homocysteine, elevated lipoprotein (a), anaemia, abnormal calcium and
phosphate metabolism, extracellular fluid volume overload, oxidative stress, inflammation (C-reactive protein),
malnutrition, and thrombogenic factors.5
CKD patient with ischemic heart disease are recommended to have aspirin, beta blockers, ACE inhibitors and
statins to achieve similar targets to those currently suggested for patients without CKD. International best practice
clinical guidelines also recommend that percutaneous coronary intervention and coronary artery bypass grafting
are appropriate revascularization techniques for patients with CKD who have obstructive lesions in their coronary
arteries.5
Aim of Presentation
The aim of this presentation is to report a case of CKD patient who had a recurrent angina with acute pulmonary
edema which finally successfully underwent percutaneous coronary intervention (PCI) with the back up of
continuous renal replacement therapy after an optimal treatment.

Case Illustration
A 61 years old patient admitted to emergency department of National Cardiovascular Centre Harapan Kita
(NCCHK) with the chief complaint of left arm pain occurred suddenly 1 hour prior to admission while having a rest
accompanied with diaphoresis and shortness of breath, subsided with isosorbid dinitrate (ISDN) 5 mg/ sl and the
duration was more than 20 minutes. No history of nausea, vomiting, and palpitations found. Dyspnoe on effort,
orthopnoe and paroxysmal nocturnal dyspnoe were present.
This patient was an old patient diagnosed as chronic heart failure due to hypertensive heart disease (HHD),
Diabetes Mellitus type 2, Chronic kidney disease (CKD) stage V with the previous history of Cerebrovascular

disease (CVD). He was medically treated with : Cardioaspirin 1 x 100 mg, Clopidogrel 1 x 75mg, Amlodipin 1 x 10
mg, Bisoprolol 1 x 5 mg, ISDN 3 x 25 mg, Hydralazine 3 x 50 mg, simvastatin 1 x 20 mg, Allopurinol 2 x 100 mg,
Sodium bicarbonate 3 x 500 mg, Furosemide 1 x 40 mg, and Insulatard 16 iu 10 iu. The patient had a regular
control and took all medications regularly. During admission at emergency ward, the complaint had relieved.
From physical examination, the patient looked moderately ill, fully alert with blood pressure 172/ 72 mmHg,
regular heart rate was 82 x/ minute, respiratory rate was 24x/ minute, peripheral O2 saturation was 99% (nasal O2
3l/ minutes), normal body temperature and body weight was 65 Kg, height was 168 cms with the body mass index
was 23 Kg/cm2.
Anemic palpebra with a normal jugular vein pressure were present. Auscultation revealed a normal heart sound
with neither gallop nor murmur. A normal vesicular respiratory sound was found with rales at both basal side of
the lung field without any wheezing. Abdomen was soft, without hepatospleenomegaly with a normal peristaltic
sound. Warm acrals and equal pulsation were found without any edema.
The electrocardiogram showed a sinus rhytm with QRS rate 87 x/ , normal QRS axis, normal P wave (0.08),
normal PR interval (0.18), normal QRS duration (0.08), ST Depression I, aVL, V4 V6, II aVF, poor R wave V1V3, LVH (+).
Laboratory examination showed hemoglobin value of 9.2 g/ dl, white blood cell count 8300, hematocrit value 27%,
ureum 144 mg/ dl, BUN 62.29, creatinin 6.4 mg/ dl, uric acid 9.4, random blood glucose 315 mg/ dl, total protein
6.3 g/ dl, Na 135 mmol/ l, K 4.2 mmol/l, Total Ca 2.6 mg/ dl, Chloride 101 mg/ dl, Mg 2.1 mg/ dl. Creatinine
clearance was 11, Osmolarity was 308, CK MB 20  34, Trop T 0.03  0.4. Lipid profile revealed
total cholesterol of 185, High density lipoprotein (HDL) 32, low density lipoprotein (LDL) 118, Triglyceride 151.
Chest X-ray demonstrated mild cardiomegaly with CTR 55%, normal aortic segment, normal pulmonary segment,
normal cardiac waist, downward apex, and congestion was positive without any infiltrate.
Echocardiography study in this patient showed mild LV dilatation, concentric LVH, normal LV systolic contractility
with EF 60% (EDD 59, ESD 39), normal RV contractility with TAPSE 1.8 cm, Global normokinetic of the wall motion,
diastolic dysfunction (E/A < 1), with mild aortic regurgitation.
Renal ultrasonography performed on November 11th 2008 concluded bilateral chronic kidney disease with left
renal cyst.
The patient was diagnosed as NSTEMI TIMI 4/7, Hypertension Stage II, CHF Fc III due to HHD, DM Type 2 and CKD
stage V. He was positioned at ICVCU ward and medically treated with Cardioaspirin 1 x 100 mg, Clopidogrel 1 x
75mg, Amlodipin 1 x 10 mg, Bisoprolol 1 x 5 mg, ISDN 3 x 25 mg, Hydralazine 3 x 50 mg, simvastatin 1 x 20 mg,
Allopurinol 2 x 100 mg, Sodium bicarbonate 3 x 500 mg, Diazepam 2 x 5 mg, Laxadin once daily, Regular Insulin
drips, Heparinization with Unfractionated heparin (UFH) 4000 iu/ bolus, continued with 800 iu, heart diabetic diet I
1800 Kcal/ 24 hours and total fluid 1800 cc/ 24 hour.
During the follow up at ICVCU ward, the patient had a recurrent angina which relieved with ISDN 5 mg and
uptitrating the nitroglycerin NTG, but at the fourth day he had an acute pulmonary edema which stabilized with
the administration of continuous pulmonary airway pressure, NTG and furosemide 5 mg/ drips/ hourly. Kidney
function worsened characterized with the increased of ureum level up to 180 mg/ dl, creatinine was 8 mg/ dl with
oligouria (less than 300 cc/ 24 hour). He was undergone continuous venous to venous hemofiltration (CVVH) and
planned for PCI. Blood transfusion was given to achieve hemoglobin level > 10 g/dl and continued with
erythropoietin administration. Percutaneous Transluminal Coronary Angiography (PTCA) was performed after the
patients condition had been stable and successfully revascularized Left anterior descending artery with double
stents; Tsunami 2.5/ 30 and Mustang 2.75/ 30 and dilated left circumflex artery with voyager balloon. TIMI 3 flow
was found after the procedure. Patient underwent CVVH again and was sent home after his condition was
clinically stable with optimal medical treatment. He was recommended to see a nephrologists for further
management of his kidney problem and regular control to NCCHK.
Discussion
CKD is a clinical human model of accelerated arteriosclerosis. In CKD the presentation of coronary artery disease is
often atypical. Patients may not experience chest pain owing to diabetic or uremic neuropathy.6-7 As presented in
this case, patient admitted due to left arm pain accompanied with diaphoresis and shortness of breath. Diagnosis
of NSTEMI was established based on clinical presentations, supported with the electrocardiogram (ECG) showed

ST depression at V4 V6 , II aVF with poor R wave V1 V3 and laboratory examination revealed the elevation of
serial cardiac enzymes (CKMB 20 &#61664; 34, Trop T 0.03 &#61664; 0.4).
Reference no.2
Hypertension which is one of the conventional cardiovascular risk factors in CKD patients resulted in increased
afterload, left ventricular enlargement, greater myocardial oxygen consumption, and augmented sheer stress at
the endothelial level. Many CKD patients with hypertension develop left ventricular hypertrophy, resulting in an
increased myocardial mass to endothelial surface area, and an unfavourable myocardial oxygen supply and
demand relation. Hyperactivation of the Renin-angiotensin system (RAS) leads to expression of oxidized low
density lipoprotein receptors and acceleration of atherosclerosis. As GFR declines, systemic blood pressure rises
causing greater sheer stress, increased risk of plaque rupture, and episodic coronary occlusion. Consequently,
blood pressure control to a target systolic blood pressure < 130 mmHg (ideally < 120 mmHg) is currently
recommended.2 In this case, patients blood pressure was attempt to reach the target by combining several oral
antihypertensive agents such as amlodipin, bisoprolol and hydralazin.
Reference no.2
Over 40% of end stage renal disease (ESRD) is secondary to diabetic nephrosclerosis and 48-57% of patients with
diabetes mellitus (DM) have overt diabetic nephropathy. Patients with diabetes mellitus have significantly raised
concentration of serum insulin, a potent growth factor of atherosclerosis. Optimal glycaemic control
(glycohaemoglobin < 7%) has been shown to reduce microvascular events (retinopathy) and, along with blood
pressure lowering, decrease the incidence of macrovascular events (myocardial infarction, stroke, and CVD death)
in patients with type 1 or type 2 diabetes.2 In this case presented, diabetes was controlled with insulin with the
target of randomized blood glucose of < 150 mg/ dl.
Dislipidaemias occur in up to 67% CKD patients. This patient population often demonstrates diminished
concentrations of cardioprotective high density lipoprotein cholesterol (HDL-C) , and atherogenic increases in
triglycerides and low density lipoprotein cholesterol (LDL-C). Furthermore, uraemic stress results in increased
concentrations of oxidized LDL-C, a highly reactive and atherogenic species.2
In the presented case, total cholesterol was 185, High density lipoprotein (HDL) was 32, low density lipoprotein
(LDL) was 118 and Triglyceride was 151, indicating the high level of atherogenic factors.
Reference no.2
Other novel coronary disease risk factors is homocysteinaemia which is a product of methionine metabolism, that
will be increase two to fourfold in patients with CKD. Patients with raised homocystein concentrations have a
three to fourfold increased cardiovascular event rate. Accordingly, supratheurapeutic doses of folic acid (5-20 mg
daily) and vitamin B12 may decrease homocystein concentrations by 20-55% in ESRD patients.2,6
Lipoprotein Lp(a) concentrations are increased 43% in patients on renal replacement therapy (RRT) as compared
with the general population. The putative atherogenic mechanism of Lp(a) includes macrophage foam cell
production, inhibition of fibrinolysis, and adverse effects on endothelial dependent vascular reactivity. Preliminary
studies demonstrate that Lp(a) concentrations may be reduced with niceritrol (a niacin prodrug) , plasma
apheresis and renal transplantation.2,7
Patients with CKD and ESRD experience significant oxidative stress manifested by abundant glycosylation products
and oxidized protein such as LDL-C. Oxidative stress has profound atherogenic effects as reactive oxygen species
combine with nitric oxide resulting in endothelial dysfunction. Meanwhile, patients with CKD have increased
concentrations of asymptomatic dimethyl arginine, a nitric oxide synthase inhibitor, and correspondingly
diminished concentrations of nitric oxide, a potent coronary vasodilator and important local factor in endothelial
function. Other aberrancies of CKD include raised endothelin production and reduced thrombomodulin
expression. The end result is impairment of coronary flow reserve and myocardial microcirculation.2,7
Reference no 2
Transforming growth factor beta 1 (TGF-&#946;1) is implicated in the pathogenesis of diabetic nephropathy. TGF&#946;1 is an anti inflammatory cytokine that may show repair or protective effects in atherosclerosis. In ESRD

patients, serum concentrations of TGF-&#946;1 are reduced as compared with the general population, and may
result in accelerated atherosclerosis. TGF-&#946;1 values are reduced in CKD patients with cardiovascular or
peripheral arterial disease.2
Markers of inflammation (C-Reactive Protein, fibrinogen and cytokines) are frequently increased in CKD and
associated with a poor cardiovascular prognosis especially in patients with ESRD. Microalbuminuria, one of the
first signs of renal disease in diabetic patients, is associated with a high prevalence of cardiovascular disease.
Proteinuria is frequently associated with other risk factors, which may reflect endothelial dysfunction and
anomalies in fibrinolysis.7
In CKD patients, phosphate and calcium metabolism is disturbed due to secondary hyperparathyroidism.
Hyperphosphatemia seems to be the main deleterious consequence with a 30% increase in cardiovascular
mortality for patients who have phosphatemia > 2 mmol/l. Calcium deposits are common in atherosclerosis
lesions, in the media of arteries, and in valves. Serum calcium and phosphate concentrations as well as the
calcium-phosphate product significantly impact vascular calcification.2,7
Anemia is a classical risk factor of left ventricular hypertrophy, CHF, coronary artery disease (CAD) and cardiac
mortality. Correction of anemia with erythropoietin has been demonstrated to improve clinical tolerance and to
reduce global mortality. Current practice guidelines therefore recommend a hemoglobin target of 11-12 g/ dl for
all patient s with CKD.1,7 Patients in this case had been received blood transfusion and erythropoetin to reach
hemoglobin 0f 11 g/ dl .
Another interesting issue in CKD patients who present with acute coronary syndrome are less likely to receive
standard treatment such as aspirin, heparin, &#946; blockers and angiotensin converting enzyme (ACE) inhibitors,
and are 51% less likely to receive reperfusion therapy as compared with normal renal function. Many CKD patients
at risk for cardiovascular disease (CVD) do not receive antiplatelet treatment because of concerns over platelet
dysfunction and potential for bleeding complications. The combination of excess thrombin generation and
decreased platelet aggregability make the patient with CKD at risk simultaneously, for thrombotic events and
hemorrhage. In general, low dose daily aspirin is recommended for those with CKD, since it is considered a CVD
risk equivalent state.2 In this presented case, patient was administered low dose aspirin, clopidogrel and
unfractionated heparin without any bleeding complications occurred. Thrombocytes level was within normal
during medical treatment in CVCU.
Invasive management of coronary artery disease has been routinely performed in these patients in an attempt to
reduce the likelihood of subsequent cardiac events. Manske et al showed that in diabetics with end-stage renal
disease due to diabetic nephropathy interventional therapy (PTCA/CABG) is superior to conservative drug therapy.
In the analysis of from the US Renal Data System database, Herzog et al showed that CABG was associated with a
significantly higher 2 year survival than PTCA.
However patients with varying degrees of renal failure make up an increasing percentage of the population
undergoing percutaneous coronary intervention (PCI). Another issue related to this procedure is nephropathy
induced by exposure to radiocontrast agents which associated with significant in-hospital and long term morbidity
and mortality. Patients with preexisting renal failure are at particularly high risk. Marenzi et al reported that in
patients with chronic renal failure who are undergoing PTCA, periprocedural hemofiltration given in an ICU setting
appears to be affective in preventing the deterioration of renal function due to contrast-induced nephropathy and
is associated with improved in-hospital and long-term outcomes.8-12 Patients with pre-existing renal insufficiency
or a history of renal dysfunction following contrast exposure must be well hydrated before intervention. Initiation
of intravenous crystalloid infusion (75-150 cc/ hr of normal saline) is advisable. Supplemental diuretics may be
necessary to prevent pulmonary congestion if concomitant LV dysfunction is present. Upon completion of the
case, crystalloid infusion is usually continued for an additional 8-24 hours to facilitate excretion of the contrast
agent. Choice of contrast based on a recent prospective multicenter randomized trial reported a 45% reduction inhospital ischemic complication with low-osmolar nonionic iodixanol (Visipaque) compared to low-osmolar ionic
ioxaglate (Hexabrix).13 In the presented case, patient underwent PTCA with a good result backed up by
periprocedural and postprocedural hemofiltration with a tight monitoring of volume status.
Another important issue regarding PTCA in CKD patients is restenosis. As noted, patients who underwent
conventional PTCA in early trials frequently required subsequent revascularization, in comparison with CABGtreated patients. Among the clinical factors that determined outcomes with PTCA were renal failure and diabetes.

Each condition now has become a recognized risk factor for restenosis of coronary stents. Patients who develop
ischemic symptoms between the first and eight months after PTCA need to be evaluated for restenosis. Restenosis
is a response to vascular injury. Candidate mechanism in the patient with diabetes involve the vascular endothelial
response to ballon and stent instrumentation during the intervention. Factors that were cited in a recent review
by Karha and Bhatt were increased neointimal proliferation, extensive platelet aggregation and adhesion,
increased vascular inflammation, impaired endothelial function, impaired fibrinolytic activity, hyperinsulinemia,
and hyperglycemia. Smaller vessel caliber was the principal determinant of in-stent restenosis in the study by
West et al. 14 The recent introduction of drug-eluting stents has dramatically decreased the incidence of
restenosis and the need for repeat revascularization. However the superiority of drug-eluting stents has yet to be
established in patients with CKD. Although there were no difference in the rates of restenosis, Na et al showed
that drug-eluting stents significantly reduced the rate of all cause mortality and myocardial infarction and propose
the more frequent use of drug-eluting stents should be recommended to improve the long-term outcomes in
patients with renal dysfunction.15
As CKD accelerates cardiovascular disease, management of the risk factors should be achieved. Smoking cessation,
weight control management, restriction of salt intake, physical activity, blood pressure control, reduction of
proteinuria, cholesterol and glycaemic control, and limitation of alcohol consumption should be fulfilled.1
CONCLUSION
Patients with renal disease have a high prevalence of CVD and its associated sequele , which may be partially
explained by conventional CVD risk factors such as hypertension, diabetes mellitus and dyslipidemia. Thus,
aggressive treatment of these risk factors with diet, exercise, weight reduction, and drug treatment should reduce
the CVD burden in CKD patients. Novel CVD risk factors such as homocysteinemia, raised Lp(a), oxidative stress,
endothelial dysfunction, decreased concentration of TGF-&#946;1, chronic inflammation, and vascular calcification
appear to play an escalating role in the accelerated rates of atherogenesis in these patients. Aggressive risk factor
modification, preventive treatments, and arterial graft revascularization may result in improved outcomes.
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