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Japanese Society for Dialysis Therapy Guidelines forManagement of Cardiovascular Diseases in Patients on

Chronic Hemodialysis

Hideki Hirakata,1 Kosaku Nitta,2 Masaaki Inaba,3 Tetsuo Shoji,3 Hideki Fujii,4

Shuzo Kobayashi,5 Kaoru Tabei,6 Nobuhiko Joki,7 Hiroki Hase,7 Masato Nishimura,8

Shigeyuki Ozaki,9 Yuji Ikari,10 Yoshitaka Kumada,11 Kazuhiko Tsuruya,12

Shouichi Fujimoto,13 Tohru Inoue,14 Hiroyoshi Yokoi,15 Sumio Hirata,16

Kazuaki Shimamoto,17 Kiyotaka Kugiyama,18 Takashi Akiba,19 Kunitoshi Iseki,20

Yoshiharu Tsubakihara,21 Tadashi Tomo,22 and Tadao Akizawa23

1Division of Nephrology and Dialysis Center, Fukuoka Red Cross Hospital, Fukuoka, 2Department ofMedicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, 3Department of Metabolism,

Endocrinology and Molecular Medicine, Faculty of Internal Medicine, Osaka City University Graduate Schoolof Medicine, Osaka, 4Division of Nephrology and Kidney Center, Kobe University Graduate School of

Medicine, Kobe, 5Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kanagawa,6Division of Nephrology, First Department of Integrated Medicine, Omiya Medical Center, Jichi Medical

University, Tochigi, 7Department of Nephrology, Toho University Ohashi Medical Center, Tokyo,8Cardiovascular Division, Toujinkai Hospital, Kyoto, 9Department of Cardiovascular Surgery, Toho University

Ohashi Medical Center, Tokyo, 10Department of Cardiovascular Medicine, Tokai University School of Medicine,Kanagawa, 11Department of Cardio-Vascular Surgery, Nagoya Kyoritsu Hospital, Nagoya, 12Department ofIntegrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University,

Fukuoka, 13Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University ofMiyazaki, Miyazaki, 14Department of Neurosurgery, Fukuoka University Hospital, Fukuoka, 15Cardiovascular

Medicine, Kokura Memorial Hospital, Kitakyushu, 16Division of Clinical Pharmacology, Faculty ofPharmaceutical Sciences, Kumamoto University, Kumamoto, 17Sapporo Medical University, Hokkaido,

18Department of Internal Medicine II, Faculty of Medicine, University of Yamanashi, Yamanashi, 19Departmentof Blood Purification, Kidney Center, Tokyo Women’s Medical University, Tokyo, 20Dialysis Unit, University ofThe Ryukyus, Okinawa, 21Departments of Kidney Disease and Hypertension, Osaka General Medical Center,

Osaka, 22Department of Nephrology, Oita University Hospital, Oita, and 23Division of Nephrology, Departmentof Medicine, Showa University School of Medicine, Tokyo, Japan

INTRODUCTION

The annual all-cause mortality in chronic dialysispatients in our country is within 10%, indicating thatthe outcome of dialysis therapy in Japan is one of thebest in the world. It is nothing short of extraordinaryto maintain favorable survival like this despite chal-

lenging conditions such as aging of the patients andincrease in the proportion of patients on long-termdialysis and with diabetes mellitus. We can be proudof our achievement. Novel therapeutic strategies fordialysis patients have been developed, such as anti-hypertensive drugs (e.g. angiotensin II receptorblockers, calcium channel blockers and beta block-ers), treatment of anemia (e.g. erythropoiesis stimu-lating agents), and management of chronic kidneydisease-mineral and bone disorder (CKD-MBD)(e.g. activated vitamin D, calcimimetics, and newphosphate binders). While the beneficial effect ofthese new approaches is well acknowledged, we mustnot forget that the favorable outcome is also due to

Received March 2012.Address correspondence and reprint requests to Dr Hideki

Hirakata, Division of Nephrology and Dialysis Center, FukuokaRed Cross Hospital, Fukuoka 815-8555, Japan. Email: [email protected]

Published in J Jpn Soc Dial Ther 2011;44:337–425 (in Japanese).Reprinted with permission from the Journal of the Japanese Societyfor Dialysis Therapy.

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Therapeutic Apheresis and Dialysis 2012; 16(5):387–435doi: 10.1111/j.1744-9987.2012.01088.x© 2012 The AuthorsTherapeutic Apheresis and Dialysis © 2012 International Society for Apheresis

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the considerable efforts and excellence in manage-ment of all the medical staff, including physicians,nurses, and clinical engineers, who are engaged indialysis therapy in Japan.

While mortality due to infectious diseases isincreasing at present,about half of dialysis patients diefrom cardiovascular disease (CVD). Thus, the man-agement of CVD has become the most challengingclinical issue in dialysis patients.With regard to CVD,the main focus has so far been on blood vessel diseasesof the heart and brain; however, peripheral arterydisease (PAD) is now also attracting attentionbecause the number of patients with atheroscleroticobstruction of the peripheral arteries in the lowerextremities has increased in recent years and endovas-cular catheter therapy has been introduced and devel-oped.The number of specialists in the field of PAD hasincreased along with the development of new bio-medical technology and expansion of their use. Endo-vascular catheter therapy is currently offered topatients with chronic dialysis and we expected anincrease in the number of patients benefiting fromthis therapy. Evidence suggests that the pathologicalprocess of CVD is also involved in the aggravationof systemic atherosclerosis associated with renaldysfunction, prompting the use of potent anti-atherogenic agents, such as statins in dialysis patientssimilar to the general population.

With regard to CVD in dialysis patients, unfortu-nately, there is little clinical evidence to justify thecompilation of clinical guidelines. For example, theappropriate blood pressure level in such patientsremains unknown, and the target blood pressurelevel for management of hypertension has not yetbeen defined even in the guidelines issued byWestern countries. Although we discussed this issuein detail in several committee meetings, we onlyagreed on setting the target blood pressure thoughwe presented this as an opinion rather than guide-line by the committee. There is no doubt that weneed to validate in the future whether the level isappropriate or not. In fact, we do not know whetherany statement on the clinical guideline is right ornot especially when evidence is insufficient, and anystatement is nothing but “themes of clinical ques-tions”. We need to validate this issue by prospectivehigh-evidence grade studies. The Japanese Societyfor Dialysis Therapy (JSDT) maintains a patientregistry database kept with the standing committeeresponsible for statistics and investigation. We usedthe data stored in this database to generate thepresent guideline. We stress that we should continueto maintain this important registry system in orderto revise the clinical guidelines in the future.

The chapters on cardiac failure, ischemic heartdisease, arrhythmia, valvular heart disease, cere-brovascular disease, and peripheral artery disease inthe guideline are separated into those for “renaldialysis physicians” and “cardiologists (or strokolo-gists)” in order to demonstrate the importance ofcooperation between these two specialties. We thinkthat the excellent outcome of dialysis therapy inJapan is in part attributed to the implementation ofexcellent daily clinical procedures, which are basedon “evidence” and/or “experience” in each dialysisfacility. We have to validate the daily proceduresand present them as treatment guidelines. We hopethis guideline is useful in daily clinical practice.

We determined the grading evidence and recom-mendation levels according to the position statementfrom Kidney Disease: Improving Global Outcomes(1,2).

REFERENCES

1. Uhlig K, Macleod A, Craig J et al. Grading evidence and rec-ommendations for clinical practice guidelines in nephrology. Aposition statement from Kidney Disease: Improving GlobalOutcomes (KDIGO). Kidney Int 2006;70:2058–65.

2. Fukagawa M, Tsukamoto Y, Tsubakihara Y et al. Evaluation ofevidence level and recommendation grade of clinical practiceguidelines. J Jpn Soc Dial Ther 2010;43:347–9.

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Chapter 1: Dyslipidemia/Atherosclerosis-Arteriosclerosis

I. DYSLIPIDEMIA

Statements

1. In dialysis patients, dyslipidemia is an indepen-dent risk factor for cardiovascular diseases, par-ticularly incident myocardial infarction (B).

2. We recommend measurement of low-densitylipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C),HDL-C, and triglyceride (TG) before dialysis(casual blood sampling) for routine evaluation(1B).

3. We suggest the control target levels shouldbe LDL-C < 120 mg/dL or non-HDL-C <150 mg/dL for the primary prevention,and LDL-C < 100 mg/dL or non-HDL-C <130 mg/dL for the secondary prevention ofischemic heart disease (2C).

4. We suggest that administration of statin shouldbe considered if lipid control cannot be achievedby dietary/exercise therapy (2B).

5. We suggest that the evaluation and interven-tion of undernutrition should be consideredif hypolipidemia is present.

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© 2012 The AuthorsTherapeutic Apheresis and Dialysis © 2012 International Society for ApheresisTher Apher Dial, Vol. 16, No. 5, 2012

Comments

EpidemiologyObservational studies in Japan have demon-

strated a close relationship between dyslipi-demia (hyper-LDL-cholesterolemia, hypo-HDL-cholesterolemia, hypertriglyceridemia, and/or hyper-non-HDL-cholesterolemia) and the severity ofatherosclerosis (1,2) and also the risk of myocardialinfarction (3) in dialysis patients. In addition, dyslipi-demia is more closely related to coronary arterydisease than cerebrovascular disorders. However,observational cohort studies of dialysis patientsshowed a higher risk of death due to all causes (4) ordeath due to cardiovascular disease (5) in patientswith low total cholesterol (TC) level, reflecting areverse tendency compared with epidemiological datain the general population. Such relationship is,however, not observed in dialysis patients whoare free of inflammation or are not undernourished(as defined by the levels of C-reactive protein [CRP]and serum albumin, respectively) (4,6). In Westerncountries, the survival curve of dialysis patients whodevelop acute coronary syndrome is poorer inpatients with low body mass index (BMI) than in thosewith high BMI (7). Similarly, in Japanese dialysispatients, old age, low BMI, and high CRP are reportedto be factors that enhance the risk of death after acardiovascular event (3). These reports suggest thatundernutrition, represented by hypoalbuminemia,low BMI, and hypocholesterolemia, correlates withincreased risk of death by increasing the risk of deathafter an event (fatality rate), although hypocholester-olemia per se is not considered to promote atheroscle-rosis (8).

CausesDyslipidemia can be classified into primary and

secondary dyslipidemia, depending on the cause.Primary dyslipidemia includes familial hypercholes-terolemia (FH) and familial combined hyperlipi-demia (FCHL), with a reported respective prevalenceof each type of 1:500 and 1:100. Secondary dyslipi-demia is caused by various conditions such as diabetes,endocrine (thyroid, adrenal) disorders, liver diseases,kidney diseases, and drugs. Hypercholesterolemiaassociated with nephrotic syndrome and hypertriglyc-eridemia and hypo-HDL-cholesterolemia associatedwith chronic kidney failure are well-known dyslipi-demias caused by kidney diseases. Low lipoproteinlipase activity (high apo C-III levels), low hepaticlipase level, and low lecithin cholesterol acyltrans-ferase (LCAT) activity contribute to dyslipidemia inpatients with chronic renal failure.

DiagnosisAccording to the Guidelines for Prevention of

Atherosclerotic Cardiovascular Diseases by theJapan Atherosclerosis Society (9), hyper-LDL-cholesterolemia is defined as LDL-C �140mg/dL,hypo-HDL-cholesterolemia as HDL-C <40 mg/dL,and hypertriglyceridemia as TG �150 mg/dL infasting blood samples. However, fasting bloodsamples are often difficult to obtain from dialysispatients. In general, post-prandial changes in TC orHDL-C level are very small, compared with theincrease in TG levels. Thus, LDL-C level calculatedby the Friedewald equation decreases while littlechange is observed in non-HDL-C level (TC minusHDL-C). Also, since non-HDL-C level is the sum ofLDL-C and cholesterol present in TG-rich lipopro-teins (Fig. 1), it is regarded as an integrated index ofthe atherogenic lipoprotein level. Therefore, forroutine evaluation in dialysis patients, non-HDL-Clevel in a casual blood sample is considered accept-able in addition to the standard fasting LDL-C level.

TreatmentIn subjects with dyslipidemia in general, secondary

dyslipidemia is usually excluded first, followed byrecommendations for long-term dietary/exercisetherapy. Drug treatment is also considered if thetarget level cannot be achieved. However, in patientswith coronary artery disease, the first option shouldbe drug treatment. A strict target lipid level is set inpatients that have not developed coronary arterydisease but are at high risk, while a stricter target isset for patients with established coronary arterydisease (secondary prevention group).

According to the recent epidemiological studyof the Japanese Society for Dialysis Therapy (3), therisk of occurrence of acute myocardial infarctionincreases 1.24 times (95% confidence interval: 1.14–

Serum TC Non-HDL

HDL

LDL

VLDL

HDL

LDL(Excluding IDL)

VLDL

HDL

IDL

Density (g/mL)

1.006

1.019

1.063

1.210

FIG. 1. Serum total cholesterol and its components. Serum con-tains a mixture of lipoproteins of different densities (specificgravity), and the total sum of cholesterol in the various lipopro-teins represents serum total cholesterol. Several methods are usedto fractionate lipoproteins. HDL has an anti-atherosclerotic prop-erties, and all other fractions apart from HDL (collectively callednon-HDL) are atherogenic.The cholesterol present in non-HDL isexpressed as non-HDL-C. Thus, non-HDL-C is the sum of choles-terol in atherogenic lipoproteins.

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1.35) with every increase in non-HDL-C level of1 mmol/L (38.7 mg/dL). Based on the results of thisobservational study, the present guidelines propose atarget level of LDL-C <120 mg/dL or non-HDL-C<150 mg/dL for primary prevention, and LDL-C < 100 mg/dL or non-HDL-C level <130 mg/dL forsecondary prevention.

There are only a few randomized controlled trialsin dialysis patients regarding whether lipid loweringtherapy significantly reduces the risk of cardiovascu-lar events. The 4D (Die Deutsche Diabetes Dialyse)study using atorvastatin (10) and AURORA Studyusing rosuvastatin (11) suggested that the risk of allcardiovascular diseases (including those not directlyrelated to atherosclerosis such as heart failure andcerebral hemorrhage) can only be reduced slightlyeven by lipid lowering therapy using statins.However, the risk of ischemic cardiac accidentsdecreased significantly by 18% in the 4D Study.Taking these results and the results of the observa-tional cohort study in Japan into consideration, itwould be reasonable to treat dialysis patients withhigh LDL-C or non-HDL-C levels with statins toreduce the risk of ischemic heart disease. Further-more, there is little medical basis for discontinuationof statins therapy, since statin use is reported to asso-ciate with better survival in both incident (12) andprevalent dialysis patients (13).

In conducting drug therapy, statins are the firstchoice. Statins reduce LDL-C level by 25–40%although this effect varies with the drug and dose.In the above 4D (10) and AURORA (11) studies,the frequency of adverse effects were comparablebetween the statins and placebo groups, suggestingno safety problems with the use of statins. Exclud-ing clinofibrate, fibrates available in Japan are con-traindicated in patients with renal failure due tothe high risk of rhabdomyolysis based on theirexcretion via the kidney. Bile acid-binding resins,eicosapentaenoic acid preparations, and intestinalcholesterol transporter inhibitors can also be usedin dialysis patients. Niceritrol, a nicotinic acidderivative, reduces serum phosphate levels butcould cause anemia and thrombocytopenia andmust be administered with caution in dialysispatients. Many patients are treated with more thanone drug. For safe treatment, one should monitorsymptoms and laboratory tests including serum cre-atine kinase, aspartate aminotransferase and alanineaminotransferase, and also pay attention to druginteractions.

If the patient develops hypolipidemia, a nutritionaldisorder should be suspected, and measures toimprove the nutritional state should be considered.

The following issues are proposed as topics offuture studies; whether a very high TG level is a riskfactor of acute pancreatitis in dialysis patients, andwhether patients undergoing peritoneal dialysis andchildren with renal failure should be treated in amanner similar to that of adult hemodialysispatients. We expect further data from sub-analysesand meta-analysis of the 4D, AURORA, andStudy of Heart and Renal Protection (SHARP)studies.*

*SupplementPapers on subanalyses of the 4D Study (14) and

AURORA Study (15), and the original report ofSHARP (16) appeared during the publication of theguidelines, on which the present simplified guidelinesare based, and the preparation of this simplifiedversion. The subanalyses of 4D and AURORAstudies suggested that lipid lowering therapy pre-vents atherosclerotic cardiovascular events in dia-betic patients on dialysis, and that it significantlyprevents such events more effectively in patients withhigher LDL-C levels before the treatment. SHARPalso showed that lipid lowering therapy using thecombination of simvastatin and ezetimibe signifi-cantly reduced the risk of atherosclerotic cardiovas-cular events and that such reduction showed nosignificant heterogeneity between the patient groupsbefore and after the initiation of dialysis therapy.

REFERENCES

1. Shoji T, Emoto M, Shinohara K et al. Diabetes mellitus, aorticstiffness, and cardiovascular mortality in end-stage renaldisease. J Am Soc Nephrol 2001;12:2117–24.

2. Shoji T, Emoto M, Tabata T et al. Advanced atherosclerosis inpredialysis patients with chronic renal failure. Kidney Int 2002;61:2187–92.

3. Shoji T, Masakane I, Watanabe Y, Iseki K, Tsubakihara Y.Elevated non-high-density lipoprotein cholesterol (non-HDL-C) predicts atherosclerotic cardiovascular events inhemodialysis patients. Clin J Am Soc Nephrol 2011;6:1112–20.

4. Iseki K, Yamazato M, Tozawa M, Takishita S. Hypocholester-olemia is a significant predictor of death in a cohort of chronichemodialysis patients. Kidney Int 2002;61:1887–93.

5. Degoulet P, Legrain M, Reach I et al. Mortality risk factors inpatients treated by chronic hemodialysis. Report of theDiaphane collaborative study. Nephron 1982;31:103–10.

6. Liu Y, Coresh J, Eustace JA et al. Association between cho-lesterol level and mortality in dialysis patients: role of inflam-mation and malnutrition. JAMA 2004;291:451–9.

7. Beddhu S, Pappas LM, Ramkumar N, Samore MH. Malnutri-tion and atherosclerosis in dialysis patients. J Am Soc Nephrol2004;15:733–42.

8. Shoji T, Nishizawa Y. Chronic kidney disease as a metabolicsyndrome with malnutrition-need for strict control of riskfactors. Intern Med 2005;44:179–87.

9. Japan Atherosclerosis Society. Guidelines for Prevention ofAtherosclerotic Cardiovascular Diseases. Tokyo: KyowaKikaku, 2007.



10. Wanner C, Krane V, Marz W et al. Atorvastatin in patientswith type 2 diabetes mellitus undergoing hemodialysis. N EnglJ Med 2005;353:238–48.

11. Fellstrom BC, Jardine AG, Schmieder RE et al. Rosuvastatinand cardiovascular events in patients undergoing hemodialy-sis. N Engl J Med 2009;360:1395–407.

12. Seliger SL, Weiss NS, Gillen DL et al. HMG-CoA reductaseinhibitors are associated with reduced mortality in ESRDpatients. Kidney Int 2002;61:297–304.

13. Mason NA, Bailie GR, Satayathum S et al. HMG-coenzyme areductase inhibitor use is associated with mortality reductionin hemodialysis patients. Am J Kidney Dis 2005;45:119–26.

14. Marz W, Genser B, Drechsler C et al. Atorvastatin and low-density lipoprotein cholesterol in type 2 diabetes mellituspatients on hemodialysis. Clin J Am Soc Nephrol 2011;6:1316–25.

15. Holdaas H, Holme I, Schmieder RE et al. Rosuvastatin indiabetic hemodialysis patients. J Am Soc Nephrol 2011;22:1335–41.

16. Baigent C, Landray MJ, Reith C et al. The effects of loweringLDL cholesterol with simvastatin plus ezetimibe in patientswith chronic kidney disease (study of heart and renalprotection): a randomised placebo-controlled trial. Lancet2011;377:2181–92.

II. ATHEROSCLEROSIS-ARTERIOSCLEROSIS

Statements

1. To evaluate the risk of cardiovascular death indialysis patients, we recommend the inclusion ofrisk factors specific to renal failure (e.g. anemia,inflammation, undernutrition, abnormal min-eral metabolism), in addition to classic riskfactors (1C).

2. The extent of arterial wall thickening, arterialwall stiffening, and vascular calcification may beused for the evaluation of cardiovascular risk(Opinion).

Comments

EpidemiologyIn dialysis patients, the risk of death due to car-

diovascular disease (CVD) such as ischemic heartdisease, cerebrovascular diseases, and heart failure ismarkedly increased, and the relative risk compared tothe general population is reported to be 10–30 (1).Dialysis patients are characterized by a high risk ofCVD events and low survival rate after the onset (highfatality rate). Compared to the general population,dialysis patients show 2–5 times higher risk of incidentacute myocardial infarction and poorer survival rateafter acute myocardial infarction (2). This is also truefor cerebrovascular diseases (3). The high incidenceand high fatality rate are considered to synergisticallyincrease the risk of death due to CVD (4).

CausesOne of the reasons for the high risk of CVD in

dialysis patients is advanced atherosclerosis before

the initiation of dialysis. About half of the patientshave significant coronary artery stenosis at the initia-tion of dialysis (5,6), and the presence or absence ofcoronary artery disease at the initiation of dialysis isa strong predictor of cardiovascular events after theinitiation of dialysis (7).

Vascular calcification is classified into atheroscle-rotic calcification affecting the intimal layer of theartery and Mönckeberg’s sclerosis affecting themedial layer of the artery, especially the latter ismore frequently observed in dialysis patients. Bothtypes of calcification are significant predictors ofdeath in dialysis patients. Abnormal mineral andbone metabolism including vascular calcificationassociated with chronic kidney diseases (CKD) hasbeen integrated as a new concept named CKD-mineral and bone disorder (CKD-MBD) (8), and itis considered important in clinical practice of dialy-sis patients.

Because the risk of CVD in dialysis patients issignificantly high even after correction for classicrisk factors such as old age, hypertension, dyslipi-demia, and diabetes, factors specific to CKD areconsidered to be involved in the elevated risk ofCVD (9). Sarnak et al. (10) noted many factorsincluding anemia, inflammation, undernutrition, andabnormal mineral metabolism as non-classic riskfactors. Among them, undernutrition (wasting) isdiagnosed in daily clinical practice based on thepresence of hypoalbuminemia or low BMI. Accord-ing to reports from Japan, low BMI is a predictor ofall-cause death (11,12) and CVD death (11), but nota predictor of future myocardial infarction (12). Areport from the United States (13) observed thatthe survival curve after the onset of acute coronarysyndrome was poorer in the low BMI group. InJapan, also, low BMI is independently related to therisk of death after CVD including myocardial inf-arction, cerebral infarction, and cerebral hemor-rhage (12). Thus, certain non-classic risk factors areconsidered factors that enhance the fatality rateafter the onset of CVD.

DiagnosisClinically, atherosclerosis-arteriosclerosis can be

evaluated quantitatively and qualitatively by exami-nation of the thickness and stiffness of the arterialwall and vascular calcification (Table 1). These mea-surements may serve as surrogate markers betweenrisk factors and CVD events.

Carotid artery intima-medial thickness is mea-sured by B mode ultrasonography, which providesquantitative evaluation of arterial wall thickening,



and is a predictor of the risk of CVD death and totaldeath in dialysis patients (14).

Aortic pulse wave velocity (cfPWV, hfPWV) is arepresentative index of arterial stiffness and a predic-tor of CVD death and total death in dialysis patients(15). While a high baPWV measured in the brachiumand ankle is also a prognostic factor in dialysispatients (16), its value falsely decreases in patientswith obstructive arteriosclerosis in the lower limbs.Therefore, caution is needed and simultaneous mea-surement of the ankle brachial pressure index (ABI)may be helpful. The Cardio-ankle vascular index(CAVI) and augmentation index (AI) have also beenused as new indices of arterial stiffness.

Various methods are available to evaluate vascularcalcification. Among these, electron beam computedtomography (EBCT) has excellent temporal resolu-tion and provides specific assessment of the heart andlarge blood vessels. Coronary artery calcification isusually evaluated using the coronary artery calcifica-tion score (CACS) calculated by Agatston’s method.CACS has been reported to be a predictor of cardio-vascular events (cardiac death, non-fatal myocardialinfarction) in non-dialysis patients with coronaryartery disease (17). However, while dialysis patientswith high CACS have poor survival, CACS is notnecessarily related to cardiovascular events (18).The sensitivity of multi-detector computed tomogra-phy (MDCT) has improved in recent years, and thismodality has become the mainstay of coronary arterycomputed tomography (CT). Abdominal plain CT isused to measure the area of aortic calcification, usingthe aortic calcification index (ACI), which is deter-mined in 10 slices at 1-cm intervals above the originof the common iliac artery. In dialysis patients, thereis a strong correlation between ACI and coronaryartery calcification (19). The presence or absence of

vascular calcification examined by thoracoabdominalCT (20,21) has also been shown to be an independentpredictor of all-cause death and CVD death in dialy-sis patients and is considered to be useful in dailyclinical practice.

Although evaluation of these non-invasive surro-gate indices may help estimate the individual CVDrisk, the criteria used for their evaluation or appropri-ate frequency of their use have not been established.Longitudinal changes in these measures are not wellknown in dialysis patients.We propose that the evalu-ation method(s) should be selected taking into con-sideration the characteristics of individual patientsand availability in the medical facilities, and toperform the measurement once every year, if possible.

TreatmentWe do not describe here the treatment for each

risk factors and their preventive effects onatherosclerosis-arteriosclerosis because they are dis-cussed in detail in relevant chapters. As for othermatters, lifestyle modifications, including smokingcessation and regular exercise at an intensity appro-priate for each patient are considered important. Fur-thermore, early detection and, if possible, earlytreatment of CVD are particularly important indialysis patients.

REFERENCES

1. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovas-cular disease in chronic renal disease. J Am Soc Nephrol 1998;9:S16–S23.

2. Iseki K, Fukiyama K, The Okinawa Dialysis Study Group.Long-term prognosis and incidence of acute myocardial inf-arction in patients on chronic hemodialysis. Am J Kidney Dis2000;36:820–5.

TABLE 1. Methods for clinical evaluation of atherosclerosis, arteriosclerosis, and vascular calcification

Arterial wall thickening Carotid artery intima-media thickness (IMT) B mode USPresence or absence of plaques

Arterial wall stiffening Pulse wave velocity (cfPWV, hfPWV, baPWV) Pulse wave analysisCardio-ankle vascular index (CAVI), augmentation index (AI)Compliance, stiffness parameter b, etc. M-mode US (echo-tracking system)

Arterial calcification Presence or absence of calcification, semiquantificationof calcification

Plain X-ray

Aortic calcification index (ACI) Plain CTCoronary artery calcification score (CACS) Electron beam CT (EBCT), Multi-detector

CT (MDCT)Vascular luminal

narrowingPresence or absence of narrowing, number of affected vessels,

Gensini scoreContrast-enhanced CT, Coronary angiography

Myocardial ischemia ST-T changes Electrocardiogram (ECG)Ischemic area, coronary blood flow reserve Myocardial scintigraphy (SPECT)

Note that while arterial wall thickening, arterial wall stiffening, and arterial calcification represent changes in the arterial wall itself dueto atherosclerosis-arteriosclerosis, vascular luminal narrowing and myocardial ischemia are changes resulting from atherosclerosis-arteriosclerosis.



3. Iseki K, Fukiyama K, The Okinawa Dialysis Study Group.Clinical demographics and long-term prognosis after stroke inpatients on chronic haemodialysis. Nephrol Dial Transplant2000;15:1808–13.

4. Nishizawa Y, Shoji T, Ishimura E, Inaba M, Morii H. Paradoxof risk factors for cardiovascular mortality in uremia: is ahigher cholesterol level better for atherosclerosis in uremia?Am J Kidney Dis 2001;38:S4–S7.

5. Joki N, Hase H, Nakamura R, Yamaguchi T. Onset of coronaryartery disease prior to initiation of haemodialysis in patientswith end-stage renal disease. Nephrol Dial Transplant 1997;12:718–23.

6. Ohtake T, Kobayashi S, Moriya H et al. High prevalenceof occult coronary artery stenosis in patients with chronickidney disease at the initiation of renal replacement therapy:an angiographic examination. J Am Soc Nephrol 2005;16:1141–8.

7. Hase H, Tsunoda T, Tanaka Y et al. Risk factors for de novoacute cardiac events in patients initiating hemodialysis with noprevious cardiac symptom. Kidney Int 2006;70:1142–8.

8. Moe S, Drueke T, Cunningham J et al. Definition, evaluation,and classification of renal osteodystrophy: a position statementfrom kidney disease: improving global outcomes (KDIGO).Kidney Int 2006;69:1945–53.

9. Schiffrin EL, Lipman ML, Mann JF. Chronic kidney disease:effects on the cardiovascular system. Circulation 2007;116:85–97.

10. Sarnak MJ, Levey AS, Schoolwerth AC et al. Kidney diseaseas a risk factor for development of cardiovascular disease: astatement from the American Heart Association Councils onKidney in Cardiovascular Disease, High Blood PressureResearch, Clinical Cardiology, and Epidemiology and Preven-tion. Circulation 2003;108:2154–69.

11. Kakiya R, Shoji T, Tsujimoto Y et al. Body fat mass and leanmass as predictors of survival in hemodialysis patients. KidneyInt 2006;70:549–56.

12. Shoji T, Masakane I, Watanabe Y, Iseki K, Tsubakihara Y.Elevated non-high-density lipoprotein cholesterol (non-HDL-C) predicts atherosclerotic cardiovascular events inhemodialysis patients. Clin J Am Soc Nephrol 2011;6:1112–20.

13. Beddhu S, Pappas LM, Ramkumar N, Samore MH. Malnutri-tion and atherosclerosis in dialysis patients. J Am Soc Nephrol2004;15:733–42.

14. Nishizawa Y, Shoji T, Maekawa K et al. Intima-mediathickness of carotid artery predicts cardiovascular mortalityin hemodialysis patients. Am J Kidney Dis 2003;41:S76–S79.

15. Shoji T, Emoto M, Shinohara K et al. Diabetes mellitus, aorticstiffness, and cardiovascular mortality in end-stage renaldisease. J Am Soc Nephrol 2001;12:2117–24.

16. Kitahara T, Ono K, Tsuchida A et al. Impact of brachial-anklepulse wave velocity and ankle-brachial blood pressure indexon mortality in hemodialysis patients. Am J Kidney Dis 2005;46:688–96.

17. Keelan PC, Bielak LF, Ashai K et al. Long-term prognosticvalue of coronary calcification detected by electron-beamcomputed tomography in patients undergoing coronaryangiography. Circulation 2001;104:412–7.

18. Matsuoka M, Iseki K, Tamashiro M et al. Impact of high coro-nary artery calcification score (CACS) on survival in patientson chronic hemodialysis. Clin Exp Nephrol 2004;8:54–8.

19. Nitta K, Akiba T, Suzuki K et al. Assessment of coronaryartery calcification in hemodialysis patients using multi-detector spiral CT scan. Hypertens Res 2004;27:527–33.

20. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM.Arterial calcifications, arterial stiffness, and cardiovascular riskin end-stage renal disease. Hypertension 2001;38:938–42.

21. Okuno S, Ishimura E, Kitatani K et al. Presence of abdominalaortic calcification is significantly associated with all-causeand cardiovascular mortality in maintenance hemodialysispatients. Am J Kidney Dis 2007;49:417–25.

tap_1088_3 393..441Chapter 2: Blood Pressure Abnormalities

I. HYPERTENSION

Statements

1. In dialysis patients, we recommend bloodpressure should be evaluated not only in thedialysis room but also at home (1B).

2. In patients under stable long-term maintenancedialysis with no impairment of the cardiac func-tion, we suggest the target of antihypertensivetreatment should be blood pressure <140/90 mm Hg before dialysis at the beginning of theweek (Opinion).

3. We recommend dry weight (DW) should beappropriately set in achieving the target bloodpressure (1B).

4. We recommend antihypertensive agents shouldbe administered when the reduction in bloodpressure is inadequate even after achievement/maintenance of DW (1B).

Comments

EpidemiologyAccording to reports on the present state of

chronic dialysis therapy in Japan published at the endof 2005, 74.5% of all dialysis patients were hyperten-sive based on systolic blood pressure measured at theinitiation of dialysis and the criteria of the JapaneseSociety of Hypertension (JSH 2004) (1). Persistenthypertension is a major cause of left ventricularhypertrophy, ischemic heart disease, heart failure, anddeath, and thus the control of hypertension is impor-tant in dialysis patients (2).

However, a rapid fall in blood pressure duringdialysis does not only have serious effects onoutcome (3), it may also affect the quality of life orshunt insufficiency. In dialysis patients, aortic calcifi-cation also has a marked impact on outcome, as doespulse pressure, and systolic and diastolic pressures(4–7). The outcome is poorer in patients with lowdiastolic pressure but normal systolic pressure andalso in patients with high systolic pressure withnormal diastolic pressure (5). Also, the mortality rateis reported to rise significantly if the average weeklyblood pressure of the pulse pressure measured beforeand after dialysis three times a week and at hometwice daily at awakening and before going to bedexceeds 70 mm Hg (7). This is also true for variousother indices, including the predialysis (8) and post-dialysis (9) blood pressures, ambulatory blood pres-sure monitoring (ABPM) (10), and average weekly

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blood pressure (7,11). At least, it is important toinclude home blood pressure in the evaluation(7,11–13). It is more important to base any clinicalor therapeutic decision on the mean of multiplemeasurements than a single casual blood pressuremeasurement (7,11).

Many cohort studies demonstrated poorer progno-sis of patients with high predialysis blood pressurecompared with hypotensive patients. This observa-tion is probably due to the inclusion among thehypotensive group of patients with malnutrition orthose with severe chronic heart failure (so-calledreverse epidemiology). Future prospective interven-tional studies are needed to further evaluate hyper-tensive patients (14–16).

CausesMany factors are suspected to be responsible for

hypertension in dialysis patients. Since blood pres-sure is reported to normalize in more than 60% ofpatients following strict management of body fluidvolume (17,18), optimization of DW is important, andthe present guidelines propose how DW should bedetermined.

DiagnosisStandardization of blood pressure measurement

is necessary for the diagnosis of blood pressureabnormalities.

Standardization of blood pressure measurement:

1. Blood pressure should be measured under fixedconditions although it can be measured in eitherthe seated or supine position depending on thesetup at each facility. Before the commencementof dialysis therapy, blood pressure should bemeasured after a period of rest of at least 5 minbefore the start of dialysis. Subjects shouldrefrain from drinking caffeine 30 min before themeasurement and from smoking during the mea-surement.

2. Blood pressure should be measured with the heartrate at least once every hour.

3. At the end of dialysis, the blood pressure shouldbe measured in a similar manner immediatelybefore returning of blood and within 5 min afterthe end of returning of blood, needle removal, andhemostasis. Blood pressure measured immedi-ately before returning of blood at the end of dialy-sis is called “blood pressure at end of dialysis”.

4. After setting or changing DW, blood pressureshould be measured also in the standing positionat the end of dialysis.

5. Home blood pressure should be measured as rec-ommended by the guidelines of the JapaneseSociety of Hypertension. Measurements beforegoing to bed at night and at awakening in themorning are recommended.

6. While ABPM has also been reported to be useful(10,19), it cannot be strongly recommended, due tothe restricted use of one upper limb for shunting.

7. In dialysis patients with repetitive periodicchanges in body fluid volume, it is important toevaluate blood pressure not only in the dialysisroom but also at home (7,11–13). In dialysispatients, evaluation on a weekly basis is important,because dialysis is performed after 1–2 rest days.

8. Blood pressure decreases progressively from thebeginning to the end of the week. Reports on howthe blood pressure should be evaluated or usedare very scarce. The weekly average blood pres-sure (WAB) represents the mean blood pressuremeasured before and after dialysis three times aweek and daily home blood pressures in themorning and night. Prospective observationalstudies demonstrated that WAB is a more signifi-cant predictor of left ventricular hypertrophy andcardiovascular disorders than casual predialysis orpostdialysis blood pressure measured at the begin-ning of the week (7,11). Blood pressure measuredat awakening on a non-dialysis day in the middleof the week could be also used since it correlateswith WAB (R2 = 0.71).

Treatment

Target of antihypertensive treatment—clarification ofsubjects and objectives

In dialysis patients, a U-shaped relationship isobserved between blood pressure and prognosis (20).However, this relationship needs proper interpreta-tion, that is, it is important to clarify the subjects andobjectives when determining the target blood pres-sure of antihypertensive treatment.

The aim of antihypertensive treatment is to reducethe long-term risk of cardiovascular diseases inpatients on chronic maintenance dialysis, rather thanreduce all-cause mortality (21). Therefore, patientswith cardiac dysfunction, for example, are excluded.The target level should be set after comprehensiveevaluation of cardiac function in both patients withmarkedly reduced left ventricular ejection fractionand those with reduced diastolic function due tosevere left ventricular hypertrophy. In particular,since the outcome is reported to worsen in patientswith increased aortic stiffness due to aortic calcifica-tion, by excessive decrease in diastolic blood pressure

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and increase in pulse pressure, caution against exces-sive reduction in blood pressure is necessary in con-sideration of the effects of the diastolic bloodpressure on various pathologic conditions such aschronic heart failure and coronary blood flow. Forthese reasons, the criteria for blood pressure controlshould not be applied uniformly to all patients butapplied selectively by excluding patients with clearlyreduced cardiac function, for example, and furtherevaluated at follow-up.

While it is difficult to propose specific target bloodpressure values in the present guidelines due to thescarcity of evidence, a dialysis blood pressure lessthan 140/90 mm Hg at the beginning of the week isrecommended as a provisional target. However, arapid decrease in blood pressure (30 mm Hg orgreater fall in systolic pressure) during dialysis (3,22)and orthostatic hypotension after dialysis arereported to worsen prognosis, and further studies arenecessary. On the other hand, observational studiesindicated that predialysis blood pressure does notcorrelate with the effect of falls in blood pressureduring dialysis (23).

The target blood pressure is set to reduce the long-term risk of cardiovascular diseases in patients onmaintenance dialysis, and should not be applied topatients with pre-existing cardiovascular disorders. Inhigh-risk patients, the lowest blood pressure recordedduring dialysis (�110/60 mm Hg) correlates signifi-cantly with the risk of death within 5 years (3).

Algorithm of antihypertensive treatmentOne precondition of antihypertensive treatment is

securing appropriate amount of dialysis, and thus theconditions of dialysis such as duration, frequency,blood flow volume, and dialysis membrane need to bere-evaluated. Only then should an appropriate DWbe set, achieved, and maintained. This should be fol-lowed by administration of appropriate antihyper-tensive drugs when necessary. If a fall in bloodpressure is observed during dialysis, antihypertensivemedication should be suspended, or its dose reduced,the DW should be set again, the patient should befollowed up, and antihypertensive medicationresumed, if necessary.

1. Weight control, control of salt intake, and cessa-tion of smoking are the most important basic itemsof guidance during dialysis.

2. To achieve the target of antihypertensive treat-ment, the DW must be set appropriately first (thisissue is discussed in a different chapter).

3. It is imperative to control changes in body fluidvolume between dialyses (interdialysis weight

gain) to prevent any fall in blood pressure duringdialysis, and guidance should be given to control itwithin 3% of the DW when the interval of dialysisis one day and within 5% when the interval is2 days.

4. Attempts should be made to control the inter-dialysis fall in blood pressure due to increased DW.Physicians should be aware that a rise in bloodpressure leads to worsening of long-term outcome.

5. Antihypertensive drugs should be administeredwhen the target blood pressure cannot beachieved after achievement of the DW.

Principles of selection of antihypertensive drugsAntihypertensive drugs should be administered

if appropriate control of blood pressure cannot beachieved by maintaining DW alone with the follow-ing points in mind:

1. Large-scale clinical studies or randomized con-trolled trials are lacking on this topic.

2. Angiotensin receptor blockers (ARBs) andangiotensin-converting enzyme inhibitors, whichare reported to prevent left ventricular hypertro-phy, are the preferable first line of antihyperten-sive drugs (24–30). Particularly, ARBs are easy touse, because they are excreted primarily in bile,are not dialyzable, and have only a few adverseeffects such as cough.

3. A history of myocardial infarction and significantcoronary artery lesion warrant the use of b-blockers, but caution should be applied when usingthese agents in patients with heart failure (31,32).

4. Calcium antagonists are also recommended. Pro-spective observational studies indicate that thesedrugs significantly reduce total death and cardio-vascular death rates (33–35).

5. Since dialysis patients may also have sympathetichyperactivity, the use of central sympathomimeticdrugs and a-blockers should be considered ifblood pressure cannot be controlled with theabove drugs. However, since there is little or noinformation on the subject, and since such drugscan cause various adverse effects such as orthos-tatic hypotension, they should be regarded assecond choice drugs.

Guidelines for appropriate setting of the DW

Definition of DWDW is defined based on the following three

criteria: (i) body weight with appropriate body fluidvolume, (ii) no rapid and excessive decrease in blood



pressure during dialysis, and (iii) lack of markedlong-term burden on the cardiovascular system.

The following criteria are widely applied whendetermining DW:

• No marked fall in blood pressure during dialysis.• No hypertension (predialysis blood pressure at the

beginning of the week <140/90 mm Hg).• No peripheral edema.• No pulmonary congestion on chest X-ray.• Cardiothoracic ratio �50% (�53% in females).

Evaluation of body fluid volumeDW should be determined by taking the following

items into consideration in addition to the cardiotho-racic ratio.

1. Physical findings

Edema may be observed even without volumeoverload in the presence of hypoproteinemia or inbed-ridden patients.

2. Atrial natriuretic peptide (hANP)

hANP is used to evaluate body fluid volume andshould be measured monthly (covered by medicalinsurance). However, the criteria used vary amongreports. Plasma hANP concentration is generally50–100 pg/mL or less when DW is achieved (36),although the level is higher in the presence of cardiacdiseases. Therefore, the use of hANP as an index isdifficult.

3. Diameter of the inferior vena cava

The inferior vena cava (IVC) is delineated bysagittal upper abdominal ultrasonography, and itsdiameter is measured at 2 cm distal to its junctionwith the hepatic vein.The IVC diameter changes withrespiration but its absolute value and collapsibilityindex (CI = IVCi/IVCe) (where IVCe represents themaximum diameter during expiration and IVCi is theminimum diameter during inspiration) are measured(37). In many patients, the IVC diameter decreaseswith water removal, and this is associated with com-plete collapse of IVCi about 2 h after dialysis. There-after, the IVCe stabilizes around 7 mm and shows aplateau. In individual patients, the IVC diameter andCI reflect changes in body fluid volume and circulatingblood volume.

4. Others

The CRIT-LINE Monitor is reported to showchanges in blood volume, while body impedanceanalysis provides a measure of body fluid volumeincluding intracellular and extracellular fluid (38).

II. DIALYSIS-RELATED HYPOTENSION

Statements

1. Dialysis-related hypotension can be dividedinto orthostatic hypotension, chronic sustainedhypotension, and intradialytic hypotension(IDH, crash) (Opinion).

2. A rapid drop in systolic blood pressure(�30 mm Hg) during dialysis and orthostatichypotension after dialysis are two factorsassociated with poor prognosis (B).

3. Undernutrition (hypoalbuminemia) hampersmaintenance of blood pressure by reducing theplasma refilling rate (Opinion).

4. A recent history of rapid intradialytic fall inblood pressure necessitates evaluation of car-diac function by echocardiography. We suggestconsultation with a cardiologist (Opinion).

5. We recommend that the amount of waterremoved per unit time should be mitigated toavoid drop in blood pressure during dialysis,and prolongation of the duration of dialysisshould be considered.

Comments

Classification of dialysis-related hypotensionDialysis-related hypotension can be classified into

the following types:

• Intradialytic hypotension (IDH, crash)• Orthostatic hypotension• Chronic sustained hypotension

CausesThe fall in blood pressure during dialysis is usually

considered to be caused by setting of DW at an unnec-essarily low level or low circulating blood volume dueto excessive removal of fluid. However, blood pres-sure cannot be maintained appropriately if the inter-dialysis body weight gain is large and the amount ofthe fluid removed per unit time is high. Any decreasein blood pressure should be managed by prolongationof duration of dialysis or increase in DW. Anotherimportant factor is hypoalbuminemia associated withmalnutrition. Hypoalbuminemia can induce the fol-lowing changes: (i) reduce the colloid osmotic pres-sure, and thus reduce the plasma refilling rate, (ii)prevent appropriate body fluid movement from theinterstitial tissue into blood vessels due to excessivefluid removal, (iii) reduce the circulating bloodvolume. These changes hinder the control of bloodpressure. Therefore, sufficient serum albumin levelsmust be maintained. With regard to intradialytic



hypotension, it must be remembered that blood pres-sure may fall during dialysis even without a decreasein the circulating blood volume. In addition, it must beemphasized that myocardial infarction or rapid pro-gression of aortic stenosis must be considered inpatients who develop inexplicable intradialytichypotension.Reduced cardiac function. In patients with cardiacdysfunction, the blood pressure falls immediatelyafter the initiation of dialysis or following removal ofwater. Few methods have been described recently toestimate the levels and changes in circulating bloodvolume, thus allowing the detection of early changes.Any rapid falls in blood pressure occurring duringdialysis necessitates evaluation of cardiac function byechocardiography.Aggressive examination and treat-ment of coronary artery disease and aortic stenosis areimportant, and consultation with a cardiologist isadvised.Abnormalities of the autonomic nervous system.Abnormalities of the autonomic nervous system areobserved frequently particularly in diabetic patients.Low circulating blood volume following excess waterremoval stimulates the autonomic nervous system toreverse the condition, through contraction of periph-eral vessels, although hypotension can occur inpatients with autonomic nervous system dysfunction.Others. A high dialysis fluid temperature, anemia,acetate dialysate, food intake during dialysis, anaphy-lactic shock due to drugs (e.g. nafamostat mesilateand angiotensin converting enzyme [ACE] inhibi-tors), first use syndrome related to the dialysis mem-brane, and ethylene oxide gas used for disinfection,could also reduce blood pressure.

DiagnosisIntradialytic hypotension is defined as symptom-

atic sudden drop in systolic blood pressure (by30 mm Hg or more) during dialysis or a decrease inthe mean blood pressure (by 10 mm Hg or more).

Treatments

Drug therapyDroxidopa, a noradrenergic nerve function

improving agent (39,40), is reported to be effective inthe treatment of dizziness, lightheadedness, andmalaise in dialysis patients with orthostatic hypoten-sion. Amezinium metilsulfate enhances the noradr-energic activity at nerve terminals (41) and iseffective in preventing any decrease in blood pres-sure during dialysis. However, since many of suchpatients have problems with the setting of DW, nutri-tional state, and/or cardiac function, the cause of dys-

dialysis syndrome should be identified, and measuresas those mentioned above should be undertaken.

Treatment of dysdialysis syndrome(Instability of hemodialysis)

Dysdialysis syndrome is a condition in which nec-essary dialysis-water removal is difficult due to a fallin blood pressure.

Hypoalbuminemia, malnutrition, and anemiashould be treated. Excessive burden to the body byhypoalbuminemia due to undernutrition,and removalof a large water volume per unit time leads to dysdi-alysis syndrome.Also, since a slight fall in hemoglobinlevel can exacerbate depression of cardiac functionand render the maintenance of blood pressure diffi-cult in patients with low cardiac function.

Other measures are listed below, but the mostimportant is evaluation of cardiac function. Echocar-diography is used for this purpose, and treatmentagainst cardiomegaly, valvular heart disease, andischemic heart disease should be conducted.

1. Slow removal of water

The K/DOQI Guidelines recommend maintainingthe maximum rate of water removal at 15 mL/kg perh or below.

2. Programmed water removal

The volume of water to be removed over a 4-hourdialysis session can be programmed to be achievedas follows: 40% of the total volume of water to beremoved during the first hour, 30% during the secondhour, 20% during the third hour, and 10% during thelast hour. Using such a program, the circulating bloodvolume decreases rapidly during the first hour but isstabilized thereafter, and the percent fall in circulat-ing blood volume can be reduced even if the sametotal volume of water is removed.

3. DW alteration system

If dialysis is performed on Mondays, Wednesdays,and Fridays, the body weight gain is large on Mondays,DW can be determined as the body weight to beachieved after dialysis on Friday, permitting DW+1.0 kg on Monday and DW+0.5 kg on Wednesday.

4. Mid-dialysis discontinuation of water removal

Two hours after the beginning of dialysis, waterremoval may be interrupted for about 15 min tostimulate plasma refilling.

5. Prevention of hypoglycemia

A fall in blood glucose level at 2 h after the start ofdialysis is seen in a proportion of diabetic patients. In



such patients, the hemodynamics may be stabilized byinfusion of 20–40 mL of 50% glucose solution.

6. Stimulation of plasma refilling

Since plasma refilling is suppressed in patients withhyponatremia, infusion of 10% NaCl is a possibletreatment, but its effect is transient. Albumin prepa-rations can be administered for the management ofhypoproteinemia to maintain blood pressure duringdialysis. Hydroxyethyl starch, glycerol, and mannitolcan also be administered continuously to stimulateplasma refilling. Dextran sulfate, the molecularweight of which is the largest next only to albumin, isalso effective although its effect is also transient. Nec-essary water removal is secured while these drugs areinfused continuously at a rate of 100 mL/h or aboveduring dialysis.

7. Administration of pressor agents

The blood pressure can fall in diabetic patients dueto autonomic nervous system dysfunction despiteno change in circulating blood volume. Oral pressordrugs such as droxidopa (39,40) and ameziniummetilsulfate (41) are often used in such patients. Onthe other hand, other drugs such as dopamine andetilefrine can also be used out of necessity, but it isimportant to try to identify the cause without usingthem exclusively.

8. Low temperature dialysis

Systematic meta-analysis of 22 research studies thatincluded 408 patients showed that the frequencyof intradialytic hypotension is 7.1 (95% CI: 5.3–8.9) times higher in the control group (dialysisfluid temperature: 36.5–38.5°C) than in the lowtemperature dialysis group (dialysis fluid tempera-ture: 34.0–35.5°C) and that the mean blood pressureafter dialysis is 11.3 mm Hg higher (95% CI: 7.7–15.0)in the low temperature dialysis group (42).

9. Method of dialysis

Although the reason for the effectiveness of hemo-dialysis filtration (HDF) in preventing a decrease inblood pressure remains unclear, the blood pressure isstabilized in some patients by HDF with 4–6 L of fluidreplacement (43). Hemofiltration (HF) and acetate-free biofiltration are effective in preventing falls inblood pressure in acetate-intolerant patients (44,45).

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2. Chobanian AV, Bakris GL, Black HR et al. Joint NationalCommittee on Prevention, Detection, Evaluation, and Treat-ment of High Blood Pressure. National Heart, Lung, and BloodInstitute; National High Blood Pressure Education ProgramCoordinating Committee. Seventh report of the Joint NationalCommittee on prevention,detection,evaluation,and treatmentof high blood pressure. Hypertension 2003;42:1206–52.

3. Shoji T, Tsubakihara Y, Fujii M, Imai E. Hemodialysis-associated hypotension as an independent risk factor for two-year mortality in hemodialysis patients. Kidney Int 2004;66:1212–20.

4. Klassen PS, Lowrie EG, Reddan DN et al. Associationbetween pulse pressure and mortality in patients undergoingmaintenance hemodialysis. JAMA 2002;287:1548–55.

5. Tozawa M, Iseki K, Iseki C, Takishita S. Pulse pressure and riskof total mortality and cardiovascular events in patients onchronic hemodialysis. Kidney Int 2002;61:717–26.

6. Iseki K, Miyasato F, Tokuyama K et al. Low diastolic bloodpressure, hypoalbuminemia, and risk of death in a cohort ofchronic hemodialysis patients. Kidney Int 1997;51:1212–7.

7. Moriya H, Oka M, Maesato K et al. Weekly averaged bloodpressure is more important than a single-point blood pressuremeasurement in the risk stratification of dialysis patients. ClinJ Am Soc Nephrol 2008;3:416–22.

8. Conion PJ, Walshe JJ, Heinle SK, Minda S, Krucoff M, SchwabSJ. Predialysis systolic blood pressure correlates strongly withmean 24-hour systolic blood pressure and left ventricular massin stable hemodialysis patients. J Am Soc Nephrol 1996;7:2658–63.

9. Kooman JP, Gladziwa U, Böcker G et al. Blood pressureduring the interdialytic period in haemodialysis patients: esti-mation of representative blood pressure values. Nephrol DialTransplant 1992;7:917–23.

10. Agarwal R, Lewis RR. Prediction of hypertension in chronichemodialysis patients. Kidney Int 2001;60:1982–9.

11. Moriya H, Ohtake T, Kobayashi S. Aortic stiffness, left ven-tricular hypertrophy and weekly averaged blood pressure(WAB) in patients on haemodialysis. Nephrol Dial Transplant2007;22:1198–204.

12. Agarwal R, Andersen MJ, Bishu K, Saha C. Home blood pres-sure monitoring improves the diagnosis of hypertension inhemodialysis patients. Kidney Int 2006;69:900–6.

13. Alborzi P, Patel N, Agarwal R. Home blood pressures are ofgreater prognostic value than hemodialysis unit recordings.Clin J Am Soc Nephrol 2007;2:1228–34.

14. Agarwal R. Hypertension and survival in chronic hemodialysispatients—past lessons and future opportunities. Kidney Int2005;67:1–13.

15. Toto RD. Improving outcomes in hemodialysis patients: theneed for well-designed clinical trial. Am J Kidney Dis 2008;52:400–2.

16. Iseki K, Tokuyama K, Shiohira Y et al. Olmesartan clinicaltrial in Okinawan patients under OKIDS group (OCTOPUS):design and methods. Clin Exp Nephrol 2009;13:145–51.

17. Zucchelli P, Santoro A, Zuccala A. Genesis and control ofhypertension in hemodialysis patients. Semin Nephrol 1988;8:163–8.

18. Agarwal R, Alborzi P, Satyan S, Light RP. Dry-weight reduc-tion in hypertensive patients (DRIP). A randomized, con-trolled trial. Hypertension 2009;53:500–7.

19. Tripepi G, Fagugli RM, Dattolo P et al. Prognostic value of24-hour ambulatory blood pressure monitoring and of night/day ratio in nondiabetic, cardiovascular events-free hemodi-alysis patients. Kidney Int 2005;68:1294–302.

20. Zager PG, Nikolic J, Brown RH et al. “U” curve association ofblood pressure and mortality in hemodialysis patients. KidneyInt 1998;54:561–9.

21. Takeda A, Toda T, Fujii T, Shinohara S, Sasaki S, Matsui N.Discordance of influence of hypertension on mortality andcardiovascular risk in hemodialysis patients. Am J Kidney Dis2005;45:112–8.



22. Inrig JK, Oddone EZ, Hasselblad V et al. Association of intra-dialytic blood pressure changes with hospitalization and mor-tality rates in prevalent ESRD patients. Kidney Int 2007;71:454–61.

23. Takeda A, Toda T, Fujii T, Sasaki S, Matsui M. Can predialysishypertension prevent intradialytic hypotension in hemodialy-sis patients? Nephron Clin Pract 2006;103:137–43.

24. Takahashi A, Takase H, Toriyama T et al. Candesartan, anangiotensin II type 1 receptor blocker, reduces cardiovascularevents in patients on chronic hemodialysis—a randomizedstudy. Nephrol Dial Transplant 2006;21:2507–12.

25. Efrati S, Zaidenstein R, Dishy V et al. ACE inhibitors andsurvival of hemodialysis patients. Am J Kidney Dis 2002;40:1023–9.

26. Matsumoto N, Ishimitsu T, Okamura A, Seta H, Takahashi M,Matsuoka H. Effects of imidapril on left ventricular mass inchronic hemodialysis patients. Hypertens Res 2006;29:253–60.

27. London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME,Cuche JL. Cardiac hypertrophy, aortic compliance, peripheralresistance, and wave reflection in end-stage renal disease.Comparative effects of ACE inhibition and calcium channelblockade. Circulation 1994;90:2786–96.

28. Paoletti E, Cassottana P, Bellino D, Specchia C, Messa P,Cannella G. Left ventricular geometry and adverse cardiovas-cular events in chronic hemodialysis patients on prolongedtherapy with ACE inhibitors. Am J Kidney Dis 2002;40:728–36.

29. Shibasaki Y, Masaki H, Nishiue T, Nishikawa M, Matsubara H,Iwasaka T. Angiotensin II type 1 receptor antagonist, losartan,causes regression of left ventricular hypertrophy in end-stagerenal disease. Nephron 2002;90:256–61.

30. Kanno Y, Kaneko K, Kaneko M et al. Angiotensin receptorantagonist regresses left ventricular hypertrophy associatedwith diabetic nephropathy in dialysis patients. J CardiovascPharmacol 2004;43:380–6.

31. Cice G, Ferrara L, D’Andrea A et al. Carvedilol increasestwo-year survival in dialysis patients with dilated cardio-myopathy: a prospective, placebo-controlled trial. J Am CollCardiol 2003;41:1438–44.

32. Foley RN, Herzog CA, Collins AJ, United States Renal DataSystem. Blood pressure and long-term mortality in UnitedStates hemodialysis patients: USRDS Waves 3 and 4 Study.Kidney Int 2002;62:1784–90.

33. Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC,Barre PE. Impact of hypertension on cardiomyopathy, morbid-ity and mortality in end-stage renal disease. Kidney Int 1996;49:1379–85.

34. Kestenbaum B, Gillen DL, Sherrard DJ, Seliger S, Ball A,Stehman-Breen C. Calcium channel blocker use and mortalityamong patients with end-stage renal disease. Kidney Int 2002;61:2157–64.

35. Kojima M, Taniguchi M, Sato K, Ueda R, Dohi Y. Antihyper-tensive effects of long-acting calcium channel blockers onhemodialysis days-a randomized crossover trial between beni-dipine and nifedipine CR. Nephron Clin Pract 2004;97:49–53.

36. Akai Y, Kusano E, Furuya H et al. Could atrial natriureticpeptide serve as an indicator of fluid retention in patients onmaintenance hemodialysis? J Jpn Soc Dial Ther 1991;24:1143–8.

37. Ando Y, Tabei K, Shiina A, Asano Y, Hosoda S. Ultrasono-graphic evaluation of changes in the inferior vena caval con-figuration during hemodialysis: relationship between theamount of water removed and the diameter of the inferiorvena cava. J Jpn Soc Dial Ther 1985;18:173–9.

38. Maejima S, Iwamoto T, Kobayashi S. Analysis of the optimalbody fluid level using a body composition analyzer as well asCRIT-LINE in patients undergoing hemodialysis. J Jpn SocDial Ther 1999;32:199–203.

39. Akizawa T, Koshikawa S, Iida N et al. Clinical effects ofL-threo-3,4-dihydroxyphenylserine on orthostatic hypoten-sion in hemodialysis patients. Nephron 2002;90:384–90.

40. Iida N, Koshikawa S, Akizawa T et al. Effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodi-alysis patients. Am J Nephrol 2002;22:338–46.

41. Watari H, Mizuno K, Niimura S, Kanno R. Antihypertensiveand hormonal effects of ameziniumu metilsulfate in hypoten-sive hemodialysis patients. Curr Ther Res 1993;53:367–74.

42. Nicholas M, McIntyre CW. A systemic review of the clinicaleffects of reducing dialysate fluid temperature. Nephrol DialTransplant 2006;21:1883–98.

43. Ronco C, Cruz D. Hemodiafiltration history, technology, andclinical results. Adv Chronic Kidney Dis 2007;14:231–43.

44. Santoro A, Guarnieri F, Ferramosca E, Grandi F. Acetetae-free biofiltration. Contrib Nephrol 2007;158:138–52.

45. Galli G, Panzetta G. Acetate free biofiltration (AFB): fromtheory to clinical results. Clin Nephrol 1998;50:28–37.

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Chapter 3: Heart Failure

Statements

1. Heart failure is a complex clinical syndromebased on structural and functional disordersthat impair the systolic and diastolic functions ofthe ventricle.The primary sign of heart failure iscongestion in various organs (A).

2. Congestion is diagnosed through medicalinterview, physical examination, and chestradiography, we recommend it should beevaluated before the beginning of dialysis isrecommended (1C).

3. Although non-cardiac edema is not a rare causeof congestion, ischemic heart disease, in particu-lar, is a frequent cause of heart failure (B).

4. We recommend body fluid volume should becarefully managed based on restriction of saltintake in the treatment of heart failure indialysis patients (1A).

5. We recommend aggressive treatment with renin-angiotensin inhibitors and b-blockers should beconsidered as the mainstay of medical treatmentfor disorders causing heart failure (1B).

Comments

EpidemiologyHeart failure is a complex clinical syndrome asso-

ciated with structural and functional disorders of theheart that impair ventricular filling (diastolic) andejection (systolic) functions. According to the reportby the Statistical Survey Committee of the JapaneseSociety for Dialysis Therapy (JSDT) (1), the mostfrequent cause of death in chronic dialysis patients isheart failure, accounting for about 25% of all deaths.Structural/functional disorders of the heart areobserved more frequently in dialysis patients than innon-dialysis patients, and only 16% of patients havenormal cardiac function at the initiation of dialysis

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(2). Furthermore, volume overload is also noted indialysis patients. Based on these two factors, about30% of patients present with congestive heart failureat the initiation of dialysis.

CausesDialysis patients exhibit a wide variety of cardiac

disorders such as ischemic heart disease, valvularheart disease, hypertensive cardiomyopathy, meta-bolic cardiomyopathy, bradycardiac/tachycardiacarrhythmias of long duration, and pericarditis, and ifthey develop heart failure, differentiation of theseconditions becomes important. On the other hand,dialysis patients can also develop non-cardiac edema,which is not accompanied by a clear organic or func-tional disorder of the heart but is caused by relativeexcess of body fluid. The most common causes ofnon-cardiac edema are: (i) volume overload due toexcessive salt intake, (ii) severe anemia, (iii) arterio-venous fistula with high blood flow, and (iv) hyperg-lycemia (3). One report estimated that about 25% ofsymptoms of congestion in dialysis patients are dueto non-cardiogenic edema (4). These conditions usedto be known as high output heart failure, but sincethis condition is not accompanied by cardiac dysfunc-tion, in principle, the term non-cardiac circulatoryfailure is increasingly being applied to this condition(5). It must be emphasized that volume overload isan important risk factor of cardiovascular death indialysis patients (6).

DiagnosisThe diagnosis of heart failure requires careful

evaluation of congestion of major organs based onmedical interviews and physical findings. In dialysispatients, these examinations should be conductedbefore dialysis, at the peak of body fluid volume. Theprotocol used for the diagnosis of heart failure indialysis patients is similar to that applied to non-dialysis patients (7,8).

Medical interviews and physical examinationsThe clinical signs of heart failure include pulmonary

congestion and a decrease in blood pressure associ-ated with left-side failure, peripheral edema associ-ated with right-side failure, hepatomegaly, jugularvein distension, and peritoneal or pleural effusion.Patients with mild pulmonary congestion complain ofdyspnea on exertion. As the condition advances,dyspnea at rest or paroxysmal nocturnal dyspnea andorthopnea appear. Acute heart failure is suspected ifonly the clinical signs of left-side heart failure areobserved, whereas chronic heart failure is suspectedwhen clinical signs of both-side heart failure are

noted. The clinical findings that are specific to hemo-dialysis patients include repeated attacks of hypoten-sion during dialysis, difficulty in achieving DW due todecreases in blood pressure during dialysis, and rapidwidening of the cardiothoracic ratio. In such events,heart failure should be suspected even if the clinicalsigns of heart failure are not clear, and cardiac func-tion should be evaluated (9).

Significance of brain natriuretic peptideHuman brain natriuretic peptide (BNP) or

N-terminal fragment of proBNP (Nt-proBNP) is alsouseful for the diagnosis of heart failure (10–12),evaluation of the severity of heart failure (10,13),prediction of future cardiovascular events (14,15),and prognosis (15,16). For the diagnosis of heartfailure in dialysis patients, it is important to establisha standard value based on values measured duringappropriate DW and lack of clinical signs of heartfailure. In symptomatic patients, the cardiac load isestimated by evaluating the relative changes com-pared with the standard (17).

Risk factorsAge, diabetes, history of coronary artery disease,

reduced left ventricular systolic function, high dias-tolic pressure, hypoalbuminemia, and low hemoglo-bin concentration are important risk factors of denovo occurrence of heart failure in dialysis patients(18,19).

Diagnosis of causative disordersTo determine the cause of heart failure, the patient

should be examined for the presence (or absence) andtype of heart murmur(s),arrhythmias,12-lead electro-cardiogram (ECG) abnormalities, regional chest wallmotion abnormalities and valvular disease by echo-cardiography. Coronary artery disease is observed in40–60% of dialysis patients (20–24), and acute coro-nary syndrome is very likely to be manifested as heartfailure (25). In chronic heart failure, factors that causenon-cardiac edema must be evaluated first. In patientswith pulmonary congestion due to volume overload,the clinical symptoms reappear with increases in bodyfluid volume. The appearance of clinical symptomsand signs of congestion despite appropriate control ofDW and the presence of only a mild increase in bodyfluid volume necessitates thorough examination todifferentiate organic cardiac disorders.

Treatments

General managementThe principle of treatment is management of body

fluid volume based on strict restriction of salt intake



(5 g/day), and guidance to control interdialysis bodyweight gain at less than 3% of the DW when theinterdialysis interval is 1 day and less than 5% whenthe interval is 2 days. In patients with clinical signs ofcongestion, treatment is started with downwardadjustment of the DW for fluid overload, but thecorrection of anemia, optimization of the arterio-venous fistula flow, and management of blood glucoselevel are also important.

Medical treatmentLeft ventricular remodeling is often observed in

patients with chronic heart failure and impairment ofleft ventricular systolic or diastolic function, in orderto compensate for the decrease in cardiac output.However, compensation by left ventricular remodel-ing may eventually worsen systolic and diastolic func-tions. Breaking this vicious cycle is the mostimportant step to improve prognosis. Left ventricularremodeling is promoted primarily by marked activa-tion of the neuroendocrine systems such as the sym-pathetic nervous system and renin-angiotensin (RA)system (26). Thus, inhibitors of the RA system andb-blockers are used to suppress the activation ofthese neuroendocrine systems (8).

DigitalisTreatment with digoxin does not improve the

prognosis of non-dialysis patients with left ventricularsystolic dysfunction (27). Based on reports demon-strating that digoxin treatment increases the risk ofdeath by 28% in dialysis patients and that the risk ofdeath increases with higher blood digoxin levels orwith plasma potassium level of 4.3 mEq/L or less (28),any aggressive administration of digoxin for the treat-ment of heart failure should be avoided in dialysispatients.

Inhibitors of the renin-angiotensin system(RA system inhibitors)

In non-dialysis patients, aggressive treatment ofheart failure using RA system inhibitors is recom-mended regardless of the disease causing left heartdysfunction (8). However, there is only little informa-tion on the effectiveness of RA system inhibitors indialysis patients with heart failure. In dialysis patientswith myocardial infarction, treatment using angio-tensin converting enzyme inhibitors was reported toreduce the risk of death within 3 months by 42%(29), and treatment using ACE inhibitors and angio-tensin receptor blockers (ARBs) reduced the risk ofdeath within 1 year by 30% (30). However, these ben-eficial effects could not be observed in other studies(31). At present, there is little evidence that RA

system inhibitors prevent exacerbation of heartfailure in dialysis patients, but there is also no reportthat the same drugs enhance the development heartfailure or cardiovascular events.

b-blockersThe beneficial effects of b-blockers in patients with

heart failure are well documented in non-dialysispatients (32,33).Cice et al. (34) compared the effect ofcarvedilol (which includes an a-blocking action) withthat of placebo in dialysis patients with dilated cardi-omyopathy complicated by NYHA grade II–III heartfailure and reported significantly fewer cardiovascu-lar events in the carvedilol group. Berger et al. (29)also reported that b-blockers reduced the risk of deathof dialysis patients after myocardial infarction by 22%in an observational cohort study. In Japan, Nakayamaet al. (35) reported that low-dose (5 mg) carvedilolimproved left ventricular systolic function, morpho-logical abnormalities of the left ventricle, and signifi-cantly decreased plasma BNP levels in dialysispatients with asymptomatic left ventricular systolicdysfunction. Thus, b-blockers are also expected toimprove the prognosis of dialysis patients with heartfailure.

Indication of ultrafiltrationUltrafiltration may be employed in patients with

unsatisfactory response to drug therapy, in additionto usual dialysis to alleviate preload.

REFERENCES

1. Nakai S, Masakane I, Akiba T et al. Overview of regular dialy-sis treatment in Japan as of 31 December 2006. Ther ApherDial 2008;12:428–56.

2. Parfrey PS, Foley RN, Harnett JD, Kent GM, Murray DC,Barre PE. Outcome and risk factors for left ventricular disor-ders in chronic uraemia. Nephrol Dial Transplant 1996;11:1277–85.

3. Tzamaloukas AH, Rohrscheib M, Ing TS, Siamopoulos KC,Elisaf MF, Spalding CT. Serum tonicity, extracellular volumeand clinical manifestations in symptomatic dialysis-associatedhyperglycemia treated only with insulin. Int J Artif Organs2004;27:751–8.

4. Banerjee D, Ma JZ, Collins AJ, Herzog CA. Long-term sur-vival of incident hemodialysis patients who are hospitalizedfor congestive heart failure, pulmonary edema, or fluid over-load. Clin J Am Soc Nephrol 2007;2:1186–90.

5. Francis GS, Gassler JP, Sonnenblick EH. Pathophysiology anddiagnosis of heart failure. In: Fuster V, Alexander RW,O’Rourke RA, eds. The Heart, 10th edn. New York: McGraw-Hill, 2001; 655.

6. Kalantar-Zadeh K, Regidor DL, Kovesdy CP et al. Fluidretention is associated with cardiovascular mortality inpatients undergoing long-term hemodialysis. Circulation 2009;119:671–9.

7. Joint Study Group for the Guidelines Concerning the Diagno-sis and Treatment of Cardiovascular Diseases. Guidelines forthe Treatment of Acute Heart Failure (2006 Revised Edition).2004–2005.



8. Joint Study Group for the Guidelines Concerning the Diagno-sis and Treatment of Cardiovascular Diseases Guidelines forthe Treatment of Chronic Heart Failure (2005 RevisedEdition). 2004.

9. K/DOQI Workgroup. K/DOQI clinical practice guidelines forcardiovascular disease in dialysis patients. Am J Kidney Dis2005;45:S1–S153.

10. Mallamaci F, Zoccali C, Tripepi G et al. Diagnostic potential ofcardiac natriuretic peptides in dialysis patients. Kidney Int2001;59:1559–66.

11. Sharma R, Gaze DC, Pellerin D et al. Raised plasman-terminal pro-b-type natriuretic peptide concentrationspredict mortality and cardiac disease in end-stage renaldisease. Heart 2006;92:1518–9.

12. Takami Y, Horio T, Iwashima Y et al. Diagnostic and prog-nostic value of plasma brain natriuretic peptide in non-dialysis-dependent CRF. Am J Kidney Dis 2004;44:420–8.

13. David S, Kumpers P, Seidler V, Biertz F, Haller H, Fliser D.Diagnostic value of N-terminal pro-B-type natriuretic peptide(NT-proBNP) for left ventricular dysfunction in patients withchronic kidney disease stage 5 on haemodialysis. Nephrol DialTransplant 2008;23:1370–7.

14. Winkler K, Wanner C, Drechsler C, Lilienthal J, Marz W,Krane V. Change in N-terminal-pro-B-type-natriuretic-peptide and the risk of sudden death, stroke, myocardial inf-arction, and all-cause mortality in diabetic dialysis patients.Eur Heart J 2008;29:2092–9.

15. Zoccali C, Mallamaci F, Benedetto FA et al. Cardiac natri-uretic peptides are related to left ventricular mass and functionand predict mortality in dialysis patients. J Am Soc Nephrol2001;12:1508–15.

16. Madsen LH, Ladefoged S, Corell P, Schou M, Hildebrandt PR,Atar D. N-terminal pro brain natriuretic peptide predicts mor-tality in patients with end-stage renal disease in hemodialysis.Kidney Int 2007;71:548–54.

17. Wang AY, Lai KN. Use of cardiac biomarkers in end-stagerenal disease. J Am Soc Nephrol 2008;19:1643–52.

18. Harnett JD, Foley RN, Kent GM, Barre PE, Murray D, ParfreyPS. Congestive heart failure in dialysis patients: prevalence,incidence, prognosis and risk factors. Kidney Int 1995;47:884–90.

19. Abbott KC, Trespalacios FC, Agodoa LY, Taylor AJ, BakrisGL. b-blocker use in long-term dialysis patients: associationwith hospitalized heart failure and mortality. Arch Intern Med2004;164:2465–71.

20. Soubassi LP, Papadakis ED, Theodoropoulos IK et al.Incidence and risk factors of coronary artery disease inpatients on chronic hemodialysis. Int J Artif Organs 2007;30:253–7.

21. Gowdak LH, de Paula FJ, Cesar LA et al. Screening for sig-nificant coronary artery disease in high-risk renal transplantcandidates. Coron Artery Dis 2007;18:553–8.

22. Hase H, Tsunoda T, Tanaka Y et al. Risk factors for de novoacute cardiac events in patients initiating hemodialysis with noprevious cardiac symptom. Kidney Int 2006;70:1142–8.


24. Ohtake T, Kobayashi S, Moriya H et al. High prevalence ofoccult coronary artery stenosis in patients with chronic kidneydisease at the initiation of renal replacement therapy: anangiographic examination. J Am Soc Nephrol 2005;16:1141–8.

25. Herzog CA, Littrell K, Arko C, Frederick PD, Blaney M. Clini-cal characteristics of dialysis patients with acute myocardialinfarction in the united states: a collaborative project of theunited states renal data system and the national registry ofmyocardial infarction. Circulation 2007;116:1465–72.

26. Jessup M, Brozena S. Heart failure. N Engl J Med 2003;348:2007–18.

27. The Digitalis Investigation Group. The effect of digoxin onmortality and morbidity in patients with heart failure. N EnglJ Med 1997;336:525–33.

28. Chan KE, Lazarus JM, Hakim RM. Digoxin associates withmortality in ESRD. J Am Soc Nephrol 2010;21:1550–9.

29. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker,and angiotensin-converting enzyme inhibitor therapy inpatients with end-stage renal disease and an acute myocardialinfarction. J Am Coll Cardiol 2003;42:201–8.

30. Winkelmayer WC, Charytan DM, Levin R, Avorn J. Poorshort-term survival and low use of cardiovascular medicationsin elderly dialysis patients after acute myocardial infarction.Am J Kidney Dis 2006;47:301–8.

31. Tai DJ,Lim TW,James MT,Manns BJ,Tonelli M,HemmelgarnBR. Cardiovascular effects of angiotensin converting enzymeinhibition or angiotensin receptor blockade in hemodialysis:a meta-analysis. Clin J Am Soc Nephrol 2010;5:623–30.

32. Packer M, Bristow MR, Cohn JN et al.; U.S. Carvedilol HeartFailure Study Group. The effect of carvedilol on morbidity andmortality in patients with chronic heart failure. N Engl J Med1996;334:1349–55.

33. Packer M, Coats AJ, Fowler MB et al. Effect of carvedilol onsurvival in severe chronic heart failure. N Engl J Med 2001;344:1651–8.

34. Cice G, Ferrara L, D’Andrea A et al. Carvedilol increasestwo-year survival in dialysis patients with dilatedcardiomyopathy: a prospective, placebo-controlled trial. J AmColl Cardiol 2003;41:1438–44.

35. Nakayama M, Ishii A, Takeguchi F, Nakano H. Efficacy ofadditional low-dose carvedilol in maintenance hemodialysispatients with asymptomatic left ventricular systolic dysfunc-tion. J Cardiol 2006;47:285–91.

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Chapter 4: Ischemic Heart Disease

Statements

1. Asymptomatic myocardial ischemia is notuncommon in patients on maintenancehemodialysis. We recommend active screeningfor ischemic heart disease starting from theinitiation of dialysis (1B).

2. We recommend evaluation of possible myocar-dial ischemia in the presence of shortness ofbreath,heart failure, fall in blood pressure duringdialysis, or changes in electrocardiogram (ECG)and chest X-ray (1C).

3. We recommend echocardiography should beperformed when myocardial ischemia is sus-pected. Non-invasive techniques should beused for examination, including myocardialscintigraphy (1B).

4. We recommend the application of cardiovascu-lar drug therapy and correction of coronary riskfactors by non-invasive treatment (1B).

5. We recommend acute coronary syndromeshould be excluded in the acute phase of heartfailure (1B). Biomarkers of myocardial ischemiaoften show false positive results, and caution isnecessary for the diagnosis (B).

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Comments

EpidemiologyCardiovascular deaths are 10–20 times more fre-

quent in dialysis patients than in the general popula-tion (1). The prevalence of coronary artery disease isalso high in this population (2). Coronary arterydisease in dialysis patients is often asymptomatic orpresents non-specific symptoms. Significant coronarystenosis was noted in 50% or more of asymptomaticdialysis patients who underwent coronary angiogra-phy within 1 month after the introduction of dialysis(3), and significant coronary artery stenosis of morethan 50% narrowing on coronary angiography wasreported in 53% of asymptomatic patients at theintroduction of dialysis (4). The prevalence of coro-nary artery disease is markedly higher in dialysispatients than in non-dialysis patients, and markedasymptomatic coronary artery stenosis may bepresent already at the initiation of dialysis therapy,possibly leading to serious cardiac events or cardiacdeath. We consider dialysis patients as a high-riskgroup for coronary artery disease and recommendaggressive screening of these patients for coronaryartery disease.

Diagnosis

In the presence of clear symptoms of angina pectorisThe appearance of symptoms of angina pectoris

(e.g. precordial pain, pain radiating to the left shoul-der, back pain, and epigastric pain) warrants promptreferral to a cardiologist.

In the absence of clear symptoms of angina pectorisMany dialysis patients show no clear symptoms or

signs of myocardial ischemia. When shortness ofbreath on exertion, palpitation and signs of heartfailure are observed, ischemic heart disease should besuspected. Changes in ECG and chest X-ray findingsmay indicate myocardial ischemia. Such changes insymptoms or signs and test findings may also becaused by inappropriate setting of DW, excessiveinternal shunt flow, valvular heart disease advancedby valve calcification, pericardial fluid retention fromuremic pericarditis, pulmonary hypertension, or leftventricular hypertrophy. Therefore, it is important todifferentiate the causes of these changes in symptomsand signs, ECG, or chest X-rays (Table 1) by perform-ing resting echocardiography, evaluating cardiacfunction and circulating blood volume, and examin-ing the presence or absence of valvular disease, pul-monary hypertension and pericardial/myocardialdisorders. Abnormalities of circulating blood volume

require modification of the DW. For patients whoshow no improvement in signs or symptoms andabnormalities of ECG or chest X-ray findings evenafter modification of the DW, we recommend referralof the patient to a cardiologist. Referral to a cardi-ologist is also recommended if cardiac dysfunction,pulmonary hypertension, and disorders of the heartvalves, pericardium, or myocardium are consideredpossible. Moreover, when no abnormality is detectedby echocardiography, referral to a cardiologist is nec-essary to exclude possible ischemic heart disease(Fig. 1).

Diagnostic procedureECG. Changes in resting 12-lead ECGs are impor-tant in the diagnosis of myocardial ischemia. Myocar-dial ischemia should be suspected in patients withECG findings of acute/old myocardial infarction ornon-specific ST-T changes. Disorders of peripheralarteries, such as arteriosclerosis obliterans, dialysis-related amyloidosis, bone/joint disorders, such as ver-tebral canal stenosis, and low exercise tolerance areoften encountered in patients on dialysis. In patientswith left ventricular hypertrophy, ST-T changes aredifficult to detect, and exercise stress ECG is oftendifficult to evaluate.Echocardiography. Resting echocardiography isuseful for the evaluation of circulating blood volume,diagnosis of systolic/diastolic cardiac dysfunction,and evaluation of valvular heart disease, pulmonaryhypertension, and pericardial/myocardial disorders.Stress echocardiography may be recorded duringexercise or drug loading such as dobutamine anddipyridamole, but caution is needed since paroxysmalatrial fibrillation frequently occurs in dialysispatients.

TABLE 1. Symptoms and findings suggestive of ischemicheart disease

1. Symptomsa. Non-specific symptomsShortness of breath on exertion, palpitation, discomfort of thechest, epigastric region, and back, languidness of lower limbs,etc.b. De novo heart failurec. Heart failure not responding to a reduction in the DWd. Repeated hypotension during dialysise. Sustained hypotension

2. New abnormalities detected by regular ECGa. ST-T changes (including non-specific changes)b. Appearance of Q wavesc. Arrhythmias

3. New abnormalities detected by regular chest radiographya. An increase in the cardiothoracic ratio (�5%)b. Pulmonary congestionc. Interstitial pulmonary edema (Kerley’s A, B, C lines)



Radionuclear studies of the heart. First, we recom-mend drug-loaded myocardial perfusion scintigraphyusing adenosine. In addition, myocardial scintigraphyusing fatty acid analogue without any loading may beuseful for the detection of myocardial ischemia indialysis patients (5). Myocardial scintigraphy is usefulfor the evaluation of risk of cardiac events. The inci-dence of cardiac events is 4% in those with a normaladenosine-loaded myocardial perfusion scintigrambut high at 67% in those with abnormal scintigraphy(6). Also, abnormalities of myocardial fatty acidmetabolism detected by fatty acid imaging mayindicate the risk of cardiac death in dialysis patients(7).Coronary artery computed tomography (CT)angiography. Contrast-enhanced coronary artery CTangiography is inappropriate for dialysis patients dueto the associated problem of volume loading by thecontrast medium, and because the diagnosis of coro-nary artery stenosis/obstruction is difficult in patientswith marked coronary artery calcification.Coronary artery magnetic resonance angiography(MRA). Very little information is available on theapplication of coronary artery MRA for coronaryartery diseases in dialysis patients, and its usefulness

is unclear. In principle, however, the use of the mag-netic resonance imaging (MRI) contrast medium iscontraindicated in dialysis patients.Diagnosis of acute coronary syndrome. Develop-ment of acute myocardial infarction in a dialysispatient is often associated with the primary symp-toms of heart failure such as dyspnea and coughrather than left shoulder pain, chest pain, or backpain, and Q waves are observed infrequently onECG (8). Acute heart failure in dialysis patientsshould be differentiated from acute coronary syn-drome. Biomarkers of acute myocardial ischemiainclude myocardial troponin T, myocardial fattyacid-binding protein, and CPK-MB fraction, but caremust be exercised to avoid false positive dialysispatients based on measurement of marker levels(9,10).

Treatment

Non-invasive treatmentsDialysis as well as non-dialysis patients are treated

with antiplatelet agents, b-blockers, nitrites, Cachannel blockers, angiotensin I converting enzymeinhibitors, angiotensin II receptor antagonists, and

Myocardial ischemia

suspected

(Table 1)

Physical findings (presence or absence of hypertension, edema, etc.)

Resting echocardiography

Excess/deficiency of circulating blood volume

Adjustment of DW

Symptoms, ECG, chest X-ray findings

Abnormalities of cardiac function

Pulmonary hypertension

Heart valve abnormalities

Pericardial/myocardial

abnormalities

Improved No improvement

Observation

No abnormality

Close cardiovascular examinations



FIG. 1. Diagnostic processes for ischemic heart disease in dialysis patients.



nicorandil. Dose modification may be necessary inusing b-blockers and angiotensin I converting enzymeinhibitors.Reports on the preventive effect of cardiovasculardrugs on cardiac events are scarce. Angiotensin IIreceptor antagonists are reported to have reducedthe incidence of cardiovascular events in dialysispatients (11), but one meta-analysis study casteddoubt on their effectiveness in this population (12).Nicorandil is reported to reduce cardiac events inasymptomatic dialysis patients (13) and cardiacevents/cardiac deaths after coronary artery interven-tions (14,15).

Correction of coronary risk factors such asanemia, hyperlipidemia, and hypertension is alsoimportant. The 2008 Guidelines for the Treatment ofRenal Anemia of the Japanese Society for DialysisTherapy recommend a target Hb level of 10–11 g/dLfor dialysis patients in general and 11–12 g/dL foractive and relatively young patients. We suggestmanaging the Hb at a stable level without allowingit to fall below 10–11 g/dL, the lower limit proposedby the guidelines. Very little evidence is availableconcerning the effectiveness of lipid loweringtherapy using HMG-coenzyme A reductase inhibi-tor (statins). There are two large-scale interventionalstudies in dialysis patients (German Diabetes andDialysis Study (16) and AURORA Study (17)), andneither reported a significant decrease in the risk ofcardiovascular diseases. However, in the formerstudy, which included many patients with hyper-LDL-cholesterolemia, statins significantly reducedthe incidence of ischemic cardiac events, which wasthe secondary end-point. Consideration of statintherapy may be necessary in dialysis patients withhyper-LDL-cholesterolemia or hyper-non-HDL-cholesterolemia.

Coronary revascularizationInvasive revascularization is effective against coro-

nary artery diseases. Revascularization may beachieved by percutaneous coronary intervention(PCI) or coronary artery bypass grafting (CABG),and the therapeutic outcome has improved followingthe use of drug-releasing stents in the former andoff-pump bypass surgery in the latter.

Treatment of acute coronary syndromeAcute coronary syndrome often leads to sudden

death, and, upon its development, the patient shouldbe immediately transported by ambulance to a hospi-tal with a special cardiology unit. The outcome ispoorer in dialysis patients than in non-dialysis patients(18), and emergency PCI is usually considered.

REFERENCES

1. Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovas-cular disease in chronic renal disease. J Am Soc Nephrol 1998;9(Suppl 12):S16–S23.

2. Stack AG, Bloembergen WE. Prevalence and clinical corre-lates of coronary artery disease among new dialysis patients inthe United States: a cross-sectional study. J Am Soc Nephrol2001;12:1516–23.


4. Ohtake T, Kobayashi S, Moriya H et al. High prevalence ofoccult coronary artery stenosis in patients with chronic kidneydisease at the initiation of renal replacement therapy: anangiographic examination. J Am Soc Nephrol 2005;70:1142–8.

5. Nishimura M, Hashimoto T, Kobayashi H et al. Myocardialscintigraphy using a fatty acid analogue detects coronaryartery disease in hemodialysis patients. Kidney Int 2004;66:811–9.

6. Hase H, Joki N, Ishikawa H et al. Prognostic value of stressmyocardial perfusion imaging using adenosine triphosphate atthe beginning of haemodialysis treatment in patients withend-stage renal disease. Nephrol Dial Transplant 2004;19:1161–7.

7. Nishimura M, Tsukamoto K, Hasebe N, Tamaki N, Kikuchi K,Ono T. Prediction of cardiac death in hemodialysis patients bymyocardial fatty acid imaging. J Am Coll Cardiol 2008;51:139–45.

8. Sosnov J, Lessard D, Goldberg RJ, Yarzebski J, Gore JM.Differential symptoms of acute myocardial infarction inpatients with kidney disease: a community-wide perspective.Am J Kidney Dis 2006;47:378–84.

9. Apple FS, Murakami MM, Pearce LA, Herzog CA.Predictive value of cardiac troponin I and T for subsequentdeath in end-stage renal disease. Circulation 2002;106:2941–5.

10. Green TR, Golper TA, Swenson RD, Pulliam JP, Morris CD.Diagnostic value of creatine kinase and creatine kinase MBisoenzyme in chronic hemodialysis patients: a longitudinalstudy. Clin Nephrol 1986;25:22–7.

11. Suzuki H, Kanno Y, Sugahara S, Okada H, Nakamoto H.Effect of angiotensin receptor blockers on cardiovascularevents in patients undergoing hemodialysis: an open-labelrandomized control trial. Am J Kidney Dis 2008;52:501–6.

12. Tai DJ, Lim TW, James MT, Mannis BJ, Tonelli M, Hemmel-garn BR. Cardiovascular effects of angiotensin convertingenzyme inhibition or angiotensin receptor blockade inhemodialysis: a meta-analysis. Clin J Am Soc Nephrol 2010;5:623–30.

13. Nishimura M, Tokoro T, Nishida M et al. Clinical potential ofnicorandil to inhibit major cardiac events in hemodialysispatients with suspected myocardial ischemia. Nephron ClinPract 2009;111:212–21.

14. Ishii H, Toriyama T, Aoyama T et al. Efficacy of oral nic-orandil in patients with end-stage renal disease: a retrospectivechart review after coronary angioplasty in Japanese patientsreceiving hemodialysis. Clin Ther 2007;29:110–22.

15. Nishimura M, Tokoro T, Nishida M et al. Oral nicorandil toreduce cardiac death after coronary revascularization inhemodialysis patients: a randomized trial. Am J Kidney Dis2009;54:307–17.

16. Wanner C, Krane V, März W et al. Atrovastatin in patientswith type 2 diabetes mellitus undergoing hemodialysis. N EnglJ Med 2005;353:238–48.

17. Fellström FC, Jardine AG, Schmieder RE et al. Rosuvastatinand cardiovascular events in patients undergoing hemodialy-sis. N Engl J Med 2010;360:1395–407.

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18. Bonello L, De Labriolle A, Roy P et al. Impact of optimalmedical therapy and revascularization on outcome of patientswith chronic kidney disease and on dialysis who presentedwith acute coronary syndrome. Am J Cardiol 2008;102:535–40.

Chapter 5: Arrhythmias/ValvularHeart Disease

I. SUDDEN CARDIAC DEATH ANDARRHYTHMIAS

Statements

1. We recommend performing exercise elec-trocardiogram (ECG) and Holter ECG forinduction of arrhythmias and evaluation of theeffects of therapy, respectively (1B).

2. Since dialysis patients with arrhythmias arelikely to have organic heart diseases, werecommend echocardiography, stress nuclearimaging tests, and, when necessary, coronaryangiography (1B).

3. We recommend aggressive treatment ofventricular fibrillation/flutter, sustained ven-tricular tachycardia, sick sinus syndrome,sinoatrial block, and marked atrioventricularbock (1A).

4. We suggest that warfarin should not be used inthe treatment of atrial fibrillation without carefulevaluation, but, if warfarin therapy is judgedto be beneficial, the prothrombin time-inter-national normalized ratio (PT-INR) should bemaintained at less than 2.0 (2C).

5. We recommend measurement of PT-INR indirectly sampled blood from a blood vessel (1C).

Comments

EpidemiologySudden cardiac death (SCD) and fatal ventricular

arrhythmias occur in 5–7% of dialysis patients (1,2),and this incidence rate is 25–70 times higher than inthe general population (3). SCD occurs frequently12 h after the initiation of dialysis and 36–48 h afterprevious dialysis (4) and is thought to be related toheart failure, coronary artery disease, diabetes, fluidoverload, activation of the sympathetic nervoussystem, hyperkalemia, and hypokalemia. Fatal ven-tricular arrhythmia is a collective term for cardiacarrest, ventricular fibrillation, ventricular flutter, andventricular tachycardia.

Important bradycardia includes sick sinus syn-drome, sinoatrial block, and marked atrioventricular

(AV) block, but there is no evidence that they areobserved frequently in dialysis patients.

Atrial fibrillation (AF) and atrial flutter are impor-tant causes of acute congestive heart failure, chroniccongestive heart failure due to tachycardia-inducedcardiomyopathy, and dysdialysis syndrome. AF canbe classified into (i) paroxysmal AF, (ii) persistentAF, and (iii) permanent AF.AF is noted in about 12%of patients at the initiation of dialysis (5), and thisincidence increases with age and history of dialysis(6). The risk of death is significantly higher in dialysispatients with AF than in those with sinus rhythm (5).

Pathological featuresArrhythmias observed in dialysis patients are

caused secondarily by ischemic or other cardiomy-opathy, valvular heart disease, electrolyte abnormali-ties, and rapid changes in circulating blood volume,and differential diagnosis from organic heart diseasesis important.

Diagnosis

Clinical symptomsThe primary clinical features of fatal arrhythmia

are sudden cardiopulmonary arrest, syncope, convul-sion, and acute congestive heart failure; those ofsevere bradycardiac arrhythmia are syncope, convul-sion, and acute congestive heart failure; while thoseof tachycardiac arrhythmia are palpitation, skippedbeat, and congestive heart failure. However, morethan a few patients remain asymptomatic.

ExaminationsStandard resting 12-lead ECG is important for the

detection of organic heart diseases, arrhythmias, andelectrolyte abnormalities. The ECG should be per-formed at the introduction of dialysis and periodi-cally thereafter. Exercise ECG should be used toinduce and diagnose arrhythmias, while Holter ECGshould be used to evaluate the risk of arrhythmiasand the effectiveness of treatment. In dialysis patientswith arrhythmias, organic heart diseases should bedetected by echocardiography and, stress nuclearimaging tests. If the results of these examinationsstrongly suggest coronary artery disease, it is neces-sary to perform coronary angiography (7).

Treatment

Preventive treatments against fatal ventriculararrhythmia

b-blockers are recommended as the mainstay fordrug therapy, because they are safe and effective insuppressing any ventricular extrasystoles and other

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arrhythmias and in preventing SCD (8). In dialysispatients with left ventricular systolic dysfunction (leftventricular ejection fraction <35%), administrationof carvedilol significantly reduces not only total car-diovascular deaths but also sudden cardiac deaths(9). According to a report that evaluated the drugsused before cardiac arrest and the outcome aftercardiac arrest, b-blockers and RAS inhibitors dose-dependently improved the outcome (10) Group Iantiarrhythmic drugs should be used carefully,because they are likely to increase the mortality rateassociated with fatal arrhythmias (11,12). Cathetercauterization as a treatment for ventricular tachycar-dia is useful in non-dialysis patients (13) and is alsoconsidered useful in dialysis patients, but there is noevidence to support this conclusion.

Emergency treatment of fatal ventriculararrhythmias

The automated external defibrillator (AED) is adevice that can save patients if it is applied immedi-ately after the onset of ventricular fibrillation.However, evidence of the benefit of equipping dialy-sis facilities with AEDs is insufficient (14).

Implantable cardioverter-defibrillator for fatalventricular arrhythmias

The implantable cardioverter-defibrillator (ICD) isreported to improve the outcome of fatal ventriculararrhythmias in dialysis patients (2). However, the riskof death after treatment in patients with stage 4–5CKD including dialysis patients is about 40 timeshigher than in patients with normal renal function(15), and this must be explained to the patients them-selves and their families when attempting treatmentwith the ICD.

Treatment of marked bradycardiac arrhythmiaThe indications for permanent pacemaker implan-

tation in patients with progressive second- or thirddegree AV block are as follows: (i) presence of clearclinical symptoms related to bradycardia, (ii) brady-cardia caused by irreplaceable drugs, (iii) cardiacarrest sustained for 3 s or longer or ventricular pulserate less than 40/min during wakefulness, (iv) historyof catheter ablation of the AV junction, (v) history ofheart surgery, and (vi) presence of progressive neu-romuscular disease (16).

Warfarin therapy for atrial fibrillationWarfarin is recommended for the treatment of

non-dialysis patients with AF to prevent thrombotic

complications (17). However, in a study that followedup 1671 dialysis patients with AF over a mean periodof 16 years, the risk of de novo stroke was 193 timeshigher in warfarin users than in non-users, and therisk of stroke increased 279 times in patients usingwarfarin without monitoring the PT-INR comparedwith patients not using warfarin (18). The DialysisOutcomes and Practice Patterns Study (DOPPS) alsoreported that warfarin was administered in 16% ofpatients with AF but the risk of stroke increased 217times in warfarin users aged 75 years and above (19).However, the above results were those of observa-tional studies, and thus larger-scale interventionalstudies are necessary in the future to evaluate theusefulness of warfarin. Until then, warfarin must beused carefully in dialysis patients with AF. Falseelevations of the PT-INR are observed frequentlyduring dialysis, and they are reportedly caused byinappropriate blood sampling using an indwellingcatheter (20). We recommend that blood used for thedetermination of PT-INR be collected directly from ablood vessel.

Defibrillation treatment of atrial fibrillationDefibrillation is attempted by medication or elec-

tric shock. The indications for electric defibrillationare the following: (i) severe tachycardiac atrial fibril-lation not responding to medications accompanied byprogressive myocardial ischemia, symptomatichypotension, angina pectoris, or heart failure, (ii)severe tachycardiac atrial fibrillation or unstablehemodynamics,and (iii) intolerable clinical symptomsdue to atrial fibrillation despite stable hemodynamics(17). Antiarrhythmic drugs described in the presentguidelines are used for defibrillation, but monitoringof the dose, blood concentration of the drug duringtreatment, and ECG recording are necessary intreated patients, because all such drugs havearrhythmia-inducing effects by prolonging the QTinterval or extending the QRS duration. One meta-analysis that compared the rhythm control and heartrate control in non-dialysis patients with AF showedno significant difference in mortality rate, incidence ofnon-CNS bleeding, and incidence of ischemic strokeexcept that the proportion of patients who requiredhospitalization was significantly lower in the heartrate control group (P < 001),and ventricular tachycar-dia or bradycardia and QT prolongation wereobserved frequently in the rhythm control group (21).In dialysis patients treated with various antihyperten-sive drugs and who show marked changes in potas-sium concentration associated with dialysis therapy,rate control should be the basic treatment.



Rate control therapy for atrial fibrillationRate control therapy using b-blockers and non-

dihydropyridine Ca-antagonists should be theprimary treatment. In dialysis patients, treatmentwith digoxin results in immediate digoxin toxicity(22). Thus, it is desirable to avoid digoxin because ithas a long disappearance time from blood and inter-acts with many other drugs. The target heart rate is90–100 beats/min or below in the acute period, aresting heart rate of 60–80 beats/min eventually, anda heart rate of 90–110 beats/min during moderateexercise (7). Catheter ablation is a reasonable alter-native for drug therapy in patients with symptomaticrecurrent atrial fibrillation not accompanied by leftatrial dilation (17). While there is no evidence of theusefulness of catheter ablation in dialysis patients,there is also no reason to exclude it.

REFERENCES

1. Nakai S, Masakane I, Akiba T et al. Overview of regular dialy-sis treatment in Japan as of 31 December 2006. Ther ApherDial 2008;12:428–56.

2. Herzog CA, Li S, Weinhandl ED, Strief JW, Collins AJ, Gil-bertson DT. Survival of dialysis patients after cardiac arrestand the impact of implantable cardioverter defibrillators.Kidney Int 2005;68:818–25.

3. Myerburg RJ, Mitrani R, Interian A Jr, Castellanos A. Inter-pretation of outcomes of antiarrhythmic clinical trials: designfeatures and population impact. Circulation 1998;97:1514–21.

4. Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, SatkoSG, Russell G. Charcteristics of sudden death in hemodialysispatients. Kidney Int 2006;69:2268–73.

5. Vazquez E, Sanchez-Perales C, Garcia-Garcia F et al. Atrialfibrillation in incident dialysis patients. Kidney Int 2009;76:324–30.

6. Genovesi S, Pogliani D, Faini A et al. Prevalence of atrialfibrillation and associated factors in a population of long-term hemodialysis patients. Am J Kidney Dis 2005;46:897–902.

7. Zipes DP, Camm AJ, Borggrefe M et al. American Collegeof Cardiology/American Heart Association Task Force;European Society of Cardiology Committee for PracticeGuidelines; European Heart Rhythm Association; HeartRhythm Society. ACC/AHA/ESC 2006 Guidelines for Man-agement of Patients With Ventricular Arrhythmias and thePrevention of Sudden Cardiac Death: a report of the Ameri-can College of Cardiology/American Heart Association TaskForce and the European Society of Cardiology Committee forPractice Guidelines (writing committee to develop Guidelinesfor Management of Patients With Ventricular Arrhythmiasand the Prevention of Sudden Cardiac Death): developed incollaboration with the European Heart Rhythm Associationand the Heart Rhythm Society. Circulation 2006;114:e385–e484.

8. Ellison KE, Hafley GE, Hickey K et al.; Multicenter UnSus-tained Tachycardia Trial Investigators. Effect of beta-blockingtherapy on outcome in the Multicenter UnSustained Tachycar-dia Trial (MUSTT). Circulation 2002;106:2694–9.

9. Cice G, Ferrara L, D’Andrea A et al. Carvedilol increasestwo-year survival in dialysis patients with dilated cardio-myopathy: a prospective, placebo-controlled trial. J Am CollCardiol 2003;41:1438–44.

10. Pun PH, Lehrich RW, Smith SR, Middleton JP. Predictors ofsurvival after cardiac arrest in outpatient hemodialysis clinics.Clin J Am Soc Nephrol 2007;2:491–500.

11. Echt DS, Liebson PR, Mitchell LB et al.; The CAST Investi-gators. Mortality and morbidity in patients receiving encain-ide, flecainide, or placebo. The cardiac arrhythmia suppressiontrial. N Engl J Med 1991;324:781–8.

12. The Cardiac Arrhythmia Suppression Trial II Investigators.Effect of the antiarrhythmic agent moricizine on survival aftermyocardial infarction. N Engl J Med 1992;327:227–33.

13. Stevenson WG, Wilber DJ, Natale A et al.; Multicenter Ther-mocool VT Ablation Trial Investigators. Irrigated radiofre-quency catheter ablation guided by electroanatomic mappingfor recurrent ventricular tachycardia after myocardialinfarction: the multicenter thermocool ventricular tachycardiaablation trial. Circulation 2008;118:2773–82.

14. Lehrich RW, Pun PH, Tanenbaum ND, Smith SR, MiddletonJP. Automated external defibrillators and survival fromcardiac arrest in the outpatients hemodialysis clinic. J Am SocNephrol 2007;18:312–20.

15. Cuculich PS, Sánchez JM, Kerzner R et al. Poor prognosis forpatients with chronic kidney disease despite ICD therapy forthe primary prevention of sudden death. Pacing Clin Electro-physiol 2007;30:207–13.

16. Epstein AE, DiMarco JP, Ellenbogen KA et al.; AmericanCollege of Cardiology/American Heart Association TaskForce on Practice Guidelines (Writing Committee to Revisethe ACC/AHA/NASPE 2002 Guideline Update for Implanta-tion of Cardiac Pacemakers and Antiarrhythmia Devices);American Association for Thoracic Surgery; Society of Tho-racic Surgeons. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report ofthe American College of Cardiology/American Heart Associa-tion Task Force on Practice Guidelines (Writing Committee toRevise the ACC/AHA/NASPE 2002 Guideline Update forImplantation of Cardiac Pacemakers and AntiarrhythmiaDevices) developed in collaboration with the American Asso-ciation for Thoracic Surgery and Society of Thoracic Surgeons.J Am Coll Cardiol 2008;51:e1–e62.

17. Fuster V, Rydén LE, Cannom DS et al.; American College ofCardiology/American Heart Association Task Force on Prac-tice Guidelines; European Society of Cardiology Committeefor Practice Guidelines; European Heart Rhythm Association;Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines forthe Management of Patients With Atrial Fibrillation: a reportof the American College of Cardiology/American Heart Asso-ciation Task Force on Practice Guidelines and the EuropeanSociety of Cardiology Committee for Practice Guidelines(Writing Committee to Revise the 2001 Guidelines for theManagement of Patients With Atrial Fibrillation). Circulation2006;114:e257–e354.

18. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin useassociates with increased risk for stroke in hemodialysispatients with atrial fibrillation. J Am Soc Nephrol 2009;20:2223–33.

19. Wizemann V, Tong L, Satayathum S et al. Atrial fibrillation inhemodialysis patients: clinical features and associations withanticoagulant therapy. Kidney Int 2010;77:1098–106.

20. Delate T, Witt DM, Jones JR, Bhardwaja B, Senser M. Falselyelevated international normalized ratio values in patientsundergoing anticoagulation therapy: a descriptive evaluation.Chest 2007;131:816–22.

21. Kumana CR, Cheung BM, Cheung GT, Ovedal T, Pederson B,Lauder IJ. Rhythm vs. rate control of atrial fibrillation meta-analysed by number needed to treat. Br J Clin Pharmacol2005;60:347–54.

22. Kaneko T, Kudo M, Okumura T et al. Successful treatmentof digoxin intoxication by haemoperfusion with specificcolumns for beta2-microglobin-adsorption (Lixelle) in main-tenance haemodialysis patient. Nephrol Dial Transplant 2001;16:195–6.



II. VALVULAR HEART DISEASE

Statements

1. In dialysis patients with asymptomatic heartmurmur or heart murmur accompanied by con-gestive heart failure, syncope, arterial embolism,or dysdialysis syndrome on auscultation, we rec-ommend differential diagnosis of valvular heartdisease (1A).

2. We recommend the diagnosis of valvular heartdisease and evaluation of its severity byDoppler echocardiography (1A)1.

3. In dialysis patients with acute valvular heartdisease, we suggest that infective endocarditisshould be differentiated (2B).

4. We recommended periodic performance ofechocardiography in patients with mild or mod-erate valvular heart disease and not to postponesurgical treatment in patients with severe valvu-lar heart disease (1A).

Comments

EpidemiologyIn general, the mean left ventricular-aortic pressure

gradient in patients with aortic stenosis (AS) increasesby 7 mm Hg per year, in association with a meanannual narrowing of the valvular area narrows of0.1 cm2 (1). In dialysis patients,AS occurs at a youngerage and deteriorates more rapidly with progression ofcalcification.The incidence ofAS in dialysis patients is1.5–8.0%/year, and the rate of narrowing of the valvu-lar area is 0.23 cm2/year (2). Reduced mobility andcontact insufficiency of the aortic valve due to calcifi-cation are major causes of aortic regurgitation (AR).AS occurs more frequently with AR than alone. Theprogression of aortic valve calcification correlateswith the following factors: (i) aging, (ii) male sex, (iii)an increase in the Ca¥P product,(iv) period of dialysis,(v) progressive increase in CRP, (vi) oral intake ofcalcium preparations (2–5). A proportion of dialysispatients shows no adhesion in the commissural regionbut mitral stenosis (MS) with marked valvular ringcalcification. The progression of MS, similar to AS, ischaracteristically rapid in dialysis patients. Infectiveendocarditis due to bacterial infection from shuntpuncture or venous catheter placement, occurs 17times more frequently in dialysis patients comparedwith non-dialysis patients (6).

Pathological featuresThe cause of valvular heart disease accompanied

by severe calcification in dialysis patients is age-related degeneration. The mechanism of degenera-tion is destruction of the most external endothelialcell layer of the valve, followed by infiltrationof inflammatory cells, such as monocytes andT-lymphocytes, into the interior of the valve, uptakeof low-density lipoprotein, release of inflammatorycytokines, proliferation of interstitial cells of thevalve, and remodeling and calcification of the extra-cellular matrix (7,8). In addition to the age-relateddegeneration, infective endocarditis, aortic dissec-tion, and bicuspid aortic valve may also cause AR.On the other hand, mitral regurgitation (MR)occurs when the valve cusps fail to close tightly dueto tethering of the papillary muscle, which pulls thecusps, in addition to the widening of the mitral ringdue to enlargement of the left ventricular cavityas a result of infective endocarditis or ischemic car-diomyopathy, in association with age-related degen-eration (9). To determine the cause of acuteAR or MR in dialysis patients, differentiation ofinfective endocarditis is desirable (10). Furthermore,infective endocarditis in patients who receive artifi-cial valve replacement may lead to more seriousacute dysfunction of the heart (cardiogenic shockand congestive heart failure). The condition may notrespond to treatment with antibiotics and may causevalvular ring and endocardial abscesses. The caus-ative bacteria are frequently staphylococci, strepto-cocci, or Gram-negative bacilli. Functional MRmay also occur when the setting of dry weight (DW)is inappropriate.

Diagnosis

Clinical symptomsChronic valvular disease is characterized by a long

asymptomatic period, although heart murmur isheard from an early stage. Clinically, heart murmur isheard before the appearance of symptoms. The com-monest clinical features are anginal attacks, syncope,congestive heart failure, palpitation (arrhythmias),and arterial embolization (1), and dysdialysis syn-drome is specific to dialysis patients.These symptomsare due to low cardiac output and pulmonary hyper-tension. In dialysis patients with asymptomatic heartmurmur and those with heart murmur accompaniedby congestive heart failure or syncope, angina pecto-ris, arterial embolism, or dysdialysis syndrome, differ-entiation of valvular heart disease is recommended(1). In dialysis patients with MR, symptoms of con-gestion can be resolved or alleviated by lowering the

1Doppler echocardiography should be performed on achieve-ment of dry weight.



DW, and accordingly, it is important not to postponesurgical treatment in patients with severe valvularheart disease

ExaminationsThe area of the normal orifice of the aortic valve is

2.5–3.5 cm2, and that of the mitral valve is 4.0–6.0 cm2. Doppler echocardiography should be usedfor the diagnosis of valvular heart disease and evalu-ation of its severity (1). The valve orifice area can beeither determined by direct tracing the valve orificein a short-axis tomogram of echocardiography orestimated by the continuous wave Doppler methodfrom the pressure halftime (PHT). However, since itis impossible to accurately trace the valve orifice indialysis patients with severe valve ring calcification,estimation of the valve orifice area from the PHT ismore appropriate. Since functional MR can occur ifthe DW is set inappropriately, Doppler echocardio-graphy should be performed on the achievement ofthe DW.

TreatmentsWhile there is no effective drug therapy for AS,

MS, or MR in dialysis patients, patients with valvulardiseases accompanied by calcification treated withcalcium carbonate as a phosphorus-binding agentshould be switched to sevelamer hydrochloride orlanthanum carbonate (11). b-blockers and non-dihydropyridine Ca-antagonists are effective againstany associated tachycardia (1). Also, valvuloplastyusing a balloon is not recommended for severe calci-fication, and surgical valve replacement is indicatedinstead for such patients (1).

REFERENCES

1. Bonow RO, Carabello BA, Chatterjee K et al.; AmericanCollege of Cardiology/American Heart Association TaskForce on Practice Guidelines. 2008 focused update incorpo-rated into the ACC/AHA 2006 guidelines for the managementof patients with valvular heart disease: a report of the Ameri-can College of Cardiology/American Heart Association TaskForce on Practice Guidelines (Writing Committee to revisethe 1998 guidelines for the management of patients with val-vular heart disease). Endorsed by the Society of Cardiovascu-lar Anesthesiologists, Society for Cardiovascular Angiographyand Interventions, and Society of Thoracic Surgeons. J AmColl Cardiol 2008;52:e1–e142.

2. Urena P, Malergue MC, Goldfarb B, Prieur P, Guédon-Rapoud C, Pétrover M. Evolution aortic stenosis in HDpatients: analysis of risk factors. Nephrologie 1999;20:217–25.

3. London GM, Pannier B, Marchais SJ, Guerin AP. Calcificationof the aortic valve in the dialysis patients. J Am Soc Nephrol2000;11:778–83.

4. Barreto DV, Barreto FC, Carvalho AB et al. Coronary calci-fication in hemodialysis patients: the contribution of tradi-tional and uremia-related risk factors. Kidney Int 2005;67:1576–82.

5. Ishimura E, Okuno S, Kitatani K et al. C-reactive pro-tein is a significant predictor of vascular calcification ofboth aorta and hand arteries. Semin Nephrol 2004;24:408–12.

6. Abbott KC, Agodoa LY. Hospitalizations for bacterialendocarditis after initiation of chronic dialysis in the UnitedStates. Nephron 2002;91:203–9.

7. Rajamannan NM, Otto CM. Targeted therapy to preventprogression of calcific aortic stenosis. Circulation 2004;110:1180–2.

8. Osman L, Yacoub MH, Latif N, Amrani M, Chester AH.Role of human valve interstitial cells in valve calcificationand their response to atorvastatin. Circulation 2006;114:I547–I552.

9. Hung J, Chaput M, Guerrero JL et al. Persistentreduction of ischemic mitral regurgitation by papillarymuscle repositioning. Circulation 2007;116(Suppl I):I259–I263.

10. Nucifora G, Badano LP, Viale P et al. Infective endocarditis inchronic haemodialysis patients: an increasing clinical chal-lenge. Eur Heart J 2007;28:2307–12.

11. K/DOQI Workgroup. K/DOQI clinical practice guidelines forcardiovascular disease in dialysis patients. Am J Kidney Dis2005;45(Suppl 3):S1–S153.

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Chapter 6: Surgical Treatments

I. ISCHEMIC HEART DISEASE

Statements

1. Chronic kidney disease is a poor prognosticfactor of coronary artery bypass grafting(CABG) (B).

2. In dialysis patients, the long-term survival rate ishigher after CABG than after percutaneouscoronary intervention (PCI) (B).

3. In dialysis patients, we suggest that use ofartificial heart-lung machine should be avoidedto alleviate perioperative complications (2B).

4. In dialysis patients, the greater saphenous veinused as a graft may deteriorate rapidly, and wesuggest use of the internal thoracic artery forCABG (2B).

Comments

Coronary artery revascularizationIn Japanese dialysis patients who had undergone

coronary artery bypass grafting (CABG), thereported hospital death rate is 9% (1), and the 5-yearsurvival rate is 40–60% (1). Furthermore, in dialysispatients who had undergone CABG using an artifi-cial heart-lung machine, the mortality rate is 3.1 times

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higher, the incidence of mediastinitis is 2.4 timeshigher, and incidence of cerebral infarction is 2.1times higher, than in patients with normal kidneyfunction (2). Therefore, safety management duringthe CABG perioperative period is the most impor-tant in dialysis patients.

In the field of percutaneous coronary intervention(PCI), postoperative re-stenosis has markedly dimin-ished following the advent of drug-eluting stents(DES) and the development of new antiplateletagents, making PCI the first choice treatment forcoronary artery disease. In dialysis patients, however,the re-stenosis rate has been reported to be high evenafter PCI using DES (3).While the benefits of DES indialysis patients including the long-term follow-upresults remain unclear, the long-term survival rate ofdialysis patients is presently higher after CABG thanafter PCI (4,5). In Japan, the long-term survival rateis reported to be comparable between the two pro-cedures (6). However, since diabetes is often theprimary disease in dialysis patients, many patientsare considered to require repeated coronary arteryrevascularization, and a higher priority may beplaced on CABG as long as the general conditionpermits it.

Coronary artery bypass graftingDialysis patients often develop generalized

advanced arteriosclerosis. Therefore, off-pumpCABG without the use of the artificial heart-lungmachine is needed to reduce the risk of release ofatheromatous emboli by procedures such as inser-tion of a blood feeding tube into the ascendingaorta for extracorporeal circulation and to facilitateperioperative hydration management. In fact, perio-perative complications including deaths havereduced following the introduction of off-pumpCABG (7–11). Shroff et al. (11) reported that thehospital death and 3-year postoperative mortalityrates were significantly lower in the group of dialy-sis patients treated with the internal thoracic vein.Therefore, it is recommended to use the internalthoracic vein as long as possible in bypass surgery ofthe left anterior descending artery.

Percutaneous coronary intervention should beconsidered first for patients with acute coronarysyndrome. Also, left ventriculoplasty must be con-sidered for patients with ischemic cardiomyopathy.However, in dialysis patients, many of whom havemyocardial infarction with lesions in multiple areasof the coronary artery and/or left ventricular dys-function, the surgical procedure (e.g. off-pumpCABG or on-pump beating CABG alone) should

be selected after sufficient evaluation of whetherpostoperative death associated with the initialsurgery can be avoided.

REFERENCES

1. Endo M. Coronary artery bypass grafting in patients onchronic hemodialysis in Japan. Artif Organs 2001;25:237–8.

2. Liu JY, Birkmeyer NJ, Sanders JH et al. Risks of morbidityand mortality in dialysis patients undergoing coronary arterybypass surgery. Northern New England CardiovascularDisease Study Group. Circulation 2000;102:2973–7.

3. Aoyama T, Ishii H, Toriyama T et al. Sirolimus-eluting stentsvs bare metal stents for coronary intervention in Japanesepatients with renal failure on hemodialysis. Circ J 2008;72:56–60.

4. Herzog CA, Ma JZ, Collins AJ. Long-term outcome of dialysispatients in the United States with coronary revascularizationprocedures. Kidney Int 1999;56:324–32.

5. Hemmelgarn BR, Southern D, Culleton BF, Mitchell LB,Knudtson ML, Ghali WA, Alberta Provincial Project for Out-comes Assessment in Coronary Heart Disease (APPROACH)Investigators. Survival after coronary revascularization amongpatients with kidney disease. Circulation 2004;110:1890–5.

6. Aoki J, Ikari Y, Sugimoto T, Fukuda S, Hara K. Clinicaloutcome of percutaneous transluminal coronary rotationalatherectomy in patients with end-stage renal disease. Circ J2003;67:617–21.

7. Nishida H, Uchikawa S, Chikazawa G et al. Coronary arterybypass grafting in 105 patients with hemodialysis-dependentrenal failure. Artif Organs 2001;25:268–72.

8. Papadimitriou LJ, Marathias KP, Alivizatos PA et al.Safety and efficacy of off-pump coronary artery bypass graft-ing in chronic dialysis patients. Artif Organs 2003;27:174–80.

9. Beckermann J, Van Camp J, Li S, Wahl SK, Collins A, HerzogCA. On-pump versus off-pump coronary surgery outcomes inpatients requiring dialysis: perspectives from a single centerand the United States experience. J Thorac Cardiovasc Surg2006;131:1261–6.

10. Dewey TM, Herbert MA, Prince SL et al. Does coronaryartery bypass graft surgery improve survival among patientswith end-stage renal disease? Ann Thorac Surg 2006;81:591–8.

11. Shroff GR, Li S, Herzog CA. Survival of patients on dialysishaving off-pump versus on-pump coronary artery bypasssurgery in the United States. J Thorac Cardiovasc Surg 2010;139:1333–8.

II. VALVULAR HEART DISEASE

Statements

1. We suggest valvular heart disease in dialysispatients should be regarded as part ofgeneralized ectopic vascular calcification (2B).

2. In surgical treatment for valvular disease indialysis patients, we recommend preoperativeevaluation of arterial calcification by coronaryangiography, whole body computed tomography(CT) and ultrasonography of the carotid artery(1C).

3. Frequent intradialytic hypotension suggestsvalvular heart disease, and we recommendechocardiography in such patients (1C).



CommentsSince dialysis patients often have generalized

severe arteriosclerosis and calcification lesions, it isimportant to preoperatively evaluate not only thecardiac and valvular functions but also head and necklesions by imaging procedures such as coronaryangiography, ultrasonography of the carotid artery,head CT, and head magnetic resonance imaging(MRI). Other pathologies such as calcification of theaorta and atherosclerotic lesions of the abdominalorgans should be assessed by thoracic and abdominalCT, and peripheral obstructive arteriosclerosis byusing indices such as the ankle brachial index (ABI).Then, it is necessary to judge whether an artificialheart-lung channel can be established (particularly,when a blood feeding tube should be placed) orwhether aortic clamping is possible (1). More impor-tantly, the state of the ascending aorta must bechecked, and the position of insertion of the bloodfeeding tube and the site of aortic clamping must bedetermined carefully by intraoperative examinationssuch as ultrasonography. Blood feeding via a vesselother than the ascending aorta must be considered inpatients with porcelain aorta, and deep hypothermiccirculatory arrest, blocking with, for example, aballoon, must be considered if aortic clamping isimpossible.

Dialysis patients readily develop septicemia andare likely to develop infective endocarditis due tobacteria attached to degenerated areas of the valvu-lar cusps. Acute valvular disease must always betreated with infective endocarditis in mind.

Aortic valveAortic stenosis. The clinical features of aortic steno-sis (AS) are angina pectoris, syncope, and heartfailure, and these are absolute indications of surgicaltreatment. However, dialysis patients often exhibitfewer symptoms because of low ADL level. The pro-gression of calcification, on the other hand, is veryrapid, and when calcification of the ascending aortaprogresses to marked calcification involving the valvering to the aortic wall, valve replacement becomesdifficult with a rise in intraoperative complications.Therefore, surgery should be considered as early aspossible in dialysis patients with maximum bloodflow rate of 4.0 m/s or higher, or valve orifice area of0.6 cm2 or smaller (2), as determined by echocardio-graphy, after taking into consideration the generalcondition of the patient.

In valve replacement, maximum resection of thecalcified areas of the valve ring is necessary. Anyremaining calcified tissue can induce regurgitationaround the artificial valve and cause hemolysis. Also,

if an artificial valve of a sufficient size cannot be useddue to hardening of the sinus of Valsalva or valvering, widening of the valve ring is dangerous, and theuse of an artificial valve for a small annulus may be apractical alternative.

Mitral valveMitral stenosis. In dialysis patients, calcification isoften observed in the valvular cusps, papillarymuscle, and tendinous cords, and mitral stenosis (MS)is frequently induced by mitral annular calcification(MAC). Since cardiac dysfunction occurs moreslowly in patients with mitral valve abnormalitiesthan those with aortic valve disorders, internal treat-ment such as adjustment of dry weight is attemptedfirst. If body fluid management is still difficult,surgery is considered if the valve orifice area dimin-ishes to 1.0 cm2 or less. However, valve replacement istechnically difficult in patients with severe MAC, andthe risk of surgery is high.Mitral regurgitation. Close examination is needed inpatients with calcification- and ischemic-relatedmitral regurgitation (MR). If degeneration of thevalve is mild, valvuloplasty may be possible, but, inthis situation, coronary bypass grafting or left ven-triculoplasty must be considered also.

Warfarin administration after mechanicalvalve replacement

Since there are racial differences in warfarincontrol after mechanical valve replacement, carefulevaluation of the results in Japanese patients mustbe considered (3–5). Also, careful monitoringaccording to the prothrombin time-internationalnormalized ratio (PT-INR) by integrating conflictingrisks of bleeding and thromboembolism is neces-sary. The Guidelines for Anticoagulant/AntiplateletTherapies for Cardiovascular Diseases list the crite-ria for warfarin therapy (Table 1) (6). Hemorrhagiccomplications and cerebral hemorrhage are fre-quently encountered in dialysis patients (7,8). Theseare due to various abnormalities such as low bloodvitamin K level, excess administration of warfarin,anemia, and defective clotting mechanisms. There-fore, it is necessary to maintain the PT-INR at a lowlevel in dialysis patients. Also, since the risk ofembolism is high during the first few months aftersurgery, during which sufficient endothelialization ofthe sutured areas of the valve is necessary (9), war-farin control by a specialist is desirable for at least3 months after surgery.

The table used in this chapter was reproduced fromthe Guidelines for Non-Drug Therapies of ValvularDisease (2007 revised edition) published by the Japa-



nese Circulation Society. Reproduction was madewith permission by the Scientific Committee of theJCS.

REFERENCES

1. Okawa I. Indications of surgery for valvular disease and sur-gical strategy—Latest treatments for cardiovascular diseasesin dialysis patients. Nankodo 2006;167–81.

2. Matsuda A, Okita Y, Kawazoe K. Guidelines for the Diagnosisand Treatment of Cardiovascular Diseases. 2006 Report by theJoint Research Group: Guidelines for surgical and interven-tional treatment of valvular heart disease (2007 revisededition) (presented at the homepage of the Japanese Circula-tion Society. [Accessed 21 May 2012.] Available from URL:http://www.j-circ.or.jp/guideline/index.htm

3. Uetsuka Y, Hosoda S, Kasanuki H et al. Optimal therapeuticrange for oral anticoagulants in Japanese patients with pros-thetic heart valves: a preliminary report from a single institu-tion using conversion from thrombotest to PT-INR. HeartVessels 2000;15:124–8.

4. Matsuyama K, Matsumoto M, Sugita T et al. Anticoagulanttherapy in Japanese patients with mechanical mitral valves.Circ J 2002;66:668–70.

5. Kitamura M, Koyanagi H, Kudo T et al. Optimal anticoagulanttherapy after bicuspid mechanical valve replacement-evaluation from a multi-facility prospective investigation.Kyobu Geka 1999;52:1001–4.

6. Kasanuki H, Aosaki M, Ikeda Y et al. Guidelines for thediagnosis and treatment of cardiovascular diseases (2002–2003 report by the Joint Research Group: guidelines foranticoagulant/antiplatelet therapies of cardiovascular dis-eases. Circ J 2004;68(Suppl IV):1153–219.

7. Brinkman WT, Williams WH, Guyton RA, Jones EL, CraverJM. Valve replacement in patients on chronic renal dialysis:implications for valve prosthesis selection. Ann Thorac Surg2002;74:37–42.

8. Lucke JC, Samy RN, Atkins BZ et al. Results of valve replace-ment with mechanical and biological prostheses in chronicrenal dialysis patients. Ann Thorac Surg 1997;64:129–33.

9. Heras M, Chesebro JH, Fuster V et al. High risk of throm-boemboli early after bioprosthetic cardiac valve replacement.J Am Coll Cardiol 1995;25:1111–9.

Supplement: Perioperative management for heartsurgery in dialysis patients

Preoperative management

1. Preoperative evaluation: Before surgery for coro-nary artery or valvular disease, it is important toevaluate not only cardiac and valve functions butalso head and neck lesions by various imagingmodalities such as coronary angiography, ultra-sonography of the carotid artery, head CT, andhead MRI. It is also important to assess calcifica-tion of the aorta and arteriosclerotic lesions ofabdominal organs by thoracoabdominal CT, aswell as peripheral obstructive arteriosclerosis byindices such as the ankle brachial index (ABI). Itis also necessary to establish the artificial heart-lung channel (particularly, the site of bloodfeeding) and judge whether aortic clamping ispossible.

2. Perioperative dialysis must be planned carefully incooperation with related departments.

3. Dialysis should be performed on the day beforesurgery as much as possible. Hypotension canoccur in dehydrated patients following the induc-tion of anesthesia due to a decrease in circulatingblood volume.

Intraoperative management

1. The shunt flow must be checked at each entryinto the operation room and at the end of eachoperation. During surgery, utmost care should beexercised to avoid mechanical compression ofthe shunt. Obstruction may be caused byhypotension, low cardiac output, and othermechanisms. The duration of such events shouldbe shortened.

TABLE 1. Anticoagulant/antiplatelet therapies

Class I1. Warfarin therapy for patients within 3 months after artificial

valve replacement with PT-INR of 2.0–3.02. Warfarin therapy for patients within 3 months after mitral

valvuloplasty with PT-INR of 2.0–3.03. Warfarin therapy for patients within 3 months or longer after

surgery under the following conditionsMechanical valveAVR (bicuspid or Medtronic Hall valve), no risk factor†

PT-INR = 2.0–2.5Other disk valves or Starr-Edwards valve, no risk factorPT-INR = 2.0–3.0AVR + risk factorsPT-INR = 2.0–3.0MVR + risk factorsPT-INR = 2.0–3.0Biological valveAVR + risk factorsPT-INR = 2.0–3.0MVR + risk factorsPT-INR = 2.0–3.0ValvuloplastyMitral valvuloplasty + risk factors†

PT-INR = 2.0–2.5Class Iia1. Warfarin administration with PT-INR of 2.5–3.5 for patients

with thromboembolism despite appropriate warfarin therapy.2. Combination of aspirin or dipyridamole coadministration with

warfarin for patients with thromboembolism despiteappropriate warfarin therapy.

Class III1. No warfarin for patients with mechanical valve replacement2. Administration of aspirin alone for patients with mechanical

valve replacement3. Administration of neither warfarin nor aspirin for patients

with biological valve replacement

†Risk factors: atrial fibrillation, history of thromboembolism,reduced left heart function, hypercoagulation state. AVR, aorticvalve replacement; MVR, mitral valve replacement; PT-INR, pro-thrombin time-international normalized ratio.



2. Since water excretion is impaired during surgery,care should be taken to avoid excessive fluid over-load since it may cause congestive heart failure.However, excessive fall in circulating bloodvolume is likely to invite fatal complications.Therefore, circulating blood volume should becritically monitored intraoperatively.

3. It must be remembered that dialysis patients oftensuffer from anemia and hypoproteinemia beforesurgery. Moreover, the release of inflammatorymediators following bleeding, surgical stress, andexcess interstitial edema, transfusion or the use ofcolloid solution may be necessary. Also, the use ofartificial colloid solution, which is excreted via thekidney, should be avoided in dialysis patients.

4. In surgery using an artificial heart-lung apparatus,the water load should be kept at minimum duringextracorporeal circulation by hemodialysis andextracorporeal ultrafiltration method (HD,ECUM). Also, hyperkalemia should be corrected.

Postoperative management

1. Restoration of body weight to preoperative base-line level shortly after surgery results in a decreasein circulating blood volume, often causinghypotension or low cardiac output. Therefore,water should be removed slowly over a period ofabout one week after surgery. The use of drugswith a peripheral vasoconstrictor activity such asnoradrenaline is likely to induce fatal complica-tions such as non-occlusive mesenteric ischemia(NOMI). Also, the myocardium of dialysispatients often shows diastolic dysfunction, and adecrease in preload is likely to trigger hypotensionor low cardiac output. Therefore, it is necessary tomaintain a sufficient circulating blood volumeearly after surgery.

2. If necessary, daily dialysis, CHDF and other pro-cedures should be considered early after surgery.For such procedures, anticoagulants with a shorthalf-life, such as nafamostat mesilate, which isinactivated rapidly in the channel, should be usedfor hemorrhage.

3. Emergency dialysis should be considered whenthe patient develops hyperkalemia, congestiveheart failure due to hypervolemia, pulmonary con-gestion, or severe acidosis.

4. Since the immunological capacity is depressed indialysis patients, greater emphasis should beplaced on clean manipulations. In using antibiot-ics, changes in their pharmacokinetics should beconsidered, and their dose and administrationperiod should be modified.

tap_1088_8 414..462 Chapter 7: Cerebrovascular Disorders

I. CEREBRAL HEMORRHAGE

Statements

1. Dialysis should be avoided within 24 h after theonset (1C).

2. Shortly after the onset of cerebral hemorrhage,we recommend dialysis methods that causeonly a mild increase in the intracranial pressuresuch as continuous hemodiafiltration, perito-neal dialysis, and hemodialysis with restrictedblood flow should be selected (1B). We alsorecommend that glycerol should be adminis-tered during dialysis and nafamostat mesilateshould be used as an anticoagulant (1B).

3. We suggest that blood pressure should beaggressively controlled from the acute period ofcerebral hemorrhage (2C).

4. We suggest that surgery should be consideredfor the treatment in the acute period of majorcerebral hemorrhage accompanied by anincrease in the intracranial pressure (2C).

5. We recommend that blood pressure should bestrictly controlled to prevent cerebrovascularaccident and recurrence (1B).

Comments

EpidemiologyThe annual incidence of cerebral hemorrhage in

dialysis patients (3.0–10.3/1000 people) is signifi-cantly higher than in the general population (1.2 inthe Hisayama Study) (1–7). Cerebral hemorrhage indialysis patients is mainly caused by hypertension,produces larger hematoma than in non-dialysispatients, and is associated with poor prognosis. Theassociated mortality rate (27–83%, mean: 53%) isalso higher than in the general population (19%) (7),and the prognosis is particularly poor in patients witha hematoma volume of 50 mL or greater and thosewith ventricular rupture (1,2,4–6,8–28).

Pathological featuresThe pathological changes in the acute period of

cerebral hemorrhage are classified into primarydamage, which is destruction of the brain paren-chyma due to hematoma, and secondary damagecaused by subsequent intracranial hypertension,impairment of cerebral circulation and metabolism,and brain edema.

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DiseasesH. Hirakata et al414


Initial treatment and diagnosisIn patients with provisional diagnosis of stroke,

highest priority should be placed on securing respira-tion and circulation, followed by neurological evalua-tion. Detection of a high density area in the cerebralparenchyma on head computed tomography (CT)establishes the diagnosis of cerebral hemorrhage. Ifdifferentiation from hemorrhagic infarction is neces-sary, or if cerebral aneurysm, cerebral arteriovenousanomaly, or tumoral bleeding is suspected, evaluationby magnetic resonance imaging (MRI), magneticresonance angiography (MRA), or cerebral angiogra-phy becomes necessary (29). Also, a small hematomadetected soon after the onset may increase in sizethereafter, and thus periodic follow-up examinationof the hematoma size by CT is important (29). In thisregard, nephrogenic systemic fibrosis (NSF) inpatients with renal failure due to gadolinium contrastmedia used for MRI has attracted attention, andwarning not to use gadolinium contrast medium inpatients with glomerular filtration rate of less than30 mL/min per 1.73 m2, in principle, has been issued(30).

Treatments

Management of brain edema during the acute periodGlycerol is effective for acute treatment of large

cerebral hemorrhage associated with intracranialhypertension (31–33). Since glycerol is not expectedto increase urinary volume in dialysis patients andcauses volume overload, its administration duringdialysis, when excretion of glycerol with waterremoval is expected, is desirable.

Neurosurgical emergency procedures (removal ofhematoma, ventricular drainage) are necessary inpatients with serious disturbance of consciousness,those in whom the estimated hematoma volumeexceeds 30 mL, and those who subsequently develop

hydrocephalus due to ventricular rupture ofhematoma (33). While the results of craniotomy areunfavorable in dialysis patients (1), the results of ste-reotactic removal of hematoma for putaminal hem-orrhage are comparable to those in non-dialysispatients especially when the hematoma volume is30–50 mL (34).

Blood pressure control during the acute periodDuring the acute period of cerebral hemorrhage, it

is very important to control blood pressure toprevent re-bleeding, expansion of hematoma, andexacerbation of brain edema. Although it is impor-tant to maintain systolic pressure at 180 mm Hg orbelow (mean blood pressure �130 mm Hg), it is alsorecommended to slowly reduce the blood pressure at80% of the pretreatment value to avoid the risk ofcerebral ischemia due to excessive decrease in bloodpressure (Table 1) (35,36).

Brain examination for asymptomatic microbleedsMicrobleeds appearing as low-signal-intensity

areas by T2*-weighted MRI are frequently detectedin patients with long-term hypertension and thosewith a history of cerebrovascular disorders, but theyare also noted frequently in dialysis patients (37,38).While microbleeds have been reported to affect theoccurrence of cerebral hemorrhage (39–41), whetherthe risk of cerebral hemorrhage is increased by anti-thrombotic therapy is unclear.

Management of renal failure during the acute periodSince the risk of expansion of hematoma is high

within 24 h after the onset of cerebral hemorrhage(42), it is desirable to avoid dialysis. Since dialysisexacerbates intracranial hypertension by removingsolutes and water, it is important to select a procedurethat has minimum effect on intracranial pressure.Peri-toneal dialysis, continuous hemodiafiltration, and

TABLE 1. Blood pressure management in the acute period of cerebrovascular disorders

Blood pressure management in patients with acute-phase cerebral infarctionNo indication

for thrombolytictherapy

SBP <220 mm Hg orDBP <120 mm Hg

No aggressive antihypertensive treatment (except when there is a systemic complicationsuch as hypertensive encephalopathy, aortic dissection, acute renal failure, acutepulmonary edema, and acute myocardial infarction)

SBP >220 mm Hg orDBP >120 mm Hg

Target of antihypertensive treatment: 85–95% of the previous valueAntihypertensive agents (i.v. drip infusion of nicardipine, diltiazem, nitroglycerin,

or nitroprusside)With indications

for thrombolytictherapy

SBP >185 mm Hg orDBP >110 mm Hg

Target of antihypertensive treatment: <180/105 mm HgAntihypertensive agents (i.v. drip infusion of nicardipine, diltiazem, nitroglycerin,

or sodium nitroprusside)

Blood pressure management in patients with acute-phase cerebral hemorrhageSBP >180 mm Hg or

MBP >130 mm HgTarget of antihypertensive treatment: 80% of the previous valueAntihypertensive agents (i.v. drip infusion of nicardipine, diltiazem, nitroglycerin,

or nitroprusside)

DBP, diastolic blood pressure; MBP, mean blood pressure; SBP, systolic blood pressure.



hemodialysis with restricted blood flow, which are lesslikely to increase intracranial pressure compared withusual intermittent hemodialysis, are recommended asthe dialysis techniques to be used during the acuteperiod (43–45).

Blood pressure control for primary andsecondary prevention

Management of blood pressure is extremelyimportant for the secondary prevention of cerebralhemorrhage. The recurrence rate is high amongpatients with inadequate blood pressure control, andcontrolling the diastolic pressure at 90 mm Hg orbelow is recommended to prevent the recurrence(33,46,47). With regard to primary prevention, bloodpressure has also been shown to markedly affect therisk of de novo cerebral hemorrhage (48). It has alsobeen reported that the incidence increases threetimes at systolic pressure of 160 mm Hg or highercompared with less than 140 mm Hg (49) and that thepre-dialysis systolic pressure correlates significantlywith hematoma volume (4).

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4. Kawamura M, Fujimoto S, Hisanaga S, Yamamoto Y, Eto T.Incidence, outcome, and risk factors of cerebrovascular eventsin patients undergoing maintenance hemodialysis. Am JKidney Dis 1998;31:991–6.

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6. Noda T, Suzuki M, Miyazaki S et al. Cerebrovascular diseaseswith special reference to clinical disorders in maintenancedialysis patients. J Jpn Soc Dial Ther 2000;33:1389–99.

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8. Onoyama K, Ibayashi S, Nanishi F et al. Cerebral hemorrhagein patients on maintenance hemodialysis. CT analysis of 25cases. Eur Neurol 1987;26:171–5.

9. Tanimoto K, Obayashi S, Obayashi M, Utsumi K. Treatmentfor cerebrovascular disorders in dialysis patients. Cerebralhemorrhage. Jpn J Clin Dial (Rinsho Toseki) 1994;10:1375–82.

10. Kameyama M, Sakaguchi K, Nishinaka K, Tsujimura T, UdakaF, Fushimi H. Cerebrovascular diseases in patients underchronic hemodialysis. J Jpn Soc Dial Ther 1994;27:1363–71.

11. Kawabata S. Cerebral hemorrhage associated withhemodialysis-evaluation of head CT findings. Nosotchu 1994;16:79–86.

12. Mitsuiki K, Kubo S, Tsuruya K, Takeda K, Harada A. Evalu-ation of cerebrovascular disorders in patients on chronic dialy-sis therapy. Med J Matsuyama Red Cross Hosp 1995;20:53–7.

13. Lin CL, Kwan AL, Howng SL. Prognosis of spontaneousintracerebral hemorrhage in hemodialysis patients. KaohsiungJ Med Sci 1999;15:484–90.

14. Gondo G, Yamanaka Y, Fujii S et al. Therapeutic strategy forpatients with stroke complicated by renal failure. Nosotchu noGeka 2000;28:248–53.

15. Shimojo S, Ebisawa T. Management of renal failure in theacute period of stroke—from the internist’s viewpoint. No toJunkan 2000;55:239–42.

16. Nomura T, Mimata H, Imagawa M et al. Clinical study ofcerebrovascular events in patients undergoing maintenancedialysis—comparing cerebral hemorrhage and cerebral infarc-tion. J Jpn Soc Dial Ther 2000;33:1093–9.

17. Watanabe S, Soejima K, Machida J et al. Evaluation of acuteperiod management and prognosis of chronic dialysis patientswho developed cerebral hemorrhage. ICU to CCU 2002;26:S273–S275.

18. Mizobuchi K, Uno M, Kono T, Izumiya T, Tamura T, NagahiroS. Evaluation of treatments and prognosis of cerebral hemor-rhage in kidney dialysis patients. Nosotchu no Geka 2003;31:290–4.

19. Pai MF, Hsu SP, Peng YS, Hung KY, Tsai TJ. Hemorrhagicstroke in chronic dialysis patients. Ren Fail 2004;26:165–70.

20. Murakami M, Hamasaki T, Kimura S, Maruyama D, Kakita K.Clinical features and management of intracranial hemorrhagein patients undergoing maintenance dialysis therapy. NeurolMed Chir (Tokyo) 2004;44:225–32.

21. Toyoda K, Fujii K, Fujimi S et al. Stroke in patients on main-tenance hemodialysis: a 22-year single-center study. Am JKidney Dis 2005;45:1058–66.

22. Ohki T. State of diagnosis and treatment for stroke in chronicdialysis patients. Pharma Medica 2006;24:117–24.

23. Ikeda K, Tsuchimochi H, Fukushima T. Cerebral hemorrhagein hemodialysis patients. Nippon Rinsho 2006;64(Suppl8):542–5.

24. Sugiyama T, Sato A, Ogura T. Evaluation of acute phase man-agement of intracerebral hemorrhage in chronic dialysispatients. Neurosurg Emerg 2007;12:190–3.

25. Miyahara K, Murata H, Abe H. Predictors of intracranialhematoma enlargement in patients undergoing hemodialysis.Neurol Med Chir (Tokyo) 2007;47:47–51.

26. Kawano H, Arikawa S, Ochiai H et al. Evaluation of patientswith cerebral hemorrhage with bleeding tendency. MiyazakiMed J 2008;32:12–7.

27. Huang BR, Liao CC, Huang WH et al. Prognostic factors ofspontaneous intracerebral haemorrhage in haemodialysispatients and predictors of 30-day mortality. Intern Med J 2008;38:568–74.

28. Huang BR, Lo YL, Chang CH, Chen TY. Testing the outcomescore of spontaneous intracerebral haemorrhage in haemodi-alysis patients. Intern Med J 2009;39:692–5.

29. Editorial Committee for ISLS Course Guidebook. JapaneseAssociation for Acute Medicine, Japanese Congress on Neu-rological Emergencies: ISLS course guidebook—for the initialdiagnosis and treatment for stroke. Herusu Shuppan, 2006.

30. Joint Committee on the Use of NSF and gadolinium contrastmedia (Japan Radiological Society/Japanese Society of Neph-rology). Guidelines for the use of Gadolinium contrast mediain kidney disease patients. 2nd edition: revised on September2, 2009.

31. Fukuuchi Y, Hirai H, Ito K et al. Treatment for neurologicaldisorders by intravenous administration of hypertonicglycerol—clinical effects of physiologic saline containing1–10% (w/v) glycerol (CG-A2P). Rinsho to Kenkyu 1978;55:929–37.

32. Goto F, Tasaki Y, Fukuuchi Y. Treatment for neurologicaldisorders by intravenous administration of hypertonicglycerol—clinical effects of physiologic saline containing



1–10% (w/v) glycerol and 5% (w/v) fructose (CG-A30).Rinsho to Kenkyu 1978;55:2327–35.

33. Joint Guideline Committee on Stroke. Guidelines for the Treat-ment of Stroke 2009. Shinohara Y, Ogawa A, Suzuki N et al.,eds. Tokyo: Kyowa Kikaku, 2009.

34. Tsurushima H, Kamezaki T, Yamabe H, Meguro K, Ohashi N,Nose T. Evaluation of putaminal hemorrhage in patients withchronic renal failure. No Shinkei Geka 1998;26:897–901.

35. Broderick J, Connolly S, Feldmann E et al.; American HeartAssociation; American Stroke Association Stroke Council;High Blood Pressure Research Council; Quality of Care andOutcomes in Research Interdisciplinary Working Group.Guidelines for the management of spontaneous intracerebralhemorrhage in adults: 2007 update: a guideline from theAmerican Heart Association/American Stroke AssociationStroke Council, High Blood Pressure Research Council, andthe Quality of Care and Outcomes in Research Interdiscipli-nary Working Group. Stroke 2007;38:2001–23.

36. Ogihara T, Kikuchi K, Matsuoka H et al.; Japanese Society ofHypertension Committee. The Japanese Society of hyperten-sion guidelines for the management of hypertension (JSH2009). Hypertens Res 2009;32:3–107.

37. Yokoyama S, Hirano H, Uomizu K, Kajiya Y, Tajitsu K, Kusu-moto K. High incidence of microbleeds in hemodialysispatients detected by T2*-weighted gradient-echo magneticresonance imaging. Neurol Med Chir (Tokyo) 2005;45:556–60.

38. Watanabe A. Cerebral microbleeds and intracerebral hemor-rhages in patients on maintenance hemodialysis. J Stroke Cere-brovasc Dis 2007;16:30–3.

39. Nighoghossian N, Hermier M, Adeleine P et al. Old microb-leeds are a potential risk factor for cerebral bleeding afterischemic stroke: a gradient-echo T2*-weighted brain MRIstudy. Stroke 2002;33:735–42.

40. Imaizumi T, Horita Y, Hashimoto Y, Niwa J. Dotlike hemo-siderin spots on T2*-weighted magnetic resonance imaging asa predictor of stroke recurrence: a prospective study. J Neuro-surg 2004;101:915–20.

41. Naka H, Nomura E, Takahashi T et al. Combinations of thepresence or absence of cerebral microbleeds and advancedwhite matter hyperintensity as predictors of subsequent stroketypes. AJNR Am J Neuroradiol 2006;27:830–5.

42. Kazui S, Naritomi H, Yamamoto H, Sawada T, Yamaguchi T.Enlargement of spontaneous intracerebral hemorrhage. Inci-dence and time course. Stroke 1996;27:1783–7.

43. Krane NK. Intracranial pressure measurement in a patientundergoing hemodialysis and peritoneal dialysis. Am J KidneyDis 1989;13:336–9.

44. Kitamura S, Hirasawa H. Emergency blood purificationmethods. Blood purification methods for the acute period ofneurosurgical disorders accompanied by renal failure. KyukyuIgaku 1993;17:207–9.

45. Yoshida S, Tajika T, Yamasaki N et al. Dialysis dysequilibriumsyndrome in neurosurgical patients. Neurosurgery 1987;20:716–21.

46. PROGRESS Collaborative Group. Randomised trial of aperindopril-based blood-pressure-lowering regimen among6,105 individuals with previous stroke or transient ischaemicattack. Lancet 2001;358:1033–41.

47. Chapman N, Huxley R, Anderson C et al.; Writing Committeefor the PROGRESS Collaborative Group. Effects of aperindopril-based blood pressure-lowering regimen on therisk of recurrent stroke according to stroke subtype andmedical history: the PROGRESS trial. Stroke 2004;35:116–21.

48. Statistical Survey Committee, Japanese Society for DialysisTherapy. Current state of chronic dialysis treatment in Japan,illustrated (as of Dec. 31, 2001). Japanese Society for DialysisTherapy, 2002.

49. Iseki K, Fukiyama K. Predictors of stroke in patients receivingchronic hemodialysis. Kidney Int 1996;50:1672–5.

II. CEREBRAL INFARCTION

Statements

1. Soon after the onset of cerebral infarction, werecommend dialysis methods that result in onlymild increase in intracranial pressure such ascontinuous hemodiafiltration, peritoneal dialy-sis, and hemodialysis with restricted blood flowshould be selected (1B).

2. We suggest that measures should be taken duringadministration of antithrombotic agents toprevent hemorrhagic complications such asusing low-dose heparin during dialysis (2C).

3. We suggest that warfarin therapy should not beperformed routinely for atrial fibrillation;however, if considered beneficial, it is desirableto use such therapy by maintaining the pro-thrombin time-international normalized ratio(PT-INR) at <2.0 (2C).

4. We recommend that indications for carotidendarterectomy and endovascular treatmentsfor severe carotid artery stenosis should becarefully evaluated (1C).

Comments

EpidemiologyAmong cerebrovascular disorders in dialysis

patients, cerebral hemorrhage has long been consid-ered more frequent than cerebral infarction com-pared with the general population. However, theincidence of cerebral infarction has increased inrecent years (1–7).

Pathological featuresThe pathogenic mechanisms of cerebral infarction

are classified into thrombotic, embolic, and hemody-namic, and clinically, it is divided into atherothrom-botic infarction, cardiogenic infarction, lacunarinfarction, and others (8). Since treatment during theacute period and prognosis differ among the clinicaltypes, it is extremely important to differentiate thedisease type at the onset (9). Cerebral infarctionoften occurs within 6 h after the end of dialysis (1),and the decrease in blood pressure has been reportedto be milder in patients who develop the infarctionsoon after the end of dialysis than those who developit 6 h or longer after the onset (10). The mechanismsof hemodialysis-induced cerebral infarction includereduction of cerebral blood flow due to increasedblood viscosity and fall in blood pressure associatedwith water removal or orthopedic hypotension fol-lowing sit up or stand up after dialysis (11). The cere-bral blood flow is reported to decrease before a rapid



fall in blood pressure during dialysis, and impairmentof the mechanism of auto-regulation of cerebralblood flow may also be a causative factor (4,12).

Initial treatment and diagnosisClinical management of patients suspected with

cerebrovascular disorders includes examination ofthe consciousness level, securing the airway, evalua-tion of respiration and circulation, and evaluation ofneurological symptoms. The presence of disturbanceof consciousness warrants exclusion of other causes,and head CT should be performed. If head CT sug-gests cerebral infarction, MRI and MRA should beperformed to determine the type of cerebral infarc-tion, and the therapeutic strategy should be deter-mined. If necessary, carotid artery ultrasonography,echocardiography (transthoracic, transesophageal),Holter electrocardiogram (ECG), and cerebralangiography, should be added, and the pathogenicmechanism should be clarified (Fig. 1) (13).

Treatments

Treatments during the acute stageBlood pressure control. During the acute phase ofcerebral infarction, regional cerebral blood flow atthe lesion and surrounding penumbra region maydecrease further due to treatment with antihyperten-sive agents, which may cause expansion of thelesion (14). Therefore, in principle, aggressive antihy-pertensive treatment is not recommended. However,if systolic pressure is 220 mm Hg or higher or dias-tolic pressure is 120 mm Hg or higher, antihyper-tensive treatment is recommended to reduce the riskof hemorrhagic complications (15,16). To performthrombolytic therapy, however, the systolic and dias-tolic pressures must be reduced to less than 185and 110 mm Hg, respectively. It is important toslowly reduce the blood pressure by setting thetarget at about 85–90% of the pre-treatment level(15,16).

Neurological abnormalities suggestive of cerebrovascular disorders(Paralysis, aphasia, dysarthria, anisocoria, convulsive attacks, headache, etc.)

1. Securing of the airway, respiration, and circulation and evaluation of vital signs(a) Addressing the patient and examining responses such as replies, eye opening, and body movements(b) Checking signs of respiration and circulation(c) Measurement of vital signs (pulse, blood pressure, respiratory rate, body temperature)2. Oxygen administration3. Securing the IV route and blood tests (general hematology, electrolytes, clotting)4. Simple neurological examinations (level of consciousness, paralysis, pupil findings)5. Measurement and correction of the blood sugar level6. 12-Lead ECG; Examination of arrhythmias, in particular7. Taking a detailed history, estimation of the time of onset

Examination for hemorrhage by head CT

Cerebral hemorrhage Cerebral infarction Subarachnoid hemorrhage

3D-CTA, MRACerebral angiography

Evaluation of surgical indications

MRI(T1, T2-weighted imaging,

diffusion-weighted imaging, MRA)Neck ultrasonography, SPECT, PET

ECG, Holter ECGEchocardiography

3D-CTA, MRACerebral angiography

Evaluation of surgical indications

Cardiogenic cerebral embolism Atherothrombotic cerebral infarction Lacunar infarction

FIG. 1. Algorithm for the diagnosis of cerebrovascular disorders.



Management of edema. Intravenous administrationof glycerol is effective in alleviating brain edema andmay save patients with large cerebral infarction asso-ciated with intracranial hypertension (17). In dialysispatients, it is important to manage azotemia and elec-trolyte balance with attention to exacerbation ofbrain edema due to dialysis.Antithrombotic therapy. Antiplatelet agents (aspirin,ozagrel sodium) and anticoagulants (heparin, arga-troban) are used for antithrombotic therapy(Table 2) (18–20). Since the urinary excretion rate ofozagrel sodium is high in the unchanged form, itsdose must be reduced in dialysis patients to abouthalf the recommended dose (21).

Argatroban, a selective antithrombin, is excretedprimarily via the biliary system, and thus reduction inits dose is not considered necessary in patients withrenal failure (19). However, since about half the usualdose of argatroban results in the optimal activatedpartial thromboplastin time (APTT) in many dialysispatients (21), its dose must be fine-tuned by frequentmeasurements of APTT.

During the first 3 h of the onset, thrombolytictherapy using recombinant tissue plasminogen acti-vator (rt-PA, alteplase) may be indicated. It is recom-mended that the patients should be transported toexpert facilities early after the onset.Management of renal failure during the acute-phasetreatment. Since intracranial pressure autoregula-tion collapses immediately after the onset of cere-bral infarction (12), and due to the high risk of rapidprogression of intracranial hypertension and exacer-bation of brain edema, dialysis should be avoided onthe day of the onset. Thereafter, also, the need fordialysis should be evaluated carefully, and, if it isperformed, procedures such as peritoneal dialysis,continuous hemodiafiltration, and hemodialysis withrestricted blood flow, which have mild effects onintracranial pressure and maintain cerebral perfu-sion pressure, should be selected. Rapid and massiveremoval of water should be avoided, because it exac-erbates brain ischemia.

Treatments during the chronic phase/prevention ofrecurrence (secondary prevention)

During the chronic phase (more than 1 month afterthe onset of cerebral infarction), patients are treatedwith antiplatelets, anticoagulants and antihyperten-sive agents to prevent the recurrence of cerebrovas-cular disorders. Antiplatelets and anticoagulants areeffective in the prevention of non-cardiogenic andcardiogenic cerebral infarction, respectively (9).Antiplatelets include aspirin, ticlopidine, clopidogrel,

and cilostazol, which can be used as in non-dialysispatients (Table 2) (18–20).

Primary preventionAntithrombotic therapy for atrial fibrillation. Theincidence of atrial fibrillation in dialysis patients isextremely high (22–31), but the involvement of atrialfibrillation in stroke is unclear based on the effects ofplatelet dysfunction and the use of heparin duringdialysis (24–26,29–32). There is little evidence con-cerning the preventive effect of warfarin against cere-bral infarction, and as it increases the risk ofhemorrhagic complications, many authors have dis-couraged its use (32–34). Recent large-scale studiesalso reported the danger of warfarin administration(35,36). If warfarin is used as a beneficial drug, it isimportant not to increase the risk of hemorrhagiccomplications by periodically measuring the PT-INRand maintaining it at <2.0 (36).Carotid endarterectomy and endovascular treatment.Poor prognosis is reported for carotid endarterec-tomy (CEA) conducted for severe carotid arterystenosis in patients with renal failure (37–39), butCEA is also reported to be more effective in patientswith renal failure than in those without renal failure(40). Since the results of carotid artery stenting(CAS) are also unsatisfactory in patients with renalfailure (41), the indications for these procedures mustbe evaluated carefully.

Blood pressure control for primary andsecondary prevention

Since a J-curve relationship is observed betweenthe blood pressure and recurrence of stroke (42), awarning against excessive decrease in blood pressurewas issued, but recently, this view has been refuted bysome (43). Usually, it is important to initiate antihy-pertensive treatment more than 1 month after thebeginning of treatment and to gradually reduce bloodpressure over a period of 1–3 months. Blood pressureof less than 140/90 mm Hg is recommended as thefinal target of blood pressure control except inpatients with marked stenosis of both carotid arteriesand those with obstruction of a major artery (15).Also, with regard to primary prevention, hyperten-sion is reported to be a risk factor of cerebral infarc-tion, but its role in cerebral infarction is smaller andmore limited than that in cerebral hemorrhage (44).

REFERENCES

1. Onoyama K, Kumagai H, Miishima T et al. Incidence ofstrokes and its prognosis in patients on maintenance hemodi-alysis. Jpn Heart J 1986;127:685–91.



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2. Iseki K, Kinjo K, Kimura Y, Osawa A, Fukiyama K. Evidencefor high risk of cerebral hemorrhage in chronic dialysispatients. Kidney Int 1993;44:1086–90.

3. Iseki K, Fukiyama K. Predictors of stroke in patients receivingchronic hemodialysis. Kidney Int 1996;50:1672–5.

4. Hirakata H, Iseki K, Ibayashi S, Wada A. Study of cerebrovas-cular disorders in dialysis patients. Report of the GeneralResearch Project on Long-Term Chronic Diseases (ChronicRenal Failure) on a Grant-in-Aid for Scientific Research bythe Ministry of Health and Welfare, 1996, 49–54, 1997.

5. Kawamura M, Fujimoto S, Hisanaga S, Yamamoto Y, Eto T.Incidence, outcome, and risk factors of cerebrovascular eventsin patients undergoing maintenance hemodialysis. Am JKidney Dis 1998;31:991–6.

6. Iseki K, Fukiyama K, Okinawa Dialysis Study (OKIDS)Group. Clinical demographics and long-term prognosis afterstroke in patients on chronic haemodialysis. Nephrol DialTransplant 2000;15:1808–13.

7. Toyoda K, Fujii K, Fujimi S et al. Stroke in patients on main-tenance hemodialysis: a 22-year single-center study. Am JKidney Dis 2005;45:1058–66.

8. National Institute of Neurological Disorders and Stroke. Clas-sification of cerebrovascular diseases III. Stroke 1990;21:637–76.

9. Joint Guideline Committee on Stroke. Guidelines for the Treat-ment of Stroke 2009. Shinohara Y, Ogawa A, Suzuki N et al.,eds. Tokyo: Kyowa Kikaku, 2009.

10. Nagumo K, Kawamura M. Cerebral infarction in chronic dialy-sis patients—time of onset and pathological mechanisms. J JpnCongr Neurol Emerg 2005;18:17–19.

11. Ishida I, Hirakata H, Sugimori H et al. Hemodialysis causessevere orthostatic reduction in cerebral blood flow velocity indiabetic patients. Am J Kidney Dis 1999;34:1096–104.

12. Rose JC, Mayer SA. Optimizing blood pressure in neurologi-cal emergencies. Neurocrit Care 2004;1:287–99.

13. Hori M, Ito S, Inaba M et al.Guidelines for the Diagnosis andTreatment of Cardiovascular Disorders (2006–2007 Report bythe Joint Research Group): guidelines for the management ofheart diseases complicated by cerebrovascular disorders, renaldysfunction, and peripheral vascular disorders. Circ J 2008;72Suppl IV:1465–518.

14. Bath P, Chalmers J, Powers W et al.; International Society ofHypertension Writing Group; International Society of Hyper-tension Writing Group. International Society of Hypertension(ISH): statement on the management of blood pressure inacute stroke. J Hypertens 2003;21:665–72.

15. Ogihara T, Kikuchi K, Matsuoka H et al.; Japanese Society ofHypertension Committee. The Japanese Society of Hyperten-sion Guidelines for the Management of Hypertension (JSH2009). Hypertens Res 2009;32:3–107.

16. Adams HP Jr, del Zoppo G, Alberts MJ et al.; American HeartAssociation; American Stroke Association Stroke Council;Clinical Cardiology Council; Cardiovascular Radiology andIntervention Council; Atherosclerotic Peripheral VascularDisease and Quality of Care Outcomes in Research Interdisci-plinary Working Groups. Guidelines for the early managementof adults with ischemic stroke: a guideline from the AmericanHeart Association/American Stroke Association StrokeCouncil, Clinical Cardiology Council, Cardiovascular Radiol-ogy and Intervention Council, and the Atherosclerotic Periph-eral Vascular Disease and Quality of Care Outcomes inResearch Interdisciplinary Working Groups: the AmericanAcademy of Neurology affirms the value of this guidelineas an educational tool for neurologists. Stroke 2007;38:1655–711.

17. Righetti E, Celani MG, Cantisani T, Sterzi R, Boysen G, RicciS. Glycerol for acute stroke. Cochrane Database Syst Rev 2000;(4): CD000096.

18. Takahashi Y, Miyajima H. New drugs for various organs—neurological diseases. Jpn J Clin Dial (Rinsho Toseki) 2006;22:51–8.

19. Hirata S. Renal Failure and Uses of Drugs Q&A. Tokyo: Jiho,2005.

20. Hirata S, Izumi S, Furukubo T. Medication Guidebook forDialysis Patients. Tokyo: Jiho, 2009.

21. Toyoda K. Treatment maintenance dialysis patients in theacute period of cerebral infarction—effectiveness of anti-thrombotic therapy. Kekkan Igaku 2004;5:293–8.

22. Abe S, Yoshizawa M, Nakanishi N et al. Electrocardiographicabnormalities in patients receiving hemodialysis. Am Heart J1996;131:1137–44.

23. Fabbian F, Catalano C, Lambertini D et al. Clinical character-istics associated to atrial fibrillation in chronic hemodialysispatients. Clin Nephrol 2000;54:234–9.

24. Vázquez E, Sánchez-Perales C, Borrego F et al. Influence ofatrial fibrillation on the morbido-mortality of patients onhemodialysis. Am Heart J 2000;140:886–90.

25. Atar I, Konas D, Açikel S et al. Frequency of atrial fibrillationand factors related to its development in dialysis patients. Int JCardiol 2006;106:47–51.

26. Abbott KC, Trespalacios FC, Taylor AJ, Agodoa LY. Atrialfibrillation in chronic dialysis patients in the United States: riskfactors for hospitalization and mortality. BMC Nephrol 2003;4:1–14.

27. Vázquez-Ruiz de Castroviejoa E, Sánchez-Perales C, Lozano-Cabezas C et al. Incidence of atrial fibrillation in hemodialysispatients. A prospective long-term follow-up study. Rev EspCardiol 2006;59:779–84.

28. Genovesi S, Pogliani D, Faini A et al. Prevalence of atrialfibrillation and associated factors in a population of long-term hemodialysis patients. Am J Kidney Dis 2005;46:897–902.

29. To AC, Yehia M, Collins JF. Atrial fibrillation in haemodialysispatients: do the guidelines for anticoagulation apply? Neph-rology 2007;12:441–7.

30. Genovesi S, Vincenti A, Rossi E et al. Atrial fibrillation andmorbidity and mortality in a cohort of long-term hemodialysispatients. Am J Kidney Dis 2008;51:255–62.

31. Sánchez-Perales C, Vázquez E, García-Cortés MJ et al.Ischaemic stroke in incident dialysis patients. Nephrol DialTransplant 2010;25:3343–8.

32. Wiesholzer M, Harm F, Tomasec G, Barbieri G, Putz D, BalckeP. Incidence of stroke among chronic hemodialysis patientswith nonrheumatic atrial fibrillation. Am J Nephrol 2001;21:35–9.

33. Vázquez E, Sánchez-Perales C, García-Cortes MJ et al. Oughtdialysis patients with atrial fibrillation be treated with oralanticoagulants? Int J Cardiol 2003;87:135–9.

34. Elliott MJ, Zimmerman D, Holden RM. Warfarin anticoagu-lation in hemodialysis patients: a systematic review of bleedingrates. Am J Kidney Dis 2007;50:433–40.

35. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Anticoagu-lant and antiplatelet usage associates with mortalityamong hemodialysis patients. J Am Soc Nephrol 2009;20:872–81.

36. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin useassociates with increased risk for stroke in hemodialysispatients with atrial fibrillation. J Am Soc Nephrol 2009;20:2223–33.

37. Sternbergh WC 3rd, Garrard CL, Gonze MD, Manord JD,Bowen JC, Money SR. Carotid endarterectomy in patientswith significant renal dysfunction. J Vasc Surg 1999;29:672–7.

38. Tarakji A, McConaughy A, Nicholas GG. The risk of carotidendarterectomy in patients with chronic renal insufficiency.Curr Surg 2006;63:326–9.

39. Mathew A, Devereaux PJ, O’Hare A et al. Chronic kidneydisease and postoperative mortality: a systematic review andmeta-analysis. Kidney Int 2008;73:1069–81.

40. Mathew A, Eliasziw M, Devereaux PJ, Merino JG, Barnett HJ,Garg AX, North American Symptomatic Carotid Endarterec-tomy Trial (NASCET) Collaborators. Carotid endarterectomy



benefits patients with CKD and symptomatic high-gradestenosis. J Am Soc Nephrol 2010;21:145–52.

41. Saw J, Gurm HS, Fathi RB et al. Effect of chronic kidneydisease on outcomes after carotid artery stenting. Am JCardiol 2004;94:1093–6.

42. Irie K, Yamaguchi T, Minematsu K, Omae T. The J-curvephenomenon in stroke recurrence. Stroke 1993;24:1844–9.

43. Arima H, Chalmers J, Woodward M et al.; PROGRESS Col-laborative Group. Lower target blood pressures are safe andeffective for the prevention of recurrent stroke: thePROGRESS trial. J Hypertens 2006;24:1201–8.

44. Statistical Survey Committee, Japanese Society for DialysisTherapy. Current state of chronic dialysis treatment in Japan,illustrated (as of Dec. 31, 2001). Japanese Society for DialysisTherapy, 2002.

Supplementary noteGuidelines for the management of cerebrovascular

disorders in dialysis patients were prepared in rela-tion to cerebral hemorrhage and cerebral infarction.The preparation of guidelines concerning subarach-noid hemorrhage was deferred, because there is littleevidence in dialysis patients.tap_1088_9 422..470

Chapter 8: Peripheral Artery Disease

Statements

1. Dialysis is an independent risk factor forperipheral arterial disease (PAD) regardless ofthe presence or absence of diabetes (B).

2. In PAD patients, we recommend that cardio-vascular disorders should be simultaneouslyevaluated (1B).

3. In dialysis patients, severe calcification lesionsare often observed distal to the knees (B), butsince symptoms are inconspicuous, efforts forearly detection are important (Opinion).

4. We suggest that ankle-brachial systolic pressureindex (ABI) should be examined, at least oncea year (Opinion).

5. We recommend that treatment of PAD shouldinclude careful evaluation of the pathologicalfeatures of ischemia (1B).

CommentsPeripheral arterial disease (PAD) can be divided

into arteriosclerosis obliterans (ASO) of the lowerlimbs and Buerger’s disease or thromboangitis oblit-erans (TAO). Since ASO is the main entity, PAD isoften considered to mean ASO in a narrow sense.Also, ASO frequently shows a chronic course. Thischapter deals with chronic ASO of the lowerlimbs.

Epidemiology and risk factorsIncidence. Chronic kidney disease is regarded as anindependent risk factor for PAD, and the possibilityof PAD should be considered when the GFR is lessthan 30 mL/min per 1.73 m2 regardless of the pres-ence or absence of diabetes (1). However, since PADis associated with only few symptoms and progressesrapidly, it is often detected after the appearance ofcritical limb ischemia (CLI) when it becomes intrac-table. Also, the lesions are located distal to the kneeand are often accompanied by severely calcifiedlesions.

Only a few large-scale studies are available on theprevalence of PAD in patients with chronic kidneydisease (CKD). In 2004, O’Hare et al. (2) investi-gated the prevalence of PAD in non-dialysis CKDpatients and reported that renal dysfunction is anindependent risk factor for the occurrence of denovo PAD. In a study by Koch et al. (3), CLIcoupled with angiographically-confirmed significantstenosis or ulcerated/necrotic lesions of the lowerlimbs was noted in 34 (10.5%) of 322 patients at theinitiation of dialysis, and, on a 5-year follow-up, denovo CLI developed in 25 (8.9%) of 288 patientswith no lesion at the initiation of dialysis. Withregard to reports on Japanese patients, the cross-sectional study of Okamoto et al. (4,5) involvingpatients on maintenance hemodialysis using theABI and skin perfusion pressure (SPP), reportedABI values less than 0.9 in 16.7%, and SPP valuesless than 50 mm Hg in 41.4% of the patients, andthat 37.2% of hemodialysis patients had PAD basedon the diagnostic sensitivity and specificity of theSPP and that about half of these patients wereasymptomatic.

The above studies point to a higher prevalenceof PAD in dialysis patients than in the general popu-lation (6). PAD has been diagnosed in 15–23% ofthe patients according to clinical symptoms (7–9)(Table 1) and in 33.0–38.3% in Western countries(10–12) and 16.6–16.7% in Japan (4,13) using an ABI<0.9 as a criterion (Table 2).

Risk factors in dialysis patientsO’Hare et al. (14) evaluated the pathogenic factors

of PAD in patients started on hemodialysis and thoseon maintenance dialysis and reported that coronaryartery disease elevates the incidence of PAD in dialy-sis patients 2.85 times, that the incidence of PAD is4.18 times higher in diabetic than in non-diabeticdialysis patients, that the duration of dialysis andundernutrition correlated positively with the inci-dence of PAD but negatively with the pre-dialysis

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diastolic pressure and blood levels of parathyroidhormone.

Diagnosis

Diagnosis of PADClinical examination of the feet (inspection,palpation). Inspection and palpation are the mostbasic diagnostic techniques. However, it must be

remembered that PAD cannot be excluded even ifthe dorsal artery of the foot or posterior tibial arteryare palpable (Fig. 1) (15).Ankle-brachial systolic pressure index (ABI). TheABI is the most important screening test. We recom-mend that ABI be measured in dialysis patients at theinitiation of dialysis and once annually thereafterregardless of the presence or absence of symptoms.However, as dialysis patients often have severe

TABLE 1. Prevalence of peripheral artery disease (PAD) in dialysis patients

Authors Number of patients Subjects Percentage of patients with PAD

USRDS (2000) (7) 35,438 Patients who initiated dialysis 15.0Webb et al. (1993) (8) 325 Patients on maintenance dialysis 19.0Hemo study (2000) (9) 936 Patients on maintenance dialysis 23.0

Diagnosis of PAD: History of PAD (amputation/revascularization), pain during walking, rest pain, ulcer/gangrene. USRDS, United StatesRenal Data System.

TABLE 2. Prevalence of peripheral artery disease (PAD) in hemodialysis patients according to the ankle brachialpressure index (ABI)

Authors Number of patients Country Percentage of patients with ABI < 0.9

Fishbane et al. (1996) (10) 132 US 35.0Al Zahrani et al. (1997) (11) 60 Saudi Arabia 38.3Testa et al. (1998) (12) 226 France 33.0Ono et al. (2000) (13) 774 Japan 16.6Okamoto et al. (2006) (4) 140 Japan 16.7

Feet hanging testLift the feet in the supine position and rotate the ankles 20-40 times (until the soles become pale).Sit up immediately and observe changes in the color of the insteps.

FIG. 1. Ratschow’s test. (reproducedfrom Peripheral Artery Diseases in Dialy-sis Patients, Iyaku (Medicine & Drug)Journal, Co., Ltd.). Feet hanging test. Liftthe feet in the supine position and rotatethe ankles 20–40 times (until the solesbecome pale). Sit up immediately andobserve changes in the color of the insteps.A: Lift the feet and rotate the ankles. B:Immediately after hanging the feet. C:2 min after hanging the feet. If normal,redness returns to the instep, and veinsstand out.



vascular calcification and peripheral lesions, it is inap-propriate to directly apply the criteria fornon-dialysis patients.

In dialysis patients, the normal range of ABI isreported to be shifted to the right to 1.02–1.42 (4,5),and cutoff PAD value for confirmation of the diag-nosis is less than 0.9.

There are also other physiological indices of skinmicrocirculation including the SPP, toe-brachialpressure index (TBI), and transcutaneous PO2

(tcPO2). Each has been reported to be useful in theevaluation of ischemia of peripheral tissues(Table 3) (5). The SPP, which was reported by Cas-tronuovo et al. (16), is determined by measuring theinflux of red blood cells at the capillary level usinglaser, and it is 79 � 14 (SD) mm Hg in healthy indi-viduals. With regard to morphological diagnosticmethods, imaging of the blood flow waveform usingvascular ultrasonography, multidetector-row com-puted tomography (MDCT), and magnetic reso-nance imaging (MRI) is useful, but angiography isimportant for the localization of lesions. Sufficientdelineation to the ankle is necessary for localization.

Staging of PADThe severity of PAD is evaluated using the Fon-

taine classification (Table 4). In the general popula-tion, the Fontaine stage is evaluated on a treadmill atan inclination of 12% and a speed of 2.4 km/h (Japa-nese). However, since dialysis patients often sufferbone and joint disorders, causing difficulty in theevaluation of the walking distance, it must be remem-bered that evaluation of intermittent claudicationmay be difficult. CLI means stage III or IV PADaccording to the Fontaine scale.

Treatments

General treatmentsIf the clinical evaluation excludes the presence of

CLI, treatment should be started with foot care,

medication, and exercise therapy. If improvement isnot clear or exacerbation is observed, the stage oftreatment should be elevated by evaluating ischemiaby techniques such as angiography. Exercise therapythree times/week, 30–45 min/session, over 12 weeks isreported to be effective in non-dialysis patients (17–19). Guidance to quit smoking is particularly impor-tant (20,21). It is important to continuously observethe condition of the feet and evaluate the presence orabsence of ischemia and infection. It is also importantto treat wounds by appropriate debridement ordressing technique. While it is important to attemptlimb conservation by these conservative approaches,caution is necessary not to let prognosis deteriorateby ruling out timely limb amputation. However, theprognosis after limb amputation is extremely poor indialysis patients, and careful evaluation of the extentof amputation is necessary.

Drug therapyThere is no large-scale randomized controlled trial

of any drug in dialysis patients. In Japan, the anti-platelet agents covered by medical insurance are cil-ostazol, sarpogrelate, beraprost, ticlopidine, eicos-apentaenoic acid, and juvela nicotinate. All havebeen approved based on the results obtained in non-dialysis patients and have been reported to be effec-tive for alleviating symptoms due to ischemia. Ingeneral, cilostazol is reported to be effective in non-dialysis patients, not only in alleviating symptoms butalso improving the distance of walking and mitigatingintermittent claudication (22–24). However, cilosta-zol is contraindicated in patients with heart failure,because it increases the heart rate, and caution isnecessary in dialysis patients showing a tendency ofvolume overload.

A meta-analysis study demonstrated the effective-ness of intravascular administration of prostaglandinE1 for the treatment of ulcer and alleviation of painin CLI patients (25).

Treatment should be conducted taking into consid-eration limb conservation, prognosis, and quality

TABLE 3. Cut-off values, sensitivity, and specificity oftests to evaluate ischemia of peripheral skin tissues

Test Cut-off value Sensitivity Specificity

ABI 0.9 29.9 100TBI 0.6 45.2 100tcPO2 50 mm Hg 61.1 70.0SPP 50 mm Hg 78.6 91.6

ABI, ankle brachial pressure index; SPP, skin perfusion pressure;TBI, toe-brachial pressure index.

TABLE 4. Fontaine classification

Stage Clinical findings

I No symptomII Intermittent claudicationIIa Induced by walking �200 mIIb Induced by walking <200 mIII Rest painIV Ulcer/gangrene



of life. No single treatment is complete, and a multi-disciplinary approach is important. Foot care must beprovided persistently.

The Trans-Atlantic Inter-Society Consensus(TASC) Guidelines (26) are useful for evaluation ofthe therapeutic effects, but the evaluation criteria fortreadmill exercise are impractical, because they areoften difficult to achieve in dialysis patients due tocomplications such as bone and joint disorders.

In patients diagnosed with CLI, the earliest possiblerevascularization surgery is necessary. However, theindications for such surgery and whether surgical orendovascular treatment should be provided dependson overall assessment including consideration of limbconservation, prognosis, and quality of life in connec-tion with cardiovascular complications, sites, length,and distribution of the lesions, whether the lesion isstenosis or obstruction (TASC classification) (26).Thefinal decision is usually left to the specialists.

In general, treatment of PAD in dialysis patients(indications, endovascular treatment, revasculariza-tion) can be the same as that in non-dialysis patients.However, it must be understood that dialysis patientstend to have more severe calcification, lesions inmore distal areas, relative immunodeficiency, under-nutrition, and compromised host immunity againstinfections.The general principles for the treatment ofPAD in dialysis patients are as follows:

1. Endovascular treatment (primary stenting) shouldbe the first choice for iliac artery lesions.

2. Endovascular treatment should be the first choicefor TASC A and B lesions with a length of lessthan 15 cm in the femoropopliteal region. Surgeryis the first choice for long obstructive lesions andcomplicated lesions, but the revised TASC IIGuidelines mention: Since techniques, such as sub-intimal angioplasty using the subintimal recanali-zation technique, have been developed, even along completely obstructed lesion can also be anindication of endovascular treatment (26).

3. In CLI, endovascular treatment should be consid-ered for localized infrapopliteal lesions. Whilesurgery should be considered for chronic longlesions and obstructive lesions, endovascular treat-ment may be selected in high-risk patients forsurgery.

4. For patients with CLI complicated by woundinfection, some treatment that improves bloodflow must be considered along with treatment forinfection.

5. Revascularization by endovascular or surgicalprocedure should be followed by continuous treat-ment with an antiplatelet agent as adjuvant drug

therapy (26,27). Also, the concomitant use ofother procedures including low-density lipopro-tein (LDL) apheresis and hyperbaric oxygentherapy should also be considered.

Revascularization should be considered in patientswith PAD, particularly, severe intermittent claudica-tion or CLI. The therapeutic principles concerningrevascularization in infrapopliteal arteries are notdiscussed in detail even in the latest guidelines.According to the BASIL trial (28), which is the onlycomparative study on the treatment for CLI, thepatency and survival rates between endovasculartreatment and surgical revascularization were com-parable, but the study was not restricted to infrapo-pliteal arterial lesions.

The reported initial success rate of endovasculartreatment for PAD in dialysis patients was 92–97%,the 30-day mortality rate was 6.3–10%, 1-year limbconservation rate was 53–73%, and 1-year survivalrate was 80–94%, suggesting that percutaneous trans-luminal angioplasty (PTA) is useful as a treatmentfor PAD in dialysis patients (29–31).

In surgical revascularization for CLI in dialysispatients, the reported mortality within 30 days is highat 18% (32,33). Causes of death are often related toheart diseases such as acute myocardial infarctionand heart failure (34,35), and sufficient preoperativeevaluation of cardiac complications is important insurgical revascularization. The reported patency rateafter surgical revascularization is relatively favorable,being 62–85% after 1 year and 56–81% after 2 years.The reported limb conservation rate was 56–77%after 1 year and 50–71% after 2 years, and the sur-vival rate was 39–73% after 1 year and 33–65% after2 years (32,35,36).

While there have been few studies that comparedthe results of PTA and surgical revascularization indialysis patients with PAD, Jaar et al. (37) reportedthat the mortality rate was also higher in the surgicalrevascularization group. However, the study was ret-rospective, and the possibility that the condition wasmore severe in the surgical revascularization groupcannot be excluded.

Other treatmentsIn addition to endovascular treatment or surgical

revascularization for limb conservation, other treat-ment modalities such as LDL apheresis and hyper-baric oxygen (HBO) therapy may be indicated assupplementary treatments. LDL apheresis is indi-cated for abnormal lipid metabolism, and its effecton lipid metabolism is not considered to be directlyrelated to LDL removal (38). The procedure is



reported to have vasodilating, rheology-improving,and anti-inflammatory effects. LDL apheresis ismore likely effective in relatively early cases (38).HBO therapy is indicated for PAD patients withrefractory ulcer. While it has been reported to beeffective in diabetic patients (39,40), there is noreport about its effectiveness in dialysis patients.Bathing in a carbonate spring is reported to beeffective, and bathing in hot water at a CO2 concen-tration higher than a certain level (1200 ppm) isconsidered to improve blood flow (41). Also, even inpatients with one limb amputation, continuation ofclose observation, prevention, and treatment of theunamputated limb is important.

Prognosis

Limb amputation and prognosisIn Japan, the percentage of dialysis patients who

have undergone lower limb amputation was 1.6% atthe end of 2000 but increased progressively to 2.2%at the end of 2003 and 2.6% (4755/183 492) at theend of 2005. Of these patients, 70% were diabetic(42).

The prognosis of dialysis patients after lower limbamputation is extremely poor (43,44), and the hos-pital death rate is high (43). Dossa et al. (43)reported that the hospital death rate after lowerlimb amputation was 7% in non-dialysis patientsbut was very high at 24% in dialysis patients. The2-year survival rate after lower limb amputation was79% in non-dialysis patients but was markedlylower at 27% in dialysis patients. Aulivola et al. (44)also reported extremely poor prognosis of dialysispatients after lower limb amputation (particularlymajor amputation).

Life prognosisIn dialysis patients with PAD, the reported hospi-

talization rate (45) and risk of death (3,10,12) arehigh, and the death rates within 6 months after initia-tion of dialysis (46) and after acute myocardial inf-arction (47) are also high.

As for the relationship between ABI and life prog-nosis, the reported total risk of death is 7.09 and 2.20times higher in those with an ABI of less than 0.9 and1.3 or above, respectively, compared with those withan ABI of 1.1–1.3. The risk of death due to cardio-vascular disorders was also reported to be 10.6 and3.1 times higher in the respective groups (48). There-fore, it is necessary to examine patients for not onlyPAD but also other cardiovascular disorders and totreat them as much as possible.

REFERENCES

1. Wattnakit K, Folsom AR, Selvin E, Coresh J, Hirsch AT,Weatherlet BD. Kidney function and risk of peripheral arterialdisease: results from the atherosclerosis risk in communities(ARIC) study. J Am Soc Nephrol 2007;18:629–36.

2. O’Hare AM, Vittinghoff E, Hsia J, Shlipak MG. Renal insuf-ficiency and the risk of lower extremity peripheral arterialdisease: results from the heart and estrogen/progestinreplacement study (HERS). J Am Soc Nephrol 2004;15:1046–51.

3. Koch M, Trapp R, Kulas W, Grabensee B. Critical limbischemia as a main cause of death in patients with end-stagerenal disease: a single-centre study. Nephrol Dial Transplant2004;19:2547–52.

4. Okamoto K, Oka M, Maesato K et al. Peripheral arterialocclusive disease is more prevalent in patients withhemodialysis: comparison with the findings of multidetector-row computed tomography. Am J Kidney Dis 2006;48:269–76.

5. Okamato K, Oka M, Maesato K et al. Arteriosclerosis obliter-ans of the lower limbs in dialysis patients—non-invasive diag-nostic techniques. J Jpn Coll Angiol 2006;46:829–35.

6. O’Hare AM, Johansen K. Lower-extremity peripheral arterialdisease among patients with end-stage renal disease. J Am SocNephrol 2001;12:2838–47.

7. United States Renal Data System. Annual data report.Bethesda, MD, National Institutes of Health, National Insti-tute of Diabetes and Digestive and Kidney Diseases, Divisionof Kidney, Urologic, and Hematologic Diseases, 2000, 339–48.

8. Webb AT, Franks PJ, Reaveley DA, Greenhalgh RM, BrownEA. Prevalence of intermittent claudication and risk factorsfor its development in patients on renal replacement therapy.Eur J Vasc Surg 1993;7:523–7.

9. Cheung AK, Sarnak MJ, Yan G et al. Atherosclerotic cardio-vascular disease risks in chronic hemodialysis patients. KidneyInt 2000;58:353–62.

10. Fishbane S, Youn S, Flaster E, Adam G, Maesaka JK. Ankle-arm blood pressure index as a predictor of mortality in hemo-dialysis patients. Am J Kidney Dis 1996;27:668–72.

11. Al Zahrani HA, Al Bar HM, Bahnassi A, Abdulaal AA. Thedistribution of peripheral arterial disease in a defined popula-tion of elderly high-risk Saudi patients. Int Angiol 1997;16:123–8.

12. Testa A, Ottavioli JN. Ankle-arm blood pressure index(AABPI) in hemodialysis patients. Arch Mal Coeur Vaiss 1998;91:963–5.

13. Ono K, Yano S, Nojima Y. Ankle-arm blood pressure index asa marker of atherosclerosis in hemodialysis patients [abstract].J Am Soc Nephrol 2000;11:A1535.

14. O’Hare AM, Hsu CY, Bacchetti P, Johansen KL. Peripheralvascular disease risk factors among patients undergoing hemo-dialysis. J Am Soc Nephrol 2002;13:497–503.

15. Bernstein EF, Fronek A. Current status of noninvasive tests inthe diagnosis of peripheral arterial disease. Surg Clin NorthAm 1982;62:473–87.

16. Castronuovo JJ Jr, Adera HM, Smiell JM, Price RM. Skinperfusion pressure measurement is valuable in the diagnosis ofcritical limb ischemia. J Vasc Surg 1997;26:629–37.

17. Regensteiner JG. Exercise in the treatment of claudication:assessment and treatment of functional impairment. Vasc Med1997;2:238–42.

18. Gardner AW, Poehlman ET. Exercise rehabilitation programsfor the treatment of claudication pain. A meta-analysis. JAMA1995;274:975–80.

19. Hiatt WR, Wolfel EE, Meier RH, Regensteiner JG. Superior-ity of treadmill walking exercise versus strength training forpatients with peripheral arterial disease. Implications forthe mechanism of the training response. Circulation 1994;90:1866–74.



20. Law M, Tang JL. An analysis of the effectiveness of interven-tions intended to help people stop smoking. Arch Intern Med1995;155:1933–41.

21. Olin JW. Thromboangitis obliterans (Buerger’s disease). NEngl J Med 2000;343:864–9.

22. Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr. Cil-ostazol has beneficial effects in treatment of intermittentclaudication: results from a multicenter, randomized, prospec-tive, double-blind trial. Circulation 1998;98:678–86.

23. Money SR, Herd JA, Isaacsohn JL et al. Effect of cilostazol onwalking distances in patients with intermittent claudicationcaused by peripheral vascular disease. J Vasc Surg 1998;27:267–74.

24. Beebe HG, Dawson DL, Cutler BS et al. A new pharmaco-logical treatment for intermittent claudication: results of arandomized, multicenter trial. Arch Intern Med 1999;159:2041–50.

25. Creutzig A, Lehmacher W, Elze M. Meta-analysis ofrandomized controlled prostaglandin E1 studies in peripheralarterial occlusive disease stage III and IV. Vasa 2004;33:137–44.

26. Norgren L, Hiatt WR, Dormandy JA et al.; TASC II WorkingGroup. Inter-society consensus for the management of periph-eral arterial disease. Int Angiol 2007;26:81–157.

27. Ishii H, Kumada Y, Toriyama T et al. Cilostazol improveslong-term patency after percutaneous transluminal angio-plasty in hemodialysis patients with peripheral artery disease.Clin J Am Soc Nephrol 2008;3:1034–40.

28. Adam DJ, Beard JD, Cleveland T et al.; Basil Trial Partici-pants. Bypass versus angioplasty in severe ischemia of the leg(BASIL): multicenter, randomized controlled trial. Lancet2005;365:1925–34.

29. Aulivola B, Gargiulo M, Bessoni M, Rumolo A, Stella A.Infrapopliteal angioplasty for limb salvage in the setting ofrenal failure: do results justify its use? Ann Vasc Surg 2005;19:762–8.

30. Brosi P, Baumgartner I, Silvestro A et al. Below-the-kneeangioplasty in patients with end-stage renal disease. J Endo-vasc Ther 2005;12:704–13.

31. Graziani L, Silvestro A, Bertone V et al. Percutaneous trans-luminal angioplasty is feasible and effective in patients onchronic dialysis with severe peripheral artery disease. NephrolDial Transplant 2007;22:1144–9.

32. Kimura H, Miyata T, Sato O, Furuya T, Iyori K, Shigematsu H.Infrainguinal arterial reconstruction for limb salvage inpatients with end-stage renal disease. Eur J Vasc EndovascSurg 2003;25:29–34.

33. Georgopoulos S, Filis K, Vourliotakis G et al. Lower extremitybypass procedures in diabetic patients with end-stage renaldisease: is it worthwhile? Nephron Clin Pract 2005;99:37–41.

34. Whittemore AD, Donaldson MC, Mannick JA. Infrainguinalreconstruction for patients with chronic renal insufficiency.J Vasc Surg 1993;17:32–9.

35. Yamamura M, Miyamoto Y, Mukai S et al. Results oflower limb revascularization for arteriosclerosis obliterans inchronic hemodialysis patients. Jpn J Vasc Surg 2005;14:99–103.

36. Albers M, Romiti M, Bragança Pereira CA, Fonseca RL, daSilva Júnior M. A meta-analysis of infrainguinal arterial recon-struction in patients with end-stage renal disease. Eur J VascEndovasc Surg 2001;22:294–300.

37. Jaar BG, Astor BC, Berns JS, Powe NR. Predictors of ampu-tation and survival following lower extremity revascularizationin hemodialysis patients. Kidney Int 2004;65:613–20.

38. Kobayashi S. Applications of LDL-apheresis in nephrology.Clin Exp Nephrol 2008;12:9–15.

39. Faglia E, Favales F, Aldeghi A et al. Adjunctive systemichyperbaric oxygen therapy in treatment of severe prevalentlyischemic diabetic foot ulcer. Diabetes Care 1996;19:1338–43.

40. Abidia A, Laden G, Kuhan G et al. The role of hyperbaricoxygen therapy in ischemic diabetic lower extremity ulcers: adouble-blind randomized-controlled trial. Eur J Vasc Surg2003;25:513–18.

41. Toriyama T, Kumada Y, Matsubara T et al. Effect of artificialcarbon dioxide foot bathing on critical limb ischemia (Fon-taine IV) in peripheral arterial disease patients. Int Angiol2002;21:367–73.

42. Nakai S, Masakane I, Akiba T et al. An overview of dialysistreatment in Japan (as of Dec. 31, 2005). J Jpn Soc Dial Ther2007;40:1–30.

43. Dossa CD, Shepard AD, Amos AM et al. Results of lowerextremity in patients with end-stage renal disease. J Vasc Surg1994;20:14–9.

44. Aulivola B, Hile CN, Hamdan AD et al. Major lower extrem-ity amputation. Arch Surg 2004;139:395–9.

45. Rocco MV, Soucie JM, Reboussin DM, McClellan WM. Riskfactors for hospital utilization in chronic dialysis patients. J AmSoc Nephrol 1996;7:889–96.

46. Barrett BJ, Parfrey PS, Morgan J et al. Prediction of earlydeath in end-stage renal disease patients starting dialysis. AmJ Kidney Dis 1997;29:214–22.

47. Chertow GM, Normand SL, Silva LR, McNeil BJ. Survivalafter acute myocardial infarction in patients with end-stagerenal disease: results from the cooperative cardiovascularproject. Am J Kidney Dis 2000;35:1044–51.

48. Ono K, Tsuchida A, Kawai H et al. Ankle-brachial bloodpressure index predicts all-cause and cardiovascular mortalityin hemodialysis patients. J Am Soc Nephrol 2003;14:1591–8.

tap_1088_10 427..475

Chapter 9: Use of Cardiovascular Drugs inDialysis Patients

Statements

1. In dialysis patients, excretion of renallyexcreted drugs is likely to be delayed, causinghigh drug concentrations and adverse effectsdue to their toxicity. Therefore, we suggestthat hepatically metabolized drugs should beselected as much as possible (Opinion).

2. In administering a renally excreted drug, werecommend assessment of renal function andurinary excretion rate of the drug, we recom-mend that the dose should be appropriatelyadjusted, and periodic monitoring of adversereactions should be conducted (1A).

3. While administration of contraindicated drugsis necessary in some situations, we recommendavoidance of such drugs except when theestimated benefit of administration surpassesthe risk of adverse effects (1A).

4. We recommend that gadolinium contrastagents for magnetic resonance imaging (MRI)should not be used in dialysis patients, sincethey can induce nephrogenic systemic fibrosis(NSF) (1C).

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CommentsUnderstanding the pharmacokinetics (absorption,

distribution, metabolism, excretion) of drugs, whichis the most significant determinant of their bloodlevels, is important for effective and safe administra-tion. Since renal excretion is remarkably reduced indialysis patients, the absorption, distribution, andmetabolism of drugs are likely to be affected, andtheir blood concentrations are likely to rise, causingadverse effects due to their toxicity. Therefore, inusing drugs, their doses should be adjusted in con-sideration of their urinary excretion rates in activeforms (often the unchanged drugs), total clearance,bioavailability, protein binding rate, volume of dis-tribution, and dialyzability, and those that aremetabolized primarily by the liver and metabolitesof which are inactive should be used when possible(Table 1).

Points of caution in the use of major drugs indialysis patients are described below.

Antiarrhythmic drugsAntiarrhythmic drugs pose the greatest problems

among cardiovascular drugs. In dialysis patients,optimal adjustment of their blood levels is extremelydifficult due to the effects of both their excretionand dialysis. Since careless administration ofantiarrhythmic drugs may allow the appearance ofserious adverse effects and exacerbate the outcome,the need for their use should be carefully evaluated(1,2).

When the use of antiarrhythmic drugs is importantin dialysis patients, a full 12-lead electrocardiogram(ECG) should be recorded before the initiation ofdrug therapy. This should be repeated when four tofive times the period of the half-life of the drug afterits first use has passed and its concentration is con-sidered to have reached a stable state. Furthermore,the ECG should be recorded again at least once amonth after stabilization of the condition.

Antihypertensive drugsIn case of using renin-angiotensin system inhibi-

tors, though it is important to confirm their excretionroutes, dose reduction is basically unnecessary interms of angiotensin II receptor blockers (Table 2).Although almost all angiotensin converting enzymeinhibitors are excreted through the kidney, whetherdose reduction is necessary or not is not clear atpresent, because a dose-related adverse reaction israre in these drugs. Dose adjustment is also unneces-sary for calcium channel blockers and a1-receptorblockers. b-blockers have various routes of elimina-tion, including hepatic metabolism, renal excretion,

or both. Considering their indication, they should beused carefully (Table 2) (3–6). If possible, drugs thatare eliminated primarily by hepatic metabolismshould be selected in dialysis patients.

Lipid-lowering drugsSeveral types of lipid-lowering drugs are available

in the clinical setting. However, renally excretedfibrates (e.g. fenofibrate, bezafibrate) are contraindi-cated for dialysis patients. Clinofibrate is an excep-tional fibrate excreted in bile, but it should beadministered carefully in patients with renal failure.Niceritrol has been reported to reduce serum phos-phate levels (7). However, since it is also reported tocause thrombocytopenia (8), it must be administeredcarefully. Although probucol can be administered atthe usual dose, it may cause QT prolongation onECG, and caution is needed (9).

Statins, with the exception of rosuvastatin, andother drugs can also be administered at the usualdose even in dialysis patients.

Contrast media and other contraindicated drugsPatients with severe renal dysfunction may

develop NSF after the use of a gadolinium-basedcontrast medium (10–12). Since there is no estab-lished treatment for this adverse effect, prevention ismost important, and the Japanese Society of Neph-rology, Japan Radiological Society, and JapaneseSociety for Dialysis Therapy jointly issued guidelinesfor the use of gadolinium contrast media (13). Inprinciple, the use of such contrast media should beavoided. However, if the benefit of their use isexpected to surpass the risk of NSF, an informedconsent should be obtained, and contrast media withfewer reports of NSF should be selected.

Iodinated contrast media and fluorescent contrastagents can be used in dialysis patients usually withoutany problems despite a delay in excretion.

In principle, cardiovascular drugs contraindicatedfor dialysis patients should not be used. However, ifthe benefit of their use surpasses the risk of avoid-ance, they should be administered carefully. Otherdrugs like warfarin and cilostazol, which are usedfrequently, should also be used carefully in dialysispatients after sufficient evaluation of indications.Concerning drugs that can be administered to dialysispatients, also, the dose must be determined withattention to adverse effects after sufficient consider-ation of the routes of metabolism, excretion, dialyz-ability, and benefit (Table 3).

Table 4 provides information about lipid-loweringagents and Table 5 about antidiabetic drugs.



TABLE 1. Elimination route, dialyzability, and optimal dosage of antiarrhythmic agents for patients undergoinghemodialysis (Vaughan Williams Classification)*

Drug

Major eliminationroute Dialyzability

Dose for normalrenal function (mg/day)

Adjustment fordialysis patients (mg/day)Generic name

Administrationroute

Ia Quinidine Sulfate Oral Liver (kidney15–40%) - Maintenance dose: 200–600 Usual doseDisopyramide Phosphate Oral Kidney 50–60% � 300 100–150

Oral,sustainedrelease

300 Contraindication

Injection 50–100 mg/administration 100Cibenzoline Succinate Oral Kidney 60% liver 40% - 300–450 Contraindication

Injection 1.4 mg/kg per administrationPirmenol Hydrochloride

HydrateOral Liver (kidney 17–31%) - 200 100–150

ProcainamideHydrochloride

Oral Kidney 50–60% (Activemetabolites: 80%)

+ 750–2000 Administration intervalextended 4 times

Injection i.v. injection at200–1,000 mg/administrationor i.m. injection at500 mg/administration every4–6 h

200–400 mg/administration1–2 times/day

Ib Aprindine Hydrochloride Oral Liver - 40–60 Usual doseinjection Up to 100 mg/administration Usual dose

Mexiletine Hydrochloride Oral Liver � 300–450 Usual doseDrip infusion See the package insert Usual dose

Lidocaine Injection Liver - Up to 50–100 mg/administrationor 300 mg/h

Usual dose

Ic Pilsicainide HydrochlorideHydrate

Oral Kidney 80% � 150–225 25Injection Maximum dose: 1.0 mg/kg Unknown

Flecainide Acetate Oral Liver 70% kidney 30% - 100–200 50–100Injection 1.0–2.0 mg/kg per administration

with a maximum of150 mg/day

Administration intervalextended 2 times

Propafenone Hydrochloride Oral Liver - 450 Usual doseII Acebutolol Hydrochloride Oral Kidney 36% - 200–600 100–400

Atenolol Oral Kidney 90% + 25–100 25 mg after dialysis 3times/week

Alprenolol Hydrochloride Oral Unknown Unknown 75–150 UnknownArotinolol Hydrochloride Oral Liver - 20–30 Usual doseEsmolol hydrochloride Injection Liver (kidney <10%) - 0.15 mg/kg per min Usual doseOxprenolol Hydrochloride Oral Liver Unknown 60–120 Usual doseCarteolol Hydrochloride Oral Kidney 60–70% - 10–30 2.5–15Nadolol Oral Kidney 90% - 30–60 30–60 mg after dialyses 3

times a weekBisoprolol Fumarate Oral Kidney 50% - 5 2.5Pindolol Oral Kidney 35–54% + 5–15 5–10Bufetolol Hydrochloride Oral Unknown Unknown 15 UnknownPropranolol Hydrochloride Oral Liver - 30–120 Usual doseMetoprolol Tartrate Oral Liver - 60–240 Usual doseLandiolol Hydrochloride Injection Liver (kidney 8.7%) + See the package insert Usual dose

III Amiodarone Hydrochloride Oral Liver - 400 mg at the initiation, 200 mgduring the maintenanceperiod

Usual dose

Injection See the package insertNifekalant Hydrochloride Injection Liver (kidney 28–37%) - Single administration at

0.3 mg/kg per 5 min,maintenance dose 0.4 mg/kgper h

Single administration at0.1 mg/kg per 5 min,maintenance dose0.15–0.2 mg/kg per h

Sotalol hydrochloride Oral Kidney 80% + 80–320 ContraindicationIV Diltiazem Hydrochloride Injection Liver - 10 mg/about

3 min/administrationUsual dose

Bepridil HydrochlorideHydrate

Oral Liver - 100–200 mg/day divided into 1–2doses

Usual dose

Verapamil Hydrochloride Oral Liver - 120–240 Usual dose (also reported tobe reduced to a half due todepression of non–kidneyCL)

Injection 5 mg/administration if necessary

Digoxin Oral Kidney 75% - Maintenance dose 0.25–0.50 0.125 mg as a maintenancedose 2–4 times/week

Injection Maintenance dose 0.25 0.1–0.125 mg as a maintenancedose 2–4 times/week

Deslanoside Injection Kidney 60% - Maintenance dose 0.2–0.3 mgonce a day

Dose reduction needed, butdetails unknown

Metildigoxin Oral Kidney 40% (Activemetabolites 45%)

- Maintenance dose 0.1–0.2 0.05 mg as a maintenancedose 2–4 times/week

Noindication

Adenosine TriphosphateDisodium Hydrate

Injection Each cell +? i.v. injection: 5–40/administration1–2times i.v. drip infusion: 4–80

usual dose

Since antiarrhythmic drugs such as aprindine, cibenzoline (contraindicated for dialysis patients), flecainide, mexiletine, procainamide, and propafenone and manyb–blockers are metabolized by CYP2D6, their blood levels may be increased rapidly by strong CYP2D6 inhibitors such as cinacalcet hydrochloride, paroxetinehydrochloride hydrate, and quinidine sulfate. Particularly, as aprindine and propafenone show nonlinear pharmacokinetic curves with saturation of the enzyme thatmetabolizes them, monitoring (TDM) of the blood levels of these antiarrhythmic drugs is recommended in their concomitant use.

*This table presents information obtained from package inserts and by a review of the literature available at the time of editing in a simplified form. Therefore, weask the readers to understand that the data may not be universal and to check the latest package inserts and literature for details.



TABLE 2. Elimination routes and dialyzability of antihypertensive drugs and their optimal dosages for patientsundergoing hemodialysis*

Classification

Drug

Major elimination route Dialyzability

Dose for normalrenal function

(mg/day)

Adjustment fordialysis patients

(mg/day)Generic nameAdministration

route

Angiotensin–convertingenzymeinhibitors(ACE–I)

Alacepril Oral Kidney (59.2% in activeforms)

+ 25–100 25–50

Imidapril Hydrochloride Oral Kidney 25.5% + 2.5–10 5Enalapril Maleate Oral Kidney (88% in active

forms)+ 2.5–10 Reduced to

25–50%Captopril Oral Kidney 40–75% + 12.5–150 12.5–75Quinapril Hydrochloride Oral Kidney (30–96% in active

forms)– 5–20 2.5–10

Cilazapril Hydrate Oral Kidney (70–80% in activeforms)

+ 0.25–2 0.25

Temocapril Hydrochloride Oral Kidney � 35% - 2–4 Reduced to 75%Delapril Hydrochloride Oral Unknown - 15–120 Started at 7.5Trandolapril Oral Kidney (14–29% in active

forms), feces 66%– 1–2 Started at 0.5

Benazepril Hydrochloride Oral Kidney (17–21% in activeforms)

- 2.5–10 Started at 2.5

Perindopril Erbumine Oral Kidney (3–10% in activeforms)

+ 2–4 Reduced to 50%

Lisinopril Hydrate Oral Kidney 88–100% + 5–20 Reduced to 25–50%Angiotensin II receptor

antagonists (ARB)Dose reduction is unnecessary, as all are metabolized by the liver and disappear.

Renin Inhibitors (DRI) Aliskiren Fumarate Oral Fecal - 150–300 Usual doseCalcium channel blockers

(CCB)Dose reduction is unnecessary, as all are metabolized by the liver and disappear.

Preparations containingangiotensin II receptorantagonists (ARB)/calcium channel blockers(CCB)

Dose reduction is unnecessary, as all are metabolized by the liver and disappear.

Preparations containingangiotensin II receptorantagonists (ARB)/hydrochlorothiazide(HCTZ)

Contraindicated for anuric and dialysis patients

Beta blockers non–b1selective ISA(–)

Propranolol Hydrochloride Oral Liver - 30–120 Usual doseBufetolol Hydrochloride Oral Unknown Unknown 15 UnknownNadolol Oral Kidney 90% - 30–60 30–60 after

dialysis3 times/week

Beta blockers b1 selectiveISA(+)

Alprenolol Hydrochloride Oral Unknown Unknown 75–150 UnknownOxprenolol Hydrochloride Oral Liver Unknown 60–120 Usual doseCarteolol Hydrochloride Oral Kidney 60–70% - 10–30 2.5–15Pindolol Oral Kidney 35–54% + 5–15 5–10Penbutolol Oral Liver - 20–40 Usual doseBopindolol Malonate Oral Liver + 1–2 Usual dose

Beta blockers non–b1selective ISA(–)

Atenolol Oral Kidney 90% + 25–100 25 after dialysis3 times/week

Bisoprolol Fumarate Oral Kidney: 50% - 5 2.5Betaxolol Hydrochloride Oral Kidney 26–27% - 5–20 2.5–15Metoprolol Tartrate Oral Liver - 60–240 Usual doseLandiolol Hydrochloride Injection Liver (kidney 8.7%) + See the

packageinsert

Usual dose

Beta blockers non–b1selective ISA(+)

Acebutolol Hydrochloride Oral Kidney 36% - 200–600 100–400Esmolol hydrochloride Injection Liver (kidney <10%) – 0.15 mg/kg

per minUsual dose

Celiprolol Hydrochloride Oral Liver (kidney 10–20%) Unknown 100–400 Usual doseBeta blockers with

vasodilating actionTilisolol Hydrochloride Oral Kidney 50% Unknown 10–30 5–15Nipradilol Oral Liver - 6–18 Usual dose

Mixed Alpha + Betablockers

Amosulalol Hydrochloride Oral Liver (kidney 30%) - 20–60 10–40Arotinolol Hydrochloride Oral Liver - 20–30 Usual doseCarvedilol Oral Liver - 2.5–20 Usual doseBevantolol Hydrochloride Oral Liver Unknown 100–200 Usual doseLabetalol Hydrochloride Oral Liver - 150–450 Usual dose

Diuretics Generally, the doses are not reduced while some thiazide and loop diuretics are excreted via the kidney. However, diuretics arecontraindicated for anuric patients. Spironolactone is contraindicated for anuric, hyperkalemic patients. Eplerenone iscontraindicated for moderate or severer kidney dysfunction and hyperkalemia.

Alpha blockers: Dose reduction is unnecessary, as all are metabolized by the liver and disappear.Centrally acting

adrenergic drugsaMethyldopa Hydrate Oral Kidney 20–60% + 250–2000 Reduced to 50%Guanabenz Acetate Oral Liver - 4–8 Usual doseClonidine Hydrochloride Oral Kidney 40–62% - 225–450 mg Reduced to 50%

Vasodilators Hydralazine Hydrochloride Oral Liver - 30–200 Usual doseBudralazine Oral Unknown Unknown 90–180 Unknown

In this table, the dose of ACE–I is adjusted according to the urinary excretion rate of the active drug, but there is the opinion that the maintenance dose neednot be adjusted, because no marked adverse effect occurs without a dose reduction in dialysis patients.

*This table presents information obtained from package inserts and by a review of the literature available at the time of editing in a simplified form.Therefore,we ask the readers to understand that the data may not be universal and to check the latest package inserts and literature for details.



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iver

-1

patc

hU

sual

dose

Inje

ctio

nL

iver

-A

ppro

pria

tedo

seU

sual

dose

Car

diot

omic

,C

ardi

acG

lyco

side

Dig

oxin

Ora

lK

idne

y:75

%-

Mai

nten

ance

dose

0.25

–0.5

00.

125

mg

asa

mai

nten

ance

dose

2–4

tim

es/w

eek

Inje

ctio

nM

aint

enan

cedo

se0.

250.

125

mg

asa

mai

nten

ance

dose

2–4

tim

es/w

eek

Met

ildig

oxin

Ora

lK

idne

y:40

%(A

ctiv

em

etab

olit

es:4

5%)

-M

aint

enan

cedo

se0.

1–0.

20.

05m

gas

am

aint

enan

cedo

se2–

4ti

mes

/wee

kD

esla

nosi

deIn

ject

ion

Kid

ney:

60%

-M

aint

enan

cedo

se0.

2–0.

3m

gon

cea

day

Red

ucti

onis

need

ed,b

utde

tails

ofth

eph

arm

acok

inet

ics

are

unkn

own.

Car

diot

omic

cate

chol

amin

eA

dren

alin

eIn

ject

ion

Liv

er+

See

the

pack

age

inse

rtU

sual

dose

l–Is

opre

nalin

eH

ydro

chlo

ride

Inje

ctio

nK

idne

y40

–50%

+0.

2–1.

0R

educ

edto

1/2–

2/3

Den

opam

ine

Ora

lN

on–k

idne

y-

15–3

0U

sual

dose

Doc

arpa

min

eO

ral

Liv

er,s

mal

lint

esti

ne,b

lood

cont

ent

+22

50U

sual

dose

Dop

amin

eH

ydro

chlo

ride

Inje

ctio

nL

iver

+1–

5mg

/kg

per

min

(up

to20

mg/k

gpe

rm

in)

Usu

aldo

se

Dob

utam

ine

Hyd

roch

lori

deIn

ject

ion/

drip

infu

sion

Liv

er(b

ile)

+1–

5mg

/kg

per

min

Usu

aldo

se

Nor

adre

nalin

eIn

ject

ion

Liv

er(k

idne

y�

16%

)+

See

the

pack

age

inse

rtSt

arte

dat

alo

wdo

seC

ardi

otom

icP

hosp

hodi

este

rase

III

Inhi

bito

r

Olp

rino

neH

ydro

chlo

ride

Hyd

rate

Inje

ctio

nK

idne

y70

–80%

Unk

now

nIn

itia

llyat

10mg

/kg

per

5m

in,

cont

inue

dat

0.1–

0.4

mg/k

gR

educ

edto

1/3

Pim

oben

dan

Ora

lK

idne

y(a

ctiv

edr

ug20

–40%

)-

2.5–

5St

arte

dat

1.25

–2.5

Milr

inon

eIn

ject

ion

Kid

ney

95%

-Se

eth

epa

ckag

ein

sert

Star

ted

at0.

25mg

/kg/

min

Car

diot

omic

Cyc

licA

MP

Buc

lade

sine

Sodi

umIn

ject

ion

Kid

ney

16.6

%U

nkno

wn

0.00

5–0.

2mg/

kgpe

rm

inU

sual

dose

Car

diot

omic

,oth

ers

Col

fors

inD

arop

ate

Hyd

roch

lori

deD

rip

infu

sion

Kid

ney

10.8

–17.

8%U

nkno

wn

0.5–

0.75

mg/k

gpe

rm

inU

sual

dose

Oth

ers,

a–hA

NP

prep

arat

ions

Car

peri

tide

(gen

etic

alre

com

bina

tion

)In

ject

ion

Non

–kid

ney

Unk

now

n0.

1–0.

2mg/

kgpe

rm

inR

educ

edto

1/2

Thr

ombo

lyti

cD

rug

Alt

epla

se(g

enet

ical

reco

mbi

nati

on)

Inje

ctio

nL

iver

-Se

eth

epa

ckag

ein

sert

Usu

aldo

se

Uro

kina

seIn

ject

ion

Liv

er-

Init

ially

at6

¥10

4un

its

(up

to24

¥10

4un

its)

,con

tinu

edfo

rab

out

7da

ysw

ith

grad

ual

dose

redu

ctio

ns

Usu

aldo

se

Bat

roxo

bin

Dri

pin

fusi

onN

on–k

idne

y(k

idne

y<1

%)

-10

–20

BU

/hat

ati

me

ever

yot

her

day

Usu

aldo

se

Pam

itep

lase

Inje

ctio

nN

on–k

idne

y-

3500

0IU

/kg

per

min

Usu

aldo

seM

onte

plas

e(g

enet

ical

reco

mbi

nati

on)

Inje

ctio

nN

on–k

idne

y–

1375

0–27

500

IU/k

gU

sual

dose



TAB

LE

3.C

ontin

ued

Cla

ssifi

cati

on

Dru

g

Maj

orel

imin

atio

nro

ute

Dia

lyza

bilit

yD

ose

for

norm

alre

nalf

unct

ion

(mg/

day)

Adj

ustm

ent

for

dial

ysis

pati

ents

(mg/

day)

Gen

eric

nam

eA

dmin

istr

atio

nro

ute

Ant

ipla

tele

tD

rug

Asp

irin

Ora

lL

iver

+10

0U

sual

dose

Alu

min

umG

lyci

nate

Ora

lL

iver

+81

Usu

aldo

seO

zagr

elSo

dium

Inje

ctio

nK

idne

y61

.1%

+80

–160

Red

uced

to1/

2,ad

min

iste

red

afte

rH

Don

days

wit

hH

DC

lopi

dogr

elSu

lfat

eO

ral

Liv

er-

50–7

5U

sual

dose

Sarp

ogre

late

Hyd

roch

lori

deO

ral

Liv

er-

300

Usu

aldo

seC

ilost

azol

Ora

lL

iver

-20

0U

sual

dose

(con

trai

ndic

ated

for

cong

esti

vehe

art

failu

re)

Tic

lopi

dine

Hyd

roch

lori

deO

ral

Liv

er-

200–

600

Usu

aldo

seL

imap

rost

Alf

adex

Ora

lL

ung

-30

mgU

sual

dose

Dru

gsfo

rpe

riph

eral

occl

usiv

ear

teri

aldi

seas

e(p

rost

agla

ndin

prep

arat

ions

)

Alp

rost

adil

Alf

adex

Inje

ctio

nL

ung

-40

–120

mgU

sual

dose

Alp

rost

adil

Inje

ctio

nL

ung

-5–

10mg

Usu

aldo

seB

erap

rost

Ora

lL

iver

-12

0mg

Usu

aldo

seA

ntic

oagu

lant

Arg

atro

ban

Hyd

rate

Inje

ctio

nL

iver

-Se

eth

epa

ckag

ein

sert

Usu

aldo

seR

ecom

odul

inth

rom

bom

odul

inal

faD

rip

infu

sion

Kid

ney

-38

0U

/kg

per

30m

inon

cea

day

130

U/k

g

Hum

anan

ti–t

hrom

bin

III,

free

ze–d

ried

conc

entr

ated

Inje

ctio

nU

nkno

wn

-10

00–3

000

U/d

ay(2

0–60

U/k

g)D

IC:1

500

U/d

ay(3

0U

/kg)

Usu

aldo

se

Hum

anac

tiva

ted

prot

ein

C,

free

ze–d

ried

conc

entr

ated

Inje

ctio

nU

nkno

wn

-Se

eth

epa

ckag

ein

sert

Usu

aldo

se

Dan

apar

oid

Sodi

umIn

ject

ion

Kid

ney

-25

00an

ti–f

acto

rX

aun

its

Con

trai

ndic

atio

nD

abig

atra

nE

texi

late

Met

hane

sulf

onat

eO

ral

Kid

ney

+11

0–15

0m

g/ad

min

istr

atio

ntw

oti

mes

ada

yC

ontr

aind

icat

ion

Fond

apar

inux

Sodi

umSu

bcut

aneo

usin

ject

ion

Kid

ney

-2.

5C

ontr

aind

icat

ion

War

fari

nPo

tass

ium

†O

ral

Liv

er-

App

ropr

iate

dose

Usu

aldo

se(c

ontr

aind

icat

edfo

rse

vere

kidn

eydi

sord

er)

Cer

ebro

prot

ecti

vedr

ugs

Eda

ravo

neO

ral

Liv

er(k

idne

y<1

%)

Unk

now

n60

Usu

aldo

se(c

ontr

aind

icat

edfo

rse

vere

kidn

eydi

sord

er)

Vas

opre

ssor

Eti

lefr

ine

Hyd

roch

lori

deO

ral

Liv

er(k

idne

y7%

)-

15–3

0U

sual

dose

Inje

ctio

n2–

10/a

dmin

istr

atio

nU

sual

dose

Dro

xido

paO

ral

Liv

er(k

idne

y15

–20%

)+

100–

900

Usu

aldo

seP

heny

leph

rine

Hyd

roch

lori

deIn

ject

ion

Unk

now

nU

nkno

wn

2–10

/adm

inis

trat

ion

Not

dete

rmin

edM

idod

rine

Hyd

roch

lori

deO

ral

Liv

er+

4–8

Usu

aldo

seA

mez

iniu

mM

etils

ulfa

teO

ral

Kid

ney

77%

-20

10m

gat

the

init

iati

onof

dial

ysis

Hep

arin

prep

arat

ions

,ant

i–he

pari

npr

epar

atio

ns,a

ndan

ti–p

ulm

onar

yhy

pert

ensi

ondr

ugs

wer

eex

clud

edfr

omth

ista

ble.

† The

risk

ofga

stro

inte

stin

albl

eedi

ngdu

eto

war

fari

nis

incr

ease

dby

the

gast

roto

xic

and

anti

plat

elet

acti

viti

esof

non–

ster

oida

lant

i–in

flam

mat

ory

drug

s(N

SAID

s).N

SAID

ssu

chas

mel

oxic

am,l

orno

xica

m,c

elec

oxib

,ibu

prof

en,i

ndom

etha

cin,

mef

enam

icac

id,b

uloc

ome,

piro

xica

m,a

ndte

noxi

cam

may

furt

her

inte

nsif

yth

eac

tion

ofw

arfa

rin

byin

hibi

ting

CY

P2C

9,a

prim

ary

war

fari

n–m

etab

oliz

ing

enzy

me.

(1)

Lor

noxi

cam

repo

rted

lyin

crea

sed

the

seru

mw

arfa

rin

conc

entr

atio

n(A

UC

)1.

58ti

mes

,(2)

and

its

conc

omit

ant

use

wit

hce

leco

xib

incr

ease

dth

epr

othr

ombi

nti

me–

inte

rnat

iona

lno

rmal

ized

rati

o(P

T–I

NR

),w

hich

had

been

cont

rolle

din

ano

rmal

rang

e,to

10,c

ausi

ngse

vere

anem

iain

som

epa

tien

ts,(

3)bu

tin

form

atio

nco

ncer

ning

othe

rN

SAID

sis

scar

ce.C

auti

onis

urge

dag

ains

tth

eco

ncom

itan

tus

eof

allo

ther

NSA

IDs

incl

udin

gbu

colo

me

and

tram

adol

.The

conc

omit

ant

use

ofpy

rim

idin

eflu

orid

ean

tica

ncer

drug

s(T

S–1,

cape

cita

bine

,teg

afur

,5–F

U,e

tc.)

,the

anti

bact

eria

lage

ntsu

lfam

etho

xazo

le(p

rim

ary

com

pone

ntof

STco

mpo

und

prep

arat

ions

),an

dth

ean

tiar

rhyt

hmic

drug

amio

daro

nesh

ould

also

beav

oide

d,be

caus

eth

eyel

evat

eth

ebl

ood

leve

lof

war

fari

nan

dm

arke

dly

incr

ease

the

PT

–IN

R.O

nth

eot

her

hand

,the

anti

tube

rcul

ous

agen

tri

fam

pici

nan

dth

ean

tiep

ilept

ics

phen

obar

bita

l,ca

rbam

azep

ine,

and

prim

idon

eoc

casi

onal

lyat

tenu

ate

the

effe

ctof

war

fari

nby

indu

cing

CY

P2C

9.Si

nce

ther

ear

em

any

othe

rdr

ugs

that

inte

ract

wit

hw

arfa

rin,

see

the

pack

age

inse

rtof

war

fari

nfo

rde

tails

.(1)

Lac

yC

F,A

rmst

rong

LL

,Gol

dman

MP,

Lan

ceL

L:L

exi

Com

p’s

Dru

gIn

form

atio

nH

andb

ook

18ed

,200

9–20

10.H

udso

n,O

hio,

2009

.(2)

.Mal

hiH

,Ata

cB

,Dal

yA

K,G

upta

S:W

arfa

rin

and

cele

coxi

bin

tera

ctio

nin

the

sett

ing

ofcy

toch

rom

eP

450

(CY

P2C

9)po

lym

orph

ism

wit

hbl

eedi

ngco

mpl

icat

ion.

Post

grad

Med

J80

:107

–109

,200

4.(3

)K

ohlC

,Ste

inke

llner

M:P

redi

ctio

nof

phar

mac

okin

etic

drug

/dru

gin

tera

ctio

nsfr

omIn

vitr

oda

ta:i

nter

acti

ons

ofth

eno

nste

roid

alan

ti–i

nflam

mat

ory

drug

lorn

oxic

amw

ith

oral

anti

coag

ulan

ts.D

rug

Met

abD

ispo

s28

:161

–168

,200

0.*T

his

tabl

epr

esen

tsin

form

atio

nob

tain

edfr

ompa

ckag

ein

sert

san

dby

are

view

ofth

elit

erat

ure

avai

labl

eat

the

tim

eof

edit

ing

ina

sim

plifi

edfo

rm.T

here

fore

,we

ask

the

read

ers

toun

ders

tand

that

the

data

may

not

beun

iver

sala

ndto

chec

kth

ela

test

pack

age

inse

rts

and

liter

atur

efo

rde

tails

.



TAB

LE

4.E

limin

atio

nro

utes

and

dial

yzab

ility

oflip

id–l

ower

ing

drug

san

dth

eir

optim

aldo

sage

sfo

rpa

tient

sun

derg

oing

hem

odia

lysi

s*

Cla

ssifi

cati

on

Dru

g

Maj

orel

imin

atio

nro

ute

Dia

lyza

bilit

yD

ose

for

norm

alre

nal

func

tion

(mg/

day)

Adj

ustm

ent

for

dial

ysis

pati

ents

(mg/

day)

Gen

eric

nam

eA

dmin

istr

atio

nro

ute

Stat

ins

(hyd

roxy

met

hylg

luta

ryl

CoA

redu

ctas

ein

hibi

tors

)

Ato

rvas

tati

nC

alci

umH

ydra

teO

ral

Liv

er-

10–4

0U

sual

dose

Sim

vast

atin

Ora

lL

iver

-5–

20U

sual

dose

Pit

avas

tati

nC

alci

umO

ral

Liv

er-

1–4

Usu

aldo

seP

rava

stat

inSo

dium

Ora

lL

iver

�10

–20

Usu

aldo

seF

luva

stat

inSo

dium

Ora

lFe

cal

-20

–60

Usu

aldo

seR

osuv

asta

tin

Cal

cium

Ora

lL

iver

(kid

ney

�10

%–3

3%)

-2.

5–20

2.5–

5.0

Cho

lest

erol

abso

rpti

onin

hibi

tors

Eze

tim

ibe

Ora

lFe

cal

-10

Usu

aldo

se

Fibr

ate

Clin

ofibr

ate

Ora

lFe

cal(

kidn

ey�

1%)

-60

0U

sual

dose

Clo

fibra

teO

ral

Kid

ney?

-75

0–15

00C

auti

onne

eded

for

adm

inis

trat

ion

(car

eful

adm

inis

trat

ion?

)B

ezafi

brat

eO

ral,

sust

aine

dre

leas

e

Kid

ney

50–7

0%-

400

Con

trai

ndic

atio

n

Feno

fibra

teO

ral

Liv

er-

134–

201

Con

trai

ndic

atio

nN

icot

inic

acid

agen

tsN

icom

olO

ral

Non

–kid

ney?

Irre

leva

nt(n

otap

plic

ant?

)

600–

1200

Usu

aldo

se

Nic

erit

rol

Ora

lFe

cal

Irre

leva

nt(n

otap

plic

ant?

)

750

250

Bile

acid

sequ

estr

ants

Col

esti

mid

eO

ral

Feca

lIr

rele

vant

(not

appl

ican

t?)

3–4g

Usu

aldo

se

Col

esty

ram

ine

Ora

lFe

cal

Irre

leva

nt(n

otap

plic

ant?

)

18–2

7g

Usu

aldo

se

Pro

buco

lP

robu

col

Ora

lL

iver

-50

0–10

00U

sual

dose

Oth

ers,

mis

cella

neou

s?E

thyl

icos

apen

tate

Ora

lU

nkno

wn

-18

00–2

700

Usu

aldo

se

*Thi

sta

ble

pres

ents

info

rmat

ion

obta

ined

from

pack

age

inse

rts

and

bya

revi

ewof

the

liter

atur

eav

aila

ble

atth

eti

me

ofed

itin

gin

asi

mpl

ified

form

.The

refo

re,w

eas

kth

ere

ader

sto

unde

rsta

ndth

atth

eda

tam

ayno

tbe

univ

ersa

land

toch

eck

the

late

stpa

ckag

ein

sert

san

dlit

erat

ure

for

deta

ils.



TAB

LE

5.E

xcre

tion

rout

es,d

ialy

zabi

lity,

and

dosa

ges

ofan

tidia

betic

drug

s*

Cla

ssifi

cati

on

Dru

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ucos

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Aca

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rele

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150–

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Irre

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tion

need

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Dip

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PP

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Con

trai

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ral

Liv

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%)

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ject

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Non

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bcut

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ject

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Deg

rade

dby

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ey-

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0mg

Con

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n

† Sinc

ein

sulin

ispa

rtly

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abol

ized

inth

eki

dney

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sere

duct

ion

isne

cess

ary

indi

alys

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tien

ts,b

utth

edo

sesh

ould

bead

just

edba

sica

llyin

cons

ider

atio

nof

the

stat

eof

bloo

dsu

gar

cont

rol.

*Thi

sta

ble

pres

ents

info

rmat

ion

obta

ined

from

pack

age

inse

rts

and

bya

revi

ewof

the

liter

atur

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aila

ble

atth

eti

me

ofed

itin

gin

asi

mpl

ified

form

.The

refo

re,w

eas

kth

ere

ader

sto

unde

rsta

ndth

atth

eda

tam

ayno

tbe

univ

ersa

land

toch

eck

the

late

stpa

ckag

ein

sert

san

dlit

erat

ure

for

deta

ils.



Acknowledgments: We apologize for the long time ittook us to prepare and publish the guideline. This wasmainly because the field of medical treatment ishumongous.The specialization of this guideline is very highto such an extent that each chapter could be considered byitself a separate guideline. To obtain the consensus of asmany members of the JSDT as possible, a consensus con-ference was held over three consecutive years. We want tothank the efforts of all 23 members of the committee whowere involved in the preparation of the guideline, espe-cially Dr Kazuaki Shimamoto, the President of SapporoMedical University School of Medicine, and Dr KiyotakaKugiyama, the Professor of Yamanashi University Schoolof Medicine, who represented the Japanese Society of Car-diology. We also want to mention Dr Jun Minakuchi, theChairperson of the 53rd Annual Meeting of the JSDT, DrTsutomu Sanaka, the Chairperson of the 54th AnnualMeeting of JSDT, and Hideki Kawanishi, the Chairpersonof the 55th Annual Meeting of JSDT.

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