Malnutrition, Inflammation and Malnutrition, Inflammation and

Atherosclerosis (MIA) syndrome in Atherosclerosis (MIA) syndrome in

dialysis patients dialysis patients

國泰綜合醫院國泰綜合醫院

楊垂勳楊垂勳

Introduction Introduction

Atherosclerotic cardiovascular disease ( ACD ) is a major cause of morbidity and mortality in patients undergoing renal replacement therapy. Despite significant progress in dialysis technology, the prevalence of ACD has not decreased during the last decade

HEMO study failed to show an HEMO study failed to show an improvement in mortality or improvement in mortality or hospitalization by increasing dialysis hospitalization by increasing dialysis dose or using highdose or using high--flux dialysis flux dialysis membranesmembranes

NEJM 347:2010-19,2002

Epidemiological studies repeatedly and Epidemiological studies repeatedly and consistently showed that a strong association consistently showed that a strong association between clinical outcome and measures of between clinical outcome and measures of bothbothmalnutrition malnutrition and and inflammationinflammationin in dialysis patients dialysis patients

AJKD 40:307-14,2002AJKD 38:1343-50,2001KI 55:648-58,1999JASN 13:S28-36,2002

�� CRF patients often have low energy and protein intakeCRF patients often have low energy and protein intake

�� Significant trend toward worsening nutritional status as Significant trend toward worsening nutritional status as the GFR decreased the GFR decreased

�� Renal replacement therapy add further risks for Renal replacement therapy add further risks for malnutritionmalnutrition

�� ProteinProtein--energy malnutrition is very common among energy malnutrition is very common among dialysis patientsdialysis patients

�� High prevalence 18High prevalence 18--70%70%

The distribution of three anthropometricThe distribution of three anthropometricmeaasurements related to meaasurements related to referent valuesreferent valuesas percentile in all hemodialysis patientsas percentile in all hemodialysis patients

PercentilePercentilePercentilePercentile

27

49.4

17.620

7.1 5.9

34.1

22.4

7.1 7.1

32.9

14.1

23.5

2.3

29.4

0

10

20

30

40

50

60

10 11-30 31-50 51-90 90

Percentage (%)Percentage (%)Percentage (%)Percentage (%)TSFTSFTSFTSF

MACMACMACMAC

MAMCMAMCMAMCMAMC

≦≦≦≦ >>>>

Causes of malnutrition in patients with chronic renal Causes of malnutrition in patients with chronic renal failure and those with maintenance dialysisfailure and those with maintenance dialysis

�� Decreased nutrient intakeDecreased nutrient intake�� altered taste and anorexia, prescribed reduction in protein intaaltered taste and anorexia, prescribed reduction in protein intake, intercurrent ilness, ke, intercurrent ilness,

emotional depression, loss of teeth, poverty, multiple medicatioemotional depression, loss of teeth, poverty, multiple medicationn

�� Abnormal renal metabolism of nutrients and hormonesAbnormal renal metabolism of nutrients and hormones�� resistantance to anabolic hormones: insulin, GH, IGFresistantance to anabolic hormones: insulin, GH, IGF--1, elevated catabolic hormones: 1, elevated catabolic hormones:

glucagon, PTH)glucagon, PTH)

�� Abnormal mineral metabolosmAbnormal mineral metabolosm�� Loss of nutrients into dialysateLoss of nutrients into dialysate�� Increased catabolism due to dialysis procedureIncreased catabolism due to dialysis procedure�� Metabolic acidosisMetabolic acidosis�� Inadequate dialysisInadequate dialysis�� Frequently blood samplingFrequently blood sampling�� Low physical activityLow physical activity�� BiocompatibilityBiocompatibility

Nutritional status at the onset of RRT predicts outcome

MalnutritionMalnutrition increases morbidity and mortality increases morbidity and mortality in dialysis patientsin dialysis patients

Serum albumin concentration , g/dlSerum albumin concentration , g/dlSerum albumin concentration , g/dlSerum albumin concentration , g/dl

AJKD 5:458-82 1990AJKD 5:458-82 1990AJKD 5:458-82 1990AJKD 5:458-82 1990

-10123456789

10111213141516171819

GT 4.5 4.0-4.5 3.5-4.0 3.0-3.5 2.5-3.0 LE 2.5

crudecrudecrudecrude adjustadjustadjustadjust

Relative risk of death

Cox proportional hazards modelCox proportional hazards model

ViariableViariable

RelativeRelative 9595%%

MortalityMortality ConfidenceConfidence

RiskRisk IntervalInterval

Age(per year)Age(per year) 1.031.03 1.011.01--1.051.05

IDDMIDDM 1.491.49 0.920.92--2.422.42

CVDCVD 2.122.12 1.351.35--3.433.43

Country(USA)Country(USA) 1.951.95 1.141.14--3.313.31

Serum albumin(Serum albumin(↑↑↑↑↑↑↑↑1g/L)1g/L) 0.940.94 0.900.90--0.970.97

CCr(CCr(↑↑↑↑↑↑↑↑5L/wk/1.73m2)5L/wk/1.73m2) 0.930.93 0.880.88--0.980.98

SGA(SGA(↑↑↑↑↑↑↑↑1u)1u) 0.750.75 0.660.66--0.850.85

a. CCr as estimate of adequacy of dialysis and SGA as the estimaa. CCr as estimate of adequacy of dialysis and SGA as the estimate of nutritional te of nutritional status.status.

JASN 1996;7:198-207

CANUSA Study

Kidney International, Vol. 68 (2005), pp. 1766–1776

Nutritional status indicators associated with mortality in the Hemodialysis (HEMO) Study

Kidney International, Vol. 68 (2005), pp. 1766–1776

Nutritional status indicators associated with mortality in Nutritional status indicators associated with mortality in theHemodialysis (HEMO) StudytheHemodialysis (HEMO) Study

Nutrition indicators are associated with subsequent mortality in a time-dependent manner, with greatest effects at <6 months of follow-up.

Kidney International, Vol. 68 (2005), pp. 1766–1776

Serum albuminSerum albumin

�� visceral proteinvisceral protein

�� half life: 20 dayshalf life: 20 days

Factors affecting the measured serum albuminFactors affecting the measured serum albumin

�� type of determination: bromcresol green or bromcresol purple type of determination: bromcresol green or bromcresol purple

�� Acute phase responseAcute phase response

�� systemic diseasesystemic disease

�� fluid statusfluid status

�� Serum albumin correlated with protein intake and other Serum albumin correlated with protein intake and other estimates of nutritional statusestimates of nutritional status

Kaysen AJKD 29:658-68,1997

A low serum albumin level does not always A low serum albumin level does not always reflect a poor nutrition status of the patient, as reflect a poor nutrition status of the patient, as serum albumin levels also are influenced by serum albumin levels also are influenced by several other factorsseveral other factors

Inflammation alone or in combination with a low protein intake play a significant role in causing hypoalbuminemia in CRF patients

Kaysen AJKD 29:658-68,1997

The acute-phase response varies with time and predicts serum albumin levels in hemodialysis patients

� The primary predictor of current albumin was the current

CRP level

� nPCR also was a significant predictor for albumin level after

controlling the effect of APPs, its effect on serum albumin

concentration is irrespective of the acute-phase response

� Levels of APPs are the most powerful predictors for the

levels of albumin in HD in a longitudinal setting

Kidney International, Vol. 58 (2000), pp. 346–352

The link between Malnutrition and cardiovascular disease and mortality

�� Which is the chicken and which is the egg?Which is the chicken and which is the egg?

�� Do hypoalbuminemia and malnutrition predispose to Do hypoalbuminemia and malnutrition predispose to or aggravate cardiac disease?or aggravate cardiac disease?

�� Is cardiac failure a cause of malnutrition in ESRD Is cardiac failure a cause of malnutrition in ESRD patients?patients?

�� Severe malnutrition markedly reduce the myocardial mass Severe malnutrition markedly reduce the myocardial mass and the contents of myofibrils and other functional elementsand the contents of myofibrils and other functional elements

JPEN 16:197JPEN 16:197--219,1992219,1992

�� Cardiac atrophy and hypertrophy are observed in marasmus Cardiac atrophy and hypertrophy are observed in marasmus Am J Trop Med 20:343Am J Trop Med 20:343--55,197155,1971

�� Malnutrition as an independent risk factor for mortality in Malnutrition as an independent risk factor for mortality in patients with heart failurepatients with heart failure

Lancet 349:1050Lancet 349:1050--3,19973,1997

Do hypoalbuminemia and malnutrition predispose to or Do hypoalbuminemia and malnutrition predispose to or aggravate cardiac disease? (1)aggravate cardiac disease? (1)

Do hypoalbuminemia and malnutrition predispose to or Do hypoalbuminemia and malnutrition predispose to or aggravate cardiac disease? (2)aggravate cardiac disease? (2)

�� Hypercoagulability in the setting of low serum albuminHypercoagulability in the setting of low serum albumin

�� Alteration of lipid stateAlteration of lipid state

�� Profound nutritional deficits in antioxidant levelProfound nutritional deficits in antioxidant level

�� Altering balance between endogenous vasodilatory and vasoconstriAltering balance between endogenous vasodilatory and vasoconstrictive ctive compounds (nitric oxide vs asymmetric dimethylcompounds (nitric oxide vs asymmetric dimethyl--LL--arginine)arginine)

ADMA is NO inhibitor, predisposing vasoconstriction, myocardial ADMA is NO inhibitor, predisposing vasoconstriction, myocardial ischemiaischemia

NO inhibition potentiate vascular smooth muscle proliferation anNO inhibition potentiate vascular smooth muscle proliferation and d enhance plaque formationenhance plaque formation

Association between mean serum albumin and clinicalAssociation between mean serum albumin and clinicaloutcomes (expressed as the effect of a 10 g/L fall)outcomes (expressed as the effect of a 10 g/L fall)

OutcomeOutcome

HemodialysisHemodialysis Peritoneal DialysisPeritoneal Dialysis

RelativeRelativepp

RelativeRelativepp

RiskRisk RiskRisk

Ischemic Heart DiseaseIschemic Heart Disease

De novoDe novo 5.295.29 0.0010.001 NANA NANA

RecurrentRecurrent 4.244.24 0.0050.005 NANA NANA

Cardiac FailureCardiac Failure

De novoDe novo 2.222.22 0.0010.001 4.164.16 0.0030.003

RecurrentRecurrent 3.843.84 0.0030.003 NANA NANA

MortalityMortality

AllAll --causecause 4.334.33 <0.001<0.001 2.062.06 <0.001<0.001

CardiacCardiac 5.605.60 0.0010.001 NANA NANA

NoncardiacNoncardiac 3.583.58 <0.001<0.001 3.523.52 <0.001<0.001

Foley et al:JASN 7:728-736,1996** Cox’s regressiom modeling

Is cardiac failure a cause of malnutrition in ESRDIs cardiac failure a cause of malnutrition in ESRDpatients? patients? (1)

�� Anorexia: sodium restricted diet, use of digitalisAnorexia: sodium restricted diet, use of digitalis�� Hypercatabolism: dyspnea, fever, increased Hypercatabolism: dyspnea, fever, increased

sympathetic activitysympathetic activity�� Reduced physical activity due to fatigue, and then Reduced physical activity due to fatigue, and then

reduced somatic proteins and lean body massreduced somatic proteins and lean body mass�� Tissue hypoperfusion and bowel edema impair Tissue hypoperfusion and bowel edema impair

absorptionabsorption�� Low serum albumin by dilutionLow serum albumin by dilution

Is cardiac failure a cause of malnutrition in ESRD Is cardiac failure a cause of malnutrition in ESRD patients? patients? (1)

Increased cytokine generation ( ILIncreased cytokine generation ( IL--1, IL2, TNF)1, IL2, TNF)

Mechanism:Mechanism:tissue injury from hypoxia, reduced tissuetissue injury from hypoxia, reduced tissue

perfusionperfusion�� Anorexia, increased muscle proteolysis, increased resting Anorexia, increased muscle proteolysis, increased resting

energy expenditureenergy expenditure

�� Reduced myocardial contractilityReduced myocardial contractility

�� Increasing acute phase proteins (CRP, AAP, fibrinogen)Increasing acute phase proteins (CRP, AAP, fibrinogen)

�� Reduced albumin synthesis and increased albumin degradationReduced albumin synthesis and increased albumin degradation

InflammationInflammationis associated with malnutrition is associated with malnutrition and atherosclerosis in dialysis patients and atherosclerosis in dialysis patients

�� CRP reflect generation of proinflammatory cytokinesCRP reflect generation of proinflammatory cytokines (IL(IL--1. IL1. IL--6 6

and TNFand TNF--αα), which was reported to be increased in CRF patients), which was reported to be increased in CRF patients

�� Proinflammatory cytokines may cause muscle wasting, promote Proinflammatory cytokines may cause muscle wasting, promote

protein catabolism, increasing energy expenditureprotein catabolism, increasing energy expenditure

�� In consequence, increased plasma level of In consequence, increased plasma level of

proinflammatory cytokines predict serum albumin and mortalityproinflammatory cytokines predict serum albumin and mortality

Inflammation is associated with malnutrition

Differences in Markers of Oxidative Stress and Inflammation Between CKD and Controls Group

J Am Soc Nephrol 19: 593–599, 2008.

The evidence of relationship between acute phase protein and cardiovascular disease

�� CRP is correlated with elevated Lp(a) levels in CRF patientsCRP is correlated with elevated Lp(a) levels in CRF patientsStenvinkel et al: KI 53:1336Stenvinkel et al: KI 53:1336--42,199842,1998

�� CRP is a strong risk factor for death within one year in patientCRP is a strong risk factor for death within one year in patients with CRF s with CRF Bergstrom et al : JASN 6:573,1995Bergstrom et al : JASN 6:573,1995

�� Elevated CRP levels is the risk factor for cardiovascular diseasElevated CRP levels is the risk factor for cardiovascular disease in healthy e in healthy menmen Ridker et al: ENJM 336:973Ridker et al: ENJM 336:973--9,19979,1997

�� Association of CAD with certain persistent bacterial and viral iAssociation of CAD with certain persistent bacterial and viral infections in nfections in nonnon--renal patientsrenal patients

�� InterleukinInterleukin--6 predicts hypoalbuminemia, hypocholesterolemia, and 6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients mortality in hemodialysis patients Bologa et al: AJKD 32:107Bologa et al: AJKD 32:107--14,199814,1998

�� Heinrich et al (1995): an association between elevated CRP levelHeinrich et al (1995): an association between elevated CRP levels and the s and the

severity of coronary artery severity of coronary artery

�� Liuzzo et al (1994 NEJM) : patients with elevated acute phase prLiuzzo et al (1994 NEJM) : patients with elevated acute phase protein had otein had

more ischemic episodes and higher mortalitymore ischemic episodes and higher mortality

�� Alexander et al (1994 NEJM): Presence of inflammation/infection Alexander et al (1994 NEJM): Presence of inflammation/infection

increases the risk of coronary diseaseincreases the risk of coronary disease

�� Han et al, Ikizler et al (1997): Elevated serum CRP levels predHan et al, Ikizler et al (1997): Elevated serum CRP levels predict ict

mortality in CAPD patients and hospitalization in hemodialysis pmortality in CAPD patients and hospitalization in hemodialysis patientsatients

The evidence of relationship between acute phase protein and cardiovascular disease

Inflammation enhances cardiovascular risk and mortality in hemodialysis patients

�� 280 HD patients, prospectively follow up 2 years280 HD patients, prospectively follow up 2 years

�� Serum lipid, (apo)A1 and B, Lp(a), fibrinogen, Salb, CRP, SAA Serum lipid, (apo)A1 and B, Lp(a), fibrinogen, Salb, CRP, SAA were measure were measure

Zimmermann et al: KI 55:648-58,1999

Zimmermann et al: KI 55:648-58,1999

Zimmermann et al: KI 55:648-58,1999

Yang et al: Nephron clin pract 2005;100:20-6

Yang et al: Nephron clin pract 2005;100:20-6

Yang et al: Nephron clin pract 2005;100:20-6

Yang et al: Nephron clin pract 2005;100:20-6

Propose two types of malnutrition Propose two types of malnutrition Stenvinkel et al NDT 15:953Stenvinkel et al NDT 15:953--60,200060,2000

Type 1Type 1 Type 2Type 2

Serum albuminSerum albumin normal/lownormal/low lowlow

CoCo--morbiditymorbidity uncommonuncommon commoncommon

Presence of inflammationPresence of inflammation nono yesyes

Food intakeFood intake lowlow low/normallow/normal

Resting energy expendictureResting energy expendicture normalnormal elevatedelevated

Oxidative stressOxidative stress increasedincreased markedly markedly increasedincreased

Protein catabolismProtein catabolism decreaseddecreased increasedincreased

Reversible by dialysis and nutritional Reversible by dialysis and nutritional supportsupport

yesyes nono

Non-inflammatory components

inflammation

Type 1 Mixed type Type 2

Co-morbidity none May be present Common and severe

Strong association between malnutrition, Strong association between malnutrition, inflammation, and atherosclerosis in chronic inflammation, and atherosclerosis in chronic renal failure renal failure

�� Compared with healthy controls, CRF patients had an Compared with healthy controls, CRF patients had an

increased mean carotid intimaincreased mean carotid intima--media area and a higher media area and a higher

prevalence of carotid plaques prevalence of carotid plaques

�� Malnourished patients had higher CRP levels, elevated mean Malnourished patients had higher CRP levels, elevated mean

carotid intimacarotid intima--media area and a higher prevalence of carotid media area and a higher prevalence of carotid

plaques compared with wellplaques compared with well--nourished patients nourished patients

Stenvinkle et al: KI 55:1899-911,1999

4%4%<1%<1% <1%<1%

17%17%

22%22%

9%9%

24%24%

Strong association between malnutrition, inflammation, and atherosclerosis Stenvinkle et al: KI 55:1899-911,1999

Malnutrition 44%Malnutrition 44%89% had carotid plaque 89% had carotid plaque

Inflammation 32%Inflammation 32%97% had carotid plaque 97% had carotid plaque

Carotid plaque 72%Carotid plaque 72%

Outside all: 22%Outside all: 22%

Cytokines are common factors predisposing to atherosclerotic Cytokines are common factors predisposing to atherosclerotic cardiovascular disease, hypoalbuminemia, and malnutritioncardiovascular disease, hypoalbuminemia, and malnutrition

ConclusionConclusion

�� Malnutrition in ESRD patients are largely the consquence of Malnutrition in ESRD patients are largely the consquence of heart disease ( cardiac failure ) or are caused by factors heart disease ( cardiac failure ) or are caused by factors (infection, inflammation) that at the same time trigger the (infection, inflammation) that at the same time trigger the development of atherosclerotic cardiovascular diseasedevelopment of atherosclerotic cardiovascular disease

�� Proinflammaory cytokines generated in response to cardiac Proinflammaory cytokines generated in response to cardiac failure, infection and inflammation may cause muscle failure, infection and inflammation may cause muscle wasting, hypoalbuminemia, and anorexia as well as reduced wasting, hypoalbuminemia, and anorexia as well as reduced cardiac contractility and vascular diseasecardiac contractility and vascular disease

�� A synergism between different mechanisms in developing A synergism between different mechanisms in developing atherosclerosis in uremiaatherosclerosis in uremia