L-Carnitine : Effect on L-Carnitine : Effect on Morbidities and Risk Morbidities and Risk Factors Important to Factors Important to Patients on DialysisPatients on Dialysis

Brian Schreiber,M.D.Brian Schreiber,M.D.Assistant Clinical Professor, Department of Assistant Clinical Professor, Department of

Medicine,Medicine,Division of NephrologyDivision of Nephrology

Medical College of Wisconsin, Milwaukee, Medical College of Wisconsin, Milwaukee, WisconsinWisconsin

Effect of CHF on SurvivalEffect of CHF on Survivalin Dialysis in Dialysis

Harnett 1995Harnett 1995

Time (Months)Time (Months)

00 1212 2424 3636 4848 6060

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

00

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

No CHFNo CHF

CHFCHF

7272

Five Year Survival Five Year Survival RatesRates

H.D with C.H.FH.D with C.H.F 15% 15% Stage IIIA nsc lung CaStage IIIA nsc lung Ca 15% 15% COPD, FEV-1 20-30%COPD, FEV-1 20-30% 30% 30% Stage IIA nsc lung Ca Stage IIA nsc lung Ca 39% 39% Dukes C2 colon CaDukes C2 colon Ca 48% 48%

Mean survival metastatic breast cancer is 18 to Mean survival metastatic breast cancer is 18 to 24 months. H.D. with CHF mean survival is 32 24 months. H.D. with CHF mean survival is 32 months.months.

OutlineOutline

Cardiac Substrate Utilization in Cardiac Substrate Utilization in normal and pathological disease normal and pathological disease statesstates

Effect of Carnitine on Cardiac Effect of Carnitine on Cardiac Substrate UtilizationSubstrate Utilization

Carnitine in Ischemia and CHF non-Carnitine in Ischemia and CHF non-dialysisdialysis

Carnitine and CHF and LVH in Carnitine and CHF and LVH in Dialysis patientsDialysis patients

Cardiac Substrate Preference and Effect of Carnitine

Preferred Cardiac Preferred Cardiac SubstrateSubstrate

GlucoseGlucose IntrauterineIntrauterine Left Ventricular Left Ventricular

HypertrophyHypertrophy Compensated Compensated

CardiomyopathyCardiomyopathy Pre-dialysis Renal Pre-dialysis Renal

InsufficientcyInsufficientcy

Fatty AcidsFatty Acids extrauterine normalsextrauterine normals Insulin resistant Insulin resistant

cardiomyopathycardiomyopathy Decompensated Decompensated

cardiomyopathycardiomyopathy DialysisDialysis

Insulin Resistant Insulin Resistant CardiomyopathyCardiomyopathy

Insulin Resistance Insulin Resistance Independently Predicts Independently Predicts

CardiomyopathyCardiomyopathy

Ingelsson E 2005

Insulin resistance Insulin resistance predicts Cardiac events predicts Cardiac events

in HD Patientsin HD Patients

Takaneka 2007Homa IR > 1.6;69% diabetic HD pts

27% non-diabetic HD pts

Enhanced Cardiac Glucose Enhanced Cardiac Glucose Metabolism As compensation Metabolism As compensation

for Ischemiafor Ischemia

Mechanisms For Diabetic Mechanisms For Diabetic CardiomyopathyCardiomyopathy

Boudina S. 2007

Deleterious Effects of Excess Long Deleterious Effects of Excess Long Chain Acyl-CoA on Cardiac Chain Acyl-CoA on Cardiac

MyocytesMyocytes

1)Mitochondrial Permeability Defects

2)Increase Protein Kinase C Beta activity

3)Decreased calcium re-uptake into sarcolemma

4)Decreased glut 4 receptor activity-insulin resistance

Carnitine: Metabolic FunctionsCarnitine: Metabolic Functions CYTOSOL

MITOCHONDRIAL MATRIX

Fatty Acids

Fatty ACYL Coa

Carnitine CPT-1

Fatty ACYL Carnitine

Fatty ACYL Carnitine

Carnitine

CarnitineFatty ACYL

Coa

ACETYL Coa

CAT

CAT

CPT II

PYRUVATEGLUCOSE

CAT

Carnitine

PDH

Acetylcarnitine Acetylcarnitine

β-oxidation

CO2

Carnitine

Citric Acid Cycle

Mechanism By Which Carnitine Increases Glucose Mechanism By Which Carnitine Increases Glucose Oxidation in Hearts Perfused With High Oxidation in Hearts Perfused With High

Concentrations of Fatty AcidsConcentrations of Fatty Acids

acylCoA

acylcarnitine

CoA

TCACycle

CarnitineCarnitine

acylcarnitine

Acetyl CoA

Carnitine

acetylcarnitineacetylcarnitine

Carnitine Carnitine

PDH

pyruvateGlucose

CoAFatty Acid

AcylCoA

CoA

Acetyl CoA

Co2

In the presence of high levels of carnitine, the increase in the intramitochondrial acetyl CoA levels that is seen in the presence of high concentrations of fatty acids is prevented as a result of the transfer of the acetyl groups from acetyl CoA to acetylcarnitine. The decrease in acetyl CoA levels results in activation of PDH. This increases CO2 production from glucose. PDH, pyruvate dehydrogenase: TCA, tricarboxylic acid cycle, CoA coenzyme A.

Sauer 2008

Impact of short- and medium-chain acyl-CoAs (each 250,500, and 1000umol/L, in Tris -HCI, adjusted to pH 7.4) on PDHc activity. All investigated acyl-CoAs inhibited PDHc activity. The inhibitory effect was critically dependent on chain length and number of carboxylic groups. Short-chain monocarboxylic acyl-CoAs revealed the strongest inhibitory effect on PDHc activity. Medium chain and dicaraboxylic acyl-CoAs were less effective inhibitors. Activities are given as percent of control. All data expressed as means ±S.D., experiments were performed intriplicates.

Fatty Acid Inhibition of Pyruvate Dehydrogenase (PDH)

Ischemia Effects on Acyl-Ischemia Effects on Acyl-CoACoA

Long-chain CoA

0

5

10

15

20

25

Cyto Mito

nm

ol/

g

Cellular distribution of CoA in the heart. All values are expressed as nmol of wet tissue, and represented as mean ± SEM (n=8). *P<0.01 vs no ischemia. Cyto, cytosolic compartment; Mito, mitochondrial compartment.

Kobayashi A, Fujisawa S. J Mol Cell Cardiol. 1994;26:499-508.

*

*

* *

*

Carnitine EffectCarnitine Effect

*P<0.01 vs nontreated group (control).Effect of L-carnitine on the cellular distribution of CoA esters in the ischemic heart.All values represent mean ± SEM (n=8).Homo, homogenate (cytosol + mitochondria); Cyto, cytosolic compartment; Mito, mitochondrial compartment.

Kobayashi A, Fujisawa S. J Mol Cell Cardiol. 1994;26:499-508.

Control 30 mg/kg carnitine

100 mg/kg carnitine

*

*

* *

*

* *

*

*

*

**

**

*

Carnitine and Cardiac Substrate Metabolism

Figure 2 Effect of L-carnitine on glucose oxidation rates in control and diabetic rat heart Figure 2 Effect of L-carnitine on glucose oxidation rates in control and diabetic rat heart hearts before and after ischaemia. Values are the means of 7 untreated control, 8 L-hearts before and after ischaemia. Values are the means of 7 untreated control, 8 L-carnitine treated control, 8 untreated diabetic and 8 L-carnitine treated diabetic rat hearts. carnitine treated control, 8 untreated diabetic and 8 L-carnitine treated diabetic rat hearts. Error bars = SEM. Glucose oxidation rates were determined as described in Methods.Error bars = SEM. Glucose oxidation rates were determined as described in Methods. *P <0.05 v L-carnitine treated hearts. *P <0.05 v L-carnitine treated hearts. Broderick 1995

Aerobic Reperfusion following ischaemia

L-Carnitine and Glucose Oxidation in Ischemia-Reperfusion

Lupaschuk 1994

Effects of L-carnitine on Glycolysis & Effects of L-carnitine on Glycolysis & Glucose Oxidation in Isolated Glucose Oxidation in Isolated

Working Hearts Perfused with Fatty Working Hearts Perfused with Fatty AcidsAcids

Perfusion

Conditions

Glycolysis (nmol 3H- glucose/g dry

wt- min)

Glucose Oxidation (nmol 14C-

glucose/g dry wt- min)

No addition (n=9) 291 0.23 158.4 21.4

Carnitine loaded 4.63 0.46* 454.1 85.3*

* Significantly different from those in hearts perfused in the absence of fat

Data are the mean S.E.M. of a number of hearts indicated in brackets. Carnitine-loaded hearts were pre-perfused in the working mode for 1 hour with 10 mM carnitine. Glycolysis and glucose oxidation was measured by perfusing hearts with 11 mM (2-3H/U-14C) glucose and 1.2 mM palmitate. Glycolytic rates were determined by measuring ¼ CO2 production.

Lopashuk 1992

Carnitine and Cardiac Disease: Non-dialysis

Selected Studies of Carnitine Selected Studies of Carnitine Treatment in Ischemic Heart Treatment in Ischemic Heart

Disease in HumansDisease in Humans

Author # Patients Results

Bohles et al, 1987 40 undergoing coronary artery bypass graft surgery

Pre CABG administration, increased, myocardial ATP decreased lactateand decrease inotropic medication requirement in post operative period

Iliceto et al, 1995Double-blind placebo controlled

472 with acute MI Decreased LV dilatation and decrease death from CHF in carnitine group

Cacciatore et al, 1991Randomized

200 with stable angina

Increased exercise capacity

Rizzon et al, 1989Double-blind placebo controlled

56 with acute MI Significant reduction in ventricular arrhythmias in carnitine treated group

Singh 1996Singh 1996

Randomized, double blind, placebo Randomized, double blind, placebo controlled trial lasting 28 dayscontrolled trial lasting 28 days

101 total patients: 51 carnitine, 50 101 total patients: 51 carnitine, 50 controlscontrols

Inclusion Criteria:Inclusion Criteria:Likely myocardial infarction within 24 hoursLikely myocardial infarction within 24 hours

Patients unable to give consent or with Patients unable to give consent or with symptoms of MI longer than 24 hours were symptoms of MI longer than 24 hours were

excludedexcluded

InterventionIntervention

Treatment group: L-carnitine 660 mg Treatment group: L-carnitine 660 mg PO TIDPO TID

Placebo group: aluminum hydroxide Placebo group: aluminum hydroxide 100 mg PO TID100 mg PO TID

Nitrates and aspirin used in 94% of Nitrates and aspirin used in 94% of carnitine and 100% of placebo patientscarnitine and 100% of placebo patients

Similar use of beta blocker and calcium Similar use of beta blocker and calcium blocker in both groups(40-50%)blocker in both groups(40-50%)

Infarct SizeCardiac enzyme activity and electrocardiographic data showing infarct size. Values are means (standard deviations)

Carnitine

(n = 51)

Placebo

(n = 50)

Creatine kinase

Size of necrosis (gram equivalents)

Maximum latent period before enzyme peak (min)

Enzyme peak (IU/l)

Area under the curve

MB creatine kinase

Size of necrosis (gram equivalents)

Maximum latent period before enzyme peak (min)

Enzyme peak (IU/l)

Area under the curve

QRS - score

95.5 (23.6)**

1192.5 (305)*

1.48 (0.78)*

3275 (955)**

58.6 (16.6)**

1085 (254)*

1.32 (0.4)*

2790 (715)

7.4 (1.2)**

116.2 (26.2)

1308 (328)

1.88 (0.92)

4307 (1150)

73.3 (21.5)

1180 (265)

1.55 (0.6)

3110 (680)

10.7 (2.0)

* p = <0.05, **p = <0.01. p-value obtained by two-sample t-test comparing carnitine and placebo groups.

Cardiac EnzymesEffect of carnitine treatment on cardiac enzymes and lipid peroxides

carnitine carnitine No carnitine

No carnitine

Enzyme Pre-Rx Post-Rx Pre-Rx Post-Rx

Aspartate trans-

aminase (IU/l)

Lactate dehydro-

genase (IU/l)

Lipid peroxides

(nmol/ml)

170.0 (15.8)

97.5 (10.5)

2.8 (0.25)

124.3 (10.5)*

205.0 (25.6)*

1.8 (0.22)*

172.2 (17.6)

110.3 (12.0)

2.7 (0.23)

146.2 (14.2)*

272.5 (32.6)*

2.6 (0.12)*

* p <0.05

ComplicationsComplications at 28 days of follow-up. Values are numbers (percentages)

Complications

Carnitine(n = 51)

Placebo(n = 50)

Relative risk(95) CL)

Angina pectoris

NYHA Class III and IVheart failure

Left ventricular enlargement

Total cases with poor leftventricular function

Ventricular ectopics (>8/min)

Ventricular ectopics(>3 consecutively)

Total arrhythmias

Hypotension (systolic <90 mmHg)

Cardiac end points:total cardiac deaths

nonfatal reinfarction

total cardiac events

9 (17.6)*

4 (7.8)

8 (15.6)

12 (23.4)*

6 (11.7)

1 (1.9)

7 (13.7)*

1 (1.9)

4 (7.8)

4 (7.8)*

8 (15.6)*

18 (36.0)

7 (14.0)

11 (22.0)

18 (36.0)

11 (22.0)

3 (6.0)

14 (28.0)

3 (6.0)

6 (12.0)

7 (14.0)

13 (26.0)

0.49(0.98, 0.24)0.56(1.86, 0.17)0.71(1.61, 0.31)0.65(1.24, 0.35)0.54(1.32, 0.24)0.31(2.79, 0.03)0.491.11, 0.21)0.31(2.79, 0.03)

0.65(1.88, 0.22)0.56(1.86, 0.17)0.60(1.62, 0.27)

* p = <0.05; p-value significant by Z score test for proportions by comparison of carnitine group with placebo. CL = confidence limits; NYHA = New York Heart Association.

Levocarnitine Treatment in Levocarnitine Treatment in CHF in Humans-NondialysisCHF in Humans-Nondialysis

Author Patients Results

Ferrari, et al double blind, randomized placebo controlled

574NYHA Class II-III

EF<40%

Carnitine group: exercise tolerance improved, non-improvement in mortality or hospital admission

Kobayashi, et al intent to treat analysis

40Improvement to lower NYHA class, in 55% of patients receiving carnitine

Rizos, et al, 2000double blind, randomized placebo controlled

80NYHA Class III-IV

Carnitine group had lower mortality rate (P<0.04). Statistically significant improvement in VO2 Max, Weber Class, cardiac output and lower rate of arrhythmias

Carnitine & Muscle Apoptosis in CHF

0

50

100

150

200

250O

D 4

05 n

m (

% o

f co

ntr

ol)

*

*#

#

*P < 0.01; #P < 0.05 Vescovo 2002

Carnitine and Cardiac Disease: Dialysis

Cardiac Substrate Uptake in Cardiac Substrate Uptake in Predialysis CKD,Normal Predialysis CKD,Normal

Patients, and CHFPatients, and CHF

Mean Myocardial Glucose UptakeNormal=27.6 µmol/min/100gCKD Non-dialysis=68.9µmol/min/100gDilated Cardiomyopathy=12.3µmol/min/1006

Fink 2010

Increased NEFA in Hemodialysis Increased NEFA in Hemodialysis

PatientsPatients

0

250

500

750

1000

1250

[NE

FA

] (µ

mo

l.L -

1)

healthy control CKD, non-dialysis

PD HD prior to treatment

HD post treatment

Gillett M Saudi Med J 2004 25(11)1611-1616

Fatty acid oxidation control = 1487 ± 267 dpm/mg

Fatty acid oxidation hemodialysis patients = 638 ± 285 dpm/mg (p < 0.003 control vs HD)

(Savica 1983)

Abnormality of Skeletal Abnormality of Skeletal Fatty Acid Metabolism in Fatty Acid Metabolism in

DialysisDialysis

Myocardial Fatty Acid Metabolism in Myocardial Fatty Acid Metabolism in Uremic Patients Measured With BMIPP Uremic Patients Measured With BMIPP

ScintigraphyScintigraphy H/M Ratio WOR %H/M Ratio WOR %

Chronic HD-Carn 1.91+/-.19 * 17.%+/-Chronic HD-Carn 1.91+/-.19 * 17.%+/-6.0 *6.0 *

Chronic HD+carn 1.89+/-2.0 * 21.9+/-6.6 Chronic HD+carn 1.89+/-2.0 * 21.9+/-6.6 ** **

Non HD control 1.52+/-.24 22.8+/-4.2Non HD control 1.52+/-.24 22.8+/-4.2

* p<.05 vs.non HD **p<.001 vs.-Carn* p<.05 vs.non HD **p<.001 vs.-Carn

Sakurabayashi Am J Nephrol 1999:19:480-484

20

25

30

35

40

45

50

55

60

0 0.2 0.4 0.6 0.8 1

Time on dialysis (yr)

Pla

sma C

on

c (

nm

ol/

ml)

normal range

L-carnitine Plasma Concentrations in ESRD patients During the First Year of Dialysis Treatment

Evans AM, et al. Kidney Int. 2004;66:1527-1534.

Decreased Plasma Free Decreased Plasma Free CarnitineCarnitine

Levels in Hemodialysis Levels in Hemodialysis PatientsPatients Value prior to Hemodialysis Value prior to Hemodialysis

(maximum value for HD patients)(maximum value for HD patients)

19.2 ± 6.5 μmol/liter 19.2 ± 6.5 μmol/liter (Sakurabayashi 1999)(Sakurabayashi 1999) (a/f=.87)(a/f=.87) 24.8 ± 7.9 μmol/liter 24.8 ± 7.9 μmol/liter (Suzuki 1982)(Suzuki 1982) 21.5 ± 7 μmol/liter 21.5 ± 7 μmol/liter (van Es 1992)(van Es 1992) (a/f=.98)(a/f=.98) 28 ± 6.0 μmol/liter 28 ± 6.0 μmol/liter (Bellinghieri 1983)(Bellinghieri 1983) 24.4 ± 8.524.4 ± 8.528.2 ± 6.5 μmol/liter 28.2 ± 6.5 μmol/liter (Sakurabayashi 1999)(Sakurabayashi 1999) 19.5 ± 5.6 μmol/liter 19.5 ± 5.6 μmol/liter (Evans 2000)(Evans 2000) (a/f=.77) (a/f=.77) 25.9 μmol/liter 25.9 μmol/liter (Lennon 1986)(Lennon 1986) (a/f=.96)(a/f=.96) 32.4 μmol/liter 32.4 μmol/liter (Rossle 1985)(Rossle 1985) 30.4 μmol/liter 30.4 μmol/liter (Savica 1983)(Savica 1983) (Normal control value 40 (Normal control value 40 50 μmol/liter) 50 μmol/liter) (a/f<.4)(a/f<.4)

Reason for Dialysis Related Reason for Dialysis Related Carnitine deficiencyCarnitine deficiency

70% of plasma carnitine removed with each dialysis

decreased dietary intake

decreased synthetic capacity

Mean Plasma Carnitine Mean Plasma Carnitine ConcentrationsConcentrations

0

50

100

150

200

250

300

350

Car

nit

ine

mm

ol/L

Week 0 Week 12 Week 24

TC treatment

TC placebo

FC treatment

FC placebo

SCAC treatment

SCAC placebo

LCAC treatment

LCAC placebo

TC – total carnitine, FC – free carnitine, SCAC – short chain acylcarnitine, LCAC- long chain acylcarnitine; Radioenzymatic assay technique, between treatment and placebo groups - p<0.01

Mean C8-C14 AcylcarnitineMean C8-C14 Acylcarnitine

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 12 24

mm

ole

/L

C8 4methyl of C9 C10 C12 C14

Baseline to 12 weeks and baseline to 24 weeks, p<0.01Except C14 = p<0.05, n=13

Mean C16-C18 Mean C16-C18 acylcarnitineacylcarnitine

0

0.05

0.1

0.15

0.2

0.25

0 12 24

mmo

l/L

C16 C16:2 C18 C18:2

Baseline to 12 weeks and baseline to 24 weeks, p<0.01, except C18:1 = p<0.05, n=13

Mean C16-C18 Mean C16-C18 acylcarnitineacylcarnitine

0

0.05

0.1

0.15

0.2

0.25

0 12 24

mmo

l/L

C16 C16:2 C18 C18:2

Baseline to 12 weeks and baseline to 24 weeks, p<0.01, except C18:1 = p<0.05, n=13

Changes in AcetylcarnitineChanges in Acetylcarnitine

0

10

20

30

40

50

60

70

80

Baseline 12 Weeks 24 Weeks

Acety

lcarn

itin

e (

mm

ol/L)

Baseline to 12 weeks and baseline to 24 weeks, p<0.01, n=13

Decrease in CRP in Patients with High Baseline

0

1

2

3

4

5

0 1 2 3 4 5 6

Follow-up (months)

CR

P (

mg

/dl)

Placebo Carnitine Placebo Carnitine

Savica V Journal of Renal Nutrition 2005 15(2) 225-230

L-carnitine and Markers of Free L-carnitine and Markers of Free Radical Metabolism in HDRadical Metabolism in HD

Parameter baseline 3 mos 6 mos 9 mosSOD u/g/hgb

1.044 1.034 1.043 983

GSH perox 38.4 40.8 45.8* 38.4‡GSHmmol/l 1.65 1.90* 2.23** 1.67‡Antiox cap 1.65 1.67 2.06* 1.52‡Sel mcg/l 54 38.2* 49.5 59.5MDA µmol/l 4.18 3.48* 3.07*** 2.82Tot Prot g/l 65.6 73.5* 71.8** 66.7†

Alb g/l 34.8 40.8 46.0* 43.2

Vesela 2001

Carnitine and Plasma Glucose Carnitine and Plasma Glucose Disappearance in HD Patients in HD Patients

Placebo (n=6)

L-Carnitine (n=7)

Before After P Before After P

Fasting glucose

(mmol/L)5.1 ± 0.2 4.94 ± 0.4 NS 5.19 ± 0.2 4.84 ± 0.1 NS

C-peptide (µg/L) 4.90 ± 0.9 5.01 ± 0.1 NS 5.98 ± 0.9 7.35 ± 2.3 NS

Insulin (µmol/L) 36.9 ± 7.6 38.1 ± 8.2 NS 40.60 ± 5.4 32.80 ± 4.0 NS

Kitt (%/min)* 3.30 ± .4 3.37 ± 0.4 NS 2.99 ± 0.3 3.54 ± 0.2 <0.03

Gunal A.Journal of Nephrology Vol 12 no.1 1999 38-40

*Kitt: rate constant for plasma glucose disappearance

Systolic Dysfunction Systolic Dysfunction Development of CHF Development of CHF

Harnett 1995Time (Months)

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

00 2424 36361212 4848 6060 7272

NormalNormal

Systolic Systolic DysfunctionDysfunction

ConcentricConcentric LVHLVH

LV DilationLV Dilation

van Es et al. 1992van Es et al. 1992

Three monthsThree months Symptomatic (n=7) Asymptomatic Symptomatic (n=7) Asymptomatic

(n=9)(n=9) 1 g levocarnitine intravenously after 1 g levocarnitine intravenously after

each dialysis sessioneach dialysis session

van Es A, et al. In Guarnieri G, Panzetta G, Toigo G (eds.): Metabolic and Nutritional Abnormalities in Kidney Disease. Contrib Nephrol. Basal, Karger 1992; 98:28-35.

FCFC(µmol(µmol

TC,TC, (µmol/l(µmol/l

CarnitineCarnitine(% free)(% free)

EF beforeEF beforeL-carnitineL-carnitine

EF after 3 mos.EF after 3 mos.of L-carnitine, of L-carnitine,

(%)(%)

SymptomaticSymptomaticpatientspatients(n=7(n=7

Effect of L-Carnitine Therapy on Effect of L-Carnitine Therapy on Left Ventricular Ejection FractionLeft Ventricular Ejection Fraction

A.van ES et al Contrib Nephrol, A.van ES et al Contrib Nephrol, 19921992

Romagnoli GF, Noso A, Carraro G, et al. Beneficial Effects of L-Carnitine in Dialysis Patients with Impaired Left Ventricular Function: an Observational Study. Curr Med Res Opin 18(3):1-4, 2002

Romagnoli et al. 2001

Changes in Left Ventricular Ejection Fraction During Carnitine Therapy

0

5

10

15

20

25

30

35

40

45

LV

EF

%

Baseline 2 Mo. 4 Mo. 6 Mo. 8 Mo.

LVH as a Pivotal Intermediary in LVH as a Pivotal Intermediary in Dialysis related CardiomyopathyDialysis related Cardiomyopathy

LVH

Cardiac Ischemia

Restrictive

Cardiomyopathy

Cardiac Dilatation

Congestive Heart Failure

Change in LVH and Event Free Change in LVH and Event Free SurvivalSurvival

Zoccali C 2004

Causes of LVH in ESRD Causes of LVH in ESRD PatientsPatients

AnemiaAnemia HypertensionHypertension Volume overloadVolume overload Increased growth factor levelsIncreased growth factor levels Abnormal glucose and fatty Abnormal glucose and fatty

acid metabolismacid metabolism

Hyperinsulinemia Promotes Left Ventricular Hypertrophy

Sharma N 2007

Carnitine and LVH-Carnitine and LVH-Sakurabayashi 2008Sakurabayashi 2008

10 patients given 10mg/kg L 10 patients given 10mg/kg L carnitine 3x/week post dialysis for carnitine 3x/week post dialysis for one yearone year

10 untreated controls10 untreated controls Primary endpoints-Primary endpoints-

Echocardiographic change in indices Echocardiographic change in indices of LVHof LVH

Carnitine No Carnitine

NumberM/FAge (years)Duration of HD (years)Primary renal disease

Chronic glomerulonephritisDiabetes mellitus

AntihypertensivesCalcium antagonistsACE inhibitorsARBβ-blockers

r-HuEPO

109/1

45.7±13.712.2±4.5

91665227

109/1

46.0±7.812.5±4.2

82865216

Data are mean±SD.HD, hemodialysis; Antihypertensives, number of patients taking antihypertensive medication; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; r-HuEPO, number of patients taking recombinant human erythropoietin medication.

Carnitine and LVH-DialysisCarnitine and LVH-Dialysis

Sakurabayashi T 2008 Circ J 72:926-931

Beginning End

Carnitine No Carnitine Carnitine No Carnitine

LVEDD (cm)LVESD (cm)IVS (cm)LVPW (cm)IVS + LVPW (cm)LVFS (%)LVM (g)LVMI (g/m2)

5.03±0.653.35±0.431.04±0.171.15±0.222.19±0.3533.2±5.3

243.0±34.7151.8±21.2

5.29±0.843.39±0.721.40±0.171.05±0.152.09±0.3136.2±5.0

247.8±40.2153.3±28.2

5.00±0.373.31±0.391.00±0.111.02±0.12*2.02±0.2233.9±4.7

217.1±36.8**134.0±16.0**

5.28±0.903.38±0.801.14±0.341.08±0.172.22±0.4836.6±6.2

270.6±65.9167.1±43.1

*p<0.05, **p<0.01 within the group. Data are mean±SD.LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; IVS, interventricular septal end-diastolic thickness; LVPW, left ventricular posterior wall end-diastolic thickness; LVFS, left ventricular fractional shortening; LVM, left ventricular mass; LVMI, left ventricular mass index.

Change in Cardiac Dimensions Change in Cardiac Dimensions and Mass with L-Carnitine in and Mass with L-Carnitine in

ESRDESRD

Sakurabayashi T 2008 Circ J 72:926-931

Carnitine and Diastolic Dysfunction in Pediatric

Hemodialysis

24 Children on chronic hemodialysis 24 Children on chronic hemodialysis treated with L-carnitine 50mg/kg treated with L-carnitine 50mg/kg orally after each hemodialysis for two orally after each hemodialysis for two monthsmonths

24 healthy children of similar age and 24 healthy children of similar age and socioeconomic status as controlssocioeconomic status as controls

Age range 8-19 yearsAge range 8-19 years Mean number of months on Mean number of months on

hemodialysis=19hemodialysis=19El-Metwally et al 2003

Carnitine and Diastolic Function ESRDCarnitine and Diastolic Function ESRD

El-Metwally 2003

Reduced E/A ratio pre-carnitine

Improved E/A Ratio after L-CarnitineImproved E/A Ratio after L-Carnitine

El-Metwally 2003

Importance of Red Cell Importance of Red Cell DeformabilityDeformability

in Microcirculation in Microcirculation

Baskurt O Meiselman H (2003). Blood rheology and hemomdynamics. Seminars in Thrombosis and Hemostasis 29 (5) 435-450.

Decrease in Cerebral Blood Flow Decrease in Cerebral Blood Flow in HD Patients with Normalization in HD Patients with Normalization

of Hematocritof Hematocrit

Metry et al J Am Soc Nephrol 10:854-863 1999

Deformability of RBC In Hemodialysis Patients Before Deformability of RBC In Hemodialysis Patients Before and After the Dialysis Session, as Well as in Normal and After the Dialysis Session, as Well as in Normal

ControlsControls Before HDBefore HD

nn Before HD Before HD After HD After HD (after LC)(after LC)

1 17.99 27.92 10.4

2 15.68 16.44 14.53

3 11.90 21.25 11.02

4 15.78 24.11 14.62

5 10.08 19.29 10.03

6 11.80 22.81 11.02

7 15.78 34.67 10.00

8 12.34 19.73 11.90

9 15.27 16.33 15.44

10 19.71 20.01 10.29

11 13.19 13.49 9.50

12 20.58 22.63 10.40

13 17.77 25.65 11.76

14 13.88 25.00 6.60

15 13.12 16.71 14.70Mean ± SD 15.0 ± 3.1 21.7 ± 5.4

11.5 ± 2.4(before HO vs normal controls p < 0.00001),

(before HD vs after HD p < 0.00001),

(before HD vs before HD after 3 months LC supplementation, p < 0.004),

(before HD after 3 months LC supplementation vs normal control, p < 0.02).

Sotirakopoulos, Nikolaos

Renal Failure, 22(1), 73-80(2000)

Trovato (2)

Bellinguieri (11)

Fagher (7-9)

overall effect

Labonia (17)

Patrikarea (18)

Megri (19)

Caruso (20)

Altmann (23)

Kletzmayr (22)

overall effect

-3.5 -2.5 -1.5 -0.5 0.5 1.5

The effect of L-carnitine on anemia control (top; fixed model analysis) and erythropoietin dose reduction (bottom; random model analysis). Open boxes indicate the effect of each individual trial, and the closed boxes the overall effect of treatment. The P value is given for overall treatment effect and is significant for values ≤ 0.01. Heterogeneity of treatment effect among trials is present if H test value is < 0.10.

(95 % Cl: 0.02;1.00)

p=0.01 Htest 0.20

(95 % Cl: -1.46;-0.05)

p=0.01 Htest 0.20

Decrease in Hospitalization With Levocarnitine Therapy-

Kazmi et al 2005

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Months before and after initiation of carnitine therapy

Rel

ativ

e R

isk

of

Ho

spit

aliz

atio

n Non cardiac

Cardiac History

Kazmi WH, et al. Am J Nephrol. 2005;25:106-115.

USRDS Data 1998-2003USRDS Data 1998-2003

Weinhandl 2007

Peritoneal DialysisPeritoneal Dialysis Free carnitine level below normal but not as low Free carnitine level below normal but not as low

as hemodialysisas hemodialysis

Elevated acyl/free carnitine ratio indicative of Elevated acyl/free carnitine ratio indicative of fatty acid metabolic abnormalityfatty acid metabolic abnormality

Serum free carnitine falls as effluent volumes Serum free carnitine falls as effluent volumes and adequacy increaseand adequacy increase

Limited clinical data for improvement in muscle Limited clinical data for improvement in muscle biochemistry and EPO resistancebiochemistry and EPO resistance

Constantin –Teodosiu Constantin –Teodosiu 19961996

Plasma free carnitine concentration Plasma free carnitine concentration 28.5µmol/liter,significantly lower than 28.5µmol/liter,significantly lower than controlcontrol

Daily loss of free carnitine in CAPD Daily loss of free carnitine in CAPD significantly greater than healthy controlssignificantly greater than healthy controls

Total/free carnitine ratio greater in plasma Total/free carnitine ratio greater in plasma than controlsthan controls

““These ratio differences suggests that These ratio differences suggests that an alteration in acyl group metabolism is an alteration in acyl group metabolism is occurring in CAPD patientsoccurring in CAPD patients

Constantin-Teodosiu et al Kidney Int.1996 49 (1):158-Constantin-Teodosiu et al Kidney Int.1996 49 (1):158-162162

Sotirakopoulos 2002Sotirakopoulos 2002

12 adult patients on CAPD > 6 months12 adult patients on CAPD > 6 months 2 grams L-carnitine per os x 3 months2 grams L-carnitine per os x 3 months Hct ↑ 35.4 →38.1 (p<.03)Hct ↑ 35.4 →38.1 (p<.03) Hb ↑ 11.0 →11.9 (p<.01)Hb ↑ 11.0 →11.9 (p<.01) rHuEPO dose ↓3833 →1292+/- (p<.01)rHuEPO dose ↓3833 →1292+/- (p<.01)

● ● RBC IR(index de regidite)↓16.6→13.0 RBC IR(index de regidite)↓16.6→13.0 (p<.03)(p<.03)

Sotirakopoulos N et al Renal Failure 2002 24(4) 505-Sotirakopoulos N et al Renal Failure 2002 24(4) 505-

510510

SummarySummary Cardiac substrate metabolism is an important Cardiac substrate metabolism is an important

predictor of cardiac physiologypredictor of cardiac physiology Prior to starting dialysis,CKD patients are in a Prior to starting dialysis,CKD patients are in a

state where increased cardiac glucose metabolism state where increased cardiac glucose metabolism is a partial compensation for cardiac diseaseis a partial compensation for cardiac disease

Dialysis patients, almost always carnitine Dialysis patients, almost always carnitine deficient,have excess myocardial unmetabolized deficient,have excess myocardial unmetabolized fatty acidsfatty acids

The excess fatty acids have major harmful effects The excess fatty acids have major harmful effects on myocardial cells including inhibition of glucose on myocardial cells including inhibition of glucose metabolismmetabolism

Administration of L-carnitine to dialysis patients Administration of L-carnitine to dialysis patients has been associated with improved cardiac has been associated with improved cardiac function in CHF and a reduction of LVHfunction in CHF and a reduction of LVH