Transcript L-Carnitine : Effect on Morbidities and Risk Factors Important to

L-Carnitine : Effect on Morbidities
and Risk Factors Important to
Patients on Dialysis
Brian Schreiber,M.D.
Assistant Clinical Professor, Department of Medicine,
Division of Nephrology
Medical College of Wisconsin, Milwaukee, Wisconsin
Effect of CHF on Survival
in Dialysis
Cumulative Survival
1.0
0.8
No CHF
0.6
0.4
0.2
CHF
0
0
12
24
36
48
60
72
Time (Months)
Harnett 1995
Five Year Survival Rates
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H.D with C.H.F
Stage IIIA nsc lung Ca
COPD, FEV-1 20-30%
Stage IIA nsc lung Ca
Dukes C2 colon Ca
Mean
15%
15%
30%
39%
48%
survival metastatic breast cancer is 18 to 24 months.
H.D. with CHF mean survival is 32 months.
Outline
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Cardiac Substrate Utilization in normal and
pathological disease states
Effect of Carnitine on Cardiac Substrate
Utilization
Carnitine in Ischemia and CHF non-dialysis
Carnitine and CHF and LVH in Dialysis patients
Cardiac Substrate Preference and Effect
of Carnitine
Preferred Cardiac Substrate
Glucose
 Intrauterine
 Left Ventricular Hypertrophy
 Compensated
Cardiomyopathy
 Pre-dialysis Renal
Insufficientcy
Fatty Acids
 extrauterine normals
 Insulin resistant
cardiomyopathy
 Decompensated
cardiomyopathy
 Dialysis
Insulin Resistant
Cardiomyopathy
Insulin Resistance Independently
Predicts Cardiomyopathy
Ingelsson E 2005
Insulin resistance predicts
Cardiac events in HD Patients
Homa IR > 1.6;69% diabetic HD pts
27% non-diabetic HD pts
Takaneka 2007
Enhanced Cardiac Glucose Metabolism
As compensation for Ischemia
Mechanisms For Diabetic
Cardiomyopathy
Boudina S. 2007
Deleterious Effects of Excess Long Chain
Acyl-CoA on Cardiac Myocytes
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 Functions
MITOCHONDRIAL
CYTOSOL
MATRIX
Fatty Acids
Fatty ACYL Coa
Carnitine
CPT-1
Carnitine
Fatty ACYL Carnitine
Fatty ACYL Carnitine
CAT
Carnitine
CPT II
GLUCOSE
PDH
PYRUVATE
Fatty ACYL Coa
β-oxidation
ACETYL Coa
Citric Acid
Cycle
Carnitine
Carnitine
CAT
Acetylcarnitine
Acetylcarnitine
CAT
CO2
Mechanism By Which Carnitine Increases Glucose Oxidation in Hearts
Perfused With High Concentrations of Fatty Acids
acylcarnitine
Carnitine
Acyl
Fatty Acid
Glucose
CoA
acylcarnitine
Carnitine
CoA
acylCoA
CoA
pyruvate
Acetyl CoA
PDH
Acetyl CoA
Carnitine
TCA
Cycle
Co2
acetylcarnitine
acetylcarnitine
CoA
Carnitine
Carnitine
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.
Fatty Acid Inhibition of Pyruvate
Dehydrogenase (PDH)
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.
Sauer 2008
Ischemia Effects on Acyl-CoA
Acetyl CoA
20
15
15
nmol/g
20
Long-chain CoA
10
*
5
25
*
20
0
Cyto
Mito
nmol/g
nmol/g
Free CoA
*
10
5
*
0
Cyto
15
Mito
10
5
*
0
Cyto
Mito
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 Effect
Free CoA
Acetyl CoA
*
15
*
*
10
5
* *
0
20
15
20
*
*
*
*
10
5
Cyto
Control
Mito
15
10
*
*
*
*
5
*
0
Homo
nano mol/g
25
*
nano mol/g
nmol/g
20
Long-chain CoA
0
Homo
Cyto
Mito
30 mg/kg carnitine
Homo
Mito
100 mg/kg carnitine
*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.
Cyto
Carnitine and Cardiac Substrate Metabolism
L-Carnitine and Glucose Oxidation in IschemiaReperfusion
Aerobic
Reperfusion
following ischaemia
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-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.
*P <0.05 v L-carnitine treated hearts.
Broderick 1995
Effects of L-carnitine on Glycolysis & Glucose
Oxidation in Isolated Working Hearts Perfused
with Fatty Acids
Perfusion
Conditions
Glycolysis (nmol
3H- glucose/g dry
wt- min)
Glucose Oxidation
(nmol 14Cglucose/g dry wtmin)
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 Lupaschuk 1994
Carnitine and Cardiac Disease: Non-dialysis
Selected Studies of Carnitine Treatment
in Ischemic Heart Disease in Humans
Author
# Patients
Results
Bohles et al, 1987
40 undergoing
Pre CABG administration,
coronary artery
increased, myocardial ATP
bypass graft surgery decreased lactate
and decrease inotropic medication
requirement in post operative period
Iliceto et al, 1995
Double-blind placebo
controlled
472 with acute MI
Decreased LV dilatation and
decrease death from CHF in
carnitine group
Cacciatore et al, 1991
Randomized
200 with stable
angina
Increased exercise capacity
Rizzon et al, 1989
Double-blind placebo
controlled
56 with acute MI
Significant reduction in ventricular
arrhythmias in carnitine treated
group
Singh 1996
 Randomized,
double blind, placebo controlled
trial lasting 28 days
 101 total patients: 51 carnitine, 50 controls
 Inclusion Criteria:
Likely myocardial infarction within 24 hours
Patients unable to give consent or with symptoms
of MI longer than 24 hours were excluded
Intervention
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Treatment group: L-carnitine 660 mg PO TID
Placebo group: aluminum hydroxide 100 mg
PO TID
Nitrates and aspirin used in 94% of carnitine
and 100% of placebo patients
Similar use of beta blocker and calcium blocker
in both groups(40-50%)
Infarct Size
Cardiac enzyme activity and electrocardiographic data showing infarct size. Values
are means (standard deviations)
Carnitine
(n = 51)
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
Placebo
(n = 50)
95.5 (23.6)**
1192.5 (305)*
1.48 (0.78)*
3275 (955)**
116.2 (26.2)
1308 (328)
1.88 (0.92)
4307 (1150)
58.6 (16.6)**
1085 (254)*
1.32 (0.4)*
2790 (715)
7.4 (1.2)**
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 Enzymes
Effect of carnitine treatment on cardiac enzymes and lipid peroxides
carnitine
Enzyme
Aspartate transaminase (IU/l)
Lactate dehydrogenase (IU/l)
Lipid peroxides
(nmol/ml)
* p <0.05
carnitine
No
carnitine
No carnitine
Pre-Rx
Post-Rx
Pre-Rx
Post-Rx
170.0 (15.8)
124.3 (10.5)*
172.2 (17.6)
146.2 (14.2)*
97.5 (10.5)
205.0 (25.6)*
110.3 (12.0)
272.5 (32.6)*
2.8 (0.25)
1.8 (0.22)*
2.7 (0.23)
2.6 (0.12)*
Complications
Complications at 28 days of follow-up. Values are numbers (percentages)
Carnitine
Placebo
Complications
(n = 51)
(n = 50)
Angina pectoris
9 (17.6)*
18 (36.0)
NYHA Class III and IV
heart failure
Left ventricular enlargement
4 (7.8)
7 (14.0)
8 (15.6)
11 (22.0)
12 (23.4)*
18 (36.0)
6 (11.7)
11 (22.0)
1 (1.9)
3 (6.0)
7 (13.7)*
14 (28.0)
Hypotension (systolic <90 mmHg)
1 (1.9)
3 (6.0)
Cardiac end points:
total cardiac deaths
4 (7.8)
6 (12.0)
nonfatal reinfarction
4 (7.8)*
7 (14.0)
total cardiac events
8 (15.6)*
13 (26.0)
Total cases with poor left
ventricular function
Ventricular ectopics (>8/min)
Ventricular ectopics
(>3 consecutively)
Total arrhythmias
Relative risk
(95) CL)
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)
0.49
1.11, 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 CHF in
Humans-Nondialysis
Author
Ferrari, et al
double blind, randomized
placebo controlled
Kobayashi, et al
intent to treat analysis
Rizos, et al, 2000
double blind, randomized
placebo controlled
Patients
574
NYHA Class II-III
EF<40%
40
80
NYHA Class III-IV
Results
Carnitine group: exercise
tolerance improved, nonimprovement in mortality or
hospital admission
Improvement to lower NYHA
class, in 55% of patients
receiving carnitine
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
OD 405 nm (% of control)
250
*#
200
150
#
*
100
50
ne
F
ca
rn
i ti
CH
CH
F
+
Co
nt
ro
l
0
*P < 0.01; #P < 0.05
Vescovo 2002
Carnitine and Cardiac Disease: Dialysis
Cardiac Substrate Uptake in Predialysis
CKD,Normal Patients, and CHF
Mean Myocardial Glucose Uptake
Normal=27.6 µmol/min/100g
CKD Non-dialysis=68.9µmol/min/100g
Dilated Cardiomyopathy=12.3µmol/min/1006
Fink 2010
Increased NEFA in Hemodialysis Patients
1250
[NEFA] (µmol.L -1)
1000
750
500
250
0
healthy control
CKD, non-dialysis
PD
HD post treatment
HD prior to treatment
Gillett M Saudi Med J 2004
25(11)1611-1616
Abnormality of Skeletal Fatty Acid
Metabolism in Dialysis
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)
Myocardial Fatty Acid Metabolism in Uremic
Patients Measured With BMIPP Scintigraphy
H/M Ratio
WOR %
Chronic HD-Carn
1.91+/-.19 *
17.%+/-6.0 *
Chronic HD+carn
1.89+/-2.0 *
21.9+/-6.6 **
Non HD control
1.52+/-.24
22.8+/-4.2
* p<.05 vs.non HD **p<.001 vs.-Carn
Sakurabayashi Am J Nephrol
1999:19:480-484
L-carnitine Plasma Concentrations in ESRD patients During the First Year of
Dialysis Treatment
60
Plasma Conc (nmol/ml)
55
50
normal range
45
40
35
30
25
20
0
0.2
0.4
0.6
Time on dialysis (yr)
0.8
1
Evans AM, et al. Kidney Int.
2004;66:1527-1534.
Decreased Plasma Free Carnitine
Levels in Hemodialysis Patients
Value prior to Hemodialysis
(maximum value for HD patients)
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19.2 ± 6.5 μmol/liter (Sakurabayashi 1999)
(a/f=.87)
24.8 ± 7.9 μmol/liter (Suzuki 1982)
21.5 ± 7 μmol/liter (van Es 1992)
(a/f=.98)
28 ± 6.0 μmol/liter (Bellinghieri 1983)
24.4 ± 8.528.2 ± 6.5 μmol/liter (Sakurabayashi 1999)
19.5 ± 5.6 μmol/liter (Evans 2000)
(a/f=.77)
25.9 μmol/liter (Lennon 1986)
(a/f=.96)
32.4 μmol/liter (Rossle 1985)
30.4 μmol/liter (Savica 1983)
(Normal control value 40  50 μmol/liter)
(a/f<.4)
Reason for Dialysis Related
Carnitine deficiency
70% of plasma carnitine removed with each
dialysis
decreased dietary intake
decreased synthetic capacity
Mean Plasma Carnitine Concentrations
350
Carnitine m mol/L
300
TC treatment
TC placebo
FC treatment
FC placebo
SCAC treatment
SCAC placebo
LCAC treatment
LCAC placebo
250
200
150
100
50
0
Week 0
Week 12
Week 24
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 Acylcarnitine
0.8
0.7
0.6
mmole/L
0.5
0.4
0.3
0.2
0.1
0
0
12
C8
4methyl of C9
24
C10
Baseline to 12 weeks and baseline to 24 weeks, p<0.01
Except C14 = p<0.05, n=13
C12
C14
Mean C16-C18 acylcarnitine
0.25
mmol/L
0.2
0.15
0.1
0.05
0
0
12
C16
C16:2
24
C18
Baseline to 12 weeks and baseline to 24 weeks, p<0.01,
except C18:1 = p<0.05, n=13
C18:2
Mean C16-C18 acylcarnitine
0.25
mmol/L
0.2
0.15
0.1
0.05
0
0
12
C16
C16:2
24
C18
Baseline to 12 weeks and baseline to 24 weeks, p<0.01,
except C18:1 = p<0.05, n=13
C18:2
Acetylcarnitine (mmol/L)
Changes in Acetylcarnitine
80
70
60
50
40
30
20
10
0
Baseline
12 Weeks
24 Weeks
Baseline to 12 weeks and baseline to 24 weeks, p<0.01, n=13
Decrease in CRP in Patients with High Baseline
5
CRP (mg/dl)
4
3
2
1
0
0
1
2
3
4
5
6
Follow-up (months)
Placebo
Carnitine
Placebo
Carnitine
Savica V Journal of Renal Nutrition 2005 15(2) 225230
L-carnitine and Markers of Free Radical
Metabolism in HD
Parameter baseline 3 mos
6 mos
9 mos
SOD
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
59.5
MDA µmol/l
4.18
3.48*
3.07***
2.82
Tot 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 Disappearance 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
3.30
± .4
3.37 ± 0.4
NS
2.99 ±
0.3
3.54 ± 0.2
<0.03
Kitt (%/min)*
*Kitt: rate constant for plasma glucose
disappearance
Gunal A.Journal of Nephrology Vol
12 no.1 1999 38-40
Systolic Dysfunction
Development of CHF
1.0
0.8
Normal
0.6
Concentric
LVH
0.4
0.2
Systolic
Dysfunction
0
0
12
24
36
48
60
LV Dilation
72
Time (Months)
Harnett 1995
van Es et al. 1992
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Three months
Symptomatic (n=7) Asymptomatic (n=9)
1 g levocarnitine intravenously after each 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.
Effect of L-Carnitine Therapy on Left
Ventricular Ejection Fraction
Symptomatic patients (n=7)
FC
(µmol)
TC,
(µmol/l)
1
2
5.3
10.2
16.7
30.5
31.7
33.4
15
26
35
35
3
4
5
6
7
19.4
21.4
22.4
22.5
31.6
40.3
46.2
41.5
41.2
59.3
48.1
46.3
54.0
54.6
53.3
14
46
17
49
46
27
60
25
44
66
30.4+16.0
41.7+15.9
19.0+8.7
Carnitine EF before
(% free) L-carnitine,
(%)
39.4+13.2 45.9+9.7
EF after 3 mos.
of L-carnitine,
(%)
A.van ES et al Contrib Nephrol, 1992
Romagnoli et al. 2001
Changes in Left Ventricular Ejection Fraction
During Carnitine Therapy
45
40
35
LVEF%
30
25
20
15
10
5
0
Baseline
2 Mo.
4 Mo.
6 Mo.
8 Mo.
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
LVH as a Pivotal Intermediary in Dialysis
related Cardiomyopathy
Cardiac
Ischemia
Cardiac Dilatation
LVH
Congestive Heart
Restrictive
Cardiomyopathy
Failure
Change in LVH and Event Free Survival
Zoccali C 2004
Causes of LVH in ESRD Patients
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Anemia
Hypertension
Volume overload
Increased growth factor levels
Abnormal glucose and fatty acid
metabolism
Hyperinsulinemia Promotes Left
Ventricular Hypertrophy
Sharma N 2007
Carnitine and LVH-Sakurabayashi
2008
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10 patients given 10mg/kg L carnitine 3x/week
post dialysis for one year
10 untreated controls
Primary endpoints-Echocardiographic change in
indices of LVH
Carnitine and LVH-Dialysis
Number
M/F
Age (years)
Duration of HD (years)
Primary renal disease
Chronic glomerulonephritis
Diabetes mellitus
Antihypertensives
Calcium antagonists
ACE inhibitors
ARB
β-blockers
r-HuEPO
Carnitine
No Carnitine
10
9/1
45.7±13.7
12.2±4.5
10
9/1
46.0±7.8
12.5±4.2
9
1
6
6
5
2
2
7
8
2
8
6
5
2
1
6
Data are mean±SD.
HD, hemodialysis; Antihypertensives, number of patients taking antihypertensive
medication; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; rHuEPO, number of patients taking recombinant human erythropoietin medication.
Sakurabayashi T 2008 Circ J 72:926-931
Change in Cardiac Dimensions and Mass
with L-Carnitine in ESRD
Beginning
LVEDD (cm)
LVESD (cm)
IVS (cm)
LVPW (cm)
IVS + LVPW (cm)
LVFS (%)
LVM (g)
LVMI (g/m2)
End
Carnitine
No Carnitine
Carnitine
No Carnitine
5.03±0.65
3.35±0.43
1.04±0.17
1.15±0.22
2.19±0.35
33.2±5.3
243.0±34.7
151.8±21.2
5.29±0.84
3.39±0.72
1.40±0.17
1.05±0.15
2.09±0.31
36.2±5.0
247.8±40.2
153.3±28.2
5.00±0.37
3.31±0.39
1.00±0.11
1.02±0.12*
2.02±0.22
33.9±4.7
217.1±36.8**
134.0±16.0**
5.28±0.90
3.38±0.80
1.14±0.34
1.08±0.17
2.22±0.48
36.6±6.2
270.6±65.9
167.1±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.
Sakurabayashi T 2008 Circ J 72:926-931
Carnitine and Diastolic Dysfunction in
Pediatric Hemodialysis
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

24 Children on chronic hemodialysis treated
with L-carnitine 50mg/kg orally after each
hemodialysis for two months
24 healthy children of similar age and
socioeconomic status as controls
Age range 8-19 years
Mean number of months on hemodialysis=19
El-Metwally et al 2003
Carnitine and Diastolic Function ESRD
Reduced E/A ratio pre-carnitine
El-Metwally 2003
Improved E/A Ratio after L-Carnitine
El-Metwally 2003
Importance of Red Cell Deformability
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 in HD
Patients with Normalization of Hematocrit
Metry et al J Am Soc Nephrol
10:854-863 1999
Deformability of RBC In Hemodialysis Patients Before and After the
Dialysis Session, as Well as in Normal Controls
Before HD
n
Before HD
After HD
(after LC)
1
17.99
27.92
10.4
2
3
4
5
6
7
8
9
10
11
12
13
14
15
15.68
11.90
15.78
10.08
11.80
15.78
12.34
15.27
19.71
13.19
20.58
17.77
13.88
13.12
16.44
21.25
24.11
19.29
22.81
34.67
19.73
16.33
20.01
13.49
22.63
25.65
25.00
16.71
14.53
11.02
14.62
10.03
11.02
10.00
11.90
15.44
10.29
9.50
10.40
11.76
6.60
14.70
Mean ± 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)
(95 % Cl: 0.02;1.00)
overall effect
p=0.01 Htest 0.20
Labonia (17)
Patrikarea (18)
Megri (19)
Caruso (20)
Altmann (23)
(95 % Cl: -1.46;-0.05)
p=0.01 Htest 0.20
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.
Decrease in Hospitalization With
Levocarnitine Therapy-Kazmi et al 2005
Relative Risk of Hospitalization
1
0.9
Non cardiac
0.8
Cardiac History
0.7
0.6
0.5
0.4
0.3
0.2
2
-1
to
-9
-9
to
-6
-6
to
-3
-3
to
0
0
to
+
3
+
3
to
+
6
+
6
to
+
9
+
9
to
+
12
+
12
to
+
15
+
15
to
+
18
+
18
to
+
21
+
21
to
+
24
Months before and after initiation of carnitine therapy
Kazmi WH, et al. Am J Nephrol. 2005;25:106-115.
USRDS Data 1998-2003
Weinhandl 2007
Peritoneal Dialysis

Free carnitine level below normal but not as low as hemodialysis

Elevated acyl/free carnitine ratio indicative of fatty acid
metabolic abnormality

Serum free carnitine falls as effluent volumes and adequacy
increase

Limited clinical data for improvement in muscle biochemistry
and EPO resistance
Constantin –Teodosiu 1996



Plasma free carnitine concentration
28.5µmol/liter,significantly lower than control
Daily loss of free carnitine in CAPD significantly
greater than healthy controls
Total/free carnitine ratio greater in plasma than
controls
“These ratio differences suggests that an alteration
in acyl group metabolism is occurring in CAPD patients
Constantin-Teodosiu et al Kidney Int.1996 49 (1):158-162
Sotirakopoulos 2002





●
12 adult patients on CAPD > 6 months
2 grams L-carnitine per os x 3 months
Hct ↑ 35.4 →38.1 (p<.03)
Hb ↑ 11.0 →11.9 (p<.01)
rHuEPO dose ↓3833 →1292+/- (p<.01)
RBC IR(index de regidite)↓16.6→13.0 (p<.03)
Sotirakopoulos N et al Renal Failure 2002 24(4) 505-510
Summary





Cardiac substrate metabolism is an important predictor of
cardiac physiology
Prior to starting dialysis,CKD patients are in a state where
increased cardiac glucose metabolism is a partial compensation
for cardiac disease
Dialysis patients, almost always carnitine deficient,have excess
myocardial unmetabolized fatty acids
The excess fatty acids have major harmful effects on
myocardial cells including inhibition of glucose metabolism
Administration of L-carnitine to dialysis patients has been
associated with improved cardiac function in CHF and a
reduction of LVH