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Carnitine Therapy... Let the Patients Benefit!
| The Issues in Renal Nutrition
in Nephrology Nursing department is designed to focus on nutritional
issues for nephrology patients. Address correspondence to: Susan Reams,
Department Editor, Nephrology Nursing Journal; East Holly Avenue/Box
56; Pitman NJ 08071-0056; (856) 256-2320. The opinions and assertions
contained herein are the private views of the contributors and do not
necessarily reflect the views of the American Nephrology Nurses'
Association. |
Levocarnitine is a naturally occurring substance that functions in the
transport of long-chain fatty acids across mitochondrial membranes,
resulting in the production of ATP, which the body uses as a source of
energy. Carnitine also removes the toxic byproducts of fatty acid
metabolism. Carnitine is ingested in foods of animal origin and is
synthesized in the kidney and liver (Sigma Tau Pharmaceuticals, 2003).
Carnitine deficiency can occur due to congenital defect in its
synthesis or utilization, or from dialysis. The causes of carnitine
deficiency in hemodialysis include dialytic loss, reduced renal
synthesis, and reduced dietary intake. Total carnitine levels have been
reported to decrease as much as 75% with a single hemodialysis
treatment. Patients undergoing dialysis have decreased total carnitine
in their tissues and low plasma free carnitine concentrations below the
normal of 40 mmol/L (Goral, 1998). In December 1999, the Food and Drug
Administration (FDA) approved L-carnitine injection (Carnitor) for the
prevention and treatment of carnitine deficiency in patients with ESRD
undergoing dialysis (Sigma-Tau, Inc., 2003).
The National Kidney Foundation convened a panel of experts in September
2002 to review the scientific and clinical evidence and to provide
expert opinion regarding the use of L-carnitine in dialysis patients.
The panel developed best practice recommendations for the diagnosis and
treatment of dialysis carnitine deficiency. The proceedings of the
meeting, in the form of best practice recommendations, are published in
the April 2003 edition of the American Journal of Kidney Diseases
(Eknoyan, Latos, & Lindberg, 2003).
On November 8, 2002, the Centers for Medicare and Medicaid Services
(CMS) issued a national coverage determination that provides
reimbursement for intravenous levocarnitine when used to treat
carnitine deficiency in end stage renal disease (ESRD) patients (Eknoya
et al., 2003). This determination became effective on January 1, 2003.
Intravenous levocarnitine is reimbursed for patients with ESRD who have
been on dialysis for a minimum of 3 months. Patients must have a
documented carnitine deficiency, defined as a plasma free carnitine
level < 40 mmol/L, along with signs and symptoms of either:
- erythropoietin-resistant
anemia (persistent hematocrit <30 percent with treatment) that has
not responded to standard erythropoietin dosage with iron replacement
and for which other causes have been investigated and adequately
treated, or
- hypotension
on hemodialysis that interferes with delivery of the intended dialysis
despite application of usual measures deemed appropriate. Such episodes
of hypotension must have occurred during at least two dialysis
treatments in a 30-day period.
Continued
use of levocarnitine will not be covered if improvement has not been
demonstrated within 6 months of initiation of treatment (Department of
Health and Human Services, 2002).
This article shares two cases that illustrate the effective use of
L-carnitine to treat clinical symptoms associated with dialysis
carnitine deficiency (DCD).
Case Study #1
P.J.
is an 83-year-old African American male on hemodialysis approximately 6
years due to hypertensive nephrosclerosis. His past medical history is
significant for peripheral vascular disease, cardiomyopathy, and
rheumatoid arthritis. Approximately 9 months ago, he presented to the
emergency room with abdominal pain, nausea, and vomiting. He was found
to have a perforated gallbladder and subsequently had a
cholecystectomy. He had been noted to have severe fatigue making daily
chores difficult. His son currently lives with him although he
primarily takes care of himself and does most of his own food shopping
and cooking. P.J. has remained anemic for the first 4 years of dialysis
with his hemoglobin rarely reaching 10 mg/dl, despite receiving high
doses of erythropoietin (EPO @ 275 units per kg of BW). This inadequate
response to EPO persisted despite several series of IV iron, negative
occult blood tests, and correction of any vitamin B deficiencies. His
appetite has always been poor to fair with marginal albumin levels
between 3.2 - 3.4 mg/dl. Nutritional supplements such as Boost
Plus® had been tried but occasionally caused diarrhea, nausea, and
vomiting, and therefore, did not improve nutritional status.
A carnitine deficiency was discovered (free plasma carnitine level of
26 mmol/L). His current body weight was 54.5 kg. IV L-carnitine was
initiated 11/02 at 1 g three times per week or 20 mg/kg BW (1090 mg).
After 3 months of treatment, his hemoglobin climbed to 13.2 mg/dl while
he remained on high doses of EPO (15,000 units three times per week).
His EPO dose has gradually been decreased and now, 13 months after
initiation of IV L-carnitine, his current EPO dose is 8100 units three
times weekly (149 units per kg) while maintaining a hemoglobin of 13.2
mg/dl. He remains on a maintenance IV iron dose but has not needed a
repletion course in several months.
It
must be noted that his age-related problems continue to exist, making
some medical issues difficult to correct; however, overall, his
nutritional status has improved somewhat with an albumin level of 3.5
mg/dl and an overall improvement in appetite. His albumin level had
reached 3.7 mg/dl prior to his perforated gallbladder and then dropped
following surgery. It is now on the rise. The improved response to
erythropoietin has been marked and was noted to occur following 4 or 5
months of IV L-carnitine therapy. It should also be noted that P.J.
reports an improved general sense of well-being despite the difficulty
in measuring such subjective data. He has had more energy recently to
do daily chores around the house and has not felt as fatigued.
L-carnitine therapy continues at 1 g three times weekly and P.J. has
been able to maintain a hemoglobin level > 11mg/dl for over 1 year
(see Table 1).
General
discussion. P.J.’s case is not unusual in that many patients on
hemodialysis experience extreme fatigue associated with anemia. Often,
this persistent anemia may cause other side effects, such as loss of
appetite, leading to nutritional deficiencies and malnutrition,
worsening energy levels, and leading to a poor sense of well-being. In
the best case, the use of erythropoietin efficiently corrects anemia by
increasing red blood cell production, thereby improving one’s overall
health status. In some cases, however, such as with P.J., an inadequate
response to EPO occurs making it virtually impossible to correct anemia
with standard EPO doses. Traditional measures to correct anemia such as
correcting iron and vitamin deficiencies, ruling out a GI bleed, and
examining for signs of infection and inflammation were taken but to no
avail. An improved response to erythropoietin was eluded by
conventional measures. When L- carnitine therapy was initiated, a
response to EPO therapy was seen within the first few months.
L-carnitine therapy provided increased life span of the RBC by
decreasing the fragility and increasing the deformability of the RBC
membrane (Matsumura, 1996; Nikolaos, 2000). The rise in ferritin
post-Carnitine is related to the decrease utilization of iron to
replace cells, since cells are living a more normal life span. Along
with the physical benefits, the most significant beneficial effects
continue to be the patient’s improved sense of well-being and
functional status.
Case Study #2
A.F.
is a 77-year-old female who continues to be a homemaker, providing
support for her husband, 5 children, and several grandchildren. She has
been receiving dialysis for 3 years and 7 months. When first meeting
her family, they described A.F. as an energetic, cheerful, independent
individual who cooked, cleaned, and took care of her family prior to
starting dialysis. Her primary diagnosis that contributed to her ESRD
was uncontrolled Type II diabetes and severe hypertension. A.F.’s past
medical history also includes cardiomyopathy, stroke, hyperlipidemia,
and multiple hospitalizations for congestive heart failure (CHF).
After
being on dialysis for 2 1/2 years, the staff began to notice an
increase in episodes of intradialytic hypotension. When starting
dialysis in June 2000, A.F weighed 228 lbs. Two and a half years later,
just prior to starting Carnitor therapy, her weight had decreased to
165 lbs. She often complained of muscle weakness and fatigue, a poor
appetite, a decline in ability to perform ADLs, dropping blood pressure
during treatments, and significant cramping. Her dry weight was
consistently reviewed and adjusted as needed. It was difficult to
achieve adequate fluid removal and reach her dry weight without the
patient experiencing some nausea and vomiting, a decreasing blood
pressure, and cramping. An echocardiogram from April 2002 reported a
left ventricular systolic dysfunction with diffuse left ventricular
hypokinesis. The estimated left ventricular ejection fraction (EF) was
found to be at 30%-35%. A.F.’s health and nutritional status were
beginning to decline, and she had even questioned whether it was worth
continuing dialysis.
As
the problem with the hypotensive episodes during dialysis treatments
continued, the staff used such strategies as decreasing and/or turning
off the UF, as well as using hypertonic saline solution. A.F. was also
counseled on minimizing fluid and sodium intake to maximize homeostasis
and limit large shifts in extracellular fluids and electrolytes during
treatments. Despite continuous efforts, these interventions proved to
be ineffective in improving the number of episodes of intradialytic
hypotension.
The
next step was to check a free carnitine level, as it has been shown to
be efficacious in reducing the episodes of intradialytic hypotension.
A.F.’s pre-dialysis free carnitine level results showed a level
of 28 mmol/L. This low level along with her frequent episodes of
intradialytic hypotension made her a candidate for Carnitine therapy.
She was started in November 2002 at 2 grams TIW given at the end of
each treatment. A.F. was then reassessed 6 months after initiating
therapy with Carnitine and noted progress was made in all aspects of
A.F.’s dialysis treatments and overall health status. A.F. was able to
help more around the house with meal preparation and joining in day to
day family activities. Overall, A.F. was feeling better, she became
more engaging with staff and patients, and she had a new outlook on
continuing dialysis. Not only did A.F. improve with her overall affect,
but improvement in clinical markers was also evident (see Table 2).
A.F. had improved muscle strength and her appetite greatly improved as
her weight stabilized. In addition, fluid removal was easier to achieve
without dropping her blood pressure. Her EF also improved, as an
echocardiogram from October 2003 indicated normal left ventricular
function, which is looked at as an ejection fraction > 50%.
A.F. has been maintained for the past year and 3 months without any
side effects and continues to benefit from Carnitor therapy.
References
Department of Health and Human Services (DHHS). (2002). Program memorandum. Bethesda, MD: DHHS.
Eknoyan, G., Latos, D.,
& Lindberg, J., (2003). Practice recommendations for the use of L-
carnitine in dialysis related carnitine disorder-National Kidney
Foundation carnitine consensus conference. American Journal of Kidney
Disease, 41, 868-876.
Goral, S. (1998). Levocarnitine and muscle
metabolism in patients with end-stage renal disease. The Journal of
Renal Nutrition,8(3),118-121.
Matsumura, M. (1996). Correlation between serum carnitine levels and
erythrocyte osmotic fragility in hemodialysis patients. Nephron,
72, 574-578.
Nikolaos, S. (2000). Effect of L-carnitine
supplementation on red blood cells deformability in hemodialysis
patients. Renal Failure, 22(1), 73-80.
Sigma-Tau, Inc. (2003). Carnitor
reimbursement community: A case for reimbursement. Retrieved from
www.reimbursementcommunity.com/reimbursement/case.html.
Sigma-Tau Pharmaceuticals. (2003). Dialysis-related carnitine deficiency. Retrieved from www.carnitor.com.
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