AJKD 2003 Supplement Issue - Natalia

Question 1

What are the two key functions of carnitine?

Answer 1

1. Transport long-chain fatty acids across the inner mitochondrial membrane, where beta-oxidation occurs. 2. Removal of potentially toxic by-products of fatty acid metabolism from mitochondria. (Source: AKJD/Eknoyan/2003)

Question 2

Where is the majority of carnitine found in the body and why is that important?

Answer 2

More than 90% of endogenous carnitine is found in the heart and skeletal muscle. Adequate carnitine levels are critical to normal function in tissues since beta-oxidation is the primary energy source for these tissues and carnitine is required to properly transport fatty acids into the mitochondria for beta-oxidation. (Source: AKJD/Eknoyan/2003)

Question 3

What is the effect of dialysis on carnitine removal?

Answer 3

Carnitine is a water-soluble low-molecular-weight molecule that is removed by plasma dialysis. Approximately 75% of free carnitine is removed from plasma during each dialysis session. An inverse relationship between muscle carnitine level and time on dialysis therapy has been shown (b/c overtime as more carnitine is removed by dialysis from plasma, it is leaked out of muscles to replenish levels and then removed by the next dialysis session. This vicious cycle eventually results in significant carnitine depletion in muscle and cardiac tissue to the point that there are no longer any stores to compensate for low levels in plasma). (Source: AKJD/Eknoyan/2003)

Question 4

What are the difficulties in conducting systematic evaluation of carnitine therapy on dialysis patients?

Answer 4

1. Lack of methodical rigor of well-controlled clinical trials. 2. Lack of well-defined, objective, and uniform parameters to determine efficacy. (Source: AKJD/Eknoyan/2003)

Question 5

What conclusions came out of Kidney Disease Outcomes Quality Initiative (K/DOQI) Nutritional Guidelines?

Answer 5

1. There is insufficient evidence to recommend routine administration of l-carnitine to all dialysis patients. 2. There is adequate evidence to recommend a therapeutic trial of l-carnitine in a subset of dialysis patients experiencing symptoms consistent with dialysis-related carnitine deficiency who are unresponsive to the usual measures. (Source: AKJD/Eknoyan/2003)

Question 6

In what form is carnitine present in mammals?

Answer 6

Free and acylated carnitine. (Source: AJKD/Hoppel/2003)

Question 7

How is acylated carnitine generated?

Answer 7

Product of reactions that involve transfer of acyl groups from acyl coenzyme A (CoA). (Source: AJKD/Hoppel/2003)

Question 8

What percentage of carnitine in plasma is free carnitine (in healthy individuals)?

Answer 8

80-85%. (Source: AJKD/Hoppel/2003)

Question 9

What is the result of physiological abnormalities caused by inadequate carnitine?

Answer 9

Decreased absolute content of free carnitine (deficiency) or higher ratio of acylated to free carnitine (insufficiency). (Source: AJKD/Hoppel/2003)

Question 10

What is the usual free carnitine plasma concentration?

Answer 10

40-50 micromol/L in healthy adult men. (Source: AJKD/Hoppel/2003)

Question 11

What are good dietary sources of carnitine?

Answer 11

Animal products, particularly red meat and daily. (Source: AJKD/Hoppel/2003) Carnitine is not considered an essential nutrient b/c can be made in vivo from lysine and methionine. (Source: AJKD/Hoppel/2003)

Question 12

How is carnitine handled in the kidneys?

Answer 12

Kidneys are the primary site of regulation of plasma carnitine concentrations. More than 95% of carnitine is reabsorbed in the kidneys. A high kidney carnitine content enhances the excretion of acylcarnitines in urine. (Source: AJKD/Hoppel/2003)

Question 13

How are fatty acids used?

Answer 13

Fatty acids are the primary source of energy in several systems including skeletal muscle and heart. Dietary fat is ingested and transformed into triglycerides for storage in adipose tissue, which is stimulated by insulin. When required, stored triglycerides are hydrolyzed to free fatty acids and glycerol in a process called lipolysis, which is regulated by glucagon and epinephrine. Fatty acids are released into the circulation and transported to various tissues by attachment to albumin. Once in the cells, fatty acids enter mitochondria through the carnitine system as acylcarnitines and are metabolized by beta-oxidation. In this pathway, energy is released, acetyl CoA is produced, and the fatty acid chain is shorted with each cycle. The released acetyl CoA then enters the citric acid cycle, during which further energy is generated. (Source: AJKD/Hoppel/2003)

Question 14

What is the pathway of peroxisomal fatty acid oxidation?

Answer 14

Process is different from the mitochondria in that long-chain fatty acids are chain-shortened with incomplete beta-oxidation of fatty acyl groups, leading to chain-shortened fatty acyl CoAs and acetyl CoA. (Source: AJKD/Hoppel/2003)

Question 15

What is the cause of primary carnitine deficiency?

Answer 15

Caused directly by insufficient carnitine content, typically characterized by impaired fatty acid oxidation, and are not associated with any other systemic disease state. (Source: AJKD/Hoppel/2003)

Question 16

What is the cause of secondary carnitine deficiency?

Answer 16

Include both genetic and acquired conditions that result in a disease in plasma or tissue carnitine levels. More common than primary deficiency and largely related to disorders in fatty acid metabolism. (Source: AJKD/Hoppel/2003)

Question 17

What is the association of carnitine deficiency with myocardial diseases?

Answer 17

Carnitine deficiency associated with myocardial diseases such as dilated cardiomyopathy and CHF usually involves defects in the long-chain fatty acids metabolism. In these patients total and free myocardial carnitine is significantly reduced. The increased plasma carnitine concentrations seen in these patients have been attributed to leakage of carnitine from the heart and skeletal muscle. (Source: AJKD/Hoppel/2003)

Question 18

What happens to carnitine in kidney failure?

Answer 18

As glomerular function declines with progressive kidney disease, plasma carnitine concentrations are elevated. Further decreases in kidney function lead to an accumulation of acylcarnitines in plasma. In addition, incomplete fatty acid oxidation also leads to accumulation of acylcarnitines. The combined effect for patients who are not on dialysis therapy is that the ratio of acylcarnitines to free carnitine is abnormally high. (Source: AJKD/Hoppel/2003)

Question 19

What happens to carnitine in hemodyalisis?

Answer 19

Typical hemodyalisis session can result in as much as 75% reduction in plasma free carnitine concentration, but by 8 hours after dialysis, concentrations return to predialysis values. During a long period of hemodialysis, this has pronounced effects on skeletal muscle and myocardial tissue as more and more carnitine gets depleted from there to maintain plasma levels within the normal range. Complications are further aggravated by dietary restrictions, low protein supply, and anemia. (Source: AJKD/Hoppel/2003)

Question 20

What are common complications related to carnitine deficiency in hemodialysis patients?

Answer 20

• Abnormalities in fatty acid metabolism in dialysis patients result in high concentrations of plasma free fatty acids. This correlates with cardiac arrhythmias and is reversible by levocarnitine treatment presumably by restoring impaired oxidation of free fatty acids. -Hemodyalisis patients also show decreased free and acetyl carnitine concentrations in both plasma and skeletal muscle, which progresses with dialysis vintage. - Increased oxidative stress, indicated by increased lipid peroxidation, is common in chronic hemodialysis patients, which increases CVD risk. (Source: AJKD/Hoppel/2003)

Question 21

How is carnitine status in dialysis patients correlated with clinical indicators?

Answer 21

• Decreased plasma carnitine levels correlate inversely with cardiothoracic ratio -> implicated as a cause of cardiomegaly. - Serum total, free and acylated carnitine concentrations correlate with indicators of erythrocyte osmotic fragility, supporting the contention that carnitine contributes to the metabolism of erythrocyte membranes and has an impact on the efficacy of EPO in correcting the anemia in kidney failure. (Source: AJKD/Hoppel/2003)

Question 22

What improvements have been shown with carnitine supplementation in hemodialysis patients?

Answer 22

• Improvement in myocardial fatty acid metabolism, cardiac arrhythmias, and other aspects of impaired cardiac function typically related to impaired fatty acid metabolism. - Reduced muscle cramps, improved exercise performance, increased muscle strength and mass, decreased asthenia and dyspnea, and increased peak oxygen consumption. (Source: AJKD/Hoppel/2003)

Question 23

What processes are involved in carnitine homeostasis?

Answer 23

Carrier-mediated gastrointestinal absorption of L-carnitine from dietary sources, endogenous synthesis from essential amino acids, and extensive reabsorption of L-carnitine delivered to kidney tubules through glomerular filtration and concentrative transport from plasma to tissues. Moreover, carrier-mediated membrane transport ensures that high tissue to plasma concentration ratios are maintained, particularly for skeletal and cardiac muscle, which both have a critical reliance on fatty acid oxidation as an energy source but are incapable of synthesizing L-carnitine. Long-term intermittent hemodialysis (2-3/wk for 6 months) is associated with a reduction in plasma and tissue L-carnitine levels, as well as disturbances in carnitine homeostasis and relative levels of the various carnitine esters. (Source: AJKD/Evans/2003)

Question 24

What form of carnitine has a role in medicine?

Answer 24

L-carnitine (Source: AJKD/Evans/2003)

Question 25

What is free and total carnitine?

Answer 25

L-carnitine refers to nonacetylated material (often referred to as free carnitine), whereas total L-carnitine is the sum of L-carnitine and all esters. Acyl-L-carnitine represents all short-, medium-, and long chain esters, whereas the carnitine pool represents all forms of the compound (L-carnitine and all acyl-L-carnitines) in all organs and tissues of the body. (Source: AJKD/Evans/2003)

Question 26

How much acetyl-L-carnitine and total L-carnitine is found in plasma? How much carnitine is in a body of a healthy adult?

Answer 26

Plasma concentrations of acetyl-L-carnitine typically are in the range of 3 to 6 micromol/L, whereas total L-carnitine in plasma is approximately 50 to 60 micromol/L. The sum of all acyl-L-carnitine derivatives other than acetyl-L-carnitine is normally less than approximately 5 micromol/L. Plasma or serum L-carnitine levels tend to be approximately 10% to 20% lower in women. (Source: AJKD/Evans/2003). The body of a healthy adult contains more than 120 mmol of L-carnitine (approx. 15-17 g), meaning that the amount of L-carnitine in plasma is just a minuscule fraction of the total-body pool. Short-term changes in plasma L-carnitine levels do not necessarily translate to short-term alterations in total-body carnitine status. (Source: AJKD/Evans/2003)

Question 27

What are good sources of dietary carnitine and how do carnitine levels in vegetarians compare to those who eat animal products?

Answer 27

Major dietary sources of L-carnitine are foods of animal origin: meats, fish, and dairy products. Plasma L-carnitine levels in strict vegetarians are approximately 10% to 20% lower than in adults on a mixed diet. Efficiency of absorption decreases with oral load. (Source: AJKD/Evans/2003)

Question 28

Describe endogenous carnitine synthesis

Answer 28

Humans synthesize approximately 1 to 2 micromol of L-carnitine per kg of body weight per day, representing 10 to 20 mg/d for an average adult. This is sufficient for maintaining the carnitine pool in healthy individuals. The enzyme that catalyzes the final step of L-carnitine synthesis is present within the liver, kidney, and brain, but not within skeletal or cardiac muscle. (Source: AJKD/Evans/2003)

Question 29

How is carnitine excreted?

Answer 29

L-Carnitine is not bound to plasma proteins and therefore is freely filtered at the glomerulus. However, extensive fractional tubular reabsorption (98% to 99%) results in kidney clearance of approximately 1 to 3 mL/min under baseline conditions in healthy adults. At plasma concentrations greater than ~60 micromol/L, fractional reabsorption begins to decrease because of partial saturation of the tubular transporter. (Source: AJKD/Evans/2003)

Question 30

How is carnitine distributed in the body?

Answer 30

High tissue-plasma concentration ratios of L-carnitine in tissues such as muscle are maintained by carrier-mediated transport systems, including the sodium-dependent carnitine organic cation transporter (OCTN2). This transporter also has a pivotal role in L-carnitine reabsorption from kidney tubules. Mutations in the OCTN2 gene lead to the impaired muscle uptake of L-carnitine seen in patients with primary carnitine deficiency and reduced renal tubular reabsorption. Additional transporters have been identified, and the expression and activity of these transporters has a major role in dictating the distribution of L-carnitine within the body. Skeletal muscle contains the greatest proportion (98%) of the body’s carnitine pool, with most of the remaining 2% residing in such organs as the liver, kidney, and heart. The amount present within plasma and erythrocytes is far less than 1% of the body pool. There is a very slow equilibration of L -carnitine between plasma and muscle. Therefore, under normal circumstances, a change in rate of L-carnitine input into the body (absorption from a carnitine rich meal or ingestion of an oral supplement) or alteration in the efficiency of its loss by the kidneys will not have an immediate impact on muscle L-carnitine content. (Source: AJKD/Evans/2003)

Question 31

Why is it not sufficient to focus only on L-carnitine levels in plasma when evaluating the potential impact of hemodialysis on the body’s carnitine pool?

Answer 31

(1) plasma levels may not give a true reflection of tissue content (because of compartmentalization), and (2) relative levels of the various acyl-L-carnitines also may be important indicators of the overall efficiency of fatty acid oxidation. (Source: AJKD/Evans/2003)

Question 32

Describe the efficiency of L-carnitine removal during hemodialysis and how does it compare to healthy individuals?

Answer 32

L-carnitine is efficiently removed from blood during hemodialysis due to its small molecular weight and very low binding to plasma proteins. The fraction of L-carnitine removed from blood during a single passage through the dialyzer was approximately 0.74. Within a single hemodialysis session, plasma L-carnitine levels decrease by approximately 70% to 75%. Plasma clearance of L-carnitine during hemodialysis is at least 30 times greater than the expected renal clearance of L-carnitine in a healthy individual. However, hemodialysis is an intermittent process (typically 12 h/wk), whereas renal clearance is continuous. *Hemodialysis procedure contributes to the declining plasma levels of L-carnitine seen in patients with renal disease during the first 12 months of hemodialysis therapy. (Source: AJKD/Evans/2003)

Question 33

What happens to muscle carnitine in hemodialysis patients?

Answer 33

L-Carnitine in muscle equilibrates very slowly with that in plasma, whereas L-carnitine in the liver is more easily accessible within the vascular pool. Therefore, during a single hemodialysis session, the 70% to 75% decline in plasma L-carnitine levels might be matched by a more modest decrease in liver content and a negligible change in muscle levels. However, once hemodialysis is complete, plasma L-carnitine levels slowly return to their pre-dialysis level (or slightly less than the pre-dialysis level), a consequence of movement of the compound from hepatic and muscle stores, together with dietary intake and biosynthesis. Given the progressive decline in plasma L-carnitine levels with long-term hemodialysis, ongoing removal of the compound through hemodialysis cannot be matched entirely by synthesis and movement out of tissue sites. This leads to lower muscle levels over time. Several studies found that patients with ESRD on long-term hemodialysis therapy have lower than normal L-carnitine or total L-carnitine concentrations in skeletal muscle. In the patients with kidney failure, there was a negative correlation between muscle L-carnitine level and dialysis age, exactly what would be expected on pharmacokinetic grounds because it reflects a slow depletion with time. (Source: AJKD/Evans/2003)

Question 34

How is acetyl-L-carnitine removal changed in hemodialysis patients and what happens to the acyl-carnitine to carnitine ratio?

Answer 34

In healthy adult men under baseline conditions, renal clearance of acetyl-L-carnitine was approximately 4x greater than that of L-carnitine. The preferential renal excretion of these short-chain ester forms of L-carnitine in healthy individuals serves to maintain a low ratio of acyl-L-carnitine to L-carnitine in plasma and the rest of the body. This is linked to maintaining adequate amounts of free carnitine to prevent carnitine insufficiency, removing the short-chain acyl groups arising from fatty acid oxidation, and maintaining an appropriate acyl CoA-CoA balance within cells. In contrast to the active role of the healthy kidney in the preferential retention of L-carnitine, the hemodialysis device lacks selectivity. In patients with kidney disease, there was essentially no difference in the efficiency with which L-carnitine and acetyl-L-carnitine were removed from the body by hemodialysis. Therefore, whereas healthy people lose acetyl-L-carnitine more efficiently than L-carnitine, this is not the case for hemodialysis patients. *A significant positive correlation between acyl-L-carnitine to L-carnitine ratio and months on hemodialysis therapy also has been reported, with the ratio significantly greater in patients who reported symptoms of muscle weakness, fatigue, and muscle aches. (Source: AJKD/Evans/2003)

Question 35

What is the different between bioavailability and metabolism of oral and IV carnitine?

Answer 35

Whereas intravenously administered L-carnitine is fully bioavailable and negligibly metabolized (except through incorporation into the endogenous carnitine pool), orally administered L-carnitine is poorly absorbed and possibly acetylated during the absorption process. (Source: AJKD/Evans/2003)

Question 36

How is IV L-carnitine absorbed and distributed in healthy subjects and patients undergoing hemodialysis?

Answer 36

In healthy subjects with normal kidney function, approximately 70% to 90% of a 1- to 2-g intravenous dose of L-carnitine is excreted unchanged in urine, with most urinary recovery occurring within the first 12 to 24 hours. With the exception of reversible acetylation, the metabolism of IV L-carnitine is negligible. Intravenous L-carnitine is excreted very rapidly because a typical 1- to 2-g intravenous dose produces plasma levels that are 10-fold greater than the threshold for renal tubular reabsorption. The outcome is reduced fractional reabsorption and a renal clearance value that approaches glomerular filtration rate. As a consequence of this saturation, only a small fraction of an intravenous dose of L-carnitine resides in the body of a healthy person long enough to move into the body’s carnitine pool. However, in patients with ESRD, there is no efficient removal process during non-hemodialysis times, meaning that an intravenous dose of L-carnitine administered after the completion of a hemodialysis session resides in the body long enough to allow significant distribution into extravascular tissue sites. IV dose of 20 mg/kg at the end of dialysis will lead to typical plasma concentrations of 1,000 micromol/mL. It has been suggested that these supraphysiological plasma L-carnitine levels are required to drive the compound from plasma into skeletal muscle cells. With continuous IV administration, there is a progressive increase in pre-dialysis and post-dialysis L-carnitine levels in plasma, reaching constant values after approximately 6 to8 weeks and remaining constant for at least 6 months, suggesting the attainment of an apparent steady state with respect to input and loss. After cessation of L-carnitine administration, pre-dialysis and post-dialysis plasma levels decline slowly during a period exceeding 6 weeks. This slow posttreatment decline likely arises from the gradual depletion of nonvascular tissue stores that were replenished during the treatment period. Continuous (6 weeks) intravenous administration of L-carnitine at doses of 20 mg/kg or greater leads to a 60% to 200% increase in levels of the compound in skeletal muscle. Cessation of intravenous L-carnitine administration was associated with 50% reduction in muscle stores, confirming the finding from pharmacokinetic studies that IV L-carnitine distributes extensively into extravascular compartments. Because of the slow equilibration of the compound between muscle and plasma, routine measurement of L-carnitine in plasma during or soon after intravenous administration to hemodialysis patients would be of questionable value. (Source: AJKD/Evans/2003)

Question 37

What is the bioavailability of oral L-carnitine and how is it metabolized?

Answer 37

The mean absolute bioavailability of L-carnitine is approximately 15% when administered to healthy subjects at doses of approximately 2 g. In experimental animals, a significant portion of an oral dose of L-carnitine undergoes acetylation during the gastrointestinal absorption process. If this occurred in humans, it would mean that oral L-carnitine delivers both L-carnitine and acetyl-L-carnitine to the systemic circulation. Whether this is desirable in patients who already have a high load of acetyl-L-carnitine is not known, but in theory, it is a factor that deserves consideration. (Source: AJKD/Evans/2003)

Question 38

What are the symptoms associated with suboptimal response to EPO?

Answer 38

A suboptimal response to rHuEPO is associated with many symptoms and physiological disorders that reduce quality of life, including reduced exercise tolerance, impaired cognition and mental acuity, anorexia, insomnia, and depression. Anemia is an independent risk factor for the development of heart failure and a predictor of mortality in dialysis patients. Furthermore, rHuEPO resistance has been associated with congestive heart failure and dialysis-related hypotension. (Source: AJKD/Golper/2003)

Question 39

What is the role of L-carnitine in erythrocyte membrane stability and how does stability relate to L-carnitine concentrations?

Answer 39

L-carnitine contributes to enhanced erythrocyte membrane stability. An in vitro study showed that erythrocyte membrane stability had a biphasic response to L-carnitine, showing relative improvement in stability at physiological concentrations and a loss of stability at concentrations greater than 50 micromol/L of L-carnitine. (Source: AJKD/Golper/2003)

Question 40

What are the studies suggesting with respect to EPO doses when carnitine is added?

Answer 40

A reduction in rHuEPO dose and frequency of administration may be achieved by adding a low dose of L-carnitine. Donatelli et al reported improved hematocrits and a reduction in the abnormally high erythrocyte ATP concentrations after treatment of 10 HD patients with L-carnitine, 1 g orally twice daily for 2 months. (Source: AJKD/Golper/2003)

Question 41

How is carnitine deficiency in ESRD relate to EPO requirements?

Answer 41

L-carnitine deficiency may contribute to the need for greater rHuEPO doses in patients with ESRD with anemia. Conversely, greater carnitine levels should lead to a reduction in rHuEPO requirements for the treatment of anemia in ESRD. (Source: AJKD/Golper/2003)

Question 42

What is the role of supplemental carnitine on cardiac myocytes?

Answer 42

Supplemental carnitine may protect cardiac muscles against oxidative stress, hypoxia, and ischemia. The mechanism is probably not that carnitine enhances the degree of fatty acid oxidation. Rather, one hypothesis is that carnitine exerts its cardioprotective effects by rendering cardiac cell membranes more resistant to free radicals, perhaps by an indirect effect of reducing levels of toxic coenzyme A derivatives. The net effect is that carnitine appears to shift cardiomyocyte energy production from fatty acid oxidation to glucose oxidation.

Question 43

What study looked at the role of carnitine in long-term LV dilatation? What were the findings?

Answer 43

**Iliceto et al. (1995) examined the effects of carnitine on long-term LV dilatation in a multicenter trial with 472 patients with a first acute MI. In a randomized fashion, patients were administered placebo or carnitine within 24 hours of chest pain. Carnitine was administered as 9 g/d IV x 5 days, then 6 g/d orally x 12 months. *348 patients were assessed for LV end-diastolic volume (LVEDV), systolic volume (LVESV), and ejection fraction (EF) by means of sequential electrocardiograms. ACE inhibitors were administered to only 8% of patients, and 78% received thrombolytic therapy. LVEDV, LVESV and EF Increases were less for carnitine-treated versus placebo-treated patients. EFs were significantly greater for carnitine-treated versus placebo-treated patients at 3 months, but statistical significance disappeared at 6 and 12 months. At the 12-month follow-up, there were fewer deaths (10% versus 13%) and less clinical heart failure (4% versus 10%) in carnitine-treated patients but not statistically significant. There were no differences in the incidence of reinfarction or unstable angina. Although this study was not powered to show a difference in mortality, it was able to show a significant reduction in LV dilatation, which is a powerful predictor of reduced mortality. (Source: AJKD/Pauly/2003)

Question 44

How much higher is the prevalence of CAD in patients with ESRD compared with the general population?

Answer 44

The prevalence of coronary artery disease (CAD) is up to 20 times greater in patients with ESRD compared with the general population. (Source: AJKD/Pauly/2003)

Question 45

Carnitine effect on VO2 max and QOL in dialysis?

Answer 45

Brass et al., 2001: In study A (n=56), IV carnitine, 20 mg/kg, was administered to half the patients after dialysis three times a week for 24 weeks. Study B was a dose-ranging study, and patients were administered 10 mg/kg (n=32),20 mg/kg (n=30), or 40 mg/kg (n=32). Data from the combined study populations showed that carnitine treatment was associated with a smaller deterioration in VO2max versus placebo. Carnitine also improved the fatigue domain of the QOL instrument. (Source: AJKD/Pauly/2003)

Question 46

Carnitine effect on LVEF in dialysis patients?

Answer 46

Romagnoli et al examined the addition of carnitine to conventional therapy in 11 hemodialysis patients with impaired LV function. Ten patients had a history of ischemic heart disease or hypertension, and all 11 patients had heart failure. All patients had been administered digitalis, and 10 patients had been administered ACE-inhibitor therapy. Patients were treated with L-carnitine, 1 g, IV at each dialysis for 8 months, and cardiac status was regularly assessed by echocardiography. A progressive improvement in mean LVEF was observed throughout the study. (Source: AJKD/Pauly/2003)

Question 47

What is the relationship between hypotension and mortality in hemodialysis patients?

Answer 47

Relationship between hypotension and elevated mortality was shown in a national random sample of 4,499 hemodialysis patients. A low pre-dialysis systolic BP was associated with an elevated relative risk for mortality (relative risk, 1.86 for systolic BP<110mm Hg; P<0.0001). This relationship was observed in patients with and without diabetes and patients with and without heart failure. (Source: AJKD/Pauly/2003)

Question 48

Effect of carnitine on intradialytic hypotension and muscle cramps

Answer 48

In a double-blind, parallel, placebo-controlled study by Ahmad et al (1990), episodes of intradialytic hypotension (defined as a decrease in BP necessitating a corrective intervention) and muscle cramps were measured in 38 patients treated with IV carnitine, 20 mg/kg, after each dialysis session for 6 months. The number of hypotensive episodes declined from 44% to 18%of patients (P<0.02), and muscle cramps decreased from 36% to 13% in carnitine-treated patients (P<0.02). Both were unchanged in the placebo group. (Source: AJKD/Pauly/2003)

Question 49

What do the studies of carnitine therapy show for patients without kidney disease/with kidney disease?

Answer 49

Studies of carnitine therapy in patients without kidney disease indicate that carnitine has positive effects on measures and outcomes of MI, heart failure, and angina. For patients with coexisting kidney disease, no large controlled studies of carnitine therapy for cardiac dysfunction have been performed. However, data from small studies suggest that carnitine therapy gives similar cardiac benefits in the presence of kidney disease. These benefits are best established for cardiomyopathy, associated with CHF, and for intradialytic hypotension. (Source: AJKD/Pauly/2003)

Question 50

What are some of the self-report instruments used to measure patient functionality?

Answer 50

Self-report instruments (eg, Kidney Disease Quality of Life, Medical Outcomes Study 36-Item Short Form [SF36]) are used to measure patient functionality. (Source: AJKD/Miller/2003)

Question 51

Study on ability of SF-36 to predict clinical outcomes

Answer 51

DeOreo completed a historic prospective study examining the ability of SF-36 to predict clinical outcomes in 1,000 maintenance hemodialysis patients. Results of the study showed that the predictive power of self-reported functional status data is similar to lab, dialysis adequacy, and nutritional adequacy measurements in the evaluation of mortality and hospitalization. DeOreo showed that use of validated health status instruments measuring patient functionality can predict clinical outcomes in maintenance hemodialysis patients. (Source: AJKD/Miller/2003)

Question 52

Association of carnitine deficiency with muscle symptoms

Answer 52

Muscle tissue is highly dependent on the energy generated by beta-oxidation of fatty acids and glycogen; therefore, it is important for muscle tissue to have adequate levels of carnitine. Muscle symptoms in maintenance hemodialysis patients may be associated with free carnitine deficiency. (Source: AJKD/Miller/2003)

Question 53

Studies using objective measures of muscle strength to determine the impact of L-carnitine therapy

Answer 53

Several studies used objective measures of muscle strength to determine the impact of L-carnitine therapy. Rogerson et al studied muscle strength during a 6-week period and did not show an increase, but the study by Giovenali et al of 6 months of L-carnitine therapy showed a significant increase in isometric performance parameters. Rocchi et al used computerized electromyogram studies to evaluate the effect of intravenous L-carnitine therapy and showed a significant increase in measured total power. Fagher et al studied muscular function during a 6-week period and did not show a difference between the treatment and placebo groups, but showed an improvement in the L-carnitine group. (Source: AJKD/Miller/2003)

Question 54

How does muscle carnitine content correlate with time on hemodialysis and with peak exercise performance?

Answer 54

Muscle carnitine content correlated inversely with time on hemodialysis and correlated positively with peak exercise performance. The investigators speculated that the low muscle total carnitine content may have a causal role in impaired exercise performance in hemodialysis patients. L-carnitine therapy could prevent the decline in exercise capacity in hemodialysis patients. (Source: AJKD/Miller/2003)

Question 55

What did the studies show for intradialytic muscle cramping when carnitine supplementation is given?

Answer 55

Multiple pathogenic factors are responsible for intradialytic muscle cramping. Carnitine deficiency is a potential cause of intradialytic muscle cramping, although the mechanism is unknown. All the studies showed a decrease in amount of intradialytic muscle cramping in the L-carnitine treatment groups. Three studies showed statistical significance in intradialytic muscle cramping between the L-carnitine and placebo groups. (Source: AJKD/Miller/2003)

Question 56

Use of KDQ and SF-36 to study impact of L-carnitine on QOL

Answer 56

The SF-36 and Kidney Disease Questionnaire (KDQ) have been used to study the impact of L-carnitine therapy on quality of life. Sloan et al administered the SF-36 test at baseline and 1.5-month intervals to 101 patients randomly assigned to three groups administered oral L-carnitine or placebo for 6 months. The SF-36 has eight scales. The Physical Functioning and General Health scales were improved at 1.5 months and then showed a decrease in patients’ ability to perceive an improvement in their quality of life. *Brass et al used the KDQ as a secondary end point in their study. The KDQ, which contains five domains, is a validated questionnaire for measuring the quality of life in dialysis patients and was determined at baseline and 12 and 24 weeks. At 12 and 24 weeks, Fatigue was the only domain that showed a significant difference from baseline. No significant improvement was found in the other domains, but trends toward improvement were seen in other domains. (Source: AJKD/Miller/2003)

Question 57

What constitutes a carnitine deficiency?

Answer 57

Carnitine deficiency is defined as plasma concentration of free carnitine < 40 µmol/L and/or ratio acyl-L-carnitine/free carnitine > 0.4. (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)

Question 58

What are the strongest outcome predictors of CKD patients?

Answer 58

The strongest outcome predictors in chronic kidney disease patients are malnutrition, inflammation and anemia. (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)

Question 59

How does deteriorating renal function affect carnitine and acylcarnitine clearance?

Answer 59

Deteriorating renal function is associated with decreased carnitine clearance and impairment of normal excretion of acylcarnitine, leading to elevated plasma levels of carnitine. In CKD patients the glomerular filtration rate is reduced, a lower amount of carnitine is reabsorbed and excreted, and the mechanism of acylcarnitine elimination is less effective than during normal kidney function. (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)

Question 60

What is dialysis-related carnitine deficiency?

Answer 60

Dialysis-related carnitine deficiency (DCD), defined as a predialysis plasma concentration of free carnitine <40 µmol/L, manifests itself as a syndrome of clinical problems and symptoms, most notable of which are anemia, that is hyporesponsive to erythropoietin therapy, intradialytic hypotension, cardiovascular complications, and skeletal muscle dysfunction manifested as generalized fatigability. (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)

Question 61

How is the erythrocytes life span affected by CKD?

Answer 61

Erythrocytes also have a decreased lifespan in patients with chronic kidney disease: while the normal lifespan is about 120 days, it has been demonstrated that is shortened to only 60–90 days in these patients. Erythrocyte lifespan plays an important role in the erythropoietic response to recombinant human erythropoietin. The uremic environment, combined with the impaired quality of erythrocytes, reduce the survival of mature erythrocytes by 30–70% of the expected normal half-life of the cells. Although erythropoiesis-stimulating agents are capable of increasing the number of circulating erythrocytes and hence hemoglobin levels, the quality of erythrocytes reaching the blood stream may not be significantly affected by erythropoiesis-stimulating agents treatment. (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)

Question 62

What are the top 10 reasons for anemia in CKD?

Answer 62

• Decreased erythropoietin production • Iron deficiency • Blood loss • Short erythrocyte lifespan • Bone marrow suppression by uremia • Osteitis fibrosa cystica • Deficiency of B12 and folate • Inflammation • Infection • Aluminum toxicity (Source: AboutCarnitine Flyer, 2016 Sigma-Tau Europe)