AJKD 2003 Supplement Issue - Salbi

Question 1

When was levocarnitine approved by the FDA for the prevention and treatment of carnitine deficiency in patients with end-stage renal disease who are undergoing dialysis?

Answer 1

In 1999. *bonus: Health Canada approved Levocarnitine Injection for use in ESRD patients on Hemodialysis in 2001 (Source: AJKD, Eknoyan, 2003)

Question 2

What type of molecule is Carnitine?

Answer 2

A soluble low-molecular-weight compound. (Source: AJKD/Hoppel/2003)

Question 3

How is Carnitine made available to the body?

Answer 3

From diet and also biosynthesized from the essential amino acids lysine and methionine. (Source: AJKD/Hoppel/2003)

Question 4

In a healthy person, where is most of the amount of Carnitine found?

Answer 4

Typically, approximately 80% to 85% of carnitine exists as the free form in plasma. (Source: AJKD/Hoppel/2003)

Question 5

What would indicate physiological abnormalities caused by inadequate carnitine?

Answer 5

Decreased absolute content of free carnitine or a greater than normal ratio of acylated carnitine to free carnitine (>0.4). (Source: AJKD/Hoppel/2003)

Question 6

What are the normal plasma levels of Carnitine in a healthy adult?

Answer 6

Approximately 40 to 50 mol/L in healthy adult men. (Source: AJKD/Hoppel/2003)

Question 7

What are the main dietary sources?

Answer 7

Animal products, particularly red meat and dairy. (Source: AJKD/Hoppel/2003)

Question 8

How and where is Carnitine biosynthesized?

Answer 8

From the essential amino acids lysine and methionine; in the liver and kidneys.(Source: AJKD/Hoppel/2003)

Question 9

What is the protective role of Carnitine related to Acyl CoAs

Answer 9

Carnitine is believed to have a protective role by removing long-chain acyl CoAs from cell membranes, thereby stabilizing them.(Source: AJKD/Hoppel/2003)

Question 10

How much Carnitine is lost during a hemodialysis session?

Answer 10

As much as a 75% reduction in plasma free carnitine concentration, but by 8 hours after dialysis, concentrations have returned to predialysis values.(Source: AJKD/Hoppel/2003)

Question 11

What are the benefits of Carnitine therapy to treat patients with heart failure?

Answer 11

Typical benefits include improved exercise capacity and peak oxygen consumption, reduced fatigue, and improved muscle conditioning. The role of carnitine in patients with ischemic heart disease is controversial; nonetheless, carnitine has been shown to protect the myocardium in these patients.(Source: AJKD/Hoppel/2003)

Question 12

What has been shown in chronic hemodialysis patients and carnitine supplementation?

Answer 12

Improve myocardial fatty acid metabolism, cardiac arrhythmias, and other aspects of impaired cardiac function typically related to impaired fatty acid metabolism. Skeletal muscle function has been an especially significant target for carnitine therapy; numerous studies have reported such improvements as 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 13

What is associated with patients with long-term intermittent hemodialysis (ie, two to three sessions weekly for > 6 months) ?

Answer 13

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 14

Why are high tissue to plasma concentration ratios maintained?

Answer 14

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. (Source: AJKD/Evans/2003)

Question 15

What are the normal plasma ranges in healthy adult men and women?

Answer 15

L-carnitine: 40 - 50 umol/L; Acetyl-L-carnitine: 3 - 6 umol/L Note: *Plasma or serum L-carnitine levels tend to be approximately 10% to 20% lower in women. (Source: AJKD/Evans/2003)

Question 16

How much carnitine is synthesized in a healthy adult?

Answer 16

Approximately 1 to 2 mol of L-carnitine per kg of body weight per day, representing 10 to 20 mg/d for an average adult. (Source: AJKD/Evans/2003)

Question 17

Where does the body house its greatest pool of carnitine?

Answer 17

In the skeletal muscle (98%), with most of the remaining 2% residing in such organs as the liver, kidney, and heart. (Source: AJKD/Evans/2003)

Question 18

Describe the findings from the Australian group (Fig. 3): plasma levels of L-carnitine in a group of 21 patients with ESRD during their first 12 months of hemodialysis therapy.

Answer 18

Mean (SE) predialysis plasma concentrations of L -carnitine during the first 12 months of hemodialysis in patients (n = 21) with ESRD. Within the first month of dialysis therapy, plasma L -carnitine levels had decreased to less than the normal level. Plasma levels continued to decline and showed no clear signs of becoming constant after 12 months. (Source: AJKD/Evans/2003)

Question 19

In patients with kidney failure, what is the correlation between muscle L-carnitine level and dialysis age?

Answer 19

Negative correlation. The majority of patients who have been on hemodialysis therapy for more than 12 months will have plasma L-carnitine levels less than the normal range. (Source: AJKD/Evans/2003)

Question 20

What dose should be given at the end of a dialysis and why is in IV form?

Answer 20

IV dose of 20 mg/kg at the end of dialysis will lead to typical plasma concentrations of 1,000 umol/mL. These “supraphysiological” plasma L -carnitine levels are required to drive the compound from plasma into skeletal muscle cells. Whereas intravenously administered Lcarnitine 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 21

What have been some of the findings related to cardiology patients supplemented with carnitine?

Answer 21

1. statistically significant improvement in exercise duration 2. improved long-term patient survival (Kaplan-Meier) 3. significant reduction in LV dilatation, which is a powerful predictor of reduced mortality. (Source: AJKD/Pauly/2003)

Question 22

How does carnitine affect patients with ischemic cardiomyopathy?

Answer 22

Carnitine treatment in combination with other traditional pharmacological therapy might have an additive effect for the improvement of LV function in ischemic cardiomyopathy (Gurlek et al). (Source: AJKD/Pauly/2003)

Question 23

What is the relationship between hypotension and HD patient?

Answer 23

The relationship between hypotension and elevated mortality was shown in a national random sample of 4,499 hemodialysis patients. A low predialysis systolic BP was associated with an elevated relative risk for mortality. This relationship was observed in patients with and without diabetes and patients with and without heart failure. (Source: AJKD/Pauly/2003)

Question 24

What are the effects of carnitine therapy in patients without kidney disease and those with kidney disease?

Answer 24

Without kidney disease: positive effects on measures and outcomes of MI, heart failure, and angina. (Source: AJKD/Pauly/2003)

Question 25

Describe some symptoms and physiological disorders that reduce quality of life associated with suboptimal response to rHuEPO

Answer 25

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. rHuEPO resistance has been associated with congestive heart failure and dialysis-related hypotension. (Source: AKJD/Golper/2003)

Question 26

Why are high tissue to plasma concentration ratios maintained?

Answer 26

Patients on chronic HD therapy are likely to have a dialysis-associated carnitine disorder (DCD) in which a secondary carnitine deficiency arises because of a combination of factors: inadequate intake, impaired renal synthesis of carnitine, and its efficient removal by HD. (Source: AKJD/Golper/2003)

Question 27

How does carnitine help in anemia?

Answer 27

The salutary effects of L-carnitine on anemia center on improvement of erythrocyte survival, specifically through 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 umol/L of L-carnitine). (Source: AKJD/Golper/2003)

Question 28

What is the relationship of carnitine to EPO in ESRD patients with anemia?

Answer 28

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

Question 29

What does the NKF-K/DOQI Clinical Practice Guidelines for Nutrition in Chronic Renal Failure propose?

Answer 29

The most promising of the proposed applications for L-carnitine in dialysis patients is in the treatment of rHuEPO- resistant anemia. They suggested that a 4-month trial of L-carnitine (1 g after dialysis) was reasonable in selected patients with anemia and/or very large rHuEPO requirements (hyporesponsive rHuEPO-dependent anemia) and should be of adequate duration to reliably assess the response to L-carnitine. (Source: AKJD/Golper/2003)

Question 30

Why are some chronic psychological symptoms that patients on maintenance dialysis face?

Answer 30

Impaired activities of daily living and social functioning, and incomplete occupational rehabilitation that impair their functionality. (Furthermore, lack of physical activity is a marker for disease, disability, and death in a broad range of populations, including patients with CKD). (Source: AKJD/Miller/2003)

Question 31

List & explain the methods of measurement of patient functioning

Answer 31

1. Self-report, proxy report, direct observation, and direct measurement. 2. Direct testing of physical fitness in the laboratory is considered the gold standard for physical functioning (eg, treadmill testing), but has limited use in hemodialysis patients because of their inability to perform maximal exercise testing. An alternative to laboratory testing of physical fitness is physical performance measures (eg, walking, stair climbing), which are indicators for physical fitness rather than direct measures. Self-report instruments (eg, Kidney Disease Quality of Life, Medical Outcomes Study 36-Item Short Form [SF36]) also are used to measure patient functionality. Research has shown that self-report assessments of functioning provide information closely approximating that obtained through many traditional clinical measures. 3. Research has shown that self-report assessments of functioning provide information closely approximating that obtained through many traditional clinical measures. (Source: AKJD/Miller/2003)

Question 32

Explain the DeOreo historic prospective study where he examined the ability of a self-reported functional health status instrument (SF-36) to predict clinical outcomes in 1,000 maintenance HD patients.

Answer 32

Results of the study showed that the predictive power of self-reported functional status data is similar to laboratory, 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: AKJD/Miller/2003)

Question 33

What is the role of carnitine in muscle/tissue?

Answer 33

Muscle tissue is highly dependent on the energy generated by B-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: AKJD/Miller/2003)

Question 34

Carnitine deficiency is a potential cause of intradialytic muscle cramping, although the mechanism is unknown – True or False

Answer 34

True (see Table 1 in Miller, 2003) 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: AKJD/Miller/2003)

Question 35

Two studies examined the effect of L-carnitine therapy on fatigue – what were the findings?

Answer 35

Both studies used subjective rating scale measures. The report of fatigue was decreased in each of the studies. (Source: AKJD/Miller/2003)

Question 36

What was the conclusion of the review by Miller/Ahmad about the impact of L-Carnitine therapy on patient functionality in maintenance hemodialysis?

Answer 36

Nearly every dialysis patient functions below age-matched controls without CKD and also has abnormal L-carnitine biochemistry; however, not every patient will respond to L-carnitine therapy, and the response cannot be predicted by clinical or biochemical markers. In addition, such hard end points as mortality and hospitalization and long follow-up are generally lacking in the literature. However, both clinical experience and published studies indicate that some patients show an improvement in these parameters associated with L-carnitine treatment, and this improvement can occasionally be dramatic. (Source: AKJD/Miller/2003)