The Effects of L-Carnitine Therapy on Respiratory Function Tests in Chronic Hemodialysis Patients

Abstract

Background. Respiratory functions are affected during hemodialysis. The strength of respiratory muscles, ultrafiltration rate, and acid-base balance have been suggested as important factors. L-carnitine is crucial for energy producing, utilization of fatty acid, and possible amino acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and especially by its loss during dialysis. This study was performed to investigate the chronic effects of L-carnitine treatment on respiratory functions in adults receiving chronic hemodialysis therapy. Methods. A total of 20 hemodialysis patients were scheduled to take L-carnitine supplementation (20 mg/kg three times/week) (group 1), and the rest of 20 hemodialysis patients served as the control group and were observed without supplementation with L-carnitine (group 2). Pre- and post-dialytic L-carnitine levels and post-dialytic respiratory functions tests were performed in both groups at baseline and after six months. Results. The average concentration of free and total carnitine levels increased significantly after six months of supplementation (p < 0.01). While a statistically significant increase between postdialytic forced expiratory volume in one second/forced vital capacity values after treatment period (77.10 ± 12.15 and 83.00 ± 14.49, before and after treatment, respectively, p < 0.05) was observed, the increase of vital capacity, forced expiratory volume in one second, and forced expiratory flow between 25–75% of expired vital capacity were not significant in the treatment group (p > 0.05). Conclusion. Intravenous L-carnitine supplementation could contribute to the management of respiratory dysfunction in chronic hemodialysis patients by improving FEV1/FVC. The mechanism by which LC causes these effects merits further investigation.

Keywords:

• L-carnitine
• hemodialysis
• respiratory functions

INTRODUCTION

Hemodialysis has dramatically improved the life expectancy of patients with end-stage renal disease (ESRD). However, despite advances in dialysis technology and adjunctive treatment, patients with ESRD continue to experience high morbidity.^[1] The progressive failure of kidney function eventually affects most body systems and metabolic processes. The lungs are no exception, and lung disease associated with renal failure may present many difficult diagnostic problems. It is likely that the pattern of pulmonary disease may vary with different renal diseases, although this has little been studied. Kidney failure may directly affect lung function or cause indirectly pulmonary effects, such as pulmonary venous hypertension resulting from uremic heart disease. Non-specific abnormalities such as diffuse pulmonary infiltrates or pleural effusions may develop in the course of renal disease.^[2]

The metabolism of carnitine, a small molecule that is important in the β-oxidation of fatty acids, is also altered in ESRD.^[1] As fatty acids represent a major source of energy for muscles, especially myocardial muscle, a decreased carnitine level in plasma leads to weakness, cardiomyopathy with impairment of the heart function, and other serious symptoms.^[3] A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and especially by its loss during dialysis.^[4]

Carnitine supplementation in nondialysis patients increases exercise tolerance. Similarly, the administration of L-carnitine to adult hemodialysis patients improves muscle mass and exercise capacity. Based on these concepts, this study was performed to investigate the chronic effects of L-carnitine (LC) supplementation on respiratory functions in adult hemodialysis patients.

MATERIALS AND METHODS

Patients and Controls

A total of 40 hemodialysis patients from the same dialysis unit were included in the study. Patients were asked to participate if they were undergoing hemodialysis at least three times a week and had not received any LC treatment in the previous six months. Patients were randomly assigned to either the carnitine or control group by a systematic random sampling method, as described elsewhere.^[5] A total of 20 patients were scheduled to take LC supplementation (42.5 ± 14.6 years; 13 men and 7 women) (group 1), and the rest of the patients served as the control group and observed without supplementation with LC (42.4 ± 12.9 years; 11 men and 9 women) (group 2). All patients were under regular hemodialysis treatment and were dialyzed three times weekly through a native artero-venous fistula, with each session lasting for four hours. The following dialysis membranes were used: 1.5 m² polysulfone (13 patients) and 1.6 m² polysulfone hollow-fibers membranes (7 patients) (Fresenius Medical Care, Bad Homburg, Germany); the respective type and size of the membrane were constant during the whole study. Bicarbonate hemodialysis solutions were utilized throughout the study. Routine heparin protocols were applied. During the screening period, it was also confirmed that patients were effectively dialyzed and unlikely to require changes in dialysis prescription. This assessment was based on stability in urea clearance, assessed by Kt/V at a value greater than 1.2 with less than 20 % variation during the previous six months, during which time postdialysis weight had to be stable within 3 kg.

L-carnitine (Santa Farma, Pomezia, Italy) was used intravenously three times a week after each hemodialysis session, at a 20 mg/kg dose. The tests were made at the baseline and six months after the carnitine treatment for both of the groups simultaneously.

All of the patients had normal cardiac functions echocardiographically. Before the initiation of the study, all of the patients underwent clinical and radiological evaluation for their respiratory functions, and no evident pathology was detected. Body mass index (BMI) was calculated using standard techniques.

All of the patients and controls were informed, and the study was approved by the Local Ethics Committee of our hospital.

Spirometry

After height and weights were measured, spirometry was performed using a Vitalograph model Vmax29 ergospirometer. During tests in an air conditioned room, patients remained seated and carried out the maneuvers of forced vital capacity (FVC), vital capacity (VC), forced expiratory volume in one second (FEV1), FEV1/FVC, forced expiratory flow between 25 and 75 percent of expired vital capacity (FEF25–75%), and peak expiratory flow (PEF). All participants were older than 25 years of age and cooperative. Results were reliable, and no patient needed to be excluded from the study.

Technical procedures were carried out, and criteria of acceptability and reproducibility were set according to the standards recommended by the American Thoracic Society.^[6] All pulmonary tests were repeated three times at room temperature, with the best performing test curve taken into consideration. The same pulmonary function tests and other measurements were repeated after this treatment period.

Biochemical Analyses

Samples were obtained before and after the dialysis session and stored at −20°C until the analysis. Total and free carnitine levels were measured as described by Wan and Hubbard.^[7] With this method, LC reacts with acetyl CoA catalyzed by carnitine acetyltransferase to form acetyl LC and CoASH. CoASH reacts non-enzymatically with 5, 5′-dithiobis-2-nitrobenzoate to form 5-thio-2-nitrobenzoate (TNB). The concentration of TNB is measured spectrophotometrically at 410 nm.

Statistical Analysis

Values are presented as mean ± SD, with a p value <0.05 indicating significance. Baseline clinical variables were compared using the t-test between groups. The evaluation of clinical parameters was analyzed in both groups by repeated-measures analysis of variance (ANOVA). Correlations were calculated using the Pearson correlation. All statistical calculations were made using SPSS® for Windows 11.5 software program.

RESULTS

Demographic and etiological characteristics of patients and controls are shown in Table 1. Predialytic serum free carnitine levels were 27.9 ± 10.8 and 146.6 ± 78.2 μmol/L; total carnitine levels were 37.2 ±14.5 and 158.7 ± 64.3 μmol/L before and after carnitine treatment, respectively (p < 0.001). Levels of free and total carnitine increased significantly after six months of supplementation (p < 0.01). Free carnitine levels after dialysis were < 5 at baseline and 54.2 ± 36.4 μmol/L on the sixth month (p < 0.05). Postdialytic total carnitine levels were 8.7 ± 4.9 at baseline and 66.5 ± 39.7 μmol/L on the sixth month (p < 0.05). Both free and total carnitine levels decreased significantly after dialysis (p < 0.05).

Table 1  Demographic and etiological characteristics of groups 1 and 2

	Group 1	Group 2	p
Age (years)	42.5 ± 14.6	42.4 ± 12.9	>0.05
Gender (male/female)	13/7	11/9	>0.05
BMI (kg/m^2)	23.5 ± 5.5	24.2 ± 6.4	>0.05
Dialytic age (years)	4.2 ± 2.5	3.8 ± 1.9	>0.05
Systolic blood pressure (mmHg)	124.9 ± 13.2	120.4 ± 15.9	>0.05
Diastolic blood pressure (mmHg)	85.4 ± 4.3	86.8 ± 5	>0.05
Haemoglobin (gr/dL)	10.3 ± 2.4	10.8 ± 2.2	>0.05
Interventricular septum thickness (cm)	1.2 ± 0.1	1.1 ± 0.1	>0.05
Left ventricular internal diameter (cm)	4.7 ± 0.6	4.6 ± 0.1	>0.05
Posterior wall thickness (cm)	1.2 ± 0.1	1.1 ± 0.2	>0.05
Ejection fraction (%)	57 ± 10	60 ± 8	>0.05
Etiology (N)
Glomerulonephritis	7	9	>0.05
Hypertensive nephropaty	5	6	>0.05
Diabetic nephropaty	5	4	>0.05
Tubuluinterstitial nephritis	3	1	>0.05

Group 1: L-carnitine group, Group 2: Control group.

Abbreviation: BMI = body mass index.

In the carnitine-treated group, changes in forced expiratory volume in one second/forced vital capacity (FEV1/FVC) were statistically significant (p < 0.05). Although there was an increase of vital capacity (VC), FEV1, and forced expiratory flow between 25 and 75 percent of expired vital capacity (FEF25–75%) in the same group, this was not statistically significant (p = 0.44, p = 0.85, and p = 0.18, respectively) (see Table 2). In the control group, there was not a significant change in the respiratory function tests. On the sixth month, FEV1/FVC was higher in the LC-treated group than controls (p < 0.05).

Table 2  Respiratory function test results at baseline and the sixth month of treatment in both groups

	Baseline (mean ± SD)			Six months (mean ± SD)
	Group 1	Group 2	p	Group 1	Group 2	p
VC (L)	3.79 ± 1.02	3.56 ±1.26	>0.05	3.71 ± 0.97	3.68 ± 1.47	>0.05
FVC (L)	3.45 ± 0.94	3.24 ± 0.87	>0.05	3.33 ± 0.92	3.27 ± 0.92	>0.05
FEV1 (L)	2.58 ± 0.98	2.48 ± 0.77	>0.05	2.75 ± 0.93	2.62 ± 0.78	>0.05
FEV1/FVC (%)	77.10 ± 12.15	79.24 ± 10.75	>0.05	83.00 ± 14.49	79.17 ± 10.82	<0.05
FEF25–75 (%)	2.67 ± 1.64	2.46 ± 1.85	>0.05	3.45 ± 0.28	2.57 ± 1.96	>0.05
PEF (L/sec)	6.09 ± 2.28	6.17 ± 2.46	>0.05	6.07 ± 1.99	6.12 ± 2.28	>0.05

Group 1: L-carnitine group, Group 2: Control group.

Abbreviations: VC = vital capacity, FVC = forced vital capacity, FEV1 = forced expiratory volume in one second, FEF25–75% = forced expiratory flow between 25 and 75 percent of expired vital capacity, PEF = Peak expiratory flow.

*p < 0.05 for baseline and six-month FEV1/FVC values of Group 1.

L carnitine levels were also positively correlated with FEV1/FVC and FEV1 levels on the sixth month of LC therapy in group 1 (cc: 0.378 and cc: 0.322, respectively, p < 0.01).

DISCUSSION

The current study has evaluated the effects of LC treatment on respiratory function tests in chronic hemodialysis patients. A significant improvement was observed in FEV1/FVC values after supplementation with LC. Additionally, during the periods both before and after commencing LC treatment, significant decreases in free and total carnitine levels were detected by the end of dialysis, demonstrating that carnitine was lost during hemodialysis, as is consistent with the results in the literature.^[8,9]

Many studies have shown that LC supplementation leads to improvements in several conditions seen in uremic patients.^[10] LC supplementation in selected uremic patients may yield clinical benefits by ameliorating several conditions, such as erythropoietin-resistant anemia, decreased cardiac performance, intradialytic hypotension, muscle symptoms, as well as impaired exercise and functional capacities. Furthermore, LC may reduce insulin resistance and chronic inflammation.^[11] We have previously found that CRP levels may decrease by LC treatment. Additionally, there was a significant benefit of LC on transferrin, total protein, and albumin levels of the hemodialysis patients.^[12] There are also a few reports supporting the hypothesis that treatment with LC can improve chronic inflammation in hemodialysis patients.^[13]

Lung and kidney function are intimately related in both health and disease. Respiratory changes help to mitigate the systemic effects of renal acid-base disturbances, and the reverse is also true. A large number of diseases affect both the lungs and the kidneys, presenting most often with alveolar hemorrhage and glomerulonephritis. Respiratory functions are affected during hemodialysis. Hemodialysis-related hypoxemia is explained by diffusion of CO₂ into the dialysate, with concomitant alveolar hypoventilation in the process of maintaining a normal PaCO₂. The strength of respiratory muscles and acid-base balance have been suggested as important factors in respiratory functions of hemodialysis patients.

Volume overload, metabolic acidosis, and uremic toxins are also known as the main factors affecting the respiratory function tests in ESRD patients.^[2] While alleviating these factors, hemodialysis may also cause undesirable changes in respiratory functions.^[14] Some studies suggested no change in respiratory functions,^[4] while others detected restrictive changes due to volume overload in adult hemodialysis patients.^[14] Oxidative stress has been shown in hemodialysis patients in relation with an increased production of free radicals, and this may be responsible for the appreciable airway dysfunction shown in many patients undergoing regular hemodialysis.^[15] In the present study, FEV1/FVC was decreased in the obstructive pattern in hemodialysis patients, which showed a significant improvement with LC supplementation. Because it has been shown by many studies that carnitine exerts a dose-dependent free-radical scavenging activity, it can be suggested that carnitine therapy may relieve the subclinical bronchospasm in hemodialysis by its antioxidant activity.^[16]

It has also been reported that LC decreases leukotriene synthesis by inactivation of lipoxygenase in hemodialysis patients. L-carnitine causes partial restoration of the depleted essential fatty acids and linoleic and linolenic acids, observed in untreated dialysis patients. Thus, carnitine may act on leukotriene metabolism by altering the ratio of essential fatty acids.^[17] An animal study by Uzuner et al. reported that LC improved oxygen saturation and decreased urine leukotriene E4 levels and inflammation in lung tissues in a murine model of asthma.^[18]

Kavukcu et al. reported that carnitine pretreatment prevented the subclinic bronchospasm in children who underwent chronic hemodialysis. A significant correlation was shown between the postdialysis carnitine levels and improvement of FEV1/VC. Additionally, a decline in the VC both prior to and following the carnitine treatment was explained as loss of strength during hemodialysis, which cannot be prevented by the carnitine treatment.^[19] However, the mechanism of this effect could not be sufficiently explained. Nevertheless, an animal study indicated that LC exerts no acute relaxant activity in guinea pig trachea, guinea pig lung parenchymal strips, and human bronchial tissues. As there was no asthma pathology in the smooth muscles in that study, it was speculated that LC did not affect the bronchial smooth muscles under physiologic conditions.^[20] In our study, all of the patients had normal cardiac functions echocardiographically, and no evident lung pathology was detected.

We conclude that intravenous L-carnitine supplementation could contribute to the management of respiratory dysfunction in chronic hemodialysis patients by improving FEV1/FVC. The mechanism by which LC causes these effects merit further investigation.

ACKNOWLEDGMENTS

The authors declare no conflict of interest.