The Role of L-Carnitine in Kidney Disease: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Alfred Zheng and Version 2 by Alfred Zheng.

Kidney disease is associated with a wide variety of metabolic abnormalities that accompany the uremic state and the state of dialysis dependence. These include altered L-carnitine homeostasis, mitochondrial dysfunctions, and abnormalities in fatty acid metabolism. L-carnitine is essential for fatty acid metabolism and proper mitochondrial function.  L-carnitine deficiency is also seen in acute kidney injury (AKI) resulting from trauma and/or ischemia, drugs such as cisplatin, and from infections such as covid.

  • acute kidney disease
  • L-carnitine
  • Kidney disease

1. Pathophysiology of Kidney Disease and Relationship between Carnitine Metabolism and Kidney Function

1.1. Metabolic Alterations in Kidney Disease and Potential Protective Role of L-Carnitine

Chronic kidney disease is associated not only with a wide variety of metabolic abnormalities that accompany the uremic state but also with specific changes related to the dialysis procedure. These include altered L-carnitine homeostasis, mitochondrial dysfunction, and abnormalities in fatty acid metabolism. Carnitine deficiency is common in kidney disease and dialysis. L-carnitine has been shown to be an effective adjunctive treatment for anemia, intradialytic hypotension, hyperlipidemia, and muscle weakness.
L-carnitine is an amino acid derivative naturally produced by the body and obtained from the diet, especially from red meat. Its primary function in cells is to transport long-chain fatty acids across the inner mitochondrial membrane for β-oxidation and generation of ATP energy [1][2]. L-carnitine also plays a role in transporting potentially toxic acyl molecules out of the cells and in balancing the coenzyme A (CoA) ratio within mitochondria, acting as an indirect antioxidant. Therefore, it protects cellular membranes and prevents fatty acid accumulation. L-carnitine also controls the levels of β-oxidation and the acetyl CoA/CoA ratio, which are involved in modulating ketogenesis and glucogenesis.
Kidneys are the main organs responsible for the regulation of body fluids. They balance the volume, pH, and osmolality of the extracellular fluid and regulate the amount of sodium and water excreted. The kidneys are also specifically involved in regulating L-carnitine levels by controlling the excretion and reabsorption of L-carnitine as well as the endogenous synthesis of L-carnitine. The carnitine pool results from the combination of intestinal absorption, endogenous synthesis, and high tubular reabsorption [3].
The majority of L-carnitine (90–99%) filtered in the kidney is reabsorbed in the distal parts of the nephron until saturation is reached. The renal threshold for L-carnitine excretion is around 50 μmol/L. The kidneys are very efficient in maintaining normal levels of plasma L-carnitine by modulating urinary L-carnitine excretion depending on the intake from the diet [4].
At the onset of kidney disease, the glomerular filtration rate is reduced, and due to tubular dysfunction, a lower proportion of L-carnitine is reabsorbed, and the mechanism of acylcarnitine elimination is less efficient than with normal kidney function [5][6]. Initially, carnitine levels are higher, but as kidney disease progresses, more acylcarnitine is formed in the body, especially in the muscles and kidneys, while its excretion is reduced. This results in an increase in acylcarnitine in the cells and in the blood, which can lead to cellular toxicity by altering cellular and mitochondrial functions [7]. A buildup of acylcarnitine, usually due to defective β-oxidation, can increase the level of unmetabolized long-chain fatty acids (LCFA) within the mitochondria, which exert a detrimental effect on cellular membranes and proteins possibly due to a detergent-like action on the membranes [8].
As more acylcarnitine is formed, L-carnitine is decreased resulting in a free carnitine level <40 µmol/L or an acylcarnitine/free carnitine ratio of more than 0.4 in the blood, which is a sign of L-carnitine deficiency. Numerous studies investigating these changes have established that a deteriorating renal function is associated with decreased carnitine clearance and impairment of normal excretion of acylcarnitine [9][10].
L-carnitine depletion in the body may lead to frequent complications, such as anemia hyporesponsive to erythropoietin, intradialytic hypotension, muscle weakness, and cardiac arrhythmias. L-carnitine treatment has been shown to be beneficial in these dialysis-related complications [4][5][11].

1.2. Role of the Mitochondria in Kidney Disease

Mitochondrial dysfunction has been implicated in the pathogenesis of many diseases including kidney disease. Altered mitochondrial function leads to a reduction of ATP, an increase in ROS, and an increase in acylcarnitine, which can damage cells leading to a negative impact on kidney function in acute and chronic kidney disease states [12][13][14][15][16][17].
In AKI and diabetic nephropathy, β-oxidation in the mitochondria is decreased and the formation of lipid droplets inside the cell is increased, resulting in diminished ATP production [18][19][20][21].
Mitochondrial dysfunction also plays a key role in the pathogenesis of diabetic nephropathy, which occurs in 40% of patients with diabetes. A recent study showed that in diabetic nephropathy there is downregulation of the antioxidant superoxide dismutase 2 (SOD2), whose function is to prevent the excess buildup of mitochondrial reactive oxygen species (mtROS) [22]. The increase in reactive oxygen species (ROS) can damage mitochondrial membranes and proteins, compromising mitochondrial function [23][24][25][26][27].

2. L-Carnitine in Acute Kidney Injury

AKI in adults and children is associated with conditions such as sepsis, multi-organ failure, nephrotoxins, congenital heart disease, malignancies, primary kidney disease, hypotension shock, hypoxemia, and renal ischemia. These probably contribute to the increased mortality in AKI. Several authors found that L-carnitine treatment can mitigate the negative effects of acute kidney injury in both children and adults. In children receiving continuous kidney replacement therapy (CKRT) for AKI, intravenous L-carnitine, added to total parenteral nutrition (TPN) at a dose of 20 mg/kg/day, improved myocardial strain [28]. Another study showed that L-carnitine treatment of 50 mg/kg/d L-carnitine per day added to antibiotic regimens decreased renal scarring in children with acute pyelonephritis [29]. In adults undergoing prolonged kidney replacement therapy for AKI the plasma carnitine levels can diminish, causing metabolic disturbances and potential neurological symptoms. A recent study in patients receiving long-term tube feeding and continuous renal replacement therapy (CRRT) for more than 1 week suggested that L-carnitine supplementation at a dosage of 0.5 to 1 g/day may be beneficial in reducing neurological symptoms [30]. In patients undergoing percutaneous coronary intervention (PCI), oral L-carnitine 1 g 3 times a day, 24 h before the procedure and 2 g after PCI lowered plasma neutrophil gelatinase-associated lipocalin (NGAL) concentration, a marker for kidney damage following contrast medium administration [31]. Conclusion

3. Conclusion

L-carnitine may be an adjuvant therapy in dialysis patients. The administration of L-carnitine to patients suffering kidney disease may have protective effects possibly by the amelioration of the balance in metabolism such as restoring the acetyl CoA pool, and also by its effects on decreasing ROS levels in part due to the improvement in mitochondrial function.  

References

  1. Longo, N.; Frigeni, M.; Pasquali, M. Carnitine Transport and Fatty Acid Oxidation. Biochim. Biophys. Acta 2016, 1863, 2422–2435.
  2. Virmani, M.A.; Cirulli, M. The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation. Int. J. Mol. Sci. 2022, 23, 2717.
  3. Evans, A. Dialysis-Related Carnitine Disorder and Levocarnitine Pharmacology. Am. J. Kidney Dis. 2003, 41, S13–S26.
  4. Rebouche, C.J. Kinetics, Pharmacokinetics, and Regulation of l-Carnitine and Acetyl-l-Carnitine Metabolism. Ann. N. Y. Acad. Sci. 2004, 1033, 30–41.
  5. Reuter, S.E.; Faull, R.J.; Evans, A.M. l-carnitine Supplementation in the Dialysis Population: Are Australian Patients Missing Out? Nephrology 2008, 13, 3–16.
  6. Wasserstein, A.G. l-carnitine Supplementation in Dialysis: Treatment in Quest of Disease. Semin. Dial. 2013, 26, 11–15.
  7. Wanner, C.; Hörl, W.H. Carnitine Abnormalities in Patients with Renal Insufficiency. Pathophysiological and Therapeutical Aspects. Nephron 1988, 50, 89–102.
  8. Virmani, A.; Binienda, Z. Role of Carnitine Esters in Brain Neuropathology. Mol. Asp. Med. 2004, 25, 533–549.
  9. Fouque, D.; Holt, S.; Guebre-Egziabher, F.; Nakamura, K.; Vianey-Saban, C.; Hadj-Aïssa, A.; Hoppel, C.L.; Kopple, J.D. Relationship Between Serum Carnitine, Acylcarnitines, and Renal Function in Patients with Chronic Renal Disease. J. Ren. Nutr. 2006, 16, 125–131.
  10. Hatanaka, Y.; Higuchi, T.; Akiya, Y.; Horikami, T.; Tei, R.; Furukawa, T.; Takashima, H.; Tomita, H.; Abe, M. Prevalence of Carnitine Deficiency and Decreased Carnitine Levels in Patients on Hemodialysis. Blood Purif. 2019, 47, 38–44.
  11. Almannai, M.; Alfadhel, M.; El-Hattab, A.W. Carnitine Inborn Errors of Metabolism. Molecules 2019, 24, 3251.
  12. Che, R.; Yuan, Y.; Huang, S.; Zhang, A. Mitochondrial Dysfunction in the Pathophysiology of Renal Diseases. Am. J. Physiol. Renal. Physiol. 2014, 306, 367–378.
  13. Virmani, A.; Pinto, L.; Binienda, Z.; Ali, S. Food, Nutrigenomics, and Neurodegeneration—Neuroprotection by What You Eat! Mol. Neurobiol. 2013, 48, 353–362.
  14. Dan Dunn, J.; Alvarez, L.A.; Zhang, X.; Soldati, T. Reactive Oxygen Species and Mitochondria: A Nexus of Cellular Homeostasis. Redox Biol. 2015, 6, 472–485.
  15. Duann, P.; Lin, P.H. Mitochondria Damage and Kidney Disease. Adv. Exp. Med. Biol. 2017, 982, 529–551.
  16. Bhatia, D.; Capili, A.; Choi, M.E. Mitochondrial Dysfunction in Kidney Injury, Inflammation, and Disease: Potential Therapeutic Approaches. Kidney Res. Clin. Pract. 2020, 39, 244–258.
  17. Berezhnov, A.V.; Fedotova, E.I.; Nenov, M.N.; Kasymov, V.A.; Pimenov, O.Y.; Dynnik, V.V. Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines—Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-dependent Phospholipases, and Mitochondrial Energetics Collapse. Int. J. Mol. Sci. 2020, 21, 7461.
  18. Katsoulieris, E.; Mabley, J.G.; Samai, M.; Sharpe, M.A.; Green, I.C.; Chatterjee, P.K. Lipotoxicity in Renal Proximal Tubular Cells: Relationship Between Endoplasmic Reticulum Stress and Oxidative Stress Pathways. Free. Radic. Biol. Med. 2010, 48, 1654–1662.
  19. Simon, N.; Hertig, A. Alteration of Fatty Acid Oxidation in Tubular Epithelial Cells: From Acute Kidney Injury to Renal Fibrogenesis. Front. Med. 2015, 2, 52.
  20. Yamamoto, T.; Takabatake, Y.; Takahashi, A.; Kimura, T.; Namba, T.; Matsuda, J.; Minami, S.; Kaimori, J.Y.; Matsui, I.; Matsusaka, T.; et al. High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney. J. Am. Soc. Nephrol. 2017, 28, 1534–1551.
  21. Takemura, K.; Nishi, H.; Inagi, R. Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia. Front. Physiol. 2020, 11, 565023.
  22. Melov, S.; Coskun, P.; Patel, M.; Tuinstra, R.; Cottrell, B.; Jun, A.S.; Zastawny, T.H.; Dizdaroglu, M.; Goodman, S.I.; Huang, T.-T.; et al. Mitochondrial Disease in Superoxide Dismutase 2 Mutant Mice. Proc. Natl. Acad. Sci. USA 1999, 96, 846–851.
  23. Park, Y.; Kim, H.; Park, L.; Min, D.; Park, J.; Choi, S.; Park, M.H. Effective Delivery of Endogenous Antioxidants Ameliorates Diabetic Nephropathy. PLoS ONE 2015, 10, e0130815.
  24. Alicic, R.Z.; Rooney, M.T.; Tuttle, K.R. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. Clin. J. Am. Soc. Nephrol. 2017, 12, 2032–2045.
  25. Forbes, J.M.; Thorburn, D.R. Mitochondrial Dysfunction in Diabetic Kidney Disease. Nat. Rev. Nephrol. 2018, 14, 291–312.
  26. Konari, N.; Nagaishi, K.; Kikuchi, S.; Fujimiya, M. Mitochondria Transfer from Mesenchymal Stem Cells Structurally and Functionally Repairs Renal Proximal Tubular Epithelial Cells in Diabetic Nephropathy In Vivo. Sci. Rep. 2019, 9, 5184.
  27. Ito, S.; Nakashima, M.; Ishikiriyama, T.; Nakashima, H.; Yamagata, A.; Imakiire, T.; Kinoshita, M.; Seki, S.; Kumagai, H.; Oshima, N. Effects of l-Carnitine Treatment on Kidney Mitochondria and Macrophages in Mice with Diabetic Nephropathy. Kidney Blood Press. Res. 2022, 47, 277–290.
  28. Sgambat, K.; Clauss, S.; Moudgil, A. Effect of Levocarnitine Supplementation on Myocardial Strain in Children With Acute Kidney Injury Receiving Continuous Kidney Replacement Therapy: A Pilot Study. Pediatr. Nephrol. 2021, 36, 1607–1616.
  29. Gheissari, A.; Aslani, N.; Eshraghi, A.; Moslehi, M.; Merikhi, A.; Keikhah, M.; Haghjoo Javanmard, S.; Vaseghi, G. Preventive Effect of l-Carnitine on Scar Formation During Acute Pyelonephritis: A Randomized Placebo-Controlled Trial. Am. J. Ther. 2020, 27, e229–e234.
  30. Van de Wyngaert, C.; Dewulf, J.P.; Collienne, C.; Laterre, P.F.; Hantson, P. Carnitine Deficiency after Long-Term Continuous Renal Replacement Therapy. Case Rep. Crit. Care 2022, 2022, 4142539.
  31. Mohammadi, M.; Hajhossein Talasaz, A.; Alidoosti, M.; Pour Hosseini, H.R.; Gholami, K.; Jalali, A.; Aryannejad, H. Nephro-protective Effects of l-Carnitine Against Contrast-Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention: A Randomized Open-Labelled Clinical Trial. J. Tehran Heart Cent. 2017, 12, 57–64.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback