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Kidney and Dialysis
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  • Review
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10 April 2023

The Role of L-Carnitine in Kidney Disease and Related Metabolic Dysfunctions

,
and
1
MARHEA Reference Center, Pediatric Nephrology Department, Trousseau Hospital, AP-HP. Sorbonne University, 75231 Paris, France
2
Alfasigma, 3528 BG Utrecht, The Netherlands
*
Authors to whom correspondence should be addressed.
Kidney Dial.2023, 3(2), 178-191;https://doi.org/10.3390/kidneydial3020016
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Abstract

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. Deficiency in kidney disease and dialysis is caused by a reduction in endogenous renal synthesis, impaired fatty acid metabolism, a lower intake due to dietary restrictions, and nonselective clearance by the dialysis procedure. Free carnitine levels <40 µmol/L in dialysis patients can lead to dialysis-related complications, such as anemia that is hyporesponsive to erythropoietin therapy, intradialytic hypotension, cardiovascular disease, and skeletal muscle dysfunction manifested as muscle weakness and fatigue. 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. A persistent state of L-carnitine deficiency can further damage kidneys and lead to multi-organ failure. Carnitine supplementation has been shown to be safe and effective in improving kidney disease-related complications resulting from drug-induced toxicity, trauma, ischemic injury, infection, and dialysis, by replenishing adequate carnitine levels and rebalancing carnitine homeostasis. In this review, we will examine the protective role of L-carnitine in reducing cellular oxidative damage and maintaining mitochondrial function together with the clinical evidence for its potential use in the management of 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 (Figure 1). The carnitine pool results from the combination of intestinal absorption, endogenous synthesis, and high tubular reabsorption [3].
Figure 1. Regulation of L-carnitine levels in the blood by the diet and role of the kidney, liver, and muscle (adapted from Evans 2003 [3]). The kidney plays a very important role in maintaining blood L-carnitine levels by synthesis, excretion, and re-absorption.
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].
The preferred ‘fuel’ for respiration in the kidney cortex are short- and long-chain fatty acids, endogenous lipids, ketone bodies, lactate, and some amino acids (Figure 2) [18]. Chronic hyperinsulinemia and insulin resistance lead to increased degradation of triglycerides in the adipocytes as well as reduced uptake of circulating fatty acids, causing elevated serum levels of non-esterified fatty acids. These elevated levels lead to the ectopic accumulation of lipids in organs outside of the lipid tissue, including kidneys. The excessive accumulation of lipids results in cellular damage known as lipotoxicity (Figure 3). [19,20,21]. Fatty acids accumulating in the mitochondrial matrix are vulnerable to lipid peroxidation, which can have lipotoxic effects on DNA, RNA, and proteins that affect the mitochondrial machinery and lead to mitochondrial dysfunction as well as cellular damage [22,23,24].
Figure 2. The metabolism of carbohydrates, fats, and proteins to produce ATP energy (adapted from Virmani & Cirulli 2022 [2]). Carbohydrates such as glucose can be metabolized in the cytoplasm to produce ATP whereas fatty acids need to enter the mitochondria to be broken down by β-oxidation and metabolized. There are specific enzymes, such as carnitine palmitoyl transferase 1 (CPT1) and 2 (CPT2) on the outer and inner mitochondrial membrane, respectively, to facilitate the transfer of the fatty acid combined with the L-carnitine (fatty acylcarnitine).
Figure 3. Mitochondrial dysfunction caused by fatty acids and acylcarnitines buildup due to β-oxidation blockade (adapted from Wajner & Amaral, 2016 [25]). Factors such as fatty acid oxidation disorders (FAOD) that cause inhibition of fatty acid β-oxidation in the mitochondria lead to the accumulation of the long chain acyls groups, which trigger lipotoxicity and negatively affect mitochondrial function.
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 [26,27,28,29].
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) [30]. The increase in reactive oxygen species (ROS) can damage mitochondrial membranes and proteins, compromising mitochondrial function [31,32,33,34,35].

2. Diet in Chronic Kidney Disease

A proper diet plays an important role in the management of chronic kidney disease. The diet is patient-dependent and must be personalized. There are enormous differences to consider between children and adults. Calorie and protein requirements in children are higher than in adults because they are still in the growth phase, and, therefore, protein intake must be adapted to their specific needs. This is especially true during adolescence or when they are on growth hormone therapy.
A diet low in potassium, protein, and salt is often recommended because an increased intake of these substances can lead to:
  • Hyperkalemia with a risk of arrhythmia;
  • An increase in plasma urea leading to neurotoxicity and cardiac toxicity;
  • An increase in phosphate, which can damage the arterial structure and thereby lead to an increase of the left ventricular volume due to the increased afterload;
  • Hypervolemia with a risk of arterial hypertension and pulmonary edema.
Protein in the diet can cause an increase in urea, especially as kidney function decreases [36,37]. The kidney adapts to protein intake by further increasing the glomerular filtration, leading to higher proteinuria through hyperfiltration. This mechanism is a physiological reaction to higher protein intake if the functional reserve of the kidneys is intact and helps to maintain low urea levels. However, in the case of the reduced functional nephron number, it accelerates the decline in kidney function. A decrease in protein intake reduces potentially neurotoxic urea levels and preserves the kidney from hyperfiltration. Hyperfiltration by the remaining glomeruli results in proteinuria and interstitial fibrosis. In addition, high salt intake in the diet can lead to arterial hypertension and arteriosclerosis [38,39,40]. Although these diet restrictions are necessary, they can often lead to insufficient levels of micronutrients that are needed for maintaining normal cellular metabolism, including mitochondrial function. Mitochondria together with cellular and body control systems is a key player in energy metabolism for the whole body, including kidneys. The buildup of toxic metabolites due to mitochondrial dysfunction can reduce metabolic flexibility. Sufficient micronutrient intake, including B vitamins, cysteine, methionine, arginine, CoQ10, and L-carnitine from the diet, is crucial in maintaining metabolic flexibility and energy balance.
A low-protein diet with a reduced intake of red meat, which is the primary source of L-carnitine, together with low L-carnitine reabsorption due to kidney malfunctioning, can lead to a vicious cycle of carnitine deficiency. This results in altered carnitine homeostasis and an increase in potentially toxic long-chain fatty acid acyl residues since one of the L-carnitine roles is to bind to acyl residues and shuttle them out of the mitochondria and the cells. Persistent L-carnitine and micronutrient deficiency contribute to metabolic dysfunctions and disturbed energy metabolism. This, in turn, leads to metabolic inflexibility, cellular damage, and, ultimately, a disease [2].
Given the multiple roles of carnitine, we can hypothesize that certain pathological situations may benefit from higher L-carnitine plasma levels. Since the uremic state can damage the erythrocyte membrane due to uremic toxins and energy metabolism is altered by kidney disease and diet, it is difficult to determine optimal L-carnitine plasma levels. Patients with stage 5 chronic kidney disease (CKD) face a variety of abnormalities with complex interactions between them and may benefit from L-carnitine levels above the normal range.
In addition, intradialytic hypotension episodes and muscle cramps in hemodialysis (HD) patients are extremely multifactorial. For example, excess dehydration during dialysis, left ventricular insufficiency, and rapid changes in sodium plasma levels can result in hypotensive episodes during the HD session [41,42]. This can make it difficult to distinguish the individual effects of each condition and, thereby, demonstrate the beneficial effects of L-carnitine supplementation because carnitine acts not only on muscle cramps but also on cardiac function and hypotensive episodes [43,44].
We can speculate that higher than normal plasma carnitine levels may further improve the complex situation in dialysis-dependent kidney disease. Studies are needed to investigate the full potential of the optimal L-carnitine dosage in patients with complex situations, such as dialysis dependency, acute kidney injury, or multi-organ failure.

3. 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 [45]. 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 [46].
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 [47].
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 [48].

4. Acute Kidney Injury from Infection and Drugs

Severe infection is a frequent cause of AKI, especially in intensive care patients. Kidney injury in infections such as COVID-19 is multifactorial, with cardiovascular comorbidity and predisposing factors, such as sepsis, hypovolemia, and nephrotoxins as important contributors. The cytotoxic effect of sepsis is probably related to inflammation and reduced microcirculation [49].
Drug-induced nephrotoxicity from antimicrobial and other drugs such as cisplatin can also contribute to AKI. Oxidative stress seems to play a considerable role in cisplatin-induced nephrotoxicity [50]. An inadequate diet low in proteins and/or calories with subsequent protein catabolism puts patients at risk for increased cisplatin toxicity. Cisplatin-induced toxicity can also lead to tubular dysfunction resulting in an increase in renal excretion and a decrease in the absorption of L-carnitine. This can cause carnitine deficiency, which could pose an additional risk factor [51]. Several preclinical studies have shown that supplementation with L-carnitine can attenuate cisplatin-induced renal toxicity [50,52,53,54].
One of the factors underlying kidney injury could be increased inflammation caused by infection or kidney damage. An important factor underlying inflammation is oxidative stress and the excessive release of cytokines. Studies have shown that L-carnitine can reduce levels of inflammatory mediators, such as C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) [55].

6. Future Perspectives in the Management of Kidney Disease: The Role of Genomics, Proteomics, Metabolomics, and the Microbiome

Next-generation DNA sequencing and new laboratory technologies have allowed researchers to begin analyzing the human genome, as well as the metabolome and proteome. The metabolome and the proteome are a collection of metabolites resulting from cellular metabolism and proteins expressed by activated genes, respectively. The metabolites and proteins are in a constant state of flux and at any given time reflect the status of cellular activity and health. The proteome and metabolome expression is unique for each body tissue—e.g., liver, muscle, kidney, etc.—and will change according to disease processes. It is not yet clear whether the change in proteome and metabolome causes the disease or if the disease is causing the changes.
The role of the gut and the gut microbiome should also be taken into account in the complex interplay with the body fluids, electrolytes, and uremic hemostasis [99,100]. In particular, the effects on the absorption of dietary nutrients, L-carnitine, and micronutrients will lead to influence at the metabolic level. Together, all these factors will play an important role in the overall body metabolism in kidney disease and, more importantly, impact further any underlying disease states, such as glucose tolerance, insulin resistance, and inflammatory and immune factors, which further influence kidney function [101].
Current research is focused on the analysis of metabolites, such as urea, creatinine, glucose, uric acid, and proteins (such as albumin, cystatin C, and complement) and parathyroid hormone to better understand kidney disease [102,103].
Further analysis of the complete spectrum of metabolites and proteins will not only allow the identification of biomarkers for diagnosis and treatment but also provide a better understanding of the underlying dysfunctional metabolic pathways that lead to kidney disease. The final goal should be to prevent or delay the onset of kidney disease by restoring the normal metabolome, proteome, and microbiome with multiple strategies including diet, supplementation with metabolic compounds such as L-carnitine, and possible gene therapies based on miRNA technologies [104,105,106].
The metabolome in relation to carnitine in patients with chronic kidney disease shows decreased carnitine palmitoyl transferase (CPT1) activity, a key enzyme in the carnitine cycle [107]. This reduced activity can lead to the accumulation of acylcarnitines and impairment of fatty acid oxidation in renal tubular epithelial cells in patients with kidney fibrosis. Restoring CPT1A activity has been shown to rebalance mitochondrial homeostasis in animal models [108]. Another recent study showed that restoring mitochondrial CPT1A activity protects against hypoxia and microtubular damage in the kidney [109].
L-carnitine together with a CPT1 stimulation significantly increased CPT1 activity and ATP levels and lowered renal malondialdehyde (MDA) and serum TNF-α concentration. This led to an improvement in renal histomorphology and a reduction in serum creatinine as well as blood urea nitrogen (BUN) [107].
Ischemic/reperfusion (I/R) injury can cause deleterious effects on kidney function by increasing oxidative stress and inflammatory biomarkers and decreasing L-carnitine levels in the kidneys. Studies have shown that L-carnitine supplementation can have nephroprotective effects on I/R injury by ameliorating all oxidative and inflammatory markers [108].
L-carnitine is a unique molecule essential for the metabolism of long-chain fatty acids s and the formation of ATP energy. L-carnitine administration in patients with kidney disease provides protective effects by improving metabolic balance, restoring the acetyl CoA pool, decreasing ROS levels, and improving mitochondrial metabolic flexibility. In addition, L-carnitine as an adjuvant therapy in dialysis patients can improve intradialytic complications, such as anemia hyporesponsive to EPO, intradialytic hypotension, muscle weakness, and reduced exercise capacity, leading to an improved quality of life.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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