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PATHOPHYSIOLOGICAL ASPECTS OF NEPHRO- AND
HEPATOTOXICITY DURING CHEMOTHERAPY AND THE ROLE OF
AMINO ACID SUPPORT
Ergashev Nuriddin Khamzaevich
Gaziev Zoir Tohirovich
https://doi.org/10.5281/zenodo.16610417
Chemotherapy of malignant neoplasms remains a key component in the
treatment of oncological diseases, but is accompanied by a number of side
effects, the most dangerous of which are toxic liver and kidney damage. These
complications often limit the possibility of a full course of therapy, and in severe
cases lead to the cancellation of treatment. Particularly pronounced organ
toxicity is observed with the use of platinum series drugs ( cisplatin , carboplatin
), anthracyclines ( doxorubicin ), taxanes ( paclitaxel , docetaxel ), methotrexate
and ifosfamide . Understanding the pathophysiological mechanisms of toxicity,
as well as the search for ways to correct them, including through nutritional
amino acid support, is an important area of clinical oncology.
Nephrotoxicity Cytostatics primarily result from direct damage to the
tubular epithelium of nephrons, disruption of mitochondrial function, and
induction of oxidative stress. Kidneys, with their high metabolic activity and
dense system of transport proteins, are particularly sensitive to the
accumulation of toxins and drug metabolites. Chemotherapy increases lipid
peroxidation , damages membranes, disrupts reabsorption and secretion, causes
interstitial inflammation, and in some cases, necrosis of the proximal tubules.
Under conditions of reduced perfusion and oxygen deficiency, apoptosis
mechanisms are also activated , leading to a progressive decrease in the
filtration capacity of the kidneys.
Hepatotoxicity , in turn, is realized through several pathogenetic pathways:
metabolic disorders in hepatocytes , mitochondrial damage, activation of
inflammatory cascades and autoimmune processes. Many patients experience
increased activity of liver enzymes (ALT, AST, GGT), cholestasis , fatty
degeneration, drug-induced hepatitis. Mitochondrial dysfunction with ATP
deficiency, impaired detoxification function, accumulation of ammonia and free
radicals develop, which in turn affects the metabolism of other drugs and the
patient's overall resistance to chemotherapy. Patients with underlying liver
pathology - hepatosis , hepatitis, cirrhosis - are especially vulnerable .
Given the complexity of pathogenesis and the involvement of multiple
systemic links, it becomes obvious that isolated drug treatment is not always
effective. Against the background of systemic inflammation and catabolism, it is
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necessary to involve metabolic approaches, and here amino acids play a special
role, capable of interfering with the regulation of oxidative stress, immune
reactions, energy metabolism and tissue regeneration. Research in recent years
confirms that certain amino acids can not only compensate for metabolic
deficiencies, but also have an organ-specific protective effect.
Glutamine is the most studied amino acid in this context. As the main
nitrogen donor, it is involved in the synthesis of nucleotides, amino acids and,
most importantly, glutathione . Glutathione is a central component of the cellular
antioxidant system, and its deficiency is accompanied by increased sensitivity of
cells to toxic agents. Glutamine also maintains the integrity of the intestinal
barrier, reduces the translocation of bacteria and endotoxins into the
bloodstream, thereby preventing the development of a systemic inflammatory
response.
Arginine, in addition to participating in protein synthesis, is a substrate for
the formation of nitric oxide (NO), which plays an important role in the
regulation of vascular tone, perfusion and immune response. With its deficiency,
microcirculation is disrupted, the risk of tissue ischemia increases, and
proapoptotic activity increases. Inclusion of arginine in nutritional support can
reduce vascular spasms and restore local blood flow in the tissues of the liver
and kidneys, thereby improving the conditions for reparation.
Glycine exhibits a pronounced anti-inflammatory and cytoprotective effect.
It inhibits the activation of macrophages, reduces the production of
proinflammatory cytokines and promotes the stabilization of cell membranes. In
addition, glycine is involved in detoxification , facilitating the removal of toxic
metabolites. In conditions of hepatotoxicity, it is able to inhibit the processes of
fatty infiltration and oxidative damage to hepatocytes .
Taurine is an amino acid with osmoregulatory and membrane-stabilizing
effects, especially effective in mitochondrial dysfunction. It stabilizes the inner
mitochondrial membrane, preventing the release of cytochrome C and activation
of apoptosis . In addition, taurine has antioxidant activity, protects hepatocytes
from damage, normalizes bile formation and reduces the level of transaminases
in toxic effects.
Major pathophysiological mechanisms of organ toxicity during
chemotherapy and potential targets of amino acid support
Organ
Main mechanisms of
damage
Target
amino
acids
Mechanism of protective
action
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Liver
Oxidative
stress,
mitochondrial
dysfunction,
fatty
degeneration
Glutamine ,
taurine
Antioxidant
protection,
mitochondrial stabilization
Kidneys
Tubular
injury,
inflammation, apoptosis
Arginine,
glycine
Improved microcirculation,
anti-inflammatory effect
General
Systemic inflammation,
catabolism
All of the
above
Reduction
of
cytokine
response,
support
of
protein metabolism
Thus, amino acid support is a valid tool for metabolic correction aimed at
reducing the severity of organ complications. Moreover, its use is consistent
with the principles of multimodal therapy, combining pharmacological,
nutritional and behavioral approaches. It is important to emphasize that this is
not about replacing the main therapy, but about optimizing its tolerability,
extending the possibilities of active treatment and reducing the risk of drug
withdrawal due to toxicity.
From a practical point of view, amino acids can be administered either
orally or parenterally, depending on the patient's condition, chemotherapy
regimen, and the presence of concomitant pathologies. It is important to
individualize the composition of the amino acid complex depending on the
clinical situation. For example, in patients with predominant hepatotoxicity, the
content of glutamine and taurine should be increased , and in case of
nephrotoxicity , arginine and glycine. In some cases, it is possible to include
additional nutrients - B vitamins, zinc, selenium - which participate in associated
metabolic pathways.
In conclusion, it should be noted that amino acids are not just sources of
protein, but active participants in metabolic and cellular processes that play a
role in ensuring homeostasis. Their inclusion in the schemes of accompanying
therapy of cancer patients receiving chemotherapy can reduce the risk of organ
complications, increase the effectiveness of treatment, and improve the general
condition of the patient. Further research in this area will optimize the dosage,
duration and composition of nutritional support, making it a standard of
oncological care on a large scale.
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Current Opinion in Clinical Nutrition & Metabolism Care , 22(2), 120–125.
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