Journal of Kidney

Kidney Toxicity Caused by Radiation: Molecular and Cellular Pathogenesis

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Introduction

For solid tumors, radiation therapy, either alone or in conjunction with chemotherapy, surgery, or both, is a common therapeutic option. The global incidence of cancer is increasing as people live longer and are exposed to more cancer risk factors. In 2018, about 18 million individuals were diagnosed with cancer, and over 9 million people died as a result of cancer. According to predictions, cancer will become the major cause of mortality in the twenty-first century, and more than 60% of cancer patients will undergo RT at some point during their treatment. The most frequent type of RT is external beam RT with linear accelerators. With technological advancements, Novel radiation treatments, such as Intensity-Modulated Radiotherapy (IMRT) and its rotating subform Volumetric Modulated Arc Therapy (VMAT), have been launched in recent years. VK/MV planar imaging, cone-beam CT, ultrasound, surface scanners with X-ray imaging, and Magnetic ResonanceGuided RT are the most often utilized alternatives for Image-Guided Radiation (IGRT) (MRgRT). Total Body Irradiation (TBI) is a frequently utilized method in addition to targeted RT. It's one of the conditioning treatments used to get patients ready for a Bone Marrow Transplant (BMT). More than 20,000 BMT are produced each year across the world.

TOXICITY OF RADIATION

The basic concepts of radiation poisoning are discussed first. The specific evidence for those hypothesized pathomechanisms role in radiation nephropathy will be explored individually later.

Although radiation therapy is highly efficient in controlling tumor development and extending overall survival, it has harmful side effects on healthy tissue. One of the primary hurdles with RT is selectively addressing just the malignant tissue. Toxicity to healthy tissue restricts the RT dosages used, resulting in inadequate tumor suppression. Furthermore, combining chemotherapy with normal-tissue damage enhances normal-tissue toxicity, resulting in an even lower acceptable maximum dosage. Radiation therapy's primary target is DNA. By breaking chemical bonds and knocking away electrons, ionizing radiation causes immediate harm. Ionizing radiation also causes indirect damage by causing Reactive Oxygen Species (ROS) to form. Oxidative stress occurs when ROS outnumber antioxidants. ROS causes damage to biological macromolecules such as lipids, proteins, and DNA. The most serious RT event is DNA Double-Strand Breaks (DSB). Chronic inflammation and cellular senescence are most likely to blame for these processes. Inflammation can be found in gastrointestinal and lung radiation damage, for example. Degeneration and deterioration of particular organ functions result from fibrotic rearrangement.

RADIATION POISONING PATHOMECHANISM

Chronic Kidney Disease (CKD) affects more than 700 million people globally, therefore understanding its molecular and cellular pathomechanisms is crucial. While there are several causes for CKD, there appears to be a common ultimate pathway that includes glomerulosclerosis, renal interstitial fibrosis, and tubular atrophy, all of which lead to kidney dysfunction.

Oxidative damage: When Reactive Oxygen Species (ROS) outnumber enzymatic and non-enzymatic antioxidants, Oxidative Stress (OS) occurs. Lipids, proteins, and DNA all react with ROS. This results in cellular damage and aging. The involvement of OS in the acute phase of radiation-induced tissue damage with DNA damage is well-established.

System of the renin-angiotensin-aldosterone: Multiple organs are involved in the Renin-Angiotensin-Aldosterone System (RAAS), which is made up of enzymes and their peptide substrates. The RAAS system regulates blood pressure and electrolytes. Renin is a protein produced by the kidneys. It converts angiotensinogen from the liver to Angiotensin I (AT-I), which is subsequently converted to AT-II by the Angiotensin-Converting Enzyme (ACE) from the lungs. Individual RAAS components are found in the kidneys and are referred to as intrarenal RAAS. The intrarenal activation of RAAS is important in renal disorders, particularly renal hypertension.

Senescence of cells: Cellular Senescence (CS) is characterized by cell cycle arrest, apoptotic pathway inhibition, high metabolic activity, and a secretory phenotype associated with aging (SASP).

Redness: Because inflammation is prevalent in other radiation illnesses such as gastrointestinal radiation damage and radiation pneumonitis, it has been postulated as a mechanism for RN. Furthermore, renal cell damage and CKD are linked mechanistically through inflammation. Damage-Associated Molecular Patterns (DAMPs) are released by necrotic tubular cells, which cause tissue-resident cells and recruited leukocytes to secrete proinflammatory cytokines and chemokines.

Vascular impairment: Radiation-induced kidney damage is known to cause endothelial dysfunction and altered hemodynamics. CYP epoxygenase enzymes create Epoxyeicosatrienoic acids (EETs) in the endothelium. EETs are derived from arachidonic acid and have been demonstrated to protect kidneys in a variety of kidney disease models.

Fibrosis: The creation of scars in the parenchyma is known as renal fibrosis. Myofibroblast activation and migration, extracellular matrix deposition, and kidney remodeling are all pathologic aspects of normal wound healing. Almost all aetiologies of CKD lead to fibrosis as the ultimate stage. The processes that lead to fibrosis may be beneficial for tissue regeneration in acute damage, but when they occur often in CKD, they result in a functioning tissue and a decrease in kidney function.

FUTURE CONCERNS

The apparent excess of CKD in certain Hiroshima-Nagasaki survivors highlights the potential for substantial renal impairment in persons exposed to acutely survivable irradiation during wartime or terrorist radio nuclear incidents. Another possible danger for cardiovascular and renal illness is space exploration.