What Is Nephrotoxicity?
The kidneys are an important organ of the body, performing various functions like removing waste products from the body and maintaining homeostasis. Thus, they are the main target organ for all kinds of toxins. Nephrotoxicity is a disease in which kidney functions are badly hampered due to external or internal toxins. These toxins can be fungi, certain drugs used for cancer treatment, antibiotics like aminoglycosides, metals like mercury, lead, and arsenic, or stimulant drugs like cocaine.
Nephrotoxicity could result from changes in the blood flow, direct injury to kidney cells or tissues, inflammation, or obstruction of excretion. Kidney tubules, especially proximal tubules, are more exposed to the drugs because of the reabsorption process after the filtration. Hence they are more susceptible to drug toxicity.
Cytotoxicity or toxicity of the cells is caused by damage to the tubular cells, a disturbed transport system, and an increased generation of free radicals. Drugs cause approximately twenty percent of nephrotoxicity, and medications used by senior citizens induce around sixty-six percent of nephrotoxicity. A proper understanding of the pathophysiology of nephrotoxicity is required for drug development with reduced side effects.
How Is Nephrotoxicity Diagnosed?
Nephrotoxicity can be diagnosed by blood tests measuring blood urea nitrogen levels or BUN, serum creatinine, glomerular filtration rate, and creatinine clearance. These tests to assess nephrotoxicity are helpful only when the kidneys are majorly damaged already. There is a need for biomarkers that can detect dysfunction early.
The selected types of nephrotoxicity include aminoglycoside toxicity, amphotericin B toxicity, contrast-induced nephropathy, calcineurin inhibitor nephrotoxicity, cisplatin nephrotoxicity, ifosfamide nephrotoxicity, foscarnet nephrotoxicity, crystal-forming drug nephrotoxicity, rhabdomyolysis, and multiple myeloma. Let's know about these toxicities and their pathophysiologies individually.
What Are the Selected Types of Nephrotoxicity?
Aminoglycosides are a group of antibiotics used to treat certain bacterial infections. Aminoglycosides affect the proximal tubular cells of the kidneys. The proximal tubular cells are a significant part of the kidney where the solutes' transportation and reabsorption occur.
Aminoglycosides are filtered by a bunch of blood vessels in the kidney and enter the proximal tubular cells, where they are embodied in cells containing digestive enzymes - lysosomes. These nephrotoxins change the fat metabolism within the proximal tubular cells and also cause constriction of the kidney blood vessels. The dosage and therapy duration are the two important factors of aminoglycoside toxicity causing acute kidney injury. Around five percent of the administered drug dose is accumulated within the cells. However, this uptake is saturable and limited after a single dose. Therefore a single dose per day is preferred to three doses as that leads to less drug accumulation in the proximal cells.
Amphotericin B Nephrotoxicity:
Amphotericins are antifungal medicines that act upon fungi causing infections. These drugs bind to the sterols (cholesterol) or the fat cells in the cell membrane. This leads to the development of holes in the cell membrane, making it highly permeable. This membrane deformity disturbs the electrolyte balance within and outside the cells. Hydrogen ion leaks in the collecting ducts lead to distal renal tubular acidosis (dRTA) - the presence of too much acid in the blood due to inadequate removal.
Contrast-induced nephropathy damages kidney function by administering certain contrasts or dyes during diagnostic or therapeutic evaluations. Contrast media directly damages the proximal tubule cells and resists the kidney blood flow by increasing blood viscosity. They also cause constriction of the kidney blood vessels, which can prove fatal to patients with chronic kidney disease who already have abnormalities in their blood vessels. Preexisting chronic kidney disease is a risk factor for contrast-induced nephropathy.
Calcineurin Inhibitor Nephrotoxicity:
Calcineurin inhibitors are immunosuppressant drugs used for the treatment of auto-immune conditions. These drugs cause nephrotoxicity by constricting the kidney blood vessels. Continuous injury can lead to fibrosis. Injury to the lining of the blood vessels causes small clots within them, resulting in organ damage- thrombotic angiopathy. They also induce reactive oxygen species production that causes cell membranes to rupture and cell death.
Cisplatin is a chemotherapeutic drug for treating several cancers of the bladder, head and neck, ovary, testicles, and lungs. Cisplatin affects the proximal tubules, glomeruli (a bunch of blood vessels where filtration occurs), and distal tubules. After several days of cisplatin administration, the serum creatinine and blood urea nitrogen increase have been found. Concentrated levels of the drug in the blood cause its uptake by the cells and injure the D.N.A. This further causes mass cell death and inflammatory response. Strategies that aim to reduce the cellular uptake of cisplatin and simultaneously reduce inflammation can help prevent nephrotoxicity.
Ifosfamide is an anti-cancer drug used to treat several cancers like lymphoma, sarcoma, and lung cancer. It causes toxicity to the proximal tube cells leading to Fanconi syndrome - a defect of the proximal tubule that prevents them from absorbing the electrolytes they otherwise absorb. Irreversible kidney damage has been reported in patients administered ifosfamide and cisplatin simultaneously.
Foscarnet is an antiviral drug used to treat viral infections caused by the herpes virus family. It also treats resistant cytomegalovirus infections. It causes interstitial nephritis (a kidney disorder where the spaces between the kidney tubules become swollen) and the formation of crystals of calcium or sodium salts within the renal tubules. It binds with calcium ions leading to a decrease in the calcium levels in the bloodstream.
Crystal-forming Drug Nephrotoxicity:
Drugs such as Acyclovir, Methotrexate, ethylene glycol, and protease inhibitors such as Indinavir cause the formation of crystals in the tubes leading to acute kidney injury.
It is the breakdown of the skeletal muscle tissues and releasing certain toxic contents into the blood circulation. It causes constriction of the kidney blood vessels and the formation of casts within the tubules, thus causing toxicity to the proximal tubules.
Multiple myeloma is a cancer of plasma cells, a type of white blood cell. The plasma cells outgrow other cells in the bone marrow, causing bone destruction, excess of M protein, and removal of other blood-forming cells. Multiple myeloma causes protein deposition in the kidneys leading to amyloidosis - a rare disease in which protein builds up in the organs and interferes with their functioning. Multiple myeloma leads to the formation of protein plugs in the renal tubules causing kidney failure. Plasma cells enter the kidneys directly, leading to their dysfunction. Medications used to treat multiple myeloma can cause kidney toxicity. Bortezomib treats multiple myeloma swelling in the kidneys and acute kidney injury.
Nephrotoxicity has been associated with chronic kidney diseases. Biomarkers like BUN and serum concentration cannot determine nephrotoxicity unless it has progressed to a great extent. Early diagnosis of nephrotoxicity could reduce the cost losses during the trial of new drugs. Therefore, new biomarkers are needed so that nephrotoxicity can be detected and treated at an early stage, thus reducing fatality.
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