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Condition Nephrotoxicity

Alternative nameRenal toxicity

Condition groupKidney, Toxicity, Urinary System

Link
https://healthjade.net/nephrotoxicity/

Condition information

Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medications, on the kidney. Risk factors of drug-induced nephrotoxicity include drug overdose, drug-drug interactions and drug-related adverse effects. Nephrotoxins are chemicals displaying nephrotoxicity. Drugs remain a relatively common cause of acute and chronic kidney injury. A combination of factors including the innate nephrotoxicity of drugs, underlying patient characteristics that increase their risk for kidney injury, and the metabolism and pathway of excretion by the kidneys of the various agents administered enhance risk for drug-induced nephrotoxicity. The nephrotoxic effect of most drugs is more profound in patients who already suffer from renal impairment. Some drugs may affect renal function in more than one way. There are various forms of nephrotoxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the decreased renal function (e.g. heparin).

Nephrotoxicity is usually monitored through a simple blood test. An elevated level of creatinine indicates poor renal function. Normal creatinine levels are between 80 – 120 mm/l. In interventional radiology, a patients’ creatinine levels are all checked prior to a procedure. Should an elevated creatinine level be found, a special contrast medium or radiocontrast is used which is less harmful for the patient.

Creatinine clearance is another measure of renal function, which may be more useful clinically when dealing with patients with early kidney disease.

Medications are a relatively common cause of kidney injury. The epidemiology of drug-induced nephrotoxicity is currently based on literature focusing on acute kidney injury (sudden episode of kidney failure or kidney damage that happens within a few hours or a few days). Drug-induced nephrotoxicity in adults is approximately 14%–26% in prospective cohort studies of acute kidney injury, whereas 16% of hospitalized acute kidney injury is due to drugs in the pediatric population. Drug-induced nephrotoxicity is more common in hospitalized patients, in particular intensive care unit patients.

Importantly, the general population is exposed to a large number of prescribed and over-the-counter drugs as well as a variety of substances available at health food stores (natural products, supplements, herbal remedies). Various imaging agents used for diagnostic purposes are also associated with nephrotoxicity. However, not all patients exposed to the various potential nephrotoxins develop kidney disease. Thus, the nephrotoxicity of medications, drugs, and other ingested substances is a complicated process that involves a combination of factors. These include the inherent nephrotoxic potential of the drug, underlying patient characteristics that enhance their risk for kidney injury, and the metabolism and excretion of the potential offending agent by the kidney.

Medications causing nephrotoxicity:

• Adefovir
• Kanamycin
• Cyclophosphamide
• Cisplatin: Cisplatin is one of the most widely used and most potent chemotherapy drugs. Cisplatin, while highly toxic, is one of the most heavily utilized chemotherapeutic agents for hematologic and solid tumor malignancies. It can be used as a single-agent or in combination therapy for induction and neoadjuvant therapy. Cisplatin is U.S. Food and Drug Administration (FDA) approved for the treatment of advanced ovarian cancer, testicular cancer, and bladder carcinoma. However, cisplatin is frequently used in an off-label fashion when the benefits may outweigh the risks of adverse drug effects. Severe renal toxicity, including acute renal failure, may occur with Cisplatin administration. These effects are cumulative and dose-related. Pretreatment hydration plays a significant role in preventing renal toxicity. The dose of cisplatin may have to be adjusted based on renal function with close monitoring of the glomerular filtration rate (GFR).
• Vancomycin: Vancomycin is a tricyclic glycopeptide antibiotic originally derived from the organism Streptococcus orientalis. Vancomycin is used for the treatment and prevention of various bacterial infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). It is also effective for streptococci, enterococci, and methicillin-susceptible Staphylococcus aureus (MSSA) infections. Vancomycin has numerous FDA-approved and off-label clinical uses.
• Tacrolimus: Tacrolimus is an immunosuppressive agent used for prophylaxis of organ rejection post-transplant. Tacrolimus use is in combination with one or, most commonly, two other immunosuppressive medications. It has an application as an agent for as prevention or treatment for certain autoimmune diseases. In solid organ transplantation, it serves as the treatment of organ rejection in kidney, liver, and heart allogeneic transplants. There is also an off-label indication for the prevention of rejection in lung transplant patients. Tacrolimus indications also include topical use in moderate to severe atopic dermatitis, as well as other off-label dermatologic disease states. Since tacrolimus use is typically in combination with other immunosuppressants, target levels usually decrease as post-transplant time increases to minimize Calcineurin Inhibitor mediated nephrotoxicity and adverse effects.
• Aminoglycosides antibiotics (e.g., gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin). Nephrotoxicity due to aminoglycosides may appear in up to 10 to 25% of patients. In patients receiving aminoglycoside therapy, renal tubular toxicity decreased blood flow to the kidneys, and reduced GFR most commonly causes the nephrotoxicity seen. Renal effects with aminoglycosides generally are reversible. Furthermore, there are risk factors associated with the development of aminoglycoside-induced nephrotoxicity, including dehydration, pregnancy, and hepatic dysfunction. Taking other medications concurrently with aminoglycosides that can cause nephrotoxicity, such as NSAIDs, cyclosporine, and diuretics, also put a patient at risk for renal problems. It is important to monitor patient renal function when taking aminoglycosides.

Nephrotoxic drugs

The initial step in the development of kidney injury involves exposure to a potentially toxic offending agent. The general population is exposed to a variety of potential nephrotoxic substances including prescribed therapeutic agents, over-the-counter products, diagnostic agents, and environmental substances. Examples of potentially nephrotoxic drugs that are utilized to treat various disease processes include antimicrobial agents, anticancer drugs, analgesics, and immunosuppressive agents. Furthermore, a large number of new medications with unknown nephrotoxic potential make it through clinical trials and are subsequently released into clinical practice where they cause kidney injury. This is likely related to exposure of these new drugs in patients who have comorbidities or other characteristics that increase nephrotoxic risk that were not included in clinical trials. Although clinicians prescribe the vast majority of potentially nephrotoxic medications, many are also available as over-the-counter preparations. Radiocontrast agents, in particular those delivered intra-arterially at high dose, are another potential cause of acute kidney injury.

In addition to rge U.S. Food and Drug Administration (FDA)–approved medications, unregulated sources of potentially nephrotoxic substances are the alternative/complementary products, which are widely available at most health food stores 19). Included are items described as herbal remedies, natural products, and nutritional supplements. Another concern is that these products often contain a number of harmful chemicals and/or contaminants that are not listed on the label. Not uncommonly, the substances listed on the package label are present in varying amounts ranging from large, to small, to even nonexistent. In addition to direct nephrotoxicity, herbal products may interact with conventional drugs producing another potential avenue of nephrotoxicity. Examples of such unlisted contents include Ephedra species and aristolochic acid as well herbal products adulterated with phenylbutazone and other nonsteroidal anti-inflammatory drugs (NSAIDs), cadmium, and dichromate.

Nephrotoxic drugs and intoxicants list

Therapeutic medications

• Antimicrobial
  • Aminoglycosides
  • Antiviral agents
  • Amphotericin B
  • Colistin
  • Polymixin B
  • Sulfadiazine
  • Quinolones
  • Vancomycin
• Chemotherapy
  • Platins
  • Ifosfamide
  • Mitomycin
  • Gemcitabine
  • Methotrexate
  • Pentostatin
  • Interleukin-2 (high dose)
  • Antiangiogenesis agents
  • Immunotherapies (immune checkpoint inhibitors, chimeric antigen receptor T cells)
• Analgesics
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Selective Cyclo-oxygenase-2 inhibitors
  • Phenacetin
  • Analgesic combinations
• Immunosuppressives
  • Calcineurin inhibitors
  • Sirolimus, everolimus
• Other
  • Angiotensin-converting enzyme inhibitors (ACE inhibitors) / angiotensin-receptor blockers(ARBs) / renin inhibitors
  • Sodium glucose transporter-2 (SGLT-2) inhibitors (canagloflozin, dapagliflozin)
  • Methoxyflurane
  • Sucrose (IVIg excipient), hydroxyethyl starch, mannitol, dextran
  • Pamidronate, Zolendronate
  • Topiramate, Zonisamide
  • Orlistat
  • Statins
  • Mesalamine

Alternative medicine/supplement products

• Herbal remedies
  • Aristolochic acid
  • Ephedra sp.
  • Glycyrrhiza sp.
  • Datura sp.
  • Taxus celebica
  • Uno degatta
  • Cape aloes
• Adulterants
  • Mefenamic acid
  • Dichromate
  • Cadmium
  • Phenylbutazone
  • Melamine

Diagnostic agents

• Radiocontrast
  • High osmolar
  • Low osmolar
  • Iso-osmolar
• Other agents
  • Gadolinium (in high dose)
  • Oral sodium phosphate solution (colonoscopy prep)

Environmental intoxicants

• Heavy metals
  • Lead
  • Mercury
  • Cadmium
  • Uranium
  • Copper
  • Bismuth
• Solvents
  • Hydrocarbons
• Other toxins
  • Silicon
  • Germanium

Types of nephrotoxicity

Cardiovascular

• General: diuretics, β-blockers, vasodilator agents
• Local: ACE inhibitors, ciclosporin.

Direct tubular effect

• Proximal convoluted tubule: Aminoglycoside (Amikacin sulfate) antibiotics (e.g. gentamicin), amphotericin B, cisplatin, radiocontrast media, immunoglobulins, mannitol
• Distal tubule: Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen, diclofenac), ACE inhibitors, ciclosporin, lithium salts, cyclophosphamide, amphotericin B
• Tubular obstruction: sulphonamides, methotrexate, aciclovir, polyethylene glycol.

Acute interstitial nephritis

• β-lactam antibiotics, vancomycin, rifampicin, sulphonamides, ciprofloxacin, NSAIDs, ranitidine, cimetidine, furosemide, thiazides, phenytoin.

Acute glomerulonephritis

• Penicillamine.

Causes of diabetes insipidus

• Lithium salts
• Amphotericin B
• Fluoride
• Demeclocycline
• Foscarnet.

Other nephrotoxins

• Heavy metals interfere with enzymes of energy metabolism.
• Aristolochic acid, found in some plants and, more dangerously, in some herbal supplements derived from those plants, has been shown to have nephrotoxic effects on humans.

Condition information addendum

Nephrotoxicity signs and symptoms

Symptoms of nephrotoxicity may begin so slowly that you don’t notice them right away.

Healthy kidneys prevent the buildup of wastes and extra fluid in your body and balance the salts and minerals in your blood—such as calcium, phosphorus, sodium, and potassium. Your kidneys also make hormones that help control blood pressure, make red blood cells, and keep your bones strong.

Nephrotoxicity means your kidneys no longer work well enough to do these jobs and, as a result, other health problems develop. As your kidney function goes down, you may:

• • have swelling, usually in your legs, feet, or ankles
• • get headaches
• • feel itchy
• • feel tired during the day and have sleep problems at night
• • feel sick to your stomach, lose your sense of taste, not feel hungry, or lose weight
• • make little or no urine
• • have muscle cramps, weakness, or numbness
• • have pain, stiffness, or fluid in your joints
• • feel confused, have trouble focusing, or have memory problems

Kidney disease can lead to other health problems. Your health care team will work with you to help you avoid or manage:

• High blood pressure. High blood pressure can be both a cause and a result of kidney disease. High blood pressure damages your kidneys, and damaged kidneys don’t work as well to help control your blood pressure. With kidney failure, your kidneys can’t get rid of extra water. Taking in too much water can cause swelling, raise your blood pressure, and make your heart work harder. Blood pressure-lowering medicines, limiting sodium and fluids in your diet, staying physically active, managing stress, and quitting smoking can help you control your blood pressure.
• Heart disease. Kidney disease and heart disease share two of the same main causes: diabetes and high blood pressure. People with kidney disease are at high risk for heart disease, and people with heart disease are at high risk for kidney disease. The steps that you take to manage your kidney disease, blood pressure, cholesterol, and blood glucose (if you have diabetes) will also help you prevent heart attacks or strokes.
• Anemia. When kidneys are damaged, they don’t make enough erythropoietin (EPO), a hormone that helps make red blood cells. Red blood cells carry oxygen from your lungs to other parts of your body. When you have anemia, some organs—such as your brain and heart—may get less oxygen than they need and may not function as well as they should. Anemia can make you feel weak and lack energy. Your health care provider may prescribe iron supplements. In some cases, your provider may prescribe medicines to help your body make more red blood cells.
• Malnutrition. As your kidney disease gets worse, it can be a challenge to keep yourself well fed. You may not feel hungry, food may taste different, or you may lose interest in food. Infections and other stresses on your body can make it hard for your body to use the food you do eat. Working closely with a dietitian to be sure you’re eating enough of the right foods can have long-term benefits for people with kidney disease.
• Feeling itchy. Itching is common and happens for different reasons. You may feel itchy because you have dry skin. Using a moisturizer may help. Or, you may feel itchy because you have too much phosphorus in your blood. Eating less phosphorus may help stop the itching. Your health care provider may prescribe a medicine called a phosphate binder for you to take with meals. These medicines keep the phosphorus in your food from entering your bloodstream. UV light from sunlight or a light box helps some people find relief
• Mineral and Bone Disorder. Healthy kidneys balance the levels of calcium and phosphorus in your blood and make hormones that help keep your bones strong. As kidney function drops, your kidneys
  • • make less of the hormone that helps your body absorb calcium. Like one domino knocking over another, the low level of calcium in your blood triggers the release of parathyroid hormone (PTH). Parathyroid hormone (PTH) moves calcium from your bones into your blood. Too much parathyroid hormone (PTH) can also make you feel itchy.
  • • don’t remove as much phosphorus. Extra phosphorus in your blood also pulls calcium from your bones.
  • Without treatment, bones may become thin and weak. You may feel bone or joint pain. Changes to your eating plan, medicines, supplements, and dialysis may help.

Following your treatment plan can help you avoid or address most of these symptoms. Your treatment plan may include regular dialysis treatments or a kidney transplant, a special eating plan, physical activity, and medicines.

Factors associated with drug-induced nephrotoxicity

The development of drug-induced nephrotoxicity can be best understood by examining the factors that contribute to nephrotoxicity. Exposure to a potentially nephrotoxic medication is an obvious requirement. Drugs may be modestly nephrotoxic or maintain high risk to cause kidney injury on the basis of their structure, dose, metabolic handling, excretory pathway through the kidney, and other characteristics. Underlying patient characteristics, such as comorbid conditions, genetic determinants of drug metabolism and transport, and immune response genes, are also important in drug nephrotoxicity. As the kidney metabolizes and excretes (through filtration and tubular secretion) many ingested drugs, the interaction of these substances with various parts of the nephron may be associated with nephrotoxicity. For kidney injury to occur, some combination of these three risk factors is generally present. More often than not, more than one is present. It is the differences in structure of the ingested drug, underlying patient characteristics, and alterations in kidney handling of the ingested substance that likely explain the variability and heterogeneity observed with drug-induced nephrotoxicity.

Drug combinations

Combinations of potential nephrotoxic drugs can increase risk for kidney injury with examples including vancomycin+piperacillin/tazobactam, aminoglycosides+cephalothin, NSAIDs+radiocontrast, and cisplatin+aminoglycosides 32). The pathway of excretion by the kidney represents another risk for drug nephrotoxicity. Medications compete with endogenously produced substances (and other drugs) for transport proteins and influx/efflux transporters, which can increase intracellular drug concentration and risk for kidney injury 33). These drug-drug interactions increase kidney injury and overall drug toxicity.

Innate drug nephrotoxicity

A number of medications maintain higher potential for causing kidney injury on the basis of their more significant innate nephrotoxicity. These drugs, which include the aminoglycosides, amphotericin B, the polymyxins, and cisplatin, may cause kidney injury with therapeutic doses and brief durations of exposure. Accumulation of high concentrations of the polycationic aminoglycosides within intracellular lysosomes causes lysosomal injury, which is associated with phospholipid membrane injury, oxidative stress, and mitochondrial dysfunction. This promotes proximal tubular cell apoptosis and necrosis with clinical manifestations such as an isolated proximal tubulopathy or acute kidney injury.

Amphotericin B, and the lipid/liposomal formulations to a lesser degree, cause kidney injury by disrupting tubular cell membranes and increasing permeability to cations, which result in tubular dysfunction due to cell swelling/dysfunction. In general, the lipid/liposomal formulations are less nephrotoxic. The polymixin antimicrobial agents, colistin and polymyxin B, are highly nephrotoxic with a very narrow therapeutic window. Nephrotoxicity is related to their D-amino content and fatty acid component, which increases cellular membrane permeability and allows cation influx. This effect leads to tubular cell swelling and lysis with acute kidney injury development.

The acyclic nucleotide phosphonates (adefovir, cidofovir, tenofovir) enter the cell via basolateral human organic anion transporter–1 (hOAT-1) and promote cellular injury primarily through disturbing mitochondrial function. Mitochondrial injury is manifested by mitochondrial enlargement, clumped cristae, and convoluted contours that impair cellular energetics. Tenofovir, which is employed widely to treat hepatitis B virus and HIV infection, is associated with proximal tubulopathy and acute kidney injury.

Antiangiogenesis therapy with monoclonal antibodies against vascular endothelial growth factor (VEGF), circulating soluble VEGF receptors, and small molecule tyrosine kinase inhibitors that impair intracellular VEGF signaling pathways are associated with various forms of kidney injury. In the kidney, VEGF is produced by podocytes and binds glomerular and peritubular capillary endothelial cell VEGF receptors. Glomerular endothelial VEGF receptor binding maintains normal fenestrated endothelial health and is important for normal functioning of the glomerular basement membrane. Reduction in VEGF levels or signaling pathways by antiangiogenic drugs promotes loss of the healthy fenestrated endothelial phenotype and promotes microvascular injury and thrombotic microangiopathy, causing proteinuria and acute kidney injury. Reduced nephrin expression in the slit diaphragms may also contribute to the development of proteinuria. Although other kidney lesions occur with these drugs, endothelial injury and thrombotic microangiopathy are most common. By interfering with local alternative complement pathway regulators, these drugs may also activate complement and increase risk for thrombotic microangiopathy.

Drug-induced inflammation

Another pathway of drug-induced nephrotoxicity is through induction of an inflammatory response by the host, which can target the kidney. Through multiple mechanisms (hapten/prohapten, molecular mimicry, immune-complex formation), medications can promote the development of acute interstitial nephritis leading to acute kidney injury and/or various urinary abnormalities such as tubular proteinuria, pyuria, and hematuria. Classic drugs associated with acute interstitial nephritis include antimicrobial agents (in particular B-lactams and sulfonamides), NSAIDs, proton pump inhibitors, and aminosalicylates. Newer agents such as the immune checkpoint inhibitors (ipilimumab, nivolumab, pembrolizumab) cause acute interstitial nephritis via activation of T cells and perhaps reducing tolerance to exogenous drugs. As will be discussed, the patient’s genetic makeup may enhance immunogenicity to exogenous agents.

Drug-induced cast nephropathy

Another intriguing drug-related kidney injury is vancomycin-related obstructive tubular cast formation. Using immunohistologic staining techniques to detect vancomycin in kidney tissue, casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin have been observed in patients with acute kidney injury. In these patients, high vancomycin trough plasma levels were observed. These same vancomycin casts were reproduced experimentally in mice using in vivo imaging techniques. Thus, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular injury with development of vancomycin-associated cast nephropathy.

Updated: 2022-11-12