Ifosfamide Nephrotoxicity - Causes, Symptoms, Prevention and Management

Introduction:

Drugs are a common cause of acute kidney injury. Compared to twenty years ago, the average patients are older, have more comorbidities, and are more likely to undergo diagnostic and therapeutic procedures that can impair their kidney function. Some drugs are known to cause nephrotoxicity; they exert their toxic effects through one or more common mechanisms. Drug-induced nephrotoxicity occurs more frequently in certain patients and clinical settings. Successful prevention requires knowledge of the pathogenic mechanisms of renal injury, patient-related and drug-related risk factors, preventive measures, vigilance, and early intervention.

Ifosfamide is used with other drugs to treat testicular cancer that have not shown improvement after treatment with other drugs or radiation therapy. Ifosfamide belongs to a family of drugs called alkylating agents. It works by slowing or inhibiting the growth of cancer cells in the body. Unfortunately, this medication tends to cause kidney injury and impairment.

What Is Ifosfamide Nephrotoxicity?

Ifosfamide can cause severe or life-threatening kidney problems. Kidney problems may occur during treatment or months or years after stopping the treatment. Therefore, this anti-cancer drug cannot be prescribed to an individual with a renal condition.

What Are the Causes of Ifosfamide Nephrotoxicity?

The kidneys primarily excrete Ifosfamide. It is highly concentrated in the urine, and concentrations in renal tubular epithelial cells are higher than in the blood. In the kidney, Ifosfamide is absorbed into kidney cells by passive diffusion. During excretion, Ifosfamide and its metabolites are secreted and reabsorbed during glomerular filtration in the renal tubules, resulting in high levels of Ifosfamide in the kidney. The causes of drug-induced renal damage are:

• Changes in Glomerular Hemodynamics: Antiprostaglandin drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) or drugs with anti-angiotensin activity to prevent blood pressure elevation, cause nephrotoxicity in the glomeruli (filtration unit of the kidney). The therapeutic mechanism of the drug affects the rate of filtration in the kidneys.

• Tubular Cell Toxicity: Tubules, especially proximal tubular cells in the kidney, are highly susceptible to drug toxicity because of their exposure to drugs during the process of concentration and reabsorption by the glomerulus. Cytotoxicity occurs through damage to tubular mitochondria, disruption of the tubular transport system, and increased oxidative stress by forming free radicals.

• Inflammation: Nephrotoxic drugs often induce inflammation in the glomerulus, proximal tubules, and the surrounding cellular matrix, which subsequently disrupts renal tissue. Inflammation disrupts normal renal function and causes toxicity, including glomerulonephritis and acute and chronic interstitial nephritis. Glomerulonephritis is closely associated with proteinuria.

• Crystal Nephropathy: Renal dysfunction is also affected by drugs that form insoluble crystals in human urine. The formation of insoluble crystals depends on urine acidity and drug concentration.

What Are the Risk Factors of Ifosfamide Nephrotoxicity?

The risk factors of Ifosfamide nephrotoxicity can be divided into two:

Age-Related Factors:

• Age older than 60 years.

• Underlying renal insufficiency (renal filtration rate < 60 mL per minute per 1.73 metre square).

• Volume depletion (low extracellular fluid volume).

• Diabetes.

• Heart failure.

• Sepsis.

Drug-Related Risk Factors:

Certain drugs are highly nephrotoxic, including aminoglycosides,Aamphotericin B, Cisplatin, contrast agents, and Cyclosporine. In addition, accompanying therapy with multiple nephrotoxins may cause synergistic nephrotoxicity and increase the risk of kidney damage.

What Are the Symptoms of Ifosfamide Nephrotoxicity?

Decreased renal function may not display signs and symptoms, and mild nephrotoxicity may go undetected. However, if nephrotoxicity is severe enough, it may show symptoms as below:

• High blood pressure.

• Shortness of breath.

• Excessive fatigue.

• Nausea.

• Chest pain or pressure.

• Fluid buildup causes swelling in the legs, ankles, and feet.

• Decreased urine output.

• Cardiac arrhythmia.

• In some patients, nephrotoxicity also affects other body systems, such as the liver and skin, and may also show signs in those areas.

What Are the Possible Complications of Ifosfamide Nephrotoxicity?

Some of the serious complications of acute kidney injury include the following:

• High Potassium Levels in the Blood: In severe cases, this can lead to weakness of muscles, paralysis, and arrhythmias.

• Too Much Acid in the Blood (Metabolic Acidosis): It can cause nausea, vomiting, drowsiness, and shortness of breath.

• Too Much Water in the Body: Too much water accumulation in the body can cause pulmonary edema and water to accumulate in the legs and arms.

When to Get Help for Ifosfamide Nephrotoxicity?

A physician’s opinion should be sought immediately if the following symptoms of Ifosfamide-induced nephrotoxicity are noticed:

• Water accumulation in legs and arms.

• Reduced urine out.

• Feeling of weakness and fatigue.

• High blood pressure.

• Chest pain.

How Is Ifosfamide Nephrotoxicity Diagnosed?

Ifosfamide-induced nephrotoxicity can be diagnosed with a blood test. Hematological nephrotoxicity assessment includes the measurement of the following:

• Blood urea nitrogen (BUN).

• Serum creatinine concentration.

• Glomerular filtration rate.

• Creatinine clearance.

It can also be diagnosed with the help of a urinalysis, wherein the following parameters are checked:

• Creatinine elimination levels.

• Urea elimination levels.

• Presence of protein.

How Is Ifosfamide Nephrotoxicity Treated?

• The focus of treatment is to minimize the damage caused by nephrotoxicity; therefore, early detection of nephrotoxicity is essential.

• Treatment is done using the drug in the case of severe nephrotoxicity.

• Adjustment of dosage is made according to the renal function.

• Removal of accumulated waste from the body by dialysis.

Prevention of Ifosfamide Nephrotoxicity:

Most episodes of drug-induced renal dysfunction are reversible. Renal function usually returns to baseline if the impairment is recognized early and the underlying drug is discontinued.

The following steps can be taken to minimize nephrotoxicity from Ifosfamide further:

• The drug dosage should be adjusted according to the renal function levels.

• Avoid taking nephrotoxic drug combinations together.

• Check other risk factors for nephrotoxicity before initiation of drug therapy.

• Ensuring adequate hydration before and during treatment with potential nephrotoxins.

• Usage of similarly effective non-nephrotoxic agents whenever possible.

Conclusion:

The kidney is a frequent site of drug toxicity because it is frequently exposed to drugs and toxic metabolites. Drug-induced nephrotoxicity is one of the main causes of acute kidney injury worldwide. In addition, in some cases, chronic drug toxicity can lead to chronic kidney disease and, ultimately, end-stage renal disease. Drugs can also disrupt the normal transport mechanisms of the kidneys and cause various electrolyte and acid-base disorders. Thus, Ifosfamide should be used when no other option is left and under the strict supervision of the physician. If any symptoms of renal failure are noticed, emergency medical services should be contacted.