Cisplatin Nephrotoxicity - Clinical Features and Treatment

Introduction

Cisplatin is a chemotherapeutic drug used in the treatment of various cancers of solid organs such as the head, neck, lungs, testis, ovary, and breast. Nephrotoxicity is one of the side effects of this drug. It also causes gastrotoxicity, ototoxicity, myelosuppression, and allergic reactions. However, Cisplatin remains the standard component of treatment for head and neck cancers, small-cell and non-small-cell lung cancers, testicular cancer, and ovarian and cervical cancer.

What Is Cisplatin Nephrotoxicity?

Cisplatin is a nephrotoxic drug that causes acute kidney injury and chronic kidney disease. Cisplatin accumulates in the renal tubular cells and causes renal tubular dysfunction and impairment in kidney function. It is characterized by a decline in the glomerular filtration rate, an increase in serum creatinine, and a decrease in serum magnesium and potassium levels. Accumulation of Cisplatin in the renal tubular cells results in tubular cell injury and death. It also causes injury to the renal vasculature and decreases the renal blood flow resulting in the ischemic injury of the kidneys. These events together result in a cumulative loss of renal function and trigger acute renal failure.

How Does Cisplatin Nephrotoxicity Occur?

Various mechanisms contribute to renal dysfunction following the administration of Cisplatin. The mechanisms like oxidative stress, apoptosis, and inflammation contribute to cisplatin-induced nephrotoxicity. Cisplatin is a platinum compound that is eliminated via glomerular filtration and tubular secretion. Cisplatin nephrotoxicity is due to tubular toxicity, vascular damage, glomerular injury, and interstitial injury.

• Cellular Toxicity - Renal damage is caused by the accumulation of Cisplatin in the tubular fluid, which then diffuses into the tubular cells. It causes injury to the tubular cells and induces cell death. Various apoptotic pathways are involved in tubular cell death. It includes the extrinsic pathway activated through the tumor necrosis factor and cell death receptors and the intrinsic mitochondrial and endoplasmic reticulum stress pathways. Nephrotoxic doses of Cisplatin activate these pathways and induce apoptosis.

• Vasoconstriction - Vasoconstriction occurs in the microvasculature of the kidneys following Cisplatin injection. This decreases the renal blood flow and contributes to ischemic renal tubular injury.

• Proinflammatory Effects - Cisplatin induces cellular stress by the activation of mitogen-activated protein kinase pathways. It also induces the generation of reactive oxygen species resulting in cytotoxicity. Reactive oxygen species are involved in the pathogenesis of acute renal injury. Inflammation is an important mechanism responsible for Cisplatin-induced nephrotoxicity and cellular toxicity. Various inflammatory cytokines such as tumor necrosis factor-alpha, interleukin 6, interferon-gamma, and caspases are expressed in the kidneys following Cisplatin treatment. This induces the differentiation, maturation, and activation of neutrophils and T cells (thymus-dependent lymphocytes) and results in inflammatory responses.

• Effects on the Proximal Tubule - The cells of the proximal tubule are injured by Cisplatin by necrosis and apoptosis. Cisplatin nephrotoxicity is due to the increased uptake of Cisplatin by organic transporters, followed by reduced expression and function of sodium-dependent glucose and amino acid transporters, magnesium and water transporters, and the generation of reactive oxygen species.

Other mechanisms involved in Cisplatin-induced nephrotoxicity include the following:

• Inhibition of mitochondrial enzyme and reduction of mitochondrial oxidative phosphorylation.

• Inhibition of fatty acid oxidation results in the induction of hyperlipidemia and the accumulation of fatty acids and triglycerides in the kidney tissue.

• Inhibition of peroxisome proliferator-activated receptor activity in the renal epithelial cells.

Why Does Cisplatin Nephrotoxicity Occur?

Cisplatin nephrotoxicity results in acute kidney injury due to high plasma-free platinum concentrations, pre-existing renal disease, previous exposure to Cisplatin, and the concomitant use of other nephrotoxic drugs.

• High Plasma-Free Platinum Concentrations - Peak plasma concentrations increase the risk of acute kidney injury. The cumulative dose of platinum plays a role in the development of nephrotoxicity. This decreases the glomerular filtration rate and serum magnesium levels. However, the glomerular filtration rate is maintained in patients receiving low doses of Cisplatin.

• Previous Cisplatin Chemotherapy - Patients with previous Cisplatin therapy develop kidney injury on additional exposure to Cisplatin.

• Pre-existing Kidney Disease - Cisplatin increases the risk of kidney injury in patients with underlying renal disease because of the decreased clearance of Cisplatin in renal dysfunction. Cisplatin should be avoided in patients with increased serum creatinine levels.

• Concomitant Use of Other Drugs - The concomitant use of Cisplatin and other nephrotoxic drugs such as Amphotericin B, aminoglycosides, and nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk of acute kidney injury.

What Are the Clinical Features of Cisplatin Nephrotoxicity?

The clinical features of Cisplatin nephrotoxicity include the following:

• Acute Kidney Injury - The incidence of kidney injury depends on the dose and frequency of Cisplatin administration. It causes a mild to moderate increase in serum creatinine levels. It may progress to chronic kidney disease due to chronic tubulointerstitial fibrosis.

• Hypomagnesemia - Hypomagnesemia develops due to urinary magnesium wasting in Cisplatin nephrotoxicity. It can occur without acute kidney injury. It can exacerbate Cisplatin nephrotoxicity.

• Fanconi-like Syndrome - Cisplatin nephrotoxicity induces the development of Fanconi-like syndrome due to increased excretion of glucose and amino acids and the presence of tricarboxylic acid cycle metabolites in the urine. It causes tubular dysfunction. However, classic symptoms of Fanconi syndrome have not been reported.

• Distal Renal Tubular Acidosis - Patients receiving Cisplatin developed acidifying or concentrating defects despite normal renal function.

• Salt Wasting - Salt wasting is a rare feature of Cisplatin nephrotoxicity. It is characterized by polyuria, hypovolemia, and hyponatremia.

• Thrombotic Microangiopathy - Cisplatin nephrotoxicity causes direct vascular injury with secondary platelet activation.

• Anemia - Cisplatin has myelosuppressive effects. Clinical studies have shown that the renal tubular injury caused by Cisplatin is due to the deficiency of erythropoietin, which contributes to the development of anemia.

How Is Cisplatin Nephrotoxicity Treated?

• Cisplatin is discontinued in patients with acute kidney injury.

• Electrolyte disturbances like hypomagnesemia are managed with magnesium supplementation.

• Oral or intravenous supplementation is given to patients with tubular dysfunction. Alkali therapy is given to correct metabolic acidosis in patients with renal tubular acidosis.

• Intravenous saline is given for managing volume depletion and hyponatremia in patients with salt wasting.

• Discontinuation of the drug is essential in patients with thrombotic microangiopathy.

• Volume expansion with sodium chloride and various hydration regimens can prevent Cisplatin nephrotoxicity.

Conclusion

Cisplatin is a chemotherapeutic drug that causes acute kidney injury and chronic kidney disease. Cisplatin is the most effective drug in the treatment of solid-organ cancers. Various preventive measures like monitoring the dose and adequate hydration regimens can help prevent of nephrotoxicity.