Evidence for Nephrotoxicity Prevention With Cisplatin Therapy Is Still Limited

In their article in the April 2018 issue of the Clinical Journal of Oncology Nursing, Duffy, Fitzgerald, Boyle, and Rohatgi reported (https://doi.org/10.1188/18.CJON.175-183) on their systematic literature search and evidence review in an effort to identify the optimal hydration and diuretic regimens that oncology nurses can use to prevent nephrotoxicity in patients receiving cisplatin.

Nephrotoxicity With Cisplatin

 Patients may accumulate metabolites in the renal proximal tubule cells of the kidneys, where 90% of cisplatin undergoes urinary excretion, Duffy et al. explained (https://doi.org/10.1188/18.CJON.175-183). This causes a trifecta of factors: direct inflammation, production of reactive oxygen species leading to oxidative cell damage, and cell death. See Table 1 for measures to gauge kidney function and nephrotoxicity.

“Most patients receiving cisplatin experience acute impairment of glomerular and tubular function in varying degrees,” Duffy et al. wrote (https://doi.org/10.1188/18.CJON.175-183). More severe impairment is seen with high total cisplatin doses and concurrent use of other potentially nephrotoxic medications.

It has implications for patient outcomes because chemotherapy doses may need to be reduced or withdrawn to help manage the adverse event. In most cases, nephrotoxicity is reversible, but it can sometimes result in permanent kidney injury, chronic progressive renal failure, or renal tubule function impairment. Oncology nurses must remain vigilant with preventive measures as well as monitoring for signs and symptoms to intervene and provide supportive care early if nephrotoxicity does develop.

Evidence for Interventions to Prevent Nephrotoxicity

Duffy et al. conducted (https://doi.org/10.1188/18.CJON.175-183) a systematic review to identify the body of evidence to support the development of standardized best practices to prevent nephrotoxicity with cisplatin.

Hydration: The studies reviewed found no statistically significant difference in renal function, nephrotoxicity, or Common Terminology Criteria for Adverse Events renal toxicity grade between short (i.e., 1,750–4,200 ml fluid delivered the day of cisplatin therapy) or traditional (i.e., a total of 5,500–6,300 ml fluid delivered on an inpatient basis over the course of several days) hydration approaches. One study showed a significant increase in serum creatinine (SCR) with traditional hydration but stable SCR with short hydration. Most studies demonstrated that short hydration was safe in preventing renal dysfunction and toxicity.

Magnesium: Magnesium supplementation before, during, or after cisplatin therapy either increased creatinine clearance (CRCL) and decreased SCR or resulted in stable SCR and CRCL, according to the studies Duffy et al. (2018) reviewed. When compared to controls, patients receiving magnesium supplementation had a lower relative risk of nephrotoxicity. Those who did not receive magnesium had statistically significant decreases in CRCL and increases in SCR.

Furosemide: One study showed no significant difference in SCR, CRCL, or nephrotoxicity between use of furosemide or mannitol with cisplatin therapy and that both diuretics exhibited similar effects. Another that compared hydration plus magnesium and mannitol versus hydration plus furosemide and mannitol found that the former was an independent factor in preventing nephrotoxicity. A final study showed that patients who received furosemide had significantly higher mean SCR concentrations but no significant difference in CRCL compared to patients who did not receive it.

Mannitol: Results were mixed from the studies involving mannitol. The findings from three did not support its use: One concluded that neither mannitol nor furosemide was superior in reducing nephrotoxicity after 28% of patients receiving mannitol and 19% of patients receiving furosemide developed the adverse event. Another study showed no significant difference in CRCL among patients receiving mannitol and hydration versus hydration alone. In the final study, mannitol dosages of 50 g were significantly nephrotoxic, and the study was terminated early.

But four studies supported mannitol’s protective effect against nephrotoxicity: Patients receiving mannitol plus magnesium had significantly higher increases in CRCL and decreases in SCR than those receiving hydration with mannitol, magnesium, and furosemide. Additionally, patients who did not receive mannitol with cisplatin were 2.6 times more likely to develop acute kidney injury.

Implications for Practice

Overall, Duffy et al. said (https://doi.org/10.1188/18.CJON.175-183) that the evidence regarding interventions to prevent nephrotoxicity is still limited and unable to support best practices for patients. They called for additional research in the areas of hydration, administration of magnesium and mannitol, differences among practice settings, differences among patient age ranges, and the influence of other nephrotoxic medications in patients also receiving cisplatin.

“When more evidence is available, best nephroprotective practices can be developed and implemented,” Duffy et al. said (https://doi.org/10.1188/18.CJON.175-183). “Until then, oncology nurses should closely monitor kidney function in all patients receiving cisplatin and immediately report abnormalities to the healthcare team.”

For more information about the evidence for preventing nephrotoxicity in patients receiving cisplatin, refer to the full article by Duffy et al (https://doi.org/10.1188/18.CJON.175-183).

TABLE 1. Measures of Kidney Function

Measure	Measurement Modality	Toxicity Definition
Creatinine clearance	Rate at which creatinine is cleared from the body; determined by the amount of creatinine excreted in a given time period (usually 12 or 24 hours) compared to the amount circulating in the blood, expressed in ml/min/1.73 m3	Decreased level based on age
Common Terminology Criteria for Adverse Events	Standardized definitions of toxicities among patients receiving cancer treatment	Change in serum creatinine from baseline and if dialysis is indicated
Glomerular filtration rate	Plasma or urinary clearance of exogenously administered substance, expressed in ml/min/1.73 m3	Decreased level based on age
Risk, Injury, Failure, Loss, and End-Stage (RIFLE)	Classification for acute kidney injury based on assignment of RIFLE disease determined by urine output, serum creatinine, and length of abnormal function	Changes in scores within seven days
Serum creatinine	Level of creatinine in the blood, expressed in mg/dl	Increase of a lab-determined upper limit of normal based on age; increase of more than 25% over baseline
Urinary activity of N-acetyl-beta-D-glucosaminidase	Urine test reported as u/l, u/mol of creatinine (normalized)	Increased activity correlates with renal tubular damage.

This monthly feature offers readers a concise recap of full-length articles published in the Clinical Journal of Oncology Nursing (CJON) or Oncology Nursing Forum. This edition summarizes “Nephrotoxicity: Evidence in Patients Receiving Cisplatin Therapy,” by Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN, MSN, PPCNP-BC, CPON^®, Kelley Boyle, MSN, RN, PCNS-BC, and Radha Rohatgi, PharmD, BCOP, which was published in the April 2018 issue of CJON. Questions regarding the information presented in this article should be directed to the CJON editor at CJONEditor@ons.org. Photocopying of this article for educational purposes and group discussion is permitted.