Unit 5

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C Nephrotoxicity Evidence in patients receiving cisplatin therapy Elizabeth A. Duffy, DNP, RN, CPNP, Wendy Fitzgerald, RN, MSN, PPCNP-BC, CPON®, Kelley Boyle, MSN, RN, PCNS-BC, and Radha Rohatgi, PharmD, BCOP

CISPLATIN IS A PLATINUM COMPOUND THAT HAS BEEN USED as a chemotherapeutic agent for many different cancers, including ovarian, testicular, lung, cervical, and bladder cancers (Ruggiero, Rizzo, Trombatore, Maurizi, & Riccardi, 2016; Santoso, Lucci, Coleman, Shafer, & Hannigan, 2003). The primary dose- limiting toxicity of cisplatin is nephrotoxicity, a well-known side effect (Jones, Spunt, Green, & Springate, 2008; Miller, Tadagavadi, Ramesh, & Reeves, 2010). Nephrotoxicity involves glomerular or tubular dysfunction of the kidneys after exposure to medications, other treatments, or toxins (Skinner, 2011). Nephrotoxicity associated with cisplatin is related to accu- mulation of metabolites in the renal proximal tubule cells of the kidneys, where about 90% of cisplatin undergoes urinary excretion (Ruggiero et al., 2016). Accumulation of these metabolites causes direct inflammation; the production of reactive oxygen species, which leads to oxidative cell damage; and cell death (Miller et al., 2010; Ruggiero et al., 2016). Many methods are available to measure kidney function and define nephrotoxicity or acute kidney injury (see Table 1).

Most patients receiving cisplatin experience acute impairment of glo- merular and tubular function in varying degrees. Toxicity is dependent on individual cisplatin pharmacokinetics and is usually more severe with high total cisplatin doses and when other potential nephrotoxic medications are given concurrently (Skinner, 2011; Womer, Pritchard, & Barratt, 1985). In one study, children aged 10 years or older at treatment had a lower glomerular filtration rate 10 years after therapy compared to children aged younger than 10 years at treatment (Skinner et al., 2009).

Nephrotoxicity can be reversible, but for some individuals, it can result in permanent kidney injury, chronic progressive renal failure, or renal tubule function impairment (Skinner et al., 2009). Chronic and severe reductions of renal function have several sequelae. The immediate impact may be dose reduction or cessation of potentially lifesaving nephrotoxic chemotherapy, thereby increasing the risk of relapse or progression of the cancer. In the event of a disease relapse or progression, changes to renal function may limit enrollment in phase 1 or 2 clinical trials because of inclusion parameters related to baseline renal function.

Hydration and diuretics have been used in conjunction with cisplatin administration for decades to improve the excretion of cisplatin and reduce the incidence of nephrotoxicity. One method of promoting this excretion is through osmotic diuresis with mannitol (Morgan et al., 2014). However, the amount of hydration, the infusion time for hydration, and the use of diuretics vary among treatment protocols. The optimal hydration and diuretic reg- imen necessary to prevent cisplatin nephrotoxicity is unknown.

KEYWORDS

cisplatin; hydration; nephrotoxicity;

cancer; mannitol; magnesium

DIGITAL OBJECT IDENTIFIER

10.1188/18.CJON.175-183

BACKGROUND: Cisplatin has been used as a

chemotherapeutic agent to treat many different

cancers. A well-known side effect of cisplatin is

nephrotoxicity, which is the primary dose-limiting

toxicity. Hydration in conjunction with appropriate

diuresis can decrease the incidence of nephro-

toxicity.

OBJECTIVES: This article aims to identify best

practices in supportive therapy for patients receiv-

ing cisplatin therapy.

METHODS: A team was assembled to review

research-based evidence and summarize rec-

ommendations to address appropriate hydration

regimens and forced diuresis for patients receiving

cisplatin chemotherapy.

FINDINGS: After a systematic search of the

literature, only one pediatric study was found.

The remaining 22 research-based studies of

adults were synthesized and critically appraised.

Hydration is necessary to prevent nephrotoxicity

with cisplatin administration. In addition, the

administration of magnesium and mannitol may

assist in maintaining renal function and reducing

nephrotoxicity in adults receiving cisplatin. Addi-

tional research is needed to evaluate outcomes of

these interventions in the pediatric population.

✔

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Evidence-Based Guideline Development Methods To identify best practices, the current authors conducted a systematic review to identify optimal hydration and diuretic reg- imens to prevent nephrotoxicity in patients receiving cisplatin therapy. The team included a pediatric nurse practitioner as team leader, a pharmacist, two nurses, and a mentor with experience in evidence-based reviews.

The team developed the following two clinical questions that helped identify a population, intervention, and outcome (Melnyk & Fineout-Overholt, 2015) to guide the systematic review:

ɐ Among patients receiving cisplatin chemotherapy (including various doses and infusion duration), what is an appropriate

regimen of hydration and/or forced diuresis to prevent or decrease the incidence of nephrotoxicity?

ɐ Among patients receiving cisplatin chemotherapy (including various doses and infusion duration), what regimen of hydra- tion and/or forced diuresis promotes kidney function? A systematic search of the literature was performed with guid-

ance from a medical librarian. The search included the following databases: PubMed, CINAHL®, and the Cochrane Library. Keywords and Medical Subject Heading (MeSH) terms consisted of cisplatin, nephrotoxicity and nephrotoxicity prevention, mannitol, hydration, magnesium, diuresis, mannitol, and furosemide. Limits were set for the English language and human studies. None were set regarding patient age in an effort to find all evidence related to the topic. Research studies, meta-analyses, and guidelines were included. In addition, the team searched the websites of the American Society of Clinical Oncology, the Oncology Nursing Society, and the Association of Pediatric Hematology/Oncology Nurses, and Wolters Kluwer’s UpToDate site for guidelines related to the topic.

The initial search was conducted in March 2015 with no pub- lication limit identified. A repeat search of the literature was performed in March 2016 using the same databases, keywords and MeSH terms, and limits. A publication date limit of March 2015 to March 2016 was applied to the repeat search and revealed six new articles. Figure 1 illustrates the literature exclusion process. Based on expert consensus of the team, articles that evaluated oral fluids as the sole source of hydration were excluded because of the improbability of patients tolerating large volumes of oral hydration during chemotherapy treatment. In addition, articles including hypertonic saline were excluded because no clinical indication sug- gests the use of this fluid for routine hydration (Platania, Verzoni, & Vitali, 2015). Ultimately, 23 articles were identified, which included all age ranges and which are summarized in the current evidence-based review. Only one pediatric study was discovered in the search, which is summarized. Most of this review consists of a synthesis of evidence from studies of adults. The evidence quality was graded using the Grading of Recommendations Assessment, Development, and Evaluation system (Guyatt et al., 2011).

Four clinical practice guidelines were identified from the search. One guideline (UpToDate) was not included because of its paucity of references; two guidelines from the American Society of Clinical Oncology were excluded because they did not include recommen- dations regarding hydration or diuresis. The remaining guideline by Launay-Vacher, Rey, Isnard-Bagnis, Deray, and Daouphars (2008) was evaluated with the Appraisal of Guidelines for Research and Evaluation II tool. Because of its low rating, the authors did not include this guideline in the body of evidence.

Evidence Review Pediatric Review Zareifar et al. (2013) evaluated tubular kidney function in a cohort of 20 children receiving cisplatin 50–75 mg/m2 every three weeks for

TABLE 1.

MEASURES OF KIDNEY FUNCTION REPORTED IN THE EVIDENCE REVIEW

MEASURE MEASUREMENT MODALITY TOXICITY DEFINITION

Creatinine clearance

Rate at which creatinine is cleared from the body; determined by the amount of creatinine excreted in the urine in a given time period (usually 12 or 24 hours) compared to the amount circulating in the blood, expressed in ml/min/1.73 m2

Decreased level based on age

CTCAE Standardized definitions of toxicities among patients receiving cancer treatment

Change in serum creatinine from baseline and if dialysis is indicated (CTCAE, version 4.03); studies prior to 2010 used 4.0 version.

Glomerular filtration rate

Plasma or urinary clearance of exogenously adminis- tered substance expressed in ml/min/1.73 m2

Decreased level based on age

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 7 days

Serum creatinine

Level of creatinine in the blood expressed in mg/dl

Increase of a laboratory determined upper limit of normal based on age; increase by more than 25% over baseline

Urinary activity of NAG

Urine test reported as u/L, u/mmol of creatinine (normalized)

Increased urinary NAG excretion correlates with renal tubular damage.

CTCAE—Common Terminology Criteria for Adverse Events; min—minute; NAG—N- acetyl-beta-D-glucosaminidase; RIFLE—Risk, Injury, Failure, Loss, and End-Stage Note. Based on information from Bellomo et al., 2007; Murray et al., 2013; National Cancer Institute, 2010; Stevens et al., 2006.

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treatment of neuroblastoma or germ cell tumors. Children received 3 L/m2 of hydration and mannitol every 6 hours starting 24 hours before cisplatin and continuing for one day following cisplatin. The children also received magnesium sulfate infusions every 12 hours for a total of four doses. No significant change in the mean glomer- ular function rate was observed before cisplatin treatment (119.81 ml/minute/1.73 m2, SD = 36.82) compared to the mean after the third cisplatin treatment (127.37 ml/minute/1.73 m2, SD = 38.99, p = 0.638).

Hydration Nephrotoxicity was described in nine studies among adults receiv- ing cisplatin therapy by either comparing hydration regimens, short versus traditional hydration (n = 4), or evaluating renal outcomes with one specific hydration regimen (n = 5). A short hydration reg- imen was commonly delivered on an outpatient basis and ranged from 1,750–4,200 ml of fluid delivered on the day of cisplatin therapy, whereas a traditional hydration regimen was commonly delivered on an inpatient basis and consisted of a total of 5,500– 6,300 ml of fluid delivered during multiple days (see Table 2).

No statistically significant difference in renal function or nephrotoxicity was reported among adults receiving short versus traditional hydration regimens (Al Bahrani, Moylan, Forouzesh, Della-Fiorentina, & Goldrick, 2009; Oka et al., 2014; Ouchi, Asano, Aono, Watanabe, & Kato, 2014). In two of the studies, serum creatinine (SCR) and creatinine clearance (CRCL) were stable between both groups (Al Bahrani et al., 2009; Ouchi et al., 2014); however, one study showed a significant increase in SCR among the traditional hydration group members, whereas the SCR of the short hydration group members remained stable (Sakaida et al., 2016). In addition, no significant differences were observed in renal toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, among individ- uals receiving traditional versus short hydration regimens (Oka et al., 2014; Ouchi et al., 2014). However, grade 2 toxicity was noted among one of the 17 adult patients receiving 2.2 L of fluid on the day of cisplatin followed with oral hydration (Oka et al., 2014).

Five studies described renal function or nephrotoxicity after patients received short hydration (from 1,400–3,000 ml) of fluid on the day of cisplatin administration. Most studies revealed that short hydration was safe in preventing renal dysfunction and tox- icity (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al., 2012; Tiseo et al., 2007; Vogl, Zaravinos, Kaplan, & Wollner, 1981). After several courses of cisplatin, only 3 of 242 patients had SCR levels greater than 2 mg/dl and 1 patient had a SCR level greater than 3 mg/dl (Vogl et al., 1981). Other evidence reported no significant change in median SCR or median CRCL among adults receiving multiple cycles of cisplatin at 75 mg/m2 or greater (Tiseo et al., 2007). After multiple cisplatin cycles, a grade 2 or higher renal tox- icity according to CTCAE, version 4.0, was noted in only 0.3%–8.6% of patients receiving 1,450–2,250 ml hydration on the day of cis- platin (Horinouchi et al., 2013; Hotta et al., 2013; Lavolé et al., 2012).

Magnesium Seven studies evaluated magnesium as an IV supplement, an additive to IV hydration, and/or an oral supplement. Results indi- cated either an increase in CRCL along with a decrease in SCR (Muraki et al., 2012) or stable CRCL and SCR (Bodnar et al., 2008; Oka et al., 2014; Willox, McAllister, Sangster, & Kaye, 1986; Yamamoto et al., 2015) when patients received magnesium sup- plementation before, during, or after cisplatin therapy. Among the studies reporting nephrotoxicity according to CTCAE, less nephrotoxicity was noted in patients who received magnesium supplements compared to the control groups (Kidera et al., 2014; Yoshida et al., 2014). In addition, a lower relative risk of nephro- toxicity according to the Risk, Injury, Failure, Loss, and End-Stage kidney disease classification was noted among patients receiving magnesium compared to patients who did not receive magnesium (7% versus 50% risk, p = 0.03) (Yamamoto et al., 2015). Patients who did not receive magnesium supplements had a statistically significant decrease in CRCL and statistically significant increase in SCR (Bodnar et al., 2008; Oka et al., 2014). In addition, multi- variate analysis revealed that the absence of magnesium infusion was a significant independent factor for decreased CRCL (p < 0.001) (Oka et al., 2014). Bodnar et al. (2008) and Willox et al. (1986) treated patients with magnesium three times per day in between chemotherapy cycles, but no evidence suggested that this provided any additional nephroprotection to the regimen.

Furosemide Three studies examined the role of furosemide in cisplatin- associated nephrotoxicity. Ostrow et al. (1981) found no signifi- cant differences in SCR, CRCL, or nephrotoxicity among patients receiving furosemide 40 mg immediately prior to cisplatin com- pared to mannitol 37.5 g by a six-hour infusion with cisplatin. The

FIGURE 1.

PRISMA DIAGRAM OF SEARCH STRATEGY

PRISMA—Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Records excluded because of

evaluation of animals, basic

or systematic reviews, or no

evaluation of nephrotoxicity

(n = 293)

Records identified through

database search and

screened after duplicates

removed (n = 326)

Full-text articles assessed for

eligibility (n = 33)

Studies included in evidence

(N = 23)

Full-text articles excluded

because of evaluation of drug

efficacy or dependence on

oral hydration (n = 10)

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NEPHROTOXICITY

TABLE 2.

LITERATURE ON HYDRATION AND DIURETIC SUPPLEMENTATION IN ADULTS RECEIVING CISPLATIN

STUDY SAMPLE AND CISPLATIN DOSE HYDRATION AND/OR DIURETIC FINDINGS

Short versus traditional hydration

Al Bahrani et al., 2009 145 adults, 88 outpatients on short hydration and 57 inpatients on traditional hydration

Outpatient hydration: prehydration 2,000 ml, then cisplatin 1,000 ml, then 100 ml posthydration; inpatient hydration: same as outpatient except extra 2,000 ml posthydration

Mean basal serum CRCL (input = 75 ml/ minute, output = 84 ml/minute); no statistically significant difference between groups in maximum mean percentage change from baseline to maximum SCR, from baseline to 2 months postinfusion SCR, or with different cisplatin doses

Oka et al., 2014

85 adults, 41 on high volume without magnesium, 27 on high volume with magnesium, and 17 on low volume with magnesium

High volume without magnesium: total volume 3.55 L on day 1 and 950 ml on days 2 and 3; high volume with magnesium: total 3.55 L on day 1 and 950 ml on days 2 and 3; low volume with magnesium: total 2.2 L on day 1 and oral hydration only on days 2 and 3

Maximum toxicity grade according to SCR; high volume without magnesium: 22 patients with grade 1, 17 with grade 2, 2 with grade 3; high volume with magne- sium: 26 with grade 1; low volume with magnesium: 15 with grade 1, 1 with grade 2

Ouchi et al., 2014 30 adults, 13 on short hydration and 17 on continuous (traditional) hydration

Short hydration: prehydration of 1,000 ml, then cisplatin 500 ml, then 500 ml; continuous hydration: normal saline or maintenance solution over 24 hours in hospital (rate not reported)

No SCR differences (p = 0.32): short hydra- tion = 0.83 mg/dl, continuous hydration = 0.71 mg/dl; no CRCL differences (p = 0.39): short hydration = 68 ml/minute and continuous hydration = 73 ml/minute; no patients had grade 2 or higher toxicity with short hydration, and 2 had grade 2 or higher toxicity with continuous hydration.

Sakaida et al., 2016 143 adults, 74 on short hydration and 69 on traditional hydration

Short hydration: 700 ml, then cisplatin (0–500 ml), then 500 ml followed with oral hydration only; traditional hydration: 1–1.5 L the day before cisplatin, 2.1 L and cisplatin (0–500 ml) on day 1, and 1 L on days 2 and 3

SCR over 4 cycles: short hydration was stable and traditional hydration increased.

Short hydration

Horinouchi et al., 2013 44 adults; cisplatin 75 mg/m2 or more every 3 weeks

700 ml prehydration, then cisplatin in 250 ml, then 500 ml posthydration

After cycle 1, no patients had grade 2 or greater toxicity; after cycle 3, 1 patient had grade 2 or greater toxicity; post-treatment SCR median = 0.75, range = 0.4–1.4

Hotta et al., 2013 46 adults; cisplatin 60 mg/m2 or more every 3–4 weeks up to 6 cycles

500 ml prehydration, then cisplatin in 500 ml, then 500 ml and patients requested to drink at least 1 L of water on days 1–3 posthydration

After cycle 1, 2 patients had grade 2 or greater toxicity; in cumulative cycles, 4 had grade 2 or greater toxicity

Lavolé et al., 2012 357 adults; cisplatin 75 mg/m2 or more

2 L prehydration, then cisplatin in 250 ml; patients were monitored in clinic for 6 hours, then instructed to drink fluids at home.

Cumulative cycles: 21 patients had neph- rotoxicity, 20 had grade 1 toxicity, 1 had grade 3 toxicity.

Tiseo et al., 2007 107 adults; cisplatin 75 mg/m2 or more every 3 weeks

1 L prehydration, then cisplatin in 500 ml, then 500 ml posthydration; furosemide as needed for urine output 100 ml/ hour during the 2 hours before and after cisplatin

5 patients had renal toxicity, 2 had grade 2, 1 had grade 4, and 2 had toxicity unrelated to cisplatin; no change in median SCR (p = 0.36, median = 0.9 mg/dl, range = 0.5–1.8); no change in median CRCL (p = 0.64, median = 87 ml/minute, range = 40.5–183.5)

Vogl et al., 1981 158 adults; cisplatin 50 mg/m2 every 3–4 weeks

Cisplatin given 30 minutes after starting a 2-hour infusion of 2 L fluid

8 patients had SCR greater than 1.5 mg/dl; 3 patients had SCR greater than 2 mg/dl; 1 patient had SCR greater than 3 mg/dl.

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TABLE 2. (CONTINUED)

LITERATURE ON HYDRATION AND DIURETIC SUPPLEMENTATION IN ADULTS RECEIVING CISPLATIN

STUDY SAMPLE AND CISPLATIN DOSE HYDRATION AND/OR DIURETIC FINDINGS

Magnesium

Bodnar et al., 2008 40 adults, 20 with magnesium and 20 with no magnesium; cisplatin 75 mg/m2

Magnesium sulfate 5 g in prehydration and oral supplementation with magnesium subcarbonate 500 mg 3 times per a day between cycles until three weeks after last cycle

Patients who received magnesium had no significant alterations in renal function; the control group showed significantly increased SCR (p = 0.0069) and a reduction in CRCL (p = 0.0077).

Kidera et al., 2014 401 adults, 67 with magnesium and 334 with no magnesium; cisplatin dose greater than 60 mg/m2

Magnesium group had 2.5 g magnesium sulfate posthydration

Nephrotoxicity was reported in 4 patients who received magnesium versus 123 patients who did not receive magnesium (p < 0.0001).

Muraki et al., 2012 50 adults, 20 with magnesium and 30 with no magnesium; cisplatin 75 mg/m2

Magnesium group: normal saline, mannitol, and 8 meq magnesium sulfate; no magnesium group: normal saline, mannitol, and furosemide

Patients who received mannitol and magnesium prior to cisplatin showed a significantly greater increase in CRCL (p = 0.004) and decrease in SCR (p = 0.0148).

Oka et al., 2014 85 adults, 41 high volume without mag- nesium, 27 high volume with magnesium, and 17 low volume with magnesium

High volume without magnesium: total volume 3.55 L on day 1 and 950 ml on days 2 and 3; high volume with magnesium: total 3.55 L on day 1 and 950 ml on days 2 and 3; low volume with magnesium: total 2.2 L on day 1 and oral hydration only on days 2 and 3

Maximum toxicity grade according to SCR: high volume without magnesium: 22 patients had grade 1, 17 had grade 2, and 2 had grade 3; high volume with magnesium: 26 had grade 1; low volume with magnesium: 15 had grade 1, and 1 had grade 2; absence of magnesium infusion was an independent factor for decreased CRCL (p < 0.001).

Willox et al., 1986 17 adults, 8 with magnesium and 9 with no magnesium; cisplatin 20 mg/m2 per day for 5 days

Magnesium sulfate 8 mmol/500 ml and oral supplementation with magnesium citrate 10 mmol 3 times a day when IV infusion was discontinued through the next cycle

Patients who received magnesium had significantly reduced renal tubule damage as measured by NAG (p < 0.01) and fewer treatment delays. CRCL and SCR did not differ between the groups.

Yamamoto et al., 2015 28 adults, 14 with magnesium and 14 with no magnesium; cisplatin 40 mg/m2 per week

Magnesium supplementation group had prehydration with 15 meq and a daily dose of 5 meq on days 2 and 3.

No-magnesium arm had a significant increase (p < 0.05) in SCR (0.58–0.75 mg/ dl) and a significant decrease (p < 0.05) in glomerular filtration rate (85.1 to 66.5 ml/minute); no significant change in the magnesium arm; lower relative risk of nephrotoxicity (according to RIFLE criteria) in the magnesium group versus other group (7% versus 50% risk, p = 0.03)

Yoshida et al., 2014 496 adults, 161 with magnesium and 335 with no magnesium; cisplatin greater than 60 mg/m2

Magnesium supplementation group had standard hydration, isotonic saline, and 8 meq magnesium sulfate prior to cisplatin; no-magnesium supplementation group had standard hydration.

9 patients in the magnesium preloading group had an SCR grade greater than or equal to 2; 64 patients in the nonmag- nesium loading group had an SCR grade greater than or equal to 2 (p < 0.001); OR for first cycle = 0.262 (95% CI [0.106, 0.596]); OR during all cycles = 0.234 (95% CI [0.129, 0.414])

Furosemide

Dumas et al., 1989 20 adults, 10 received furosemide and 10 received diuretic; cisplatin dose 80 mg/m2

Furosemide 20 mg/m2 prior to cisplatin

Mean SCR levels were significantly higher in patients who received furosemide versus those who did not (0.95 mg/dl versus 0.76 mg/dl, p < 0.001), but no significant differences in CRCL were observed.

Continued on the next page

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TABLE 2. (CONTINUED)

LITERATURE ON HYDRATION AND DIURETIC SUPPLEMENTATION IN ADULTS RECEIVING CISPLATIN

STUDY SAMPLE AND CISPLATIN DOSE HYDRATION AND/OR DIURETIC FINDINGS

Furosemide (continued)

Muraki et al., 2012

50 adults, 30 received hydration with furosemide and 20 received hydration with mannitol and magnesium; cisplatin 75 mg/m2

Patients received either hydration, manni- tol, and magnesium sulfate; or hydration, mannitol, and 20 mg furosemide

Patients who received mannitol and mag- nesium prior to cisplatin administration showed a significantly greater increase in CRCL (p = 0.004) and decrease in SCR (p = 0.0148); a hydration protocol supple- mented with magnesium and mannitol without furosemide was an independent factor for the protection of cisplatin- induced nephrotoxicity (OR = 0.232, 95% CI [0.055, 0.986], p = 0.039).

Ostrow et al., 1981 22 adults, 10 with mannitol plus hydration and 12 with furosemide plus hydration; cisplatin 100 mg/m2

Mannitol 37.5 g plus hydration prior to cisplatin; furosemide 40 mg plus hydration before the start of cisplatin

Nephrotoxicity occurred in 28% of patients who received mannitol and 19% of patients who received furosemide; no differences in SCR levels (p > 0.45) or CRCL levels (p > 0.25) were observed between the two groups.

Mannitol

Al-Sarraf et al., 1982 67 adults, 34 with mannitol and 33 with no mannitol; cisplatin 100 mg/m2

Mannitol 12.5 g prior to cisplatin and 25 mg following cisplatin

Significant renal toxicity after the first dose of cisplatin was observed in 4% of patients who received hydration and mannitol and in 21% of patients who received hydration alone.

Leu & Baribeault, 2010 92 adults, 46 with mannitol and 46 with no mannitol; cisplatin dose greater than 40 mg/m2

Mannitol 12.5 g

Average decrease in CRCL between the two groups; no difference between hydration plus mannitol and hydration alone (p = 0.09)

McKibbin et al., 2016 139 adults, 88 with mannitol and 41 with no mannitol; cisplatin 100 mg/m2

Mannitol 12.5 g prior to cisplatin

The addition of mannitol decreased the incidence of grade 3 acute kidney injury; nephrotoxicity was listed as a reason for the discontinuation of therapy in 47% of patients receiving mannitol compared to 60% of patients receiving saline alone (p = 0.69).

Morgan et al., 2014 143 adults, 85 with mannitol prior to cisplatin and 58 with furosemide prior to cisplatin; cisplatin 30–100 mg/m2

Mannitol 37.5 g prior to cisplatin

Patients who did not receive mannitol with cisplatin had an increased likelihood of developing acute kidney injury (OR = 2.646, 95% CI [1.008, 6.944], p = 0.048).

Muraki et al., 2012

50 adults, 20 received hydration with mannitol and magnesium, and 30 received hydration with furosemide; cisplatin 75 mg/m2

Hydration with mannitol and magnesium: 2,700 ml normal saline, 200 ml mannitol, and 8 meq magnesium sulfate; hydration with furosemide: 3,100 ml normal saline, 300 ml mannitol, and 20 mg furosemide

Patients who received mannitol and magnesium prior to the administration of cisplatin showed a significantly greater increase in CRCL (p = 0.004) and decrease in SCR (p = 0.0148).

Ostrow et al., 1981 22 adults, 10 with mannitol plus hydration and 12 with furosemide plus hydration; cisplatin 100 mg/m2

Mannitol 37.5 g

Nephrotoxicity = CRCL less than 50 and SCR greater than 2; nephrotoxicity occurred in 19% of patients who received furosemide and 28% of patients who received mannitol.

Santoso et al., 2003 49 adults, 17 with saline and mannitol, 17 with saline and furosemide, and 15 with saline alone; cisplatin 75 mg/m2

Mannitol 50 g Mannitol arm found to be significantly nephrotoxic; study was closed prematurely.

CI—confidence interval; CRCL—creatinine clearance; NAG—N-acetyl-beta-D-glucosaminidase; OR—odds ratio; RIFLE—Risk, Injury, Failure, Loss, and End-Stage; SCR—serum creatinine

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authors concluded that both diuretics exhibited similar effects. Other researchers retrospectively evaluated 50 patients to com- pare the effect of hydration with magnesium sulfate and mannitol versus hydration with furosemide 20 mg and mannitol on cispla- tin-associated nephrotoxicity (Muraki et al., 2012). Hydration with magnesium and mannitol was an independent factor in the protection of patients against nephrotoxicity induced by cisplatin. Finally, mean SCR concentrations were significantly higher in patients who received furosemide 20 mg/m2 one hour prior to cisplatin versus those who did not receive furosemide prior to cisplatin, although no significant differences in CRCL were observed between groups (Dumas et al., 1989).

Mannitol Seven studies evaluated the effect of mannitol on cisplatin- related nephrotoxicity. Three trials found no clear indication that mannitol is nephroprotective among adults receiving cisplatin (Leu & Baribeault, 2010; Ostrow et al., 1981; Santoso et al., 2003). In one study of 22 patients receiving cisplatin, 28% of patients who received mannitol developed nephrotoxicity compared to 19% of patients in the furosemide group, with the authors concluding that neither mannitol nor furosemide was superior in reducing the fre- quency of nephrotoxicity (Ostrow et al., 1981). In another study, no significant difference in CRCL was noted among patients receiving mannitol and hydration compared to hydration alone (Leu & Baribeault, 2010). Santoso et al. (2003) found mannitol dosages of 50 g to be significantly nephrotoxic and terminated the study pre- maturely because patients developed nephrotoxicity.

Four studies revealed that mannitol in conjunction with high-dose cisplatin has a protective effect that allows patients to tolerate cisplatin without nephrotoxicity (Al-Sarraf et al., 1982; McKibbin et al., 2016; Morgan et al., 2014; Muraki et al., 2012). Patients who received mannitol and magnesium demonstrated a significantly greater increase in CRCL (p = 0.004) and decrease in SCR (p = 0.0148) compared to patients receiving hydration with mannitol, magnesium, and furosemide (Muraki et al., 2012). Morgan et al. (2014) also found improved outcomes in patients who received mannitol, and reported a 2.6 increased likelihood of developing acute kidney injury among adults who did not receive mannitol with cisplatin (95% confidence interval [1.008, 6.944], p = 0.048). They recommended the addition of mannitol with hydration to prevent cisplatin-induced nephrotoxicity.

Quality of the Evidence The quality of the hydration evidence was based on nine research articles. The evidence consisted of six retrospective studies and three prospective studies (one nonrandomized, single-center, phase 2 study; one feasibility study; and one cohort study). Issues related to the quality of the evidence included no report of power analysis in all studies, inconsistency issues among comparison groups in two studies, and one potential publication bias because

of a long lag time from study completion to publication. The overall body of evidence for hydration was of low quality.

The magnesium evidence was based on seven research articles consisting of two randomized clinical trials, four retrospective chart reviews, and one historical prospective cohort study. Issues related to the quality of the evidence included lack of reported power analyses in all studies. The overall body of evidence for magnesium was of low quality.

The furosemide evidence is based on three research articles consisting of two randomized, prospective, controlled studies and one retrospective chart review. Issues related to the quality of the evidence included lack of reported power analyses in all studies. The overall body of evidence for furosemide was of low quality.

The mannitol evidence is based on seven research studies. The designs consisted of four retrospective studies and three prospec- tive studies (two randomized, controlled studies and one phase 2 study). Issues related to the quality of the evidence included lack of reported power analysis in all studies. The overall body of evidence for mannitol was of low quality.

Summary of Recommendations Hydration is necessary to prevent nephrotoxicity with cisplatin administration; however, the amount, duration, and timing of hydration for patients cannot be determined from the limited evidence. In addition, administration of magnesium and mannitol may assist in maintaining renal function and reducing nephro- toxicity in adults receiving cisplatin; however, limited evidence precludes the ability to provide recommendations for children. More research is needed to identify best practices for patients.

Limitations Limitations in the literature review include limited evidence about the variation of practice patterns in different settings. There could be differences in patient management, particularly hydration regimens and the use of diuretics, which varies depending on treat- ment setting. More research is needed to identify these differences.

“The optimal hydration and diuretic regimen necessary to prevent cisplatin nephrotoxicity is unknown.”

182 CLINICAL JOURNAL OF ONCOLOGY NURSING APRIL 2018, VOL. 22 NO. 2 CJON.ONS.ORG

In addition, the literature is limited because of the inclusion of diverse age groups. Only one pediatric study evaluated neph- rotoxicity in children receiving cisplatin therapy, requiring more evaluation so conclusions can be determined among the pediatric population. Also, insufficient literature prevented the authors from subcategorizing the adult population by age; additional research should be conducted to evaluate the nephrotoxicity dif- ferences among young, middle-aged, and older adult patients.

Last, this literature review does not include the effects of other medications on nephrotoxicity. Researchers should con- sider investigating the influence of nephrotoxic medications on people receiving cisplatin therapy.

Implications for Nurses and Conclusion Cisplatin is an integral component of chemotherapy regimens for multiple cancers, and nephrotoxicity remains the primary dose-limiting toxicity of this effective treatment. Hydration has been shown to maintain renal function and decrease nephrotox- icity in patients. In addition, magnesium supplementation has demonstrated nephroprotective effects in adults when included in hydration regimens before, during, and after cisplatin. Additional research is needed to evaluate outcomes of these interventions in the pediatric population.

Research does not currently support the administration of furosemide to prevent cisplatin-related nephrotoxicity in adults; however, mannitol may prevent nephrotoxicity. The use of man- nitol in conjunction with magnesium was an independent factor in the protection of adults against nephrotoxicity induced by high-dose cisplatin (Muraki et al., 2012). Additional research is needed to evaluate these outcomes.

Nurses play a critical role in monitoring patients to prevent cisplatin-induced nephrotoxicity. The administration of hydra- tion and the use of medications to aid in diuresis during cisplatin therapy is essential. Maintaining accurate weights and intake and outputs along with monitoring laboratory values and assessing for edema will help with early recognition of renal dysfunction. The provision of patient education focusing on nephrotoxicity prevention is an important component of the treatment regimen.

Although researchers have evaluated several supportive strategies to minimize nephrotoxicity in patients receiving cis- platin therapy, more research is needed. When more evidence is available, best nephroprotective practices can be developed and implemented. Until then, nurses should closely monitor kidney function in all patients receiving cisplatin and immediately report abnormalities to the healthcare team.

Elizabeth A. Duffy, DNP, RN, CPNP, is a clinical assistant professor in the School of

Nursing at the University of Michigan in Ann Arbor; Wendy Fitzgerald, RN, MSN,

PPCNP-BC, CPON®, is a pediatric nurse practitioner in the Center for Cancer and

Blood Disorders at the Children’s National Medical Center in Washington, DC;

Kelley Boyle, MSN, RN, PCNS-BC, is a pediatric BMT nurse coordinator at the

University of California, San Francisco, Benioff Children’s Hospital; and Radha Ro-

hatgi, PharmD, BCOP, is a hematology/oncology and bone marrow clinical phar-

macy specialist at the Children’s National Medical Center. Duffy can be reached at

[email protected], with copy to [email protected]. (Submitted March

2017. Accepted June 19, 2017.)

The authors take full responsibility for this content. This research was conducted by a team from

the Children’s Oncology Group Nursing Evidence-Based Practice Subcommittee. The Children’s

Oncology Group is supported by a National Cancer Institute/National Clinical Trials Network

Group Operations Center grant (U10CA180886; principal investigator: Peter C. Adamson).

Fitzgerald serves on a speakers bureau for United Therapeutics. During the writing of this article,

Rohatgi served on a speakers bureau for the Pediatric Pharmacy Association. The article has been

reviewed by independent peer reviewers to ensure that it is objective and free from bias.

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NEPHROTOXICITY

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