Study shows kids with central nervous system tumors or neuroblastoma were most susceptible

Acute kidney injury (AKI) was common among children receiving cisplatin for the treatment of cancer, especially children with neuroblastoma who received the highest total cisplatin cycle dose, a prospective, multicenter pediatric study has shown.

In a cohort of 159 children, mean age on early cisplatin infusion of 7.2 years, AKI as defined by an increase in serum creatinine levels (SCr-AKI) occurred in 30% (95% CI, 23-37%) of children during the first or second cycle of cisplatin infusion (early cisplatin infusion) and 16% (95% CI, 10-22%) of children on the second to last or last cycle of cisplatin infusion (late cisplatin infusion).

Defined by the presence of electrolyte abnormalities, eAKI occurred in 67% (95% CI, 59-74%) of children during early cisplatin infusions and 70% (95% CI, 62-78%) of children with late cisplatin infusions, senior author Michael Zappitelli, MD, University of Toronto, Ontario, and colleagues reported in JAMA Network Open.

“In this pediatric, multicenter study, cisplatin-associated SCr-AKI and eAKI were common and transient,” Zappitelli and colleagues observed.

“[H]owever, long-term clinical and subclinical effects remain unknown [and since] SCr-AKI occurred early during cisplatin treatment… AKI monitoring is needed at cisplatin treatment commencement,” they suggested.

ABLE Nephrotoxicity Study

The ABLE Nephrotoxicity study included children treated with cisplatin between 2013 and 2017 at 12 Canadian pediatric oncology centers.

“Children are typically hospitalized to receive cisplatin,” the authors pointed out, “[and m]ost cisplatin protocols comprise 2 to 8 cycles given every 3 to 6 weeks [although] dosages vary by tumor type,” they added.

Researchers used two cisplatin-associated AKI definitions: AKI based on serum creatinine level (SCr-AKI) using a modified Kidney Disease Improving Global Outcomes (KDIGO) definition and AKI defined by electrolyte disturbances (eAKI), including hypomagnesemia, hypokalemia and hypophosphatemia.

Of those children who developed early SCr-AKI, the median time to SCr-AKI was 2 days (Interquartile Range (IQR), 1-4 days) while 8% (95% CI, 3-12%) developed severe SCr-AKI of stage 2 or higher.

Some 42% of episodes of SCr-AKI were seen in children with central nervous system (CNS) tumors while 38% of the episodes were observed in children with neuroblastoma.

In contrast, children with osteosarcoma as well as those with germ cell tumors all had low SCr-AKI rates and none developed SCr-AKI during the late cisplatin infusion cycles.

Children under the age of 3 years, and those with higher pre-visit estimated glomerular filtration rates (eGFR) were also more likely to develop SCr-AKI during the first or second cycle of cisplatin infusion at 54% at a median eGFR or 166 ml/min/1.73m2, investigators added.

Higher cisplatin infusion dose was also independently associated with acute kidney injury at late cisplatin infusions, they noted.

Age under 3 years and a higher pre-visit eGFR were also associated with late infusion SCr-AKI, affecting 57% of those under the age of 3 at a median eGFR of 169 ml/min/1.73m2, investigators note.

The median time for children to develop late infusion SCr-AKI was only one day (IQR, 1-3 days; 5% (95% CI, 1-8%) of episodes being severe.

Interestingly, the prior cumulative dose of cisplatin was actually lower at a mean dose of 168 mg/m2 in children who developed late SCr-AKI, although the dose of cisplatin infused was higher in those who developed late SCr-AKI at 224 mg/m2 than in those who did not develop late SCr-AKI, researchers observed.

Some 20% of patients (95% CI, 14-26%) of patients had both SCr plus eAKI at the early infusion time point while 11% (95% CI, 6-16%) had SCr plus eAKI at the later infusion time point.

On multivariable analyses, the following factors were associated with either an early or a late infusion SCr-AKI:

  • CNS tumors, neuroblastoma and higher pre-early visit eGFR increased the risk of early infusion SCr-AKI by 22% (model AUC, 0.78; 95% CI, 0.69-0.86).
  • Higher pre-early visit eGFR and kidney medical history were associated with 23% higher risk of early infusion SCr-AKI plus eAKI (model UC, 0.77; 95% CI, 0.68-0.86).
  • Age under 3 years, neuroblastoma and higher late cisplatin infusion doses as well as higher pre-late infusion eGFRs were also associated with a 18% increased risk of SCr-AKI at late infusion (model AUC, 0.82; 95% CI, 0.74-0.91).

Limitations of the study include the modest sample size and the fact that the study population was mostly white, limiting its generalizability to other ethnic groups.

Commenting on the study, Shveta Motwani, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, and colleagues, pointed out that most patients had KDIGO stage 1 SCr-AKI that lasted for a median of 2 days.

“This median duration of AKI is fairly short for it to be caused by tubular injury,” the editorialists suggested, “raising the possibility of a prerenal cause alone or a mild tubular injury in addition to a prerenal cause contributing to several of these SCr-AKI events,”” they added.

The authors also pointed out that nausea, vomiting and diarrhea can exacerbate if not cause SCr-AKI or eAKI, “especially the kind that is predominantly stage 1, lasts for a few days, and recovers completely,” as they observed.

During the 10-day period after each course of cisplatin, “46% [of patients] recovered partially and 57% recovered completely from their early or late SCr-AKI episodes,” Motwani and colleagues stated.

Moreover, it did not appear that any of the children required any kind of treatment especially not renal replacement therapy to reverse the AKI episodes observed in the study.

Nevertheless, Motwani and colleagues felt that the study was “an important addition” to the literature in that it helps providers better understand the nephrotoxic effects of cisplatin-based chemotherapy in children.

They also felt that the study will help practitioners identify patients with nonmodifiable risk factors for cisplatin-associated AKI and allow them to focus on those risk factors which are modifiable to prevent this common event.

  1. Acute kidney injury was common among children receiving cisplatin for the treatment of cancer, especially children with neuroblastoma who received the highest total cisplatin cycle dose.

  2. Children with central nervous system tumors as well as neuroblastoma were most susceptible to acute kidney injury caused by cisplatin infusions.

Pam Harrison, Contributing Writer, BreakingMED™

The research was supported by the Canadian Institutes of Health Research and its multiple partners.

Zappitelli reported receiving compensation as chair of the safety preview committee for a drug to treat cystinosis from Eloxx Pharmaceuticals.

Motwani reported having a salaried position as a deputy editor in nephrology and hypertension at UpToDate.

Curhan reported receiving personal fees from OMI, AstraZeneca, Allena Pharmaceuticals, Dicerna, Orfant, Shire/Takeda and Merck. He also reported receiving a grant from Decibel Therapeutics.

Cat ID: 120

Topic ID: 78,120,730,120,138,192,925