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Invited Commentary
Nephrology
May 8, 2020

Cisplatin-Associated Nephrotoxic Effects in Children

Author Affiliations
  • 1Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Renal Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 3Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
JAMA Netw Open. 2020;3(5):e203612. doi:10.1001/jamanetworkopen.2020.3612

Cisplatin has been an important component of chemotherapy for cure and control of several pediatric and adult malignant tumors. Nephrotoxic effects of cisplatin are a limitation of cisplatin-based chemotherapy and are often prohibitive of further treatment with cisplatin, when they occur. However, this adverse effect is not uniformly manifested among all patients who receive cisplatin-based chemotherapy.1 During the past few decades, investigators have attempted to identify risk factors that predispose certain patients to nephrotoxic effects of cisplatin while sparing others. Interindividual variability in kidney injury associated with cisplatin is greater than that explained by pharmacokinetic differences among patients.2 What, if anything, can practitioners at the point of care do to ameliorate this risk of cisplatin-associated acute kidney injury (AKI) and subsequent chronic kidney disease while preserving the anticancer benefit?

Common themes have emerged from the collective body of published work. Risk factors, such as age, cisplatin dose, concomitant chemotherapy, and administration of nephrotoxins, have been identified. However, these findings largely stem from retrospective studies3 with varying study designs, patient selection algorithms, sample sizes, length of follow-up, and overall rigor. In addition, few studies thus far have homed in on risk factors in the pediatric population. McMahon et al4 report on a prospectively evaluated, multicenter, pediatric cohort of early and late risk factors for nephrotoxic effects of cisplatin. The prospective study design, multicenter recruitment, rigorous methods, and robust statistical analysis are strengths of their study.

The authors characterized AKI into 2 distinct phenotypes: AKI based on serum creatinine level (SCr-AKI) using a modified Kidney Disease: Improving Global Outcomes (KDIGO) definition and AKI based on electrolyte disturbances (eAKI), namely, hypomagnesemia, hypokalemia, and hypophosphatemia. They defined SCr-AKI by the KDIGO thresholds but with the AKI window expanded from 7 to 10 days, in keeping with the typical time course of cisplatin-associated AKI. They also removed the urine output criteria because of the nonoliguric nature of cisplatin-associated AKI. Their methods also differed from other published studies by their identification of separate risk factors for early and late nephrotoxic effects of cisplatin. Presumably, early risk factor analysis may identify patients who have demographic or constitutional characteristics associated with kidney injury during cisplatin treatment, whereas late risk factor analysis may identify patients who do not initially experience nephrotoxic effects of cisplatin until it accumulates over time. However, the distinction between early and late risk factors is likely to be fluid when the analysis compares nephrotoxic effects of cisplatin only a few cycles apart. In this study, the early visit episode occurred at the first or second cycle, and the late visit episode occurred at a median of the third cycle.

Despite hospitalization for administration of chemotherapy and infusion of intravenous fluids (IVFs) before, during, and after chemotherapy, the authors observed SCr-AKI among 30% (95% CI, 23%-37%) of patients after 1 or 2 cycles (early) and 16% (95% CI, 10%-22%) after second-to-last or last (late) cycles of cisplatin treatment. 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, 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. Nausea, vomiting, and diarrhea in this context 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. The lack of IVF data in the study limits assessment of the adequacy of hydration. Although not explicitly stated, it does not appear that any of the patients in the study required kidney replacement therapy during the study period.

In multivariable analysis, the presence of a central nervous system tumor or neuroblastoma and having a higher baseline estimated glomerular filtration rate were significantly associated with early and late SCr-AKI, and a higher late infusion cisplatin dose was significantly associated with late SCr-AKI. It does not appear that the authors entered early SCr-AKI in the multivariable model for SCr-AKI at the late visit. It would have been interesting to see if early SCr-AKI predicted late SCr-AKI, possibly adding significance to even seemingly short-lived stage 1 SCr-AKI events. During the 10-day period after each course of cisplatin, 46% recovered partially and 57% recovered completely from their early or late SCr-AKI episodes.

eAKI was noted among 67% (95% CI, 59%-74%) of patients in early cycles and 70% (95% CI, 62%-78%) in late cycles. Accounting for electrolyte supplementation (which presumably led to underestimation of the number of eAKI events by raising levels of electrolytes closer to normal), the total number of patients affected was higher. Of interest, the electrolyte levels measured by the study team correlated only modestly (phosphorous: ρ, >0.61; magnesium: ρ, >0.61; and potassium: ρ, 0.33-0.64) with the electrolytes measured as part of routine clinical care. The authors hypothesized this to be a result of hemolysis or storage increasing the electrolyte levels in the study samples. They used the worst of the clinical or study samples, thereby possibly overestimating the frequency of eAKI. Regardless of the frequency, most patients had National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 electrolyte disturbances. Although a small proportion of patients can have electrolyte disturbances that last decades after the original insult, the clinical significance of this relatively manageable adverse effect among many patients is unclear.

Limitations of their study, some of which the authors have acknowledged, include lack of data regarding of coadministered IVFs and mannitol, relatively small sample size and number of AKI events (limiting further risk factor assessment), and lack of information about cisplatin dose modifications after early SCr-AKI. In addition, they did not record information regarding gastrointestinal adverse effects that are common with cisplatin-based chemotherapy, as noted above. The assessment of the duration of AKI was done using a nonstandard approach by recording the number of days when AKI definitions were met, including noncontiguous days (episodes), rather than assessment of the continuous length of each episode.

In summary, this study by McMahon et al4 is an important addition to the literature and helps add needed granularity with a detailed descriptive analysis of nephrotoxic effects of cisplatin-based chemotherapy in children. The study supports the results of many prior retrospective studies with a systematic prospective study design. It has helped pave the path forward to determine the clinical significance of nephrotoxic effects of cisplatin for long-term outcomes when balanced against effective cancer treatment. Future studies should evaluate the effect of cisplatin-associated AKI on mortality to help guide decision-making regarding modification of treatment factors to avoid or treat such toxic effects. Are toxic effects such as cisplatin-associated AKI, chronic kidney disease, and hypertension a reasonable risk if it means that survival increases among patients with cancer or are such consequences entirely avoidable without compromising survival? In the meantime, practitioners should identify patients with nonmodifiable risk factors for cisplatin-associated AKI and focus on the modifiable risk factors to prevent cisplatin-associated AKI.

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Article Information

Published: May 8, 2020. doi:10.1001/jamanetworkopen.2020.3612

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Motwani SS et al. JAMA Network Open.

Corresponding Author: Shveta S. Motwani, MD, MMSc, Adult Survivorship Program, Dana-Farber Cancer Institute, 450 Brookline Ave, YC12, Boston, MA 02215-5450 (shveta_motwani@dfci.harvard.edu).

Conflict of Interest Disclosures: Dr Motwani reported having a salaried position as a deputy editor in nephrology and hypertension at UpToDate (Wolters Kluwer). Dr Curhan reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases during the conduct of the study; personal fees from OM1, AstraZeneca, Allena Pharmaceuticals, Dicerna, Orfan, Shire/Takeda, and Merck; and grants from Decibel Therapeutics outside the submitted work. Dr Curhan also serves as one of the section editors for chronic kidney disease and nephrolithiasis for UpToDate.

References
1.
Skinner  R, Parry  A, Price  L, Cole  M, Craft  AW, Pearson  ADJ.  Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors.   Eur J Cancer. 2009;45(18):3213-3219. doi:10.1016/j.ejca.2009.06.032 PubMedGoogle ScholarCrossref
2.
Barton  CD, Pizer  B, Jones  C, Oni  L, Pirmohamed  M, Hawcutt  DB.  Identifying cisplatin-induced kidney damage in paediatric oncology patients.   Pediatr Nephrol. 2018;33(9):1467-1474. doi:10.1007/s00467-017-3765-6 PubMedGoogle ScholarCrossref
3.
Kooijmans  ECM, Bökenkamp  A, Tjahjadi  NS,  et al.  Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer.   Cochrane Database Syst Rev. 2019;3(3):CD008944. doi:10.1002/14651858.CD008944.pub3 PubMedGoogle Scholar
4.
McMahon  KR, Rassekh  SR, Schultz  KR,  et al; Applying Biomarkers to Minimize Long-term Effects of Childhood/Adolescent Cancer Treatment (ABLE) Research Study Group.  Epidemiologic characteristics of acute kidney injury during cisplatin infusions in children treated for cancer.   JAMA Netw Open. 2020;3(5):e203639. doi:10.1001/jamanetworkopen.2020.3639Google Scholar
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