Next Article in Journal
Morphogenetic and Imaging Characteristics in Giant Cell Glioblastoma
Previous Article in Journal
Intraoperative Positive Pancreatic Parenchymal Resection Margin: Is It a True Indication of Completion Total Pancreatectomy after Partial Pancreatectomy for Pancreatic Ductal Adenocarcinoma?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Current Oncology
Volume 29
Issue 8
10.3390/curroncol29080421
curroncol-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors

by
Natalia Stepien
1,
Viktoria Handler
2,
Johannes Gojo
1,
Amedeo A. Azizi
1,
Lisa Mayr
1,
Chryssa Grylli
3,
Daniela Schwarz
1,
Monika Chocholous
1,
Irene Slavc
1,
Michael Boehm
4 and
Andreas Peyrl
1,*
1
Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University Vienna, 1090 Vienna, Austria
2
Department of Gynecology and Obstetrics, KRAGES Oberpullendorf, 7350 Oberpullendorf, Austria
3
Division of Pediatric Pulmonology, Allergology, and Endocrinology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria
4
Division of Pediatric Nephrology and Gastroenterology, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2022, 29(8), 5306-5315; https://doi.org/10.3390/curroncol29080421
Submission received: 30 June 2022 / Revised: 25 July 2022 / Accepted: 26 July 2022 / Published: 28 July 2022
(This article belongs to the Section Neuro-Oncology)
Review Reports Versions Notes

Abstract

:
Purpose: Numerous acute effects of chemotherapeutics on kidney function are well described. However, data on the long-term effects of chemotherapy in the growing population of childhood central nervous system (CNS) tumor survivors is limited. We aimed to evaluate the kidney function of a cohort of long-term CNS tumor survivors treated with different standard chemotherapeutic regimens. Methods: Patients treated for a CNS tumor were prospectively evaluated up to 12 years after completion of their therapy. Examination of kidney function was performed during routine follow-up visits. Blood pressure and blood and urine parameters were analyzed for kidney function evaluation. Glomerular function was assessed by calculating the estimated glomerular filtration rate (eGFR), tubular functions were analyzed by measuring serum electrolytes, bicarbonate and phosphate reabsorption, and proteinuria was assessed by calculating the protein/creatinine ratio and phosphate reabsorption. Results: None of the 65 patients evaluated suffered from clinically relevant kidney impairment (eGFR < 90 mL/min/L, 73 m2). There was no association between chemotherapy dose and eGFR. Only two patients showed mild signs of tubulopathy and 11 patients were diagnosed with elevated blood pressure. Conclusion: With adequate supportive measures, such as sufficient hydration according to chemotherapy protocol guidelines, as well as avoidance or close monitoring of additional nephrotoxic medication, impaired kidney function is rare in CNS tumor survivors treated with standard chemotherapy. Nonetheless, long-term follow-up is essential for early detection of mild impairment of kidney function.

1. Introduction

CNS tumors constitute the most common solid malignancy in the pediatric population with an incidence rate of 2–4/100,000. They are comprised of more than hundred different entities with very divergent biological behavior [1]. Treatment may include observation by MRI, surgery, chemotherapy, radiation or a combination of the previously mentioned, and current studies focus on risk stratification for the prevention of therapy associated side effects [2,3,4]. Generally, over the last several decades, survival of pediatric central nervous system (CNS) tumor patients has improved significantly [5]. Unfortunately, cure often comes at a cost for these patients due to induction of various late effects, necessitating accurate assessment of sequelae for early detection and possible preventive measures. In a study on chronic health conditions in adult survivors of childhood cancer, CNS tumor survivors were found to be among the population at highest risk for developing a severe health condition [6]. When focusing on the kidney function in this patient population, certain subgroups have been found to harbor an increased risk for long-term nephrotoxicity [7]. However, data on the chemotherapy protocols applied were not available in this study, and the diagnosis of kidney disease was derived from a registry, which might underestimate the presence of slightly reduced kidney function [7]. The retrospective analysis of the Childhood Cancer Survivor Study revealed a significantly higher risk for late-onset kidney disease in the patient population when compared to their siblings. The main drawback of this study is that kidney disease was self-reported by the patients and therefore mild impairment would not have been recognized [8]. A recent Cochrane analysis evaluating the adverse effects of chemotherapy on kidney function in the pediatric population highlighted the difficulties of different reporting methods for kidney function, and the complexity of an accurate assessment for each cytostatic agent due to the broad variability of entities and respective chemotherapy protocols [9]. Indisputably, cytostatic drugs may lead to acute kidney injury, particularly if administered without adequate supportive measures.
The major chemotherapeutics that impair kidney function are platinum compounds (i.e., cisplatin, carboplatin), alkylating agents (i.e., ifosfamide), and the antifolate agent methotrexate (MTX), which are all included in routine treatment protocols for childhood CNS tumors [10]. Nephrotoxicity of chemotherapeutic medication may manifest as acute kidney injury, but also as long-term kidney dysfunction [11].
The aim of this study was to determine the prevalence and severity of chemotherapy-induced nephrotoxicity in the specific group of patients following treatment for a CNS tumor in childhood or adolescence.

2. Patients and Methods

2.1. Patients

Patients included in the study were treated for a CNS tumor at the Department of Pediatrics and Adolescent Health, Medical University of Vienna.
Between 1999 and 2018, 279 children received chemotherapy for their primary CNS tumor at our institution, and 123 of these patients deceased. Of the 156 children that achieved long-term survival, 19 patients were treated for a recurrent tumor following initial chemotherapy, and 31 patients were lost to follow-up. In total, 65 of potentially 106 eligible patients agreed to participate and were enrolled in the study and prospectively investigated for their kidney function (Figure S1). Data on tumor histology and treatment was retrieved from the patient’s charts. The 65 participants did not differ significantly from the 41 potentially eligible nonparticipants in the distribution of sex, diagnosis, or chemotherapy received.
Before each initiation of a chemotherapy cycle, all patients were screened for eGFR as a standard procedure. During their chemotherapy, all patients were hydrated sufficiently according to their body surface area (BSA) as recommended in their treatment protocols (2400–3000 mL/m2/d of prespecified solution). Diuretics were used as defined in their treatment protocol (i.e., mannitol for platinum compounds and furosemide for other chemotherapeutic agents), and blood levels of additional nephrotoxic medication (i.e., vancomycin, certomycin, gentamicin, amphotericin) were closely monitored [12]. All patients had completed their treatment at least one year before kidney evaluation. The time of examination was defined by the patients’ routine follow-up protocol.

2.2. Methods

Prospective evaluation of kidney function included anthropometric parameters (height and weight, body mass index (BMI)) and blood pressure measurement. For each parameter the standard deviation score (SDS) was evaluated. Hypertension was evaluated according to the NCI CTCAE criteria 5.0 [13,14]. The original Schwartz formula was used to calculate the estimated glomerular filtration rate. Serum creatinine was measured by the Jaffe method [15]. The cut-off for impaired glomerular function was 90 mL/min/L/1.73 m2 [9]. Additional routine laboratory investigations included the following parameters (cut-off values in brackets, if not stated differently, as recommended by the institutional laboratory): serum phosphate (age adjusted [16]), serum magnesium (0.61–1.23 mmol/L), serum bicarbonate (lower limit of normal (LLN): 20 mmol/L), and urinary protein/creatinine ratio (upper limit of normal (ULN): 200 mg/g). Tubular function was further evaluated by calculating the tubular maximum reabsorption of phosphate by GFR (TmP/GFR) (age-adjusted [17]), measurement of glucosuria (ULN 25 mg/dL) and alpha-1-microglobuline (ULN: 20 mg/24 h), and evaluation of electrolyte supplementation.

2.3. Statistical Analysis

Continuous variables were described by using median and range. Furthermore, standard deviation scores (SDS) were calculated for length, BMI, and blood pressure. For each chemotherapeutic agent, dose ranges (low/middle/high or low/high—Table S1) were established, considering the target values of the applied protocols (Table S2) and cut-off values defined by previous studies [18,19,20]. Additionally, patients were classified according to their treatment protocols or a combination of protocols. The Kruskal–Wallis test and the Mann–Whitney U test were used to determine if different chemotherapy doses or protocols resulted in altered renal parameters (eGFR). The latter one was used in cases in which only two groups were compared.
Statistical analysis was performed with the IBM SPSS Statistics for Windows, version 28.0.1.0 (IBM Corp., Armonk, NY, USA). Each test result was considered as significant when the two-sided p-value was less than 0.05.
The study protocol was approved by the Ethics Committee of the Medical University of Vienna (EK 520/2009), and a written informed consent was obtained from all study participants and/or their parents.

3. Results

3.1. Patients’ Characteristics and CNS Tumor Entities

Among the 65 patients enclosed, 44 children were male (68%) and 21 female (32%, M:F ratio 2:1), and the overall median age at time of diagnosis was 4.7 years (range 0.0–20.1 years). Chemotherapy started at a median age of 4.8 years (range 0.1–20.1 years). The median patient age at the time of follow-up examination was 12.7 years (range 3.2–25.5 years) and the median time between the end of chemotherapy and follow-up was 3.2 years (range 1.0–12.3 years). Diagnoses were low-grade glioma (n = 15), medulloblastoma (n = 14), high-grade glioma (n = 10), ependymoma (n = 8), CNS germ cell tumor (n = 6), atypical teratoid rhabdoid tumor (n = 4), CNS PNET (n = 3; two of them were reclassified after the WHO 2016 classification: one high-grade neuroepithelial tumor and one CNS NB-Foxr2), pineoblastoma (n = 2), choroid plexus carcinoma (n = 1), epitheloid sarcoma (n = 1), and one diffuse leptomeningeal glioneuronal tumor (n = 1). Localization of tumors is represented in Figure S2.

3.2. Chemotherapy and Additional Nephrotoxic Agents

All patients received chemotherapy according to standard treatment protocols (HIT-91 [21], HIT-2000 [22], HIT-GBM-C [23], HIT-HGG-2007 [24], SIOP-GCT-96 [25], SIOP-LGG-2004 [26], and MUV-ATRT [27]. Five patients received high-dose chemotherapy with stem cell support [28]. Cumulative dose and dose range of each administered chemotherapeutic agent and the number of patients are listed in Table 1. Chemotherapeutic agents and cumulative doses for each protocol are listed in Table S2. Hyperhydration was performed according to each protocol with a prespecified solution, by using 2400–3000 mL/m2, starting at least 12 h before start of chemotherapy, until at least 12 h after the end of chemotherapy.
At least one of the chemotherapeutic agents with the highest risk of nephrotoxicity (cisplatin, carboplatin, ifosfamide, and methotrexate) was administered in 58 patients (89%). All patients receiving ifosfamide or cyclophosphamide were treated with the cytoprotective adjuvant mesna. None of the patients suffered from acute kidney injury according to CTCAE 5.0 during the time of treatment as assessed by chart review [14]. In total, 19 patients (29%) received craniospinal irradiation, and two patients (3%) received spinal irradiation. Among these patients, 20 (95%) were treated with chemotherapeutic agents expected to be highly nephrotoxic. Additionally, 18 patients (28%) received intraventricular chemotherapy.
At least one additional nephrotoxic medication, including vancomycin, certomycin, gentamicin and amphotericin, had been applied in 38 patients (58%) during the course of their treatment. Among this group, 14 patients (37%) received nephrotoxic medication concomitant to chemotherapy.

3.3. Glomerular and Tubular Function

The glomerular function was not affected after the administration of the above-described chemotherapy. Median eGFR was 150.1.0 mL/min/1.73 m2 (range 96.5–253.1 mL/min/1.73 m2). Patients who had received at least two chemotherapeutic agents classified as particularly nephrotoxic had a median eGFR of 150.1 mL/min/1.73 m2 (range 96.5–253.1 mL/min/1.73 m2). By using the original Schwartz formula, none of the patients evaluated had an eGFR below 90 mL/min/1.73 m2. There was no significant association between the cumulative dose of any cytostatic agent and eGFR (Table 2). Neither the chemotherapy protocol applied, nor the administration of more than two particularly nephrotoxic cytostatic agents (carboplatin, cisplatin, ifosfamide, and methotrexate) showed a significant difference in eGFR (Figure S3). There was no significant effect of nephrotoxic medication (gentamycin, certomycin, vancomycin, and amphotericin) on eGFR (Table 2).
A total of 23 patients presented with a singular event of elevated blood pressure (systolic value between 120 and 140 mmHg or diastolic value > 79 mmHg). These values were reproducible at follow-up (following office visit) in only 11 patients; one patient was lost to follow up, and 11 patients had blood pressure values within the normal range. One patient was diagnosed with a midaortic syndrome, a secondary cause other than cancer treatment (Table S3, patient 2). Of the other hypertensive patients, six reached adult age at last follow-up with systolic blood pressure values ranging from 120–133 mmHg, corresponding to CTCAE °1. Patient characteristics, including administered chemotherapeutic regimens of the remaining four pediatric patients are displayed in Table S3.
Of the 65 evaluated patients, seven showed an elevated protein/creatinine ratio >200 mg/g (range 204–311 mg/g). One patient, with a protein/creatinine ratio of 300 mg/g, presented also with increased total protein, glucose, albumin, and alpha-1-microglobulin excretion in the 24-h urine specimen. SDS electrophoresis revealed tubular proteinuria. Another one had an elevated protein/creatinine ratio, albumin/creatinine ratio and a reduction in TmP/GFR. The other four patients presented with normal protein levels in their respective 24-h urine specimens and without further signs of tubulopathy. None of the five remaining patients with a reduction in TmP/GFR had further signs of tubulopathy. One patient was diagnosed with isolated glucosuria. For further details on patient characteristics, see Table S3.
None of the patients suffered from hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, or low bicarbonate levels at follow-up. None of these patients suffered from hypophosphatemia when using age-adjusted phosphate levels [16]. None of the patients required bicarbonate or other electrolyte substitution.

4. Discussion

A decreased kidney function as a consequence of intensive chemotherapy for childhood cancer has been published in several studies [9,11,18,29,30,31,32], but data focusing in particular on the long-term nephrotoxicity of chemotherapeutic agents used for the treatment of CNS tumors in childhood is scarce [19,33]. We report on 65 children treated with nephrotoxic chemotherapeutic compounds used most frequently for childhood CNS tumors such as cisplatin, carboplatin, ifosfamide, and methotrexate, all known to be causative of acute renal toxicity. Previous reports on evaluation of their long-term nephrotoxic effect led to divergent results that very much depended on the assessment method of renal function, type of malignancy and additional therapy (i.e., abdominal radiation, nephrectomy) [9,34]. The potential effects of chemotherapeutic agents on renal function vary from mild tubular dysfunction to irreversible renal failure, necessitating dialysis.
The GFR is considered the best overall parameter for kidney function; however, variability of methods used to calculate or estimate GFR is broad [9,35]. In clinical practice, the most ubiquitous method for GFR estimation in the pediatric population is the original Schwartz formula with a cut-off for chronic kidney disease of 90 mL/min/1.73 m2. Serum creatinine, height, age, and sex are readily available parameters, making it a very convenient method for GFR estimation in clinical routine. However, a tendency for overestimation of GFR has been shown in several studies [36,37]. Although the Schwartz formula only provides an estimation of GFR, it is often preferred to the cumbersome collection of 24-h urine for creatinine clearance calculation, which is prone to collection errors, especially in children. Furthermore, it is also applicable for young adults, providing a higher accuracy up to the age of 40 years than the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [38]. Loss of muscle mass has to be considered when interpreting eGFR in oncology patients. More exact, but also more invasive methods, such as GFR calculation by inulin clearance or alternative filtration markers, are not feasible in a routine screening setting and are preserved for special indications.
In general, the reported incidence of impaired GFR in children treated with chemotherapy varies from 0 to 74% [9]. In our study, eGFR was above 90 mL/min/1.73 m2 in all our patients. There was no correlation between the dose of any chemotherapeutic agent or chemotherapy protocol applied and the eGFR (Table 2, Tables S1 and S3). Previously reported risk factors for reduced GFR include nephrectomy, high-dose ifosfamide, cisplatin, carboplatin and high-dose cyclophosphamide [9]. None of the children in our cohort underwent a nephrectomy, explaining in part the lack of impairment in kidney function parameters in our patients.
Regarding the effect of different chemotherapeutic agents on GFR, ifosfamide is known to cause rather tubulopathy than glomerular dysfunction. However, the reported incidence of reduced GFR ranged from 4% to 50% [31,39]. Two prospective studies on this topic reported impaired glomerular function in 22% and 50% of patients after administration of ifosfamide, with a median cumulative dose of 54 g/m2 and 106 g/m2, respectively [18,31]. Because our patients received a median cumulative ifosfamide dose of 20 g/m2 (range 7.5–40.7), our results may support the theory of a dose-dependent long-term effect of ifosfamide on GFR, despite the lack of a statistically significant difference in eGFR between the dosing groups in our study [18,20,34,40].
Cisplatin on its own is also reported to cause long-term reduction in GFR in 29–40% of patients, with median cumulative doses of 528 mg/m2 and 500 mg/m2, respectively [19,30]. Part of the reported frequency of chronic kidney disease can be attributed to an initial acute kidney injury; however, exact numbers are lacking. Reports that suggest a GFR recovery potential in children [41] as well as in adults [42], are in contrast to reports describing a deterioration of GFR over time, especially in children treated with higher cisplatin doses (>500 mg/m2) [34]. Adequate hydration seems to be important to prevent the first hit [29,43,44]. With adequate hydration and mannitol as a diuretic agent according to their respective treatment protocol, none of our patients suffered from an acute kidney injury, and no clinically relevant deterioration of eGFR over time was noted after treatment with a median cumulative cisplatin dose of 300 mg/m2.
Carboplatin, a second-generation platinum compound, was only rarely described to have a negative effect on GFR, which is in accordance with our study [45].
The acute nephrotoxicity of methotrexate is indisputable [46], though data on long-term effects are rare. Available data including our own study suggest no further decrease in GFR [11,34].
Despite the use of multiple chemotherapeutic agents for treatment, survivors of CNS tumors in our cohort do not suffer from reduction in GFR. This might be attributed to the comparatively lower dose of each single agent used in protocols for CNS tumor treatment compared to sarcoma protocols.
Despite eGFR being an important overall parameter of renal function, chemotherapeutic agents also have important effects on tubular function, which is not reflected by changes of the eGFR. Tubular dysfunction is characterized by electrolyte disturbances, phosphate and magnesium loss and alpha-1-microglobulinuria. The reported prevalence of hypophosphatemia and hypomagnesemia ranges between 0–37%, and 13–71%, respectively [9,19]. Therapy with ifosfamide, cisplatin, and carboplatin was reported as a risk factor [9,47].
Ifosfamide does not only induce acute tubular toxicity, but may also result in long-term proximal tubular dysfunction, resulting in Fanconi syndrome and consequently rickets and growth retardation [42,48]. Subclinical glucosuria was the most common urinary abnormality finding in 37–88% of patients treated with ifosfamide [18,40]. Glycosuria was only present in one of the patients evaluated in our study. Cisplatin may cause mainly hypomagnesemia, which was reported in 29–71.4% of the patients [19,29]. Carboplatin has similar, but less severe long-term effects [30,49]. The effect of MTX on tubular function seems to be minimal, low-molecular-weight proteinuria has been described, as well as some cases of renal phosphorus loss [11].
Of the 65 patients analyzed in our cohort, only two presented with manifest tubulopathy and one with isolated glucosuria. All three had been treated with at least two of the previously characterized especially nephrotoxic drugs and had received additional nephrotoxic medication. None of our patients received more than 50 g/m2 ifosfamide, and the median cumulative dose of cisplatin administered in our study was also lower (300 mg/m2) than in the previously mentioned studies [19,29].
A dose dependency of long-term tubular toxicity of ifosfamide was suggested by several authors [20,40,43,50] and is in accordance with the low rate of tubular toxicity reported in this study, where comparatively lower doses of ifosfamide had been used (median cumulative dose 20 g/m2 versus 62 g/m2 [20]).
An additional important aspect in the evaluation of renal function is blood pressure regulation. Severe systolic hypertension has been reported in 5–15% of patients after treatment with ifosfamide, cisplatin, or high-dose methotrexate [11,19,20,30]. The risk of increased blood pressure was higher in children who were exposed both to cisplatin and cranial irradiation [19]. In our cohort, arterial hypertension was confirmed in 11 patients (17%); however, this arterial hypertension did not require medication, but did support the necessity of regular screening. This is highlighted by the recent report from the Childhood Cancer Survivor Study, which revealed that survivors suffering from diabetes and/or hypertension are a risk population for the development of late-onset renal failure [8].
The contribution of a specific chemotherapeutic agent to the deterioration of any specific renal function parameter is difficult to assess, considering the multi-drug combinations used in most pediatric chemotherapy protocols and the variability of potential effects. The lower doses applied in our cohort of CNS tumor patients when compared to sarcoma patients [18,20], and the lacking need of nephrectomy in contrast to nephroblastoma patients [9] may have contributed to the preservation of kidney function in CNS tumor survivors.
Our study has several limitations. In awareness of the importance of uniform assessment of kidney function, but still considering the difficulty of invasive kidney function measurements in clinical practice, we decided to use the Schwartz formula with the commonest cut-off value of 90 mL/min/1.73 m2 for GFR estimation. Because our laboratory uses the Jaffé method for creatinine measurement, we used the original Schwartz formula [15], what might have led to an overestimation of eGFR.
Additionally, the study population is relatively small, thereby making it impossible to divide the cohort into further subgroups or perform multivariate analyses. This would have been of special interest due to the inhomogeneity in the interval between the end of chemotherapy and kidney function investigation, which might neglect other influencing factors, such as a higher susceptibility for a “second hit” event. Further research should focus on risk stratification and prevention methods, thereby focusing on diagnosis and treatment of hypertension.

5. Conclusions

Taken together, with adequate supportive measures, such as sufficient hydration according to the respective treatment protocol, as well as avoiding or close monitoring of additional nephrotoxic medication (vancomycin, certomycin, gentamicin, amphotericin), prevalence of long-term nephrotoxicity in CNS tumor is low. To detect mild renal function impairment, long-term follow-up, including basic renal function evaluation (eGFR, blood pressure, blood electrolytes, and urine analysis including protein) is essential.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/curroncol29080421/s1, Figure S1, flow chart of patient recruitment; Figure S2, Distribution of tumor localization; Figure S3, Correlation of therapy protocols and applied treatment protocols; Table S1, Cut-off levels for chemotherapeutic agents; Table S2, Overview of treatment protocols; Table S3, Patient characteristics of patients with mild renal impairment.

Author Contributions

Conceptualization: N.S., V.H. and A.P.; methodology: N.S., V.H., M.C., M.B. and A.P.; formal analysis and investigation: N.S., M.C. and A.P.; writing—original draft preparation: N.S. and A.P.; writing—review and editing: N.S., V.H., J.G., A.A.A., L.M., C.G., D.S., M.C., I.S., M.B. and A.P.; supervision: J.G., A.A.A., I.S., M.B. and A.P. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received to assist with the preparation of this manuscript.

Institutional Review Board Statement

The study protocol was approved by the Ethics Committee of the Medical University of Vienna (EK-Nr. 520/2009).

Informed Consent Statement

A written informed consent was obtained from all study participants and/or their parents.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgments

We thank Dipl. Ing. Walter Seeling and the team from IT4Science for the support with the calculation of the SDS values.

Conflicts of Interest

The authors have declared that no conflict of interest exists.

References

  1. Scheinemann, K.; Bouffet, E. Pediatric Neurooncology, 2015th ed.; Springer: New York, NY, USA, 2015. [Google Scholar]
  2. Cohen, A.R. Brain Tumors in Children. N. Engl. J. Med. 2022, 386, 1922–1931. [Google Scholar] [CrossRef]
  3. Duc, N.M.; Huy, H.Q.; Nadarajan, C.; Keserci, B. The Role of Predictive Model Based on Quantitative Basic Magnetic Resonance Imaging in Differentiating Medulloblastoma from Ependymoma. Anticancer Res. 2020, 40, 2975–2980. [Google Scholar] [CrossRef]
  4. Minh Thong, P.; Minh Duc, N. The Role of Apparent Diffusion Coefficient in the Differentiation between Cerebellar Medulloblastoma and Brainstem Glioma. Neurol. Int. 2020, 12, 34–40. [Google Scholar] [CrossRef] [PubMed]
  5. Girardi, F.; Allemani, C.; Coleman, M.P. Worldwide Trends in Survival From Common Childhood Brain Tumors: A Systematic Review. J. Glob. Oncol. 2019, 5, 1–25. [Google Scholar] [CrossRef]
  6. Oeffinger, K.C.; Mertens, A.C.; Sklar, C.A.; Kawashima, T.; Hudson, M.M.; Meadows, A.T.; Friedman, D.L.; Marina, N.; Hobbie, W.; Kadan-Lottick, N.S.; et al. Chronic health conditions in adult survivors of childhood cancer. N. Engl. J. Med. 2006, 355, 1572–1582. [Google Scholar] [CrossRef]
  7. Gunn, M.E.; Lähdesmäki, T.; Malila, N.; Arola, M.; Grönroos, M.; Matomäki, J.; Lähteenmäki, P.M. Late morbidity in long-term survivors of childhood brain tumors: A nationwide registry-based study in Finland. Neuro-Oncology 2015, 17, 747–756. [Google Scholar] [CrossRef] [Green Version]
  8. Dieffenbach, B.V.; Liu, Q.; Murphy, A.J.; Stein, D.R.; Wu, N.; Madenci, A.L.; Leisenring, W.M.; Kadan-Lottick, N.S.; Christison-Lagay, E.R.; Goldsby, R.E.; et al. Late-onset kidney failure in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study. Eur. J. Cancer 2021, 155, 216–226. [Google Scholar] [CrossRef]
  9. Kooijmans, E.C.; Bökenkamp, A.; Tjahjadi, N.S.; Tettero, J.M.; van Dulmen-den Broeder, E.; van der Pal, H.J.; Veening, M.A. Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database Syst. Rev. 2019, 3, Cd008944. [Google Scholar] [CrossRef]
  10. Jones, D.P.; Spunt, S.L.; Green, D.; Springate, J.E. Renal late effects in patients treated for cancer in childhood: A report from the Children’s Oncology Group. Pediatr. Blood Cancer 2008, 51, 724–731. [Google Scholar] [CrossRef] [Green Version]
  11. Grönroos, M.H.; Jahnukainen, T.; Möttönen, M.; Perkkiö, M.; Irjala, K.; Salmi, T.T. Long-term follow-up of renal function after high-dose methotrexate treatment in children. Pediatr. Blood Cancer 2008, 51, 535–539. [Google Scholar] [CrossRef] [PubMed]
  12. Ahmed, R.; Shahzad, M.; Umer, A.; Azim, A.; Jamil, M.T.; Haque, A. Frequency of Exposure of Nephrotoxic Drugs and Drug-Induced Acute Kidney Injury in Pediatric Intensive Care Unit: A Retrospective Review From a Tertiary Care Centre in Pakistan. Cureus 2020, 12, e12183. [Google Scholar] [CrossRef] [PubMed]
  13. Neuhauser, H.; Schienkiewitz, A.; Rosario, A.S.; Dortschy, R.; Kurth, B.-M. Referenzperzentile für anthropometrische Maßzahlen und Blutdruck aus der Studie zur Gesundheit von Kindern und Jugendlichen in Deutschland (KiGGS). 2013, pp. 100–112. Available online: https://edoc.rki.de/handle/176904/3254 (accessed on 25 July 2022).
  14. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Available online: https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf (accessed on 25 July 2022).
  15. Schwartz, G.J.; Brion, L.P.; Spitzer, A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr. Clin. N. Am. 1987, 34, 571–590. [Google Scholar] [CrossRef]
  16. Frisk, P.; Arvidson, J.; Stridsberg, M.; Gustafsson, J. Normal long-term parathyroid function after autologous bone marrow transplantation in children. Pediatr. Transpl. 2007, 11, 205–208. [Google Scholar] [CrossRef]
  17. Payne, R.B. Renal tubular reabsorption of phosphate (TmP/GFR): Indications and interpretation. Ann. Clin. Biochem. 1998, 35, 201–206. [Google Scholar] [CrossRef] [PubMed]
  18. Oberlin, O.; Fawaz, O.; Rey, A.; Niaudet, P.; Ridola, V.; Orbach, D.; Bergeron, C.; Defachelles, A.S.; Gentet, J.C.; Schmitt, C.; et al. Long-term evaluation of Ifosfamide-related nephrotoxicity in children. J. Clin. Oncol. 2009, 27, 5350–5355. [Google Scholar] [CrossRef] [PubMed]
  19. Pietila, S.; Ala-Houhala, M.; Lenko, H.L.; Harmoinen, A.P.; Turjanmaa, V.; Makipernaa, A. Renal impairment and hypertension in brain tumor patients treated in childhood are mainly associated with cisplatin treatment. Pediatr. Blood Cancer 2005, 44, 363–369. [Google Scholar] [CrossRef]
  20. Skinner, R.; Cotterill, S.J.; Stevens, M.C. Risk factors for nephrotoxicity after ifosfamide treatment in children: A UKCCSG Late Effects Group study. United Kingdom Children’s Cancer Study Group. Br. J. Cancer 2000, 82, 1636–1645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Kortmann, R.-D.; Kühl, J.; Timmermann, B.; Mittler, U.; Urban, C.; Budach, V.; Richter, E.; Willich, N.; Flentje, M.; Berthold, F.; et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the german prospective randomized trial hit’91. Int. J. Radiat. Oncol. Biol. Phys. 2000, 46, 269–279. [Google Scholar] [CrossRef]
  22. Mynarek, M.; von Hoff, K.; Pietsch, T.; Ottensmeier, H.; Warmuth-Metz, M.; Bison, B.; Pfister, S.; Korshunov, A.; Sharma, T.; Jaeger, N.; et al. Nonmetastatic Medulloblastoma of Early Childhood: Results From the Prospective Clinical Trial HIT-2000 and An Extended Validation Cohort. J. Clin. Oncol. 2020, 38, 2028–2040. [Google Scholar] [CrossRef]
  23. Wolff, J.E.; Driever, P.H.; Erdlenbruch, B.; Kortmann, R.D.; Rutkowski, S.; Pietsch, T.; Parker, C.; Metz, M.W.; Gnekow, A.; Kramm, C.M. Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: Results of the HIT-GBM-C protocol. Cancer 2010, 116, 705–712. [Google Scholar] [CrossRef]
  24. Seidel, C.; von Bueren, A.O.; Bojko, S.; Hoffmann, M.; Pietsch, T.; Gielen, G.H.; Warmuth-Metz, M.; Bison, B.; Kortmann, R.D.; Kramm, C.M. Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with acisplatinum-based polychemotherapy regimen: Acute toxicity in pediatric high-grade glioma patients. Strahlenther Onkol. 2018, 194, 215–224. [Google Scholar] [CrossRef] [PubMed]
  25. Calaminus, G.; Frappaz, D.; Kortmann, R.D.; Krefeld, B.; Saran, F.; Pietsch, T.; Vasiljevic, A.; Garre, M.L.; Ricardi, U.; Mann, J.R.; et al. Outcome of patients with intracranial non-germinomatous germ cell tumors-lessons from the SIOP-CNS-GCT-96 trial. Neuro Oncol 2017, 19, 1661–1672. [Google Scholar] [CrossRef] [Green Version]
  26. Gnekow, A.K.; Walker, D.A.; Kandels, D.; Picton, S.; Giorgio, P.; Grill, J.; Stokland, T.; Sandstrom, P.E.; Warmuth-Metz, M.; Pietsch, T.; et al. A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18-month treatment programme for childhood (≤16 years) low grade glioa—A final report. Eur. J. Cancer 2017, 81, 206–225. [Google Scholar] [CrossRef] [Green Version]
  27. Slavc, I.; Chocholous, M.; Leiss, U.; Haberler, C.; Peyrl, A.; Azizi, A.A.; Dieckmann, K.; Woehrer, A.; Peters, C.; Widhalm, G.; et al. Atypical teratoid rhabdoid tumor: Improved long-term survival with an intensive multimodal therapy and delayed radiotherapy. The Medical University of Vienna Experience 1992–2012. Cancer Med. 2014, 3, 91–100. [Google Scholar] [CrossRef] [PubMed]
  28. Finlay, J.L.; August, C.; Packer, R.; Zimmerman, R.; Sutton, L.; Freid, A.; Rorke, L.; Bayever, E.; Kamani, N.; Kramer, E.; et al. High-dose multi-agent chemotherapy followed by bone marrow ‘rescue’ for malignant astrocytomas of childhood and adolescence. J. Neurooncol. 1990, 9, 239–248. [Google Scholar] [CrossRef] [PubMed]
  29. Skinner, R.; Pearson, A.D.; English, M.W.; Price, L.; Wyllie, R.A.; Coulthard, M.G.; Craft, A.W. Cisplatin dose rate as a risk factor for nephrotoxicity in children. Br. J. Cancer 1998, 77, 1677–1682. [Google Scholar] [CrossRef] [Green Version]
  30. Skinner, R.; Parry, A.; Price, L.; Cole, M.; Craft, A.W.; Pearson, A.D. 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, 3213–3219. [Google Scholar] [CrossRef]
  31. Skinner, R.; Parry, A.; Price, L.; Cole, M.; Craft, A.W.; Pearson, A.D. Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose. Pediatr. Blood Cancer 2010, 54, 983–989. [Google Scholar] [CrossRef] [PubMed]
  32. Mudi, A.; Levy, C.S.; Geel, J.A.; Poole, J.E. Paediatric cancer survivors demonstrate a high rate of subclinical renal dysfunction. Pediatr. Blood Cancer 2016, 63, 2026–2032. [Google Scholar] [CrossRef] [PubMed]
  33. Musiol, K.; Sobol-Milejska, G.; Nowotka, Ł.; Torba, K.; Kniażewska, M.; Wos, H. Renal function in children treated for central nervous system malignancies. Child Nervous Syst. 2016, 32, 1431–1440. [Google Scholar] [CrossRef] [Green Version]
  34. Mulder, R.L.; Knijnenburg, S.L.; Geskus, R.B.; van Dalen, E.C.; van der Pal, H.J.; Koning, C.C.; Bouts, A.H.; Caron, H.N.; Kremer, L.C. Glomerular function time trends in long-term survivors of childhood cancer: A longitudinal study. Cancer Epidemiol. Biomark. Prev. 2013, 22, 1736–1746. [Google Scholar] [CrossRef] [Green Version]
  35. Mian, A.N.; Schwartz, G.J. Measurement and Estimation of Glomerular Filtration Rate in Children. Adv. Chron. Kidney Dis. 2017, 24, 348–356. [Google Scholar] [CrossRef]
  36. Laskin, B.L.; Nehus, E.; Goebel, J.; Furth, S.; Davies, S.M.; Jodele, S. Estimated versus measured glomerular filtration rate in children before hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 2014, 20, 2056–2061. [Google Scholar] [CrossRef] [Green Version]
  37. Bernhardt, M.B.; Moffett, B.S.; Johnson, M.; Tam, V.H.; Thompson, P.; Garey, K.W. Agreement among measurements and estimations of glomerular filtration in children with cancer. Pediatr. Blood Cancer 2015, 62, 80–84. [Google Scholar] [CrossRef]
  38. Selistre, L.; Rabilloud, M.; Cochat, P.; de Souza, V.; Iwaz, J.; Lemoine, S.; Beyerle, F.; Poli-de-Figueiredo, C.E.; Dubourg, L. Comparison of the Schwartz and CKD-EPI Equations for Estimating Glomerular Filtration Rate in Children, Adolescents, and Adults: A Retrospective Cross-Sectional Study. PLoS Med. 2016, 13, e1001979. [Google Scholar] [CrossRef]
  39. Stefanowicz, J.; Owczuk, R.; Sierota, D.; Kaczorowska-Hać, B.; Balcerska, A. Does Antineoplasm Treatment Decrease the Glomerular Filtration Rate in Children? Kidney Blood Press. Res. 2009, 32, 194–199. [Google Scholar] [CrossRef]
  40. Skinner, R. Chronic ifosfamide nephrotoxicity in children. Med. Pediatr. Oncol. 2003, 41, 190–197. [Google Scholar] [CrossRef] [PubMed]
  41. Brock, P.R.; Koliouskas, D.E.; Barratt, T.M.; Yeomans, E.; Pritchard, J. Partial reversibility of cisplatin nephrotoxicity in children. J. Pediatr. 1991, 118, 531–534. [Google Scholar] [CrossRef]
  42. Latcha, S.; Jaimes, E.A.; Patil, S.; Glezerman, I.G.; Mehta, S.; Flombaum, C.D. Long-Term Renal Outcomes after Cisplatin Treatment. Clin. J. Am. Soc. Nephrol. CJASN 2016, 11, 1173–1179. [Google Scholar] [CrossRef]
  43. Skinner, R. Late renal toxicity of treatment for childhood malignancy: Risk factors, long-term outcomes, and surveillance. Pediatr. Nephrol. 2018, 33, 215–225. [Google Scholar] [CrossRef] [Green Version]
  44. Launay-Vacher, V.; Rey, J.B.; Isnard-Bagnis, C.; Deray, G.; Daouphars, M. Prevention of cisplatin nephrotoxicity: State of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemotherap. Pharmacol. 2008, 61, 903–909. [Google Scholar] [CrossRef] [PubMed]
  45. Bergeron, C.; Dubourg, L.; Chastagner, P.; Mechinaud, F.; Plouvier, E.; Desfachelles, A.S.; Dusol, F.; Pautard, B.; Edan, C.; Plantaz, D.; et al. Long-term renal and hearing toxicity of carboplatin in infants treated for localized and unresectable neuroblastoma: Results of the SFOP NBL90 study. Pediatr. Blood Cancer 2005, 45, 32–36. [Google Scholar] [CrossRef] [PubMed]
  46. Ramsey, L.B.; Balis, F.M.; O’Brien, M.M.; Schmiegelow, K.; Pauley, J.L.; Bleyer, A.; Widemann, B.C.; Askenazi, D.; Bergeron, S.; Shirali, A.; et al. Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance. Oncologist 2018, 23, 52–61. [Google Scholar] [CrossRef] [Green Version]
  47. Malyszko, J.; Kozlowska, K.; Kozlowski, L.; Malyszko, J. Nephrotoxicity of anticancer treatment. Nephrol. Dialysis Transplant. 2017, 32, 924–936. [Google Scholar] [CrossRef]
  48. Liamis, G.; Milionis, H.J.; Elisaf, M. Medication-induced hypophosphatemia: A review. QJM Monthly J. Assoc. Phys. 2010, 103, 449–459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. English, M.W.; Skinner, R.; Pearson, A.D.; Price, L.; Wyllie, R.; Craft, A.W. Dose-related nephrotoxicity of carboplatin in children. Br. J. Cancer 1999, 81, 336–341. [Google Scholar] [CrossRef] [Green Version]
  50. Arga, M.; Oguz, A.; Pinarli, F.G.; Karadeniz, C.; Citak, E.C.; Emeksiz, H.C.; Duran, E.A.; Soylemezoglu, O. Risk factors for cisplatin-induced long-term nephrotoxicity in pediatric cancer survivors. Pediatr. Int. 2015, 57, 406–413. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Median cumulative dose and dose range for each cytotoxic agent as well as the number of patients treated with each agent.
Table 1. Median cumulative dose and dose range for each cytotoxic agent as well as the number of patients treated with each agent.
Chemotherapeutic AgentMedian Cumulative DoseDose RangeNumber of Patients
Actinomycin9 mg/m29–91
Bevacizumab130 mg/kg110–7605
Carboplatin2800 mg/m2600–935043
Cisplatin300 mg/m263–66035
Cyclophosphamide7200 mg/m2800–72,84028
Doxorubicin180 mg/m2120–4405
Etoposide1650 mg/m2300–390039
Ifosfamide20,341 mg/m27500–47,20023
Lomustine445 mg/m235–60015
Methotrexate25,000 mg/m25000–30,00017
Temozolomide7925 mg/m22050–18,55012
Vincristine15 mg/m22.6–50.747
Table
Table 2. p-values for the correlation between each chemotherapeutic agent and eGFR, as well as chemotherapy protocol, intensity of chemotherapy, and additional administration of nephrotoxic drugs and eGFR.
Table 2. p-values for the correlation between each chemotherapeutic agent and eGFR, as well as chemotherapy protocol, intensity of chemotherapy, and additional administration of nephrotoxic drugs and eGFR.
Chemotherapeutic Agent Low/Middle/High (l/m/h) or Low/High (l/h)Correlation with eGFR (p-Value)
Carboplatin (l/m/h)0.869 *
CCNU (l/h)0.232 °
Cisplatin (l/m/h)0.912 *
Cyclophosphamide (l/h)0.469 °
Etoposide (l/m/h)0.300 *
Ifosfamide (l/m/h)0.323 *
Methotrexate (l/h)0.871 °
Temozolomide (l/h)0.202 °
Vincristine (l/h)0.189 °
Chemotherapy protocol0.459 *
Administration of more than 2 nephrotoxic chemotherapeutics0.830 °
Administration of nephrotoxic supportive medication0.670 °
* Analysis by Kruskal–Wallis test, ° Analysis by Mann–Whitney U test. Two-sided significance level of 0.05.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Stepien, N.; Handler, V.; Gojo, J.; Azizi, A.A.; Mayr, L.; Grylli, C.; Schwarz, D.; Chocholous, M.; Slavc, I.; Boehm, M.; et al. Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors. Curr. Oncol. 2022, 29, 5306-5315. https://doi.org/10.3390/curroncol29080421

AMA Style

Stepien N, Handler V, Gojo J, Azizi AA, Mayr L, Grylli C, Schwarz D, Chocholous M, Slavc I, Boehm M, et al. Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors. Current Oncology. 2022; 29(8):5306-5315. https://doi.org/10.3390/curroncol29080421

Chicago/Turabian Style

Stepien, Natalia, Viktoria Handler, Johannes Gojo, Amedeo A. Azizi, Lisa Mayr, Chryssa Grylli, Daniela Schwarz, Monika Chocholous, Irene Slavc, Michael Boehm, and et al. 2022. "Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors" Current Oncology 29, no. 8: 5306-5315. https://doi.org/10.3390/curroncol29080421

APA Style

Stepien, N., Handler, V., Gojo, J., Azizi, A. A., Mayr, L., Grylli, C., Schwarz, D., Chocholous, M., Slavc, I., Boehm, M., & Peyrl, A. (2022). Prospective Evaluation of Kidney Function in Long-Term Survivors of Pediatric CNS Tumors. Current Oncology, 29(8), 5306-5315. https://doi.org/10.3390/curroncol29080421

Article Metrics

Back to TopTop