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. 2022 Jun 1;14(11):2754.
doi: 10.3390/cancers14112754.

Long-Term Tubular Dysfunction in Childhood Cancer Survivors; DCCSS-LATER 2 Renal Study

Esmee C M Kooijmans  1   2 , Helena J H van der Pal  2 , Saskia M F Pluijm  2 , Margriet van der Heiden-van der Loo  2   3 , Leontien C M Kremer  2   4   5 , Dorine Bresters  2   6 , Eline van Dulmen-den Broeder  1 , Marry M van den Heuvel-Eibrink  2   7 , Jacqueline J Loonen  8 , Marloes Louwerens  9 , Sebastian J C Neggers  10 , Cécile Ronckers  2 , Wim J E Tissing  2   11 , Andrica C H de Vries  2   7 , Gertjan J L Kaspers  1   2 , Arend Bökenkamp  12 , Margreet A Veening  1   2 , On Behalf Of The Dutch Later Study Group
Affiliations

Long-Term Tubular Dysfunction in Childhood Cancer Survivors; DCCSS-LATER 2 Renal Study

Esmee C M Kooijmans et al. Cancers (Basel). .

Abstract

The aim of this nationwide cross-sectional cohort study was to determine the prevalence of and risk factors for tubular dysfunction in childhood cancer survivors (CCS). In the DCCSS-LATER 2 Renal study, 1024 CCS (≥5 years after diagnosis), aged ≥ 18 years at study, treated between 1963 and 2001 with potentially nephrotoxic therapy (i.e., nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide, or hematopoietic stem cell transplantation) participated, and 500 age- and sex-matched participants from Lifelines acted as controls. Tubular electrolyte loss was defined as low serum levels (magnesium < 0.7 mmol/L, phosphate < 0.7 mmol/L and potassium < 3.6 mmol/L) with increased renal excretion or supplementation. A α1-microglobulin:creatinine ratio > 1.7 mg/mmol was considered as low-molecular weight proteinuria (LMWP). Multivariable risk analyses were performed. After median 25.5 years follow-up, overall prevalence of electrolyte losses in CCS (magnesium 5.6%, potassium 4.5%, phosphate 5.5%) was not higher compared to controls. LMWP was more prevalent (CCS 20.1% versus controls 0.4%). LMWP and magnesium loss were associated with glomerular dysfunction. Ifosfamide was associated with potassium loss, phosphate loss (with cumulative dose > 42 g/m2) and LMWP. Cisplatin was associated with magnesium loss and a cumulative dose > 500 mg/m2 with potassium and phosphate loss. Carboplatin cumulative dose > 2800 mg/m2 was associated with potassium loss. In conclusion, long-term tubular dysfunction is infrequent. Yet, ifosfamide, cisplatin and carboplatin are risk factors.

Keywords: childhood cancer survivor; nephrotoxicity; tubular dysfunction.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Flowchart study cohort. Abbreviations: DCCSS, Dutch Childhood Cancer Survivor Study; IC, informed consent.
Figure 2
Figure 2
Multivariable logistic regression analyses including mutually exclusive treatment groups for tubular outcomes including: (A) tubular magnesium loss; (B) tubular potassium loss; (C) tubular phosphate loss. This figure displays the odds ratios in CCS compared to controls. Exact values of the odds ratios are listed in Table S1. The square represents the odds ratio, and the horizontal lines represent the 95% confidence interval. The vertical line represents the value 1 (no difference between CCS and controls). The model for tubular magnesium loss is corrected for age at study, estimated glomerular filtration rate and albumin-to-creatinine ratio. The models for tubular potassium loss are corrected for age at study. The model for tubular phosphate loss is corrected for age at study and sex. * = p-value < 0.05. Abbreviations: CCS, childhood cancer survivors; HD-cyclo, high-dose cyclophosphamide; RT, radiotherapy; TBI, total body irradiation.
Figure 3
Figure 3
Multivariable logistic regression analyses among different tumor types for tubular outcomes including: (A) tubular magnesium loss; (B) tubular potassium loss; (C) tubular phosphate loss. This figure displays the odds ratios in CCS compared to controls. Exact values of the odds ratios are listed in Table S2. The square represents the odds ratio, and the horizontal lines represent the 95% confidence interval. The vertical line represents the value 1 (no difference between CCS and controls). The model for tubular magnesium loss is corrected for age at study, estimated glomerular filtration rate and albumin-to-creatinine ratio. The model for tubular potassium loss is corrected for age at study. The model for tubular phosphate loss is corrected for age at study and sex. * = p-value < 0.05. Abbreviations: CCS, childhood cancer survivors; CNS, central nervous system.
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