Nephrotoxicity in childhood cancer survivors
Authors:   , Kooijmans Esmee Corine Maria 
Published: May 2024

This thesis describe the results of the Dutch Childhood Cancer Survivor Study LATER 2 Renal study. This is a nationwide cross-sectional cohort study evaluating nephrotoxicity among childhood cancer survivors (CCS) treated with potentially nephrotoxic treatment (nephrectomy, abdominal radiotherapy, total body irradiation, cisplatin, carboplatin, ifosfamide, high-dose cyclophosphamide or hematopoietic stem cell transplantation) in comparison with matched controls from the general population.
At a median age of 32.0 years, the glomerular filtration rate (GFR) was under 60ml/min/1.73m2 in 3.7% of survivors and in none of the controls. Ten survivors had kidney failure. Chronic kidney disease according to age-thresholds (glomerular filtration rate respectively under 75 for age under 40, under 60 for ages 40-65, and under 40 for age over 65) was 6.6% in survivors vs. 0.2% in controls. Albuminuria (albumin-to-creatinine ratio over 3 mg/mmol) was found in 16.2% of survivors and 0.2% of controls. Risk factors for chronic kidney disease, based on multivariable analyses, were nephrectomy, abdominal radiotherapy, ifosfamide and cisplatin over 500 mg/m2. For albuminuria, risk factors were total body irradiation, abdominal radiotherapy over 30 Gy and ifosfamide. Hypertension and follow-up 30 or more years increased the risk for glomerular dysfunction. Thus, lifetime monitoring of glomerular function in survivors exposed to these identified high risk factors is warranted.
Regarding long-term tubular dysfunction the current study revealed that, 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. However, losses of small proteins in the urine (Low molecular weight protein (LMWP)) was more prevalent in 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 and survivors who were treated with these chemotherapeutics and should be monitored for tubular dysfunction.
Regarding hypertension, our results show that with standard office blood pressure measurement the prevalence of hypertension was comparable in CCS (16.3%) and controls (18.2%). In 12% of CCS and 17.8% of controls, hypertension was undiagnosed.
A decreased GFR (<60 ml/min/1.73 m2) was associated with hypertension in CCS. Risk factors for hypertension were abdominal radiotherapy ≥ 20 Gy and total body irradiation (TBI) as part of hematopoietic stem cell transplantation. 24 hour ambulatory blood pressure monitoring (ABPM) in n = 77 CCS showed 7.8% masked hypertension, 2.6% white coat hypertension and 20.8% abnormal nocturnal dipping. Therefore ABPM should be considered in the surveillance of CCS.
The results of this thesis are implemented in a new international surveillance guideline on nephrotoxicity after childhood cancer treatment. In this guideline recommendations are formulated who needs surveillance, the frequency of the surveillance, what screening modalities should be used, and what should be done if abnormalities are identified.