Abstract: Apart from the remaining 37 studies included from the original review, the search resulted in the inclusion of 24 new studies. In total, we included 61 studies; 46 for prevalence, six for both prevalence and risk factors, and nine not meeting the inclusion criteria, but assessing risk factors. The 52 studies evaluating the prevalence of renal dysfunction included 13,327 participants of interest, of whom at least 4499 underwent renal function testing. The prevalence of adverse renal effects ranged from 0% to 84%. This variation may be due to diversity of included malignancies, received treatments, reported outcome measures, follow-up duration and the methodological quality of available evidence. Seven out of 52 studies, including 244 participants, reported the prevalence of chronic kidney disease, which ranged from 2.4% to 32%. Of these 52 studies, 36 studied a decreased (estimated) GFR, including at least 432 CCS, and found it was present in 0% to 73.7% of participants. One eligible study reported an increased risk of glomerular dysfunction after concomitant treatment with aminoglycosides and vancomycin in CCS receiving total body irradiation (TBI). Four non-eligible studies assessing a total cohort of CCS, found nephrectomy and (high-dose (HD)) ifosfamide as risk factors for decreased GFR. The majority also reported cisplatin as a risk factor. In addition, two non-eligible studies showed an association of a longer follow-up period with glomerular dysfunction. Twenty-two out of 52 studies, including 851 participants, studied proteinuria, which was present in 3.5% to 84% of participants. Risk factors, analysed by three non-eligible studies, included HD cisplatin, (HD) ifosfamide, TBI, and a combination of nephrectomy and abdominal radiotherapy. However, studies were contradictory and incomparable. Eleven out of 52 studies assessed hypophosphataemia or tubular phosphate reabsorption (TPR), or both. Prevalence ranged between 0% and 36.8% for hypophosphataemia in 287 participants, and from 0% to 62.5% for impaired TPR in 246 participants. One non-eligible study investigated risk factors for hypophosphataemia, but could not find any association. Four out of 52 studies, including 128 CCS, assessed the prevalence of hypomagnesaemia, which ranged between 13.2% and 28.6%. Both non-eligible studies investigating risk factors identified cisplatin as a risk factor. Carboplatin, nephrectomy and follow-up time were other reported risk factors. The prevalence of hypertension ranged from 0% to 50% in 2464 participants (30/52 studies). Risk factors reported by one eligible study were older age at screening and abdominal radiotherapy. A non-eligible study also found long follow-up time as risk factor. Three non-eligible studies showed that a higher body mass index increased the risk of hypertension. Treatment-related risk factors were abdominal radiotherapy and TBI, but studies were inconsistent. Because of the profound heterogeneity of the studies, it was not possible to perform meta-analyses. Risk of bias was present in all studies. The prevalence of adverse renal effects after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region, nephrectomy, or any combination of these, ranged from 0% to 84% depending on the study population, received treatment combination, reported outcome measure, follow-up duration and methodological quality. With currently available evidence, it was not possible to draw solid conclusions regarding the prevalence of, and treatment-related risk factors for, specific adverse renal effects. Future studies should focus on adequate study designs and reporting, including large prospective cohort studies with adequate control groups when possible. In addition, these studies should deploy multivariable risk factor analyses to correct for possible confounding. Next to research concerning known nephrotoxic therapies, exploring nephrotoxicity after new therapeutic agents is advised for future studies. Until more evidence becomes available, CCS should preferably be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.

Plain-language summary: The evidence is current to March 2017. We included 61 studies; 46 on prevalence, six for both prevalence and risk factors, and nine studies that did not meet all the requirements for this review, but evaluated risk factors (non-eligible studies). Participants in the studies had been treated before the age of 21 years with chemotherapy (i.e. cisplatin, carboplatin, ifosfamide), radiation, or surgery involving the kidneys, or a combination of these treatments. The studies took place at least one year after the participants had finished their treatment. The 52 studies that evaluated prevalence of adverse kidney effects included 13,327 participants, of whom 4499 underwent kidney function tests. The studies were very different from each other, in the types of participants and treatments, length of follow-up and how they measured treatment results, and their methods were of variable quality. The percentage of CCS with kidney problems ranged from 0% to 84%. Reported risk factors were often inconsistent among studies. The prevalence of chronic kidney disease ranged from 2.4% to 32% in 244 participants (7/52 studies). Thirty-six out of 52 studies, including at least 432 participants, carried out a kidney function test called glomerular filtration rate (GFR). An abnormal GFR was found to be present in 0% to 73.7% of participants. One eligible study found an increased risk of abnormal GFR in participants who had been treated with total body irradiation (TBI) and received certain types of antibiotics (aminoglycosides and vancomycin). Four non-eligible studies reported an increased risk of abnormal GFR for participants treated with surgery of the kidney and ifosfamide. Some studies also reported that cisplatin and long follow-up duration were risk factors. Twenty-two out of 52 studies, including 851 participants, assessed an abnormal amount of proteins in the urine, which they found in 3.5% to 84% of participants. Risk factors, evaluated by three non-eligible studies, included cisplatin, ifosfamide, TBI, and a combination of surgery and radiation involving the kidney. However, the results of these studies did not agree, and we could not analyse their results together because they used different definitions. Eleven out of 52 studies looked at a low level of phosphate in the blood (hypophosphataemia), or problems with the reabsorption of phosphate by the kidneys in 246 participants. Prevalence of hypophosphataemia ranged between 0% and 36.8% in 287 participants. The studies found problems with the reabsorption of phosphate by the kidneys in 0% to 62.5% of participants. One non-eligible study investigated risk factors, but could not find any association with hypophosphataemia. Four out of 52 studies, including 128 CCS, evaluated a low level of magnesium in the blood (hypomagnesaemia). Prevalence ranged between 13.2% and 28.6%. Two non-eligible studies identified cisplatin as risk factor for hypomagnesaemia. Other reported risk factors were carboplatin, surgery of the kidney, and follow-up time. However, studies were contradictory. The prevalence of high blood pressure ranged from 0% to 50% in 2464 participants (30/52 studies). Risk factors reported by one eligible study were older age at screening and radiation involving the kidney. A high body mass index was reported as a risk factor by three non-eligible studies. Other reported risk factors included follow-up time, and radiation involving the kidney or TBI. However, studies were contradictory. All studies showed problems that could affect our confidence in their results. More, and especially higher-quality research is needed to gain better insight into kidney adverse effects and related risk factors.