A Systematic Review of the Accuracy and Utility of Early Markers of Ifosfamide-Induced Proximal Tubulopathy in Survivors of Childhood Cancers

Abstract

This study was conducted to identify and assess the accuracy and utility of any early markers of clinically significant proximal tubulopathy in children treated with ifosfamide chemotherapy. Ifosfamide is widely used either as a solitary agent or in conjunction with various other chemotherapeutic agents in treating solid tumors of childhood. It is highly effective but can cause short-term and long-term damage to kidneys, most commonly resulting in a tubular nephropathy and/or glomerular dysfunction. This may lead to chronic renal failure and metabolic bone disease in long-term survivors of childhood cancer. Multiple electronic databases (Cochrane, MEDLINE, EMBASE) were searched for primary studies describing the predictive value of early blood or urine tests to predict proximal tubulopathy. Citation searching (using reference lists and Science Citation Index searches) was also undertaken. Analysis was undertaken using criteria suggested by the MOOSE (Meta-analysis of Observational Studies in Epidemiology) collaboration. Studies were reviewed by at least 2 authors and disagreements resolved by consensus. Initial searches revealed approximately 310 studies of which 38 papers were selected for full analysis. Only 4 papers described the predictive value of early markers proximal tubular nephropathy. The remaining studies estimated prevalence of acute or chronic nephropathy without presenting predictive data. Of the 4 papers selected for analysis, 2 papers assessed the value of beta-2 microglobulinuria, and 3 addressed quantitative aminoaciduria. Test characteristics ranged from sensitivities of 82 to 100% and specificities of 84 to 100%, although the confidence intervals around these estimates were wide. Given the paucity of data, to consider further the use of early markers of proximal tubular nephropathy a prospective evaluation of patients who have been treated with ifosfamide based regimes should be undertaken.

Aminoaciduria in the prediction of ifosfamide-induced tubulopathy after childhood cancer: a feasibility study

“…When considered in light of the recent systematic review, the prevalence of generalised aminoaciduria within this sample was within the range previously reported [6]. In particular, we can compare this study with that done by Rossi et al, as measuring similar variables [7].…”

“…The majority of patients will develop a temporary acute proximal tubulopathy whilst receiving ifosfamide. However, the prevalence of long-term ifosfamide-induced tubulopathy has not yet been clearly defined, with estimates of 6–46 % of patients who have received ifosfamide as treatment for cancer [6]. …”

“…A recent systematic review performed by this group has looked at the accuracy and utility of early markers of ifosfamide-induced proximal tubulopathy [6]. This review found a general paucity of data in this area.…”

Renal toxicity of ifosfamide in children with cancer: an exploratory study integrating aldehyde dehydrogenase enzymatic activity data and a wide-array urinary metabolomics approach

“…However, due to methodological limitations, the available evidence does not allow precise determination of the prevalence of early and long-term renal damage after treatment [ 3 , 30 ]. Moreover, only a few studies assessed early markers of renal dysfunction that might predict the development of late nephrotoxicity [ 31 ]. To date, a decrease in amino acid reabsorption is the most common ifosfamide-induced tubular dysfunction, and early hyperaminoaciduria could thus represent a sensitive parameter of chronic tubulopathy [ 28 , 32 ].…”