Lower urinary tract dysfunction (LUTD) in children is a very common disorder and a serious challenge in paediatric urology practice. The history, physical examination, urine analysis, symptom scores, urinary system ultrasound, measurement of post voiding residual volume, and non-invasive urodynamic studies such as voiding diary and uroflowmetry have an important place in evaluation. After those first line tests, invasive urodynamic studies are the gold standard method in the evaluation of LUTD in children. Those studies are also important in the follow-up of children with LUTD. However, urodynamic studies are expensive and laborious tests demanding a cooperative child, parent and dedicated health care personnel. Therefore, alternatives to invasive urodynamic studies were sought for the evaluation of LUTD. The assessment of bladder wall thickness, measurement of isovolumetric detrusor pressure by an external condom catheter and an inflatable cuff around the penis and urinary biomarkers are some of these alternatives. Among these, especially urine biomarkers stand out with their easy measurability. Unfortunately, studies examining the relationship between urinary biomarkers and LUTD in children are limited, although they are studied exclusively in adults. The aim of this systematic review is to determine urinary biomarkers studied in children with neurogenic and non-neurogenic LUTD.

The systematic review was conducted in accordance with the PRISMA guidelines (1). The systematic screening was performed on PUBMED electronic database without any publication date limitation. The selected keywords for screening and the search strategy were shown in Figure 1. No filter was used during the search. Original articles examining the relationship between LUTD and urinary biomarkers in children were included in the study. Studies on urinary biomarkers and other pathologies such as ureteropelvic junction obstruction, urinary tract infection, vesicoureteral reflux; animal studies; review articles were excluded from the systematic review. Articles with full texts only in English were accepted. All articles were independently screened by CAS if title and abstract met the inclusion criteria. Parameters related to the following topics were obtained from each included study: study design, characteristics of participants, number of participants, age, control group, types of biomarkers, measurement technique in urine, subgroup analysis, urodynamic findings, and outcome.

All articles included in the study were evaluated for quality by an independent reviewer (SY). Dutch Cochrane Checklist (http://netherlands. cochrane.org) (2) and level of evidence by EBRO platform (3) were used for quality assessment.

A total of 492 studies were screened and 14 studies meeting the selection criteria were included in the systematic review. The screening stages are shown in Figure 1. Of these studies, the first of which was published in 2012, 9 (64.2%) were conducted in children with non-neurogenic LUTD and 5 (35.8%) were conducted children with neurogenic LUTD. While 6 studies (42.8 %) were designed as cohort, 8 (57.2%) were designed as cross-sectional. Only one biomarker was studied in 9 (64.2%) studies, multiple biomarkers were evaluated in 5 (35.8%) studies. Nerve Growth Factor (NGF) was evaluated in 11 studies, Brain-Derived Neurotrophic Factor (BDNF) in 4, Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) in 2, Transforming Growth Factor Beta-1 (TGF Beta-1) in 2, Neutrophil Gelatinase-Associated Lipocalin (NGAL) in 1, and Aquaporin-2 in 1. While urinary biomarkers were measured by ELISA method in 13 studies, only Aquaporin-2 was measured by Immunoblotting method. A control group was used in 10 (71.4%) studies and urodynamic evaluation was performed in 6 (42.8%) studies.
According to the Dutch Cochrane Checklist, 10 (71.4%) articles were evaluated on 4 (28.6%) items and 4 articles on 5 items. The average score was 3.25+/-0.5. The level of evidence was found as B for 11 (78.5%) articles and C for 3 (21.5%) articles.

In recent years, many studies on the relationship between biomarkers and urological diseases have been published. However, it has been observed that very few of these were performed in children with LUTD. In addition, no studies with the level of evidence A were found among these studies. Studies have shown that levels of urinary NGF and BDNF are higher in children with neurogenic or non-neurogenic LUTD. However, It's observed that among the currently studied biomarkers, BDNF was not evaluated in OAB, NGAL in neurogenic LUTD, and TGF Beta-1 and TIMP-2 in non-neurogenic LUTD. No biomarkers have been studied for situations such as vesicoureteral reflux and urinary tract infection, which can be associated with LUTD in children. Also, we think that studies with a large number of patients are necessary to evaluate the predictive value of urinary biomarkers. In the studies included in the review, cost analysis of biomarkers essay testing was not reported, and we believe that this is an important endpoint to be discussed particularly for a candidate for alternative or additive study.

Urinary biomarkers are promising for the future with their non-invasive and easily measurable features in the evaluation and follow-up of children with LUTD. However, the scarcity of clinical studies and inconsistent results in children reduce reliability. We think that more and better organized multicenter studies would contribute to deciding the efficacy of urine biomarkers in children with LUTD.

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