Pop-off mechanisms as renoprotective mediators in children with posterior urethral valves: A systematic review and meta-analysis

Background Pop-off mechanisms are potential pressure-relieving mediators in patients diagnosed with posterior urethral valves (PUV). These mechanisms include, among others, urachal persistence, urinomas, bladder diverticula and unilateral high-grade vesicoureteral re�ux. The aim of this systematic review was to synthesize the existing evidence regarding the protective effect of pop-off mechanisms on renal function in children with PUV.


Introduction
Posterior urethral valves (PUV) constitute a very infrequent malformation of the urinary tract that results from an abnormal fusion between the mesonephric duct and the urogenital sinus.In practice, PUV represent a urinary tract obstruction, which leads into a high-pressure nephrourological pathway.This is associated with bladder disorders such as trabeculation, low bladder capacity and low compliance, vesicoureteral re ux, early and severe nephropathy, and even end-stage renal failure.In patients with high-pressure nephrourological pathway renal function, measured by serum creatine levels, represent the major prognostic determinant [1].
The incidence of PUV is 1 per 5,000-8,000 male live births, depending on the series.Part of the renal damage that occurs in these patients happens prenatally.However, although the advances in prenatal diagnosis made it possible to establish early diagnostic suspicion, intrauterine treatment is still underdeveloped and the results are inconsistent [2].
A recent bibliometric study showed that long-term prognosis of patients with PUV is one of the elds of greatest scienti c interest nowadays [3].Previous studies tried to identify postnatal factors associated with the renal function evolution of patients with PUV.These studies include from the evaluation of different markers of renal function during the rst year of life, to the comparison between different surgical approaches (early urinary diversion and delayed valve ablation vs. early valve ablation, circumcision vs. expectant management, prophylactic antibiotherapy vs. no antibiotherapy) [4][5][6].Although previous evidence contributed to a better understanding of the prognosis of this pathology and contributed to reduce its morbidity and mortality, children with PUV still present a high risk of renal failure (up to 20-50% according to the series) [1,7] noting that there is still room for improvement in the management of these patients.
Pop-off mechanisms as described by Rittenberg in 1988 [8] are potential pressure-relieving mechanisms in PUV patients.These mechanisms, usually present from the prenatal period, include urachal persistence, urinary extravasation (urinomas), bladder diverticula and unilateral high-grade vesicoureteral re ux, including VURD syndrome (posterior urethral valves, unilateral vesicoureteral re ux and renal dysplasia).To date, multiple studies evaluated the potential effect of these mechanisms on the prognosis of patients with PUV, but those studies are heterogeneous and have little sample sizes.The aim of this systematic review was to synthesize the existing evidence regarding the protective role of pop-off mechanisms on renal function in children with PUV.

Literature search and selection
We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidance.We speci cally designed and implemented a review protocol that was registered in the international prospective register of systematic reviews (PROSPERO ID CRD42022370739).
Inclusion and exclusion criteria are shown in Supplementary le 1.The selection of articles was made by JAM, BPR and MRJ.Disagreement was resolved by confrontation.

Quality Assessment
An analysis of the selected articles to ensure their methodological quality and to assess the risk of bias according to the Newcastle Ottawa Scale (NOS) standards was done.Three reviewers (JAM, BPR, MRJ) independently evaluated the methodological quality and the risk of bias of the selected articles.

Data Extract And Synthesis
Data extract and synthesis Three reviewers (JAM, BPR, MRJ) independently extracted the relevant data from the selected articles following a standardized procedure.Extracted data included author, year of publication, country where the study was conducted, type of study (prospective or retrospective), study population (sample size, age range and sex distribution), pop-off group and control group de nitions, mean and standard deviation (or median and interquartile range) for serum creatinine and Nadir creatinine values in each group, signi cant events in each group and p-value for between-groups comparison.There were no disagreements or con icts between the reviewers after collating the extracted data.A review of the metrics used in each of the studies was carried out, and a standardization of units (conversion from mg/dL to µmol/L) was performed for the analysis.

Meta-analysis
Medians and interquartile ranges of serum creatinine and Nadir creatinine were transformed to means and standard deviations following a standard procedure [9].D´oro et al. [10] provided data not showed in their work after contacting the corresponding author.Five random-effects meta-analysis were performed: 1) all the works that provided serum creatinine levels, 2) all the works that provided serum creatinine levels after excluding that by Wells et al.,3) all the works that provided serum creatinine levels but including only baseline determinations reported by Heikkilä et al. and Wells et al.,4) all the works that provided serum creatinine levels but including only follow-up determination reported by Heikkilä et al. and Wells et al, and 5) all the works that provided Nadir serum creatinine values.The results were presented in 5 forest plots.Also, a random-effect meta-analysis was performed for the risk of chronic renal failure.A graphical representation of this analysis was made in a separate forest plot.Between study heterogeneity was assessed using the Tau2 and I 2 statistics.

Results
The research resulted in 588 articles.239 duplicates were removed.Among the remaining 349 articles, we excluded 339 following the inclusion and exclusion criteria, resulting in the 10 studies included in this review (Fig. 1).This systematic review includes data from 896 participants aged between 0 to 25 years old.
The timing to assess patients' renal function was inconsistent through the included studies.Two studies reported serum creatinine values at birth [14,15], 1 study reported serum creatinine values of at diagnosis [12], 1 study reported preoperative serum creatinine values [8] and 5 studies reported Nadir creatinine values (de ned as the lowest creatinine value during the rst year after the diagnosis) [10,14,15,17,18].Two studies did not provide any creatinine serum value [11,13].One study provided "Initial Nadir Creatinine", de ned as the minimum value to which serum creatinine fell after decompression of the urinary tract and recovery from postobstructive diuresis [16].The follow-up time ranged from 0.5 to 19.7 years.Regarding serum creatinine values at follow-up, 1 study reported strati ed values at different time periods [12], 1 study reported "current creatinine" as follow-up creatinine [16] and 1 study did not specify the follow-up time [8].

Rittenberg et al.
[8] reported 7 patients (13.7%) which required renal dialysis and/or transplantation in the non-pop-off group while 0 in the pop-off group.Wells et al. reported 9 patients (11.25%) in end stage renal failure and/or transplantation in the non-pop-off group while 0 in the pop-off group.Lundar et al. [15] reported 5 patients (10.4%) in the non-pop-off group and 0 patients in the pop-off group which required renal transplantation.Massaguer et al. [17] reported 5 (9%) patients in the non-pop-off group and 0 in the pop-off group which required RRT.

Serum Creatinine Values In Children With Puv With Or Without Pop-off Mechanisms: Meta-analysis
Five random-effects meta-analysis were performed (Fig. 3).In all the analyses the overall mean difference was favorable to the group of children with PUV and pop-off mechanism.The rst one included all the works that provided serum creatinine values [10,12,[14][15][16][17][18] and resulted in a signi cant mean difference of -52.88 µmol/L [95% CI -73.65 to -32.11] (p < 0.0001) with a Chi 2 of 260.24 and a I 2 of 97%.The second one included all the works that provided serum creatinine values after excluding the study by Wells et al [10,12,14,15,17,18] and showed a signi cant mean difference of -15.57µmol/L [95% CI -27.00 to -4.14] (p = 0.007) with a Chi 2 of 51.05 and a I 2 of 88%.The third one included all the works that provided serum creatinine values, but only considered baseline determinations of the studies by Heikkilä et al. and Wells et al. [10,12,[14][15][16][17][18].This meta-analysis showed a signi cant mean difference of -35.37 µmol/L [95% CI -53.53 to -17.22] (p = 0.0001) with a Chi 2 of 155.14 and a I 2 of 96%.The fourth meta-analysis included all the works that provided serum creatinine values, but only considered follow-up determinations of the studies by Heikkilä et al. and Wells et al. [10,12,[14][15][16][17][18].This analysis showed a signi cant mean difference of -34.66 µmol/L [95% CI -53.49 to -15.82] (p = 0.0003) with a Chi 2 of 150.54 and a I 2 of 96%.The last meta-analysis included all the works that provided Nadir serum creatinine values [10,15,17,18] and resulted in a marginally signi cant mean difference of -12.00 µmol/L [95% CI -24.04,0.04](p = 0.05) with a Chi 2 of 43.22 and a I 2 of 93%.
Chronic renal failure in children with PUV with or without pop-off mechanisms: meta-analysis.
We performed a random-effect meta-analysis for chronic renal failure including patients that had been diagnosed with chronic renal failure, those that required renal replacement therapy, and those that underwent kidney transplantation.We obtained a relative risk reduction of 52% in the group of children with PUV and pop-off mechanisms (OR = 0.48 [95% CI 0.23 to 0.98] (p = 0.04)) with a Chi 2 of 8.36 and a I 2 of 28% (Fig. 4).

Discussion
In this systematic review and meta-analysis we synthesized the existing evidence regarding the effect of pop-off mechanisms in children with PUV and found that these mechanisms may act as renoprotective mediums.This nding is supported by the results of 5 meta-analyses that resulted in signi cant lower serum creatine levels (and therefore better renal function) in the group of children with PUV and pop-off mechanisms and the meta-analysis that showed a signi cant relative risk reduction for renal failure associated with them..These results are of great signi cance for several reasons: 1) They justify strati cation of patients diagnosed with PUV into patients at higher and lower risk of renal failure based on the presence or absence of these mechanisms.This, in turn, can lead to the creation of speci c follow-up algorithms for each subgroup, being narrower in the case of patients without pop-off mechanisms.2) They lay the groundwork and allow to orient new lines of work in this eld: for example, prospective studies in patients with PUV that systematically evaluate objective parameters such as Nadir Creatinine or renal outcome by subtype of pop-off mechanism.
From a biological point of view and in terms of pathophysiological plausibility, that pop-off mechanisms are renoprotective is logical: the release of pressure through an escape pathway decreases the damage to the system.In metaphorical terms, they would act like the exhaust valve of a boiler: when the pressure exceeds an acceptable limit, the valve pops and the pressure escapes.Nevertheless, and although this re ection is reasonable, this work provides an extensive and systematic review of this fact with a quantitative analysis of the existing data in the scienti c literature, which allows us to con rm the hypothesis.
We acknowledge the high heterogeneity between studies may hampered our results.This heterogeneity may be attributable to multiple factors, including the variability in serum creatinine values, which may be explain by the timing of the determinations and differences in the processing among others.for example, some authors reported serum creatinine level at birth, which is probably artifacted by the transplacental passage.We identi ed the work by Wells et al. [16] as a potential source of heterogeneity based on the fact that they reported "Initial Nadir creatinine" using a de nition that we did not nd in any other study.However, the meta-analyses excluding data reported by Wells et al. still showed high heterogeneity, suggesting there might be other sources of heterogeneity that we did not reach to identify.In addition, although valid mean and standard deviation (needed for the meta-analysis) can be estimated from median and interquartile range, many authors only reported median and range, which is an unreliable measure of dispersion.We consider that the presence of outliers might have arti cially increased the standard deviation we calculated for the meta-analyses, making it more di cult to obtain statistically signi cant results.On the other hand, the meta-analysis for chronic renal failure showed very low heterogeneity, probably due to a relatively standard de nition of the case.
A relevant aspect to comment on is that, although several pop-off mechanism are universally accepted as such and therefore homogeneously reported, there are some mechanisms whose pop-off effect is dubious (i.e.unilateral high-grade vesicoureteral re ux) and hence their prevalence may be underestimated (which is why we chose to perform a random-effects meta-analysis)..Although Table 1 describes the type of pop-off mechanism observed in each study we could not performed a strati ed analysis due to the lack of data in the individual.Nevertheless, we cannot assume that all pop-off mechanisms will be equally protective, and consequently, strati ed analysis by the type of pop-off mechanism, while considering the age and sex of the patient, will need to be addressed in future studies.
The inclusion of the two types of meta-analysis (mean difference in serum creatinine levels and risk of chronic renal failure) represents one of the main strengths of this work since the results obtained in both analyses are consistent and support the potential mediating effect of the pop-off mechanism in the protection of the kidney of children with PUV.Last, but not least, we followed a rigorous methodology, with a precise adherence to the PRISMA guidelines and the Newcastle Ottawa scale [19,20].
In conclusion, pop-off mechanisms may be a renoprotective mediator in children with PUV.The high between-study heterogeneity, the variability in reporting metrics and outcomes, and the absence of strati ed analyses by the type of mechanism justify the need for further prospective studies.Tables Table 1.Summary of the publications included in this systematic review.
Forest plot of the 5 random-effects meta-analyses for mean serum creatinine values (pop-off vs. non-pop-off groups).