|Year : 2020 | Volume
| Issue : 2 | Page : 23-33
Future risks of chronic kidney disease and end-stage kidney disease in infants with postnatally-repaired posterior urethral valve: A systematic review
Samuel Nkachukwu Uwaezuoke, Uzoamaka Vivian Muoneke, Ngozi Rita Mbanefo
Pediatric Nephrology Firm, Department of Pediatrics, University of Nigeria Teaching Hospital, Ituku-Ozalla Enugu, Nigeria
|Date of Submission||28-Sep-2020|
|Date of Decision||04-Jan-2021|
|Date of Acceptance||23-Feb-2021|
|Date of Web Publication||25-Aug-2021|
Dr. Samuel Nkachukwu Uwaezuoke
Department of Pediatrics, University of Nigeria Teaching Hospital, PMB 02219, Ituku-Ozalla Enugu
Source of Support: None, Conflict of Interest: None
Background and Objectives: Several studies show that most infants with posterior urethral valve (PUV) do not fully recover their renal function, despite postnatal interventions to obviate the consequences of lower urinary tract obstruction. This systematic review assesses the future risks of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in infants with postnatally-repaired PUV. Methods: We electronically searched PubMed, Medline, Embase, and Google Scholar databases for articles published between 2000 and 2020 (Date of the last search: September 12, 2020) using appropriate descriptors. We selected the studies based on adopted eligibility and exclusion criteria. We independently retrieved relevant data from the selected studies using a preconceived data-extraction form. We analyzed the aggregate data among the selected studies that signified future CKD and ESKD after the postnatal intervention and computed their mean prevalence rates. We also calculated the average point estimate of CKD and ESKD relative risks (RR) as the effect estimate at a 95% confidence interval. Results: Eleven studies were selected and reviewed, in which a total of 1362 patients were managed and followed up for variable periods. The aggregate data on ESKD prevalence from seven studies showed that a total of 112 patients developed ESKD out of a total patient-population of 446, giving a calculated mean ESKD prevalence of 24%. The CKD prevalence data in nine studies showed that 210 patients had CKD, out of 741 patients that were followed up, with a calculated mean CKD prevalence of 28%. The pooled RR of ESKD in seven studies and RR of CKD in nine studies was 0.5 (−0.48, 1.48) and 0.57 (−0.41, 1.55), respectively. Conclusions: Future risks of CKD and ESKD are still high in patients with postnatally-repaired PUV. We advocate a management approach that involves a synergy between pediatric nephrologists and urologists to ensure prompt renoprotective strategies and timely surgical intervention.
Keywords: Chronic kidney disease, end-stage kidney disease, glomerular dysfunction, posterior urethral valve, postnatal interventions, renal outcomes
|How to cite this article:|
Uwaezuoke SN, Muoneke UV, Mbanefo NR. Future risks of chronic kidney disease and end-stage kidney disease in infants with postnatally-repaired posterior urethral valve: A systematic review. J Integr Nephrol Androl 2020;7:23-33
|How to cite this URL:|
Uwaezuoke SN, Muoneke UV, Mbanefo NR. Future risks of chronic kidney disease and end-stage kidney disease in infants with postnatally-repaired posterior urethral valve: A systematic review. J Integr Nephrol Androl [serial online] 2020 [cited 2021 Dec 7];7:23-33. Available from: http://www.journal-ina.com/text.asp?2020/7/2/23/324510
| Introduction|| |
Posterior urethral valve (PUV) is the most common congenital abnormality associated with lower urinary tract obstruction (LUTO) in male infants., The pathogenic trajectory involves disease progression to obstructive uropathy, early and late stages of chronic kidney disease (CKD), and then to end-stage kidney disease (ESKD).,, For instance, several studies show that PUV is responsible for 20–40% of ESKD in male children.,,, A narrative review on the epidemiology of ESKD in a sub-Saharan African country suggests that glomerulonephritis and PUV constitute the common causes of CKD in childhood.
Thus, early detection of PUV and its appropriate management are crucial for mitigating the subsequent adverse renal outcomes. Second-trimester ultrasonographic detection of the anomaly is presently the norm in advanced settings. In contrast, the benefit of prenatal interventions such as vesico-amniotic shunting remains controversial and doubtful., However, in the resource-limited setting, late postnatal detection and delayed intervention contribute to worse survival outcomes. Besides, the absence of routine parental observation and recognition of suggestive abnormal urine stream has been adjudged responsible for the late postnatal detection in such climes.
Although primary valve ablation (with pre-resection vesicostomy for selected cases) remains the postnatal intervention of choice, most patients do not fully recover their renal function later in life., Studies show that subsequent renal dysfunction is related to bladder dysfunction.,, The prevalence of bladder dysfunction was reported to be as high as 75% despite a successful primary valve ablation. A systematic review has noted a wide variation in the cumulative incidence of renal and bladder dysfunction in affected patients after endoscopic valve resection. Nevertheless, some authors suggest that prenatal and postnatal comorbidities, such as renal dysplasia and urinary tract infection respectively, rather than postnatal interventions, determine the future renal outcomes. More recently, another study has proposed that the bladder contractility index (BCI) from a well-performed urodynamic study could be a useful tool for prognostication in PUV patients.
A systematic review that focuses on future renal dysfunction, particularly the decline in glomerular function (irrespective of the type of postnatal intervention), is presently under-reported. Thus, it is essential to address the following questions about the future renal outcomes: the percentage of patients that would subsequently end up with CKD or ESKD after undergoing different postnatal interventions; the patients' estimated glomerular filtration rate (eGFR); and the predictors of prognosis. The current systematic review aims to determine the future risk of CKD and ESKD in infants with postnatally-repaired PUV. It was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.
| Methods|| |
We electronically searched PubMed, Medline, Embase, and Google Scholar databases for articles published between 2000 and 2020 (Date of the last search: September 12, 2020). Both databases were searched using these descriptors in multiple combinations: “PUV,” “LUTO,” “prognosis,” “renal outcome,” “CKD,” “ESKD,” “estimated glomerular filtration rate,” “postnatal interventions.”
Eligibility and exclusion criteria
The eligibility criteria for inclusion of primary studies in this systematic review include the following characteristics: (a) Observational studies of children without bias for race, socioeconomic, and educational background; (b) Full-text studies published in or translated into the English language; (c) Studies that reported an association between PUV in infancy and renal outcomes such as CKD and ESKD or odds of developing them in childhood among infants with postnatally-repaired PUV; (d) Prospective or retrospective studies that compared the future CKD and ESKD risks between various postnatal interventions. Excluded articles were abstracts, letters to the Editor, reviews, commentaries, editorials, and studies without either primary data or described study methods.
We independently screened the titles and abstracts of retrieved published articles. We obtained and further assessed potentially eligible full-text articles for final inclusion to the list of items to be reviewed. We removed all duplicates during the study-selection process and resolved disagreements until a consensus on selecting an eligible study was reached. Few other studies were obtained from reviewing the references cited in the initially retrieved articles.
We assessed the methodological quality of included studies using the Newcastle-Ottawa Scale to assess non-randomized studies. The rating scale assesses case–control and cross-sectional studies using criteria grouped into “selection” (maximum of 5 stars), “comparability” (maximum of 2 stars), and “exposure/outcome” (maximum of 3 stars). We categorized the star-rating as low if <7 stars or high if >7 stars, independently assessed the quality of included studies, and resolved inter-rater discrepancies.
Data extraction and data items
We independently retrieved relevant data from the selected studies using a preconceived data-extraction form. The form was designed to obtain information about the first author's name, year of publication, the period of research, study setting and country, study design, study population or sample size, and demographics of study participants such as age distribution. Other extracted information included the diagnostic methods for PUV, types of postnatal intervention, and the nadir serum creatinine before and after the intervention, the proportion of the study participants that developed CKD and ESKD later in childhood, and the differences in eGFR based on the type of postnatal intervention. Inter-rater reliability for qualitative items was estimated using Cohen's kappa coefficient (κ).
We analyzed the aggregate data among the selected studies that signified future ESKD after the postnatal intervention and computed the mean prevalence rate of these sequelae. We also calculated the average point estimate of ESKD relative risk or risk ratio (RR) as the effect estimate (EE) at a 95% confidence interval using these data (proportions of enrolled patients with and without ESKD in the reviewed studies and hypothetical controls with sample sizes similar to the study sample sizes). We compared the individual studies' values in a forest plot to determine the effectiveness of postnatal interventions in reducing future ESKD risk in patients with PUV.
Risk of bias across studies
The risk of bias across the included studies was assessed, with an emphasis on publication bias. We displayed the studies for visualization in a funnel plot to determine the likelihood of publication bias.
| Results|| |
We identified 278, 64, 14, and 2040 citations in PubMed, Medline, Embase, and Google Scholar databases, respectively. After removing duplicates from the citations obtained in these databases, the number of records was 311. We screened the remaining papers for relevance to the aim of the systematic review. Only 19 records were left after this initial screening. Eight records, including review articles, were further excluded leaving 11 full-text original articles assessed for eligibility based on the inclusion criteria. These 11 original articles were finally selected for the present systematic review [Figure 1]. For these selected studies, Cohen's κ for inter-rater reliability was calculated to be 0.86.
|Figure 1: Algorithm for the inclusion of studies reporting the future outcomes of glomerular function in patients with posterior urethral valve|
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In the 11 studies reviewed, a total of 1362 patients were managed and followed up for variable periods. The study settings were located in North America,, Europe, Africa,,, Asia,,,, and Middle East. Seven studies were retrospective in nature,,,,,,, while four were prospective studies,,, [Table 1]. The patients' ages ranged from 28 weeks gestational age to >60 months (at presentation) and from >1 year to 16 years (at follow-up). Majority (nine) of the studies were rated <7 on the Newcastle-Ottawa Scale,,,,,,,,, while two studies were rated >7.,
|Table 1: Characteristics of the selected studies reporting future renal outcomes in patients with posterior urethral valve|
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[Table 2]a and [Table 2]b detail the diagnostic methods and postnatal interventions for PUV, as reported in the reviewed studies. Both prenatal ultrasound and postnatal ultrasound were conducted as the first diagnostic procedures among 328 patients reported in five studies.,,,, In four studies,,,, only prenatal ultrasound was performed among 114 patients: with adjunct MCU or VCUG and cystoscopy reported in two studies., However, PUV diagnosis was made using postnatal ultrasound with either VCUG or cystoscopy among 918 patients in two studies.,
Regarding postnatal interventions, nine of the studies conducted both primary valve ablation and different types of urinary diversion.,,,,,,,, Two studies used primary valve ablation alone., In the study by Coquillette et al., catheter drainage with or without valve ablation in some patients (n = 23) preceded surgical urinary-diversion methods in others who underwent nephrostomy (n = 11), ureterostomy (n = 11), or vesicostomy (n = 11). Lopez Pereira et al. compared two groups of patients: a cohort initially treated with primary valve ablation (n = 16) and another cohort with a temporary pyelo-ureterostomy (n = 24). All the patients on whom pyelo-ureterostomy was performed had renal insufficiency. Similarly, Tambo et al. showed that vesicostomy was performed in 33.3% of their patients who had renal insufficiency at presentation before they were treated with primary endoscopic valve ablation using electrocautery. However, investigators such as Ebeid et al. and Kim et al., conducted primary valve ablation and vesicostomy in two groups of patients: primary valve ablation (n = 25) versus vesicostomy (n = 25), and primary valve ablation (n = 13) versus vesicostomy (n = 14). They compared the renal outcomes using these postnatal interventions in their study cohorts. Additionally, Uddin et al., and Hosseini et al., adopted fulguration (radiofrequency ablation) as the treatment modality for their patients. In the former, temporary measures before fulguration comprised urethral catheterization and treatment for urosepsis in some patients (n = 32), vesicostomy for small-sized patients until adequate growth was achieved (n = 13), and cutaneous pyelostomy or loop ureterostomy for patients with hydronephrosis (n = 3). In the latter, a comparison was made between two groups of patients managed with primary valve fulguration (n = 31) and vesicostomy (n = 23). In the report by Roth et al., surgical intervention by primary valve ablation during the neonatal period was the preferred procedure in the majority (n = 9) of their patients (n = 10). Vesicostomy was performed in a few patients (n = 4). A substantial number of the patients also had renal dysplasia/hypoplasia (40%), hematuria (80%), proteinuria (80%), and vesicoureteral reflux (VUR) (80%). The series reported by Gangopadhyay showed that patients were initially treated by primary valve ablation and assessed on follow-up (n = 516); some patients had only valve ablation (n = 168) whereas others (n = 348) were billed for urinary diversion if the outcome was unsatisfactory. Following the demise of some patients (n = 36), the rest who were followed up (n = 312) had either cutaneous vesicostomy if there was no VUR (n = 108) and cutaneous ureterostomy if there was gross VUR (n = 204). Finally, Sarhan et al., and Uthup et al., performed only primary valve ablation in their patients; the formerly conducted ablation in two intervention arms, namely “early primary valve ablation” group (n = 92) and “late primary valve ablation” group (n = 93).
Future risk of chronic kidney disease and end-stage kidney disease
The primary outcomes were nadir serum creatinine in the 1st year of life, serum creatinine, and eGFR at the end of the study. In [Table 2]a, the study by Coquillette et al., showed that few patients had a nadir serum creatinine of >1 mg/dl at 1 year (n = 5) whereas majority had values <1 mg/dl (n = 29). The mean eGFR values after 2 years of age (end of the study period) were 87 ml/min/1.73 m2 (after catheter drainage ± valve ablation) and 57 ml/min/1.72 m2 (after various methods of urinary diversion); indicating that the former postnatal intervention resulted in better future glomerular-function outcome. At the end of the study period, 15% (n = 5) of enrolled patients (n = 35) developed ESKD. In the study by Sarhan et al., the following outcomes were reported in their patients (n = 185): Nadir serum creatinine of 0.6 mg/dl and mean final serum creatinine of 0.9 mg/dl in patients who underwent early primary valve ablation (n = 92) and nadir serum creatinine of 0.8 mg/dl and mean final serum creatinine of 1.7 mg/dl in patients that had late primary valve ablation (n = 93). In addition, 18% (n = 17) in the “early primary valve ablation” group and 41% (n = 38) in the “late primary valve ablation” group ended up with CKD. Lopez Pereira et al., reported mean eGFR values of 93.3 ± 21.8 ml/min/1.72 m2 (following valve ablation) and 96.2 ± 75.7 ml/min/1.72 m2 (following pyelo-ureterostomy) after >5-year follow- up. Furthermore, 44% (n = 7) of the patients that had a normal renal function at presentation (n = 16) developed ESKD, whereas 56% (n = 9) of these patients had CKD. The study by Tambo et al., showed that 11.1% (n = 1) and 55.6% (n = 5) of the study population (n = 18) developed ESKD and CKD, respectively, with eGFR values of <15 ml/min/1.72 m2 and <60 ml/min/1.72 m2. In the study by Ebeid et al., the mean serum creatinine values after 1-year follow-up were 0.55 ± 0.22 mg/dl for patients that underwent primary valve ablation (n = 25) and 0.8 ± 0.39 mg/dl for patients that underwent vesicostomy (n = 25). Among those with valve ablation, one patient developed renal insufficiency with a serum creatinine of 1.2 mg/dl. In contrast, three patients (among those with vesicostomy) developed the same complication with serum creatinine levels of 1.4 mg/dl, 1.5 mg/dl, and 1.6 mg/dl.
As shown in [Table 2]b, Kim et al., reported mean eGFR values of 59.1 ± 24.7 ml/min/1.72 m2 in patients on whom vesicostomy was performed (n = 14) and 68.5 ± 13.2 ml/min/1.72 m2 in patients who had primary valve ablation (n = 13) after >4-year follow-up. In the former group of patients, CKD prevalence was 21% (n = 3) while in the latter group the rate was 15% (n = 2). Uthup et al., documented the following eGFR values in their patients (n = 30) 5 years after primary ablation: >60 ml/min/1.72 m2 (n = 20) and <60 ml/min/1.72 m2 (n = 10). Twenty-nine patients (96.6%) developed CKD while one (3.4%) had ESKD. After a mean 11.3 ± 2.1-year follow-up in their patients (n = 10), Roth et al., noted nadir serum creatinine levels <1 mg/dl in five patients and levels >1 mg/dl in the remaining five patients. Seven (70%) patients, however, ended up with ESKD. In the study by Gangopadhyay, CKD and ESKD prevalence rates were reported to be 14% (n = 44) and 28% (n = 87), respectively, after 5–20-year follow-up on 312 patients. Similarly, CKD prevalence of 16.6% (n = 8) and ESKD prevalence of 8.4% (n = 4) were noted by Uddin et al., among their patients (n = 48) who were followed up for an average period of 3 years. Finally, Hosseini et al., documented similar mean nadir serum creatinine of 1.57 ± 1.45 mg/dl in the primary fulguration group (n = 31) and vesicostomy group (n = 23). They, however, reported differential glomerular function outcome, with mean eGFR of 31.1 ± 4.4 ml/min/1.72 m2 and 33 ± 4.4 ml/min/1.72 m2 in the primary valve fulguration and vesicostomy groups, respectively. In addition, the CKD prevalence rates among the enrolled patients (n = 48) were 57.4% (primary valve fulguration group) and 42.6% (vesicostomy group).
The aggregate data on ESKD prevalence from seven studies showed that a total of 112 patients developed ESKD out of a total patient-population of 446, giving a calculated mean ESKD prevalence of 24%. The CKD prevalence data in nine studies showed that 210 patients had CKD, of 741 patients that were followed up, with a calculated mean CKD prevalence of 28%. As shown in [Figure 2], the pooled RR of ESKD in seven studies at a 95% confidence interval was 0.5 (−0.48, 1.48), signifying that postnatal interventions potentially decreased ESKD risk. The forest plot of RR values for individual studies suggest that ESKD risk was reduced in six studies whose RR values were <1.,,,,, Only the study by Roth et al., had RR value >1, indicating that postnatal interventions did not reduce ESKD risk. In [Figure 3], the combined RR of CKD in nine studies at a 95% confidence interval was 0.57 (−0.41, 1.55), suggesting the potential effectiveness of a postnatal intervention in reducing CKD risk. In the forest plot, RR values >1 were noted in three studies,,, implying that CKD risk was not reduced by postnatal interventions. However, RR values were <1 in six studies,,,,,, showing that these interventions reduced CKD risk.
|Figure 2: Forest plot showing the effectiveness of postnatal interventions in reducing end-stage kidney disease risk in some selected studies|
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|Figure 3: Forest plot showing the effectiveness of postnatal interventions in reducing chronic kidney disease risk in some selected studies|
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Risk of bias across studies
[Figure 4] shows a funnel plot of the CKD and ESKD RR values as the EE (on the x-axis) and sample sizes (on the y-axis) of the eleven reviewed studies. Studies with small sample sizes (n <100) appear predominantly in the direction of the RR values >1 (larger effect sizes), leading to some asymmetry, which may indicate publication bias across these studies.,.,,, Some studies also reported patient drop-outs due to mortality, raising the likelihood of attrition bias in the studies.,,
|Figure 4: Funnel plot to determine the publication bias among the reviewed studies using effect estimate on the x-axis and sample size on the y-axis|
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| Discussion|| |
Although available postnatal interventions for PUV are meant to reduce the renal and urologic sequelae significantly, several reports indicate that most patients still end up with substantial CKD and ESKD burdens.,,, Given the variable long-term outcomes due to heterogeneity in the presentation of PUV, cumulative data on the risk and predictors of future renal dysfunction will facilitate the implementation of more effective treatment strategies.
In this systematic review, we analyzed the future outcome of glomerular function in children with treated PUV using serum creatinine and eGFR as outcome measures. Based on data from the included studies, we estimated the mean CKD and ESKD prevalence rates as 28% and 24%, respectively. These figures imply that future glomerular dysfunction contributes to reduced quality of life in children with repaired PUV and are in tandem with previously reported rates of 25%–30%., A similar systematic review reported an average of 22% (0%–32%) as CKD prevalence rate and 11% (0%–20%) as ESKD prevalence rate. However, wide disparities in CKD prevalence from 20% to 65% and ESKD prevalence from 8% to 21% have also been documented in other studies., From some of the reviewed studies, we identified several factors that could represent predictors of future renal outcomes. These include renal insufficiency at presentation,, oligohydramnios and surgery beyond the neonatal period, late primary ablation (intervention after 1st year of life), presence of VUR and renal dysplasia/hypoplasia,,, bladder dysfunction, and nadir serum creatinine.,,,, Some of these factors are in tandem with those identified by Neyas et al., such as baseline eGFR, bladder dysfunction, and VUR. More importantly, nadir serum creatine has been identified as the most reliable predictor of future renal dysfunction, which agrees with the finding of the present systemic review.
Furthermore, we obtained EE values (CKD and ESKD RR values), which suggest that postnatal interventions can effectively ameliorate future glomerular dysfunction in PUV patients, as shown in the majority of the studies.,,,,,,,, However, our findings should be cautiously interpreted, given the funnel-plot disposition that signifies publication bias across the reviewed studies. The postnatal intervention (primary valve ablation/fulguration versus urinary diversion) that results in better future renal outcomes appears unresolved. For instance, the urinary diversion was associated with better renal outcomes in two reviewed studies., This finding is consistent with the observation by Godbole et al., which shows that vesicostomy led to more favorable primary outcomes (mean higher eGFR and lower 1-year creatinine) than primary valve fulguration.
In contrast, primary valve ablation/fulguration was adopted as a more effective postnatal intervention in most of the studies analyzed in this systematic review.,,,,,, More importantly, the intervention significantly resulted in better renal outcomes in four studies.,,, Early primary valve ablation (intervention within the 1st year of life) was particularly associated with a more improved glomerular function on follow-up compared to late primary valve ablation (intervention after the 1st year of life). Most urologists are yet to agree on the most appropriate and effective option for treating patients presenting with persistent renal insufficiency despite initial transurethral drainage. The available options comprise primary valve ablation/fulguration alone, and urinary diversion methods such as elective vesicostomy, or high-loop ureterostomy followed by valve ablation. Although primary valve ablation is regarded as the gold standard for managing PUV (with urinary diversion reserved for selected cases), some authors maintain that comorbid factors such as renal dysplasia and urosepsis are determinants of future renal outcomes rather than the type of postnatal intervention. Whereas early intervention by valve ablation may mitigate the risk of future renal dysfunction based on the reports from several series, vesicostomy should be reserved primarily for very low- birth-weight infants and patients with persisting renal insufficiency, post-ablation upper tract deterioration, and late presentation.,,
The limitations of the present systematic review include the following. Firstly, the possible publication bias across the included studies precludes the validity of the evidence about the effectiveness of postnatal interventions in reducing CKD and ESKD risk. However, two studies with large sample sizes showed that both primary valve ablation and urinary diversion decreased the risk of worse renal outcomes., Second, the search was limited to the previous 20 years. However, the strategy was meant to include more recent studies. Furthermore, the few numbers of reviewed studies did not allow for a more robust meta-analysis.
| Conclusions|| |
The present systematic review has shown that the future risks of CKD and ESKD are still high in patients with postnatally-repaired PUV. Among other prenatal and postnatal factors, nadir serum creatinine generally remains the best predictor of adverse renal outcomes. Thus, we advocate a management approach that involves a continued synergy between pediatric nephrologists and urologists to ensure treatment of urosepsis, management of metabolic acidosis and dyselectrolytemia, initiation of renoprotective strategies, as well as timely surgical intervention.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]