Risk Factors Associated with Chronic Kidney Disease in Infants With Posterior Urethral Valve: A Single Center Study of 110 Patients Managed By Valve Ablation And Bladder Neck Incision Hossein AmirZargar1, Elaheh Shahab2, SeyyedMohammad Ghahestani1, Pooya Hekmati1, Hamid Arshadi1* Purpose: Concurrent valve ablation and bladder neck incision is suggested as an effective and safe treatment ap- proach in posterior urethral valve children with prominent bladder neck. We evaluated chronic kidney disease risk factors in these children. Materials and methods: We retrospectively reviewed medical records of children with posterior urethral valve and included those younger than 18 years old who underwent valve ablation and bladder neck incision at our insti- tution. We recorded patient demographics, presenting symp-toms, laboratory and radiographic data. Our primary outcome was chronic kidney disease de-fined as stage 3 chronic kidney disease or higher. Renal outcome risk factors such as preoperative vesicoureteral reflux and serum creatinine, age at diagnosis, adjuvant urinary diversion were ana-lyzed. Results: A total of 110 patients met our inclusion criteria. The median age at diagnosis was 10.4 months (range 14 days to 12 years). Prenatal diagnosis in 72.7% was the most common presenta-tion. Mean follow-up duration was 3 years and 12 (10.9%) patients progressed to chronic kidney disease. Preoperative serum creatinine greater than 1 mg/dL was the only factor associated with progression to chronic kidney disease. Conclusion: In our group of children with posterior urethral valve ablation and bladder neck in-cision, initial creatinine value of greater than 1 mg/dL is more probably associated with renal im-pairment while; vesicoureteral reflux, age at diagnosis, presenting symptoms, and adjuvant uri-nary diversion were not significant prognostic factors. Further randomized controlled evaluations are required to analyze the effects of concurrent valve ablation and bladder neck incision on renal outcome. Keywords: creatinine; kidney failure, chronic; renal insufficiency, chronic; urethra; urethral obstruction INTRODUCTION PUV (Posterior Urethral Valve) is the most sig-nificant congenital cause of lower urinary tract ob-struction in male children leading to progressive re- nal damage and end-stage renal disease in a proportion of them.(1-3) Although valve ablation is the treatment of choice for relieving obstruction in PUV patients, the risk of chron- ic kidney disease (CKD) remains notable even after ab- lating the valves.(4) We have performed endoscopic valve ablation and Bladder neck incision (BNI) from 1996 for PUV pa- tients with prominent bladder neck. BNI is considered beneficial in boys with bladder neck obstruction and the combination with valve ablation in PUV patients with prominent blad-der neck is suggested as being safe and effective.(5-7) Regarding the promising results of concurrent valve ablation and BNI, it has become our premier surgical option in PUV management;(8,9) but the prognostic sig- nificance of factors determining renal outcome in PUV patients undergoing the combination surgery is unclear 1Division of Pediatric Urology, Pediatric Center of Excellence, Tehran University of Medical Sciences, No 62, Dr. Gharib’s street, Keshavarz Blvd, PO Box: 1419733151, Tehran, Iran. 2Department of surgery, Kosar general hospital, Semnan University of Medical Sciences, Go-lestan Blvd, PO Box: 3519899558, Semnan, Iran. *Correspondence: Division of Pediatric Urology, Pediatric Center of Excellence, Tehran University of Medical Sci-ences, No 62, Dr. Gharib’s street, Keshavarz Blvd, PO Box: 1419733151, Tehran, Iran. Tel: +98 21 61472017, Fax: +98 21 66565500. E-mail: drhamidarshadi@yahoo.com. Received March 2020 & Accepted September 2020 and few studies are addressing the aforementioned is- sue. Therefore, we tried to identify CKD risk factors in PUV patients who underwent valve ablation with BNI at our center. MATERIALS AND METHODS Study population Children who underwent surgical ablation of PUV with BNI at our pediatric center of excel-lence, Tehran, Iran from 2007 to 2017 were evaluated retrospectively. Inclusion and exclusion criteria In this study, we included children younger than 18 years old who underwent posterior urethral valve ab- lation with BNI at our institution over a period of 10 years. Exclusion criteria were incomplete data, previous sur- gical intervention, and less than two years of follow-up. Procedures We performed urethral catheter drainage followed by endoscopic valve ablation with BNI in all children as PEDIATRIC UROLOGY Urology Journal/Vol 18 No. 4/ July-August 2021/ pp. 429-433. [DOI: 10.22037/uj.v16i7.6038] Vol 18 No 4 July-August 2021 138 the initial treatment management, while high urinary diversion (cutaneous ureterosto-my or pyelostomy) was done if renal function or hydronephrosis did not improve after 48 hours of lower drainage or urosepsis secondary to pyonephrosis occurred. Urethral valves were fulgurated using bugbee elec- trodes with an appropriate cystoscope. Incision of blad- der neck was done at 6 o’clock position by cutting cur- rent, just proximal to verumonta-num and not deep into the adventitia. Cutaneous vesicostomy is not our advocated procedure for urinary drainage in PUV patients. Evaluations After institutional review board approval, medical re- cords including demographics, age at diag-nosis, pre- natal findings (oligohydramnios, urinary system abnor- malities), the evidence of vesicoureteral reflux (VUR), urinary ascites, laboratory data before and after relief of obstruction like serum Creatinine(Cr), Glomerular Filtration Rate (GFR), urinalysis, urine culture and type of surgical intervention were gathered. In all included patients, PUV diagnosis was made using voiding cys- tourethrogram (VCUG) and confirmed via cystosco- py, and VUR was graded from Ⅰ to Ⅴ according to the standard classification on VCUG. Serum Cr at diagnosis and last follow-up were record- ed. Regarding the diversity of age at diag-nosis of in- volved patients and different range of normal values for each age group, we catego-rized serum Cr at diagnosis as ≤ one mg/dL or more. Our primary outcome was CKD. Patients were classified into two groups; with or with- out CKD at the last follow-up. CKD was defined as stage 3 CKD (GFR less than 60 ml/minute/1.73 m² by Schwartz formula for children less than 18 years old and by the Modification of Diet in Renal Disease study equation in adults)(10) or higher according to King Dis- ease Outcome Quality Initiative guidelines. The data for the calculation of GFR at diagnosis was not accessible for many of our patients. Patients not willing to continue follow-up visits after two years were not excluded from the study but their last data sufficient for GFR calculation were included. Statistical analysis Statistical analysis was carried out by SPSS statistics for Windows, version 13.0 (SPSS Inc., Chicago, IL, USA) version 13. Numerical variables were reported as mean, standard deviation, and range. The chi-square and Fisher exact tests were used to analyze the associa- tion between categorical variables and Student’s T-test was used for comparison of means between groups. A p-value of less than .05 is considered statistically sig- nificant. RESULTS A total of 110 patients fulfilled our inclusion criteria. The mean age at diagnosis was 14.7 ± 26.13 months (range from 14 days to 12 years) which 75.5% (83 patients) were within one-year-old and 24.5% (27 pa- tients) were older. The range of follow-up period was 2-8 years (mean 3 years). The clinical presentation was prenatal diagnosis in 80 (72.7%), febrile urinary tract infection in 10 (9.1%), voiding disturbances or urinary incontinence in 24(20.9%), and one patient was diag-nosed during eval- uation for renal failure. CKD was detected in 12 (10.9%) of patients at the last follow-up. 6 patients (5.45%) aggravated into end-stage renal disease of which 4 (3.63%) died due to uremic complications. Univariate analysis of the risk factors for CKD in the two groups is listed in Table 1. 92 patients (83.6%) were treated only with endoscopic valve ablation and BNI while high urinary diversion as ureterostomy or pyelostomy was required additionally in 13 (11.8%) and 5 (4.5%) patients, respectively. Al- though not statistically significant but upper tract uri- nary diversion was more necessary in CKD group, 3 of 12 patients (16.7 %) compared to 15 of 98 patients (83.3 %) in non-CKD group (p = .25). We considered the age at diagnosis as the date of sur- gical relief of PUV; since we performed valve ablation with BNI not so far after diagnosis. CKD developed in 7 (8.4%) of patients diagnosed with- in one-year-old age and in 5 (18.5%) of those diagnosed later; which is statistically insignificant (p = .15). The mean serum Cr at diagnosis was 1.09 ± 1.8 (.3-14) mg/dL and at last follow-up was .65 ± .44 (.3-3) mg/dL. Elevated initial serum Cr greater than one mg/dL was seen in 22.7% of cases and it was more significant in the CKD group (p = .001). 84 (76.3%) of patients had VUR at diagnosis which was bilateral in 60 patients (54.5%), right sided in 10 (9.1%), and left sided in 14 patients (12.7%). Chronic kidney disease and PUVs - AmirZargar et al. Variables CKD(N = 12) Non-CKD(N = 98) p-Valueª Age at diagnosis ≤ 1year, N( % ) 7 (58.3%) 76 (77.5%) NS Age at diagnosis, month; mean ± SD(range) 24.3 ± 32.6 (1-96) 13.5 ± 25 (0.5-144) NS UTI, N( % ) 2 (16.7%) 8 (8.2%) NS VUR, N( % ) 10 (83.3%) 74 (75.5%) NS Cr at diagnosis > 1mg/dL, N( % ) 9 (75%) 16 (16.3%) <0.05 Cr at diagnosis, mg/dL; mean ± SD(range) 1.88 ± 0.92 (0.5-2.8) 0.99 ± 1.85 (0.3-14) NS Cr at last followup, mg/dL; mean ± SD(range) 1.75 ± 0.65 (0.6-3) 0.52 ± 0.11 (0.3-1.1) <0.05 Valve ablation with BNI, N( % ) 9 (75%) 83 (84.7%) NS Upper tract diversion, N( % ) 3 (25%) 15 (15.3%) NS Bilateral VUR, N( % ) 8 (80%) 52 (70.3%) NS VURD syndromeᵇ, N( % ) 0 (0%) 19 (19.4%) NS Table 1. Comparison of patients’ characteristics at diagnosis and last follow up. Abbreviations: BNI: Bladder Neck Incision; CKD: Chronic Kidney Disease; Cr: Creatinine; NS: Non Significant; UTI: Urinary Tract Infection; VUR: Vesicoureteral Reflux; VURD: Vesicoureteral Reflux Dysplasia ª: p-value < 0.05 is significant. ᵇ: Unilateral massive VUR into a dysplastic kidney. Vol 18 No 4 July-August 2021 430 The presence of VUR (p = .77) or its laterality (p = .48) was not associated with an increased risk of CKD in our study. VUR improved after valve ablation and BNI spontaneously in most of our patients and anti-reflux surgery was rarely required. DISCUSSION Despite improvements in the medical and surgical treat- ment of PUV, it remains one of the main causes of CKD in children.(3) The incidence of CKD was 10.9% in our study. Although numerous studies have been conducted ad- dressing prognostic factors affecting PUV management outcome, there is still controversy regarding which fac- tors determine the renal out-come. Application of BNI simultaneously with valve ablation has been proposed as an effective treat-ment modality that may reduce bladder dysfunction and consequently renal damage.(8,9) We conducted a retrospective and non-randomized study to help clarify the significance of vari-ous factors on long-term renal outcome in our group of patients on whom we have performed en-doscopic valve ablation with BNI. Vesicostomy is not our choice for urinary diversion in PUV patients as we believe that effective bladder drainage is obtained by proper valve ablation and cath- eterization.(11) In the severe dis-tended ureter, relief of bladder obstruction may not be able to drain the upper urinary system suf-ficiently due to failed peristalsis and coaptation, therefore cutaneous pyeloureterostomy seems more efficient.(11) Proponents of high urinary diversion believe that tem- porary pyeloureterostomy doesn’t interfere with blad- der function in long term as well as improving the renal function by adequate drainage of the pyelocaliceal sys- tem.(12-14) High urinary diversion was done in 16.3% of our pa- tients in case of pyonephrosis or when hy-dronephrosis or renal failure did not improve after 48 hours of blad- der drainage. There is conflicting data regarding urinary diversion in PUV patients.(13,14) Some authors believe that renal function is independent from the kind of treatment mo- dality chosen for patients as they emphasize on the role of congenital renal dysplasia which makes these pa- tients prone to pro-gressive renal failure.(15-17) In our study, CKD occurred in 9 (9.8%) patients treated simply with valve ablation and BNI which was not sig- nificantly different from 3 patients (16.7%) with upper urinary diversion. Our findings are similar to previous studies suggesting that long-term renal function is affected by other fac- tors like severity of disease at initial presentation oth- er than the kind of therapy start-ed for the patient.(17,18) However, to help clarify the role of urinary diversion in renal protection of patients with PUV, larger rand- omized-controlled studies comparing different treat- ment modali-ties are necessary. Age at diagnosis has been suggested to influence re- nal outcome in PUV patients.(19,20) 72.7% of our patients were diagnosed prenatally. Some authors claim that prenatal diagnosis may improve the renal prognosis due to earlier relief of obstruction and slowing the renal damage process.(21) On contrary, others have concluded that diagnosis at an older age may be an indicator of a milder and more benign form of disease which caused later presentation. (17,22) 75% of our patients were diagnosed within one year of age. Our analysis of age at diagnosis and final renal outcome did not show any difference between patients diagnosed before and after one year of age. Our study is similar to earlier ones.(17,22) Serum Cr level at diagnosis has been mentioned as the most significant prognostic indicator in PUV patients. (23-25) In our study, CKD occurred in 3.5% of patients when serum Cr at diagnosis was ≤ 1 mg/dL and the frequency increased to 36% when initial serum Cr was above 1 mg/dL which the difference was statistically significant (p = .001). Our results, similar to previous studies, indicate that higher initial serum Cr levels determine a poorer renal outcome.(23,25-27) The retrospective method of our study limited us in gathering data necessary for other important clinical factors in renal prognosis such as serum Cr level at one- year age, nadir Cr after a time of bladder decompres- sion, bladder function status and etc. In our study, 84 patients (76.3%) had VUR on their in- itial VCUG of which 27 patients (32.1%) showed com- plete resolution after surgical relief of obstruction. Our data is similar to other studies showing a preva- lence of 50-70% for PUV patients with VUR at the time of diagnosis(28) and a resolution of up to 50% for VUR after surgical correction.(29) We did not find any correlation between the presence of VUR (either bilateral or unilateral) and final renal outcome (p = .77). Otherwise, CKD developed in 8.3% of patients with unilateral VUR compared to 13.3% of patients with bilateral VUR, which the difference was not statisti-cally significant (p = .48). Though our study confirms the results of most prior ones,(26,30) but some authors believe that bi-lateral VUR implies a poorer renal outcome(4,25) and unilateral severe VUR protecting contrala-teral kidney by its pop-off mechanism is a good prognostic factor.(17) In our study, CKD did not develop in cases with vesi- coureteral reflux dysplasia syndrome (uni-lateral mas- sive VUR into a dysplastic kidney) and in 13.2% of patients with other patterns of VUR at diagnosis; but the difference was not statistically significant (p = .12). CONCLUSIONS Our findings are consistent with the emerging signifi- cance of initial serum Cr and GFR values in the final re- nal outcome of PUV patients undergoing valve ablation with BNI. Further prospective studies are necessary to clarify the prognostic significance of different renal risk factors. CONFLICT OF INTEREST None declared by the auhtors. REFERENCES 1. Hebenstreit D, Csaicsich D, Hebenstreit K, Muller-Sacherer T Berlakovich G, Springer A. 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