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Renal Scarring and Urinary Tract Infection After Successful Endoscopic Correction of Vesicoureteral Reflux
Renal Scarring and Urinary Tract Infection After Successful Endoscopic Correction of Vesicoureteral Reflux Boris Chertin,* Alaeddin Natsheh, Alon Fridmans, Ofer Z. Shenfeld† and Amicur Farkas From the Division of Pediatric Urology and Department of Urology, Shaare Zedek Medical Center (AN, AF, OZS) and Department of Urology, Faculty of Medical Science, Hebrew University (AN, AF, OZS), Jerusalem (BC, AF), Israel
Purpose: We evaluated renal function and the incidence of urinary tract infection after successful endoscopic correction of vesicoureteral reflux. Materials and Methods: From 1988 to 2007, 169 male and 338 female patients (696 refluxing renal units) with a median age of 3.7 years underwent successful endoscopic correction of primary vesicoureteral reflux using polytetrafluoroethylene and dextranomer/hyaluronic acid copolymer. Reflux was grades I to V in 36 (5.2%), 178 (25.6%), 298 (42.7%), 163 (23.4%) and 21 refluxing renal units (3.1%), respectively. Renal ultrasound and 99mtechnetium-dimercaptosuccinic acid scan were performed in all patients preoperatively, and in all patients and in 509 of 696 refluxing renal units (73%) postoperatively, respectively. All patients were followed 1 to 20 years (median 13). Results: Preoperatively 99mtechnetium-dimercaptosuccinic acid scan revealed scarring in 543 of 696 refluxing renal units (78%). Reflux resolved after 1 injection in 473 refluxing renal units (68%), in 161 (23%) after 2 and in 25 ureters (3.6%) after 3. In 37 refluxing renal units (5.4%) reflux improved to grade I, which required no further treatment. Renal deterioration was noted in 11 of 26 refluxing renal units with initially severe renal scarring (less than 20% uptake on 99mtechnetium-dimercaptosuccinic acid scan). The remaining refluxing renal units in this group showed an insignificant 2.3% change in relative function after successful reflux correction (p ⬎0.005). Patients with vesicoureteral reflux downgrading did not show new renal scars. Of the remaining 446 refluxing renal units 27 (6.1%) showed a greater than 5% decrease in relative function without new scarring. Eight children in the polytetrafluoroethylene group and 3 in the dextranomer/hyaluronic acid copolymer group (overall 2.2%) had febrile urinary tract infection after successful endoscopic correction, leading to reevaluation that resulted in the diagnosis of recurrent reflux in 8 (72.7%). A total of 28 children (5.6%) had afebrile urinary tract infection without recurrent vesicoureteral reflux. Conclusions: Our data show that successful endoscopic correction of vesicoureteral reflux is accompanied by a low incidence of new renal scarring and febrile urinary tract infection. Patients who initially have corrected reflux but who have a febrile urinary tract infection at long-term followup require prompt revaluation to rule out recurrent reflux.
Abbreviations and Acronyms DMSA ⫽ 99mtechnetiumdimercaptosuccinic acid Dx/HA ⫽ dextranomer hyaluronic acid FDA ⫽ Food and Drug Administration RRU ⫽ refluxing renal unit STING ⫽ subureteral polytetrafluoroethylene injection UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrogram VUR ⫽ vesicoureteral reflux * Correspondence: Division of Pediatric Urology, Shaare Zedek Medical Center, P. O. Box 3235, Jerusalem, 91031, Israel (telephone: 9722-6555560; FAX: 972-2-6555299; e-mail: bchertin@ yahoo.com). † Financial interest and/or other relationship with Pfizer and Nowvibromc.
Key Words: kidney, vesico-ureteral reflux, cicatrix, polytetrafluoroethylene, dextranomer-hyaluronic acid copolymer SINCE the introduction of STING 2 decades ago and in the 7 years since the approval of Dx/HA copolymer (Deflux®)
for VUR by the FDA, endoscopic management for VUR has emerged as first line treatment for all reflux grades at
0022-5347/09/1824-1703/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 1703-1707, October 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.03.011
www.jurology.com
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RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
some centers.1,2 Overall success rates reported by different groups are between 68% and 92% depending mainly on VUR grade.1–3 Complications after this procedure are infrequent and relate mainly to ureterovesical junction obstruction and new onset contralateral VUR after treatment for unilateral VUR. The concept of endoscopic correction of VUR offers a minimally invasive treatment for UTI or renal parenchymal damage associated with reflux. Recent data from many researchers clearly demonstrate that STING is a reasonable option for surgical correction of VUR. However, the question of whether surgical correction of VUR using an endoscopic approach would prevent further renal damage and UTI must still be answered. Since we have used the endoscopic approach in the last 2 decades in patients with VUR, we retrospectively evaluated changes in renal function and the UTI incidence in children who underwent successful endoscopic correction of VUR using different tissue augmenting substances.
PATIENTS AND METHODS From 1988 to 2007, 169 male and 338 female patients (696 RRUs) with a median age of 3.7 years (range 8 months to 16 years) underwent successful endoscopic correction of primary VUR. The cause of the VUR diagnosis was prenatal condition in 81 patients and UTI in 426. The surgical material was polytetrafluoroethylene in 369 patients and Deflux in 138. Only patients with primary VUR were included in analysis. To perform a homogenous analysis children with a duplex system and a bladder diverticulum were excluded from study. Reflux grade was based on VCUG only before and after surgery or during conservative treatment according to the International Classification System (International Reflux Study Committee).4 Reflux was grades I to V in 36 (5.2%), 178 (25.6%), 298 (42.7%), 163 (23.4%) and 21 RRUs (3.1%), respectively. DMSA scan and renal ultrasound were performed in all patients preoperatively. DMSA renal scans were done to assess relative renal function using background corrected regions of interest of each kidney in the posterior view and calculating the resultant percent of uptake. Renal scan was done to assess renal scarring. DMSA scan was performed at least 6 months after the last febrile UTI. Renal scintigraphy was done 2 hours after DMSA injection. Fractional left and right renal activity was calculated for each kidney with an uptake of 45% to 55% of total renal activity considered normal. Renal damage was classified as mild—focal defects on uptake, moderate—20% to 45% relative renal function and poor—renal function below 20% of relative renal function.5 The indication for endoscopic corrections were persistent high grade VUR in 89 patients and breakthrough UTI while on antibiotic prophylaxis in 418 patients. Grade I VUR was treated only in children with contralateral high grade VUR. Children with dysfunctional voiding or constipation symptoms were allocated to conservative treatment before endoscopic correction until full resolution of
voiding symptoms was achieved and preoperative reassessment was performed, including repeat VCUG. Since 2000, we have used a dysfunctional voiding symptoms survey to assess dysfunctional voiding. At this time the determination of dysfunctional voiding was done by history alone.6 None of the children in this series had voiding dysfunction at the time of injection. All patients received antibiotic prophylaxis until VCUG showed spontaneous VUR resolution or definitive treatment cured VUR. Those with downgrading of VUR to grade I after endoscopic correction were also withdrawn from antibiotic prophylaxis as part of our routine protocol. The endoscopic correction technique was similar to that described in the literature.2,7 In patients with grades I to III VUR we used the usual technique of STING when injection was performed, introducing the needle submucosally under the ureteral orifice at the 6 o’clock position. In patients with grades IV and V VUR, and in those with a widely open orifice injection was performed inside the orifice, as published previously.2,7 In 450 RRUs endoscopic correction was initially performed using polytetrafluoroethylene as a tissue augmenting substance. Since FDA approval in 2001, Dx/HA copolymer has been used in 246 RRUs. As is our standard practice, ultrasound was performed 1 month after injection to identify hydronephrosis and VCUG was performed 3 to 6 months after endoscopic correction. In those patients annual ultrasound was performed at long-term followup. To follow renal function all children with poor renal function underwent repeat DMSA scan at the beginning of adolescence and after the completion of puberty in case any signs of deteriorating kidney appearance on ultrasound was noted, such as worsening hydronephrosis, parenchymal thinning or arrested kidney growth. Also, patients with VUR downgrading underwent DMSA scan to monitor renal parenchymal damage. Some patients underwent repeat DMSA scan according to primary physician choice. Those with febrile UTI underwent compulsory VCUG, although postoperative studies showed corrected VUR. Urine samples were obtained with a urethral catheter or by suprapubic bladder aspiration as a part of the routine protocol in Israel. In older children a midstream voided specimen was examined. Since almost all male children in Israel are circumcised, the possibility of contamination in these children was low. A finding of more than 100,000 cfu/ml was defined as clinically significant UTI. In those with at least 2 episodes of recurrent afebrile UTI VCUG was performed to exclude recurrent VUR. Renal ultrasound was performed in all patients postoperatively and DMSA scan was performed in 509 of 696 RRUs (73%) postoperatively. All patients were followed for 1 to 20 years (median 13). GraphPad Prism®, version 4.0 with Fisher’s exact test was used for statistical evaluation.
RESULTS DMSA scan revealed renal scarring in 543 of the 696 RRUs (78%) preoperatively (table 1), of which 26 (4.8%) had severe, 123 (22.7%) had moderate and 394 (72.5%) had mild renal scarring. In 21 RRUs
RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
Table 1. Renal scarring by VUR grade Scarring (No. RRUs) VUR Grade
No. RRUs
Mild
Moderate
Severe
Totals
I II III IV V
36 178 298 163 21
— 81 240 73 —
— 2 34 79 8
— — 4 9 13
— 83 278 161 21
(3.7%) new renal scarring developed during observation on antibiotic prophylaxis. Reflux resolved in 473 RRUs (68%) after 1 injection, in 161 (23%) after 2 and in 25 (3.6%) ureters after 3. In 37 RRUs (5.4%) VUR improved to grade I, which required no further treatment (table 2). Renal deterioration was noted in 11 of 26 RRUs with initial severe renal scarring (less than 20% uptake on DMSA scan). The remaining RRUs in this group had an insignificant 2.3% change in relative function after successful VUR correction (p ⫽ 0.23). Patients with VUR downgrading did not show new renal scars. Of the remaining 446 RRUs 27 (6.1%) had a greater than 5% decrease in relative function without new scarring. Eight children in the polytetrafluoroethylene group and 3 in the Dx/HA copolymer group (overall 2.2%) had a febrile UTI after successful endoscopic correction, which necessitated reevaluation and resulted in the diagnosis of recurrent VUR recurrence in 8 (72.7%). Median time to recurrent VUR was 3 years (range 2 to 12) in the polytetrafluoroethylene group. Three patients in the Dx/HA copolymer group had recurrent VUR 1 and 2 years, respectively, after the first successful VUR correction. In the polytetrafluoroethylene group VUR was grades II to IV in 4, 3 and 1 patients, respectively. In the Deflux group grade III VUR was diagnosed in all children. To cure VUR in this group with later recurrence 1 injection was required in 9 of 11 children (81%) and in the remaining 2 (18%) 2 attempts of endoscopic injection resolved VUR. A total of 28 children (5.6%) experienced afebrile UTI without recurrent VUR.
DISCUSSION Some groups have already reported that open ureteral reimplantation preserves renal function even in already damaged kidneys and prevents upper UTI.8 –11 However, the role of endoscopic therapy must still be evaluated.12 Since at some centers endoscopic correction is first line therapy for all grades of VUR when surgery is indicated and with sometimes multiple attempts it can achieve almost the same success rate as open surgery, one may speculate that endoscopic correction of VUR is as durable
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as an open surgery to prevent recurrent UTI and kidney damage. Our data support that. Most kidneys had preserved function in the long term, showing only an insignificant change in renal function. We agree that by performing routine DMSA scan and not judging split renal function using single photon emission computerized tomography DMSA we may have underestimated renal function in patients with bilateral pathological conditions. Thus, in some of our patients global function may have decreased, allowing relative renal function to remain normal or almost normal. Our data show a relatively high incidence of renal scarring. However, the study represents 20 years. In the beginning the incidence of prenatal diagnosis of VUR was low. Some patients came to our attention and underwent diagnostic assessment only after several incidences of febrile UTI and renal damage. Only renal units with severe damage at endoscopic correction showed decreased function, eventually leading to nephrectomy in 4 children. Obviously in those kidneys severe congenital dysplastic features were responsible for the continuous deterioration in function that finally led to nephrectomy. It was shown that sterile reflux does not cause renal scars unless extreme hydrodynamic conditions exist in the sick kidney. VUR associated bacteriuria, which leads to a protracted inflammatory reaction, is a major cause of exudative pyelonephritis and kidney damage. In our series only 2.2% of all studied children had recurrent pyelonephritis in the long term. However, 8 of the 11 children had recurrent VUR on followup VCUG. These data are similar to those previously published. Sedberry-Ross13 and Chi14 et al evaluated the febrile UTI incidence after successful endoscopic correction of VUR and found that up to 27% of all children in whom reflux was corrected had a febrile UTI, of whom almost 90% had recurrent VUR on consequent VCUG. The question of the long-tern durability of tissue augmenting substances has been raised by many researchers on several occasions. The longest followup of up to 17 years of polytetrafluoroethylene used as a tissue augmenting substance clearly demonstrated its long-term durability to prevent recurrent VUR.7 Since concern regarding the safety of polytetrafluoroethylene use in the pediatric populaTable 2. Outcome of endoscopic correction of VUR in 696 RRUs No. RRUs (%) No. endoscopic infections: 1 2 3 VUR downgraded to grade I
473 (68) 161 (23) 25 (3.6) 37 (5.4)
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RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
tion cannot be ignored and Deflux is the only FDA approved material for endoscopic injection to manage VUR in children, the question of the long-term durability of Deflux is of interest and parental concern.12–14 The low incidence of recurrent VUR after Deflux injection in our series, which is comparable with previous published data, may be explained by the fact that our patients with Deflux had relatively short followup. Furthermore, we did not perform late routine VCUG in all patients who underwent Deflux injection and we limited repeat VCUG only to patients with febrile or recurrent episodes of afebrile UTI. Therefore, the long-term durability of VUR correction using Deflux as a tissue augmented substance must be answered. The remaining 3 of 11 children who had recurrent pyelonephritis showed no recurrent VUR on followup VCUG. In 2 cases dysfunctional voiding was blamed for UTI and in 1 no particular cause was found. The possibility of an afebrile UTI during longterm followup in children with endoscopically cured VUR has been previously pointed out.7 In our series 28 children (5.6%) had an afebrile UTI. Since these children had at least 2 episodes of afebrile UTI, they underwent VCUG as part of our routine protocol
after endoscopic correction. None showed recurrent VUR. This study is not without limitations. The data are retrospective and some incidences of UTI may be missing from the registry. Although all patients underwent DMSA renal scan before surgery, only 78% underwent DMSA scan after the procedure. We did not use a control group of patients to prove that successful VUR correction leads to renal function protection. Finally, followup in the Deflux group is significantly shorter than in the polytetrafluoroethylene group and, therefore, the issue of recurrent VUR in this group should be addressed later.
CONCLUSIONS Our data show that successful endoscopic correction of VUR is accompanied by a low incidence of new renal scarring and febrile UTI. Patients who initially show corrected VUR but who have febrile UTI at long-term followup require prompt reevaluation to rule out recurrent VUR. In the light of recent reports of the low effectiveness of antibiotic prophylaxis in children with VUR there is a desperate need for prospective clinical trails to investigate optimal treatment options in patients with VUR.
REFERENCES 1. Kirsch AJ, Perez-Brayfield MR, Smith EA et al: The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. 2. Puri P, Chertin B, Murugesh V et al: Treatment of vesicoureteral reflux by endoscopic injection of dextranomer/hyaluronic acid copolymer (Deflux): preliminary results. J Urol 2003; 170: 1541. 3. Routh JC, Vandersteen DR, Pfefferle H et al: Single center experience with endoscopic management of vesicoureteral reflux in children. J Urol 2006; 175: 1889. 4. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. International Reflux Study Committee. Pediatrics 1981; 67: 392. 5. Polito C, LaManna A, Rambaldi PF et al: High incidence of a generally small kidney and primary vesicoureteral reflux. J Urol 2000; 164: 479.
6. Farhat W, Bagli DJ, Capolicchio G et al: The dysfunctional voiding system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000; 164: 1011. 7. Chertin B, Colhoun E, Velayudham M et al: Endoscopic treatment of vesicoureteral reflux. An 11 to 17-year followup. J Urol 2002; 167: 1443. 8. Matsumoto F, Shimada K, Harada Y et al: Split renal function does not change after successful treatment in children with primary vesico-ureteric reflux. BJU Int 2003; 92: 1006. 9. Nepple KG, Austin JC, Hawtrey CE et al: Kidneys with reflux nephropathy maintain relative renal function after ureteral reimplantation. J Urol 2005; 174: 1606. 10. Webster RI, Smith G, Farnsworth RH et al: Low incidence of new renal scars after ureteral reimplantation for vesicoureteral reflux in children: a prospective study. J Urol 2000; 163: 1915.
11. Yu TJ, Chen WF and Chen HY: Early versus late surgical management of fetal reflux nephropathy. J Urol 1997; 157: 1416. 12. Wadie GM, Tirabassi MV, Courtney RA et al: The Deflux procedure reduces the incidence of urinary tract infections in patients with vesicoureteral reflux. J Laparoendosc Adv Surg Tech A 2007; 17: 353. 13. Sedberry-Ross S, Rice DC, Pohl HG et al: Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol, part 2, 2008; 180: 1605. 14. Chi A, Gupta A and Snodgrass WJ: Urinary tract infection following successful dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2008; 179: 1966.
EDITORIAL COMMENT The premise of this study, that intervention for VUR protects kidneys from future damage, is important. However, interpreting study results and conclusions should be tempered by consideration of its methodological limitations. Most impor-
tantly there is no comparison group. Therefore, we do not know what would have happened if these patients had undergone successful ureteral reimplantation or failed endoscopic injection, or for that matter if they had received no intervention.
RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
This problem is complicated by the high 78% prevalence of preoperative scarring, which is higher than might be expected based on a recent systematic review.1 The small number of patients with postoperative scarring may have had more to do with the low number of patients at risk than with the effectiveness of the intervention. At the end of the day this study does not prove the effectiveness or lack thereof of endoscopic injection. Rather, it simply documents that in a pa-
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tient population with a high rate of preoperative renal scarring few patients continue to decline after successful injection. More broadly this series poses an interesting question that must be answered by future study. Jonathan C. Routh Department of Urology Children’s Hospital Boston Boston, Massachusetts
REFERENCE 1. Faust WC, Diaz M and Pohl HG: Incidence of post-pyelonephritic renal scarring: a meta-analysis of the dimercapto-succinic acid literature. J Urol 2009; 181: 290.
Purpose: We evaluated renal function and the incidence of urinary tract infection after successful endoscopic correction of vesicoureteral reflux. Materials and Methods: From 1988 to 2007, 169 male and 338 female patients (696 refluxing renal units) with a median age of 3.7 years underwent successful endoscopic correction of primary vesicoureteral reflux using polytetrafluoroethylene and dextranomer/hyaluronic acid copolymer. Reflux was grades I to V in 36 (5.2%), 178 (25.6%), 298 (42.7%), 163 (23.4%) and 21 refluxing renal units (3.1%), respectively. Renal ultrasound and 99mtechnetium-dimercaptosuccinic acid scan were performed in all patients preoperatively, and in all patients and in 509 of 696 refluxing renal units (73%) postoperatively, respectively. All patients were followed 1 to 20 years (median 13). Results: Preoperatively 99mtechnetium-dimercaptosuccinic acid scan revealed scarring in 543 of 696 refluxing renal units (78%). Reflux resolved after 1 injection in 473 refluxing renal units (68%), in 161 (23%) after 2 and in 25 ureters (3.6%) after 3. In 37 refluxing renal units (5.4%) reflux improved to grade I, which required no further treatment. Renal deterioration was noted in 11 of 26 refluxing renal units with initially severe renal scarring (less than 20% uptake on 99mtechnetium-dimercaptosuccinic acid scan). The remaining refluxing renal units in this group showed an insignificant 2.3% change in relative function after successful reflux correction (p ⬎0.005). Patients with vesicoureteral reflux downgrading did not show new renal scars. Of the remaining 446 refluxing renal units 27 (6.1%) showed a greater than 5% decrease in relative function without new scarring. Eight children in the polytetrafluoroethylene group and 3 in the dextranomer/hyaluronic acid copolymer group (overall 2.2%) had febrile urinary tract infection after successful endoscopic correction, leading to reevaluation that resulted in the diagnosis of recurrent reflux in 8 (72.7%). A total of 28 children (5.6%) had afebrile urinary tract infection without recurrent vesicoureteral reflux. Conclusions: Our data show that successful endoscopic correction of vesicoureteral reflux is accompanied by a low incidence of new renal scarring and febrile urinary tract infection. Patients who initially have corrected reflux but who have a febrile urinary tract infection at long-term followup require prompt revaluation to rule out recurrent reflux.
Abbreviations and Acronyms DMSA ⫽ 99mtechnetiumdimercaptosuccinic acid Dx/HA ⫽ dextranomer hyaluronic acid FDA ⫽ Food and Drug Administration RRU ⫽ refluxing renal unit STING ⫽ subureteral polytetrafluoroethylene injection UTI ⫽ urinary tract infection VCUG ⫽ voiding cystourethrogram VUR ⫽ vesicoureteral reflux * Correspondence: Division of Pediatric Urology, Shaare Zedek Medical Center, P. O. Box 3235, Jerusalem, 91031, Israel (telephone: 9722-6555560; FAX: 972-2-6555299; e-mail: bchertin@ yahoo.com). † Financial interest and/or other relationship with Pfizer and Nowvibromc.
Key Words: kidney, vesico-ureteral reflux, cicatrix, polytetrafluoroethylene, dextranomer-hyaluronic acid copolymer SINCE the introduction of STING 2 decades ago and in the 7 years since the approval of Dx/HA copolymer (Deflux®)
for VUR by the FDA, endoscopic management for VUR has emerged as first line treatment for all reflux grades at
0022-5347/09/1824-1703/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 1703-1707, October 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.03.011
www.jurology.com
1703
1704
RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
some centers.1,2 Overall success rates reported by different groups are between 68% and 92% depending mainly on VUR grade.1–3 Complications after this procedure are infrequent and relate mainly to ureterovesical junction obstruction and new onset contralateral VUR after treatment for unilateral VUR. The concept of endoscopic correction of VUR offers a minimally invasive treatment for UTI or renal parenchymal damage associated with reflux. Recent data from many researchers clearly demonstrate that STING is a reasonable option for surgical correction of VUR. However, the question of whether surgical correction of VUR using an endoscopic approach would prevent further renal damage and UTI must still be answered. Since we have used the endoscopic approach in the last 2 decades in patients with VUR, we retrospectively evaluated changes in renal function and the UTI incidence in children who underwent successful endoscopic correction of VUR using different tissue augmenting substances.
PATIENTS AND METHODS From 1988 to 2007, 169 male and 338 female patients (696 RRUs) with a median age of 3.7 years (range 8 months to 16 years) underwent successful endoscopic correction of primary VUR. The cause of the VUR diagnosis was prenatal condition in 81 patients and UTI in 426. The surgical material was polytetrafluoroethylene in 369 patients and Deflux in 138. Only patients with primary VUR were included in analysis. To perform a homogenous analysis children with a duplex system and a bladder diverticulum were excluded from study. Reflux grade was based on VCUG only before and after surgery or during conservative treatment according to the International Classification System (International Reflux Study Committee).4 Reflux was grades I to V in 36 (5.2%), 178 (25.6%), 298 (42.7%), 163 (23.4%) and 21 RRUs (3.1%), respectively. DMSA scan and renal ultrasound were performed in all patients preoperatively. DMSA renal scans were done to assess relative renal function using background corrected regions of interest of each kidney in the posterior view and calculating the resultant percent of uptake. Renal scan was done to assess renal scarring. DMSA scan was performed at least 6 months after the last febrile UTI. Renal scintigraphy was done 2 hours after DMSA injection. Fractional left and right renal activity was calculated for each kidney with an uptake of 45% to 55% of total renal activity considered normal. Renal damage was classified as mild—focal defects on uptake, moderate—20% to 45% relative renal function and poor—renal function below 20% of relative renal function.5 The indication for endoscopic corrections were persistent high grade VUR in 89 patients and breakthrough UTI while on antibiotic prophylaxis in 418 patients. Grade I VUR was treated only in children with contralateral high grade VUR. Children with dysfunctional voiding or constipation symptoms were allocated to conservative treatment before endoscopic correction until full resolution of
voiding symptoms was achieved and preoperative reassessment was performed, including repeat VCUG. Since 2000, we have used a dysfunctional voiding symptoms survey to assess dysfunctional voiding. At this time the determination of dysfunctional voiding was done by history alone.6 None of the children in this series had voiding dysfunction at the time of injection. All patients received antibiotic prophylaxis until VCUG showed spontaneous VUR resolution or definitive treatment cured VUR. Those with downgrading of VUR to grade I after endoscopic correction were also withdrawn from antibiotic prophylaxis as part of our routine protocol. The endoscopic correction technique was similar to that described in the literature.2,7 In patients with grades I to III VUR we used the usual technique of STING when injection was performed, introducing the needle submucosally under the ureteral orifice at the 6 o’clock position. In patients with grades IV and V VUR, and in those with a widely open orifice injection was performed inside the orifice, as published previously.2,7 In 450 RRUs endoscopic correction was initially performed using polytetrafluoroethylene as a tissue augmenting substance. Since FDA approval in 2001, Dx/HA copolymer has been used in 246 RRUs. As is our standard practice, ultrasound was performed 1 month after injection to identify hydronephrosis and VCUG was performed 3 to 6 months after endoscopic correction. In those patients annual ultrasound was performed at long-term followup. To follow renal function all children with poor renal function underwent repeat DMSA scan at the beginning of adolescence and after the completion of puberty in case any signs of deteriorating kidney appearance on ultrasound was noted, such as worsening hydronephrosis, parenchymal thinning or arrested kidney growth. Also, patients with VUR downgrading underwent DMSA scan to monitor renal parenchymal damage. Some patients underwent repeat DMSA scan according to primary physician choice. Those with febrile UTI underwent compulsory VCUG, although postoperative studies showed corrected VUR. Urine samples were obtained with a urethral catheter or by suprapubic bladder aspiration as a part of the routine protocol in Israel. In older children a midstream voided specimen was examined. Since almost all male children in Israel are circumcised, the possibility of contamination in these children was low. A finding of more than 100,000 cfu/ml was defined as clinically significant UTI. In those with at least 2 episodes of recurrent afebrile UTI VCUG was performed to exclude recurrent VUR. Renal ultrasound was performed in all patients postoperatively and DMSA scan was performed in 509 of 696 RRUs (73%) postoperatively. All patients were followed for 1 to 20 years (median 13). GraphPad Prism®, version 4.0 with Fisher’s exact test was used for statistical evaluation.
RESULTS DMSA scan revealed renal scarring in 543 of the 696 RRUs (78%) preoperatively (table 1), of which 26 (4.8%) had severe, 123 (22.7%) had moderate and 394 (72.5%) had mild renal scarring. In 21 RRUs
RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
Table 1. Renal scarring by VUR grade Scarring (No. RRUs) VUR Grade
No. RRUs
Mild
Moderate
Severe
Totals
I II III IV V
36 178 298 163 21
— 81 240 73 —
— 2 34 79 8
— — 4 9 13
— 83 278 161 21
(3.7%) new renal scarring developed during observation on antibiotic prophylaxis. Reflux resolved in 473 RRUs (68%) after 1 injection, in 161 (23%) after 2 and in 25 (3.6%) ureters after 3. In 37 RRUs (5.4%) VUR improved to grade I, which required no further treatment (table 2). Renal deterioration was noted in 11 of 26 RRUs with initial severe renal scarring (less than 20% uptake on DMSA scan). The remaining RRUs in this group had an insignificant 2.3% change in relative function after successful VUR correction (p ⫽ 0.23). Patients with VUR downgrading did not show new renal scars. Of the remaining 446 RRUs 27 (6.1%) had a greater than 5% decrease in relative function without new scarring. Eight children in the polytetrafluoroethylene group and 3 in the Dx/HA copolymer group (overall 2.2%) had a febrile UTI after successful endoscopic correction, which necessitated reevaluation and resulted in the diagnosis of recurrent VUR recurrence in 8 (72.7%). Median time to recurrent VUR was 3 years (range 2 to 12) in the polytetrafluoroethylene group. Three patients in the Dx/HA copolymer group had recurrent VUR 1 and 2 years, respectively, after the first successful VUR correction. In the polytetrafluoroethylene group VUR was grades II to IV in 4, 3 and 1 patients, respectively. In the Deflux group grade III VUR was diagnosed in all children. To cure VUR in this group with later recurrence 1 injection was required in 9 of 11 children (81%) and in the remaining 2 (18%) 2 attempts of endoscopic injection resolved VUR. A total of 28 children (5.6%) experienced afebrile UTI without recurrent VUR.
DISCUSSION Some groups have already reported that open ureteral reimplantation preserves renal function even in already damaged kidneys and prevents upper UTI.8 –11 However, the role of endoscopic therapy must still be evaluated.12 Since at some centers endoscopic correction is first line therapy for all grades of VUR when surgery is indicated and with sometimes multiple attempts it can achieve almost the same success rate as open surgery, one may speculate that endoscopic correction of VUR is as durable
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as an open surgery to prevent recurrent UTI and kidney damage. Our data support that. Most kidneys had preserved function in the long term, showing only an insignificant change in renal function. We agree that by performing routine DMSA scan and not judging split renal function using single photon emission computerized tomography DMSA we may have underestimated renal function in patients with bilateral pathological conditions. Thus, in some of our patients global function may have decreased, allowing relative renal function to remain normal or almost normal. Our data show a relatively high incidence of renal scarring. However, the study represents 20 years. In the beginning the incidence of prenatal diagnosis of VUR was low. Some patients came to our attention and underwent diagnostic assessment only after several incidences of febrile UTI and renal damage. Only renal units with severe damage at endoscopic correction showed decreased function, eventually leading to nephrectomy in 4 children. Obviously in those kidneys severe congenital dysplastic features were responsible for the continuous deterioration in function that finally led to nephrectomy. It was shown that sterile reflux does not cause renal scars unless extreme hydrodynamic conditions exist in the sick kidney. VUR associated bacteriuria, which leads to a protracted inflammatory reaction, is a major cause of exudative pyelonephritis and kidney damage. In our series only 2.2% of all studied children had recurrent pyelonephritis in the long term. However, 8 of the 11 children had recurrent VUR on followup VCUG. These data are similar to those previously published. Sedberry-Ross13 and Chi14 et al evaluated the febrile UTI incidence after successful endoscopic correction of VUR and found that up to 27% of all children in whom reflux was corrected had a febrile UTI, of whom almost 90% had recurrent VUR on consequent VCUG. The question of the long-tern durability of tissue augmenting substances has been raised by many researchers on several occasions. The longest followup of up to 17 years of polytetrafluoroethylene used as a tissue augmenting substance clearly demonstrated its long-term durability to prevent recurrent VUR.7 Since concern regarding the safety of polytetrafluoroethylene use in the pediatric populaTable 2. Outcome of endoscopic correction of VUR in 696 RRUs No. RRUs (%) No. endoscopic infections: 1 2 3 VUR downgraded to grade I
473 (68) 161 (23) 25 (3.6) 37 (5.4)
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RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
tion cannot be ignored and Deflux is the only FDA approved material for endoscopic injection to manage VUR in children, the question of the long-term durability of Deflux is of interest and parental concern.12–14 The low incidence of recurrent VUR after Deflux injection in our series, which is comparable with previous published data, may be explained by the fact that our patients with Deflux had relatively short followup. Furthermore, we did not perform late routine VCUG in all patients who underwent Deflux injection and we limited repeat VCUG only to patients with febrile or recurrent episodes of afebrile UTI. Therefore, the long-term durability of VUR correction using Deflux as a tissue augmented substance must be answered. The remaining 3 of 11 children who had recurrent pyelonephritis showed no recurrent VUR on followup VCUG. In 2 cases dysfunctional voiding was blamed for UTI and in 1 no particular cause was found. The possibility of an afebrile UTI during longterm followup in children with endoscopically cured VUR has been previously pointed out.7 In our series 28 children (5.6%) had an afebrile UTI. Since these children had at least 2 episodes of afebrile UTI, they underwent VCUG as part of our routine protocol
after endoscopic correction. None showed recurrent VUR. This study is not without limitations. The data are retrospective and some incidences of UTI may be missing from the registry. Although all patients underwent DMSA renal scan before surgery, only 78% underwent DMSA scan after the procedure. We did not use a control group of patients to prove that successful VUR correction leads to renal function protection. Finally, followup in the Deflux group is significantly shorter than in the polytetrafluoroethylene group and, therefore, the issue of recurrent VUR in this group should be addressed later.
CONCLUSIONS Our data show that successful endoscopic correction of VUR is accompanied by a low incidence of new renal scarring and febrile UTI. Patients who initially show corrected VUR but who have febrile UTI at long-term followup require prompt reevaluation to rule out recurrent VUR. In the light of recent reports of the low effectiveness of antibiotic prophylaxis in children with VUR there is a desperate need for prospective clinical trails to investigate optimal treatment options in patients with VUR.
REFERENCES 1. Kirsch AJ, Perez-Brayfield MR, Smith EA et al: The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413. 2. Puri P, Chertin B, Murugesh V et al: Treatment of vesicoureteral reflux by endoscopic injection of dextranomer/hyaluronic acid copolymer (Deflux): preliminary results. J Urol 2003; 170: 1541. 3. Routh JC, Vandersteen DR, Pfefferle H et al: Single center experience with endoscopic management of vesicoureteral reflux in children. J Urol 2006; 175: 1889. 4. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee. International Reflux Study Committee. Pediatrics 1981; 67: 392. 5. Polito C, LaManna A, Rambaldi PF et al: High incidence of a generally small kidney and primary vesicoureteral reflux. J Urol 2000; 164: 479.
6. Farhat W, Bagli DJ, Capolicchio G et al: The dysfunctional voiding system: quantitative standardization of dysfunctional voiding symptoms in children. J Urol 2000; 164: 1011. 7. Chertin B, Colhoun E, Velayudham M et al: Endoscopic treatment of vesicoureteral reflux. An 11 to 17-year followup. J Urol 2002; 167: 1443. 8. Matsumoto F, Shimada K, Harada Y et al: Split renal function does not change after successful treatment in children with primary vesico-ureteric reflux. BJU Int 2003; 92: 1006. 9. Nepple KG, Austin JC, Hawtrey CE et al: Kidneys with reflux nephropathy maintain relative renal function after ureteral reimplantation. J Urol 2005; 174: 1606. 10. Webster RI, Smith G, Farnsworth RH et al: Low incidence of new renal scars after ureteral reimplantation for vesicoureteral reflux in children: a prospective study. J Urol 2000; 163: 1915.
11. Yu TJ, Chen WF and Chen HY: Early versus late surgical management of fetal reflux nephropathy. J Urol 1997; 157: 1416. 12. Wadie GM, Tirabassi MV, Courtney RA et al: The Deflux procedure reduces the incidence of urinary tract infections in patients with vesicoureteral reflux. J Laparoendosc Adv Surg Tech A 2007; 17: 353. 13. Sedberry-Ross S, Rice DC, Pohl HG et al: Febrile urinary tract infections in children with an early negative voiding cystourethrogram after treatment of vesicoureteral reflux with dextranomer/hyaluronic acid. J Urol, part 2, 2008; 180: 1605. 14. Chi A, Gupta A and Snodgrass WJ: Urinary tract infection following successful dextranomer/hyaluronic acid injection for vesicoureteral reflux. J Urol 2008; 179: 1966.
EDITORIAL COMMENT The premise of this study, that intervention for VUR protects kidneys from future damage, is important. However, interpreting study results and conclusions should be tempered by consideration of its methodological limitations. Most impor-
tantly there is no comparison group. Therefore, we do not know what would have happened if these patients had undergone successful ureteral reimplantation or failed endoscopic injection, or for that matter if they had received no intervention.
RENAL SCARRING AFTER VESICOURETERAL REFLUX CORRECTION
This problem is complicated by the high 78% prevalence of preoperative scarring, which is higher than might be expected based on a recent systematic review.1 The small number of patients with postoperative scarring may have had more to do with the low number of patients at risk than with the effectiveness of the intervention. At the end of the day this study does not prove the effectiveness or lack thereof of endoscopic injection. Rather, it simply documents that in a pa-
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tient population with a high rate of preoperative renal scarring few patients continue to decline after successful injection. More broadly this series poses an interesting question that must be answered by future study. Jonathan C. Routh Department of Urology Children’s Hospital Boston Boston, Massachusetts
REFERENCE 1. Faust WC, Diaz M and Pohl HG: Incidence of post-pyelonephritic renal scarring: a meta-analysis of the dimercapto-succinic acid literature. J Urol 2009; 181: 290.