Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: Long-term observational study.

BACKGROUND: Since 1993, children aged >1 year with persistent grade III-V vesicoureteral reflux (VUR) and febrile urinary tract infections (UTIs) attending Uppsala University Hospital have undergone endoscopic injection with proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx; Deflux®). OBJECTIVE: Investigate long-term incidence of UTI, bladder dysfunction, ureteral reimplantation and overall clinical findings following endoscopic injection of NASHA/Dx. STUDY DESIGN: Children with grade IV VUR diagnosed by voiding cystourethrogram (VCUG) and dilating VUR persisting for >1 year were included in this study. 15-25 years after endoscopic treatment, patients' hospital charts were studied. Information on bladder function and UTIs was obtained via questionnaire, 8-18 years after endoscopic treatment. RESULTS: 185 patients (69 boys, 116 girls) were included in the study; 237 grade IV VUR ureters were treated. All study patients were diagnosed with VUR after a febrile UTI (i.e. pyelonephritis). According to the last voiding cystourethrogram, 69% of ureters showed a positive response (VUR grade 0-I), 7% had VUR grade II and 23% had VUR grade ≥ III. 46 patients (25%) required ureteral reimplantation during follow-up. Among patients treated during the second 5-year period compared with the first (1998-2003 versus 1993-1998), there was a significant decrease in the rate of ureteral reimplantation (31% vs 16%; p = 0.0365). This difference may be attributable to developments over time in the injection technique. UTIs occurred in 30 patients (21% of the evaluable population): 28 females and 2 males. Febrile UTIs were reported in 14 patients (10%), all females. Forty-nine patients (34%) had bladder problems (e.g. underactivity, overactivity, incontinence). Five patients underwent ureteral reimplantation 'late', 6-10 years after the last endoscopic injection. In one male patient, calcification around the NASHA/Dx implantation site was observed during routine examination 2 years after endoscopic treatment; no intervention was required. No safety issues were observed in the remaining 97% of the study population. CONCLUSIONS: This study represents the longest published follow-up of Grade IV VUR patients undergoing endoscopic treatment. Three-quarters of patients did not need ureteral reimplantation. Optimal injection technique and higher injection volume were associated with a reduced ureteral reimplantation rate. Treatment with NASHA/Dx was durable and well tolerated: long-term risks of UTI, bladder dysfunction and recurrent VUR were low.

Changes of arterial pressure following relief of obstruction in adults with hydronephrosis.

BACKGROUND: As much as 20% of all cases of hypertension are associated with kidney malfunctions. We have previously demonstrated in animals and in pediatric patients that hydronephrosis causes hypertension, which was attenuated by surgical relief of the ureteropelvic junction (UPJ) obstruction. This retrospective cohort study aimed to investigate: (1) the proposed link between hydronephrosis, due to UPJ obstruction, and elevated arterial pressure in adults; and (2) if elevated blood pressure in patients with hydronephrosis might be another indication for surgery. MATERIALS AND METHODS: Medical records of 212 patients undergoing surgical management of hydronephrosis, due to UPJ obstruction, between 2000 and 2016 were assessed. After excluding patients with confounding conditions and treatments, paired arterial pressures (i.e. before/after surgery) were compared in 49 patients (35 years old; 95% CI 29-39). Split renal function was evaluated by using mercaptoacetyltriglycine (MAG3) renography before surgical management of the hydronephrotic kidney. RESULTS: Systolic (-11 mmHg; 95% CI 6-15 mmHg), diastolic (-8 mmHg; 95% CI 4-11 mmHg), and mean arterial (-9 mmHg; 95% CI 6-12) pressures were significantly reduced after relief of the obstruction (p < 0.001). Split renal function of the hydronephrotic kidney was 39% (95% CI 37-41). No correlations were found between MAG3 and blood pressure level before surgery or between MAG3 and the reduction of blood pressure after surgical management of the UPJ obstruction. CONCLUSIONS: In adults with hydronephrosis, blood pressure was reduced following relief of the obstruction. Our findings suggest that elevated arterial pressure should be taken into account as an indication to surgically correct hydronephrosis.

Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative stress following surgical correction of hydronephrosis in children.

OBJECTIVE: Recent clinical studies have suggested an increased risk of elevated arterial pressure in patients with hydronephrosis. Animals with experimentally induced hydronephrosis develop hypertension, which is correlated to the degree of obstruction and increased oxidative stress. In this prospective study we investigated changes in arterial pressure, oxidative stress, and nitric oxide (NO) homeostasis following correction of hydronephrosis. METHODS: Ambulatory arterial pressure (24 h) was monitored in pediatric patients with hydronephrosis (n = 15) before and after surgical correction, and the measurements were compared with arterial pressure measurements in two control groups, i.e. healthy controls (n = 8) and operated controls (n = 8). Markers of oxidative stress and NO homeostasis were analyzed in matched urine and plasma samples. RESULTS: The preoperative mean arterial pressure was significantly higher in hydronephrotic patients [83 mmHg; 95% confidence interval (CI) 80-88 mmHg] than in healthy controls (74 mmHg; 95% CI 68-80 mmHg; p < 0.05), and surgical correction of ureteral obstruction reduced arterial pressure (76 mmHg; 95% CI 74-79 mmHg; p < 0.05). Markers of oxidative stress (i.e., 11-dehydroTXB2, PGF2α, 8-iso-PGF2α, 8,12-iso-iPF2α-VI) were significantly increased (p < 0.05) in patients with hydronephrosis compared with both control groups, and these were reduced following surgery (p < 0.05). Interestingly, there was a trend for increased NO synthase activity and signaling in hydronephrosis, which may indicate compensatory mechanism(s). CONCLUSION: This study demonstrates increased arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls, which can be restored to normal levels by surgical correction of the obstruction. Once reference data on ambulatory blood pressure in this young age group become available, we hope cut-off values can be defined for deciding whether or not to correct hydronephrosis surgically.

Surgical treatment reduces blood pressure in children with unilateral congenital hydronephrosis.

OBJECTIVE: Renal disorders can cause hypertension, but less is known about the influence of hydronephrosis on blood pressure. Hydronephrosis due to pelvo-ureteric junction obstruction (PUJO) is a fairly common condition (incidence in newborns of 0.5-1%). Although hypertensive effects of hydronephrosis have been suggested, this has not been substantiated by prospective studies in humans [1-3]. Experimental studies with PUJO have shown that animals with induced hydronephrosis develop salt-sensitive hypertension, which strongly correlate to the degree of obstruction [4-7]. Moreover, relief of the obstruction normalized blood pressure [8]. In this first prospective study our aim was to study the blood pressure pattern in pediatric patients with hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated if preoperative blood pressure is reduced after surgery and if split renal function and renographic excretion curves provide any prognostic information. PATIENTS AND METHODS: Twelve patients with unilateral congenital hydronephrosis were included in this prospective study. Ambulatory blood pressure (24 h) was measured preoperatively and six months after surgery. Preoperative evaluations of bilateral renal function by Tc99m-MAG3 scintigraphy, and renography curves, classified according to O'Reilly, were also performed. RESULTS: As shown in the summary figure, postoperative systolic (103 ± 2 mmHg) and diastolic (62 ± 2 mmHg) blood pressure were significantly lower than those obtained preoperatively (110 ± 4 and 69 ± 2 mmHg, respectively), whereas no changes in circadian variation or pulse pressure were observed. Renal functional share of the hydronephrotic kidney ranged from 11 to 55%. There was no correlation between the degree of renal function impairment and the preoperative excretory pattern, or between the preoperative excretory pattern and the blood pressure reduction postoperatively. However, preoperative MAG3 function of the affected kidney correlated with the magnitude of blood pressure change after surgery. DISCUSSION: Correction of the obstruction lowered blood pressure, and the reduction in blood pressure appeared to correlate with the degree of renal functional impairment, but not with the excretory pattern. Thus, in the setting of hypertension, it appears that the functional share of the hydronephrotic kidney should be considered an indicator of the need for surgery, whereas the renography curve is less reliable. The strength of the present study is the prospective nature and that ambulatory blood pressure monitoring was used. Future longitudinal prolonged follow-up studies are warranted to confirm the present findings, and to understand if a real nephrogenic hypertension with potential necessity of treatment will develop. CONCLUSION: This novel prospective study in patients with congenital hydronephrosis demonstrates a reduction in blood pressure following relief of the obstruction. Based on the present results, we propose that the blood pressure level should also be taken into account when deciding whether to correct hydronephrosis surgically or not.

Endoscopic treatment of vesicoureteral reflux: current practice and the need for multifactorial assessment.

Vesicoureteral reflux (VUR) affects around 1% of all children. It carries an increased risk of febrile urinary-tract infections (UTIs) and is associated with impaired renal function. Antibiotic prophylaxis is an established approach to managing the condition, but it does not protect against UTI and encourages bacterial resistance. Ureteral re-implantation (open surgery) is a relatively traumatic procedure typically requiring hospitalization, and there is a risk of significant post-treatment complications. Endoscopic treatment with NASHA/Dx gel (Deflux®) is minimally invasive, well tolerated and provides cure rates approaching those of open surgery: 80-90% in several studies. It has also been shown to be effective in a variety of 'complicated' cases. Thus, endoscopic treatment is generally preferable to open surgery and long-term antibiotic prophylaxis. Non-treatment of VUR is being discussed as an alternative option, although this mainly appears suitable for children with low-grade reflux and normal kidneys. A new approach to managing VUR may be considered, with treatment decisions based not only on the grade of reflux but also on factors such as age, sex, renal scarring and bladder dysfunction. Open surgery would be reserved only for use in the 10-15% of children not responding to endoscopic treatment and those with severe ureteral anomalies.

Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel is effective in vesicoureteral reflux associated with bladder dysfunction.

PURPOSE: Endoscopic injection of stabilized nonanimal hyaluronic acid/dextranomer gel is an established treatment for vesicoureteral reflux in children. We performed a subgroup analysis to assess this treatment in reflux associated with bladder dysfunction. MATERIALS AND METHODS: Of 308 consecutive children treated endoscopically with stabilized nonanimal hyaluronic acid/dextranomer gel for dilating vesicoureteral reflux 54 were observed retrospectively to have bladder dysfunction. Initial followup consisted of voiding cystourethrogram at 3 and 12 months after injection, with positive response defined as reflux grade 0 or I. At 7 to 12 years following treatment patient charts were checked for urinary tract infections and bladder dysfunction, and a followup survey (postal questionnaire) was administered. RESULTS: A positive response to therapy (cure) was observed in 45 children (83%) after 1 to 3 endoscopic treatments. Concurrently, bladder dysfunction had resolved in 32 patients (59%). After the last stabilized nonanimal hyaluronic acid/dextranomer gel implantation 45 patients (83%) were free of urinary tract infections. Questionnaire results were similar to chart based findings. Stabilized nonanimal hyaluronic acid/dextranomer gel implantation was well tolerated, with no associated complications. CONCLUSIONS: Endoscopic treatment with stabilized nonanimal hyaluronic acid/dextranomer gel appears to be similarly effective in patients with vesicoureteral reflux with and without bladder dysfunction. These data indicate that bladder dysfunction should not be considered a contraindication to endoscopic treatment for reflux.

Treatment of vesicoureteral reflux in children using stabilized non-animal hyaluronic acid/dextranomer gel (NASHA/DX): a long-term observational study.

OBJECTIVE: Vesicoureteral reflux (VUR) can be treated with open surgery, antibiotic therapy or endoscopic injection. A goal in children is to reduce the incidence of febrile urinary tract infections (UTIs). The present long-term observational study investigated outcomes and experiences of endoscopic treatment with stabilized non-animal hyaluronic acid/dextranomer, NASHA/Dx. PATIENTS AND METHODS: Children treated with NASHA/Dx between 1993 and 1998 were sent a questionnaire by mail in 2005. Patients included in the study (n=231) had VUR grade III-V before treatment and grade 0-II afterwards. Patients completed 21 questions, with parental assistance if required. The questionnaire assessed clinical outcome, and the attitudes of both patients and their parents to their experiences of treatment with NASHA/Dx gel. Patients reporting UTI after treatment were contacted and their records analyzed. RESULTS: Questionnaires were completed by 179 eligible patients. Most (72%) received a single injection of NASHA/Dx gel, and all experienced febrile UTI before treatment. After treatment, 45 patients (25%) experienced UTI; 25 of these reported fever. Patient records and telephone interviews revealed no evidence of febrile UTI in 19 cases; febrile UTI was confirmed in six cases, an incidence of 3.4%. When asked about the worst aspect of VUR treatment, 9% indicated treatment with NASHA/Dx compared to 19% for medication and 72% for voiding cystourethrogram (VCUG); parent-rated responses were 19%, 24% and 57%, respectively. CONCLUSIONS: Endoscopic treatment with NASHA/Dx gel was associated with a low number of febrile UTIs following treatment, viewed positively and considered less bothersome than medication or VCUG. These findings support this treatment as a primary intervention for VUR.

Endoscopic treatment of vesicoureteral reflux with dextranomer/hyaluronic acid copolymer is effective in either double ureters or a small kidney.

PURPOSE: Endoscopic injection of dextranomer/hyaluronic acid (Dx/HA) copolymer is an increasingly established treatment for primary vesicoureteral reflux (VUR) in children. We performed a retrospective analysis to assess this treatment for VUR associated with either double ureters or a small kidney. MATERIALS AND METHODS: The study included 68 children with duplex ureters and 40 with a small kidney (1 kidney contributing 10% to 35% of total renal function) who underwent endoscopic treatment with Dx/HA copolymer for VUR. Followup consisted of voiding cystourethrography 3 and 12 months after injection. Positive response was defined as reflux grade 0 or I. As many as 2 repeat injections were offered to nonresponders, and those with persistent reflux were referred for open surgery. Long-term clinical followup with renal function testing was continued for 4 to 9 years. RESULTS: A positive response was observed in 63% of children with duplex ureters, with only 17 (25%) patients requiring open surgery. Among children with a small kidney the response rate was 70%, and open surgery was performed in 9 (23%). In both treatment groups a positive response to treatment was sustained throughout the followup period in all cases. The treatment was well tolerated, with no complications associated with the procedure. CONCLUSIONS: Endoscopic treatment with Dx/HA copolymer appears to be an effective and well tolerated alternative to open surgery for first line treatment of VUR associated with double ureters or a small kidney.

Complex segregation analysis of hypospadias.

Hypospadias, when the urethra opens on the ventral side of the penis, is a common malformation seen in about 3 per 1000 male births. It is considered a complex disorder with both genetic and environmental factors involved in the pathogenesis. Low birth weight is known to be an important risk factor for hypospadias, but several observations speak in favour of genetic factors as well. In order to delineate the relative contribution of the genetic factors behind hypospadias, we performed a complex segregation analysis of 2005 pedigrees in Sweden. The probands were ascertained through the departments of paediatric surgery and departments of plastic surgery and urology in Sweden where boys with hypospadias undergo surgery. In 7% of the ascertained families one or more additional cases of hypospadias were present. The complex segregation analysis showed a heritability of 0.99 and evidence for multifactorial inheritance. The results suggest that hypospadias might be due to monogenic effects in a small proportion of the families, but that there is a multifactorial cause for the majority of the cases.

Vesicoureteral reflux: a new treatment algorithm.

Vesicoureteral reflux (VUR) affects about 1% of all children and carries an increased risk of pyelonephritis and long-term renal impairment. There are several approaches to the treatment of VUR: antibiotic prophylaxis (conservative treatment), open surgery, and endoscopic treatment. For many patients, endoscopic treatment cures VUR with a single procedure, eliminating the need for long-term antibiotic treatment and avoiding the trauma of a major surgical procedure. The choice of material for endoscopic treatment is of key importance, and, until recently, all available materials were associated with concerns regarding safety and efficacy. Emerging data demonstrate that dextranomer/hyaluronic acid (Dx/HA) copolymer has good long-term safety and efficacy in treating VUR. A new treatment algorithm is, therefore, proposed, recommending that most children with persistent VUR (longer than 1 year) be offered endoscopic treatment with Dx/HA copolymer as an alternative to prolonged antibiotic prophylaxis or open surgery.