Endoscopic Injection of Dextranomer/Hyaluronic Acid as First Line Treatment in 851 Consecutive Children with High Grade Vesicoureteral Reflux: Efficacy and Long-Term Results.

PURPOSE: Endoscopic injection of dextranomer/hyaluronic acid is widely acknowledged as first line treatment of lower grade vesicoureteral reflux. We demonstrate its long-term efficacy and safety in eradicating high grade reflux. MATERIALS AND METHODS: A total of 518 girls and 333 boys with a median age of 2.3 years (range 2 months to 13.7 years) underwent endoscopic correction of high grade vesicoureteral reflux using dextranomer/hyaluronic acid. Reflux was unilateral in 415 cases and bilateral in 436, comprising 1,287 refluxing units. Reflux was grade IV in 1,153 ureters (89.6%) and grade V in 134 (10.4%). 99mTechnetium-dimercaptosuccinic acid scintigraphy identified renal scarring in 317 patients (37.3%). Followup ultrasound and voiding cystourethrogram were performed 3 months after intervention and renal ultrasound yearly thereafter. Median followup was 8.5 years (range 6 months to 16 years). RESULTS: Overall resolution rate after the first endoscopic injection was 69.5% (895 of 1,287 cases), with resolution in 70.4% of grade IV and 61.9% of grade V cases. Reflux resolved after a second injection in 259 cases (20.1%) and after a third injection in 133 (10.4%). Persistent reflux after initial treatment was significantly more common in patients younger than age 1 year and in individuals with renal scarring. No significant postoperative complications were observed and no patient required ureteral reimplantation. Following reflux resolution febrile urinary tract infection developed in 43 children (5.1%), including 24 (55.8%) during the first year, 15 (34.9%) during the second year and 4 (9.3%) during year 3 or later. Of these patients 6 had reflux recurrence and 8 had neocontralateral grade III reflux, which was successfully treated with a single endoscopic injection of dextranomer/hyaluronic acid. CONCLUSIONS: Endoscopic injection of dextranomer/hyaluronic acid is an efficient and safe long-term treatment for grade IV and V vesicoureteral reflux, and can easily be repeated in patients with treatment failure with a high subsequent resolution rate.

Renal cortical abnormalities in siblings of index patients with vesicoureteral reflux.

OBJECTIVE: Screening siblings of index patients with vesicoureteral reflux (VUR) has been proposed to identify children who are at risk for renal damage. However, screening siblings for VUR remains controversial. We investigated the prevalence of VUR and renal cortical abnormalities in the sibling population in a large cohort of families with VUR. METHODS: Between 1998 and 2012, parents of index patients with grade III to V VUR were asked permission to screen siblings <6 years of age for VUR. Siblings were divided into 2 groups: siblings with a documented history of a previous urinary tract infection (UTI) and siblings who were screened for VUR and never had a UTI. A logistic regression model was used to determine independent risk factors associated with renal cortical abnormalities such as history of presentation, age, gender, and grade of VUR. RESULTS: There were 318 siblings in 275 families in the study. VUR was found after screening in 190 (60%) siblings and after a UTI in 128 (40%). Multivariate analysis revealed that siblings who had a previous UTI (odds ratio: 3.38), siblings with high grade reflux (odds ratio: 3.62), and siblings over 1 year of age (odds ratio: 2.84) were the most significant independent risk factors associated with renal cortical abnormalities. CONCLUSIONS: There is increased risk of renal cortical abnormalities in siblings with a previous UTI, siblings with high-grade VUR, and siblings over age 1 year. This information may help to counsel parents about the risk of VUR and reflux nephropathy in familial VUR.

Prevalence and predictors of renal functional abnormalities of high grade vesicoureteral reflux.

PURPOSE: The association of vesicoureteral reflux, febrile urinary tract infections and renal parenchymal damage is well recognized. We determined the prevalence and predictors of renal functional abnormalities in children with high grade vesicoureteral reflux. MATERIALS AND METHODS: We retrospectively reviewed the medical records and dimercapto-succinic acid scans of 774 consecutive children with primary high grade vesicoureteral reflux (grade IV-V) seen at our institution between 1998 and 2011. For multivariate analysis we analyzed variables associated with renal functional abnormalities, such as presentation history, age, gender and reflux grade, in a logistic regression model. RESULTS: Of the children 698 (90%) and 76 (10%) had grade IV and V reflux, respectively. Dimercapto-succinic acid scans revealed renal functional abnormalities in 291 children (37.6%), including 240 (34%) with grade IV and 51 (67%) with grade V reflux. Univariate analysis showed that age greater than 1 year (OR 2.95, p <0.001), grade V reflux (OR 4.09, p <0.001) and preoperative bladder/bowel dysfunction (OR 2.94, p = 0.026) were significant predictors of renal functional abnormalities. Multivariate analysis showed that age greater than 1 year (OR 3.45, p = 0.001) and grade V reflux (OR 5.89, p <0.001) were the most significant independent predictors of such abnormalities. CONCLUSIONS: There is an increased risk of renal functional abnormalities in children older than 1 year and those with grade V vesicoureteral reflux. Patients with a history of bladder/bowel dysfunction are also at greater risk for such abnormalities. The early detection and treatment of high grade vesicoureteral reflux may prevent acquired renal parenchymal damage and limit the progression of renal damage in patients with congenital reflux nephropathy.

Single center experience with endoscopic subureteral dextranomer/hyaluronic acid injection as first line treatment in 1,551 children with intermediate and high grade vesicoureteral reflux.

PURPOSE: In recent years the endoscopic injection of dextranomer/hyaluronic acid has become an established alternative to long-term antibiotic prophylaxis and the surgical management of vesicoureteral reflux. We determined the safety and effectiveness of the endoscopic injection of dextranomer/hyaluronic acid as first line treatment for high grade vesicoureteral reflux. MATERIALS AND METHODS: Between 2001 and 2010, 1,551 children (496 male, 1,055 female, median age 1.6 years) underwent endoscopic correction of intermediate and high grade vesicoureteral reflux using dextranomer/hyaluronic acid soon after the diagnosis of vesicoureteral reflux on initial voiding cystourethrogram. Vesicoureteral reflux was unilateral in 761 children and bilateral in 790. Renal scarring was detected in 369 (26.7%) of the 1,384 patients who underwent dimercapto-succinic acid imaging. Reflux grade in the 2,341 ureters was II in 98 (4.2%), III in 1,340 (57.3%), IV in 818 (34.9%) and V in 85 (3.6%). Followup ultrasound and voiding cystourethrogram were performed 3 months after the outpatient procedure, and renal ultrasound was performed annually thereafter. Patients were followed for 3 months to 10 years (median 5.6 years). RESULTS: Vesicoureteral reflux resolved after the first, second and third endoscopic injection of dextranomer/hyaluronic acid in 2,039 (87.1%), 264 (11.3%) and 38 (1.6%) ureters, respectively. Febrile urinary tract infections developed during followup in 69 (4.6%) patients. None of the patients in the series needed reimplantation of ureters or experienced any significant complications. CONCLUSIONS: Our results confirm the safety and efficacy of the endoscopic injection of dextranomer/hyaluronic acid in the eradication of high grade vesicoureteral reflux. We recommend this 15-minute outpatient procedure as the first line of treatment for high grade vesicoureteral reflux.

Renal parenchymal damage in intermediate and high grade infantile vesicoureteral reflux.

PURPOSE: The association of vesicoureteral reflux, urinary tract infection and renal scarring is well recognized. We evaluated the incidence of renal parenchymal scarring in a large series of infants with primary high grade vesicoureteral reflux. MATERIALS AND METHODS: The medical records of 549 consecutive infants with primary high grade vesicoureteral reflux between 1985 and 2006 were reviewed. A total of 473 infants (86.1%) presented with febrile urinary tract infections, 63 (11.5%) were screened for sibling vesicoureteral reflux and 13 (2.4%) were investigated because of prenatally diagnosed hydronephrosis. Age at diagnosis was defined as patient age at the first voiding cystourethrogram. Renal parenchymal scarring was evaluated by dimercapto-succinic acid scan and classified into 3 groups, including mild--focal defects with between 40% and 45% relative uptake of renal radionuclide, moderate--relative uptake between 20% and 40%, and severe--a shrunken kidney with relative uptake less than 20%. RESULTS: Of the 549 infants 292 (53%) were boys and 257 (47%) were girls with a median age of 6 months (range 2 to 12). Reflux was unilateral in 160 and bilateral in 389 (938 ureters). Reflux grade was II to V in 19, 372, 458 and 89 ureters, respectively. All patients with grade II reflux had high grade reflux on the contralateral side. Renal parenchymal scarring was present in 122 of the 458 infants (27%) evaluated with dimercapto-succinic scan. The incidence of renal parenchymal scarring was only 9% in infants without a history of urinary tract infection and 29% in those who presented with a urinary tract infection (p <0.01). Moderate to severe renal parenchymal scarring was present in 55 infants, of whom 73% were male and 27% were female. CONCLUSIONS: The data show that moderate to severe renal scarring is associated with grade IV and V reflux, and male sex. The incidence of renal scarring is significantly lower in infants in whom high grade vesicoureteral reflux is detected by screening before the development of urinary tract infection. Early detection may prevent urinary tract infection related renal parenchymal scarring.

Late-surviving megafauna in Tasmania, Australia, implicate human involvement in their extinction.

Establishing the cause of past extinctions is critical if we are to understand better what might trigger future occurrences and how to prevent them. The mechanisms of continental late Pleistocene megafaunal extinction, however, are still fiercely contested. Potential factors contributing to their demise include climatic change, human impact, or some combination. On the Australian mainland, 90% of the megafauna became extinct by approximately 46 thousand years (ka) ago, soon after the first archaeological evidence for human colonization of the continent. Yet, on the neighboring island of Tasmania (which was connected to the mainland when sea levels were lower), megafaunal extinction appears to have taken place before the initial human arrival between 43 and 40 ka, which would seem to exonerate people as a contributing factor in the extirpation of the island megafauna. Age estimates for the last megafauna, however, are poorly constrained. Here, we show, by direct dating of fossil remains and their associated sediments, that some Tasmanian megafauna survived until at least 41 ka (i.e., after their extinction on the Australian mainland) and thus overlapped with humans. Furthermore, a vegetation record for Tasmania spanning the last 130 ka shows that no significant regional climatic or environmental change occurred between 43 and 37 ka, when a land bridge existed between Tasmania and the mainland. Our results are consistent with a model of human-induced extinction for the Tasmanian megafauna, most probably driven by hunting, and they reaffirm the value of islands adjacent to continental landmasses as tests of competing hypotheses for late Quaternary megafaunal extinctions.

Endoscopic treatment of moderate and high grade vesicoureteral reflux in infants using dextranomer/hyaluronic acid.

PURPOSE: Renal parenchymal injury in vesicoureteral reflux occurs early, in most patients before age 3 years. It is generally believed that early prevention of urinary tract infections may decrease the amount of renal parenchymal damage. Endoscopic treatment for vesicoureteral reflux has become an established alternative to long-term antibiotic prophylaxis and ureteral reimplantation. We prospectively evaluated the effectiveness and safety of dextranomer/hyaluronic acid copolymer for high grade vesicoureteral reflux in infants. MATERIALS AND METHODS: A total of 276 infants, including 124 boys and 152 girls, with a median age of 7 months (range 2 to 12) underwent endoscopic treatment for vesicoureteral reflux with dextranomer/hyaluronic acid. Reflux was detected in 225 infants following investigation for urinary tract infection, in 46 following screening for sibling vesicoureteral reflux and in 5 for prenatally diagnosed hydronephrosis. Vesicoureteral reflux was unilateral in 85 infants and bilateral in 191 (467 refluxing ureters). Reflux was grade II in 14 ureters, grade III in 188, grade IV in 248 and grade V in 17. Dimercapto-succinic acid scan was performed in 250 infants and it demonstrated renal scarring in 43 (17.2%). RESULTS: Vesicoureteral reflux completely resolved in 373 ureters (79.9%) after a single injection of dextranomer/hyaluronic acid and it was downgraded to grade I in 21 (4.4%). Of the ureters 65 (14%) required a second injection and 8 (1.7%) required a third injection to resolve reflux. All patients underwent endoscopic treatment on an outpatient basis. There were no complications except in 1 patient, who was readmitted to the hospital the next day with acute pyelonephritis. Three children had urinary tract infections during followup, of whom 1 was found to have recurrent reflux on investigation. CONCLUSIONS: Endoscopic treatment with dextranomer/hyaluronic acid is safe and highly effective for eradicating high grade vesicoureteral reflux in infants. Early intervention in infants with high grade reflux may change its natural history and protect against renal scarring.

New contralateral vesicoureteral reflux after endoscopic correction of unilateral reflux--is routine contralateral injection indicated at initial treatment?

PURPOSE: As more and more pediatric urologists use endoscopic therapy as a primary treatment option for vesicoureteral reflux, newer indications for this procedure are being considered. Recently it was suggested that contralateral nonrefluxing ureters should be treated prophylactically in patients undergoing unilateral endoscopic correction of vesicoureteral reflux. We analyzed the incidence of newly diagnosed contralateral reflux after endoscopic correction of unilateral reflux and identified possible risk factors for its development. MATERIALS AND METHODS: Between 1996 and 2004, 662 patients underwent endoscopic correction of unilateral grades II to V vesicoureteral reflux. Of the ureters 97% had grades III to V reflux. The tissue augmenting substance used for endoscopic treatment was polytetrafluoroethylene from 1996 to 2000 and dextranomer/hyaluronic acid from 2001 to 2004. There were 203 males (30.7%) and 459 females (69.3%) with an age at endoscopic treatment of 2 months to 11 years. Voiding cystourethrograms performed 3 months after endoscopic treatment of unilateral vesicoureteral reflux were analyzed in all patients to document newly diagnosed contralateral reflux. RESULTS: A total of 67 children (10.1%), including 18 boys and 49 girls, showed new contralateral reflux on voiding cystourethrogram after endoscopic correction of unilateral reflux. Contralateral VUR was grades I to IV in 16 (23.9%), 17 (25.4%), 27 (40.3%) and 7 patients (10.5%), respectively. There was no correlation between the severity of ipsilateral reflux and the development of contralateral reflux. Patient age and gender did not influence the development of new contralateral reflux. CONCLUSIONS: The low incidence and lower grade of newly diagnosed contralateral vesicoureteral reflux after endoscopic correction of unilateral reflux does not support prophylactic treatment of nonrefluxing contralateral ureters.

Familial vesicoureteral reflux: influence of sex on prevalence and expression.

PURPOSE: Familial clustering of vesicoureteral reflux implies that genetic factors have an important role in the pathogenesis of vesicoureteral reflux. We investigated the impact of sex on familial vesicoureteral reflux. MATERIALS AND METHODS: Between 1998 and 2003 we identified 159 white families with at least 2 children (range 2 to 5) with vesicoureteral reflux confirmed by a voiding cystourethrogram. Families were divided into 3 groups, including group 1 with only boys affected (29 or 18%), group 2 with only girls affected (57 or 36%) and group 3 with boys and girls affected (73 or 46%). Clinical characteristics, reflux grade and associated renal anomalies in these 3 groups were compared using the Mann-Whitney U and chi-square tests for statistical analysis. RESULTS: Sisters of index female patients were at significantly higher risk for vesicoureteral reflux than brothers (p <0.01). Boys in group 1 had a significantly higher grade of vesicoureteral reflux than boys in group 3, and girls in groups 3 and 2 (p = 0.018, <0.001 and <0.0001, respectively). Severe renal scarring was present in 7% of boys in group 1, 6.6% of boys in group 3, 1.3% of girls in group 3 and 1.9% of girls in group 2. Duplex kidneys were present in 15.3% of boys in group 1 but only in 2.3% of boys in group 3 (p <0.01), 5.7% of girls in group 3 and 5.8% of girls in group 2. Age at diagnosis was not significantly different among boys in groups 1 and 3, and girls in group 2 (median 0.9, 0.6 and 1.9 years, respectively). CONCLUSIONS: The risk and severity of vesicoureteral reflux in siblings depends on the sex of the affected child. Brothers of index male patients have higher grade of reflux and higher rate of associated duplex systems. This has implications for genetic counseling and for modeling the inheritance of vesicoureteral reflux.

Renal scarring in familial vesicoureteral reflux: is prevention possible?

PURPOSE: Detailed knowledge about risk factors for renal scarring in familial reflux is necessary to decide whether these factors could be influenced by early screening and treatment of siblings. We evaluated the prevalence of and risk factors influencing renal scarring in familial vesicoureteral reflux. MATERIALS AND METHODS: We reviewed the medical records and dimercapto-succinic acid scans of 306 children with familial vesicoureteral reflux. Scarring was classified as mild, moderate and severe. The impact of urinary tract infections, patient sex, reflux grade and age at diagnosis on renal scarring was evaluated. RESULTS: The prevalence of renal scarring was identical at 36% in 142 index patients and 74 siblings presenting with urinary tract infection but it was only 10% in 87 asymptomatic siblings (p <0.001) The difference between siblings with and without urinary tract infection was only statistically significant for mild scarring (23% vs 4.6%, p <0.001). It did not attain significance in those with moderate to severe scarring (13.5% vs 5.7%). Moderate to severe scarring was significantly more common in grade V than in grade IV refluxing units (43% vs 10%, p <0.0001) and in male than in female siblings (15.8% vs 3.4%, p = 0.012). Mild scarring was not significantly associated with reflux grade or patient sex. Children diagnosed before age 3 years showed significantly less scarring than patients diagnosed later (23% vs 41%, p <0.002). CONCLUSIONS: The development of mild renal scarring seems to mainly depend on urinary tract infections, while moderate and severe scarring are also associated with high grade reflux and male sex. Early detection and treatment may prevent further urinary tract infections as well as reflux related kidney damage.

Subureteral dextranomer/hyaluronic acid injection as first line treatment in the management of high grade vesicoureteral reflux.

PURPOSE: Endoscopic correction of vesicoureteral reflux has become an established alternative to long-term antibiotic prophylaxis and ureteral reimplantation. A number of tissue augmenting substances have been used for the endoscopic correction of vesicoureteral reflux. We prospectively evaluated the effectiveness of dextranomer/hyaluronic acid copolymer (Deflux) as first line treatment for high grade vesicoureteral reflux. MATERIALS AND METHODS: Between 2001 and 2004, 692 children with a median age of 2.1 years (3 months to 13.7 years) with high grade vesicoureteral reflux underwent endoscopic subureteral injection of Deflux soon after the diagnosis of vesicoureteral reflux was made on the initial voiding cystourethrogram. Vesicoureteral reflux was unilateral in 283 patients and bilateral in 409. Of the 1,101 ureters vesicoureteral reflux was grade II to V in 35 (3.2%), 580 (52.7%), 457 (41.5%) and 29 (2.6%), respectively. The procedure was performed on an outpatient basis. Followup ultrasound and voiding cystourethrogram were performed 3 months after the procedure, and renal and bladder ultrasound was done annually. RESULTS: Reflux resolved after first, second and third endoscopic Deflux injections in 952 (86.5%), 130 (11.8%) and 19 ureters (1.7%), respectively. Followup ultrasound revealed no evidence of delayed vesicoureteral junction obstruction. Of the patients 18 (2.6%) had urinary tract infection during followup after successful vesicoureteral reflux correction. CONCLUSIONS: Endoscopic subureteral injection of Deflux is excellent first line treatment in children with high grade vesicoureteral reflux. This 15-minute outpatient procedure is safe and simple to perform, and it can be easily repeated in failed cases.

Carbonic anhydrase II deficiency: a rare autosomal recessive disorder of osteopetrosis, renal tubular acidosis, and cerebral calcification.

The authors present a case of osteopetrosis due to carbonic anhydrase II deficiency. Clinical, laboratory and radiologic findings are reported. The genetics of osteopetrosis are reviewed.

Treatment of vesicoureteral reflux by endoscopic injection of dextranomer/hyaluronic Acid copolymer: preliminary results.

PURPOSE: Endoscopic subureteral injection of tissue augmenting substances has become an established alternative to long-term antibiotic prophylaxis and open surgery for the management of vesicoureteral reflux (VUR) in children. Recently, dextranomer/hyaluronic acid copolymer (Deflux, Q-Med AB, Uppsala, Sweden) a biodegradable injectable material has been reported to be a promising alternative to other tissue augmenting substances. However, the experience with dextranomer/hyaluronic acid copolymer is limited. We prospectively evaluate the effectiveness of dextranomer/hyaluronic acid copolymer in the endoscopic treatment of VUR. MATERIALS AND METHODS: A total of 32 males and 81 females with a median age of 1 year (range 3 months to 10 years) underwent endoscopic correction of primary VUR with dextranomer/hyaluronic acid copolymer. Reflux was unilateral in 58 cases and bilateral in 54, affecting 166 ureters. Reflux was grades II to V in 7 (4.2%) cases, 91 (54.8%), 63 (38%) and 5 (3%), respectively. All patients underwent endoscopic correction as a day procedure and have been followed for 3 months to 1 year. RESULTS: The reflux was corrected in 143 (86%) of the 166 ureters after a single injection, and resolved after a second and third injection in 22 (13%) and 1 (1%) ureter, respectively. No untoward effects were seen in any of these patients with the use of dextranomer/hyaluronic acid copolymer as an injectable material. CONCLUSIONS: Dextranomer/hyaluronic acid copolymer is an effective tissue augmenting substance in the endoscopic treatment of all grades of VUR.

Endoscopic treatment of vesicoureteral reflux: 11 to 17 years of followup.

PURPOSE: We review our 17-experience with endoscopic subureteral polytetrafluoroethylene injection for the treatment of primary vesicoureteral reflux in children. MATERIALS AND METHODS: We retrospectively reviewed the charts of 258 patients with primary vesicoureteral reflux who were treated with subureteral polytetrafluoroethylene injection from 1984 to 1990. RESULTS: The study included 205 girls and 53 boys between 3 months and 14 years old (median age 6 years). Of the patients 92 had unilateral vesicoureteral reflux, 129 had bilateral reflux and 37 had a refluxing duplex system including 6 with bilateral duplex systems. Endoscopic treatment by subureteral polytetrafluoroethylene injection was performed in 393 ureters. Reflux was corrected in 302 ureters (76.8%) after a single injection. Injection failed to stop reflux in 7 ureters (7 patients) and reimplantation was required. Patients were followed from 11 to 17 years with a mean followup plus or minus standard deviation of 13.5 +/- 3.4 years. Four patients were either lost to followup or parents refused to let them undergo voiding cystourethrography. Voiding cystourethrography in 247 patients with 379 ureters revealed that 360 ureters (95%) remain free of reflux whereas reflux recurred in 19 ureters (5%). Of these 19 ureters reflux was grade I or II in 13 for which no treatment was given and reflux was grade III or IV in 6, which required repeat injection. No untoward effects were seen in any of these patients with use of polytetrafluoroethylene as an injectable biomaterial. CONCLUSIONS: Endoscopic subureteral polytetrafluoroethylene injection is a simple and effective outpatient procedure for in the treatment of vesicoureteral reflux. No long-term morbidity was observed in our patients with small amounts of injectable polytetrafluoroethylene.

Interglacial pollen and plant macrofossils from Langdon River, western Tasmania.

Pollen and plant macrofossils from Langdon liner give an interglacial floral record for western Tasmania. The location of the site between the ice limits of the Last or Margaret Glaciation and the Penultimate or Henty Glaciation indicate that it cannot be younger than the Last Interglacial. The sequence of vegetation changes shows the succession Casuarina Phyllocladus-Nothofagus with Casuarina as pioneer and Nothofagus as representing Maximum wet forest development. After the maximum the presence of Phyllocladus-Nothofagus-Eucalyptus-Microstrobos suggests deterioration to subalpine woodland/shrubland, and Compositae, Gramineae-Microstrobos to alpine shrubland and herbland. The sequence represents most of a glacial-interglacial-glacial cycle Of environmental changes that occurred before 43 000 14 C yr B.P. Very high Casuarina values occur in the early part at the interglacial sequence which contrasts with the Holocene where Eucalyptus is more important than Casuarina. Otherwise the sequence of Phyllocladus, Nothofagus, Eucryphia-Anodopetalum is the same as for Holocene forest development. The interglaeial 'optimum' is marked by the occurrence of Pomaderris apetala type and Dicksonia antarctica. There is some similarity with the Casuarina curves in the Lake George interglacials before the Last Interglacial. But, on the whole, there is more similarity with interglacial rainforest development in western South Island, New Zealand Only one cycle of vegetation change is recognized at Langdon River which is unlike New Zealand and central Chilean records from 40-42° S which in different ways record a mid Last Interglacial climatic deterioration.