Publications by authors named "Göran Läckgren"

27 Publications

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Management of Vesicoureteral Reflux: What Have We Learned Over the Last 20 Years?

Front Pediatr 2021 31;9:650326. Epub 2021 Mar 31.

Pediatric Urology, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, United States.

Vesicoureteral reflux (VUR) is associated with increased risks of urinary tract infection, renal scarring and reflux nephropathy. We review advancements over the last two decades in our understanding and management of VUR. Over time, the condition may resolve spontaneously but it can persist for many years and bladder/bowel dysfunction is often involved. Some factors that increase the likelihood of persistence (e.g., high grade) also increase the risk of renal scarring. Voiding cystourethrography (VCUG) is generally considered the definitive method for diagnosing VUR, and helpful in determining the need for treatment. However, this procedure causes distress and radiation exposure. Therefore, strategies to reduce clinicians' reliance upon VCUG (e.g., after a VUR treatment procedure) have been developed. There are several options for managing patients with VUR. Observation is suitable only for patients at low risk of renal injury. Antibiotic prophylaxis can reduce the incidence of UTIs, but drawbacks such as antibiotic resistance and incomplete adherence mean that this option is not viable for long-term use. Long-term studies of endoscopic injection have helped us understand factors influencing use and the effectiveness of this procedure. Ureteral reimplantation is still performed commonly, and robot-assisted laparoscopic methods are gaining popularity. Over the last 20 years, there has been a shift toward more conservative management of VUR with an individualized, risk-based approach. For continued treatment improvement, better identification of children at risk of renal scarring, robust evidence regarding the available interventions, and an improved VUR grading system are needed.
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http://dx.doi.org/10.3389/fped.2021.650326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044769PMC
March 2021

Is Involved in Urinary Tract and Urorectal Development.

Front Cell Dev Biol 2020 7;8:567. Epub 2020 Aug 7.

Department of Medical Sciences, University of Torino, Turin, Italy.

Previous studies in developing and zebrafish reported that the phosphate transporter is expressed in pronephric kidneys. The recent identification of as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog . This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest is involved in urinary tract and urorectal development and implicate as a disease-gene for BEEC.
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http://dx.doi.org/10.3389/fcell.2020.00567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426641PMC
August 2020

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

J Pediatr Urol 2020 06 13;16(3):328.e1-328.e9. Epub 2020 Apr 13.

Section of Urology, University Children's Hospital, Uppsala, Sweden.

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.
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http://dx.doi.org/10.1016/j.jpurol.2020.04.008DOI Listing
June 2020

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

Ups J Med Sci 2018 Dec 8;123(4):216-224. Epub 2018 Oct 8.

e Department of Physiology and Pharmacology , Karolinska Institutet , Stockholm , Sweden.

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.
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http://dx.doi.org/10.1080/03009734.2018.1521890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327611PMC
December 2018

Standardization of pediatric uroradiological terms: A multidisciplinary European glossary.

J Pediatr Urol 2017 Dec 13;13(6):641-650. Epub 2017 Jul 13.

Pediatric Nephrology, Centro Hospitalar São João, Porto, Portugal.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Pediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication among different clinicians involved in pediatric urology and nephrology.
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http://dx.doi.org/10.1016/j.jpurol.2017.05.026DOI Listing
December 2017

Standardization of pediatric uroradiological terms: a multidisciplinary European glossary.

Pediatr Radiol 2018 02 15;48(2):291-303. Epub 2017 Nov 15.

Pediatric Nephrology, Centro Hospitalar São João, Porto, Portugal.

To promote the standardization of nephro-uroradiological terms used in children, the European Society of Paediatric Radiology uroradiology taskforce wrote a detailed glossary. This work has been subsequently submitted to European experts in pediatric urology and nephrology for discussion and acceptance to improve the quality of radiological reports and communication between different clinicians involved in pediatric urology and nephrology.
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http://dx.doi.org/10.1007/s00247-017-4006-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790858PMC
February 2018

Current trends in dextranomer hyaluronic acid copolymer (Deflux) injection technique for endoscopic treatment of vesicoureteral reflux.

Urology 2014 Aug 26;84(2):462-8. Epub 2014 Jun 26.

Section of Urology, University Children's Hospital, Uppsala, Sweden.

Objective: To determine the current preferred injection technique(s) for endoscopic management of pediatric vesicoureteral reflux (VUR). Since the approval of dextranomer hyaluronic acid copolymer (Dx/HA) in 2001, injection methods have evolved and now include the hydrodistention implantation technique (HIT) and double HIT as well as subureteral transurethral injection (STING) method.

Methods: In July 2012, 278 pediatric urologists in the United States were contacted to complete a 15-question survey regarding Dx/HA injection technique(s) currently used in their practice.

Results: Fifty board-certified pediatric urologists completed the survey for a response rate of 18%. Most respondents (60%) were in a single-specialty group practice, and 12% were affiliated with an academic- or university-based practice. Respondents reported seeing a mean of 159 pediatric patients (range, 40-400 patients) with VUR annually, and 94% used Dx/HA ≥4 times in the past year. Forty-seven respondents (94%) reported using double HIT over the course of their career compared with 36 (72%) for STING and 30 (60%) for HIT (P <.05). Double HIT gained widespread acceptance between 2007 and 2008, paralleled by a decline in use of other injection techniques. A significantly higher percentage currently perform double HIT (92%) compared with either STING (24%) or HIT (34%; P <.001). Respondents reported the use of double HIT 15 times more often than STING technique and 5 times more often than HIT during the past 12 months (P <.001).

Conclusion: The double HIT method is currently the most commonly performed technique for endoscopic correction of VUR by pediatric urologists in the United States.
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http://dx.doi.org/10.1016/j.urology.2014.04.032DOI Listing
August 2014

Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder.

Hum Mol Genet 2014 Oct 22;23(20):5536-44. Epub 2014 May 22.

Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.

Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our discovery sample identified a marker near SALL1, showing genome-wide significant association with CBE. However, analyses performed on follow-up samples did not add further support to these findings. We were also able to identify an association with CBE across our study samples (discovery: P = 8.88 × 10(-5); follow-up: P = 0.0025; combined: 1.09 × 10(-6)) in a highly conserved 32 kb intergenic region containing regulatory elements between WNT3 and WNT9B. Subsequent analyses in mice revealed expression for both genes in the genital region during stages relevant to the development of CBE in humans. Unfortunately, we were not able to replicate the suggestive signal for WNT3 and WNT9B in a sample that was enriched for non-CBE BEEC cases (P = 0.51). Our suggestive findings support the hypothesis that larger samples are warranted to identify association of common variation with CBE.
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http://dx.doi.org/10.1093/hmg/ddu259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168827PMC
October 2014

Classic bladder exstrophy: Frequent 22q11.21 duplications and definition of a 414 kb phenocritical region.

Birth Defects Res A Clin Mol Teratol 2014 Jun 25;100(6):512-7. Epub 2014 Apr 25.

Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

Background: Classic bladder exstrophy (CBE) is the most common form of the bladder exstrophy and epispadias complex. Previously, we and others have identified four patients with a duplication of 22q11.21 among a total of 96 unrelated CBE patients.

Methods: Here, we investigated whether this chromosomal aberration was commonly associated with CBE/bladder exstrophy and epispadias complex in an extended case-control sample. Multiplex ligation-dependent probe amplification and microarray-based analysis were used to identify 22q11.21 duplications in 244 unrelated bladder exstrophy and epispadias complex patients (including 217 CBE patients) and 665 healthy controls.

Results: New duplications of variable size were identified in four CBE patients and one control. Pooling of our previous and present data (eight duplications in 313 CBE patients) yielded a combined odds ratio of 31.86 (95% confidence interval, 4.24-1407.97). Array-based sequence capture and high-throughput targeted re-sequencing established that all breakpoints resided within the low-copy repeats 22A to 22D. Comparison of the eight duplications revealed a 414 kb phenocritical region harboring 12 validated RefSeq genes. Characterization of these 12 candidate genes through whole-mount in situ hybridization of mouse embryos at embryonic day 9.5 suggested that CRKL, THAP7, and LZTR1 are CBE candidate genes.

Conclusion: Our data suggest that duplication of 22q11.21 increases CBE risk and implicate a phenocritical region in disease formation.
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http://dx.doi.org/10.1002/bdra.23249DOI Listing
June 2014

A case with bladder exstrophy and unbalanced X chromosome rearrangement.

Eur J Pediatr Surg 2014 Aug 25;24(4):353-9. Epub 2013 Jun 25.

Department of Women's and Children's Health, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Introduction: Bladder exstrophy is a rare congenital malformation of the bladder and is believed to be a complex disorder with genetic and environmental background. We describe a young adult female with an isolated bladder exstrophy and with an X chromosome aberration. Patients and

Methods: Karyotyping identified an X chromosome rearrangement that was further characterized with array comparative genomic hybridization (CGH) and confirmed by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization (FISH) analysis.

Results: The identified X chromosome rearrangement in our index patient consists of a gain of chromosomal material in region Xq26.3- > qter and loss in region Xp22.12- > pter. This aberration was also carried by her mother and sister, none with bladder exstrophy. All three have a disproportionate short stature, as expected due to the deletion of one of the copies of the SHOX gene on Xp22.3. X-inactivation studies revealed a complete skewed inactivation pattern in carriers. Crossover events in the maternal germline furthermore resulted in different genetic material on the rearranged X chromosome between the index patient and her sister.

Conclusion: Our findings suggest an X-linked genetic risk factor for bladder exstrophy.
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http://dx.doi.org/10.1055/s-0033-1349056DOI Listing
August 2014

Surgery Illustrated - Surgical Atlas Endoscopic treatment of vesicoureteral reflux.

BJU Int 2010 May;105(9):1332-47

University Children's Hospital, Uppsala, Sweden.

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http://dx.doi.org/10.1111/j.1464-410X.2010.09325.xDOI Listing
May 2010

The Swedish reflux trial in children: II. Vesicoureteral reflux outcome.

J Urol 2010 Jul 20;184(1):280-5. Epub 2010 May 20.

Pediatric Uro-Nephrologic Center, Queen Silvia Children's Hospital, University of Gothenburg, Göteborg, Sweden.

Purpose: We compared reflux status in children with dilating vesicoureteral reflux treated in 3 groups, including low dose antibiotic prophylaxis, endoscopic therapy and a surveillance group on antibiotic treatment only for febrile urinary tract infection.

Materials And Methods: A total of 203 children 1 to younger than 2 years with grade III-IV reflux were recruited into this open, randomized, controlled trial. Endoscopic treatment was done with dextranomer/hyaluronic acid copolymer. The main end point was reflux status after 2 years. Data were analyzed by the intent to treat principle.

Results: Reflux status improved in all 3 treatment arms. Of patients in the prophylaxis, endoscopic and surveillance groups 39%, 71% and 47%, respectively, had reflux resolution or downgrading to grade I-II after 2 years. This was significantly more common in the endoscopic than in the prophylaxis and surveillance groups (p = 0.0002 and 0.0030, respectively). After 1 or 2 injections 86% of patients in the endoscopic group had no or grade I-II reflux but recurrent dilating reflux was seen in 20% after 2 years.

Conclusions: Endoscopic treatment resulted in dilating reflux resolution or downgrading in most treated children. After 2 years endoscopic treatment results were significantly better than the spontaneous resolution rate or downgrading in the prophylaxis and surveillance groups. However, of concern is the common reappearance of dilating reflux after 2 years.
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http://dx.doi.org/10.1016/j.juro.2010.01.059DOI Listing
July 2010

The Swedish reflux trial in children: I. Study design and study population characteristics.

J Urol 2010 Jul 15;184(1):274-9. Epub 2010 May 15.

Pediatric Uro-Nephrologic Center, Queen Silvia Children's Hospital, University of Gothenburg, Göteborg, Sweden.

Purpose: We compared the rates of febrile urinary tract infection, kidney damage and reflux resolution in children with vesicoureteral reflux treated in 3 ways, including antibiotic prophylaxis, endoscopic therapy and surveillance with antibiotics only for symptomatic urinary tract infection.

Materials And Methods: Children 1 to younger than 2 years with grade III-IV reflux were recruited into this prospective, open, randomized, controlled, multicenter study and followed for 2 years after randomization. The main study end points were recurrent febrile urinary tract infection, renal status on dimercapto-succinic acid scintigraphy and reflux status. Outcomes were analyzed by the intent to treat principle.

Results: During a 6-year period 128 girls and 75 boys entered the study. In 96% of cases reflux was detected after urinary tract infection. The randomization procedure was successful and resulted in 3 groups matched for relevant factors. Recruitment was slower than anticipated but after patients were entered adherence to the protocol was good. Of the children 93% were followed for the intended 2 years without a treatment arm change. All except 2 patients completed 2-year followup scintigraphy.

Conclusions: Recruitment was difficult but a substantial number of children were entered and randomly assigned to 3 groups with similar basic characteristics. Good adherence to the protocol made it possible to address the central study questions.
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http://dx.doi.org/10.1016/j.juro.2010.01.055DOI Listing
July 2010

Pharmacokinetics and pharmacodynamics of propiverine in children aged between 5 and 10 years with symptoms of overactive bladder.

Clin Pharmacokinet 2010 May;49(5):335-42

Department of Clinical Pharmacology, University of Greifswald, Greifswald, Germany.

Background And Objectives: Pharmacokinetic studies in children are particularly required for drugs with intensive hepatic and regioselective intestinal elimination and pharmacological effects that may be critical for absorption at therapeutic doses, such as a delay in intestinal transit. One example is the antimuscarinic drug propiverine, the pharmacokinetics of which were evaluated in the present study in children with symptoms of overactive bladder.

Methods: The pharmacokinetics of immediate-release propiverine were studied in a dose-escalating, parallel-group study (propiverine 5, 10 and 15 mg twice daily for 14 days) in 25 subjects (11 females and 14 males aged 5-10 years; bodyweight 17-44 kg; body mass index 14-21 kg/m2) with symptoms of overactive bladder during waking hours. Serum concentration-time curves of propiverine and its major metabolite propiverine N-oxide (M-5) were evaluated up to 3 hours and 8 hours after the first and last administration, respectively, using liquid chromatography with tandem mass spectrometry. The voiding frequency, number of incontinence and urgency episodes, single voided volume and urine flow variables were measured before and after treatment.

Results: Significant dose-related increases in the serum exposure (the area under the concentration-time curve, the maximum concentration and the minimum concentration) with propiverine and M-5 in the dose groups < or =0.3 mg/kg and 0.3 to < or =0.45 mg/kg after both single-dose and repeated-dose administration were found. The elimination half-lives of propiverine and M-5 at steady state were no different (mean +/- SD 12.2 +/- 11.2 and 14.5 +/- 9.94 hours, respectively). Higher doses did not result in additional dose-proportional increases in the respective pharmacokinetic parameters, particularly not after repeated-dose treatment. The voiding frequency, voided volume and urge symptoms were beneficially changed from baseline; significant dose-dependent changes were not observed. Most of the adverse events that were probably or possibly drug related were reported for patients in the high-dose group (>0.45 mg/kg).

Conclusions: The disposition of propiverine is dose related after repeated administration of the recommended doses below 0.45 mg/kg (0.3-0.45 mg/kg) twice daily in children aged 5-10 years with symptoms of overactive bladder and urinary incontinence. (

Trial Registration Numbers: [clinicaltrials.gov] NCT00795925; [EudraCT] 2004-001243-30).
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http://dx.doi.org/10.2165/11319990-000000000-00000DOI Listing
May 2010

22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment.

Eur J Med Genet 2010 Mar-Apr;53(2):61-5. Epub 2010 Jan 4.

Department of Woman and Child Health, Karolinska Institutet, Stockholm, Sweden.

Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.
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http://dx.doi.org/10.1016/j.ejmg.2009.11.004DOI Listing
July 2010

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

Ther Adv Urol 2009 Aug;1(3):131-41

Section of Urology, Uppsala University Children's Hospital, S-751 85 Sweden.

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.
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http://dx.doi.org/10.1177/1756287209342731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126056PMC
August 2009

Endoscopic treatment of vesicoureteral reflux: Current status.

Authors:
Göran Läckgren

Indian J Urol 2009 Jan;25(1):34-9

Section of Urology, University Children's Hospital, Uppsala, Sweden.

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. Endoscopic treatment with NASHA/Dx gel (dextranomer microspheres in a stabilized hyaluronic acid-based gel of nonanimal origin) is minimally invasive, well tolerated and provides cure rates approaching those of open surgery: approximately 90% in several studies. It has also been shown to be effective in a variety of 'complicated' cases. Endoscopic treatment is therefore considered preferable to open surgery and long-term antibiotic prophylaxis. Nontreatment of VUR is being discussed as an alternative option, whereby children are treated with antibiotics only when UTIs occur. Considering all the available evidence, however, active intervention with endoscopic treatment remains preferable. A new approach to managing VUR may nevertheless be considered, with treatment decisions based not only on the grade of reflux, but also factors such as age, sex, renal scarring, and bladder dysfunction. Open surgery would be reserved for use only in the ( approximately )10% of children not responding to endoscopic treatment, and patients with refluxing primary megaureter.
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http://dx.doi.org/10.4103/0970-1591.45534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684303PMC
January 2009

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

J Pediatr Urol 2007 Apr 1;3(2):80-5. Epub 2006 Nov 1.

Section of Urology, University Children's Hospital, S-751 85 Uppsala, Sweden.

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.
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http://dx.doi.org/10.1016/j.jpurol.2006.08.001DOI Listing
April 2007

Dear colleagues and friends!

J Pediatr Urol 2005 Jun 1;1(3):107. Epub 2005 Apr 1.

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http://dx.doi.org/10.1016/j.jpurol.2005.03.005DOI Listing
June 2005

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

J Urol 2007 Mar;177(3):1124-8; discussion 1128-9

Section of Urology, University Children's Hospital, Uppsala, Sweden.

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.
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http://dx.doi.org/10.1016/j.juro.2006.10.094DOI Listing
March 2007

The congenital pouch colon can be used for vaginal reconstruction by longitudinal splitting.

J Pediatr Surg 2006 Feb;41(2):e25-8

Department of Paediatric Surgery, University Children's Hospital, SE-751 85 Uppsala, Sweden.

Congenital pouch colon (CPC) is a rare malformation in which the distal part of a shortened colon forms a dilated pouch. It is associated with an anorectal malformation. We report 2 patients with CPC, one with a cloaca and one with vestibular fistula and vaginal atresia. It is the first description of CPC, vestibular fistula, and vaginal atresia. The purpose of this report was to demonstrate that the pouch can be split longitudinally--in analogy with Bianchi's intestinal lengthening procedure [Bianchi A. Intestinal loop lengthening: a technique for increasing small intestinal length. J Pediatr Surg 1980;15:145-51]--to create a vagina and to reconstruct the anorectum with preserved blood supply.
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http://dx.doi.org/10.1016/j.jpedsurg.2005.11.045DOI Listing
February 2006

Molecular genetic analysis of a de novo balanced translocation t(6;17)(p21.31;q11.2) associated with hypospadias and anorectal malformation.

Hum Genet 2006 Mar 3;119(1-2):162-8. Epub 2006 Jan 3.

Department of genetics and pathology, Section of Clinical Genetics The Rudbeck laboratory, Uppsala University, 751 85 Uppsala, Sweden.

We report a young boy with penoscrotal hypospadias, anal atresia (AA) with a recto-urethral fistula, a hypoplastic kidney and a balanced translocation t(6;17)(p21.31;q11.2). Physical mapping of the breakpoints localized the chromosome 6 breakpoint within an intron of the gene lipoma HMGIC fusion partner-like 5 (LHFPL5) whereas the chromosome 17 breakpoint was mapped to the first intron of the 182-FIP gene encoding the Fragile X Mental Retardation Protein Interacting Protein. Sequence analysis across the breakpoints revealed an almost perfectly balanced translocation with a 2 bp deletion on the derivative chromosome 6 and a 7 bp duplication on the derivative chromosome 17. We identified a fusion transcript consisting of the first exon of 182-FIP and the last exon of LHFPL5 in patient-derived cells. Quantitative expression analysis of the genes flanking the breakpoints, revealed increased transcript levels for SFRS protein kinase 1 (SRPK1) and TAO kinase 1 (TAOK1) which suggests a positional effect due to the translocation. We hypothesize that the urogenital and anorectal malformations in the patient result from one or several mechanisms including disruption of the genes 182-FIP and LHFPL5, altered expression of the genes flanking the translocation breakpoints and, a gain of function mechanism mediated by the 182-FIP-LHFPL5 fusion transcript.
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http://dx.doi.org/10.1007/s00439-005-0122-9DOI Listing
March 2006

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

J Urol 2003 Oct;170(4 Pt 2):1551-5; discussion 1555

Section of Urology, University Children's Hospital, Uppsala, Sweden.

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.
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http://dx.doi.org/10.1097/01.ju.0000084672.98131.f7DOI Listing
October 2003

The cost-effectiveness of endoscopic injection of dextranomer/hyaluronic acid copolymer for vesicoureteral reflux.

J Urol 2003 Apr;169(4):1480-4; discdussion 1484-5

HDI France, Spéracèdes, France.

Purpose: Vesicoureteral reflux is a risk factor for progressive renal damage associated with urinary tract infection. Mild to moderate reflux is routinely treated with long-term antibiotic prophylaxis to prevent recurrent infections and open surgical reimplantation for breakthrough infections despite antibiotic therapy. Endoscopic subureteral injection of implant material is a therapeutic alternative to long-term prophylaxis and open surgery but its widespread use in the United States has been prevented by the lack of a stable implant material. Dextranomer/hyaluronic acid copolymer has been shown to be a safe, effective and durable implant material and was recently approved in the United States. We estimate the effect on costs and cure rates of introducing endoscopic injection with dextranomer/hyaluronic acid copolymer as a treatment alternative in the United States.

Materials And Methods: We constructed a model that mimics current clinical practice of vesicoureteral reflux treatment for 6 years, and incorporates spontaneous resolution and surgical intervention rates obtained from 2 long-term followup studies. The treatment algorithm was established using medical data from the literature, and clinical management practices from a Delphi survey of 27 pediatric urologists and nephrologists across the United States. Endoscopic injection was introduced into the model as replacement to surgery or alternative to long-term antibiotic prophylaxis. The effectiveness of dextranomer/hyaluronic acid copolymer was calculated from 140 patients (208 ureters) with grade III reflux treated in a clinical study of 221 children in Sweden.

Results: With current practice, the average cost per patient in 6 years was 6,640 US dollars and 23.5% of patients continued to have reflux. Replacing open surgery with endoscopic injection led to similar cure rates (22.2% failures) but costs were reduced to 5,522 US dollars. When injection was performed after 1 year of antibiotic therapy failure rates were reduced to 8.5% but costs increased to 7,644 US dollars.

Conclusions: Our results show that a persistent approach to endoscopic surgery can be expected to result in overall success that equals or exceeds open surgery at a lower cost. This finding is particularly true if open reimplant is reserved for patients with high grade or persistent vesicoureteral reflux.
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http://dx.doi.org/10.1097/01.ju.0000056638.75652.54DOI Listing
April 2003

Complex segregation analysis of hypospadias.

Hum Genet 2002 Sep 10;111(3):231-4. Epub 2002 Aug 10.

Department of Molecular Medicine, Karolinska Institutet, Karolinska Hospital CMM:02, SE-171 76 Stockholm, Sweden.

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.
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http://dx.doi.org/10.1007/s00439-002-0799-yDOI Listing
September 2002

Vesicoureteral reflux: a new treatment algorithm.

Curr Urol Rep 2002 Apr;3(2):107-14

Section of Urology, University Children's Hospital, S-75185 Uppsala, Sweden.

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.
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http://dx.doi.org/10.1007/s11934-002-0020-9DOI Listing
April 2002

Heredity of hypospadias and the significance of low birth weight.

J Urol 2002 Mar;167(3):1423-7

Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Purpose: We analyzed a large group of patients with hypospadias regarding familial aggregation, phenotype, twin rate and ethnic origin and assessed the correlation of low birth weight with hypospadias.

Materials And Methods: We mailed questionnaires to 2,503 boys operated on for hypospadias in Sweden asking for additional cases of hypospadias in the family, the number of brothers in the nuclear family, and birth weight of the boys with hypospadias and their brothers.

Results: Of the boys 7% reported 1 or more additional family members with hypospadias. The birth weight of the boys with hypospadias was significantly lower (p = 5 x 10-13) than the birth weight of their unaffected brothers. Phenotyping of 676 individuals revealed glandular hypospadias in 53%, penile forms in 39%, penoscrotal or perineal variants in 6% and cleaved prepuce as the only manifestation in 2%. There were 50% more twins than expected compared to the general population and established zygosity in 83% (67% monozygotic, 33% dizygotic). Non-Swedish ethnicity was noted in 22% of the subjects, a third of whom were from Middle Eastern countries.

Conclusions: We present data on heredity, birth weight, phenotype and ethnic origin in a large group of patients with hypospadias. The finding of additional members with hypospadias in 7% of the families supports the concept that genetic factors are involved in the pathogenesis. The strong association with low birth weight may be explained by genetic and environmental factors.
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March 2002