Göran Läckgren

LONG-TERM FOLLOWUP OF CHILDREN TREATED WITH DEXTRANOMER/HYALURONIC ACID COPOLYMER FOR VESICOURETERAL REFLUX

PURPOSE Dextranomer/hyaluronic acid copolymer is a novel substance that has favorable properties for endoscopic treatment of vesicoureteral reflux. We assess the long-term efficacy and safety of this treatment of children. MATERIALS AND METHODS Children 1 to 15 years old with grade III or greater vesicoureteral reflux were eligible for enrollment in our study. All patients received endoscopic treatment with dextranomer/hyaluronic acid copolymer and were scheduled to have a voiding cystourethrogram 3 and 12 months after implantation. Children with reflux grade III or greater after treatment received up to 2 more implantations, and those with persistent reflux were referred for open surgery. In some cases long-term clinical followup was accompanied by a late voiding cystourethrogram. RESULTS A total of 228 patients received endoscopic treatment. The efficacy population was comprised of 221 children, including 67 who received 2 and 8 who received 3 implantations. Endoscopic treatment was performed without complications in all cases. Patients were followed clinically for 2 to 7.5 years (mean 5). On the last voiding cystourethrogram 68% of patients had a positive response (grade I or less) and 81% had no dilating reflux. The corresponding results for treated ureters were 75% and 85%, respectively. Only 27 (12%) patients were referred for open surgery. A late voiding cystourethrogram was performed in 49 patients 2 to 5 years after treatment. Of the ureters free of reflux (grade 0) 3 to 12 months after treatment 96% remained free of dilating reflux. Adverse events occurred in association with implantation in only 2% of patients, although urinary tract infection subsequently developed in 8%. CONCLUSIONS Endoscopic treatment with dextranomer/hyaluronic acid copolymer was effective and well tolerated in children with vesicoureteral reflux. Long-term followup indicated that there was no deterioration in patients responding positively to treatment.

A New Bioimplant for the Endoscopic Treatment of Vesicoureteral Reflux: Experimental and Short-term Clinical Results

We investigated the safety and clinical effects of a new biocompatible, biodegradable treatment, the Deflux system (dextranomer microspheres in sodium hyaluronan solution), for the endoscopic treatment of grades III and IV vesicoureteral reflux. In preclinical safety studies in pigs histopathological examination demonstrated excellent tolerance. Two weeks after submucous implantation in the pig bladder early ingrowth of fibroblasts and recently generated collagen were noted at the implantation sites. At 14 weeks of followup this ingrowth had slightly increased. Long-term followup in rats showed that the volume of subcutaneous implants was slightly reduced (23%) 1 year after implantation. In a clinical study we investigated the implantation technique and the short (3 months) and long-term (1 year) effects of Deflux implantation in 75 children (101 ureters) with grades III and IV vesicoureteral reflux. We report data from up to 3 months of followup. Implant volumes of 0.4 to 1.0 ml. were sufficient to create distinct boluses and crescent-like ureteral orifices. Although viscous, due to its viscoelastic properties the substance was easy to inject in a well controlled manner. At cystography 3 months later reflux had resolved in 68% of implants, was reduced to grades I and II in 13% of implants and was unchanged in 19% of treated ureters (grades III and IV reflux). No signs of ureteral obstruction or adverse reactions were noted. Results from 1 year of followup will be reported later. Our results indicate that the dextranomer microspheres act as micro-carriers that promote ingrowth of fibroblasts and generate new collagen. We conclude that the Deflux system may represent a new, safe, simple alternative to endoscopic treatment of vesicoureteral reflux in children.

Enuresis - Background and Treatment

Nocturnal urinary continence is dependent on 3 factors: 1) nocturnal urine production, 2) nocturnal bladder function and 3) sleep and arousal mechanisms. Any child will suffer from nocturnal enuresis if more urine is produced than can be contained in the bladder or if the detrusor is hyperactive, provided that he or she is not awakened by the imminent bladder contraction. Urine production is regulated by fluid intake and several interrelated renal, hormonal and neural factors, foremost of which are vasopressin, renin, angiotensin and the sympathetic nervous system. Detrusor function is governed by the autonomic nervous system which under ideal conditions is under central nervous control. Arousal from sleep is dependent on the reticular activating system, a diffuse neural network that translates sensory input into arousal stimuli via brain stem noradrenergic neurons. Disturbances in nocturnal urine production, bladder function and arousal mechanisms have all been firmly implicated as pathogenetic factors in nocturnal enuresis. The group of enuretic children are, however, pathogenetically heterogeneous, and two main types can be discerned: 1) Diuresis-dependent enuresis - these children void because of excessive nocturnal urine production and impaired arousal mechanisms. 2) Detrusor-dependent enuresis - these children void because of nocturnal detrusor hyperactivity and impaired arousal mechanisms. The main clinical difference between the two groups is that desmopressin is usually effective in the former but not in the latter. There are two first-line therapies in nocturnal enuresis: the enuresis alarm and desmopressin medication. Promising second-line treatments include anticholinergic drugs, urotherapy and treatment of occult constipation.

HEREDITY OF HYPOSPADIAS AND THE SIGNIFICANCE OF LOW BIRTH WEIGHT

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.

Injectable Dextranomer-based implant : histopathology, volume changes and DNA-analysis

OBJECTIVE To study the tissue reaction in and around the implant, the changes in implant volume and the DNA profile of the invading cells when a new substance, dextranomers in sodium hyaluronan solution (DiHA), was injected into experimental animals. MATERIALS AND METHODS Nine pigs were followed up from 2 weeks to 3.5 months and 34 rats were followed up from 3 weeks to 16 months after injection of DiHA into the bladder in pigs and into the subcutaneous tissue in rats. Histopathological analysis was performed in 16 pig and 63 rat implants. In 31 of the rat implants the DNA profile was analysed. Changes in implant volume over time were estimated in 51 rat implants during the period up to 12 months after implantation. RESULTS Histologically, in the early phases the area within and around the implant was fairly rich in cells, predominantly fibroblasts, inflammatory cells and giant cells of the foreign body type. Later in the process an increase in extracellular matrix around the microspheres and ingrowth of blood vessels was seen. No tissue necrosis or significant eosinophilia was observed around the implants. DNA measurements by flow cytometry revealed no aneuploid cells. There was a decrease in implant volume by 23% over a period of 12 months. CONCLUSIONS DiHA does not induce any major tissue changes in and around the implants. No DNA changes were observed during the study period of 16 months. DiHA seem to be a safe and suitable injectable substance with good tissue-augmenting properties.

The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q.

Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.

The Swedish Reflux Trial in Children: II. Vesicoureteral Reflux Outcome

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.

Occurrence of Testicular Cancer in Patients Operated on for Cryptorchidism and Inguinal Hernia

We studied the incidence of testicular cancer in 2 population-based cohorts comprising 2,918 men who underwent an operation for a cryptorchid testis and 30,199 who underwent surgery for an inguinal hernia. Complete followup during the 19-year period was achieved by record linkage to the National Swedish Cancer Registry. In the cryptorchidism cohort 4 cases of testicular cancer occurred versus 0.54 expected, yielding a relative risk of 7.4 (95% confidence interval 2.0 to 19.0). Of these patients 3 had undergone a bilateral operation due to intra-abdominal testes. There was no evidence of an association between inguinal hernia and risk of testicular cancer (relative risk = 1.1, 95% confidence interval 0.4 to 2.2). The validity of our data was further supported by relative risk estimates close to unity in a comparison group of appendectomy patients. We conclude that patients with a cryptorchid testis experience a substantially increased relative risk of testicular cancer. However, the low absolute risk, 4 cases during 25,360 person-years of observation, does not appear to justify special surveillance after an operation for an undescended testis.

Endoscopic treatment of children with vesico-ureteric reflux

Endoscopic subureteric injection of tissue‐augmenting substances has become an alternative to long‐term antibiotic prophylaxis and open surgery in the treatment of children with vesico‐ureteric reflux. Successful elimination of reflux in about 80% of patients after a single injection (and in 90% after a repeat) has been achieved using the foreign‐body non‐degradable substances Teflon and silicone. Few patients have required open surgery and recurrence of reflux after initial successful treatment has occurred in only 5‐10%. Concern has arisen, however, about possible distant migration and granuloma formation after injection of particulate plastic materials. Cross‐linked bovine collagen is a biodegradable alternative substance, but with a lower response rate of 60% after the first treatment and a recurrence rate of 10‐20%. Dextranomer in sodium hyaluronan is a new biological substance with microparticles with a response rate of 69% after the first injection. Biological substances have caused few complications. Present literature on injection treatment unfortunately focuses on elimination of reflux, with little attention to subsequent frequency of pyelonephritis or to the long‐term development of the kidneys. Furthermore, there are no controlled, randomized studies with subureteric injection as one of the treatment alternatives. Thus, although having the advantage of being a minimally invasive procedure that can be performed on an outpatient basis, this technique needs to be tested in a large prospective study with the long‐term renal outcome as the main end‐point.

Renal Tubular Apoptosis after Partial Ureteral Obstruction

Partial ureteral obstruction in the weanling rat leads to hydronephrosis of the ipsilateral kidney and renal cell deletion through the process of programmed cell death known as apoptosis. The apoptotic response following partial ureteral obstruction in weanling Sprague-Dawley rats was studied using the traditional markers of apoptosis, including deoxyribonucleic acid (DNA) laddering pattern on agarose gel electrophoresis, in situ gap labeling of fragmented DNA for quantitative apoptotic body determination, polyadenylated messenger ribonucleic acid (mRNA) expression of sulfated glycoprotein-2, and polyadenylated mRNA expression of epidermal growth factor and transforming growth factor-beta. Partial ureteral obstruction resulted in a progressive increase in the intensity of DNA fragmentation associated with apoptosis during the initial 3 weeks. Quantitative apoptotic body counting revealed a 3-fold increase by week 3 of partial obstruction. This increase represented a level of apoptosis, which is 65% of that observed in complete ureteral obstruction. By week 2 of partial obstruction there was a 13-fold increase in the expression of sulfated glycoprotein-2 mRNA, as well as changes in the growth factor environment characterized by a decline in the constitutive expression of epidermal growth factor mRNA and an increase in the expression of transforming growth factor-beta mRNA. These altered levels represent changes in expression comparable to those observed during the apoptotic response following complete ureteral obstruction, although the time course is delayed by 2 to 3 weeks.