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Congenital lower urinary tract obstruction is associated with oligohydramnios and significant perinatal mortality and long-term chronic kidney disease. The counseling of families facing this diagnosis, especially when prenatal intervention is proposed, is fraught with ambiguity. This review aims to equip the provider with the current evidence behind the conventional and novel biomarkers predictive of chronic kidney disease. The relevant clinical predictors are categorized by when they are identified, antenatally or postnatally, and as either anatomic or chemical. They are considered for their prognostic value and the challenges in obtaining them, specifically the risk to the fetus in the case of prenatal biomarkers. Serum creatinine in infancy is the traditional chemical biomarker of kidney function and continues to be a consistent predictor of future serum creatinine. β-2 microglobulin may provide earlier information regarding fetal glomerular and tubular function and is also predictive of long-term serum creatinine. Renal parenchymal area is an anatomic surrogate of nephron mass that is used in both prenatal and postnatal settings. Understanding the anatomic and chemical biomarkers is essential for future refinement of the staging algorithm used to distinguish which patients may benefit from early in utero intervention.

We reviewed data from a cohort of fetuses with ureterocele diagnosed and operated prenatally in four fetal therapy centers. Inclusion criteria were (1) ureterocele confirmed on detailed fetal ultrasound examination, (2) absence of additional fetal malformations, and (3) fetal intervention to decompress the ureterocele with local institutional review boards' approval. Data on sonographic follow-up, obstetrical, neonatal outcome, and postnatal evaluation were collected. Ten cases of prenatally treated ureterocele are described. Six cases benefited from a fetoscopy for laser incision and decompression, two cases had an ultrasound guided puncture before resorting to a fetoscopy with laser incision, one case had a balloon catheterization under ultrasound guidance, and one case had an ultrasound-guided opening of the ureterocele with a laser fiber passed through a 20-gauge needle. Mean gestational age at diagnosis was 21.6 GW. Two cases underwent termination of pregnancy. The remaining eight cases recovered normal amniotic fluid volume and delivered a liveborn child at a mean gestational age of 38.6 GW with normal creatinine levels during the first week of life. Prenatal incision provided complete treatment of severely obstructive ureteroceles in 80% of the cases and allowed improvement of urinary electrolytes, renal size and echogenicity, bladder filling in all survivors, and recollection of normal amniotic fluid volume, in case of oligoanhydramnios. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Fetal bladder outlet obstruction (BOO), most commonly caused by posterior urethral valves (PUV), remains a challenging and multi-faceted condition. Evolving techniques, and refinement in ultrasound, optics and instrumentation, have increased our rate of prenatal diagnosis, and enabled valve ablation not only in smaller newborns, but also in fetuses. Long-term outcome studies have raised our awareness of the silent damage caused by bladder dysfunction and polyuria and encouraged their proactive management. In spite of our best efforts, the proportion of boys with PUV who progress to chronic and end-stage renal disease (ESRD) has not changed in the last 25 years. Evidence suggests a reduction in perinatal mortality following prenatal intervention, probably resulting from amelioration of oligohydramnios at the crucial time of lung development between 16 and 28 weeks' gestation, but no improvement in postnatal renal outcome. There are no bladder functional outcome studies in patients who have undergone prenatal intervention and hence the long-term effect of in utero defunctionalisation of the bladder is not known. This aim of this review is to revisit the embryopathology of fetal BOO, in particular the renal and bladder structural and functional changes that occur with in utero obstruction. The effect of earlier prenatal diagnosis, and therapy, on postnatal outcome is also explored and compared with outcomes published for traditional postnatal treatment., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Purpose: We outline the development of a reliable model of obstructive uropathy in fetal lambs highlighting our understanding of the critical time points for interventions and the variability of any such model. We identify some discoveries that may have clinical implications., Methods: The model requires 60-day-gestation fetal lambs. In lambs, glomerulogenesis is complete by 90 days gestation. (Term is 145 days.) The ability to develop a reliable method of creating bladder outlet obstruction in females, ligating both the urethra and urachus was critical. The lambs are bred to an accuracy of ±24 h., Results: Creating the model at 50-60 days gestation, produces different expressions of renal dysplasia in groups of lambs undergoing identical interventions at the same stage of gestation. Early complete urethral obstruction can produce the Potter phenotype. An appropriately timed vesico-amniotic shunt preserves renal development, producing a shrunken, non-compliant bladder. Shunting the normal fetal bladder at 80 days gestation produces a similar bladder. Provision of a low-pressure valve in the shunt preserves bladder development and compliance. Using a high-pressure shunt produces results similar to non-shunted lambs., Discussion: We developed a reliable animal model for obstructive uropathy. Being alert to peripheral results can lead to new findings.

Purpose: The purpose of this manuscript was to examine the outcomes of patients with lower urinary tract obstruction (LUTO) treated with vesicoamniotic shunt (VAS) to improve the quality of prenatal consultation and therapy., Methods: The medical records of all patients diagnosed with LUTO at our center between January 2004 and March 2012 were reviewed retrospectively., Results: Of 14 male fetuses with LUTO, all with characteristic ultrasound findings, 11 underwent intervention. One patient received vesicocentesis alone, while 10 had VAS. Two fetuses additionally underwent cystoscopy (one with attempted valve ablation), and two had peritoneoamniotic shunts. Of 16 total VAS, 13 were placed successfully, 8 dislodged (median 7 days), and 1 obstructed (84 days). Two fetuses suffered in utero demise, and two have unknown outcomes. LUTO was confirmed in six of eight live-born fetuses. One patient died in the neonatal period, while seven survived. All six available at follow-up (median 3.7 years), had significant genitourinary morbidity. Five patients had chronic kidney disease, but only one has required dialysis and transplant. Three had respiratory insufficiency, and one required a tracheostomy., Conclusion: Despite significant perinatal and long-term morbidity, VAS offers patients faced with a poor prognosis an improved chance of survival. Our results underscore the need for further research into the diagnosis and treatment of LUTO., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: A valved ventriculo-peritoneal shunt (V-P shunt) as a vesico-amniotic shunt (V-A shunt) preserves the filling/emptying cycle and normal bladder development in fetal lambs with bladder outlet obstruction. The optimal pressure for such shunts is unknown., Materials and Methods: We created obstructive uropathy in 60-day gestation fetal lambs. A V-A shunt was placed 3 weeks later, using a low-pressure (Group L: 15-54 mmH2O) or a high-pressure (Group H: 95-150 mmH2O) V-P shunt. We included non-shunted (obstructive uropathy, Group O) and control lambs (Group C). All were delivered at 130 days. Bladder volumes, bladder thickness, renal and bladder histology were compared., Results: Seventeen lambs had an obstructive uropathy created. Five Group L (four survived), four Group H (three survived) and five Group O survived. Body weight and crown-to-rump lengths of the three groups were not significantly different. Group H lambs had a dilated urachus, urinary ascites and severe ureteral dilatation similar to Group O lambs. There were four Group C lambs. Bladder volume was 10, 15 and 1,150 ml in Group H, 115 ± 67.9 ml in Group L, 128 ± 99.8 ml in Group O and 24.5 ± 3.84 ml in Group C. Unlike Group O lambs, Group L did not have urinary ascites, urinomas or renal dysplasia., Conclusion: Low-pressure shunts preserved both bladder volume and renal development. High-pressure shunts did neither.

Background: Lower urinary tract obstruction causes both renal failure and bladder dysfunction after birth. This study examined the early bladder wall changes after creating an obstructive uropathy focusing on bladder wall thickness and muscle integrity., Methods: We created obstructive uropathy in fetal lambs at 60 days' gestation, ligating the urethra and urachus. The fetuses (n = 28) were delivered at 48 hours and 3, 4, 5, 7, and 14 days after obstruction and at term (145 days' gestation). Sham-operated lambs were used as controls (n = 20). Histology samples were stained using α-smooth muscle actin) immunohistochemistry and also hematoxylin-eosin, Masson trichrome, and colloidal Fe stain., Results: The bladder wall initially expanded and stretched. By day 4, the bladder wall became thicker. Histologically, the bladder in obstructed lambs demonstrated a prominent submucosal fibrotic change by 7 days. The mean bladder wall thickness at 14 days after obstruction was thicker than controls, and fibrosis was prominent., Conclusion: The initial changes in the bladder wall were expansion of the muscle component followed by fibrosis. The bladder wall thickness dramatically increased 4 to 7 days after obstruction. We conclude that shunting operations to preserve bladder function may be needed earlier than expected., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Bladder outlet obstruction can have devastating consequences. Given the poor outcome, intervention in utero has been advocated in an attempt to salvage pulmonary and renal function. We evaluated whether laparoscopic decompression of the obstructed bladder could be performed efficiently by adapting current robot assisted laparoscopic techniques to access the fetus in utero., Materials and Methods: At 95 days of gestation 20 fetal sheep underwent ligation of the urethra and urachus. Two to 5 days later robot assisted laparoscopic vesicostomy was performed. Ultrasound of the kidneys and bladder was performed before each procedure. At 135 days of gestation the urinary tract was evaluated to assess the adequacy of bladder decompression and a patent vesicostomy., Results: After 48 hours of undergoing ligation all fetuses had bilateral moderate hydronephrosis and a markedly distended bladder. In the first 10 fetuses vesicostomy could not be completed laparoscopically due to limited visualization. Additional modifications in trocar placement and gas infusion allowed vesicostomy to be completed laparoscopically in the last 8 fetuses in 2.5 to 4 hours. Urinary tract decompression and a patent vesicostomy were observed in all of these fetuses postoperatively., Conclusions: We developed specific modifications in current robot assisted laparoscopic techniques and instrumentation to allow the treatment of bladder outlet obstruction in utero. This procedure may be performed efficiently and it may provide advantages over conventional surgery for fetal intervention.

Purpose: The evaluation of renal function in fetuses with lower urinary tract obstruction by analysis of electrolytes and beta2-microglobulin in fetal urine has limitations. We measured fetal serum beta2-microglobulin before and after bladder shunting to evaluate renal function., Materials and Methods: A total of 12 fetuses with lower urinary tract obstruction underwent vesicoamniotic shunting. In addition to the standard evaluation of urinary electrolytes and beta2-microglobulin, fetal renal status was assessed by pre-shunt and post-shunt fetal serum beta2-microglobulin., Results: At 2 to 4 weeks after shunting 2 of the 12 fetuses had persistent oligohydramnios, demonstrated increased values of serum beta2-microglobulin and were confirmed to have renal dysplasia. In the remaining 10 fetuses there was reaccumulation of amniotic fluid for a minimum of 4 weeks after shunting. Serum beta2-microglobulin values increased after shunting in 4 fetuses, all of which developed renal failure, whereas serum beta2-microglobulin did not change or was decreased after shunting in 6, of which 4 had normal renal function at latest followup., Conclusions: Urinary electrolytes, urinary beta2-microglobulin and pre-shunt serum beta2-microglobulin, whether increased or normal, failed to be predictive of potential response to prenatal intervention. Serial samples of fetal blood may provide distinction between patients who do and do not respond to prenatal treatment of lower urinary tract obstruction.

Objectives: The primary objective is to determine whether intrauterine vesicoamniotic shunting for fetal bladder outflow obstruction, compared with conservative, noninterventional care, improves prenatal and perinatal mortality and renal function. The secondary objectives are to determine if shunting for fetal bladder outflow obstruction improves perinatal morbidity, to determine if improvement in outcomes is related to prognostic assessment at diagnosis and, if possible, derive a prognostic risk index and to determine the safety and long-term efficacy of shunting., Design: A multicentre randomised controlled trial (RCT)., Setting: Fetal medicine units., Population: Pregnant women with singleton, male fetus with isolated lower urinary tract obstruction (LUTO)., Methods: Following ultrasound diagnosis of LUTO in a male fetus and exclusion of other structural and chromosomal anomalies, participation in the trial will be discussed with the mother and written information given. Consent for participation in the trial will be taken and the mother randomised via the internet to either insertion of a vesicoamniotic shunt or expectant management. During pregnancy, both groups will be followed with regular ultrasound scans looking at viability, renal measurements and amniotic fluid volume. Following delivery, babies will be followed up by paediatric nephrologists/urologists at 4-6 weeks, 12 months and 3 and 5 years to assess renal function via serum creatinine, renal ultrasound and need for dialysis/transplant., Main Outcome Measures: The main outcome measures will be perinatal mortality rates and renal function at 4-6 weeks and 12 months measured via serum creatinine, renal ultrasound and need for dialysis/transplant., Funding: Wellbeing of Women. ESTIMATED COMPLETION DATE: September 2010. TRIAL ALGORITHM: [flowchart: see text].

Objective: To test the hypothesis that fetal bladder outlet obstruction (BOO) in sheep causes abnormal urodynamics correlating with the initiation of renal pathology, as most boys with posterior urethral valves (PUV) have bladder dysfunction when assessed after birth., Materials and Methods: Male ovine fetuses at 94 days of gestation were assigned to BOO (four) or sham control (five) groups. In BOO fetuses, radiotelemetry catheters were inserted transurachally and intraperitoneally, and the urethra was partly occluded. In two sham controls catheters were inserted directly through the bladder wall; the remaining three had sham surgery only. Radiotelemetered cystometry was recorded daily where possible. At the end of the experiment (9 days), ex vivo cystometry, bladder contractility studies and renal tract histology were assessed., Results: Ultrasonography showed dilated renal tracts only in BOO fetuses; three of four BOO fetuses had renal cortical cysts. The control fetuses with bladder catheters died in utero, so urodynamics were recorded only in fetuses with BOO. The baseline filling/storage detrusor pressures increased slightly (by a mean of 5 mmHg) during the first 4 days of BOO, thereafter returning to those at the outset. There were marked changes in the patterns of bladder activity from 1 to 9 days. The frequency and duration of 'voiding' increased; as such the higher sustained pressures of emptying activity were progressively extended and the periods of low pressure filling/storage accordingly shortened. The patterns among individual fetuses with BOO were not substantially different, except that the one with the non-cystic kidneys had a more moderate frequency and duration of voiding. Ex vivo compliance and contractility showed no consistent differences in detrusor compliance or contractility between BOO and sham bladders., Conclusion: In this fetal model of PUV, there was a progressive increase in the duration and frequency of sustained elevated 'voiding' pressures, with no change in bladder compliance. Fetal kidneys were sensitive to these altered dynamics, with the formation of cortical cysts by 9 days after initiating BOO.

Purpose: We characterized intracellular Ca(2+) regulation in fetal bladders following outflow obstruction by examining the Ca(2+) response to agonists in smooth muscle cells., Materials and Methods: Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery. Intracellular Ca(2+) in single smooth muscle cells isolated from the bladder wall was measured with epifluorescence microscopy using fura-2(AM) during exposure to agonists, such as carbachol and adenosine triphosphate, and to other activators, such as caffeine and KCl., Results: Detrusor smooth muscle cells from obstructed bladders had resting intracellular Ca(2+) similar to that in sham operated controls. The maximal response to carbachol was decreased following obstruction (p <0.05). Construction of dose-response curves also demonstrated higher EC(50) (p <0.05). However, these changes were not mirrored by caffeine evoked Ca(2+) release, which was not significantly different between the obstruction group and sham operated controls. Kinetic analysis of carbachol transients further revealed an attenuated maximal rate of increase in obstructed bladders (p <0.01). The magnitude of intracellular Ca(2+) to purinergic neurotransmitter adenosine triphosphate was also found to be smaller in cells from obstructed bladders (p <0.05), although transmembrane influx by high K depolarization was not significantly affected., Conclusions: Muscarinic and purinergic pathways were down-regulated in fetal detrusor muscle following outflow obstruction. These major functional receptors appeared to be more susceptible to obstruction than other Ca(2+) regulators. Their impairment may contribute to the compromised contractile function seen in in utero bladder outflow obstruction.

Bladder outlet obstructions are a diverse and heterogeneous group of developmental abnormalities that generally involve obstruction of the proximal urethra in the male fetus. Indications for prenatal intervention are few and are usually restricted to the male fetus because bladder outlet obstruction in female fetuses is usually caused by complex cloacal development anomalies. We report on a female fetus with an enlarged bladder and a dilated proximal urethra (known as typical keyhole sign). A vesicoamniotic shunt was performed despite non-reassuring prognostic factors, but the procedure resulted in a successful outcome. We propose that in selected cases of bladder outlet obstruction, fetal intervention should be considered even when the fetus is female., (Copyright 2005 John Wiley & Sons, Ltd)

Objective: To determine whether fetal cystometric studies by radiotelemetry are feasible in the fetal lamb, and potentially suitable for chronically monitoring fetal bladder pressures in an experimental fetal model of bladder outlet obstruction (BOO), as in utero BOO (e.g. caused by posterior urethral valves) results in significant postnatal bladder dysfunction but the pathophysiological progression of fetal bladder maldevelopment remains poorly understood., Materials and Methods: The procedure required fetal sheep surgery and anaesthesia. Radiotelemetry implants comprised catheters that transmitted pressure fluctuations to an implant body; data were then transmitted using radio frequency to a receiver that passed this information to a computer. Four fetuses were used with different methods of catheter placement to optimize the technique., Results: Recordings were possible in three of the four sheep; during observation there were: (i) quiet periods with no abdominal or bladder pressure rises; (ii) synchronous activity in the bladder and abdomen; and (iii) discriminate activity, associated with intravesical activity only. Four patterns of discriminate bladder activity were observed, defined as void, immature void, staccato activity and 'unstable' type activity., Conclusions: Radiotelemetry cystometry for long-term monitoring is feasible in the experimental fetus without causing death or morbidity, or inhibiting growth. The method can discriminate reproducible patterns of detrusor activity. Recorded 'voiding' types were consistent between experiments and as reported in other fetal animal studies.

Objective: To estimate the effect of prenatal bladder drainage on perinatal survival in fetuses with lower urinary tract obstruction., Data Sources: Relevant articles were identified by searching the databases MEDLINE (1966-2002), EMBASE (1988-2002), and the Cochrane library (2000;4)., Methods of Study Selection: Studies were selected if the effect of prenatal bladder drainage (vesicocentesis, vesicoamniotic shunt, or open fetal bladder surgery) on perinatal survival was reported in fetuses with ultrasonic evidence of lower urinary tract obstruction. Study selection, quality assessment, and data abstraction were performed independently and in duplicate., Tabulation, Integration, and Results: Sixteen observational studies that included nine case series (147 fetuses) and seven controlled series (195 fetuses) were identified. Study characteristics and quality were recorded for each study. Data on the effect of bladder drainage on perinatal survival were abstracted. Where controlled data were available, 2 x 2 tables were generated to compare the effects of bladder drainage versus no bladder drainage on perinatal survival. Pooled odds ratios (ORs) were used as summary measures of effect, and the results were stratified according to predicted fetal prognoses (based on ultrasound features and fetal urinary electrolytes). Among controlled studies, bladder drainage appeared to improve perinatal survival relative to no drainage (OR 2.5; 95% confidence interval [CI] 1.1, 5.9; P =.03). However, this observation was largely because among the subgroup of fetuses with a poor prognosis there was a marked improvement (OR 8.1; 95% CI 1.2, 52.9; P =.03). Improved perinatal outcome was also suggested in those fetuses considered to have a good prognosis (OR 2.8; 95% CI 0.7, 10.8; P =.13)., Conclusion: There is a lack of high quality evidence to reliably inform clinical practice regarding prenatal bladder drainage in fetuses with ultrasonic evidence of lower urinary tract obstruction. The limited available evidence suggests that prenatal bladder drainage may improve perinatal survival in these fetuses, particularly those with poor predicted prognoses. Further research in the form of a multicenter randomized controlled trial is required to assess the short- and long-term effects of this intervention.

Fetal bladder outflow obstruction, predominantly caused by posterior urethral valves, results in significant urinary tract pathology; these lesions are the commonest cause of end-stage renal failure in children, and up to 50% continue to suffer from persistent postnatal bladder dysfunction. To investigate the physiological development of the fetal bladder and the response to urinary flow impairment, we performed partial urethral obstruction and complete urachal ligation in the midgestation fetal sheep for 30 days. By electrical and pharmacological stimulation of bladder strips, we found that muscarinic, purinergic, and nitrergic mechanisms exist in the developing fetal bladder at this gestation. After bladder outflow obstruction, the fetal bladder became hypocontractile, producing less force after nerve-mediated and muscarinic stimulation with suggested denervation, and also exhibited greater atropine resistance. Furthermore, fetal bladder urothelium exerted a negative inotropic effect, partly nitric oxide mediated, that was not present after obstruction. Increased compliance, reduced elasticity, and viscoelasticity were observed in the obstructed fetal bladder, but the proportion of work performed by the elastic component (a physical parameter of extracellular matrix) remained the same. In addition to denervation, hypocontractility may result from a reduction in the elastic modulus that may prevent any extramuscular components from sustaining force produced by detrusor smooth muscle.

In a case of severe bilateral hydronephrosis in a female fetus associated with ureterocele at 28 weeks, under local anesthetic, ultrasound-guided neodymium:yttrium-aluminum-garnet laser was used to perforate the ureterocele and successfully overcome the obstruction. There was no recurrence of obstruction, and renal function was normal postnatally.

Purpose: Congenital bladder outflow obstruction caused by posterior urethral valves is a common cause of end stage renal failure in boys. We hypothesized that fetal bladder outflow obstruction perturbs detrusor contractility and innervation and bladder storage volume-pressure relationships., Materials and Methods: Severe bladder outflow obstruction was induced in male fetal sheep by placing a urethral ring and urachal ligation midway through gestation at 75 days. Fetuses were examined 30 days after surgery, when urinary tract dilatation, enlarged bladders and histologically abnormal kidneys were documented. Isolated strips of bladder detrusor from sham operated and obstructed fetuses were subjected to electrical field stimulation, carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Whole bladder storage characteristics were determined by filling cystometry and bladder innervation was investigated by immunohistochemistry and Western blot., Results: Tension-frequency contractility studies showed that obstructed fetal bladder strips were significantly hypocontractile versus sham operated controls in response to electrical field stimulation and the specific agonists carbachol, KCl and alpha-beta methylene-adenosine triphosphate. Hypocontractility was greater with nerve mediated stimulation than with carbachol, suggesting relative denervation. Reduced innervation was confirmed by S100 and protein gene product 9.5 immunohistochemistry and by measuring a significant reduction in protein gene product 9.5 protein expression using Western blot. Filling cystometry showed that obstructed fetal bladders appeared more compliant (Delta V/Delta P, where Delta V is the change in volume and Delta P is the change in pressure) with larger capacity, more flaccidity and yet retained stress relaxation., Conclusions: In response to severe experimental fetal bladder outflow obstruction the bladder becomes large and hypocontractile, and has aberrant innervation.

We report a case of prenatal bladder obstruction due to a single system ureterocele associated with hydrocolpos. Ultrasound at 22 weeks demonstrated an enlarged bladder. Serial scans showed progressive ipsilateral obstructive uropathy, contralateral hydronephrosis, and oligohydramnios. Neonatal endoscopic decompression and hymenotomy was performed with residual decreased ipsilateral renal function and dilation. Prenatal bladder obstruction may cause permanent renal damage.

Purpose: We developed and tested an animal model of bladder dysfunction due to posterior urethral valves using partial outlet obstruction of the fetal rabbit bladder., Materials and Methods: Partial bladder outlet obstruction of fetal rabbit bladders was created on day 23 of gestation. Of the litter of 8 to 10 fetuses half was obstructed and the remainder served as controls. The doe and fetuses were sacrificed on day 30 of gestation (full term 31 to 32 days) and the fetal bladders were removed. Bladders that had doubled in weight from the average bladder weight of the control littermates were deemed sufficiently obstructed. Hematoxylin and eosin staining was performed and bladder strip response to 32 Hz. field stimulation, 200 microM. bethanechol and 200 mM. potassium chloride was measured., Results: Average body weight did not differ between the control and obstructed fetuses, indicating that surgery did not hinder fetal development. Hematoxylin and eosin staining confirmed smooth muscle cell hypertrophy and increased connective tissue in the obstructed bladders. Obstructed bladder strips responded significantly less to field stimulation, and significantly more to bethanechol and potassium chloride (mean plus or minus standard deviation 5.18 +/- 1.52, 6.29 +/- 1.3 and 10.15 +/- 2.18 x force per/100 mg. tissue, respectively)than control bladder strips (9.0 +/- 1.19, 3.5 +/- 0.46 and 6.16 +/- 1.33 x force per/100 mg. tissue, respectively) suggesting that denervation supersensitivity may have resulted from obstruction., Conclusions: Partial outlet obstruction of the fetal rabbit bladder results in bladder hypertrophy and dysfunction but these changes are markedly different from those in the adult rabbit. Since rabbit fetal development is delayed compared to human fetal development, this model can be used to assess the consequences of posterior urethral valves.

We evaluated compliance in the developing bladder using a newly developed animal model of posterior urethral valves: partial infravesical obstruction in the fetal rabbit bladder. Partial bladder outlet obstruction was created in fetal rabbits at day 23 of a 31 to 32-day gestation period. An in vitro whole bladder preparation provided data on compliance and an isolated bladder strip preparation provided data on the mechanical properties of the bladder wall. In addition, the influence of calcium on both preparations was evaluated. Partial bladder outlet obstruction in the fetal rabbit resulted in a markedly larger bladder weight (246.4 +/- 22.3 mg, n = 14) than control bladders (90.2 +/- 5.7 mg, n = 13). Isolated smooth muscle strips from obstructed and normal bladders revealed identical stretch-stress patterns. In contrast, obstructed bladders had significantly increased compliance in the whole bladder preparation. Since the increase in compliance was not correlated to mechanical properties of the isolated bladder strips, it must therefore result from the pattern of mass increase of the whole bladder wall. During filling, both the control and obstructed bladders had the same slow, large amplitude spontaneous contractions. In addition, both had rapid contractions: those in the obstructed bladders had significantly lower frequency and higher amplitude than the ones in the control bladders. Removing the calcium from the organ bath eliminated the spontaneous contractions but did not change the baseline pressure or force values, indicating that the compliance of these fetal rabbit bladders is a function of the passive properties of the bladder wall. Three main patterns occur in cystometrograms of patients with posterior urethral valves: myogenic failure, hyperreflexic bladders, and low compliance bladders. Using our model of partial outlet obstruction in the fetal rabbit bladder, we could not imitate the group with low compliance. We therefore hypothesize that the different patterns of bladder dysfunction associated with posterior urethral valves are due to infravesical obstruction occurring with different severities or at different ages of gestation.

Previous studies of fetal urinary tract obstruction (bladder outlet obstruction and ureteral obstruction) in lambs have shown that obstructions created relatively early in gestation (4/10 to 6/10 term) can significantly affect growth of the developing kidney. This suggests that urinary tract obstruction in utero can alter normal mechanisms of kidney growth. However, a mechanism for these effects has not yet been proposed. In this study we have used mRNA expression analysis to characterize the temporal sequence of expression of several growth-regulated genes during normal ovine kidney development. The purpose of this study was to test the hypothesis that early obstructions, such as those believed to arise in congenital obstructive uropathy in humans, might have a disproportionate effect on hyperplastic growth if the cellular growth fraction (percent of cells in the organ undergoing DNA synthesis) was greater in the second trimester than in the last. Northern blot analysis of the cell cycle-dependent genes histone H3, c-myc and ornithine decarboxylase (ODC) indicated a progressive, gradual decline in cellular proliferation in the kidney from approximately 60 to 135 days (4/10 term to term) gestation, as evidenced by decreases in the respective mRNA levels. The greatest levels of cell proliferation occurred near the midpoint of gestation. This indirect measurement of decline in cellular growth fraction was reflected in direct measurements of change in relative kidney weight. To test whether this decline in mRNA levels occurs widely among genes expressed in the fetal kidney during this period, relative expression levels of more than 300 anonymous mRNA transcripts were evaluated by differential display analysis. This method showed that genes whose expression patterns resembled the growth-regulated genes constituted less than 5% of the expressed mRNAs identified. These data indicate that intrauterine urinary tract obstructions that arise at or near the midpoint of gestation coincide with the highest rates of cell proliferation occurring in the second and third trimesters and, therefore, might adversely affect mechanisms of cell proliferation.

We studied fetal lambs to define the renal pathophysiology of chronic in utero partial bladder outlet obstruction. These fetal lambs, 115 to 120 days gestation (term = 145 days), underwent urethral ligation, placement of a urachal catheter and positioning of an ultrasonic flow transducer around the left renal artery. Partial obstruction was created by placing a narrow connector between the urachal and an amniotic catheter. In control animals a large connector was placed to allow free drainage of the bladder into the amniotic cavity. Renal blood flow was measured daily, and urine was collected at days 5 and 10 to evaluate renal function. In control animals, no significant changes in any parameters were observed. In the partially obstructed fetal lambs, renal blood flow increased to 165% of baseline after 5 days; from 5 to 10 days, it decreased, but remained above baseline values through 10 days (128%). Urine production dropped significantly after 10 days (67%). Glomerular filtration rate increased slightly after 5 days (127%), but decreased after 10 (56%). Filtration fraction steadily decreased after 5 (70%) and 10 days (33%). Fractional and total sodium excretion did not change. Renal blood flow increases, filtration fraction decreases and renal function trends progressively diminish in response to partial bladder outlet obstruction over a period of 10 days in the fetal lamb.

The pathophysiology of fetal urinary obstruction has not been elucidated. Using a unique, reproducible and easily reversible animal preparation, we studied the acute hemodynamic and endocrinological responses to partial fetal bladder obstruction in 16 ovine fetuses at 115 days of gestation (term 147 days). After partial obstruction blood pressure and renal weight increased significantly for at least 72 hours. Renal blood flow trended upwards, particularly from 24 to 72 hours, although this change was not statistically significant. Plasma renin activity was significantly increased during the first 24 hours after obstruction but it returned to baseline thereafter. Plasma cortisol or catecholamine concentrations remained unchanged. The time course and pattern of hemodynamic changes in this fetal sheep preparation of partial urinary obstruction differ significantly from those reported in other preparations.

Congenital bladder obstruction causes significant immediate and long-term consequences yet its pathophysiology remains poorly understood. A model of early fetal bladder obstruction in sheep has been developed to study the response of the developing bladder to high grade obstruction, with particular emphasis on the regulation of growth and development. Congenital bladder obstruction was produced in fetal sheep at 60 days of gestation and studied at 95 days of gestation (14 sheep) or term (12 sheep). A total of 24 age-matched normal sheep served as controls. Bladders were analyzed by total weight, stereological estimation of smooth muscle cell size, number and total mass, deoxyribonucleic acid concentration, muscarinic cholinergic receptor density, myosin isoform analysis and/or passive cystometrics. Congenital bladder obstruction caused a 4.6 times increase in bladder weight at term reflecting a 5.8 times increase in smooth muscle mass. This increase was predominantly that of cellular hypertrophy and less so of hyperplasia, based upon increased cell volume, increased protein-to-deoxyribonucleic acid ratio, and no significant increase in total cell number. Muscarinic cholinergic receptor number per smooth muscle cell increased 3.2 times but it did not change relative to myosin content. The ratio of myosin heavy chain isoforms SM1:SM2 is developmentally regulated and was seen to change from 1.6 at 100 days of gestation to 1.13 at term in normals. After 5 weeks of obstruction SM1:SM2 was 1.27 and it was 1.25 at term, indicating an effect on the developmental regulation of smooth muscle. Rapid fill cystometry in vivo measured the rate of stress relaxation to assess accommodative properties. The half-decay time was increased in all 3 obstructed bladders tested to greater than 15 seconds at 50% capacity (normal less than 5 seconds), suggesting reduced compliance. This study shows that an in utero model of bladder obstruction is feasible. Congenital bladder obstruction produces a variety of structural, biochemical and functional changes in the developing bladder indicative of alterations in the regulation of growth and differentiation.

In a fetal ovine model the renal effects of different anatomic levels of fetal urinary obstruction were studied. Parameters of prenatal renal growth and differentiation were characterized and correlated with the patterns of renal response to in utero obstruction. Complete ureteral or urethral obstruction was produced in the sheep fetus at 55 to 60 days of gestation. Animals were delivered and sacrificed at near term (140 days), and the kidneys were removed and prepared for analysis. Parameters examined included weight, histology, glomerular number and total surface area, as well as urinary sodium, creatinine, osmolarity and N-acetyl glucosaminidase. Three patterns of response were identified, producing hydronephrotic, cystic or dysgenetic kidneys. Hydronephrotic kidneys were usually the result of bladder outlet obstruction or ureteral obstruction with spontaneous urinary decompression. These kidneys were large (20.7 gm. versus normal 10.8 gm., p less than 0.0001), with thinning of cortical parenchyma that was structurally intact. Glomerular number and surface area were normal. Cystic kidneys were large (14.2 gm., p less than 0.05) with grossly visible cysts and an effaced medulla. Cortical structure was distorted by cysts but basic elements were intact. Glomerular number and surface area were not reduced. Dysgenetic kidneys were small (3.9 gm., p less than 0.0001) with markedly abnormal cortical structure and little recognizable medulla. Histological elements similar to fetal structures were present, including cuboidal/columnar tubular epithelium and peritubular mesenchymal collars. Glomerular number and surface area were significantly less than normal (p less than 0.001). The kidneys contralateral to unilaterally obstructed kidneys were significantly larger than normal (16.2 gm., p less than 0.0001), with normal histology, glomerular number and surface area, indicating in utero contralateral renal hypertrophy. Urinary sodium was variably affected in the hydronephrotic kidneys and was identical to plasma in the dysgenetic kidneys. These results indicate the technical feasibility of in utero models of urinary obstruction. Renal growth and patterns of differentiation were markedly affected by in utero obstruction. They should be a major focus in the investigation of congenital obstructive uropathy, since normal processes of renal growth and differentiation form the basis for postnatal function.

A model of early gestation bladder outlet obstruction and oligohydramnios in the fetal lamb is characterized by small, immature lungs (pulmonary hypoplasia). The current study examines how in utero relief of urinary tract obstruction produced early in gestation modifies pulmonary hypoplasia. Bladder obstruction was created at 60 days gestation in fetal sheep (term = 140 days); 11 fetuses then underwent in utero decompression at 95 to 100 days; six were left obstructed. Five normal fetuses served as controls and two underwent sham obstruction and vesicostomy. All were delivered and sacrificed near term (135 days), the right lung was inflation-fixed and its volume determined. Relative volumes of alveoli, alveolar ducts, and tissue, alveolar surface area, and alveolar numerical density were estimated morphometrically. Kidneys were examined histologically. In all animals persistent bladder obstruction produced oligohydramnios. Bladder obstruction to term produced pulmonary hypoplasia with a mean right lung volume-to-body weight ratio (LV:BW) of 14.3 cc./kg. (normal = 36.4, p less than 0.001). Structural immaturity was evidenced by an airspace fraction of only 57% (normal = 68%, p less than 0.05). Kidneys in these animals were not dysplastic; there was hydronephrosis or evidence of spontaneous urinary decompression. In eight of the 11 animals, decompression improved the LV:BW ratio to 28.4 cc./kg. (vs. obstructed, p less than 0.001; vs normal, p less than 0.05) and normalized maturity. All had increased amniotic fluid at delivery; kidneys in 7/8 animals were normal, and the other had moderate hydronephrosis. One of the 11 animals had normal kidneys, oligohydramnios, immature lungs, but with normal volume. Oligohydramnios was present in the other two of 11 fetuses despite successful decompression and they had markedly dysmorphic kidneys and profoundly hypoplastic and immature lungs (LV:BW 5.1 cc./kg.). Even after 35 days (25% gestation) of obstruction, in utero urinary tract decompression permits better lung growth and maturation than in persistently obstructed animals. The degree of renal damage from obstruction appears to be a critical determinant in the correction of pulmonary hypoplasia.

The contribution of the kidneys to lung development, which includes growth and maturation, is uncertain but it appears to be complex. Obstructive uropathy with oligohydramnios produces pulmonary hypoplasia characterized by small lungs (decreased lung volume/body weight) and retarded maturation (reduced total airspace). Lung growth and maturation were studied in a model of early gestation obstructive uropathy to understand better their relationship and their prenatal regulation. Of 26 fetal sheep studied at near term (135 days of gestation) 9 had bladder obstruction created at 60 days of gestation, 11 had bladder obstruction at 60 days with in utero decompression at 95 days, and 6 served as controls and shams. Amniotic fluid volume was measured, kidneys were prepared and evaluated histologically, lungs were inflation-fixed and volumes were measured, and airspace volume percentage was measured morphometrically. Experimental and serendipitous variations in the condition of the kidneys and amniotic fluid at delivery permitted an analysis of the contribution of the kidneys and the amniotic fluid to lung growth and maturation. Impairment of growth and maturation was dissociated in certain animals, and this dissociation was referable to the histological status of the kidneys and the presence or absence of amniotic fluid at delivery. Growth was normal when amniotic fluid was present or likely to have been present in late gestation, even with structurally damaged kidneys. With severe renal damage amniotic fluid was not restored even with in utero decompression and it resulted in severely impaired lung growth. Maturation was normal only in the presence of amniotic fluid and intact kidneys. The dissociation of lung growth and structural maturity suggests their independent regulation. The data suggest that the kidneys are important in early lung growth, while the presence of amniotic fluid contributes to growth later in gestation. Lung maturity requires both factors, suggesting a primary kidney contribution with the amniotic fluid acting in a permissive or supportive role.

Histological findings of muscle, collagen and elastin in obstructed fetal bladders were compared with those of age-matched controls. Muscle thickness was markedly increased, however, the relative collagen content in the muscle was decreased. The ratio of thick-to-thin collagen fibers was markedly increased as was the amount of elastin. These findings suggest that the ratio of thick collagen to elastin has an important role in determining the compliance of the obstructed fetal bladder.

A bladder neck obstruction was suspected after ultrasound investigation at 16 weeks' gestation. Evaluation of protein content in the amniotic fluid, fetal ascites, and fluid from the overdistended bladder supported the diagnosis. Bladder outflow obstruction in the second trimester of pregnancy was not associated with raised alphafetoprotein levels in the amniotic fluid and maternal serum.

The earliest diagnosis and treatment of obstructed fetal bladder is reported. Placement of vesico-amniotic shunt at 14.5 weeks of gestation enabled preservation of bilateral renal function and maintenance of normal amniotic fluid volume with normal pulmonary development. The shunt functioned adequately for more than 12 weeks. At birth, a mild 'prune' belly was the only deformity noted.