Lower urinary tract obstruction in the fetus and neonate.

This article summarizes the most recent literature regarding congenital lower urinary tract obstruction in the fetus and newborn. Lower urinary tract obstruction is a heterogeneous group of rare diagnoses that have significant potential for in utero mortality and long-term morbidity in survivors. The diagnosis and management of the most common causes are reviewed. In addition, the current state of prenatal intervention for congenital lower urinary tract obstruction is discussed.

The antenatally detected pelvi-ureteric junction stenosis: advances in renography and strategy of management.

This review includes an analysis of new developments in the field of renography, the predictive factors suggesting the need for pyeloplasty in cases of pelvi-utereric stenosis detected antenatally and integration of the pelvi-ureteric junction stenosis within the framework of antenatally detected hydronephrosis.

Unilateral anomalies of kidney development: why is left not right?

Abnormal renal development results in congenital anomalies of the kidney and urinary tract. As many studies suggest that renal malformations are more often found on the left side, a meta-analysis was performed on the distribution of five different unilateral anomalies: multicystic dysplastic kidney, renal agenesis/aplasia, renal ectopia, pelviureteral junction obstruction, and non-obstructive non-refluxing megaureter. Of these anomalies, the left side was affected in 53%, 57%, 56.9%, 63.2%, and 62.5% of patients, respectively, significantly different when compared with an anticipated 50% of left-sided anomalies. An exception to this left-side predominance was found in females with combined genital anomalies and unilateral renal agenesis that commonly present on the right side. The exact mechanisms leading to these lateralizations remain to be determined but may involve vascular development, differential gene expression, or susceptibility to environmental factors such as hypoxia. This remains largely speculative, however, illustrating our limited knowledge of embryogenesis in general and nephrogenesis in particular.

Correlation between prenatal urinary matrix metalloproteinase activity and the degree of kidney damage in a large animal model of congenital obstructive uropathy.

BACKGROUND/PURPOSE: We aimed to determine whether the profile of matrix metalloproteinase (MMP) activity in fetal urine correlates with the degree of kidney damage in the setting of congenital obstructive uropathy. METHODS: Fetal lambs underwent either a sham operation or creation of a complete urinary tract obstruction. Necropsies were performed before term, when urinary MMP profiling was performed by zymography; and kidney damage was assessed histologically by multiple semiquantitative analyses and histomorphometric measurements. RESULTS: There was a significant correlation between inner medullary thickness and MMP-9 (P = .005) and 63-kd MMP-2 (P = .019) activities. In like manner, the only MMPs associated with kidney fibrosis were MMP-9 and 63-kd MMP-2. Matrix metalloproteinase-9 activity was a highly significant independent predictor of the total combined kidney fibrosis score (P < .001) as well as of higher fibrosis grades in each of 6 kidney areas analyzed (all with P < .01). The activity of 63-kd MMP-2 correlated significantly with higher fibrosis in select areas. CONCLUSIONS: In a fetal ovine model, urinary MMP activity correlates with the degree of kidney damage. The presence of MMP-9 (in particular) and that of 63-kd MMP-2 are independent predictors of severity. Prenatal urinary MMP profiling may enhance patient stratification and counseling in the setting of congenital obstructive uropathy.

Does intervention in utero preserve the obstructed kidneys of fetal lambs? A histological, cytological, and molecular study.

Ureteropelvic junction obstruction is a common cause of end-stage nephropathy in children. Our aim was to investigate whether relief of obstruction in utero can alleviate the development of nephropathy. A silastic tube was tied around the left superior segment ureter to induce unilateral partial ureteral obstruction in 22 fetal sheep at 75- 85 d of gestation. Three weeks later, the tubes were removed to relieve the obstruction in 10 of the 22 lambs. A sham operation was performed on four fetuses (the control). At birth, the lambs were killed, and their kidneys were removed to study the changes in histology, podocytes, and expression of paired-box 2 (PAX2) and VEGF. In the obstructed kidneys, we observed cysts of various sizes in the cortex, fibrosis in the interstitial tissue, much decreased number of glomeruli, severe podocyte foot process fusion, and markedly increased PAX2 and decreased VEGF expressions. However, relief of obstruction preserved the number of glomeruli, significantly increased VEGF expression, reduced fusion of the podocyte foot processes, andrestored expression of PAX2 to some extent. Thus, relief ofobstruction in utero may prevent or attenuate the development ofnephropathy in lambs.

Genetic and developmental basis for urinary tract obstruction.

Urinary tract obstruction results in obstructive nephropathy and uropathy. It is the most frequent cause of renal failure in infants and children. In the past two decades studies of transgenic models and humans have greatly enhanced our understanding of the genetic factors and developmental processes important in urinary tract obstruction. The emerging picture is that development of the urinary tract requires precise integration of a variety of progenitor cell populations of different embryonic origins. Such integration is controlled by an intricate signaling network that undergoes dynamic changes as the embryo develops. Most congenital forms of urinary tract obstruction result from the disruption of diverse factors and genetic pathways involved in these processes, especially in the morphogenesis of the urinary conduit or the functional aspects of the pyeloureteral peristaltic machinery.

Mild fetal renal pelvis dilatation: much ado about nothing?

BACKGROUND: Renal pelvis dilatation (RPD) occurs in 1% of fetuses. Severe RPD (>15 mm) is frequently associated with urinary tract pathology. For the majority with mild (5 to 9 mm) to moderate (10 to 15 mm) RPD, however, there is uncertainty about the risk of abnormalities and how much postnatal investigation is required. STUDY DESIGN: Systematic review of cohort studies of fetuses with RPD < or = 15 mm and metaregression to estimate risks of postnatal RPD, obstruction, and VUR. RESULTS: Of 506 potentially relevant papers, 18 met the inclusion criteria. Risk of postnatal RPD increased with fetal RP size and earlier gestation. Odds ratios for postnatal RPD doubled per millimeter increase in fetal RP size: At 20 wk gestation, for example, 18% of fetuses with mean RP of 6 mm were estimated to have persistent postnatal RPD, compared with 95% of fetuses with 12 mm RPD, but risks were decreased by 16% to 18% per week of presentation gestation. Estimated risks of obstruction and VUR were substantially lower, particularly in the mild group such as the 6 mm example above: obstruction 2%, VUR 4%. CONCLUSIONS: Our novel risk estimates are useful for antenatal counseling at presentation. The low frequency of obstruction/VUR in mild RPD raises questions over the most appropriate investigation of these cases but further data are required before establishing definitive postnatal management pathways. We suggest the need for a large prospective multicenter study to collect individual patient parameters/results and search for additional prognostic indicators.

Activated extracellular signal-regulated kinase correlates with cyst formation and transforming growth factor-beta expression in fetal obstructive uropathy.

Human renal dysplasia is frequently associated with urinary tract obstruction and the abnormal expression of mitogen-activated protein kinase (MAPK). Here, we determined the renal responses and MAPK expression in developing kidneys that were obstructed in fetal lambs. Kidneys were harvested at various times after obstruction (gestation day 60) through normal term (day 145). Dilation of Bowman's capsule and proximal tubules was seen 2 days after obstruction and involved the whole cortex 18 days later, with numerous cysts present throughout the kidney at term. The proliferation marker Ki-67 and transforming growth factor-beta (TGF-beta) were detected 2 days after obstruction and progressively increased in tubules, cysts, and the interstitium. In control kidneys, p38 was expressed in tubules only during the fetal stage, whereas phosphorylated extracellular signal-regulated kinase (P-ERK) was limited to ureteric buds and collecting ducts at all stages examined. However, Jun-N-terminal kinase (JNK) was absent in the fetal kidney but present in tubules at term. In obstructed kidneys, cyst epithelia were positive for p38 and P-ERK but negative for JNK throughout all stages. These studies show that P-ERK correlated spatially and temporally with Ki-67 and TGF-beta expression, which suggests that ERK may contribute to cyst formation and fibrosis in the obstructed fetal kidney.

Complete unilateral ureteral obstruction in the fetal lamb. Part I: long-term outcomes of renal hemodynamics and anatomy.

PURPOSE: We evaluated the long-term consequences of complete fetal UUO on renal hemodynamics and anatomy. MATERIALS AND METHODS: A total of 26 fetal lambs underwent surgical UUO at 90 days of gestation and 14 twin matched animals served as controls. Synchronous bilateral ARBF was measured using mean transit time technology. Standard anatomical analysis, including evaluation of RPV, was performed in the kidneys. Measurements were done 10, 20 and 40 days following UUO in groups 1 to 3, respectively and in 1-month-old lambs in group 4. RESULTS: All obstructed kidneys underwent typical hydronephrotic transformations with a progressive decrease in parenchymal volume compared to that of contralateral and control kidneys. ARBF in obstructed kidneys was significantly decreased compared to their contralateral counterparts in all groups (p <0.01). Comparing ARBF to RPV showed that the decrease in ARBF was proportional to the loss of parenchymal volume in fetal obstructed kidneys but it remained significant in lambs (p <0.05). CONCLUSIONS: Complete UUO alters ARBF, while vascularization of the remaining renal parenchyma is maintained in fetuses. Profound impairment of the renal arterial supply observed in lambs may be due to physiological changes linked to birth.

Complete unilateral ureteral obstruction in the fetal lamb. Part II: Long-term outcomes of renal tissue development.

PURPOSE: We analyzed the dynamics of the renal tissue response to experimental fetal urinary flow impairment concerning renal morphology, extracellular matrix composition, regulators of connective tissue degradation and PAX2 protein expression. MATERIALS AND METHODS: A total of 26 fetal lambs underwent surgical unilateral ureteral obstruction at 90 days of gestation and 14 twin matched animals served as controls. Kidneys were harvested 10, 20 and 40 days after the prior procedure in groups 1 to 3, respectively and in 1-month-old lambs (group 4). Morphological analysis was done using light microscopy. Picrosirius red staining was used to evaluate the area occupied by extracellular matrix components. Collagen I, III and IV, alpha-smooth muscle actin, MMP-1, 2 and 9, TIMP-1 and 2 and PAX2 protein were assessed using immunochemistry. RESULTS: All obstructed kidneys were hydronephrotic without dysplasia. Hypoplasia resulting from a decreased NGG was observed. The inflammatory response to obstruction was poor in fetal obstructed kidneys. From 10 days after obstruction interstitial fibrosis was noted and confirmed by an increase in picrosirius red staining. In obstructed kidneys immunochemistry showed an increase in collagen deposition beginning from the papillae and extending through the whole parenchyma. Aberrant interstitial collagen IV deposition was observed. The increase in alpha-smooth muscle actin staining was mainly localized in the blastema and interstitial cells in obstructed kidneys. MMP and TIMP immunostaining was mainly present in tubules throughout the whole nephrogenic period and persisted in mature kidneys. Beginning from 20 days after obstruction a progressive increase in MMP and TIMP expression was noted. This was associated with ectopic expression in the medullary tubules. PAX2 protein was highly expressed in the nephrogenic zone, decreasing progressively to being markedly decreased in control lamb kidneys. No difference was found in PAX2 expression during the fetal period when comparing unobstructed and obstructed kidneys, it but remained strongly expressed in the dilated collecting ducts of obstructed lambs. CONCLUSIONS: Complete unilateral ureteral obstruction performed in fetal lambs at 90 days of gestation led to pure hydronephrotic transformation, hypoplasia and a marked increase in connective tissue deposition. Inflammatory infiltrates and PAX2 dysregulation were not seen as having a decisive role in these modifications.

[Obstructive uropathy in childhood]. / Obstruktive Uropathien im Kindesalter.

"Obstructive uropathy" is a generic term which combines different diseases in infants and childhood. Both the upper and lower urinary tract may be affected. Diseases of the urinary tract can cause an intrinsic obstruction. Sometimes tumours may cause a compression and as secondary effect an obstruction (extrinsic). Ultrasound is the key diagnostic tool and shows dilatation of the obstructed urinary tract. But for the functional exploration of babies and toddlers, renal scanning and X-ray examinations are necessary. These examinations lead to an exposure to radiation which necessitates careful indication. Some of the congenital diseases (for example ureteropelvic junction obstruction, megaureter) show a maturation without any intervention. So one has to decide whether to wait and see or to operate. A percutaneous nephrostomy or a DJ-catheter is not often used in the treatment of obstruction in general. These forms of drainage are more often used in the treatment of stones or of extrinsic obstruction. A pyelocutaneostomy or ureterocutaneostomy is a special surgical procedure in pediatric urology for transient drainage of the upper urinary tract (megaureter). The operation of a seriously ill new-born should be done in a centre for pediatric urology and pediatric nephrology. When the upper urinary tract is dilated, patients may need an antibiotic prophylaxis, because the dilatation of the upper urinary tract increases the risk of urinary tract infections (UTI). The indication for antibiotic prophylaxis should by guided by the criteria of the APN-Consensus Paper. Long-term follow-up is necessary and should comprise ultrasound, physical examination, controlling the blood pressure, urine analysis and blood tests. The aims of diagnostics, treatment and long-term follow-up are the preservation of renal function and to protect the children from UTI. This goal must be reached under conditions that are appropriate for children and their parents.

Biomarkers of congenital obstructive nephropathy: past, present and future.

PURPOSE: Congenital obstructive nephropathy constitutes one of the major causes of renal insufficiency in infants and children. This review addresses the need to define biomarkers that serve as surrogate end points for measuring the severity of obstruction, the evolution of renal maldevelopment and injury, and the response to medical or surgical intervention. MATERIALS AND METHODS: The literature from the last 10 years was reviewed for biomarkers of congenital obstructive nephropathy. Sources of biomarkers included urine, blood, amniotic fluid, tissue and imaging techniques. RESULTS: Previous markers of congenital obstructive nephropathy include sonographic renal pelvic diameter, quantitative diuretic renography, and markers of glomerular and tubular function. Attempts to correlate renal histological changes with differential renal function have been disappointing. Immunohistochemical analysis and laser capture microscopy should improve specificity. Most promising is the application of new insights into the cellular response of the developing kidney to urinary tract obstruction. These findings include components of the renin-angiotensin system, transforming growth factor-beta 1, monocyte chemoattractant protein-1 and epidermal growth factor. Microarray studies show unique patterns of gene expression by the neonatal rat kidney subjected to ureteral obstruction, and proteomics should provide even more sensitive biomarkers of obstructive nephropathy. CONCLUSIONS: We must define the cellular and molecular bases of renal maldevelopment, focusing on the link between functional and developmental pathophysiology. These findings will lead to biomarkers that will optimize our management of congenital obstructive nephropathy.

Obstructive ureterocele-an ongoing challenge.

Ureterocele is a cystic dilatation of the intravesical ureter that is most commonly observed in females and children, and usually affects the upper moiety of a complete pyeloureteral duplication. According to their position, ureteroceles are divided into intravesical, when the ureterocele is completely contained inside the bladder, and extravesical when part of the cyst extends to the urethra or bladder neck. Most ureteroceles are diagnosed in utero or immediately after birth during an echographic screening of renal malformations. Severe, febrile urinary tract infection is the most common postnatal presentation of ureteroceles, but they may, rarely, prolapse and acutely obstruct the bladder outlet. Once an ureterocele is identified sonographically, a voiding cystourethrogram to detect vesicoureteral reflux (VUR) and a 99m-technetium dimercapto-succinic acid renal scan to evaluate the function of the different portions of the kidney are mandatory. VUR in the lower pole is observed in 50% of cases and in the contralateral kidney in 25%. Simple endoscopic puncture of the ureterocele has recently been advocated as an emergency therapy for infected or obstructing ureteroceles and as an elective therapy for intravesical ureteroceles. The rate of additional surgery after elective endoscopic puncture of an orthotopic ureterocele ranges from 7 to 23%. Treatment of ectopic ureteroceles is more challenging and both endoscopic puncture and upper pole partial nephrectomy frequently require additional surgery at the bladder level. The reoperation rate after endoscopic treatment varies from 48 to 100%. It is 15 to 20% after upper pole partial nephrectomy if VUR was absent before the operation, but is as high as 50-100% when VUR was present. Thus, endoscopic incision is appropriate as an emergency treatment or when dealing with a completely intravesical ureterocele. Upper pole partial nephrectomy is the elective treatment for an ectopic ureterocele without preoperative VUR. In an ectopic ureterocele with VUR, no matter which type of primary therapy has been chosen, a secondary procedure at the bladder level, involving ureterocele removal and reimplantation of the ureter(s), should be anticipated.

Altered primate glomerular development due to in utero urinary tract obstruction.

BACKGROUND: In utero urinary tract obstruction is an important cause of newborn and childhood renal failure. Ureteric obstruction during active nephrogenesis results in cystic renal dysplasia; the earlier and longer the obstruction the more severe the histopathological changes of dysplasia. We have reported on a non-human primate model of non-surgical in utero fetal ureteric obstruction that accurately reflects the human equivalent of obstructive renal dysplasia. A striking feature of this model is the effect of obstruction on normal glomerular development and podocyte survival. METHODS: To study the effect of urinary obstruction on glomerular development, kidneys were studied from fetuses undergoing unilateral ureteric obstruction by ultrasound guided injection of alginate beads as early as 75 days gestation (term gestation = 165 +/- 10 days). These kidneys displayed all the features of human obstructive cystic dysplasia, had reduced weights, and significant deficiencies in terminal ureteric duct branching. RESULTS: A combination of histochemistry, histomorphometry, and immunocytochemistry was used to demonstrate deficient cortical ureteric duct development and branching, reduced glomerular number, and altered glomerular basement membrane formation with in utero urinary tract obstruction. CONCLUSIONS: These data suggest that urinary tract obstruction during active nephrogenesis results in a defect in ureteric duct branching morphogenesis, and altered vascularization of the glomerulus with consequent podocyte dropout and decreased glomerular number. These abnormalities reflect human renal dysplasia, which is associated with compromised postnatal renal function and, thus, should be predictive of postnatal outcome.

Deregulation of renal transforming growth factor-beta1 after experimental short-term ureteric obstruction in fetal sheep.

Renal malformations are the commonest cause of chronic renal failure in children and they are often associated with urinary tract abnormalities that impair fetal urine flow. Up-regulation of transforming growth factor-beta1 (TGF-beta1) occurs after experimental postnatal urinary tract obstruction and we recently reported increased levels of TGF-beta1 in human renal malformations (Yang SP et al, Am J Pathol 2000, 157:1633-1647). These findings led us to propose that obstruction-induced stretch of developing renal epithelia causes up-regulation of TGF-beta1, which then perturbs renal development. In this study, therefore, we examined expression of components of the TGF-beta1 signaling axis in a previously characterized ovine model of fetal short-term urine flow impairment in which complete unilateral ureteric obstruction was induced at 90 days when a few layers of glomeruli had formed. Up-regulation of TGF-beta1 mRNA and protein was observed in obstructed kidneys, compared to sham-operated control organs, after only 10 days. Increased levels of TGF-beta1 receptors I (TGF-betaR1) and II (TGF-betaR2) were also detected on Western blot, and the cytokine and TGF-betaR1 co-localized in disrupted epithelia on immunohistochemistry. De novo expression of alpha-smooth muscle actin, a structural protein up-regulated during TGF-beta1-induced phenotypic switching between human renal dysplastic epithelial and mesenchymal lineages in vitro, was also observed in these aberrant epithelia. These findings implicate increased TGF-beta1 signaling in the early biological changes generated by fetal urinary tract obstruction.

Renal pelvic pressure responds with augmented increases to increments in intraabdominal pressure.

BACKGROUND/PURPOSE: Flow of a fluid through a collapsible tube is under the influence of various factors including the external compressing pressure. Because the intraabdominal pressure may compress the ureter, an experimental study has been planned to determine and compare the normal intraabdominal and renal pelvic pressures and the alterations in renal pelvic pressure in response to the increments in intraabdominal pressure in the rabbits. METHODS: Eight adult rabbits were used for the experiment. Under general anesthesia, an urethral catheter, a nasogastric tube, and an intraperitoneal catheter were placed to measure intravesical (IVP), intragastric (IGP), and intraabdominal pressures (IAP), respectively. Intracranial pressure monitorization catheter was placed into the renal pelvis to monitor intrapelvic pressure (IPP). Basal pressure measurements have been recorded. The pressures have been recorded in every 5 minutes, and IAP has been increased gradually about 3 to 4 cm of water pressure in every step for 30-minute periods. RESULTS: Increases in the intrapelvic pressure values have been significantly higher than the increases in the IAP (P < .001). A significant correlation has been found between IPP and IAP (P = .000, r = 0.866). By using linear regression analysis the relationship has been found to be IPP = 7.303 + 1.985 (IAP). Intragastric pressure values have been higher compared with IAP values (P < .001), whereas intravesical pressures have not differed from IAP (P > .05). CONCLUSIONS: Elevations in IAP results in augmented increases in the IPP. Poiseuille and Laplace Laws suggest this augmented increase to resemble proximal ureteric obstruction. Increases in IAP may simulate proximal ureteric obstruction and may take part in the pathogenesis of hydronephrosis. J Pediatr Surg 36:901-904.

Early fetal obstructive uropathy produces Potter's syndrome in the lamb.

BACKGROUND: If creating an obstructive uropathy early in glomerulogenesis produces MCDK (Multicystic Dysplastic Kidney), then a very early obstruction may produce Potter's Syndrome (PS) with oligohydramnios. METHODS: Fetal lambs at 50 days' gestation underwent urethral and urachal ligation using fine SILASTIC (Dow Corning, Midland, MI) tubing and were delivered by cesarean section at 145 days' gestation. At the time of death, kidney weight, length, and lung volumes were measured. These samples were examined histologically. Urinary sodium, chloride, potassium, and osmolarity also were measured. These were compared with normal-term fetuses. RESULTS: One ewe miscarried. Two of 3 of 50-day obstructive uropathy lambs survived. The 2 survivors had dysplastic kidneys. One with large gastroschisis did not have PS but the other had renal, pulmonary, and chest wall hypoplasia. Both male lambs had undescended testes with a large bladder. Kidney weights were 2 g in the PS lamb and 16 g in controls. Lung volume was 84 mL in the PS lamb and 340 mL in controls. The lamb's face was compressed and the fetus was hydropic. Urine sodium, potassium, and osmolarity levels were higher than that of controls. CONCLUSIONS: This is the first successful model ligating the penile urethra and urachus in a 50-day lamb. The authors' previous 60-day model did not have PS, but an earlier obstructive uropathy caused MCDK with PS.

How they begin and how they end: classic and new theories for the development and deterioration of congenital anomalies of the kidney and urinary tract, CAKUT.

CAKUT are problems that often require surgical intervention or, in the worst case, lead to renal failure and the need for dialysis and/or renal transplantation. It is believed that these anomalies share a common genetic cause and to date there has been no good animal model with which to study these abnormalities. Although the abnormal interaction between the ureteral bud and metanephric blastema leads to renal hypodysplasia, vesicoureteral reflux, and ectopic ureters to name a few, the genetic and biochemical modulation of urinary tract development is not understood. Studies using the mouse strain mutant for angiotensin type 2 (AT2) receptors have given new insight into this mystery. The animals show defective apoptosis of undifferentiated mesenchymal cells in the area surrounding the developing kidney and urinary tract. This abnormal apoptosis may well interfere with the normal interaction between the ureteral bud and metanephric blastema resulting in CAKUT. This abnormal interaction would theoretically lead to preexisting intrinsic abnormalities of the kidney, which are programmed and take effect early in embryonic development. In the worst cases, the renal abnormalities would lead to progressive deterioration of renal function. Undoubtedly, there are more genes and biochemical modulators involved in this process other than the RAS and AT2 receptors. Our current animal model gives new and unique possibilities with which to study development of the kidney and urinary tract and ultimately seek ways of preventing an often debilitating disease process.

Short-term urinary flow impairment deregulates PAX2 and PCNA expression and cell survival in fetal sheep kidneys.

Renal malformations account for most children with chronic renal failure and are often associated with urinary tract anatomical obstruction. We examined cellular and molecular events after experimental urinary flow impairment in fetal sheep. Ovine gestation lasts 144 to 150 days with the metanephros appearing at 27 to 30 days. We generated complete unilateral ureteric anatomical obstruction at 90 days when a few layers of glomeruli had formed. After 10 days, we recorded ureteric and pelvic dilatation with renal parenchymal weight greater than contralateral organs or those from unoperated fetuses. The nephrogenic cortex was replaced by disorganized cells separated by edema and prominent vascular spaces. Cortical histology was dominated by cysts associated with malformed glomerular tufts. Cystic epithelia expressed PAX2, a growth-stimulating transcription factor down-regulated during normal maturation, and proliferating cell nuclear antigen, a surrogate marker of cycling cells. Detection of apoptosis using propidium iodide and in situ end labeling showed a significant increase of the point prevalence of death in the obstructed cortex. Hence, PAX2 and proliferating cell nuclear antigen expression as well as death were deregulated, as we previously reported in human kidney malformations. Medullary collecting ducts and loops of Henle were also disrupted, correlating with impaired urinary dilution and sodium reabsorption. Therefore, complex aberrations of morphogenesis, gene expression, cell turnover, and urine composition occur relatively early after experimental impairment of fetal urinary flow.

Rearrangement of the human CDC5L gene by a t(6;19)(p21;q13.1) in a patient with multicystic renal dysplasia.

Genetic studies have implicated the short arm of chromosome 6 in congenital hydronephrosis. In previous studies, we described a fetus carrying a t(6;19)(p21;q13.1) as the sole cytogenetic anomaly and suffering from bilateral multicystic renal dysplasia caused by a bilateral complete pelviureteric junction obstruction, resulting in a massive hydronephrosis. Characterization of the chromosome 19 breakpoint region revealed that the transcription factor-encoding USF2 gene is affected. In this report, we show that the CDC5L gene on chromosome 6p is rearranged in the cells of the fetus. CDC5L encodes a protein that is related to the product of the Schizosaccharomyces pombe Cdc5 gene, which exerts its effects at the G2/M transition during cell cycle progression. We have established the genomic organization of the CDC5L gene and found that it consists of at least 16 exons spanning approximately 50 kb of chromosome segment 6p21. Northern blot analysis indicated that the gene is ubiquitously expressed as a single mRNA of about 3.4 kb in both fetal and adult tissues. The translation product of the CDC5L gene has an electrophoretic mobility of about 100 kDa and is predicted to be a nuclear protein, since it contains a Myb-related DNA binding domain and potential nuclear localization signals in its aminoterminal region. Immunocytochemical analysis confirmed the nuclear localization of the CDC5L protein. CDC5L was also predicted to contain a hydrophilic, proline-rich region in its central part, which might function as a transcriptional activating domain. The chromosome 6 breakpoint was found in the intron between exons 9 and 10, indicating that, as a direct result of the 6;19 translocation, the Myb-related DNA binding domains and the nuclear localization signals are separated from the putative transactivating domain. Northern blot and RT-PCR experiments revealed that the other CDC5L allele is unaffected, and in Western blot experiments, expression of the 100-kDa protein was detected in fibroblasts of the fetus. Expression of a truncated or hybrid CDC5L transcript resulting from the CDC5L rearrangement could not be demonstrated.