FGF-7 modulates ureteric bud growth and nephron number in the developing kidney

The importance of proportioning kidney size to body volume was established by clinical studies which demonstrated that in-born defecits of nephron number predispose the kidney to disease. As the kidney develops, the expanding ureteric bud or renal collecting system induces surrounding metanephric mesenchyme to proliferate and differentiate into nephrons. Thus, it is likely that nephron number is related to ureteric bud growth. The expression patterns of mRNAs encoding Fibroblast Growth Factor-7 (FGF-7) and its high affinity receptor suggested that FGF-7 signaling may play a role in regulating ureteric bud growth. To test this hypothesis we examined kidneys from FGF-7-null and wild-type mice. Results of these studies demonstrate that the developing ureteric bud and mature collecting system of FGF-7-null kidneys is markedly smaller than wild type. Furthermore, morphometric analyses indicate that mature FGF-7-null kidneys have 30+/-6% fewer nephrons than wild-type kidneys. In vitro experiments demonstrate that elevated levels of FGF-7 augment ureteric bud growth and increase the number of nephrons that form in rodent metanephric kidney organ cultures. Collectively, these results demonstrate that FGF-7 levels modulate the extent of ureteric bud growth during development and the number of nephrons that eventually form in the kidney.     

Cloning of mouse c-ros renal cDNA, its role in development and relationship to extracellular matrix glycoproteins

Renal organogenesis ensues following reciprocal interactions between the uninduced metanephric mesenchyme and the ureteric bud. Conceivably, the presence of ligands or growth factors on a given cell type, and expression of receptors, including receptor proto-oncogenes, on the other cell type of different lineage would facilitate such epithelial-mesenchymal interactions. During these interactions, other macromolecules, such as extracellular matrix (ECM) proteins, present at the epithelial-mesenchymal surface, also play a role in the kidney morphogenesis. In this study the proto-oncogene, c-ros, was cloned and sequenced; its role in the metanephric development was examined, and correlated with the changes in the expression of ECM proteins. The mouse c-ros renal cDNA, belonging to phosphotyrosine kinase (PTK) receptor family, had a translation product of 2340 amino acids. The extracellular domain had 32 N-linked glycosylation sites and 30 cysteine residues. The transmembrane segment had a hydrophobicity approaching approximately 3.5. Multiple phosphorylation sites, typical of a PTK catalytic unit, were present in the cytoplasmic domain. The 3' noncoding region did not contain any A(U)nA mRNA instability motifs. The c-ros mRNA was highly expressed on the ureteric bud branches and their tips and on the developing glomeruli. Competitive RT-PCR analyses revealed the c-ros expression was the highest at 13th day of gestation, and it declined to very low levels during the neonatal period. Exposure of metanephric kidneys to c-ros antisense-oligonucleotide, derived from the PTK domain, caused dysmorphogenesis of the kidney and loss of c-ros expression on the ureteric bud branches. Concomitant with the reduced c-ros gene expression, a decreased expression of ECM glycoproteins, in particular the proteoglycans, was observed. These findings suggest that the c-ros plays a role in the metanephric development, and its effects may be modulated by the ECM macromolecules present at the epithelial-mesenchymal interface.     

Do long-chain polyunsaturated fatty acids influence infant cognitive behaviour?

OBJECTIVE: To determine: (i) the proportion of vesicoureteric reflux (VUR) associated with congenital renal damage and whether it can be severe enough to cause renal impairment from birth: (ii) to evaluate the distribution of males and females affected; and (iii) to describe the course of congenital damage in the first years of life. PATIENTS AND METHODS: A total of 108 children (76 male and 32 female, M:F 2.3:1), whose VUR was diagnosed before any infection, were followed from birth for a mean (range) of 4.3 (1-10) years. Renal damage was defined by serum creatinine concentration, creatinine clearance and renal imaging (ultrasonography and renal scintigraphy) performed within the first month of life and periodically thereafter. RESULTS: Of the 108 children, 58 had bilateral and 50 unilateral reflux (total number of refluxing units, 166). High-grade VUR (grade > or = 4) was found in 96 (58%) refluxing renal units (RRUs). Males had a prevalence of bilateral severe (> or = grade 4) reflux (M:F 5.2:1), while in those wit unilateral VUR, the M:F ration was 1.5:1. At birth, mild to moderate damage was present in 56 (36%) RRUs and only associated with VUR of grade > or = 3. Bilateral reflux of grade > or = 4 was associated with congenital moderate/severe renal failure in nine neonates (seven males). In infants with grade > or = 4 VUR who underwent surgical correction, VUR resolved in 92% of cases. In infants with VUR of grade > or = 4 followed medically, the reflux spontaneously resolved in 42% and ameliorated in 16% after 18 months. Serial renal scans during the follow-up showed no progression of renal damage. CONCLUSIONS: VUR diagnosed at birth on prenatal ultrasonography is associated with congenital damage, with males affected more often than females. The damage involves both kidneys in a consistent proportion and is an important cause of chronic renal impairment from birth. It does not progress in the first years of life if infections are prevented. It is suggested that males with this condition may constitute a major group at risk of developing chronic renal failure in later life.     

Kidney damage in sterile reflux

On the basis of the data mentioned and taking into consideration the fact that the whole complex of problems is not yet clarified unequivocally we come to the following conclusions: 1. Up to now there are no proofs for the fact that the most frequent type of reflux, i.e. the simple reflux of the urine from the urinary bladder into the upper urinary passage causes a renal damage. 2. The complicated VUR may certainly cause a urinary stasis kidney. In simultaneous calyco-tubular reflux probably focal shrinkings of the parenchyma may develop.     

The use of a multipurpose stent in children

OBJECTIVES: To assess the use of a multipurpose stent (the 'Blue stent', Angiomed Urosoft Pyeloplasty Stent, Bard, UK) in children undergoing pyeloplasty and ureteric reimplantation. PATIENTS AND METHODS: Between August 1994 and August 1996, the Blue stent was used in 50 renal units in 46 children aged 2 months to 12 years and 6 months. Twenty-five children underwent pyeloplasty, 11 had ureteric reimplantation for vesico-ureteric reflux (VUR), eight had ureteric reimplantation with remodelling for obstructed megaureters and in two patients it was used during the removal of stones. The mean follow-up was 18 months (range 6-30 months). RESULTS: After pyeloplasty, 22 patients (88%) had improved renal function and drainage with a decrease in hydronephrosis; two patients had a decrease in hydronephrosis only, one had an anastomotic leak and needed a repeat pyeloplasty and four developed a urinary tract infection (UTI). After ureteric reimplantation, VUR was not detected in any patient. Two patients had no change in drainage after remodelling and reimplantation of a megaureter, one was later diagnosed as having a neuropathic bladder and one child developed a UTI after ureteric reimplantation. The hospital stay was 3 days after pyeloplasty and 5 days after reimplantation. CONCLUSION: The design of the multipurpose Blue stent provides versatility; it can be used as a stent, and both an internal and external drain. Its use does not prolong the hospital stay. Insertion causes minimal trauma to the renal parenchyma, and removal is easy, pain-free and requires no anaesthesia. The complication rates in the present series compare favourably with other reported series.     

Effects of oxygen and carbon dioxide on mean cell volume

PURPOSE: Renal sonography is an accepted primary imaging modality for evaluating the pediatric urinary tract. We report a new sonographic finding associated with vesicoureteral reflux (VUR). METHODS: Ten patients underwent sonographic evaluation of the kidneys and were noted to have intermittent renal collecting system dilatation that expanded and contracted during real-time scanning. These patients were further evaluated with voiding cystourethrography. RESULTS: All 10 patients were proven to have VUR on the side of the sonographic abnormality. Four patients had bilateral VUR for a total of 14 refluxing renal units. Of these 14 renal units, 1 was sonographically normal. Five of the 14 renal units had grade V VUR that required surgical reimplantation of the ureter. CONCLUSIONS: This new finding of intermittent renal collecting system dilatation may become an important predictor of VUR. The finding warrants further evaluation even when detected in patients not suspected of having VUR who are undergoing renal sonography for other reasons.     

Mild renal pelvic dilatation is not predictive of vesicoureteral reflux in children

OBJECTIVE: To determine if mild renal pelvic dilatation at renal ultrasound (RUS) is a reliable sign of vesicoureteral reflux (VUR) at voiding cystourethrogram (VCUG) in children. MATERIALS AND METHODS: All patients less than 10 years of age who had RUS and VCUG on the same day during a 2-year period were identified in a computerized database. The appearance of the collecting system of each kidney was classified into two groups: group 0 - no dilatation (相似文献   

An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation

Through allele-segregation and loss-of-heterozygosity analyses, we demonstrated loss of the translocation-derivative chromosome 3 in five independent renal cell tumors of the clear-cell type, obtained from three members of a family in which a constitutional t(2;3)(q35;q21) was encountered. In addition, analysis of the von Hippel-Lindau gene, VHL, revealed distinct insertion, deletion, and substitution mutations in four of the five tumors tested. On the basis of these results, we conclude that, in this familial case, an alternative route for renal cell carcinoma development is implied. In contrast to the first hit in the generally accepted two-hit tumor-suppressor model proposed by Knudson, the familial translocation in this case may act as a primary oncogenic event leading to (nondisjunctional) loss of the der(3) chromosome harboring the VHL tumor-suppressor gene. The risk of developing renal cell cancer may be correlated directly with the extent of somatic (kidney) mosaicism resulting from this loss.     

Vesico-ureteral reflux in pediatrics

Vesico-ureteral reflux (VUR) is the most frequent uropathy involving 1-2% of children. Genetics, familiarity, race gender and age intervene in the pathogenesis of VUR. In particular, neonatal VUR seems to represent a specific entity. Different factors determine a renal damage due to RVU: direct action of VUR (back pression), urinary tract infection (UTI), inflammatory mechanisms and renal dysplasia. Micturing cystourethrography and nuclear cystography are currently performed for the diagnosis of VUR, being ultrasound examination aspecific. Functional parameters are now investigated in association with new morphologic studies. The strict relationship of VUR and UTI is discussed. The treatment (medical, surgical) of VUR is not well established, although some guidelines can be suggested. Finally an adequate support must be given to the family for an optimal management.     

A model of sterile vesicoureteric reflux in the sheep

Eighteen Coopworth ewe lambs were divided into three groups based on the initial cystourethrogram and cystometry findings at 5-7 weeks of age: group 1, 6 lambs with spontaneous low-pressure bilateral vesicoureteric reflux (VUR) on bladder filling were used to study the natural history of reflux; group 2, 5 lambs with no VUR detected were used to establish an experimental model of bilateral VUR using an unroofing surgical procedure; group 3, 7 lambs with spontaneous VUR detected during micturition had the same surgical procedure to increase the degree of VUR. All three animal groups were followed for 4-10 months. Spontaneous VUR was demonstrated in 13 of 18 lambs (25/36 ureters). The presence and severity of spontaneously occurring reflux in group 1 lambs diminished with increasing age. VUR was created successfully in group 2 and increased in degree in group 3 animals. The only significant histological finding in all three animal groups with grades II and III VUR was distal renal tubular dilatation. The sheep is a useful and readily available animal for studying VUR. During 4-10 months of follow-up, sterile reflux without bladder outflow obstruction resulted in distal renal tubular dilatation, but no renal parenchymal damage.     

The characteristics of primary vesico-ureteric reflux in male and female infants with pre-natal hydronephrosis

OBJECTIVE: To examine the characteristics of primary vesico-ureteric reflux (VUR) in young infants following prenatal hydronephrosis. PATIENTS AND METHODS: The study comprised 155 consecutive infants with VUR detected at a mean age of 8.7 weeks (SD 6.3). Reflux units (n = 236) were analysed for relationships between gender, severity of reflux, exposure to urinary tract infection (UTI) and the presence of focal and generalized types of kidney damage on imaging. Bladder wall thickness (from ultrasonography) was examined in comparison with a further group of 29 males without VUR. RESULTS: Male infants predominated (117 of 155, 75%); bilateral VUR affected the same proportion (52%) of males and females. Most kidneys exposed to VUR (158 of 236. 67%) were normal and of the 78 abnormal kidneys (57 without UTI), 53 showed generalized damage (only eight exposed to UTI) and 71 (91%) were associated with severe (grades IV and V) reflux that predominantly affected males (P < 0.001). Grade V reflux was almost exclusively a male disorder. Most female units (45 of 58, 78%) compared with 46% (82/178) of male units had mild (grades I to III) reflux that was independently associated with normal kidneys. The mean bladder wall thickness was significantly greater for males with VUR than for females with VUR and for males without VUR. CONCLUSIONS: Two distinct but not exclusive patterns of VUR were identified: (i) mild reflux associated with normal kidneys that affected most females and a proportion of males; (ii) severe reflux combined with kidney damage, most likely fetal in origin, that is almost exclusively a male disorder.     

Expression of fetal kidney growth factors in a kidney tumor line: role of FGF2 in kidney development

To identify growth factors which may play a role in kidney organogenesis, we have analyzed culture supernatants from the pediatric kidney tumor cell line G401. G401 cells were found to secrete fibroblast growth factor 2 (FGF2), a potent mitogen for mesenchymal cells, OP-1/BMP7, an epithelial cell growth inhibitor, and midkine (MK). Northern blotting confirmed expression of FGF2, OP-1/BMP7 and MK mRNA, as well as Wnt5A mRNA in G401 cells. In situ hybridization and immunocytochemistry on human fetal kidney demonstrated FGF2 expression in epithelial cells of the branching ureteric bud epithelium, nephron precursors ("S-shaped bodies"), proximal tubule epithelium and the parietal epithelium of the glomerulus. FGF2 protein in condensed "caps" of induced mesenchymal cells was also detected by immunocytochemistry. FGF2 protein was found to be concentrated in nuclei, particularly in proximal tubule epithelial cells. Recombinant FGF2 was found to act as a mitogen on primary mouse fetal kidney cell cultures. The results demonstrate G401 cells secrete a variety of fetal kidney growth factors and that FGF2 may act as a mitogen for fetal kidney cells and thus could play a role in the morphogenesis of the kidney.     

Oral administration of tritiated water (HTO) in mouse. III: Low dose-rate irradiation and threshold dose-rate for radiation risk

Primary vesicoureteric reflux (VUR) diagnosed on investigation of foetal hydronephrosis accounts for many antenatally detected uropathies. In order to study foetal VUR and its consequences, newborns with foetal hydronephrosis were investigated by ultrasound, micturating cystourethrogram and 99mTechnetium-dimercapto-succinic acid (DMSA), after beginning of chemoprophylaxis. Twenty-eight infants with VUR (bilateral in 15 cases) were identified giving a total 43 renal units for study. There was a predominance of males (86%), moderate/severe reflux (84%) and renal damage (51%). Presence of renal damage was correlated with the severity of reflux. VUR should be investigated in cases of foetal hydronephrosis and our results support that renal damage is frequently congenital and not secondary to urinary tract infection.     

PAX genes and human neural tube defects: an amino acid substitution in PAX1 in a patient with spina bifida

From studies in the mouse and from the clinical and molecular analysis of patients with type 1 Waardenburg syndrome, particular members of the PAX gene family are suspected factors in the aetiology of human neural tube defects (NTD). To investigate the role of PAX1, PAX3, PAX7, and PAX9, allelic association studies were performed in 79 sporadic and 38 familial NTD patients from the Dutch population. Sequence variation was studied by SSC analysis of the paired domain regions of the PAX1, PAX7, and PAX9 genes and of the complete PAX3 gene. In one patient with spina bifida, a mutation in the PAX1 gene was detected changing the conserved amino acid Gln to His at position 42 in the paired domain of the protein. The mutation was inherited through the maternal line from the unaffected grandmother and was not detected in 300 controls. In the PAX3 gene, variation was detected at several sites including a Thr/Lys amino acid substitution in exon 6. All alleles were present among patients and controls in about the same frequencies. However, an increased frequency of the rare allele of a silent polymorphism in exon 2 was found in NTD patients, but no significant association was observed (p = 0.06). No sequence variation was observed in the paired domain of the PAX7 and PAX9 genes. Our findings so far do not support a major role of the PAX genes examined in the aetiology of NTD. However, the detection of a mutation in PAX1 suggests that, in principle, this gene can act as a risk factor for human NTD.