Postnatal development and progression of renal dysplasia in cyclooxygenase-2 null mice.
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BACKGROUND: Genetic ablation of cyclooxygenase-2 (COX-2) resulted in cystic renal dysplasia and early death in adult mice. The ontologic development of the renal pathology and the biochemical and physiological abnormalities associated with the dysplasia are unknown. METHODS: Mice homozygous for a targeted deletion of COX-2 (-/-) were compared with wild-type littermates (+/+). Somatic and kidney growth and renal histology were studied at the day of birth and at a number of postnatal ages. Systolic blood pressure, urinalysis, urine osmolality, serum and urine chemistries, and inulin clearance were evaluated in adult animals. RESULTS: Beginning at postnatal day 10 (PN10), kidney growth was suppressed in -/- animals, while somatic growth and heart growth were unaffected. By PN10, -/- kidneys had thin nephrogenic cortexes and crowded, small, subcapsular glomeruli. The pathology increased with age with progressive outer cortical dysplasia, cystic subcapsular glomeruli, loss of proximal tubular mass, and tubular atrophy and cyst formation. Adult -/- kidneys had profound diffuse tubular cyst formation, outer cortical glomerular hypoplasia and periglomerular fibrosis, inner cortical nephron hypertrophy, and diffuse interstitial fibrosis. The glomerular filtration rate was reduced by more than 50% in -/- animals (6.82 +/- 0.65 mL/min/kg) compared with wild-type controls (14.7 +/- 1.01 mL/min/kg, P < 0. 001). Plasma blood urea nitrogen and creatinine were elevated in null animals compared with controls. Blood pressure, urinalysis, urine osmolality, and other plasma chemistries were unaffected by the deletion of COX-2. CONCLUSIONS: Deficiency of COX-2 results in progressive and specific renal architectural disruption and functional deterioration beginning in the final phases of nephrogenesis. Tissue-specific and time-dependent expression of COX-2 appears necessary for normal postnatal renal development and the maintenance of normal renal architecture and function. (+info)
Multicystic dysplastic kidney and Kallmann's syndrome: a new association?
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BACKGROUND: Kallmann's syndrome is characterized by anosmia and hypogonadotrophic hypogonadism. Radiographic studies of teenagers and older subjects with the X-linked form of the syndrome have shown that up to 40% have an absent kidney unilaterally. Although this has been attributed to renal "agenesis", a condition in which the kidney fails to form, little is known about the appearance of the developing urinary tract either pre- or post-natally in individuals with Kallmann's syndrome. METHODS: We describe two brothers who had features of Kallmann's syndrome, most probably of the X-linked variety, who both had a major urinary-tract malformation detected before birth. RESULTS: The brothers were found to have unilateral multicystic dysplastic kidneys on routine antenatal ultrasound scanning and both underwent surgical nephrectomy of these organs post-natally. Immunohistochemical studies on the younger sibling revealed hyperproliferative dysplastic kidney tubules which overexpressed PAX2, a potentially oncogenic transcription factor, and BCL2, a cell-survival factor, surrounded by metaplastic, alpha smooth-muscle actin-positive stroma: similar patterns have been observed in patients with non-syndromic multicystic dysplastic kidneys. CONCLUSIONS: Our results describe a new type of urinary-tract malformation associated with Kallmann's syndrome. However, since multicystic kidneys tend to involute, only when more Kallmann's syndrome patients are screened in utero or in early childhood using structural renal scans, will it be possible to establish whether multicystic kidney disease is a bona-fide part of the syndrome. (+info)
Deficiency of phospholipase C-gamma1 impairs renal development and hematopoiesis.
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Phospholipase C-gamma1 (PLC-gamma1) is involved in a variety of intracellular signaling via many growth factor receptors and T-cell receptor. To explore the role of PLC-gamma1 in vivo, we generated the PLC-gamma1-deficient (plc-gamma1(-/-)) mice, which died of growth retardation at embryonic day 8.5-9.5 in utero. Therefore, we examined plc-gamma1(-/-) chimeric mice generated with plc-gamma1(-/-) embryonic stem (ES) cells for further study. Pathologically, plc-gamma1(-/-) chimeras showed multicystic kidney due to severe renal dysplasia and renal tube dilation. Flow cytometric analysis and glucose phosphate isomerase assay revealed very few hematopoietic cells derived from the plc-gamma1(-/-) ES cells in the mutant chimeras. However, differentiation of plc-gamma1(-/-) ES cells into erythrocytes and monocytes/macrophages in vitro was observed to a lesser extent compared with control wild-type ES cells. These data suggest that PLC-gamma1 plays an essential role in the renal development and hematopoiesis in vivo. (+info)
Unilateral multicystic dysplastic kidney: a combined pre- and postnatal assessment.
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OBJECTIVE: To review the prenatal assessment of associated renal pathology, non-renal pathology and renal biometry, fetal outcome and postnatal urological management in the presence of unilateral fetal multicystic dysplastic kidney. METHODS: A total of 38 singleton pregnancies with fetal unilateral multicystic dysplastic kidney was studied over a 13-year period. Prenatally, fetal biometry, including head and abdominal circumferences and largest longitudinal diameter of the affected and contralateral kidneys, was performed. The amount of amniotic fluid was assessed. Fetal karyotyping was offered in cases of contralateral renal or non-renal pathology. A MAG 3 scan and voiding cystogram was performed approximately 4 weeks after delivery to establish renal function and to exclude urinary reflux. RESULTS: Unilateral fetal multicystic dysplastic kidney was left-sided in 53% and right-sided in 47% of cases. The fetus was male in 63% and female in 37% of cases. Associated renal and non-renal pathology existed in 21% and 5% of cases, respectively. The fetal karyotype in these subsets was always normal. The longitudinal diameter of the multicystic dysplastic kidney was above the 95th centile in 87%. There was polyhydramnios in three cases and oligohydramnios in two cases. The prematurity rate was 16%. Postnatal examination revealed a non-functional multicystic kidney in 87% (33/38) of cases. Following surgical removal of the affected kidney, these infants progressed normally. Of the remaining five infants, four died because of associated anomalies and one infant developed normally without surgery. CONCLUSIONS: Fetal outcome is determined by associated renal and/or non-renal structural pathology and not by the size/location of the unilateral multicystic dysplastic kidney or amniotic fluid volume. (+info)
Risk of Wilms' tumour with multicystic kidney disease: a systematic review.
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BACKGROUND: Children with multicystic kidney disease (MCKD) are increasingly managed conservatively and are followed up throughout childhood because they are perceived to be at increased risk of developing Wilms' tumour. With this risk still poorly defined and somewhat controversial, the strategy and the duration of follow up do not seem to be based on evidence. METHODS: Systematic review of the literature for all published cohort studies (prospective and retrospective) of children diagnosed to have unilateral MCKD and managed conservatively. EXCLUSION CRITERIA: bilateral MCKD, nephrectomy (not for malignancy) during the follow up period. We estimated for children with MCKD the probability of developing Wilms' tumour during the follow up period, with 95% CI using the Poisson distribution. RESULTS: From 26 reviewed studies, no cases of Wilms' tumour developed in 1041 eligible children. The mean probability of a child with unilateral MCKD to develop Wilms' was therefore nil, with a 97.5% upper CI estimated at 0.0035 (or 3.5 per 1000 children). CONCLUSION: The development of a national or a European registry for children with MCKD would increase the precision of their risk estimate to develop Wilms' tumour. In the meantime, there is no evidence to support any of the different modalities for following up these children by ultrasound, if indeed such a strategy is necessary. (+info)
Concomitant anomalies in 100 children with unilateral multicystic kidney.
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OBJECTIVES: To determine the incidence and type of associated urogenital anomalies in children with a unilateral multicystic kidney and to assess in children with nephrectomy the additional diagnostic value of cystoscopy and, in girls, of colposcopy. METHODS: This was a follow-up study of 100 fetuses with antenatally detected unilateral multicystic kidneys. After ultrasound confirmation of the diagnosis within a few days after birth voiding cystourethrography and isotope scan were performed in 83 of the surviving children to exclude vesicoureteral reflux and to establish renal function. Eighty-one children underwent nephrectomy and, prior to surgery, all underwent cystoscopy and girls also underwent colposcopy. RESULTS: Seventy-five children had one or more additional urogenital anomalies: 39 had anomalies of the contralateral kidney, 40 had anomalies of the ipsilateral kidney and 30 had one or more anomalies of the lower urogenital tract. With cystoscopy 54 anomalies of the genitourinary tract were detected in 48 children and with colposcopy three anomalies were detected in 35 girls. Eighty-one children had a nephrectomy or heminephrectomy and 33 of them needed other urological intervention. Thirteen fetuses died (mostly from agenesis of the contralateral kidney) and six infants had no surgery at all. CONCLUSION: Children with a unilateral multicystic kidney are at considerable risk of having other urogenital anomalies. When cystoscopy and colposcopy are added to routine investigations the rate of detection of anomalies is 75%, twice that reported in the literature. (+info)
The sensitivity of antenatal ultrasound for predicting renal tract surgery in early childhood.
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OBJECTIVE: To establish the sensitivity of antenatal ultrasound for identifying the need for renal tract surgery in infancy and early childhood. METHODS: A retrospective analysis of the surgical records in children under 5 years of age undergoing renal tract surgery in a regional pediatric urological surgery referral unit was carried out. All records between May 1997 and July 2002 were examined to assess the relationship between prenatal ultrasound findings and postnatal surgical pathology. RESULTS: A total of 106 operations had been performed. The detection rate of multicystic renal dysplasia was 100% (17/17). The equivalent detection rates for pelviureteral junction obstruction, duplex renal system and vesicoureteral reflux were 82.8, 67 and 26.1%, respectively. None of the babies with renal tumors had abnormal antenatal ultrasound findings. The diagnosis of postnatal renal surgical pathology was made on the basis of prenatal scan findings in 59.6% of cases, while recurrent urinary tract infection led to the diagnosis in 26.0%. CONCLUSIONS: Approximately 40% of children requiring surgery for renal tract pathology will have a normal antenatal ultrasound examination. The prevalence of abnormal antenatal ultrasound findings varies depending on the type of renal tract pathology. Despite these findings, the commonest indicator for surgery remains abnormal prenatal scan findings, followed by recurrent urinary tract infections. (+info)
Risk of hypertension with multicystic kidney disease: a systematic review.
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BACKGROUND: Children with multicystic kidney disease (MCKD) are increasingly managed conservatively, and are followed up throughout childhood because of the risk of hypertension highlighted in some reports. With this risk still poorly defined, the strategy and the duration of follow up do not seem to be based on evidence. METHODS: Systematic review of the literature for all published cohort studies (prospective and retrospective) of children diagnosed to have unilateral MCKD and managed conservatively. Exclusion criteria were bilateral MCKD, and nephrectomy (not for hypertension) during the follow up period. For children with MCKD, the probability of developing hypertension during the follow up period was estimated. RESULTS: From 29 reviewed studies, six cases of hypertension developed in 1115 eligible children. The mean probability of a child with unilateral MCKD developing hypertension was therefore 5.4 per 1000 (95% CI estimated at 1.9 to 11.7 per 1000). CONCLUSION: Although the risk of hypertension in MCKD is low, the results of this study do not allow firm recommendations on the frequency and duration of blood pressure measurement follow up for these children. Large prospective cohort studies with a very long duration of follow up are needed. (+info)