Mutation analyses of Uroplakin II in children with renal tract malformations.

BACKGROUND: Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations. METHODS: Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies. RESULTS: No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa. CONCLUSION: This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.     

Impact of Genetics on the Diagnosis and Treatment of Renal Cancer

Kidney cancer is a heterogeneous disease comprised of a number of histologic subtypes, each associated with unique genetic mutations, clinical features, and sensitivity to treatment. By examining families affected with the hereditary kidney cancer syndromes von Hippel-Lindau, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, and Birt-Hogg-Dubé, researchers have been able to identify the genes responsible for these syndromes. This work has revealed that kidney cancer is fundamentally a metabolic disorder, and as such, novel targeted therapies specific to their molecular biology have been developed and employed in both the hereditary and sporadic forms of renal cell carcinoma.     

Unilateral multicystic dysplastic kidney: experience in children

OBJECTIVES: To report a retrospective study of unilateral multicystic dysplastic kidneys (MCDK) in children, assessing the contralateral kidneys and urinary tract, the functional consequences, and the urological and nephrological management and outcome, as unilateral MCDK is the most common cause of renal cystic disease in children, and malformations of the contralateral urinary tract and kidney (pelvi-ureteric obstruction, megaureter, reflux, renal dysplasia) have been reported. PATIENTS AND METHODS: The study included 97 patients (60 boys, 37 girls) with MCDK seen between 1985 and 1998; 82 were diagnosed in utero by ultrasonography (US). After birth, the diagnosis was verified by US, renal scanning (in 93) or intravenous urography (in four), and 89 (92%) had voiding cysto-urethrography (VCUG). Of the 97 children, 87 (90% had a mean (range) follow-up of 44.3 (15-115) months. RESULTS: The MCDK was removed in 17 children; the follow-up of 75 children (five lost to follow-up) showed total involution of the MCDK in 25%, shrinkage in 60% and a stable size in 15%. None had any sign of malignancy. The contralateral kidney showed anomalies in 19 of 97 children (20%); 12 had a dilated renal pelvis (two with megaureter), six had a high echogenicity of the contralateral kidney (one had reflux, and two also pelvic dilatation). In only four of the 89 children was reflux found by VCUG; 16 of the 19 anomalies were detected by US. Five children needed surgery on the contralateral urinary tract (three a pyeloplasty, and one each a pyeloplasty plus ureteroneocystostomy, and an antireflux procedure). Of the contralateral kidneys 43% showed compensatory hypertrophy. There was mild renal insufficiency in three children; renal function seemed to be slightly impaired in many. Five infants had hypertension (four with spontaneous resolution) caused by renal scarring after pyelonephritis or inborn dysplasia of the contralateral kidney. There were symptomatic urinary tract infections in seven children. CONCLUSION: US can be used safely to diagnose unilateral MCDKs and malformations of the contralateral urinary tract and kidney. In cases where US of the dysplastic kidney remains uncertain renal scintigraphy is necessary to detect the lack of renal function. The low rate of reflux makes routine VCUG unnecessary if the contralateral upper urinary tract and kidney appear to be normal on US. Nephrectomy of the dysplastic kidney in typical cases is also unnecessary. A long-term nephro-urological follow-up of children with MCDK is recommended.     

Emerging roles of obstruction and mutations in renal malformations

In this short review I will highlight some of the ”molecular lesions” that occur in patients with malformations of the urinary tract in terms of: (1) aberrant gene expression in dysplastic and obstructed kidneys and (2) the effects of mutations and genetic polymorphisms on renal growth and response to injury. It is suggested that the prenatal obstruction of urinary flow transduces a signal which elicits a proliferative response in existing metanephric epithelia, with a concomitant block in new nephron formation and apoptosis of precursor cells. Understanding these processes may lead to the therapeutic modulation of disease. Secondly, I will review possible genetic influences in the generation of isolated (non-syndromic) renal malformations. In this respect, primary vesicoureteric reflux represents numerically the most important disorder, and the discovery of disease loci should facilitate early diagnosis and identification of asymptomatic carriers. It is possible that the apparent variable penetrance and expression of some familial renal malformations are the result of the action of modifying genes which act during kidney development or even after the nephrogenic period. Received January 9, 1998; accepted February 11, 1998     

Xanthogranulomatous pyelonephritis treated by partial nephrectomy

Xanthogranulomatous pyelonephritis is an uncommon disease in children. We report of a 2-month-old girl with urinary tract infection and with a renal mass detected by ultrasound scan. The preoperative differential diagnoses were Wilms tumor, multicystic dysplastic kidney, renal abscess, and mesoplastic nephroma. The subsequent histopathological findings allowed the diagnosis of xanthogranulomatous pyelonephritis (XGP). Although XGP is rare at this age, it must be considered in the differential diagnosis of a child presenting with renal mass, either with or without associated urolithiasis, anemia, and elevated inflammatory markers. The long-standing mainstay of therapy for diffuse XGP has been nephrectomy. However, we report the successful preservation of renal mass with partial nephrectomy for diffuse XGP. The affected kidney grew normally and preserved residual function after the operation. Hence we strongly suggest parenchymal saving in pediatric cases of XGP to preserve renal function.     

Urological anomalies and chronic kidney disease in children with anorectal malformations

Background

This study aims to predict risk factors for urological anomalies in children with anorectal malformations (ARM) and describes the clinical features of patients who have developed chronic kidney disease.

Methods

We retrospectively reviewed infants with ARM who received surgery and were followed at the Sabah Women and Children’s Hospital, Malaysia, from 1986 to 2010.

Results

One hundred and twenty-two children with anorectal malformations were studied, after excluding 24 children with incomplete data. Three factors were significant as predictors of the presence of a urological anomaly: high ARM lesion (OR 3.12, 95%CI 1.1–8.9), the presence of genital abnormality (OR 2.95, 95%CI 1.10–7.91) and cloacal anomaly in girls (OR 8.27, 95% CI 1.91–35.6). The most common anomalies were vesicoureteric reflux, single kidney and neurogenic bladder. Chronic kidney disease (CKD) was noted in 5.7%, in children who had recurrent urinary tract infections, neurogenic bladder or complex renal tract pathology; end-stage renal failure was seen in only 0.8% of children with ARM.

Conclusion

Urological anomalies were seen in 23% of patients, but the overall incidence of CKD and end-stage renal disease is low. Early identification of infants with ARM at risk of renal failure may be important for renal survival.     

Absence of mutations in the <Emphasis Type="Italic">HOXA11</Emphasis> and <Emphasis Type="Italic">HOXD11</Emphasis> genes in children with congenital renal malformations

Experimental studies have shown that homeobox genes are essential for the development of the kidney and urinary tract. Hoxa11/Hoxd11 double mutant mice demonstrate renal agenesis or hypoplasia. Since, to our knowledge, these genes have never been examined for alterations in humans with congenital anomalies of the kidney and urinary tract (CAKUT), we investigated whether mutations of HOXA11/HOXD11 genes are associated with non-syndromal congenital renal parenchymal malformations. DNA samples from 26 unrelated children with unilateral renal agenesis (URA), 20 with renal hypodysplasia (RHD) and 13 with multicystic dysplastic kidney (MCDK) were included in the study. Exons 1 and 2 of the HOXA11/HOXD11 genes were amplified individually by polymerase chain reaction (PCR) using 12 unique oligonucleotide primers. Single-strand conformation polymorphism (SSCP) analysis of overlapping polymerase chain reaction products was performed. SSCP analysis revealed no variant band shifts in the samples of the amplified segments of the 59 patients, suggesting lack of either mutation or polymorphisms. Our findings do not support the hypothesis that mutations in the HOXA11/HOXD11 coding regions are involved in the pathogenesis of human non-syndromal congenital renal parenchymal malformations. Further studies are necessary, since other genes known to affect nephrogenesis, as well as genetic and environmental factors, may be involved.     

Bladder dysfunction in children and adolescents after renal transplantation

The underlying mechanisms of urinary-tract infections (UTI) in renal transplant recipients are still not fully understood. In otherwise healthy children, bladder dysfunction increases the susceptibility to UTI. The aim of this study was to evaluate lower-urinary-tract function in children and adolescents after renal transplantation. Sixty-eight recipients of renal transplants, 5–20 years of age and 1–15 years after transplantation, were evaluated for their bladder function with a questionnaire, uroflowmetry and bladder ultrasound, and for renal function (glomerular filtration rate) by measuring clearance of inulin or iohexol. Forty-nine patients (72%) had some type of abnormality of bladder function. Abnormal bladder capacity was found in 26%, abnormal urinary flow in 50% and residual urine in 32% of the patients. There was no significant difference in bladder or renal function in children with urinary-tract malformations compared with those with normal urinary tract. Furthermore, there was no significant difference in renal function in patients with bladder dysfunction compared with those without. The incidence of bladder dysfunction is high in children and adolescents after renal transplantation, but the clinical significance of this finding and whether there is a correlation between bladder dysfunction and UTI in these patients need to be clarified further.     

Risk factors in internal urinary system malformations

Risk factors were studied in 370 children with internal urinary system (IUS) anomalies, coming from 105,374 consecutive births of known outcome. The incidence of IUS malformations was 3.51 per 1,000 births. Diagnosis was performed prenatally in 54.4% of patients. Two hundred and fifty-two patients had isolated IUS anomalies; 118 (31.8%) of the children had at least one non-urinary malformation. Fifty-five infants (14.8%) had recognized chromosomal and non-chromosomal syndromes. The more frequent non-urinary malformations were cardiac, digestive and limb anomalies. For each case a control was studied. The following features were assessed: sex ratio, parity and previous pregnancies, parental age, residency, education, ethnic origin, length, head circumference and weight at birth, genetic and environmental factors. Odds ratio values were calculated for risk factors. Weight, length and head circumference at birth were less than in the controls and the weight of the placenta was lower. Pregnancies with IUS anomalies were more often complicated by oligo-amnios and threatened abortions. Oligo-amnios was more frequent in pregnancies in which babies had multiple malformations and recognized syndromes with IUS anomalies. One child of every three with IUS anomalies had an extra-urinary malformation, which is 12 times the incidence of such malformation in our population. There was an increase in consanguinity in the parents of our patients. The incidence of IUS anomalies in first-degree relatives was 2.9%. First-degree relatives had more non-urinary malformations than controls (7.02 vs 3.2%). Our study demonstrated the high capacity of a general ultrasound screening programme to detect fetal malformations affecting the urinary tract.     

Molecular anatomy of the kidney: what have we learned from gene expression and functional genomics?

The discipline of paediatric nephrology encompasses the congenital nephritic syndromes, renal dysplasias, neonatal renal tumours, early onset cystic disease, tubulopathies and vesicoureteric reflux, all of which arise due to defects in normal kidney development. Indeed, congenital anomalies of the kidney and urinary tract (CAKUT) represent 20–30% of prenatal anomalies, occurring in 1 in 500 births. Developmental biologists have studied the anatomical and morphogenetic processes involved in kidney development for the last five decades. However, with the advent of transgenic mice, the sequencing of the genome, improvements in mutation detection and the advent of functional genomics, our understanding of the molecular basis of kidney development has grown significantly. Here we discuss how the advent of new genetic and genomics approaches has added to our understanding of kidney development and paediatric renal disease, as well as identifying areas in which we are still lacking knowledge.     

Poststreptococcal glomerulonephritis in children with congenital anomalies of the kidney and urinary tract

Abstract

Background: The objective of this study was to assess clinical course and outcome of children with congenital anomalies of the kidney and urinary tract (CAKUT) who had an attack of acute poststreptococcal glomerulonephritis (PSGN). Method: Renal status including blood pressure, proteinuria and glomerular filtration rate was retrospectively analyzed in five children with CAKUT and PSGN at the presentation and during the follow up. Results: In the period 2004–2013, 678 patients were diagnosed and recruited in our CAKUT cohort. During this period, 188 patients were hospitalized with the diagnosis of PSGN. A total of five patients had CAKUT and an episode of PSGN (2.6%). Analysis of the follow-up data revealed that three children fully recovered (bilateral vesicoureteral reflux n?=?1, ectopic/hypodysplastic kidney n?=?1, ureteropelvic junction obstruction n?=?1). One child with bilateral hypodysplasia had progressive worsening of the renal function and has been prepared for renal replacement therapy. Another child with single kidney has stable renal function but has significant rising proteinuria, which was not evident on the routine analysis 2 months before the attack of PSGN. Conclusion: Poststreptococcal glomerulonephritis in children is generally benign disease with low mortality in acute stage and excellent medium and long-term prognosis. We analyzed our series of PSGN patients and found that 2.6% had anomaly of the urinary tract. The unfavorable outcome was noted in children with single kidney and bilateral renal impairment.     

Pediatric renal transplantation and the dysfunctional bladder

We retrospectively reviewed our long-term experience with pediatric renal transplantation into a dysfunctional lower urinary tract to evaluate graft survival, function, and special urological complications. Between 1967 and March 2000, a total of 349 renal transplantations were performed in children younger than 18 years. Malformations of the lower urinary tract were the reasons for end-stage renal failure in 66 children (18.6%). The cause of urinary tract disorders included: meningomyelocele connected with neuropathic bladder (n=4 transplantations); prune belly syndrome (n=5 transplantations); VATER association (n=2 transplantations); posterior urethral valves (n=27 transplantations); and vesico-uretero-renal reflux (n=28 transplantations). The majority of the patients underwent surgical interventions to preserve renal function or to prepare renal transplantation. The 1- and 5-year graft survival rate was evaluated with special reference to the underlying disease. The 1-year graft survival rate in all children with lower urinary tract malformations was 83.3%, compared with 88% for all children. In those children with vesico-ureteral reflux, it was 92.8% and in the children with Vater association and prune belly syndrome, it was 85.7%. One graft was lost in the children who had neurogenic bladder, so the 1-year graft survival rate was 75%. The worst 1-year graft survival rate was obtained for boys who had posterior urethral valves (1-year graft survival rate: 74%; 5-year graft survival rate: 62.9%). Concerning the 5-year graft survival rate, it was 70% for all children with malformations of the urinary tract. The best rate was obtained for children with reflux in the native kidneys (78.5%), followed by those with VATER association and prune belly syndrome. As an additional child with neurogenic bladder lost his graft, the 5-year graft survival rate was 50%. Pediatric renal transplantation into a dysfunctional bladder can be connected with high urological complication rates which may contribute to worse graft survival. The 1- and 5-year graft survival rate in children with malformations of the lower urinary tract is worse than in children without bladder dysfunction. We regarded a striking difference between graft survival and the urological disorders which led to renal insufficiency. We obtained the worst graft survival rates in children with posterior urethral valves which are usually connected with bladder emptying problems and dysfunctional voiding. Potential pediatric transplant recipients must be classified according to pathophysiological as well as anatomical abnormalities of the urinary tract and all urological problems have to be solved prior to transplantation. At our center, living donors are favored to plan transplantation of these children properly.     

Echography and fetal urinary malformations

A great number of malformations of the foetal urinary tract can now be discovered during the antenatal period, due to the technological development of ultrasound in the light of foetal physiology: firstly the case of a severe oligohydramnios indicating a bilateral renal malformation and underlining its seriousness which is lethal in most cases: early severe oligohydramnios leads to very serious pulmonary hypoplasia of which the child will die at birth even if he only presents a surgically curable malformation such as lower urinary tract valves. This severe oligohydramnios is seen in bilateral renal agenesis, infantile polycystic kidney disease, multicystic bilateral dysplasia, lower urinary tract obstructions. Absence of oligohydramnios: unilateral malformation (it must be taken into consideration that normality of the contralateral kidney is not always easy to confirm by ultrasound). This is the case of unilateral hydronephrosis, unilateral renal agenesis, unilateral multicystic dysplasia, solid renal dysplasia, unilateral primary megaureter. Finally, complex malformations, where the diagnosis and management are problematic because the intensity of the effects is difficult to evaluate, the complexity of the malformation makes the diagnosis uncertain and lastly there exists an oligohydramnios which is more or less severe which makes for a difficult examination. This is the case of bilateral hydronephrosis, lower urinary tract obstructions, Prune Belly syndrome, bilateral primary megaureters, and megabladders.     

Prenatal diagnosis of urinary tract malformation

Malformation of the urinary tract (UT) is among the most common of all congenital malformations. Prior to the common usage of prenatal ultrasound, these anomalies were undetected until pediatric complications prompted investigation. When diagnosed and treated in early infancy, children with urinary tract malformations have a much better prognosis than when diagnosis is delayed beyond 1–2 years. Since the first report of the prenatal diagnosis of polycystic kidney disease by Garrett et al. in 1970, most forms of congenital urinary tract malformation have been diagnosed antenatally with the use of sonography. A review of the normal and abnormal development of the urinary system, some genetic aspects of UT malformations, and an overiew of the major UT anomalies and their prenatal diagnosis is presented.     

Intestinal reconstruction of the lower urinary tract as a prerequisite for renal transplantation

OBJECTIVE

To report a two‐stage protocol for children in whom bladder reconstruction was followed by kidney transplantation, as about a quarter of children requiring a kidney transplantation show significant lower urinary tract dysfunction, and consequently their bladder is unsuitable for a kidney transplant.

PATIENTS AND METHODS

Twelve children (median age 9.5 years, range 4.2–16.8) with end‐stage renal disease had a lower urinary tract reconstruction before kidney transplantation. The cause of bladder dysfunction and renal failure included posterior urethral valves in five, neuropathic bladder in two, prune‐belly syndrome in two, anal‐rectum and urethral atresia syndrome in one, primary obstructive uropathy in one and caudal regression syndrome in one. Two children were diverted with an ileal conduit; four had a bladder augmentation, and four had a bladder augmentation with additional continent cutaneous stoma. A continent urinary reservoir was constructed in one boy, and one boy had a Mitrofanoff‐only procedure. Subsequently, 11 children were transplanted.

RESULTS

The graft survival rate was 11 of 12 at 1 year and eight of 12 at 5 years. No patient lost the graft related to the reconstructed lower urinary tract. During the median (range) follow‐up of 5.4 (1.6–12.5) years all but one child had free drainage of the upper urinary tract. All 10 children who did not have an ileal conduit are continent.

CONCLUSION

Reconstruction of the lower urinary tract followed by renal transplantation is a safe and efficient approach. It has the advantage of restoring the lower urinary tract before immunosuppressive therapy, and supplies the best possible reservoir for a transplanted kidney.     

Antenatal oligohydramnios of renal origin: postnatal therapeutic and prognostic challenges.

Urinary tract anomalies (UTA) including polycystic kidney disease nowadays can be detected antenatally by ultrasound. The concomitant presence of oligohydramnios has been regarded as a severe risk factor for renal dysfunction and pulmonary hypoplasia, although clinical data after birth are scarce. We report the postnatal course and long-term follow-up of 10 infants with oligohydramnios due to congenital UTA from two pediatric nephrology centers. The underlying final diagnoses were autosomal-recessive polycystic kidney disease (ARPKD, n = 2), familial tubular dysgenesis (n = 2) and bilateral renal hypoplasia (n = 6) including 3 children with posterior urethral valves. Two children died in the neonatal period while 8 children are currently alive at a median age of 2.5 (range 1.1-10) years. In the postnatal period, respiratory failure necessitating mechanical ventilation occurred in 7 infants (including the 2 non-survivors). All surviving children had chronic renal failure, which could be managed conservatively in 6 children (median GFR 45 (range 15-53) ml/min/1.73 m2) while 2 reached end-stage renal disease; one undergoing preemptive kidney transplantation and one peritoneal dialysis. Seven of 8 children reached normal developmental milestones. In conclusion, the presence of antenatal oligohydramnios in infants with UTA does not always carry a poor prognosis. The high incidence of perinatal complications, the complexity of underlying causes and the prevalence of postnatal chronic renal dysfunction calls for a multidisciplinary approach in the management of these children.     

Progression of chronic renal failure in children with dysplastic kidneys

The aim of this study is to describe progression of chronic renal failure (CRF) in children with renal malformations and to study factors influencing this progression. We reviewed retrospectively 176 children with CRF secondary to renal dysplasia, reflux nephropathy or renal obstruction with at least 5 years of follow-up. Serum creatinine was recorded at least every third month, and an estimated glomerular filtration rate (eGFR) was calculated. Number of febrile urinary tract infections (UTI), blood pressure, albuminuria (UaUc), and number of functioning kidneys was also recorded. We found that the development of renal function could be separated into three time periods: (1) During the first years of life, 82% of the children showed early improvement of their kidney function, which lasted until a median age of 3.2 years (median improvement 6.3 ml/year). (2) From the age of 3.2 years until 11.4 years, 52.5% of the studied children showed a stable kidney function, whereas in 47.5%, kidney function immediately started to deteriorate. (3) Around puberty, 42.9% started deterioration in kidney function, whereas 57.1% even after puberty showed a stable function. Patients with UaUc >200 mg/mmol deteriorated faster (−6.5 ml/min per 1.73 m² per year compared with −1.5 ml/min per 1.73 m² per year) in those with UaUc <50 mg/mmol. Children with more than two febrile UTIs, hypertension or an eGFR at onset of less than 40 ml/min per 1.73 m² deteriorated faster than the others. Most children experienced early improvement of kidney function. The further prognosis, early or late deterioration of kidney function or stable function during the whole follow-up, was related to albuminuria, number of febrile UTIs, eGFR at onset of deterioration, hypertension and puberty.