Transverse comparisons between ultrasound and radionuclide parameters in children with presumed antenatally detected pelvi-ureteric junction obstruction.

PURPOSE: The main criteria used for deciding on surgery in children with presumed antenatally detected pelviureteric junction obstruction (PPUJO) are the level of hydronephrosis (ultrasonography), the level of differential renal function (DRF) and the quality of renal drainage after a furosemide challenge (renography), the importance of each factor being far from generally agreed. Can we predict, on the basis of ultrasound parameters, the patient in whom radionuclide renography can be avoided? METHODS: We retrospectively analysed the medical charts of 81 consecutive children with presumed unilateral PPUJO detected antenatally. Ultrasound and renographic studies performed at the same time were compared. Anteroposterior pelvic diameter (APD) and calyceal size were both divided into three levels of dilatation. Parenchymal thickness was considered either normal or significantly decreased. Acquisition of renograms under furosemide stimulation provided quantification of DRF, quality of renal drainage and cortical transit. RESULTS: The percentages of patients with low DRF and poor drainage were significantly higher among those with major hydronephrosis, severe calyceal dilatation or parenchymal thinning. Moreover, impaired cortical transit, which is a major risk factor for functional decline, was seen more frequently among those with very severe calyceal dilatation. However, none of the structural parameters obtained by ultrasound examination was able to predict whether the level of renal function or the quality of drainage was normal or abnormal. Alternatively, an APD <30 mm, a calyceal dilatation of <10 mm and a normal parenchymal thickness were associated with a low probability of decreased renal function or poor renal drainage. CONCLUSION: In the management strategy of patients with prenatally detected PPUJO, nuclear medicine examinations may be postponed in those with an APD <30 mm, a calyceal dilatation of <10 mm and a normal parenchymal thickness. On the contrary, precise estimation of DRF and renal cortical transit should be performed in patients with APD >30 mm, major calyceal dilatation and/or parenchymal thinning.

Epidemiological urinalysis of children from kindergartens of Can Gio, Ho Chi Minh City - Vietnam.

BACKGROUND: Recent studies on Vietnamese children have shown that kidney diseases are not detected early enough to prevent chronic renal failure. The dipstick test is a simple and useful tool for detecting urinary abnormalities, especially in isolated or remote areas of Vietnam, where children have limited access to health care. METHODS: This cross-sectional study was conducted in 2011 at seven kindergartens in Can Gio district, Ho Chi Minh City, Vietnam. Two thousand and twelve children, aged 3 to 5, were enrolled. Morning mid-stream urine samples were examined by dipstick. Children with abnormal findings were re-examined with a second dipstick and underwent further investigations. RESULTS: Urinalysis was available for 1,032 boys and 980 girls. Mean age was 4.4 ± 0.8 years. Urinary abnormalities were detected in 108 (5.5%) of the subjects. Among them, nitrituria and leucocyturia accounted for more than 50%. Positive fractions of proteinuria, hematuria, nitrituria, leucocyturia, and combined nitrituria and leucocyturia after two dipsticks were 0.1%, 0.1%, 2%, 1% and 0.3%, respectively. Abnormal findings were more common in girls than boys (p < 0.001), and higher in communes with very low (< 50 persons/km2) population density (14.3% vs 4.1%, p < 0.001). A renal ultrasound detected four cases of hydronephrosis and one case of duplication of ureter. CONCLUSIONS: The prevalence of urinary abnormalities in asymptomatic children in South Vietnam demonstrates the need for hygiene education among parents. Training for dipstick usage for all medical staff at health stations, especially in remote areas and in places with very low population density, is also clearly necessary. Routine urinalysis can be set up if a close control is conducted at locations.

Predicting the clinical outcome of antenatally detected unilateral pelviureteric junction stenosis.

OBJECTIVE: To determine, in children with antenatally detected pelviureteric junction (PUJ) stenosis, what factors may be predictive for deterioration of differential renal function (DRF) in case of conservative treatment or improvement of DRF in case of pyeloplasty. METHODS: This study analyzed and compared the initial level of hydronephrosis, DRF, quality of renal drainage, and cortical transit with the late DRF outcome. We reviewed the medical charts of 161 consecutive children with antenatally diagnosed PUJ stenosis during a 10-year period (between 1997 and 2007). From this cohort, we retained 81 children with unilateral PUJ and strictly normal contralateral kidney, with a median follow-up of 67 months. Repeated ultrasounds, voiding cystourethrography, and radionuclide renograms were performed in all children. RESULTS: Fifty patients never underwent a surgical intervention (62%), whereas surgical repair (Anderson-Hynes dismembered pyeloplasty) was performed in 31 (38%). During conservative follow-up, DRF deterioration was observed in 11% of patients. After pyeloplasty, DRF improvement was observed in 25% of patients. Abnormal cortical transit was the only predictive factor of DRF deterioration in case of conservative approach, whereas the initial degree of hydronephrosis, or renal drainage, and the initial DRF level were not predictive. In children who were operated on, only impaired cortical transit was predictive of DRF improvement postoperatively. CONCLUSION: Conservative management of children with unilateral PUJ stenosis is a safe procedure. Impaired cortical transit although imperfect, seems the best criterion for identifying children for whom pyeloplasty is warranted.

Update on congenital nephrotic syndromes and the contribution of US.

The clinical classification of nephrotic syndrome (NS) is based on age at presentation. However, this classification is arbitrary because the majority of early onset NS has a genetic origin and has a widespread age of onset (from fetal life to several years). The aims of this review are to illustrate the knowledge accumulated on congenital nephrotic syndrome (CNS) in terms of genetics, classification, findings at histology and US-based on a review of the literature.

Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin beta2 function is the molecular basis of Pierson syndrome. Although truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.

CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.

Antibody deficiencies constitute the largest group of symptomatic primary immunodeficiency diseases. In several patients, mutations in CD19 have been found to underlie disease, demonstrating the critical role for the protein encoded by this gene in antibody responses; CD19 functions in a complex with CD21, CD81, and CD225 to signal with the B cell receptor upon antigen recognition. We report here a patient with severe nephropathy and profound hypogammaglobulinemia. The immunodeficiency was characterized by decreased memory B cell numbers, impaired specific antibody responses, and an absence of CD19 expression on B cells. The patient had normal CD19 alleles but carried a homozygous CD81 mutation resulting in a complete lack of CD81 expression on blood leukocytes. Retroviral transduction and glycosylation experiments on EBV-transformed B cells from the patient revealed that CD19 membrane expression critically depended on CD81. Similar to CD19-deficient patients, CD81-deficient patients had B cells that showed impaired activation upon stimulation via the B cell antigen receptor but no overt T cell subset or function defects. In this study, we present what we believe to be the first antibody deficiency syndrome caused by a mutation in the CD81 gene and consequent disruption of the CD19 complex on B cells. These findings may contribute to unraveling the genetic basis of antibody deficiency syndromes and the nonredundant functions of CD81 in humans.

Clinical characteristics and outcomes of children with stage 3-5 chronic kidney disease.

The aim of this study was to report on the clinical characteristics and outcomes of Belgian children with chronic kidney disease (CKD). Between 2001 and 2005, we followed 143 new successive patients younger than 20 years of age with a glomerular filtration rate of <60 ml/min/1.73 m(2) prospectively in a Belgian department of pediatric nephrology. The incidence of diagnosed CKD was 11.9 per million child population (pmcp), and the incidence of renal replacement therapy was 6.2 pmcp. There were 67% patients in CKD stage 3, 19% in CKD stage 4 and 14% in CKD stage 5. Patients with congenital anomalies of the kidney and urinary tract (CAKUTs), hereditary diseases and glomerular diseases were diagnosed at a median age of 1, 2 and 10 years, respectively. CAKUTs were the main causes of CKD, accounting for 59% of all cases. After 3, 4 and 5 years of follow-up, 27, 31 and 38% of patients treated conservatively, respectively, reached end-stage renal failure (ESRF). The progression rate to ESRF was eightfold higher in patients with CKD stage 4 than in those with CKD stage 3. Among our patient group, hereditary diseases progressed more rapidly to ESRF than CAKUTs. Transplantation was performed preemptively in 22% of these children. Infections and cardiovascular diseases were the main causes of death.

Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome.

We sought to ascertain the long-term outcome and genotype-phenotype correlations available for primary hyperoxaluria type 1 in a large retrospective cohort study. We examined the clinical history of 155 patients (129 families primarily from Western Europe, North Africa, or the Middle East) as well as the enzymatic or genetic diagnosis. The median age at first symptom was 4 years, and at diagnosis 7.7 years, at which time 43% had reached end-stage renal disease. Presentations included: (1) early nephrocalcinosis and infantile renal failure, (2) recurrent urolithiasis and progressive renal failure diagnosed during childhood, (3) late onset with occasional stone passage diagnosed in adulthood, (4) diagnosis occurring on post-transplantation recurrence, and (5) family screening. The cumulative patient survival was 95, 86, and 74% at ages 10, 30, and 50 years, respectively, with the cumulative renal survival of 81, 59, 41, and 10% at ages 10, 20, 30, and 50 years, respectively; 72 patients had undergone a total of 97 transplantations. Among the 136 patients with DNA analysis, the most common mutation was p.Gly170Arg (allelic frequency 21.5%), with a median age at end-stage renal disease of 47 years for homozygotes, 35 years for heterozygotes, and 21 years for other mutations. Our results underscore the severe prognosis of primary hyperoxaluria type 1 and the necessity for early diagnosis and treatment, as well as confirm a better prognosis of the p.Gly170Arg mutation.

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 results from alanine:glyoxylate aminotransferase deficiency. Due to genotype/phenotype heterogeneity in this autosomal recessive disorder, the renal outcome is difficult to predict in these patients and the long-term impact of conservative management in children is unknown. We report here a multicenter retrospective study on the renal outcome in 27 affected children whose biological diagnosis was based on either decreased enzyme activity or identification of mutations in the patient or his siblings. The median age at first symptoms was 2.4 years while that at initiation of conservative treatment was 4.1 years; 6 children were diagnosed upon family screening. The median follow-up was 8.7 years. At diagnosis, 15 patients had an estimated glomerular filtration rate (eGFR) below 90, and 7 children already had stage 2-3 chronic kidney disease. The median baseline eGFR was 74, which rose to 114 with management in the 22 patients who did not require renal replacement therapy. Overall, 20 patients had a stable eGFR, however, 7 exhibited a decline in eGFR of over 20 during the study period. In a Cox regression model, the only variable significantly associated with deterioration of renal function was therapeutic delay with a relative risk of 1.7 per year. Our study strongly suggests that early and aggressive conservative management may preserve renal function of compliant children with this disorder, thereby avoiding dialysis and postponing transplantation.

Genetic forms of nephrotic syndrome: a single-center experience in Brussels.

The aim of the study was to present our experience in treating children with genetic forms of nephrotic syndrome and diagnosing these diseases. We retrospectively reviewed the clinical data, mutational analyses, histopathological features, treatment modalities, and outcome of 26 consecutive children (20 families) suffering from congenital and/or steroid-resistant nephrotic syndrome who were assessed by genetic analysis. Ten out of 26 children (38%) had congenital nephrotic syndrome, 4/26 (15%) had infantile nephrotic syndrome, 10/26 (38%) had late-onset nephrotic syndrome, and 2/26 (9%) had asymptomatic proteinuria. We detected a mutation in 21/26 (81%) patients and in 15/20 (75%) families. NPHS1 mutation analyses were positive in 4/20 (20%), NPHS2 mutations in 4/20 (20%), WT1 mutations in 4/20 (20%), and PLCE1 mutations in 3/20 (15%) families. NPHS1 and PLCE1 mutations were solely found in patients with the earliest onset. The majority of patients, especially those with early onset of nephrotic syndrome, had serious adverse events related to the nephrotic status, and 19/26 (73%) reached end-stage renal failure at a median age of 27 months. Genetic forms of nephrotic syndrome comprise a heterogeneous group of genetic mutations. The progression toward end-stage renal failure is the rule but is highly variable between patients.

Multicentre prospective randomised trial of tacrolimus, azathioprine and prednisolone with or without basiliximab: two-year follow-up data.

A total of 192 children and adolescents undergoing renal transplantation were randomly chosen to receive tacrolimus, azathioprine and corticosteroids (TAS, n = 93) or tacrolimus, azathioprine, corticosteroids and two doses of basiliximab (TAS + B, n = 99). Six-month outcome data have previously been reported; this manuscript reports the 2-year data. Complete 2-year data were available on 164 (85.4%) of the original 192 patients. There was a single death in the TAS arm. Kaplan-Meier estimates of survival free of graft loss at 2 years were 94.9% in the TAS + B arm and 89.6% in the TAS arm [hazard ratio (HR) 0.52; 95% confidence interval (CI) 0.17 to 1.54, P = 0.23]. Estimates of survival free from rejection at 2 years were 75.2% in the TAS + B arm and 68.7% in the TAS arm (HR 0.81; 95% CI 0.46 to 1.40, P = 0.44). The mean estimated glomerular filtration rate (GFR) at 2 years, was 65.8 ml/min per 1.73 m(2) body surface area in the TAS arm and 66.7 ml/min per 1.73 m(2) in the TAS + B arm (P = 0.78). Blood pressure and cholesterol levels were similar in the two arms, and there was no evidence of a difference in the incidence of infection or malignancy. These data provide further evidence of a lack of benefit associated with the addition of basiliximab to a TAS regimen for European paediatric renal transplant recipients at low immunological risk.

Etiology and outcome of chronic renal failure in hospitalized children in Ho Chi Minh City, Vietnam.

The aim of this study was to investigate the etiology and treatment modalities and to determine mortality risks in hospitalized children with chronic renal failure (CRF) in Ho Chi Minh City, Vietnam. We reviewed the records of 310 children with CRF hospitalized in Ho Chi Minh City from January 2001 to December 2005. The average annual number cases was 4.8 per million child population native to Ho Chi Minh City. Median age was 14 years; 85% of patients were in end-stage renal failure. Associated illnesses were anemia (96%), hypertension (74%), and cardiopulmonary diseases (39%). Causes of included glomerulonephritis (30%) and congenital/hereditary anomalies (20%), but in 50% of children, the etiology was unavailable. Seventy-three percent of cases with end-stage renal failure did not benefit from renal replacement therapy. During hospitalization, 47 patients (15%) died. Mortality risks were higher in young children (1-4 years), in boys, and in patients with acquired pathologies. Severe metabolic acidosis was the main predictive factor of mortality by multivariate regression analysis. Our data shows a poor outcome due to late referral and limited facilities for renal replacement therapy in children with CRF hospitalized in Ho Chi Minh City.

WT1 gene mutations in three girls with nephrotic syndrome.

Denys-Drash syndrome and Frasier syndrome are two related conditions caused by mutations of the Wilms tumor gene, WT1. Both syndromes are characterized by male pseudohermaphrodism, a progressive glomerulopathy, and the development of genitourinary tumors. This study examines three girls with steroid-resistant nephrotic syndrome related to mutations in the WT1 gene, but with normal 46, XX karyotype and normal female phenotype. WT1 mutation analysis should be routinely done in females with steroid-resistant nephrotic syndrome.

Neonatal disease in neutral endopeptidase alloimmunization: lessons for immunological monitoring.

Neutral endopeptidase (NEP) alloimmunization has recently been determined to cause severe forms of neonatal disease as a result of the transplacental passage of anti-NEP antibodies. However there is a wide spectrum of neonatal disease variability. We present the medical histories of a large family, specifically of two alloimmunized sisters in their second pregnancy in whom we established the basis of immunological surveillance and therapeutic intervention during pregnancy and after delivery. One mother developed dramatically high titers of IgG1 and IgG4, and was treated with IvIg and one plasma exchange, both of which substantially reduced the anti-NEP Ab titer. However, the neonatal syndrome observed in her infant was severe, partly due to treatment delay. Anti-NEP Ab were also found in the mother's milk and the infant's urine. In contrast, the other mother had a normal second pregnancy and delivered a healthy neonate, which was related to the fact that she only produced the non-complement activating IgG4 subclass of anti-NEP antibodies. Thus, anti-NEP Ab (titer and subclass) seem to be highly sensitive biomarkers of neonatal risk. Interventional strategy aimed at reducing anti-NEP titer, should be started early during pregnancy and, possibly, even before pregnancy in those mothers producing anti-NEP IgG1. Careful monitoring of anti-NEP Ab titer and subclass is mandatory in NEP-deficient mothers during their pregnancies.

Role of truncating mutations in MME gene in fetomaternal alloimmunisation and antenatal glomerulopathies.

BACKGROUND: Membranous glomerulonephritis is an immune-mediated disease. In a recent case of antenatal membranous glomerulonephritis, we identified neutral endopeptidase (NEP) as the podocyte target antigen of circulating antibodies produced by the mother who failed to express NEP on granulocytes. We aimed to investigate whether the disease could affect other families, to search for mutations in the metallomembrane endopeptidase (MME) gene for NEP, and to analyse the outcome of the antenatal renal insult. METHODS: From three families with a case of neonatal membranous glomerulopathy, we detected mutations by direct sequencing of genomic PCR products. Single nucleotide polymorphism (SNP) analysis was undertaken with five SNPs located in the MME gene. IgG subclasses with anti-NEP activity were determined by western blotting. FINDINGS: In five mothers, we identified two compound heterozygous or homozygous mutations in the MME gene. The first, a 1342C-->T nonsense mutation, was detected in one family. The second, 446delC, was detected in all three families; all chromosomes bearing this mutation had the same alleles for the five SNPs. Severity of neonatal renal disease was determined by the mothers' IgG response to fetal NEP antigens expressed on glomerular podocytes. The oldest affected individual, now aged 20 years, has developed severe chronic renal failure. INTERPRETATION: Truncating mutations in the MME gene are the cause of alloimmunisation during pregnancy. Idiopathic renal failure in early adulthood might be caused by immune-mediated fetal nephron loss. We show that disease caused by fetomaternal alloimmunisation secondary to a genetic defect is not restricted to blood cells. RELEVANCE TO CLINICAL PRACTICE: During pregnancy, the absence of the NEP protein induces an alloimmunisation process against NEP presented by fetal cells, including syncytiotrophoblasts. The fetal podocyte insult and ensuing nephron loss could lead to chronic renal failure in early adulthood. Alloimmunisation against NEP should be considered as a leading cause of membranous glomerulopathy early in life. Concentrations of circulating anti-NEP antibodies should be carefully monitored during subsequent pregnancies, and specific therapeutic approaches developed. This new disease might also account for idiopathic chronic renal failure detected during adolescence, in individuals who can be identified by searching for anti-NEP antibodies in their mother and by MME gene mutation analysis. NEP deficiency should also be considered in patients developing de-novo membranous glomerulopathy after renal transplantation.

Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood.

OBJECTIVE: To determine which US changes occur with time in children affected by autosomal recessive (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) and whether any of these changes correlate with the onset of renal failure. MATERIALS AND METHODS: We reviewed the US features of 29 patients (16 ARPKD, 13 ADPK) imaged by at least two US examinations. We analysed the size and echogenicity of the kidneys, corticomedullary differentiation (CMD), the presence, location and size of cysts and any other anomaly that developed with time. In order to determine whether a relationship could be found between any of the US changes and the onset of the renal failure (based on a glomerular filtration rate < 50 ml/min per 1.73 m2), a Pearson exact chi-square test was calculated. RESULTS: For ARPKD, renal size was above 4 standard deviations (SD) in 10 of 16 patients, but it remained stable during evolution (10/16). The kidneys appeared hyperechoic (16/16), without CMD in the majority (11/16) of patients. Changes in the appearance of CMD over time were observed in five patients. Small cysts (< 1 cm) were present at the time of diagnosis in seven patients, larger cysts (> 1 cm) in three. A diffuse microcystic pattern was observed in three patients. Diffuse hyperechoic foci developed in 14 patients--13 of whom had developed renal failure at the time of the examination or rapidly thereafter (statistical correlation P=0.0125). For ADPKD, renal size was between 0-2 SD in 7 of 13 patients and above 2 SD in the other 6. Renal echogenicity was normal in five, difficult to assess in five and the kidneys appeared hyperechoic without CMD in three patients. Cysts larger than 1 cm were present in 8 of 12 patients (> 3 cm in 5). In four patients, the cysts measured less than 1 cm. In the last child, the diagnosis had been made antenatally and the first cysts appeared at the age of 6 months. The size of the kidneys (13/13) and of the cysts (11/13) remained stable. No renal failure occurred. CONCLUSIONS: ARPKD may manifest with various US patterns and there may be evolution in the appearances over time. Our study confirms a significant relationship between the development of diffuse hyperechoic foci and the onset of renal failure. In older children, ARPKD and ADPKD may closely resemble each other. Large (> 3 cm) cysts are the US hallmark for the diagnosis of ADPKD; furthermore, fewer US changes occur with time during childhood in ADPKD.