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Congenital disorders of glycosylation (CDG) are a group of metabolic diseases resulting from defects in glycan synthesis or processing. The number of subgroups and their phenotypic spectrums continue to expand with most related to deficiencies of N-glycosylation. ALG9-CDG (previously CDG-IL) is the result of a mutation in ALG9. This gene encodes the enzyme alpha-1,2-mannosyltransferase. To date, a total of 10 patients from 6 different families have been reported with one of four ALG9 mutations. Seven of these patients had a similar phenotype with failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; the other three patients died in utero from a lethal skeletal dysplasia. This report describes an additional patient with ALG9-CDG who has a milder phenotype. This patient is a term female born to Caucasian, Canadian, non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. The metabolic work-up included analysis of a transferrin isoelectric focusing, which showed a type 1 pattern. This was confirmed by glycan profiling, which identified ahomozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) (NM_1234567890). This had been previously published as a pathogenic mutation in two Canadian patients. Our goal is to contribute to the growing body of knowledge for this disorder by describing the phenotypic spectrum and providing further insight on prognosis.

The abstract with Submission ID#809896 has been revised due to duplicate title and the missing main author.

Clinicians often use information about developmental outcomes in decision-making around offering complex, life-saving interventions in children such as dialysis and renal transplant. This information in children with end-stage renal disease (ESRD) is limited, particularly when ESRD onset is in infancy or early childhood. Using data from an ongoing prospective, longitudinal, inception cohort study of children with renal transplant before 5 years of age, we evaluated (1) the risk of adverse neurocognitive and functional outcomes at 5 years of age and (2) predictors of developmental outcomes. We found evidence of neurocognitive sequelae of ESRD in very young children; however, developmental outcomes appear remarkably better when compared with findings of two or three decades ago. Less time on dialysis predicted higher developmental scores, and hemodialysis was associated with poorer developmental outcomes. Our data suggest that renal replacement therapies in young children are associated with acceptable developmental outcome. Programs to identify those with developmental delays and provide early intervention may allow achievement of the child’s full potential.

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

Item does not contain fulltext Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.

Summary: Eighty children with nephrotic syndrome underwent lumbar spine densitometry and vertebral morphometry soon after glucocorticoid initiation. We found an inverse relationship between glucocorticoid exposure and spine areal bone mineral density (BMD) Z-score and a low rate of vertebral deformities (8%). Introduction: Vertebral fractures are an under-recognized complication of childhood glucocorticoid-treated illnesses. Our goal was to study the relationships among glucocorticoid exposure, lumbar spine areal BMD (LS BMD), and vertebral shape in glucocorticoid-treated children with new-onset nephrotic syndrome. Methods: Lateral thoracolumbar spine radiography and LS BMD were performed in 80 children with nephrotic syndrome (median age 4.4 years; 46 boys) within the first 37 days of glucocorticoid therapy. Genant semiquantitative grading was used as the primary method for vertebral morphometry; the algorithm-based qualitative (ABQ) method was used for secondary vertebral deformity analysis. Results: Six of the 78 children with usable radiographs (8%; 95% confidence interval 4 to 16%) manifested a single Genant grade 1 deformity each. All deformities were mild anterior wedging (two at each of T6, T7, and T8). Four of the 78 children (5%; 95% confidence interval 2 to 13%) showed one ABQ sign of fracture each (loss of endplate parallelism; two children at T6 and two at T8). Two of the children with ABQ signs also had a Genant grade 1 deformity in the same vertebral body. None of the children with a Genant or ABQ deformity reported back pain. An inverse relationship was identified between LS BMD Z-score and glucocorticoid exposure. Conclusions: Although we identified an inverse relationship between steroid exposure and LS BMD soon after glucocorticoid initiation for childhood nephrotic syndrome, there was only a low rate of vertebral deformities. The clinical significance of these findings requires further study. © 2011 International Osteoporosis Foundation and National Osteoporosis Foundation.

NPHP is an autosomal recessive chronic tubulointerstitial nephropathy that progresses to ESRD. In the 2006 NAPRTCS report, NPHP was the primary diagnosis in 2.8% of all renal transplant patients. At our pediatric center, that covers a population in which the NPHP1 gene is prevalent, 24% of transplant recipients had a primary diagnosis of NPHP. Since no previous literature reports have documented kidney transplant outcomes in patients with NPHP, a review of the 2006 NAPRTCS database was performed. The results of this review illustrate that patients with NPHP as their underlying kidney disease have a significantly better overall graft survival when compared with all other patients registered in the NAPRTCS database. Sub-analysis demonstrated that this benefit is statistically significant only for LD kidney transplant recipients. CrCl was better in NPHP at all time points from transplant up to five-yr follow-up. Moreover, in NPHP LD transplant recipients the decline of CrCl over five yr was slower compared with non-NPHP LD transplant recipients. Rates of thrombosis, acute, and chronic rejection as well as causes of graft failure were similar in NPHP patients and all other patients. This review demonstrates that NPHP transplant recipients have excellent outcomes that are shown to be better compared with the general pediatric transplant population.

Children undergoing kidney transplantation are at increased risk for symptomatic seizures with a previously reported incidence of approximately 20%. Little data exist to help predict which children may be at risk. We retrospectively reviewed all children who underwent kidney transplantation evaluation at our center between October 1993 and August 2007 and identified 41 children who had an EEG prior to transplant. Demographic data as well as the following were collected: immunosuppressive medications, developmental status, history of seizures, family history of seizures, post-transplant seizures and EEG results. EEGs were classified as normal or abnormal. Prior to transplantation, one child had a history of febrile seizures and six experienced afebrile seizures. Nine (22%) children identified had an abnormal EEG prior to transplant. In eight cases the EEG was non-epileptiform and in one case was epileptiform. Abnormal EEGs did not correlate with a family history of seizures. Delayed development was noted in seven children and was not associated with an epileptiform EEG. Following kidney transplantation, no child experienced a seizure. Our single center study suggests that current rates of seizures following kidney transplantation are lower than previously reported and that routine EEG as part of the pretransplant evaluation in these children is of limited use to predict those at risk.

The Hutterian Bretheren is an isolated population living on the North American prairies, the current community exceeding 40,000 in number. Their unique genetic history has contributed to a founder effect, which is reflected in the Mendelian disorders present in this population today. Genetic studies in the Hutterite population have led to the identification of a number of genes over the last several years and highlights the power of this population for gene identification. However, for the more than 30 autosomal recessive conditions currently recognized in this population, the gene or Hutterite specific mutation remains to be identified for over half and novel autosomal recessive syndromes continue to be recognized. This review summarizes what is currently understood about the molecular etiology of the Mendelian disorders and highlights the cardinal features of those disorders that are unique to or over-represented in this population.

Meckel syndrome (MKS) is a rare lethal autosomal recessive disorder characterized by the presence of occipital encephalocele, cystic kidneys, fibrotic changes of the liver and polydactyly. Joubert syndrome (JS)-related disorders (JSRDs) or cerebello-oculo-renal syndromes (CORS) are a group of recessively inherited conditions characterized by a molar tooth sign (MTS) on cranial MRI, a set of core clinical features (developmental delay/mental retardation, hypotonia, ataxia, episodic breathing abnormalities, abnormal eye movements) and variable involvement of other systems including renal, ocular, central nervous system, craniofacial, hepatic, and skeletal. A significant clinical overlap between MKS and JSRD/CORS has been recognized in the literature. We describe a group of 10 Hutterite patients, of which 7 had been previously diagnosed with MKS, with a JSRD. Clinical features include variable early mortality, cognitive handicap, a characteristic dysmorphic facial appearance, hypotonia, ataxia, abnormal breathing pattern, nystagmus, and MTS on MRI. Additional features include occipital encephalocele, posterior fossa fluid collections resembling Dandy-Walker malformation, hydrocephalus, coloboma, and renal disease. This JSRD is a recognizable dysmorphic syndrome characterized by hypertelorism, deep-set eyes, down-slanting palpebral fissures, ptosis, arched eyebrows with medial sparseness, square nasal tip, short philtrum with tented upper lip, open mouth with down-turned corners, and posteriorly rotated low-set ears. Renal disease is present in 70% of patients and is characterized by cystic kidneys, abnormalities in renal function and hypertension. Homozygous deletions of NPHP1 and the known loci for JS/JSRD and MKS were excluded by identity-by-descent mapping studies suggesting that this condition in the Hutterites represents yet another locus for a JSRD.

Background. Genotypes of the renin-angiotensin system have been implicated in essential hypertension and in progression of native kidney diseases, but gene effects on progression in chronic renal allograft dysfunction are unclear. Methods. To examine gene effects on long-term renal allograft function, we conducted a prospective cohort study of 210 nondiabetic renal allograft recipients younger than 36 years of age who underwent transplantation between 1980 and 1993 and were followed up through 1999. All grafts survived more than 1 year and all subjects received cyclosporine-based immunosuppression. DNA was analyzed by polymerase chain reaction for the angiotensin-converting enzyme insertion/deletion and angiotensinogen (AGT) M235T polymorphisms. Linear regression multivariate modeling of the slope of the inverse creatinine-versus-time, survival analyses for time-to-sustained doubling of baseline serum creatinine, time-to-graft loss, and a composite endpoint including patient death were performed. Results. Mean follow-up time was 8.4±3 years. Genotype frequencies for each marker system did not deviate significantly from the Hardy-Weinberg equilibrium. The slope of the inverse creatinine-versus-time for AGT 235T/T and M/T was significantly increased compared with M/M (P

INTRODUCTION:Streptococcus pneumoniaeis an uncommon cause of hemolytic uremic syndrome (HUS) with a unique pathophysiology that differs from Shiga toxin-related HUS.METHODS: Case descriptions for each patient are provided. Each strain ofS pneumoniaewas subjected to a pulsed-field gel electrophoresis (PFGE) analysis, Shiga toxin assay and polymerase chain reaction to detect Shiga toxin genes. A review of the current literature was conducted.CASE PRESENTATIONS: Two patients withS pneumoniae-related HUS that presented to the Alberta Children's Hospital, Calgary, Alberta, within four weeks of each other in 2001 are described. Both presented with pneumonia and empyema with associated HUS. Both patients required dialysis, one patient for 10 days and the other for 18 days. Neither patient demonstrated evidence of Shiga toxin-related disease.S pneumoniaeisolated from blood or pleural fluid was penicillin susceptible. One isolate was serotype 3 and the other was serotype 14. The two strains had different PFGE patterns. Both patients recovered well with no persistent renal dysfunction.CONCLUSIONS:S pneumoniaecontinues to be an uncommon but important cause of HUS. Most cases can be confirmed or at least considered probable without performing a renal biopsy.

Overall prognosis of children with steroid-sensitive nephrotic syndrome (SSNS) is regarded as generally favorable. However, only a few recent studies have evaluated changes in kidney function and blood pressure over time in children with SSNS.We describe clinical features of SSNS patients and characterize changes in calculated estimated glomerular filtration rate (eGFR) and use of antihypertensive medications during follow-up.This is a retrospective cohort study.This study was conducted in a Canadian pediatric nephrology center.This study included patients aged 1 to 18 years with SSNS.eGFR was calculated from recorded serum creatinine and height measurements using the modified Schwartz equation.eGFR was calculated at yearly intervals, and the trend of eGFR was assessed using linear mixed effects model. Patients were also evaluated for use of antihypertensive medications during follow-up.Seventy-eight patients-median age, 3.2 years (interquartile range [IQR], 2.65) and median follow-up of 4.37 (IQR, 5.6)-were evaluated. Sixty-three (80.8%) had at least 1 relapse. Twenty-two (28.2%) and 20 (25.6%) were steroid dependent and frequently relapsing, respectively. Forty-three patients (55.1%) received at least 1 steroid-sparing agent, and of these, 18 (41.8%) received a calcineurin inhibitor. One patient had eGFR ≤90 mL/min/1.73 mPatients who had frequent relapses had more measurements available for serum creatinine and height, creating a sampling bias. The number of eGFR measurements was overall small, making it difficult to ascertain eGFR trend.eGFR remained unchanged over time in this cohort, and a small proportion of patients required antihypertensive therapy at the end of follow-up. Our study highlights the needs for carefully constructed long-term observational studies of children with nephrotic syndrome.De manière générale, on considère le pronostic du syndrome néphrotique stéroïdosensible chez l’enfant comme favorable. Toutefois, seules quelques études récentes ont mesuré les changements dans la fonction rénale et la pression sanguine au fil du temps chez les enfants atteints du syndrome néphrotique stéroïdosensible.Décrire les manifestations cliniques du syndrome néphrotique stéroïdosensible, de même que caractériser les changements dans le débit de filtration glomérulaire estimé (DFGe) et la prise de médicaments contre l’hypertension au cours de la période de suivi.Il s’agit d’une étude de cohorte prospective qui s’est tenue dans un centre de néphrologie pédiatrique canadien.Des enfants âgés de 1 à 18 ans atteints du syndrome néphrotique stéroïdosensible.On a utilisé l’équation de Schwartz modifiée pour calculer le DFGe des participants à partir de leur taille et de mesures de créatinine sérique déjà enregistrées.On a procédé au calcul du DFGe chaque année et on en a évalué la tendance à l’aide d’un modèle linéaire à effets mixtes. La prise de médicaments contre l’hypertension a également été évaluée au cours de la période du suivi.Un total de 78 patients, dont l’âge médian se situait à 3,2 ans (écart interquartile = 2,65 ans), ont été évalués sur une période de 4,37 ans (EI = 5,6 ans) en moyenne, desquels 80,8% (63 patients) ont fait au moins une rechute. Des patients évalués, 28,2% (n = 22) étaient dépendants des stéroïdes et 25,6% (n = 20) faisaient des rechutes fréquentes. Quarante-trois patients (55,1%) ont reçu au moins un agent de préservation de stéroïdes, dont dix-huit (41,8%) ont reçu un inhibiteur de la calcineurine. Un seul patient a présenté une valeur de DFGe de plus de 90 ml/min/1,73 mUn biais d’échantillonnage est introduit par le fait qu’un nombre plus élevé de mesures de taille et de DFGe étaient disponibles pour les patients ayant fait plusieurs rechutes. Par ailleurs, l’établissement de tendances en regard des valeurs de DFGe s’avère difficile étant donné le nombre relativement faible de mesures disponibles.Les valeurs de DFGe sont demeurées inchangées tout au long de la période de suivi pour cette cohorte de patients, et seulement quatre d’entre eux ont dû être traités pour l’hypertension à la fin du suivi. Cette étude met en lumière le besoin pour la tenue d’études observationnelles à long terme et judicieusement élaborées chez les enfants atteints du syndrome néphrotique stéroïdosensible.

Alport syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport syndrome, estimated to affect 1 in 5000-10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3-5, was organized by individuals and families living with Alport syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities-patient families, physicians, geneticists, researchers, Pharma, and funding organizations-were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function. peerReviewed

Introduction. The effect of renal transplantation on areal bone mineral density (aBMD) in children has previously been studied. However, most previous reports did not include estimation of volumetric bone mineral density (vBMD) or analyze longitudinal data in these patients. In addition, updated reference standards for aBMD in children have recently been made available. Methods. This retrospective study describes the longitudinal effect of renal transplantation on aBMD and vBMD in a cohort of 40 pediatric kidney transplant recipients. Lumbar spine aBMD measurements were obtained using dual-energy X-ray absorptiometry prior to transplant and yearly thereafter. vBMD values and z-scores were estimated as described in the most recently published references. Results. A significant decrease in average aBMD and vBMD z-scores was observed within 1 year posttransplant, which did not recover during follow-up. The negative effect of transplantation on vBMD was blunted and vBMD z-scores were higher compared to aBMD. Linear mixed-effects model analysis demonstrated that lumbar spine aBMD and vBMD z-scores were inversely related to yearly prednisone dose (g/m 2 ) but this effect was diminished as glomerular filtration rate was increased. Conclusions. Bone mineral density was negatively affected by renal transplantation in this cohort of pediatric patients. Estimation of vBMD appears to be appropriate for interpretation of the BMD changes occurring after renal transplant in children. The inverse relation between BMD z-scores and yearly prednisone dose suggests that ongoing posttransplant corticosteroid therapy may be responsible for the negative effect of transplantation on bone mineral density in this cohort.

CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis. Background X-linked nephrolithiasis, or Dent's disease, encompasses several clinical syndromes of low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure, and is associated with mutations in the CLCN5 gene encoding a kidney-specific voltage-gated chloride channel. Some patients from Europe have rickets, and all symptomatic patients confirmed by mutation analysis have been male. Methods We analyzed the CLCN5 DNA sequence in six new families with this disease. Results In three probands, a single-base substitution yielded a nonsense triplet at codons 28, 34, and 343, respectively, and in two families, one of which was Hispanic, we found single-base deletions at codons 40 and 44, leading to premature termination of translation. In the sixth family, a single-base change from C to T predicted substitution of leucine for serine at codon 244, previously reported in two European families with prominent rickets, though this patient of Ashkenazi origin did not have rickets. Each of these mutations was confirmed by restriction endonuclease analysis, or repeat sequencing and CFLP. The R34X mutation occurred in a Canadian infant with severe rickets. The family with the R28X nonsense mutation included one woman with recurrent kidney stones and another woman with glomerular sclerosis. In another family, a woman heterozygous for the W343X mutation also had nephrolithiasis. Conclusions These studies expand the range of mutations identified in this disease, and broaden the phenotypic range to include clinically affected women and the first North American case with severe rickets.

Cystinosis is a rare autosomal recessive disease caused by mutations of the CTNS gene in which cystine accumulates throughout the body as a result of a defective efflux of cystine from lysosomes. Three phenotypic forms have been described according to the age of onset and the severity of the clinical symptoms: infantile, intermediate, and ocular non-nephropathic cystinosis. Here we report the natural history of cystinosis in a 55-year-old man with intermediate nephropathic cystinosis diagnosed at 9 years of age. Although tubulopathy was unnoticed in the early years, he required transplantation at age 16. Sequencing analysis of all the CTNS exons revealed that the proband is homozygous for a 21-bp in-frame deletion in exon 5 (c. 198_218del21), resulting in an in-frame deletion of 7 amino acids from the N-terminal domain of the cystinosin protein. Our patient has had relatively mild extra-renal disease despite lack of early cysteamine therapy. He has been able to attend university and pursue a professional career into the 6th decade.

Acute kidney injury (AKI) is becoming more prevalent among hospitalized children, its etiologies are shifting, and new treatment modalities are evolving; however, diarrhea-associated hemolytic uremic syndrome (D+HUS) remains the most common primary disease causing AKI in young children. Little has been published about acute renal replacement therapy (ARRT) and its challenges in this population. We describe our single center's experience managing 134 pediatric patients with D+HUS out of whom 58 (43%) required ARRT over the past 16 years. In our cohort, all but one patient were started on peritoneal dialysis (PD). Most patients, 47 (81%), received acute PD on a pediatric inpatient ward. The most common recorded complications in our cohort were peritoneal fluid leaks 13 (22%), peritonitis 11 (20%), and catheter malfunction 5 (9%). Nine patients (16%) needed surgical revision of their PD catheters. There were no bleeding events related to PD despite a mean platelets count of 40.9 (±23.5) × 103/mm3and rare use of platelets infusions. Despite its methodological limitations, this paper adds to the limited body of evidence supporting the use of acute PD as the primary ARRT modality in children with D+HUS.

BACKGROUND Reports of long-term incidence trends of endemic diarrhea-associated hemolytic uremic syndrome (D+HUS) are few and inconclusive. OBJECTIVE To define and analyze the incidence and outcomes of D+HUS over a period of approximately 25 years in a highly endemic region of southern Alberta. METHODS Annual incidence rates of confirmed cases of D+HUS were compared between two 12-year periods (1980 to 1992 and 1994 to 2006). Differences in therapies used, and some short- and long-term complications observed were also compared between the two periods. RESULTS The absolute yearly number of D+HUS cases was highly variable. The comparison between the 1980 to 1992, and 1994 to 2006 periods demonstrated a modest 8.8% decrease in the total number of cases. The population-based average annual incidence rates were not significantly different between the two time periods (3.33 cases versus 2.58 cases per 100,000 population per year, respectively; P=0.30). Only supportive care measures were used in the latter period. A mortality rate of lower than 1% in the latter period was one of the lowest ever reported for a large cohort of D+HUS patients. CONCLUSION The present long-term retrospective study of D+HUS in a highly endemic area documented a modest decrease in the absolute number of cases but no difference in the average annual incidence over an extended period of time.

All patients received pulse therapy with: IV cyclophosphamide 0.5 g/m2 with IV methylprednisolone (IVMP) 250 mg on days 1 and 23; IV rituximab 375 mg/m2 on days 2, 9, 16 and 23. Results All 3 patients had a dramatic improvement in urine protein-creatinine ratios, and normalization of blood pressure. Despite low-dose daily corticosteroids, all patients had an increase in generalized SLE activity by 4 weeks following rituximab therapy, which responded to re-introduction of MMF. No side effects apart from expected decrease in B-cell counts were noted.

Alport syndrome (AS) is the most common form of hereditary nephritis. Females with X-linked AS are heterozygous carriers of the disease mutation. Carrier status in females without a family history has traditionally been diagnosed by kidney biopsy; more recently skin biopsy has been utilized. We report on a 14-year-old girl with long-standing hematuria and intermittent proteinuria who underwent kidney and skin biopsy to establish a definitive diagnosis. Electron microscopy showed extensive thinning of glomerular basement membrane (GBM), with no evidence of lamination. Immunofluorescence staining showed continuous GBM staining for the alpha3(IV) and alpha5(IV) collagen chains, whereas the epidermal basement membrane showed discontinuous alpha5(IV) collagen staining consistent with an X-linked carrier of AS. Few reports have shown discordance between kidney and skin biopsy findings as seen in this case, presumably due to X chromosome lyonization. We therefore suggest that simultaneous kidney and skin biopsies may be more accurate in the assessment of potential female carriers of AS than either kidney biopsy or skin biopsy alone.

Polyuria is not considered an absolute indication for pre-transplant nephrectomy; however, it may complicate post-transplantation fluid management. Bilateral native-kidney laparoscopic nephrectomy was performed at our centre in two patients (four kidneys) 1 month after they had received a living related-donor renal transplant. The indication for nephrectomy was severe post-transplant polyuria secondary to the patient’s underlying disease: juvenile nephronophthisis. Both patients had a persistent post-transplant daily urine output of 7–8 l/day and continued to have a variable serum creatinine level, dependent on intravenous hydration, more then 3 weeks after transplantation. Bilateral laparoscopic native-kidney nephrectomy in children has previously been reported. However, to the best of our knowledge, laparoscopic nephrectomy has not been described after kidney transplantation and certainly not in the immediate post-transplantation period. The procedure was well tolerated and did not affect renal graft function. In fact, following the procedure, serum creatinine levels stabilized, while daily fluid requirements decreased to 2.5–3.5 l/day in both patients. We concluded that bilateral native-kidney nephrectomy can be safely performed in paediatric renal transplant recipients in the immediate post-transplantation period. This new approach may allow preemptive transplantation and avoid the need for a transition period on dialysis in patients for whom pre-transplant nephrectomy is not absolutely indicated.

Recent reports suggest that calcium channel blockers are harmful in the treatment of acute hypertension in adults. However, short-acting nifedipine is an effective and useful medication in pediatric hypertension and is currently utilized for hypertensive emergencies. This study will address these safety concerns in hypertensive children. Medical records (from five Canadian pediatric hospitals) of all pediatric hypertensive hospitalized children who were treated with short-acting nifedipine from January 1995 to December 1998 were retrospectively reviewed for patient demographics, dosing regimen, use of concomitant medications, co-morbid conditions, and presence/absence of minor and serious adverse events. Final data were extracted from 182 patients. Each patient had an average of 2.6 episodes of hypertension in hospital that required treatment, totaling 477 episodes. Within the 477 episodes, 1,162 doses of short-acting nifedipine were administered. The mean dose was 0.22 mg/kg (range 0.043–0.67 mg/kg, median 0.19 mg/kg) with 55.6% (260/468 episodes) receiving the drug via the sublingual route. Hypertension resolved in 85.5% (408/477) of the episodes. There were only 29 of 574 (5.1%) minor adverse events that were definitely or probably related to short-acting nifedipine administration. Two patients experienced a serious adverse event that involved of a reduction in blood pressure of more than 40%, but neither had any symptomatology from the serious adverse event and recovered spontaneously within 2 h. Short-acting nifedipine in hypertensive, hospitalized children appears to be a safe and efficacious medication with minimal side effects.

Summary. In a meta-analysis of randomized trials of the effects of dietary sodium interventions on blood pressure, we found substantial heterogeneity among the studies. We were interested in evaluating whether measurement error, known to be a problem for dietary sodium measures, publication bias, or confounding factors could be responsible for the heterogeneity. A measurement error correction was developed that corrects both the slope and the intercept and takes into account the sample size of each study and the number of measurements taken on an individual. The measurement error correction had a minimal effect on the estimates, although it performed well in simulated data. A smoothed scatter plot was used to assess publication bias. Metaregressions provide a convenient way to jointly assess the effects of several factors, but care must be taken to fit an appropriate model.

Objective. —To ascertain whether restriction of dietary sodium lowers blood pressure in hypertensive and normotensive individuals. Data Sources. —An English-language computerized literature search, restricted to human studies with Medical Subject Heading terms, "hypertension," "blood pressure," "vascular resistance," "sodium and dietary," "diet and sodium restricted," "sodium chloride," "clinical trial," "randomized controlled trial," and "prospective studies," was conducted. Bibliographies of review articles and personal files were also searched. Trial Selection. —Trials that had randomized allocation to control and dietary sodium intervention groups, monitored by timed sodium excretion, with outcome measures of both systolic and diastolic blood pressure were selected by blinded review of the methods section. Data Extraction. —Two observers extracted data independently, using purposedesigned forms, and discrepancies were resolved by discussion. Data Synthesis. —The 56 trials that met our inclusion criteria showed significant heterogeneity. Publication bias was also evident. The mean reduction (95% confidence interval) in daily urinary sodium excretion, a proxy measure of dietary sodium intake, was 95 mmol/d (71-119 mmol/d) in 28 trials with 1131 hypertensive subjects and 125 mmol/d (95-156 mmol/d) in 28 trials with 2374 normotensive subjects. After adjustment for measurement error of urinary sodium excretion, the decrease in blood pressure for a 100-mmol/d reduction in daily sodium excretion was 3.7 mm Hg (2.35-5.05 mm Hg) for systolic ( P P =.09) in the hypertensive trials, and 1.0 mm Hg (0.51-1.56 mm Hg) for systolic ( P P =.64) in the normotensive trials. Decreases in blood pressure were larger in trials of older hypertensive individuals and small and nonsignificant in trials of normotensive individuals whose meals were prepared and who lived outside the institution setting. Conclusion. —Dietary sodium restriction for older hypertensive individuals might be considered, but the evidence in the normotensive population does not support current recommendations for universal dietary sodium restriction. ( JAMA . 1996;275:1590-1597)

AIM: To evaluate the prevalence of hypertension and/or left ventricular hypertrophy (LVH) in children with a diagnosis of obstructive sleep apnea (OSA). METHODS: A cross-sectional case series of consecutive, otherwise healthy children aged > 4 years, with polysomnography-proven OSA [apnea hypopnea index (AHI) > 1.5/h] is described. Echocardiography was performed on all subjects and left ventricular mass was calculated. Study subjects underwent additional investigation with 24-h ambulatory blood pressure (BP) monitoring. RESULTS: Thirty children (21 males) were studied. Mean age was 8.9 years. Mean body mass index was 19.87 kg/cm2. Mean AHI was 14.3/h. 10/30 (33%) of the study population met criteria for pre-hypertension (n = 3) or masked hypertension (n = 7) based on standard ambulatory monitoring criteria. All 10 children had systolic hypertension throughout the night with 5 of these also having elevated daytime systolic readings. There was a relationship between AHI and BP showing an increase of 1.162 percentile units in mean diastolic night BP (age, gender and height specific) per unit increase in AHI (P = 0.018). There were no subjects with LVH and/or right ventricular hypertrophy. CONCLUSION: In our population of otherwise healthy Caucasian children, there was a high prevalence of hypertension that would not have been identified using standard office/clinic protocols.

Incidence, Risk Factors and Long Term Outcome of Nephrocalcinosis in Infants Born Weighing 1250 g or Less in Southern Alberta, Canada

In Reply. —Dr Stamler and colleagues state that we made several factually incorrect statements in our letter to JAMA , which was written in response to letters commenting on our recent meta-analysis of randomized controlled trials of dietary sodium restriction. They cite examples of errors based on information contained in articles that were not yet published at the time our meta-analysis and our letter were published, and then conclude incredulously that our viewpoint is biased. Our comment on the Intersalt study results stems from statements made in the 1988 article. 1 For example, the original Intersalt report states that there was no relationship between median sodium excretion and prevalence of hypertension when the 4 geographically isolated populations were excluded. 1 We can only take such statements at face value. The critical point in TOHP surely is the primary prevention of hypertension by dietary means rather than changes in BP at selected intervals; this

In Reply. —Our critics assert that data from RCTs, especially when pooled, must be viewed cautiously, even skeptically, when making statements that bear directly on health policy. They are particularly critical about trials with a short time horizon and allude to study selection bias. All RCTs that met our stringent eligibility criteria were included in the primary analysis, and extensive subgroup analyses were performed and reported, although, because of editorial constraints, not in the detail that both we and Dr Stamler would have desired. Dr Whelton and colleagues and Drs Kotchen and Krauss chose to ignore the point made in our article that the inclusion of short-term trials amplified the effect of dietary salt restriction. For example, excluding the short-term trials in normotensive subjects (