The extracardiac conduit (ECC) modification of the Fontan procedure has been theorized to reduce the risk of sinus node dysfunction and atrial arrhythmia compared with the intra-atrial lateral tunnel ...(ILT) Fontan. This study aimed to compare the prevalence of early and late arrhythmias in patients who underwent ECC and ILT Fontan from a similar era with long-term follow-up at a single institution. A retrospective cohort study was conducted of all patients who underwent ECC or ILT Fontan from 1995 to 2005 at The Children's Hospital of Philadelphia. Bradyarrhythmias (including sinus node dysfunction), tachyarrhythmias, and pacemaker burden prevalence was determined throughout early (<30 days) and late (>30 days) postoperative periods. Of 434 patients undergoing the Fontan procedure during the study period, a total of 87 and 106 patients who underwent ECC and ILT Fontan, respectively, met the inclusion criteria. There were no significant differences in risk of sinus node dysfunction or tachyarrhythmia in both early and late postoperative periods. Although the overall risk of late postoperative pacemaker therapy was lower for the ECC cohort (4.9% vs 15.7%, p = 0.03), when adjusting for follow-up time, no significant difference was observed (odds ratio 3.1, 95% confidence interval 0.6 to 15.2, p = 0.16). In conclusion, the overall prevalence of late postoperative arrhythmias observed after contemporary Fontan modifications is low. Intra-atrial reentrant tachycardia, a potentially fatal complication of the atriopulmonary Fontan operation was infrequently encountered in both ECC and ILT Fontan cohorts. Pacemaker use was higher in the ILT group, although this difference may be explained by differences in follow-up time. Despite the low prevalence of arrhythmias after contemporary Fontan modifications, ongoing surveillance is warranted as the onset of arrhythmias may emerge after longer follow-up time.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Lupus nephritis (LN) is a life-threatening manifestation of systemic lupus erythematosus (SLE) and is more common in children than adults. The epidemiology and management of childhood-onset SLE ...(cSLE) have changed over time, prompting the need to reassess expected outcomes. The purpose of this study is to use the Childhood Arthritis and Rheumatology Research Alliance (CARRA) prospective registry to validate historical principles of LN in a contemporary, real-world cohort. After an extensive literature review, six principles of LN in cSLE were identified. The CARRA registry was queried to evaluate these principles in determining the rate of LN in cSLE, median time from cSLE diagnosis to LN, short-term renal outcomes, and frequency of rituximab as an induction therapy. Of the 677 cSLE patients in the CARRA registry, 32% had documented LN. Decline in kidney function was more common in Black cSLE patients than non-Black patients (p = 0.04). Black race was associated with worse short-term renal outcomes. In short-term follow up, most children with LN had unchanged or improved kidney function, and end stage kidney disease (ESKD) was rare. Ongoing follow-up of cSLE patients in the CARRA registry will be necessary to evaluate long-term outcomes to inform risk, management, and prognosis of LN in cSLE.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Galloway‐Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal‐glomerular disease, manifesting with proteinuria. To ...identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease‐causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease almost inevitably progressing to end-stage renal disease. More than 58 monogenic causes of SRNS have been discovered ...and majority of known steroid-resistant nephrotic syndrome causing genes are predominantly expressed in glomerular podocytes, placing them at the center of disease pathogenesis. Herein, we describe two unrelated families with steroid-resistant nephrotic syndrome with homozygous mutations in the KIRREL1 gene. One mutation showed high frequency in the European population (minor allele frequency 0.0011) and this patient achieved complete remission following treatment, but later progressed to chronic kidney disease. We found that mutant KIRREL1 proteins failed to localize to the podocyte cell membrane, indicating defective trafficking and impaired podocytes function. Thus, the KIRREL1 gene product has an important role in modulating the integrity of the slit diaphragm and maintaining glomerular filtration function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, ∼15% of ...childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In ∼30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-α5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria.
Methods
To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation.
Results
In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably.
Conclusion
We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.
Background Acute kidney injury (AKI) is common in critically ill premature infants. There is a lack of consensus on the diagnostic definition of AKI in very low birth weight (VLBW) infants. The ...primary aim of this study was to determine the incidence and risk factors for AKI in VLBW infants using the AKI network (AKIN) and pRIFLE (pediatric Risk, Injury, Failure, Loss, End-Stage) criteria and to evaluate whether Clinical Risk Index for Babies (CRIB II) score is a predictor of AKI. The secondary objective was to determine the extent of agreement between the AKIN and pRIFLE criteria in the diagnosis of AKI in VLBW infants. Methods This was a retrospective chart review of 115 VLBW (< 1500 g) infants born in an academic center with a Level 3B neonatal intensive care unit. Multiple congenital anomalies, transfer to other centers, or death within the first 2 weeks were the exclusion criteria. Relevant data were collected and analyzed in the first 2 weeks postnatally. Results AKI incidence, according to AKIN and pRIFLE criteria, was 20.1% and 22.6%, respectively. As per the interrater reliability analysis, there was a fair agreement between the two criteria (kappa = 0.217). AKI was nonoliguric. The length of stay was significantly longer in the AKI group. Prenatal nonsteroidal anti-inflammatory drug exposure, lower gestational age, lower birth weight, respiratory distress syndrome, mechanical ventilation, patent ductus arteriosus, hypotension, late onset sepsis, and higher CRIB II scores were significantly associated with AKI. Our regression analysis found CRIB II scores to be an independent risk factor for AKI (odds ratio = 1.621; 95% confidence interval, 1.230–2.167; p = 0.001). Conclusion The determination of AKI using the pRIFLE and AKIN criteria yielded different results. pRIFLE appears to be more sensitive in VLBW infants. A high CRIB II score was recorded for AKI. Future studies are necessary to develop a uniform definition and identify the risk factors to improve the outcomes in this population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective The study objective was to determine whether the extracardiac conduit Fontan confers an arrhythmia advantage over the intracardiac lateral tunnel Fontan. Methods This multicenter study of ...1271 patients compared bradyarrhythmia (defined as need for pacing) and tachyarrhythmia (defined as needing antiarrhythmic therapy) between 602 patients undergoing the intracardiac Fontan and 669 patients undergoing the extracardiac Fontan. The median age at the time of the Fontan procedure was 2.1 years (interquartile range, 1.6-3.2 years) for the intracardiac group and 3.0 years (interquartile range, 2.4-3.9) for the extracardiac group ( P < .0001). The median follow-up was 9.2 years (interquartile range, 5-12.8) for the intracardiac group and 4.7 years (interquartile range, 2.8-7.7) for the extracardiac group ( P < .0001). Results Early postoperative (<30 days) bradyarrhythmia occurred in 24 patients (4%) in the intracardiac group and 73 patients (11%) in the extracardiac group ( P < .0001). Early postoperative (<30 days) tachyarrhythmia occurred in 32 patients (5%) in the intracardiac group and 53 patients (8%) in the extracardiac group ( P = not significant). Late (>30 days) bradyarrhythmia occurred in 105 patients (18%) in the intracardiac group and 63 patients (9%) in the extracardiac group ( P < .0001). Late (>30 days) tachyarrhythmia occurred in 58 patients (10%) in the intracardiac group and 23 patients (3%) in the extracardiac group ( P < .0001). By multivariate analysis factoring time since surgery, more patients in the extracardiac group had early bradycardia (odds ratio, 2.9; 95% confidence interval, 1.8-4.6), with no difference in early tachycardia, late bradycardia, or late tachycardia. Conclusions Overall arrhythmia burden is similar between the 2 groups, but the extracardiac Fontan group had a higher incidence of early bradyarrhythmias. There was no difference in the incidence of late tachyarrhythmias over time between the 2 operations. Therefore, the type of Fontan performed should be based on factors other than an anticipated reduction in arrhythmia burden from the extracardiac conduit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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