Lupus Nephritis in an Adolescent Girl With Hyper-Immunoglobulin E.

We report the case of an adolescent girl with frequent hospital admissions for severe eczematous skin rashes with recurrent epistaxis and chest infections. Investigations revealed persistent severely elevated serum total immunoglobulin E (IgE) levels but normal levels of other immunoglobulins, suggesting hyper-IgE syndrome. The first skin biopsy revealed superficial dermatophytic dermatitis (tinea corpora). Another biopsy performed after six months revealed a prominent basement membrane with dermal mucin, suggesting an underlying autoimmune disease. Her condition was complicated by proteinuria, hematuria, hypertension, and edema. A kidney biopsy revealed class IV lupus nephritis, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS). Based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, she was diagnosed with systemic lupus erythematosus (SLE). She was first administered with intravenous pulse methylprednisolone (600 mg/m2) for three consecutive days, followed by oral prednisolone (40 mg/m2) daily, mycophenolate mofetil tablets (600 mg/m2/dose) twice daily, hydroxychloroquine (200 mg) once daily, and three classes of antihypertensive medications. She maintained normal renal functions with no lupus morbidity for 24 months, then rapidly progressed to end-stage kidney disease, and was then started on three to four sessions of regular hemodialysis per week. Hyper-IgE is known to be a marker of immune dysregulation as it facilitates the generation of immune complexes (ICs) that mediate lupus nephritis and juvenile SLE. Regardless of the different factors that are impacting the production of IgE, the present case illustrated that juvenile patients with SLE may have increased IgE levels, indicating that higher IgE levels might have a role in lupus pathogenesis and prognosis. The mechanisms regarding the increased levels of IgE in subjects with lupus need further investigation. Further studies are thus required to assess the incidence, prognosis, and possible new specific management for hyper-IgE in juvenile SLE.

Outcome of Urinary Bladder Dysfunction in Children.

Bladder dysfunction in children is common, the most frequent underlying causes are neurologic bladder (NB), dysfunctional voiding syndrome (DVS), and the valve bladder syndrome (VBS). The aim of this study was to determine the 10-y survival rate and the associated morbidities in children with bladder dysfunction. One hundred ninety-nine children were included in the study; 60 with VBS, 75 DVS, and 64 NB. The mean age was 44 mo (CI: 37-50.9) and mean GFR 50.1 (CI 44.6-55.6) mL/min/1.73m2. The 10-y survival rate was 89%. Compared with patients with VBS, the mortality was 11 times higher among patients with NB (p = 0.02) but not significantly higher than patients with DVS (p = 0.2). GFR < 15 mL/min/1.73 m2 increases mortality rate by 6 times compared with normal GFR (p = 0.007). Late age at presentation (> 5 y) increases mortality risk and/or the need for renal replacement therapy (RRT) by almost 5 times (p = 0.013). It was concluded that the etiology of bladder dysfunction, baseline GFR, and the age at presentation significantly influence the survival rate and morbidities.

Voiding dysfunction in children causes, management, and prognosis: A single-center retrospective study.

OBJECTIVES: To review voiding dysfunction caused by 3 different etiologies; dysfunction voiding syndrome (DVS), neurogenic bladder secondary to spinal dysraphisim (NB), and valve bladder syndrome (VBS). METHODS: A single-center retrospective study on children with voiding dysfunction followed up at King Abdulaziz University Hospital, Jeddah, Saudi Arabia from 2005 to 2017. RESULTS: One hundred and ninety-nine children (67.3% boys) were included: Group 1 (n=75, DVS), Group 2 (n=64, NB), and Group 3 (n=60, VBS). Further classification according to the age at presentation; infants (46%), toddlers (27%) and school aged (28%). Management categories: 31% children needed observation only, 25% needed clean intermittent catheterization (CIC), 13% needed only surgery and 31% needed both surgery and CIC. Associated comorbidities: hydronephrosis (81%), vesicoureteral reflux (47%), pyelonephritis (37%) and renal scar (60%), all have negative impact on estimated glomerular filtration rate (eGFR). Urodynamic studies revealed poor bladder compliance in 57.6% and atonic bladder in 1.1%, progression to chronic kidney disease (22%), commenced on renal replacement therapy 11.5% and 4% died with ESKD. Overall improvement in the last eGFR is observed (p<0.001), but VBS group was the least to improve (p=0.021). There was a negative correlation between the last eGFR and age at presentation (p=0.002). CONCLUSION: Early diagnosis and management of childhood voiding dysfunction was associated with better prognosis. Children managed conservatively have better preservation of kidney function than those who needed surgery.

Homozygous WNT9B variants in two families with bilateral renal agenesis/hypoplasia/dysplasia.

WNT9B plays a key role in the development of the mammalian urogenital system. It is essential for the induction of mesonephric and metanephric tubules, the regulation of renal tubule morphogenesis, and the regulation of renal progenitor cell expansion and differentiation. To our knowledge, WNT9B has not been associated with renal defects in humans; however, WNT9B-/- mice have renal agenesis/hypoplasia and reproductive tract abnormalities. We report four individuals from two unrelated consanguineous families with bilateral renal agenesis/hypoplasia/dysplasia and homozygous variants in WNT9B. The proband from Family 1 has bilateral renal cystic dysplasia and chronic kidney disease. He has two deceased siblings who presented with bilateral renal hypoplasia/agenesis. The three affected family members were homozygous for a missense variant in WNT9B (NM_003396.2: c.949G>A/p.(Gly317Arg)). The proband from Family 2 has renal hypoplasia/dysplasia, chronic kidney disease, and is homozygous for a nonsense variant in WNT9B (NM_003396.2: c.11dupC/p.(Pro5Alafs*52)). Two of her siblings died in the neonatal period, one confirmed to be in the context of oligohydramnios. The proband's unaffected brother is also homozygous for the nonsense variant in WNT9B, suggesting nonpenetrance. We propose a novel association of WNT9B and renal anomalies in humans. Further study is needed to delineate the contribution of WNT9B to genitourinary anomalies in humans.

COL4A1 mutations as a potential novel cause of autosomal dominant CAKUT in humans.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease (~ 45%) that manifests before 30 years of age. The genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), but mutations in COL4A1 have not been reported in CAKUT. We hypothesized that COL4A1 mutations cause CAKUT in humans. We performed whole exome sequencing (WES) in 550 families with CAKUT. As negative control cohorts we used WES sequencing data from patients with nephronophthisis (NPHP) with no genetic cause identified (n = 257) and with nephrotic syndrome (NS) due to monogenic causes (n = 100). We identified a not previously reported heterozygous missense variant in COL4A1 in three siblings with isolated VUR. When examining 549 families with CAKUT, we identified nine additional different heterozygous missense mutations in COL4A1 in 11 individuals from 11 unrelated families with CAKUT, while no COL4A1 mutations were identified in a control cohort with NPHP and only one in the cohort with NS. Most individuals (12/14) had isolated CAKUT with no extrarenal features. The predominant phenotype was VUR (9/14). There were no clinical features of the COL4A1-related disorders (e.g., HANAC syndrome, porencephaly, tortuosity of retinal arteries). Whereas COL4A1-related disorders are typically caused by glycine substitutions in the collagenous domain (84.4% of variants), only one variant in our cohort is a glycine substitution within the collagenous domain (1/10). We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT that is allelic to the established COL4A1-related disorders and predominantly caused by non-glycine substitutions.

A case of urinary bladder agenesis and bilateral ectopic ureters: a case report.

BACKGROUND: Urinary bladder agenesis is a very rare congenital anomaly with very few cases reported in the literature. CASE PRESENTATION: We report a one-month-old baby presenting with ambiguous genitalia and recurrent urinary tract infections. Her clinical course was complicated by renal impairment. Magnetic resonant imaging (MRI) revealed a diagnosis of bladder agenesis with bilateral ectopic insertion of the ureters into the vagina, associated with several other anomalies. The patient underwent bilateral high anterior ureterostomies in an hospital abroad at 5.5 months of age. She then developed ureteral necrosis that had to be corrected with left pyeloplasty and by placing a left nephrostomy tube for drainage. Eventually, the patient's renal function declined, and she developed chronic kidney disease (CKD).The case with its imaging findings and pathogenesis as well as a review of the literature are presented. CONCLUSIONS: Urinary bladder agenesis is a rare congenital condition that can be associated with multiple anomalies. Early diagnosis and therapeutic intervention can prevent progression to chronic kidney disease.

GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. METHODS: To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. RESULTS: We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. CONCLUSIONS: Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

A Rare Benign Tumor in a 14-Year-Old Girl.

BACKGROUND: Oncocytomas are the second most common benign renal neoplasm but, unfortunately, they are difficult to differentiate from renal cell carcinoma. Renal oncocytomas are rare and have mostly been reported in adults. To our knowledge, this is only the sixth pediatric reported case of renal oncocytoma worldwide. CASE PRESENTATION: A 14-year-old Yemeni girl with a recurrent history of urinary tract infections came to our clinic complaining of left flank pain with a frontal headache. Ultrasound showed a 3 cm, well-defined echogenic lesion with mild vascularity. This lesion increased in size on her subsequent follow-ups. Computed tomography showed no intralesional fat, vessels invasion, or enlarged lymph nodes. The patient underwent laparoscopic radical nephrectomy, and a pathology report confirmed the diagnosis of renal oncocytoma. CONCLUSION AND RECOMMENDATIONS: We present the rare occurrence of renal oncocytoma in a pediatric patient and highlight the importance of considering oncocytomas in the diagnosis of a renal mass.

Advillin acts upstream of phospholipase C ϵ1 in steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein.

Prevalence of Hyperparathyroidism, Mineral and Bone Disorders in Children with Advanced Chronic Kidney Disease.

OBJECTIVE: To identify the prevalence and risk factors for secondary hyperparathyroidism in children with advanced stages of chronic kidney disease (CKD). METHODS: A retrospective cross-sectional observational study of clinical and laboratory data of pediatric patients with CKD stage 3, 4 was conducted from 2005 through 2013 at a single center in the Kingdom of Saudi Arabia. RESULTS: One hundred nineteen children (60.5 % boys) with mean age of 10.1 ± 5.1 y were included in the study. The mean eGFR (estimated Glomerular Filtration Rate) was 18.3 ± 15.4 ml/min/1.73m(2) and the mean intact parathyroid hormone (iPTH) level was 62.2 ± 89.4 pmol/L. Patients with a high iPTH had lower eGFR than those who were euparathyroid (16 ± 13.4 vs. 29.7 ± 19 ml/min/1.73m(2), respectively; p = 0.006), had lower calcium levels (2.2 ± 0.3 vs. 2.4 ± 0.3 mmol/L; p = 0.03) and a lower bicarbonate level (21.2 ± 4.2 vs. 23.3 ± 3.2 mmol/L; p = 0.04). Three children with hyperparthyrodism (4.9 %) had fractures, 16 (26.2 %) had bone deformities compared to 5 in the euoparathyroid group (p = 0.012). Parathyroid hormone negatively correlated with the patient's eGFR (r = -0.55), serum calcium (r = -0.43), and positively correlated with serum phosphate (r = 0.38). CONCLUSIONS: The single most important predictor of hyperparathyroidism in children in the present sample was eGFR.

Outcome of Multi-Cystic Dysplastic Kidneys in Children.

BACKGROUND: Renal cystic diseases are important causes of chronic kidney disease (CKD). OBJECTIVES: We report the pattern of renal cystic disease in children and evaluate the outcome of children with multicystic dysplastic kidney (MCDK). PATIENTS AND METHODS: Retrospective study of all children with cystic kidney diseases at King Abdulaziz University hospital from 2006 to 2014. RESULTS: Total of 55 children (30 males); 25 MCDK, 22 polycystic kidney diseases (PKD), 4 nephronophthises and 4 renal cysts. Consanguinity was positive in 96.2%. MCDK and simple renal cyst patients had good renal function while PKD and nephronophthisis developed renal impairment. Most MCKD were diagnosed ante-natally, 16 of them were followed up for 3.4 (1.97) year. Their last creatinine was 33.9 (13.5) umol/L. MCDK was spontaneously involuted at mean age of 2.6 (1.3) years in 56%. CONCLUSIONS: MCDK is the commonest cystic renal disease and diagnosed ante-natally in the majority of cases. It has a good prognosis.

A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

Steroid-resistant nephrotic syndrome: impact of genetic testing.

BACKGROUND AND OBJECTIVES: Mutations in several genes are known to cause steroid-resistant nephrotic syndome (SRNS), most commonly in NPHS1, NPHS2, and WT1. Our aims were to determine the frequency of mutations in these genes in children with SRNS, the response of patients with SRNS to various immunosuppressants, and the disease outcome, and to review the predictive value of genetic testing and renal biopsy result. DESIGN AND SETTINGS: A retrospective review was performed of the medical records for all children with SRNS who were treated and followed-up in the Pediatric Nephrology Unit of King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia from 2002-2012. PATIENTS AND METHODS: We retrospectively reviewed the medical records of children above 1 year of age, who presented with SRNS to KAUH, Jeddah, Saudi Arabia, in the 10-year interval from 2002-2012 and for whom the results of genetic testing for NPHS1, NPHS2, and WT1 were available. We compared the clinical phenotype, including response to treatment and renal outcome to genotype data. RESULTS: We identified 44 children with a clinical diagnosis of SRNS in whom results of genetic testing were available. Presumably disease-causing mutations were detected in 5 children (11.4%) of which 3 (6.8%) had NPHS2 mutation and 2 (4.5%) had NPHS1 mutation. Renal biopsy revealed minimal change disease (MCD) or variants in 17 children, focal segmental glomerulosclerosis (FSGS) in 23 children, membranoproliferative changes (MPGN) in 2 children, and IgA nephropathy in another 2 children. Children with MCD on biopsy were more likely to respond to treatment than those with FSGS. None of those with an identified genetic cause showed any response to treatment. CONCLUSION: The frequency of identified disease-causing mutations in children older than 1 year with SRNS presented to KAUH was 11.4%, and these patients showed no response to treatment. Initial testing for gene mutation in children with SRNS may obviate the need for biopsy, and the use of immunosuppressive treatment in children with disease due to NPHS1 or NPHS2 mutations. Renal biopsy was useful in predicting response in those without genetic mutations.

Renal impairment in children with posterior urethral valves.

BACKGROUND: Posterior urethral valves (PUV) are a common cause of end-stage renal failure in childhood. Our aim was to describe a cohort of patients with PUV and to investigate the predictors of renal impairment. METHODS: We performed a retrospective chart review of children with PUV who were followed at King Abdulaziz University hospital between 2002 and 2011. RESULTS: The cohort comprised 68 boys. There was a significant difference in the duration of follow-up (p = 0.024), nadir serum creatinine (p < 0.001), and last known serum creatinine level (p = 0.001) between the patients with and without renal impairment. The duration of follow-up appeared to be a significant predictor for serum creatinine doubling (p = 0.003; odds ratio, 1.8). There was no difference in the age of presentation, age at the time of the study, and first or last serum creatinine between children who initially had vesicostomy and children who had ablation. CONCLUSIONS: Ablation of PUV or vesicostomy did not influence kidney function in our study cohort. Children with a normal nadir serum creatinine who presented early had a better outcome.

Simultaneous onset of steroid resistant nephrotic syndrome and IDDM in two young children.

The cases are reported of two young children who developed insulin-dependent diabetes mellitus (IDDM) within 2 weeks of receiving a diagnosis of nephrotic syndrome. Neither patient responded to 8 weeks of daily prednisolone. The first patient presented at 2 years and 9 months of age. Her renal biopsy showed mesangial proliferation. The second child presented with steroid resistant nephrotic syndrome at 18 months of age and developed IDDM 2 weeks later. He achieved partial remission with cyclosporine therapy. His initial renal biopsy at 3 years of age showed minimal change disease and follow-up renal biopsy at 5 years of age showed early diabetic glomerulosclerosis. Tests for NPHS2 and WT1 genetic mutations were negative in both patients. To our knowledge this is the first report of steroid resistant nephrotic syndrome with almost simultaneous onset of IDDM in young children.