Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome.

BACKGROUND: Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications. METHODS: A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m2/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months. RESULTS: Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09-1.45; p = 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N = 10) and 6.3 months in the rituximab group (N = 3). Both treatments were associated with a significant (p < 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (p = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group. CONCLUSIONS: Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide. Graphical abstract.

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.

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.

Cinacalcet for Severe Secondary Hyperparathyroidism in Children with End-stage Kidney Disease.

Advanced chronic kidney disease with mineral and bone disorder have a significant obstacles to control serum bone profile [serum intact parathyroid hormone (iPTH), calcium and phosphorus] which subsequently have major effect on optimal bone strength, final adult height, and cardiovascular health. A retrospective, observational study, including a total of 36 children with end-stage kidney disease (ESKD). Fourteen children who were prescribed cinacalcet had been compared with the remaining 22 children who were managed with standard care. We report the efficacy and safety of cinacalcet for treatment of refractory secondary hyperparathyroidism (SHPT) in children with ESKD. After 6 months of cinacalcet treatment, the mean level of iPTH serum level decreased by 56% from 202 pmol/L [95% confidence interval (CI): 150-253] to 88 pmol/L (95% CI: 41-136), compared to the change observed in the control group (P <0.001). None of our patients reported serious adverse effects or developed hypocalcemia. Cinacalcet could be an effective and safe alternative to treat severe SHPT in children with ESKD. Further long-term and large-scale studies are necessary to confirm its safety and efficacy.

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.

Genetics of congenital and infantile nephrotic syndrome.

BACKGROUND: Congenital and infantile nephrotic syndrome (CNS and INS) are rare inherited defects in glomerular filtration involving a variety of gene mutations. This study aimed to analyze all genetic mutations associated with congenital and infantile nephrotic syndrome treated at our institution. We also discussed our different approach secondary to culture and resources. METHODS: A retrospective single-center study of all children diagnosed as NS before the age of 1 year over a duration of over one decade. RESULTS: Twenty-nine children (12 boys) were included in the study. Their median age (range) was 2.4 (0.1-12) months (20 CNS and 9 INS). Consanguinity was present in 90% of children. The genetic analysis' results were only available for 20 children. An underlying causative homozygous mutation was detected in 18 children (90%): NPHS1 (9), NPHS2(2), LAMB2(3), PLCE1(1), WT1(1), and ITSN1 novel mutation (2). One child had heterozygous mutation of NPHS2 and another child had heterozygous mutation of NPHS1 which could not explain the disease. All CNS cases were all managed with intermittent intravenous albumin infusion, ACEi, diuretics, and indomethacin. None of the children were managed by nephrectomy followed by peritoneal dialysis (PD) because of limited resources. Only one child achieved partial remission, while 15 children died at a median (range) age of 5.8 (1.25-29) months. The remaining 14 children were followed up for an average of 36 (3.9-120) months. Three children progressed to end-stage kidney disease and PD was performed in only two children. CONCLUSIONS: NPHS1 is the main underlying cause of CNS and INS in our study population. CNS and INS were associated with high morbidity and mortality.

Etiology, ethics, and outcomes of chronic kidney disease in neonates.

OBJECTIVES: To report the epidemiology of chronic kidney disease (CKD)  in neonates at a single tertiary center and the outcomes of renal replacement therapy (RRT) in these patients and discuss ethical considerations regarding RRT in this population. METHODS: In this retrospective study, we reviewed clinical data from all neonates with evidence of CKD who were followed up at King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between 2005 and 2015. Follow-up serum creatinine levels were recorded every 6 months. Results: A total of 181 neonates presented with CKD. Their mean age at the time of presentation was 11.1 days (95% confidence interval [CI]: 9.5-12.8) and the mean creatinine level was 106.5 µmol/ (95% CI: 91.3-121.7). Congenital anomalies of the kidneys and urinary tract (CAKUT) were the underlying causes of CKD in 84.5% of the neonates. Mortality was high, particularly in the first 6 months (10%), and reached 16% by 4 years of follow-up. At the time of the last follow-up, 42 (41%) neonates had hypertension and 27 (26.5%) had significant proteinuria. Five patients received dialysis in the neonatal period and another 6 were commenced on dialysis later. CONCLUSION: Congenital anomalies of the kidneys and urinary tract is the most common etiology in neonates with CKD. Chronic kidney disease in neonates is associated with high morbidity and mortality rates.

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.

Predictors of renal replacement therapy and mortality in children with chronic kidney disease.

OBJECTIVES: To study the epidemiology of chronic kidney disease (CKD) in children, and to look for risk factors to predict renal replacement therapy (RRT) and mortality. METHODS: This is a retrospective cohort study conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia between 2006 and 2014, where the files of 1,000 children with CKD were reviewed. We determined the effect of consanguinity and hypertension, and being a Saudi indigene on mortality and RRT. We compared children with congenital versus non-congenital causes of CKD. RESULTS: The mean±standard deviation age at presentation was 4.9±4.3 years. The median duration of follow up was 1.5 (interquartile range [IQR]: 0.4-4.0) years. Only 9.7% of children received RRT, and 8.3% died. The underlying etiology for CKD was congenital in 537 children. The congenital CKD group presented at a younger age group (3.5±4.0 versus 6.6±3.9 years, p<0.0001), had more advanced stages of CKD (p<0.0001), higher rates of consanguinity (75.4% versus 47.1%, p<0.0001), and RRT (p<0.004) than children with non-congenital CKD. Risk factors for RRT among children with CKD include being a Saudi indigene (relative risk [RR]=1.49, 95% confidence interval (CI): 1.01-2.21), and hypertensive (RR=5.29, 95% CI: 3.54-7.91). The risk factor for mortality was hypertension (RR=2.46, 95% CI: 1.66-3.65). CONCLUSION: Congenital causes of CKD represent the main etiology of CKD in children living in the western province of Saudi Arabia. Significant risk factors for RRT include congenital CKD, Saudi nationality, and hypertension. Hypertension is also a predictor of mortality in children with CKD.

Vesicoureteric reflux in children.

AIM: This study aimed to identify the differences between primary and secondary vesicoureteric reflux (VUR) and the effect of associated bladder abnormalities on kidney function. PATIENTS AND METHODS: We retrospectively reviewed the medical records of children with VUR who were followed up at King Abdulaziz University Hospital from January 2005 to December 2010. The review included results of radiological investigations and kidney function tests. We used Chi-square test for statistical analysis and paired t-test to compare group means for initial and last creatinine levels. RESULTS: Ninety-nine children were included in this study. Twenty (20.2%) had primary VUR, 11 had high-grade VUR, while 9 had low-grade reflux. All children with low-grade VUR had normal dimercaptosuccinic acid (DMSA). Renal scars were present in 72% of the children with high-grade VUR. The mean creatinine levels (initial and last) for both groups were normal. Seventy-nine (79.8%) children had secondary VUR, which was due to posterior urethral valves (PUV) (46.8%), neurogenic bladder caused by meningomyelocele (25.3%), non-neurogenic neurogenic bladder (NNB) (21.5%), or neurogenic bladder associated with prune belly syndrome (6.3%). Children with NNB, meningomyelocele and PUV had high creatinine at presentation with no considerable worsening of their kidney functions during the last visit. Renal scars were present in 49.4% of the children with secondary VUR. CONCLUSION: Children with primary VUR and normal bladder had good-functioning kidneys, while those with secondary VUR associated with abnormal bladder caused by NNB, spina bifida or PUV had abnormal kidney functions. DMSA scans were useful in predicting higher grades of VUR in children with primary reflux.

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.

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.