A Multicenter Study Evaluating the Discontinuation of Eculizumab Therapy in Children with Atypical Hemolytic Uremic Syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA), which has been treated successfully with eculizumab. The optimal duration of eculizumab in treating patients with aHUS remains poorly defined. METHODS: We conducted a multicenter retrospective study in the Arabian Gulf region for children of less than 18 years of age who were diagnosed with aHUS and who discontinued eculizumab between June 2013 and June 2021 to assess the rate and risk factors of aHUS recurrence. RESULTS: We analyzed 28 patients with a clinical diagnosis of aHUS who had discontinued eculizumab. The most common reason for the discontinuation of eculizumab was renal and hematological remission (71.4%), followed by negative genetic testing (28.6%). During a median follow-up period of 24 months after discontinuation, 8 patients (28.5%) experienced HUS relapse. The risk factors of recurrence were positive genetic mutations (p = 0.020). On the other hand, there was no significant relationship between the relapse and age of presentation, the need for acute dialysis, the duration of eculizumab therapy before discontinuation, or the timing of eculizumab after the presentation. Regarding the renal outcomes after discontinuation, 23 patients were in remission with normal renal function, while 4 patients had chronic kidney disease (CKD) (three of them had pre-existing chronic kidney disease (CKD) before discontinuation, and one case developed a new CKD after discontinuation) and one patient underwent transplantation. CONCLUSIONS: The discontinuation of eculizumab in patients with aHUS is not without risk; it can result in HUS recurrence. Eculizumab discontinuation can be performed with close monitoring of the patients. It is essential to assess risk the factors for relapse before eculizumab discontinuation, in particular in children with a positive complement variant and any degree of residual CKD, as HUS relapse may lead to additional loss of kidney function. Resuming eculizumab promptly after relapse is effective in most patients.

Peritonitis in children on peritoneal dialysis: 12 years of tertiary center experience.

BACKGROUND AND OBJECTIVE: Peritoneal dialysis (PD) associated peritonitis is the most common cause of morbidity, mortality, and treatment failure in patients undergoing PD. We aimed to identify the incidence, pathogens, antibiotic susceptibility, and the outcome of peritoneal dialysis (PD)-associated peritonitis in children. METHODS: Data from medical records of children who underwent PD between 2007 and 2018 in King Fahad Medical City were retrospectively collected. All children aged <14 years undergoing chronic PD were included. The demographic characteristics of patients, peritonitis rates, and clinical outcomes were collected. RESULTS: In total, 131 children [boys, 68 (51.9%)] underwent automated PD for 305 years. The most common age group was 6-12 years (61 patients, 46.6%). A total of 74.0% of patients were new to dialysis; 25.2% were transferred from hemodialysis. Peritonitis incidence was 0.6 episodes/patient-year. Gram-positive and -negative organisms were identified in 50.1% and 22% episodes, respectively, whereas cultures remained negative in 20.5% episodes. Coagulase-negative Staphylococcus was the most common isolated organism (22.1%), followed by methicillin-sensitive S. aureus (11.1%). Peritonitis was resolved in 153 (73.6%) episodes, whereas 52 (25.0%) episodes required removal through the catheter. The multivariate logistic regression analysis found the exit site infection to be a risk factor for catheter removal. Three (1.4%) episodes caused death due to peritonitis complicated by septic shock . CONCLUSIONS: Our data showed that the most common organisms causing peritonitis were similar to those reported in the previous international registry. The rate of peritonitis was high, but markedly improved in the past two years.

A discarded synonymous variant in NPHP3 explains nephronophthisis and congenital hepatic fibrosis in several families.

Half of patients with a ciliopathy syndrome remain unsolved after initial analysis of whole exome sequencing (WES) data, highlighting the need for improved variant filtering and annotation. By candidate gene curation of WES data, combined with homozygosity mapping, we detected a homozygous predicted synonymous allele in NPHP3 in two children with hepatorenal fibrocystic disease from a consanguineous family. Analyses on patient-derived RNA shows activation of a cryptic mid-exon splice donor leading to frameshift. Remarkably, the same rare variant was detected in four additional families with hepatorenal disease from UK, US, and Saudi patient cohorts and in addition, another synonymous NPHP3 variant was identified in an unsolved case from the Genomics England 100,000 Genomes data set. We conclude that synonymous NPHP3 variants, not reported before and discarded by pathogenicity pipelines, solved several families with a ciliopathy syndrome. These findings prompt careful reassessment of synonymous variants, especially if they are rare and located in candidate genes.

Clinical improvement of encapsulating peritoneal sclerosis after challenging course and 6 months of total parenteral nutrition in child with nephronophthisis: a case report.

BACKGROUND: Encapsulating peritoneal sclerosis is a rare but potentially lethal complication of long-term peritoneal dialysis that is associated with significant morbidity and mortality. The occurrence of encapsulating peritoneal sclerosis varies worldwide, but is increased in patients maintained on peritoneal dialysis for 5-8 years. The etiology of encapsulating peritoneal sclerosis remains unidentified, and a high index of clinical suspicion is required for diagnosis. CASE PRESENTATION: We report a 5-year-old Saudi female with end-stage renal disease secondary to nephronophthisis type 2. She underwent peritoneal dialysis for 30 months, with four episodes of peritonitis. She presented with clinical signs of peritonitis. Three days later, she developed septic shock, which required pediatric intensive care unit admission. The peritoneal dialysis catheter was removed because of refractory peritonitis. Her course was complicated by small bowel perforation, and severe adhesions were revealed on abdominal ultrasound and computed tomography, consistent with a diagnosis of EPS. This finding was later confirmed by diagnostic laparotomy performed twice and complicated by recurrent abdominal wall fistula. She received total parenteral nutrition for 6 months and several courses of antibiotics. The patient received supportive treatment including nutritional optimization and treatment for infection. No other treatments, such as immunosuppression, were administered to avoid risk of infection. Following a complicated hospital course, the patient restarted oral intake after 6 months of total parenteral nutrition dependency. Her abdominal fistula resolved completely, and she was maintained on hemodialysis for few years before she received a kidney transplant. CONCLUSION: When treating patients using peritoneal dialysis, it is important to consider encapsulating peritoneal sclerosis with refractory peritonitis, which is not always easy to identify, particularly if the patient has been maintained on peritoneal dialysis for less than 3 years. Early identification of encapsulating peritoneal sclerosis and appropriate conservative treatment, including nutritional optimization and treatment of infections, are essential to achieve a better prognosis.

Improved Renal Recovery with Eculizumab Therapy among Children with High Prevalence of Mutation-Associated Atypical Hemolytic Uremic Syndrome: A Retrospective Cohort Study.

INTRODUCTION: Genetic defects that determine uncontrolled activation of the alternative complement pathway have been well documented, which account for approximately 40-60% of atypical hemolytic uremic syndrome (aHUS) cases worldwide. In Saudi Arabia, nearly half of the marriages are consanguineous, resulting in a high prevalence of such genetic diseases. Recent studies have demonstrated the effectiveness of eculizumab against aHUS. OBJECTIVE: We report our experience of using plasma therapy or/and eculizumab to treat children with aHUS in a tertiary care center in Saudi Arabia and to compare their clinical characteristics, genetic mutations, and treatment outcomes. METHODS: A retrospective cohort study was conducted between January 2010 and May 2017. Data, including demographic parameters, clinical presentation, hospital stay duration, need for dialysis, renal recovery, genetic mutations, and outcomes, were obtained from electronic medical records of all eligible patients. RESULTS: Overall, 21 children with aHUS were included, of which 12 (57.1%) received eculizumab therapy and 9 (42.9%) received only plasma therapy. End-stage renal disease occurred in 7 children (33.3%), of which 4 (57.1%) received only plasma therapy and 3 (42.9%) received eculizumab therapy whose genetic mutations were not related to the complement dysregulation system. No child who received eculizumab therapy showed recurrence; however, 3 children (33.3%) who received plasma therapy alone showed recurrence. Genetic mutations were detected in 12/20 (60%) of those who underwent genetic screening. CONCLUSIONS: Children who received eculizumab therapy showed good renal recovery and maintained remission compared with children who received plasma therapy alone. Genetic mutations were detected in 60% of the patients, which was associated with a high prevalence of consanguineous marriages.

Fungal peritonitis in children on peritoneal dialysis at a tertiary care Centre.

BACKGROUND: Fungal peritonitis (FP) is an infrequent but serious complication in children undergoing peritoneal dialysis (PD). This study aimed to explore the risk factors, clinical manifestations, causative organisms, fungal susceptibility findings, and outcomes of FP in children from Saudi Arabia. METHODS: In this case-control study, the medical records and laboratory results of paediatric patients aged 0-14 years who underwent PD were reviewed for FP episodes. All FP episodes were matched with PD-related bacterial peritonitis episodes (1:4 ratio). RESULTS: A total of 194 episodes of PD-related peritonitis occurred between 2007 and 2017, among which 11 were FP episodes (5.6%), representing a rate of 0.03 episodes per patient-year. Of these 11 episodes, 9 were caused by Candida species (82%). Compared with the bacterial peritonitis group, the FP group had a higher proportion of patients with congenital/infantile nephrotic syndrome (p = 0.005) and those younger than 5 years of age (p = 0.001). We observed a higher rate of catheter removal in the FP group than in the bacterial peritonitis group (p <  0.001); however, 1 patient died despite catheter removal. Moreover, 75% of Candida species isolates were susceptible to fluconazole. CONCLUSIONS: This study revealed that FP is associated with a significant risk of peritoneal membrane failure among children undergoing PD. Therefore, early diagnosis and prompt management are essential. We also found that congenital/infantile nephrotic syndrome and young age (5 years old or younger) were risk factors for FP in children undergoing PD.

Spectrum of pediatricbiopsy-proven renal diseases: A single center experience.

Glomerular diseases are considered to be a significant cause of chronic kidney disease. Kidney biopsy continues to be an essential diagnostic tool. We review the renal biopsies which were done on children below the age of 14 years in the past 10 years (from January 2008 to September 2018) in a single tertiary pediatric hospital in Saudi Arabia to determine the patterns of renal disease among Saudi children as well-correlating clinical presentation with histopathological diagnosis. A total of 203 pediatric kidney biopsies were performed. The mean age was 7.3 ± 3.9 years (3 months to 14 years). There were 105 males and 98 females. The most frequent indication for renal biopsy was nephrotic syndrome in 58.9% of patients, followed by acute glomerulo- nephritis in 20.8%. Other indications included significant proteinuria, persistent microscopic hematuria, acute kidney injury of uncertain etiology, in the remaining 20% of biopsies. Clinical diagnosis was consistent with histopathological diagnosis in 92% of the cases. Minimal change disease was the most common cause of primary glomerular diseases in 37.4%, followed by focal segmental glomerulosclerosis in 20.2%. Lupus nephritis represents the most common cause of the secondary renal disease (8.4%). Complications of kidney biopsy were observed in only 16.3% of patients, of whom 9.9% had perirenal hematomas and 6.4% of the patients developed either microscopic hematuria or macroscopic hematuria.

Collagenofibrotic (Collagen Type III) glomerulopathy in association with diabetic nephropathy.

Collagenofìbrotic (collagen type III) glomerulopathy (CG) is a rare nonimmune-mediated glomerular disease. It is characterized by massive deposition of organized collagen type III fibers, which is localized in the mesangial and subendothelial glomerular areas and associated with increased serum levels of procollagen type III peptide. Association with systemic diseases and malignancies is extremely rare. Herein, we present a case of a nine-year-old girl, known case of type I diabetes mellitus, who presented with fever, nephrotic range proteinuria, generalized edema, and hypertension. Clinical examination did not show nail abnormalities or bone abnormalities. Renal biopsy revealed mesangial expansion and remarkable narrowing and obliteration of the glomerular capillaries by pale, amorphous material. Immunohistochemical study demonstrated diffuse linear glomerular capillary and tubular basement membrane staining for immunoglobulin G (IgG) and albumin. Ultrastructural examination identified massive mesangial and sub-endothelial deposition of dense frayed, curvilinear banded fibers with characteristic features of type III collagen. The patient was diagnosed to have combined CG and diabetic nephropathy (DN). This is the first report of CG in association with diabetic changes in renal biopsy. In this report, we describe the clinicopathological characteristics of this disease, review CG in pediatric population, and explore its association with DN.

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies.

Rare single-gene disorders cause chronic disease. However, half of the 6000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole-exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole-exome resequencing in 10 sib pairs with a nephronophthisis-related ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sibships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy, we detect the causative gene. In six sibships, we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sibships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus, whole-exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

Rituximab for refractory cases of childhood nephrotic syndrome.

Rituximab has been used over the last decade as a rescue therapy for refractory cases of nephrotic syndrome (NS). Here we report the use of rituximab in four children with idiopathic steroid-resistant nephrotic syndrome (SRNS) with various histological backgrounds (two cases with focal segmental glomerulosclerosis, one case with IgM nephropathy, and one case with minimal change disease), who failed to respond to other immunsuppressions. Their median age (range) was 10 (8-11) years. NPHS2 genetic mutation was negative in all of them. All patients received a single dose of rituximab (375 mg/m(2)) and achieved complete B cell depletion as CD19 was <1% for 3 months following rituximab infusion. Only one patient achieved non-sustained remission as he relapsed after 4 months despite zero CD19 level. Patients received no further doses of rituximab as B cell was depleted in the peripheral circulation. We conclude that a single dose of rituximab was not effective in inducing sustained remission in children with idiopathic SRNS, despite complete B cell depletion in the peripheral circulation. Further doses might be indicated to deplete non-circulating B cells.

Risk factors for catheter-related complications in pediatric peritoneal dialysis.

Catheter-related complications, including infection, dialysate leak, and malfunction, are the principal causes of peritoneal dialysis (PD) failure. To determine risk factors predisposing to these complications, we conducted a retrospective study of 90 children on chronic PD who received 127 catheters from January 1990 to December 2000. There was a significant risk for dialysate leak when PD catheters were used early (14 days). There was no significant difference in malfunction and infection rate between early and delayed use groups. Weight and height <5th percentile, low serum albumin, and history of abdominal surgery were not associated with an increased risk of complications. History of dialysis prior to catheter placement and presence of a gastrostomy tube (G-tube) were both associated with significant infection risk. Patients