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Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes (AGXT, GRHPR or HOGA1). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT, with none detected in GRHPR or HOGA1. We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.

Background An essential milestone in pediatric transplantation is to find noninvasive biomarkers to monitor acute rejection (AR). In this retrospective (Case-control) study, we examined the role of Fas − 670A/G and Fas Ligand (FasL) − 843C/T gene polymorphisms in allograft nephropathy in pediatric renal transplant recipients. Methods In 47 pediatric kidney transplant recipients and 20 healthy controls, Fas − 670A/G and FasL − 843C/T gene polymorphisms as well as serum soluble Fas Ligand level (sFasL) were measured. Results Serum sFasL levels were significantly higher in transplant recipients children than that in controls (548.25 ± 298.64 pg/ml vs 143.17 ± 44.55 pg/ml, p = 0.0001). There was no significant difference between patients with AR and those without AR in regards to serum sFasL levels (567.70 ± 279.87 pg/ml vs 507.85 ± 342.80 pg/ml, p = 0.56). Fas − 670A/G genotypes or alleles were not significantly different between controls and transplant recipients and among transplant recipients with and without AR. (P > 0.05 for all). FasL − 843C/T genotypes were not different between transplant recipients and controls and among transplant recipients with and without AR (P > 0.05 for all). However, Frequency of C allele in transplant patients was significantly higher than that in the control group (44.68% vs 25%, P = 0.03). FasL − 843C/T alleles were significantly different between patients with and without AR (P = 0.03). The percentages of C allele were higher in children with AR (58.82% vs 36.67%). We found that serum FasL and serum creatinine were variables that were independently associated with AR. Conclusion This study suggests that FasL gene polymorphisms in peripheral blood might be accurate in detecting cellular AR.

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9–30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1 , NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL , COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

Vascular access represents a lifeline for children undergoing hemodialysis. A failure of vascular access among patients receiving regular hemodialysis is associated with increased morbidity, mortality and costs. We assessed the possibility of using soluble adhesion molecules as reliable predictors of vascular access failure in children on hemodialysis. Moreover, we evaluated whether there is an association among the different studied adhesion molecules in hemodialysis patients with thrombosed and non-thrombosed arteriovenous fistula fistulas (AVFs). This study included 55 hemodialysis children, 36 with good access and 19 with access failure, and 20 healthy volunteers. Forty-four patients had native AVFs and 11 patients had tunneled permanent catheter (11with thrombosed and 33 with non-thrombosed AVFs). Serum-soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) were measured using ELISA technique. A significant increase was found in the levels of sVCAM-1, sICAM-1, sE-selectin and sP-selectin versus controls and all hemodialysis patients, hemodialysis patients with good access and hemodialysis patients with access failure (P=0.001 for sVCAM-1 and sICAM-1 and P=0.0001 for sE-selectin and sP-selectin). A significant increase was found in the levels of sVCAM-1, sE-selectin and sP-selectin in both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs versus controls (P=0.0001 for all parameters). There was significant difference between both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs as regard to sVCAM-1 (54.64±30.82 versus 25.69±27.96ng/ml, P=0.04). Both sICAM-1 and sP-selectin were positively correlated with the erythropoietin (EPO) dose in hemodialysis children (r=0.31, P=0.04 and r=0.32, P=0.04, respectively). A significant positive association was found between E-selectin and sP-selectin in hemodialysis patients with thrombosed AVFs (r=0.83, P=0.04). There was a significant correlation between sVCAM-1 and EPO dose in thrombosed AVF group (r=0.84, P=0.01). The assessment of serum sVCAM-1 might be useful for the identification of the chronic hemodialysis patients at an increased risk for native AVFs thrombosis. The role of EPO in vascular access failure should be taken into consideration. The clinical relevance of these observations warrants further investigations.

Primary hyperoxalurias are rare inborn errors of metabolism resulting in increased endogenous production of oxalate that leads to excessive urinary oxalate excretion. Diagnosis of primary hyperoxaluria type 1 (PH1) is a challenging issue and depends on diverse diagnostic tools including biochemical analysis of urine, stone analysis, renal biopsy, genetic studies and in some cases liver biopsy for enzyme assay. We characterized the clinical presentation as well as renal and extrarenal phenotypes in PH1 patients.This descriptive cohort study included patients with presumable PH1 presenting with nephrolithiasis and/or nephrocalcinosis (NC). Precise clinical characterization of renal phenotype as well as systemic involvement is reported. AGXT mutational analysis was performed to confirm the diagnosis of PH1.The study cohort included 26 patients with presumable PH1 with male to female ratio of 1.4:1. The median age at time of diagnosis was 6 years, nevertheless the median age at initial symptoms was 3 years. Thirteen patients (50%) were diagnosed before the age of 5 years. Two patients had no symptoms and were diagnosed while screening siblings of index patients. Seventeen patients (65.4%) had reached end-stage renal disease (ESRD): 6/17 (35.3%) during infancy, 4/17 (23.5%) in early childhood and 7/17 (41.29%) in late childhood. Two patients (7.7%) had clinically manifest extra renal (retina, heart, bone, soft tissue) involvement. Mutational analysis of AGXT gene confirmed the diagnosis of PH1 in 15 out of 19 patients (79%) where analysis had been performed. Fifty percent of patients with maintained renal functions had projected 10 years renal survival.PH1 is a heterogeneous disease with wide spectrum of clinical, imaging and functional presentation. More than two-thirds of patients presented prior to the age of 5 years; half of them with the stormy course of infantile PH1. ESRD was the commonest presenting manifestation in two-thirds of our cohort.

Primary hyperoxalurias are rare inborn errors of metabolism with deficiency of hepatic enzymes that lead to excessive urinary oxalate excretion and overproduction of oxalate which is deposited in various organs. Hyperoxaluria results in serious morbid-ity, end stage kidney disease (ESKD), and mortality if left untreated. Combined liver kidney transplantation (CLKT) is recognized as a management of ESKD for children with hyperoxaluria type 1 (PH1). This study aimed to report outcome of CLKT in a pediatric cohort of PH1 patients, through retrospective analysis of data of 8 children (2 girls and 6 boys) who presented by PH1 to Wadi El Nil Pediatric Living Related Liver Transplant Unit during 2001-2017. Mean age at transplant was 8.2 ± 4 years. Only three of the children underwent confirmatory genotyping. Three patients died prior to surgery on waiting list. The first attempt at CLKT was consecutive, and despite initial successful liver transplant, the girl died of biliary peritonitis prior to scheduled renal transplant. Of the four who underwent simultaneous CLKT, only two survived and are well, one with insignificant complications, and other suffered from abdominal Burkitt lymphoma managed by excision and resection anastomosis, four cycles of rituximab, cyclophosphamide, vincristine, and prednisone. The other two died, one due to uncontrollable bleeding within 36 hours of procedure, while the other died awaiting renal transplant after loss of renal graft to recurrent renal oxalosis 6 months post-transplant. PH1 with ESKD is a rare disease; simultaneous CLKT offers good quality of life for afflicted children. Graft shortage and renal graft loss to oxalosis challenge the outcome.

Background Nephropathic cystinosis is an inherited autosomal recessive lysosomal storage disorder characterized by the pathological accumulation and crystallization of cystine inside different cell types. WBC cystine determination forms the basis for the diagnosis and therapeutic monitoring with the cystine depleting drug (cysteamine). The chitotriosidase enzyme is a human chitinase, produced by activated macrophages. Its elevation is documented in several lysosomal storage disorders. Although, about 6% of Caucasians have enzyme deficiency due to homozygosity of 24-bp duplication mutation in the chitotriosidase gene, it is currently established as a screening marker and therapeutic monitor for Gaucher’s disease. Methods Plasma chitotriosidase activity was measured in 45 cystinotic patients, and compared with 87 healthy controls and 54 renal disease patients with different degrees of renal failure (CKD1-5). Chitotriosidase levels were also correlated with WBC cystine in 32 treated patients. Furthermore, we incubated control human macrophages in-vitro with different concentrations of cystine crystals and monitored the response of tumor necrosis factor-alpha (TNF-α) and chitotriosidase activity. We also compared plasma chitotriosidase activity in cystinotic knocked-out (n = 10) versus wild-type mice (n = 10). Results Plasma chitotriosidase activity in cystinotic patients (0–3880, median 163 nmol/ml/h) was significantly elevated compared to healthy controls (0–90, median 18 nmol/ml/h) and to CKD patients (0–321, median 52 nmol/ml/h), P

Renal cystic disorders (RCD) constitute an important and leading cause of end-stage renal disease (ESRD) in children. It can be acquired or inherited; isolated or associated with extrarenal manifestations. The precise diagnosis represents a difficult clinical challenge.The aim of this study was to define the pattern of clinical phenotypes of children with renal cystic diseases in Pediatric Nephrology Center, Cairo University. We have studied the clinical phenotypes of 105 children with RCD [45 (43%) of them had extrarenal manifestations].The most common disorders were the presumably inherited renal cystic diseases (65.7%) mainly nephronophthisis and related ciliopathies (36.2%), as well as polycystic kidney diseases (29.5%). Moreover, multicystic dysplastic kidneys accounted for 18% of study cases. Interestingly, eight syndromic cases are described, yet unclassified as none had been previously reported in the literature.RCD in this study had an expanded and complex spectrum and were largely due to presumably inherited/genetic disorders (65.7%). Moreover, we propose a modified algorithm for clinical and diagnostic approach to patients with RCD.

Nephronophthisis (NPHP) is a recessive disorder of the kidney that is the leading genetic cause of end-stage renal failure in children. Egypt is a country with a high rate of consan-guineous marriages; yet, only a few studies have investigated the clinical and molecular charac-teristics of NPHP and related ciliopathies in the Egyptian population. We studied 20 children, from 17 independent families, fulfilling the clinical and the ultrasonographic criteria of NPHP. Analysis for a homozygous deletion of the NPHP1 gene was performed by polymerase chain reaction on the genomic DNA of all patients. Patients were best categorized as 75% juvenile NPHP, 5% infantile NPHP, and 20% Joubert syndrome-related disorders (JSRD). The mean age at diagnosis was 87.5 + 45.4 months, which was significantly late as compared with the age at onset of symptoms, 43.8 ± 29.7 months (P

Sirs, Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes the most frequent genetic cause for end-stage renal disease (ESRD) in the first three decades of life. Homozygous deletions in the NPHP1 gene account for approximately 21% of all NPHP cases, whereas the other genes contribute less than 3% each. Interestingly, positional cloning of the nine genes (NPHP 1 through 9) and functional characterization of their encoded proteins (nephrocystins) have contributed to a unifying theory that defines cystic kidney diseases as “ciliopathies” [1]. Since there are no clinical or molecular data about NPHP in Egyptian children, we investigated the prevalence of homozygous NPHP1 deletion among a cohort of children with presumptive diagnosis of NPHP at Center of Pediatric Nephrology & Transplantation (CPNT), Cairo University. We studied 20 children, from 17 independent families, fulfilling the clinical and the ultrasonographic criteria of NPHP. All patients had full ophthalmologic examination, brain MRI was carried out in children with neurological involvement. Analysis for a homozygous deletion of the NPHP1 gene was performed by multiplex polymerase chain reaction (PCR) approach on genomic DNA of patients described earlier [2]. Sex distribution among affected patients showed a slight preponderance of females, with a ratio of 1.2:1 (11 females and 9 males). Seventy five percent of our study patients were the products of consanguineous marriages, the percentage of affected siblings was strikingly high 65% (13/20 patients) and 40% (8/20 patients) had a history of sibling death due to a similar condition. Fifteen of 20 patients (75%) presented with signs of ESRD. All the patients suffered from anemia and growth retardation when they first came to medical attention. Nineteen of 20 patients (95%) had a history typical of nephronophthisis, with symptoms of polydipsia, polyuria, and secondary enuresis. Four of 20 patients (20%) were hypertensive with elevated blood pressure above the 95th percentile for age, gender, and height. Clinically, study patients were best categorized as: 13/20 (65%) patients with isolated juvenile NPHP, 3/20 (15%) patients as infantile NPHP, while the remaining 4/20 (20%) patients had extrarenal associations (molar tooth sign on brain MRI, ataxia, mental retardation, retinal dystrophy, oculomotor apraxia, and facial dysmorphy) hence were clinically categorized as Joubert Syndrome Related Disorder (JSRD). The mean age at diagnosis 87.5 + 45.4 months was significantly late as compared to the age of onset of symptoms 43.8 ± 29.7 months (P