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Background Primary hyperoxalurias (PHs) constitute rare disorders resulting in abnormal glyoxalate metabolism. PH-associated phenotypes range from progressive nephrocalcinosis and/or recurrent urolithiasis to early kidney failure. Methods A retrospective study was conducted for patients with confirmed PH diagnoses from three tertiary centers in Saudi Arabia. Detailed clinical molecular diagnosis was performed for 25 affected individuals. Whole exome sequencing (WES)–based molecular diagnosis was performed for all affected individuals. Results The male:female ratio was 52% male (n = 13) and 48% female (n = 12), and consanguinity was present in 88%. Nephrolithiasis and/or nephrocalcinosis were present in all patients. Kidney stones were present in 72%, nephrocalcinosis in 60%, hematuria in 32%, proteinuria in 16%, abdominal pain in 36%, developmental delay in 8%, and chronic kidney disease stage 5 (CKD stage 5) was observed in 28% of the patients. The most common PH disorder was type I caused by variants in the AGXT gene, accounting for 56%. The GRHPR gene variants were identified in 4 patients, 16% of the total cases. Seven patients did not reveal any associated variants. Missense variants were the most commonly observed variants (48%), followed by frame-shift duplication variants (28%). Conclusions Characterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research. Graphical abstract

Background: This practice guideline was developed by the Chronic Kidney Disease (CKD) Task Force, which was composed of clinical and methodological experts. The Saudi Arabian Ministry of Health and its Health Holding Company commissioned this guideline project to support the realization of the Vision 2030's healthcare transformation pillar. Methods: The guideline synthesis was guided by the GRADE-ADOLOPMENT methodology. Results: The final adoloped guideline addressed 12 clinical questions on blood pressure management in patients with CKD through a set of recommendations and performance measures. The recommendations included antihypertensive agents in children, non-renin angiotensin system inhibition (Non-RASi) vs RASi in adults, intensive vs standard blood pressure targets, early vs late assessment for kidney replacement therapy (KRT), late vs early preparation strategy for KRT, CKD symptoms during assessment for KRT or conservative management, initiation of KRT in patients with deteriorating CKD, choice of KRT modality or conservative management in certain CKD patient groups, changing or discontinuing KRT modalities, review frequency for KRT or conservative management, and Information, education and support. Conclusions: These conditional recommendations were based on low to very low certainty of evidence that highlights the need for high-quality randomized trials comparing different antihypertensive agents in patients with CKD.

Background Nephrotic syndrome is the most common kidney disease in children worldwide. Our aim was to critically appraise the quality of recent Clinical Practice Guidelines (CPGs) for idiopathic steroid-sensitive nephrotic syndrome (SSNS) in children in addition to summarize and compare their recommendations. Methods Systematic review of CPGs. We identified clinical questions and eligibility criteria and searched and screened for CPGs using bibliographic and CPG databases. Each included CPG was assessed by four independent appraisers using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE-II) instrument. We summarized the recommendations in a comparison practical table. Results Our search retrieved 282 citations, of which three CPGs were eligible and appraised: Kidney Disease: Improving Global Outcomes (KDIGO) 2012, Japan Society for Pediatric Nephrology (JSPN) 2014, and American Academy of Pediatrics (AAP) 2009. Among these, the overall assessment of two evidence-based CPGs scored > 70% (KDIGO and JSPN), which was consistent with their higher scores in the six domains of the AGREE II Instrument. In domain 3 (rigor of development), KDIGO, JSPN, and AAP scored 84%, 74%, and 41%, respectively. In domain 5 (applicability), they scored 22%, 16%, and 19%, respectively, and in domain 6 (editorial independence), they scored 94%, 65%, and 88%, respectively. Conclusions The methodological quality of the KDIGO CPG was superior, followed by JSPN and AAP CPGs with the relevant recommendations for use in practice. Systematic review registration The protocol was registered in the Center for Open Science (OSF) DOI: 10.17605/OSF.IO/6QTMD and in the International prospective register of systematic reviews PROSPERO 2020 CRD42020197511.

Objectives: To evaluate the practice and attitude of pediatrics nephrologists about cinacalcet use in children. Methods: An electronic structured questionnaire was answered by pediatric nephrologists practicing in the Kingdom of Saudi Arabia (KSA) and Gulf Council countries (GCC). Results: A total of 42 pediatric nephrologists responded, of them, 42% used cinacalcet for young children ≤5 years of age and 79% used for children. There were wide variations in the method of administration (examples: crushed, divided, whole tablets), monitoring, doses and response definition, and follow-up. No serious complications after starting cinacalcet was observed in 50%, while 40% reported various complications, mainly hypocalcemia (70%). Cinacalcet was stopped without achieving the target parathyroid hormone in more than half (55%) of children because of intractable adverse effects (40%), poor response (30%), non-adherence (25%), or high cost (5%). Conclusion: Cinacalcet is used by the majority of pediatric nephrologists in KSA and GCC. A standard clinical guideline is needed to be followed by all users.

To present our experience of treating steroid-dependent nephrotic syndrome (SDNS) in children with repeated doses of rituximab (RTX) with a relatively long follow-up, and to discuss the role of the histopathology type and previous immune-suppressor (IS) drugs on the outcome of these patients.The patients included in this prospective study were children with SDNS who were in remission on a high-dose steroid or with additional IS drugs. All patients underwent renal biopsy before RTX treatment. Intravenous RTX was administered monthly at 375 mg/mSeventeen (14 males) patients were enrolled. Approximately 76% had minimal change disease (MCD) and 3 (18%) patients had immunoglobulin M (IgM) nephropathy. Approximately 85% of MCD and 33% of IgM nephropathy showed complete response to RTX.Compared to other IS used to treat SDNS, RTX showed a significant decrease in relapse rate with fewer side effects. The dose and interval should be modified according to the patient's characteristics, such as medical history, pathology type, and previous IS agents.

Background: SARS-CoV-2 infection has a high mortality rate and continues to be a global threat, which warrants the identification of all mortality risk factors in critically ill patients. Methods: This is a retrospective multicenter cohort study conducted in five hospitals in the Kingdom of Saudi Arabia (KSA). We enrolled patients with confirmed SARS-COV-2 infection admitted to any of the intensive care units from the five hospitals between March 2020 and July 2020, corresponding to the peak of recorded COVID-19 cases in the KSA. Results: In total, 229 critically ill patients with confirmed SARS-CoV-2 infection were included in the study. The presenting symptoms and signs of patients who died during hospitalization were not significantly different from those observed among patients who survived. The baseline comorbidities that were significantly associated with in-hospital mortality were diabetes (62% vs. 48% among patients who died and survived (p = 0.046)), underlying cardiac disease (38% vs. 19% (p = 0.001)), and underlying kidney disease (32% vs. 12% (p < 0.001)). Conclusion: In our cohort, the baseline comorbidities that were significantly associated with in-hospital mortality were diabetes, underlying cardiac disease, and underlying kidney disease. Additionally, the factors that independently influenced mortality among critically ill COVID-19 patients were high Activated Partial Thromboplastin Time (aPTT )and international normalization ratio (INR), acidosis, and high ferritin.

Hypokalemic periodic paralysis (HypoPP) is a relatively rare but treatable disorder caused by mutations in the CACNA1S gene. HypoPP patients may experience paralytic episodes associated with hypokalemia and, infrequently, may develop late-onset proximal myopathy. The paralytic attacks are characterized by reversible flaccid paralysis and, in most cases, spare the respiratory muscles and heart. We report a case of CACNA1S periodic paralysis precipitated by vigorous exercise in a 14-year-old boy who presented with sudden-onset paralysis of both his upper and lower extremities. Laboratory evaluation revealed a markedly low serum potassium level. The patient’s symptoms resolved after correction of the potassium abnormality, and he was discharged with no neurological deficits. Although rare, HypoPP must be differentiated from other causes of weakness and paralysis so that proper treatment can be promptly initiated to ensure good outcomes.

Background: Nephrolithiasis and nephrocalcinosis is uncommon in children; however, its incidence is increasing. Patients and Methods: A multicenter retrospective study of the clinical presentation, etiology, and outcome of childhood nephrolithiasis and compare it with nephrocalcinosis.Results: The study included 144 children; 93 with nephrolithiasis (formation of stones within renal pelvis or tubular lumen) and 51 with nephrocalcinosis. (deposition of calcium in the renal parenchyma) Mean age at presentation were 72 months and 54 months for nephrolithiasis and nephrocalcinosis, respectively. In 64.8% of the nephrolithiasis and 76% of nephrocalcinosis cases, a history of consanguinity was found. Congenital anomalies of the kidneys and urinary tract were present in 28% and 9.8% of those with nephrolithiasis and nephrocalcinosis, respectively. The most common symptoms of nephrolithiasis were flank pain (29%), hematuria (15%), and dysuria (11%). Urinary tract infection was the primary presentation in the nephrocalcinosis group (18%) followed by failure to thrive (16%), polyuria (12%), and dehydration (12%).The majority of nephrolithiasis cases were caused by metabolic disorders. In contrast, the most common underlying disorders for nephrocalcinosis were familial hypomagnesemia hypercalciuria nephrocalcinosis (35%), distal renal tubular acidosis (23%), and Bartter syndrome (6%).Clinical outcomes were significantly better in children with nephrolithiasis than those with nephrocalcinosis who had radiological evidence of worsening/persistent calcinosis and progressed more frequently to chronic kidney disease (stage II-IV) and end stage kidney disease.Conclusion: The etiology of nephrolithiasis can be identified in many children. Nephrocalcinosis is associated with worse clinical outcomes related to kidney function and disease resolution as compared to nephrolithiasis.

Background: Nephrotic syndrome is the most common kidney disease in children worldwide. Our aim was to critically appraise the quality of recent Clinical Practice Guidelines (CPGs) for idiopathic steroid-sensitive nephrotic syndrome (SSNS) in children in addition to summarize and compare their recommendations. Methods: Systematic review of CPGs. We identified clinical questions and eligibility criteria and searched and screened for CPGs using bibliographic and CPG databases. Each included CPG was assessed by four independent appraisers using the Appraisal of Guidelines for REsearch & Evaluation II (AGREE-II) instrument. We summarized recommendations in a comparison matrix. Results: Our search retrieved 282 citations, of which three CPGs were eligible and appraised: Kidney Disease: Improving Global Outcomes (KDIGO) 2012, Japan Society for Pediatric Nephrology (JSPN) 2014, and American Academy of Pediatrics (AAP) 2009. Among these, the overall assessment of two evidence-based CPGs scored > 70% (KDIGO and JSPN), which was consistent with their higher scores in the six domains of the AGREE II Instrument. In domain 3 (rigor of development), KDIGO, JSPN, and AAP scored 84%, 74%, and 41%, respectively. In domain 5 (applicability), they scored 22%, 16%, and 19%, respectively, and in domain 6 (editorial independence), they scored 94%, 65%, and 88%, respectively. Conclusions: The methodological quality of the KDIGO CPG was superior, followed by JSPN and AAP CPGs with the relevant recommendations for use in practice. Systematic review registration: The protocol was registered in the Center for Open Science (OSF) DOI: 10.17605/OSF.IO/6QTMD.

Background: Acute kidney injury (AKI) is a complication of coronavirus disease 2019 (COVID-19). The reported incidence of AKI, however, varies among studies. We aimed to evaluate the incidence of AKI and its association with mortality and morbidity in children infected with severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) who required hospital admission.Methods: This was a multicenter retrospective cohort study from three tertiary centers, which included children with confirmed COVID-19. All children were evaluated for AKI using the Kidney Disease Improving Global Outcomes (KDIGO) definition and staging. Results: Of 89 children included, 19 (21%) developed AKI (52.6% stage I). A high renal angina index score was correlated with severity of AKI. Also, multisystem inflammatory syndrome in children (MIS-C) was increased in children with AKI compared to those with normal kidney function (15% vs 1.5%). Patients with AKI had significantly more pediatric intensive care admissions (PICU) (32% vs. 2.8%, p< 0.001) and mortality (42% vs. 0%, p< 0.001). However, AKI was not associated with prolonged hospitalization (58% vs. 40%, p=0.163) or development of MIS-C (10.5% vs. 1.4%, p=0.051). Residual renal impairment at discharge occurred in 9% of patients. This was significantly influenced by the presence of comorbidities, hypotension, hypoxia, heart failure, acute respiratory distress, hypernatremia, abnormal liver profile, high C-reactive protein, and positive blood culture.Conclusions: AKI occurred in one-fifth of children with SARS-CoV-2 infection requiring hospital admission, with one-third of those requiring PICU. AKI was associated with increased morbidity and mortality, and residual renal impairment at time of discharge.

Objectives: To determine physicians’ attitudes and stated practice in the management of patients with spinal muscular atrophy (SMA). We also aimed to explore their knowledge about consensus statement for standard of care in SMA and the role of new treatment modalities in changing the method of practice in the management of these cases. Methods: This is a quantitative observational cross-sectional study, conducted from February to May 2017 among physicians who manage SMA patients in Kingdom of Saudi Arabia. The study cohort included pediatric neurologists, adult neurologists, and physicians of other sub-specialties who manage SMA patients. We used online and paper-based questionnaires. Results: Half of the 169 participants were aware of the consensus guidelines for the care of SMA patients. With regard to the newly released Nursinersen treatment protocol for SMA-diagnosed patients, half of the participants were uncertain, and the other half were hesitant about its outcomes. Junior physicians tended to be significantly more inclined to reverse the do-not-resuscitate (DNR) status of an SMA-diagnosed child than more senior physicians. Conclusion: Our results indicate the existence of wide differences in physician practice with children of SMA disease. Our data demonstrate a need for increased awareness of consensus guidelines and further awareness about the physician’s role in the variability of care for children with SMA.

Objectives: To assess the knowledge and attitudes of physicians in different specialties who are involved in the care of children with FS. Methods: We assessed knowledge and attitudes in the management of Febrile seizure (FS) among physicians working in different specialties in the Kingdom of Saudi Arabia using a questionnaire-based cross-sectional study conducted from September-December 2016. Results: Of the 300 physicians who responded to the questionnaire, 178 (59.3%) were males, 119 (39.7%) were consultants, 92 (30.7%) were specialists, and 89 (29.7%) were residents. The majority were general pediatric consultants. Our study showed that the consultants were more aware of the definition of simple FS in comparison to other groups of physicians, and the difference was statistically significant. However, there was no difference between pediatric neurologists and general pediatricians. There was a statistically significant difference among various specialties in the perceived need to perform routine lumbar puncture, neuroimaging, and serum electrolyte determination in the evaluation of children with FS. On the other hand, there was no difference in the perceived need to perform an electroencephalogram among physicians in different specialties. Conclusion: The study highlighted the wide variation in knowledge and attitudes of physicians in different specialties with different levels of experience toward the management of FS. The use of clinical practice guidelines will help minimize this diversity.

Item does not contain fulltext Steroid-resistant nephrotic syndrome (SRNS) almost invariably progresses to end-stage renal disease. Although more than 50 monogenic causes of SRNS have been described, a large proportion of SRNS remains unexplained. Recently, it was discovered that mutations of NUP93 and NUP205, encoding 2 proteins of the inner ring subunit of the nuclear pore complex (NPC), cause SRNS. Here, we describe mutations in genes encoding 4 components of the outer rings of the NPC, namely NUP107, NUP85, NUP133, and NUP160, in 13 families with SRNS. Using coimmunoprecipitation experiments, we showed that certain pathogenic alleles weakened the interaction between neighboring NPC subunits. We demonstrated that morpholino knockdown of nup107, nup85, or nup133 in Xenopus disrupted glomerulogenesis. Re-expression of WT mRNA, but not of mRNA reflecting mutations from SRNS patients, mitigated this phenotype. We furthermore found that CRISPR/Cas9 knockout of NUP107, NUP85, or NUP133 in podocytes activated Cdc42, an important effector of SRNS pathogenesis. CRISPR/Cas9 knockout of nup107 or nup85 in zebrafish caused developmental anomalies and early lethality. In contrast, an in-frame mutation of nup107 did not affect survival, thus mimicking the allelic effects seen in humans. In conclusion, we discovered here that mutations in 4 genes encoding components of the outer ring subunits of the NPC cause SRNS and thereby provide further evidence that specific hypomorphic mutations in these essential genes cause a distinct, organ-specific phenotype.

Acute kidney injury (AKI) is a common problem encountered in critically ill children with an increasing incidence and evolving epidemiology. AKI carries a serious morbidity and mortality in patients requiring admission to a pediatric intensive care unit (PICU). We undertook a prospective cohort study of PICU admissions at three tertiary care hospitals in the Kingdom of Saudi Arabia over 2 years. The Kidney Disease Improving Global Outcomes (KDIGO) definition was used to diagnose AKI. A total of 1367 pediatrics PICU admissions were included in the study. AKI affected 511 children (37.4%), with 243 children (17.8%) classified as stage I (mild), 168 patients (12.3%) stage II (moderate), and 100 children (7.3%) were classified as stage III (severe). After adjustment for age, sex, and underlying diagnosis, in-hospital mortality was six times more likely among patients with AKI as compared to patients with normal renal function (adjusted OR: 6.5, 95% CI: 4.2–10). AKI was also a risk factor for hypertension (adjusted OR: 4.1, 95% CI: 2.8–5.9) and prolonged stay in the PICU and hospital, as it increased the average number of admission days by 10 (95% CI: 8.6–11) days in the PICU and 12 (95% CI: 10–14) days in the hospital. One-third of PICU admissions were complicated with AKI. AKI was associated with increased hospital mortality and the length of stay in both PICU and hospital.

Objective We aim to report our experience managing cases of recurrent focal segmental glomerulosclerosis (FSGS) in a group of pediatric renal transplant recipients. Methods This study was a retrospective chart review of pediatric patients who had their first kidney transplant at King Faisal Specialist Hospital & Research Center between 2014 and 2016. Results We reviewed the files of 6 patients, 3 of whom were male. The median age of the children was 2.75 years (range, 2–4 years) at disease onset, with an average time of progression to end-stage renal disease of 19 months (range, 8–30 months). Five of the patients received a living related donor transplant, and 1 received a living nonrelated donor transplant. Patients had FSGS recurrence at varying intervals (1 to 3 days) post transplant. All cases had plasmapheresis prior to receiving abatacept or rituximab. The therapeutic strategy in 4 patients involved switching tacrolimus to cyclosporine. A complete response was observed in 5 of the 6 patients (83.3%), and treatment was well tolerated in 5 patients. Patient 1 had severe oliguria and required intermittent hemodialysis during the first 3 weeks post transplant. He showed minimal response to the therapeutic plasma exchange and rituximab and was subsequently treated with abatacept. However, he died 8 months post transplant of pneumonia and sepsis. Conclusion Rituximab and switching tacrolimus to cyclosporine, in conjunction with plasmapheresis, appeared to be effective and safe in children with recurrent FSGS. Conversely, abatacept did not appear to provide clinical benefit.

Nephrotic syndrome (NS) is a renal disease characterized by heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. Its presentation within the first 3 months of life or in multiple family members suggests an underlying inherited cause. To determine the frequency of inherited NS, 62 cases (representing 49 families with NS) from Saudi Arabia were screened for mutations in NPHS1, NPHS2, LAMB2, PLCE1, CD2AP, MYO1E, WT1, PTPRO and Nei endonuclease VIII-like 1 (NEIL1). We detected likely causative mutations in 25 out of 49 families studied (51%). We found that the most common genetic cause of NS in our cohort was a homozygous mutation in the NPHS2 gene, found in 11 of the 49 families (22%). Mutations in the NPHS1 and PLCE1 genes allowed a molecular genetic diagnosis in 12% and 8% of families, respectively. We detected novel MYO1E mutations in three families (6%). No mutations were found in WT1, PTPRO or NEIL1. The pathogenicity of novel variants was analyzed by in silico tests and by genetic screening of ethnically matched control populations. This is the first report describing the molecular genetics of NS in the Arabian Peninsula.

Acute kidney injury (AKI) is common in critically ill children with significant mortality and morbidity. Serum creatinine is an insensitive and late biomarker compared to newly proposed AKI biomarkers. Prospective study in pediatric intensive care unit (PICU) over three months to compare between serum cystatin-C (s-Cys-C) and urinary neutrophil gelatinase-associated lipocalin (uNGAL) as AKI biomarkers at multiple time points with pediatric risk, injury, failure, loss, end-stage renal disease (pRIFLE) classification in diagnosing AKI. Forty children were recruited. Of these 40 children, 22 developed AKI according to pRIFLE criteria. There was no significant difference between AKI and non-AKI in age (P = 0.29). Post cardiac surgery, renal insult was the main cause of AKI (27.3%). There was a twofold increased risk of incident AKI in those patients with high baseline uNGAL at PICU admission and almost a fourfold increased risk in patients with high baseline s-Cys-C at PICU admission. uNGAL levels were highly predictive of AKI during the follow-up period [area under the curve (AUC) = 0.76, 95% confidence interval (CI) 0.61–0.92]. The cutoff point with the highest correctly classified proportion was 223 ng/mL (≥ 12 centiles) which correctly predict 80.0% patients with AKI, with a corresponding sensitivity of 72.7% and a specificity of 89.9%. AUC for s-Cys-C was 0.86 (95% CI 0.75–0.97), and the highest correctly classified proportion was 1009 µg/L (≥ 13 centiles); 75% of patients with AKI, with a corresponding sensitivity of 63.6% and a specificity of 88.9%. uNGAL and s-Cys-C predicts AKI early in critically ill children.

Intellectual disability (ID) is a measurable phenotypic consequence of genetic and environmental factors. In this study, we prospectively assessed the diagnostic yield of genomic tools (molecular karyotyping, multi-gene panel and exome sequencing) in a cohort of 337 ID subjects as a first-tier test and compared it with a standard clinical evaluation performed in parallel. Standard clinical evaluation suggested a diagnosis in 16% of cases (54/337) but only 70% of these (38/54) were subsequently confirmed. On the other hand, the genomic approach revealed a likely diagnosis in 58% (n=196). These included copy number variants in 14% (n=54, 15% are novel), and point mutations revealed by multi-gene panel and exome sequencing in the remaining 43% (1% were found to have Fragile-X). The identified point mutations were mostly recessive (n=117, 81%), consistent with the high consanguinity of the study cohort, but also X-linked (n=8, 6%) and de novo dominant (n=19, 13%). When applied directly on all cases with negative molecular karyotyping, the diagnostic yield of exome sequencing was 60% (77/129). Exome sequencing also identified likely pathogenic variants in three novel candidate genes (DENND5A, NEMF and DNHD1) each of which harbored independent homozygous mutations in patients with overlapping phenotypes. In addition, exome sequencing revealed de novo and recessive variants in 32 genes (MAMDC2, TUBAL3, CPNE6, KLHL24, USP2, PIP5K1A, UBE4A, TP53TG5, ATOH1, C16ORF90, SLC39A14, TRERF1, RGL1, CDH11, SYDE2, HIRA, FEZF2, PROCA1, PIANP, PLK2, QRFPR, AP3B2, NUDT2, UFC1, BTN3A2, TADA1, ARFGEF3, FAM160B1, ZMYM5, SLC45A1, ARHGAP33 and CAPS2), which we highlight as potential candidates on the basis of several lines of evidence, and one of these genes (SLC39A14) was biallelically inactivated in a potentially treatable form of hypermanganesemia and neurodegeneration. Finally, likely causal variants in previously published candidate genes were identified (ASTN1, HELZ, THOC6, WDR45B, ADRA2B and CLIP1), thus supporting their involvement in ID pathogenesis. Our results expand the morbid genome of ID and support the adoption of genomics as a first-tier test for individuals with ID.

Therapeutic plasma exchange (TPE) is a procedure that involves the removal of a large volume of plasma that is replaced with a replacement fluid, which is usually 5% albumin or fresh-frozen plasma. This therapeutic modality presents several technical challenges in children but has become increasingly used in pediatric nephrology. Owing to advances in technology, scientists have gained substantial knowledge of the molecular pathogenesis underlying many pediatric renal diseases, supporting the use of TPE in treating these disorders. This review presents a synopsis of the literature as it relates to the accepted indications for TPE in children, the technical aspects of the procedure, and the associated complications. Increased collaboration between pediatric nephrologists will hopefully allow scientists to obtain more data in children to assess the benefits of TPE in various renal disorders and improve the quality of care provided in children with renal disorders.