The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in ...16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes (AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1), in one dominant gene (SLC9A3R1), and in one gene (SLC34A1) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.
Metabolic syndrome and chronic kidney disease Singh, Ajay K; Kari, Jameela A
Current opinion in nephrology and hypertension,
2013-March, 2013-Mar, 2013-03-00, 20130301, Letnik:
22, Številka:
2
Journal Article
Recenzirano
PURPOSE OF REVIEWThe association of the metabolic syndrome (MetS) with cardiovascular risk, mortality, type 2 diabetes mellitus, stroke, nonfatty liver disease and gout is well known. However, the ...association of the MetS with chronic kidney disease (CKD) is now emerging. This review discusses the epidemiology, pathology and potential mechanisms for the relationship of MetS with CKD.
RECENT FINDINGSStudies show that patients with MetS have a 2.5-fold higher risk of developing CKD. The risk of microalbuminuria is also increased two-fold in the MetS. Renal dysfunction becomes apparent long before the appearance of hypertension or diabetes in MetS. Compared with healthy controls, patients with MetS have increased microvascular disease-tubular atrophy, interstitial fibrosis, arterial sclerosis and global and segmental sclerosis. Studies suggest that the renal fibrosis seen in MetS might be caused by a constellation of insulin resistance, hypertension, dyslipidemias and inflammation, and result in a heightened expression of adipocytokines, angiotensin and inflammatory cytokines such as interleukin-6 and tumour necrosis factor-alpha.
SUMMARYDespite the strong association of MetS with CKD, a causal relationship has not been proven. More studies are needed to precisely elucidate the mechanisms that might lead upstream factors such as insulin resistance, hypertension, dyslipidemia and inflammation to cause renal fibrosis.
Background
Acute kidney injury (AKI) is common in neonates admitted to the neonatal intensive care unit (NICU). AKI is associated with increased morbidity and mortality and a greater long-term risk ...of chronic kidney disease.
Objectives
To study the incidence and outcome of neonatal AKI in a single Saudi Arabian center, level 2\3 NICU.
Methods
This single-center prospective cohort study included all infants who received level II or III NICU care during 2015 (January to December). We excluded infants who survived less than 48 h after admission, had evidence of congenital renal anomalies, or had insufficient data. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Both AKI and non-AKI neonates were prospectively followed up until NICU discharge. Outcomes studied included mortality and length of NICU stay. The results of adjusted risk analyses were expressed as relative risk (RR) with 95% confidence interval (95% CI).
Results
The incidence of AKI (modified neonatal KDIGO stages) was 56% (120/214 patients). Compared with neonates without AKI, those with AKI had a lower birth weight (2202 ± 816 vs. 1570 ± 776 g;
p
< 0.001) and a lower gestational age (35 ± 3 vs. 32 ± 4 weeks;
p
< 0.001). After adjustment for potential confounders, only gestational age (RR, 4.8; 95% CI, 3–9) and perinatal depression (RR, 10; 95% CI, 2–46) were significantly associated with an increased risk of AKI. For infants with gestational age < 32 weeks, only the Clinical Risk Index for Babies (CRIB II) score was associated with an increased risk of AKI (RR, 1.9; 95% CI, 1–3). After adjustment for gestational age, AKI was significantly associated with mortality (RR, 5.4; 95% CI, 2–14), but not with the length of hospital stay (LOS) (
p
= 0.133). However, the AKI group had a significantly longer LOS (mean difference: 14 days; 95% CI, 5.5–23 days), and 33 patients (27.5%) with AKI were discharged with abnormally high serum creatinine levels (> 65 μmol/L).
Conclusion
AKI occurred in more than half of all NICU admissions, was associated with an increased risk of mortality, and had a higher incidence among smaller and sicker infants. Therefore, close monitoring of renal function during hospitalization and after discharge is warranted in such infants.
Background: COVID-19 is a respiratory disease that eventually became a pandemic, with 300 million people infected around the world. Alongside the improvement in COVID-19 management and vaccine ...development, identifying biomarkers for COVID-19 has recently been reported to help in early prediction and managing severe cases, which might improve outcomes. Our study aimed to find out if there is any correlation between clinical severity and elevated hematological and biochemical markers in COVID-19 patients and its effect on the outcome. Methods: We have collected retrospective data on socio-demographics, medical history, biomarkers, and disease outcomes from five hospitals and health institutions in the Kingdom of Saudi Arabia. Results: Pneumonia was the most common presentation of COVID-19 in our cohort. The presence of abnormal inflammatory biomarkers (D-dimer, CRP, troponin, LDH, ferritin, and t white blood cells) was significantly associated with unstable COVID-19 disease. In addition, patients with evidence of severe respiratory disease, particularly those who required mechanical ventilation, had higher biomarkers when compared to those with stable respiratory conditions (p < 0.001). Conclusion: Identifying biomarkers predicts outcomes for COVID-19 patients and may significantly help in their management.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation ...in up to 12% of patients with CAKUT.
We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.
In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).
We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.
Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity ...mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.
In steroid-resistant nephrotic syndrome (SRNS), >21 single-gene causes are known. However, mutation analysis of all known SRNS genes is time and cost intensive. This report describes a new ...high-throughput method of mutation analysis using a PCR-based microfluidic technology that allows rapid simultaneous mutation analysis of 21 single-gene causes of SRNS in a large number of individuals.
This study screened individuals with SRNS; samples were submitted for mutation analysis from international sources between 1996 and 2012. For proof of principle, a pilot cohort of 48 individuals who harbored known mutations in known SRNS genes was evaluated. After improvements to the method, 48 individuals with an unknown cause of SRNS were then examined in a subsequent diagnostic study. The analysis included 16 recessive SRNS genes and 5 dominant SRNS genes. A 10-fold primer multiplexing was applied, allowing PCR-based amplification of 474 amplicons in 21 genes for 48 DNA samples simultaneously. Forty-eight individuals were indexed in a barcode PCR, and high-throughput sequencing was performed. All disease-causing variants were confirmed via Sanger sequencing.
The pilot study identified the genetic cause of disease in 42 of 48 (87.5%) of the affected individuals. The diagnostic study detected the genetic cause of disease in 16 of 48 (33%) of the affected individuals with a previously unknown cause of SRNS. Seven novel disease-causing mutations in PLCE1 (n=5), NPHS1 (n=1), and LAMB2 (n=1) were identified in <3 weeks. Use of this method could reduce costs to 1/29th of the cost of Sanger sequencing.
This highly parallel approach allows rapid (<3 weeks) mutation analysis of 21 genes known to cause SRNS at a greatly reduced cost (1/29th) compared with traditional mutation analysis techniques. It detects mutations in about 33% of childhood-onset SRNS cases.
Coronavirus disease 2019 (COVID-19) has caused an unprecedented health crisis around the world, not least because of its heterogeneous clinical presentation and course. The new information on the ...pandemic emerging daily has made it challenging for healthcare workers (HCWs) to stay current with the latest knowledge, which could influence their attitudes and practices during patient care.This study is a follow-up evaluation of changes in HCWs' knowledge, attitudes, and practices as well as anxiety levels regarding COVID-19 since the beginning of the pandemic. Data were collected through an anonymous, predesigned, self-administered questionnaire that was sent online to HCWs in Saudi Arabia.The questionnaire was sent to 1500 HCWs, with a 63.8% response rate (N = 957). The majority of respondents were female (83%), and the most common age group was 31 to 40 years (52.2%). Nurses constituted 86.3% of the respondents. HCWs reported higher anxiety during the COVID-19 pandemic which increased from 4.91 ± 2.84 to 8.6 ± 2.27 on an 11-point Likert scale compared to other viral outbreaks. HCWs believed that their own preparedness as well as that of their hospital's intensive care unit or emergency room was higher during the COVID-19 pandemic than during the Middle East respiratory syndrome coronavirus pandemic (2012-2015). About 58% of HCWs attended one or more simulations concerning the management of COVID-19 patients in their intensive care unit/emergency room, and nearly all had undergone N95 mask fit testing. The mean score of HCWs' knowledge of COVID-19 was 9.89/12. For most respondents (94.6%), the perception of being at increased risk of infection was the main cause of anxiety related to COVID-19; the mean score of anxiety over COVID-19 increased from 4.91 ± 2.84 before to 8.6 ± 2.27 during the pandemic in Saudi Arabia.HCWs' anxiety levels regarding COVID-19 have increased since a pandemic was declared. It is vital that healthcare facilities provide more emotional and psychological support for all HCWs.
Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has ...revealed insights into disease mechanisms of nephrotic syndrome (NS).BACKGROUNDSteroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS).To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS.METHODSTo elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS.We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants.RESULTSWe identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants.We here identified recessive variants in MYO1C as a potential novel cause of NS in children.CONCLUSIONWe here identified recessive variants in MYO1C as a potential novel cause of NS in children.
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized ...that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.
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