Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively ...sequencing complete coding regions (i.e., "whole exome") have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in SLC26A3 (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in SLC26A3. These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.
Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in ...the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.
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.
In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, ...highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups.
This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV.
Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117 ml/m,
= 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (
> 0.05 for all).
This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.
To assess depression, anxiety, and other psychological disorders in adolescents with chronic kidney disease (CKD) and determine the significant factors and the effect of digital media use on its ...scores among these patient groups.
The study was conducted as a cross-sectional study and included 84 adolescents with CKD and 68 healthy controls. The participants completed the Revised Child Anxiety and Depression Scale (RCADS). We recorded their age, gender, the most problematic issue in their lives, coping methods with problems, and online applications they prefer in their leisure time.
Elevated rates (scores > 70) of separation anxiety, panic disorder, obsession, depression, total anxiety, and total depression scales were statistically higher in the CKD group. Separation anxiety, panic disorder, obsession, total anxiety, and total depression scales were higher in girls, and panic disorder, obsession, depression, total anxiety, and total depression scores were higher in younger ages in multivariate analysis. In the CKD group, family issues/problems increased panic disorder, obsession, depression, total anxiety, and total depression scales. Crying in tears/yelling response in children while facing a problem was associated with increased separation anxiety and social phobia rates. Also, preferring video applications was associated with separation anxiety and messaging applications with depression, total anxiety, and total depression.
Adolescents with CKD are at risk for depression, anxiety, obsession, and panic disorders. Also, crying in tears/yelling response may be at greater risk for anxiety among CKD adolescents. Early psychiatric evaluation and routine psychiatric follow-ups initiated early may improve the mental health of this vulnerable population.
The study aims to present the incidence of COVID-19 in pediatric patients undergoing renal replacement therapy (RRT) and to compare the severity and outcomes of the disease between the dialysis and ...kidney transplant (KTx) groups. This multicenter observational study was conducted between 1 April and 31 December 2020 in Istanbul. Members of the Istanbul branch of the Turkish Pediatric Nephrology Association were asked to report all confirmed cases of COVID-19 who were on RRT, as well as the number of prevalent RRT patients under the age of 20. A total of 46 confirmed cases of COVID-19 were reported from 12 centers, of which 17 were dialysis patients, and 29 were KTx recipients. Thus, the incidence rate of COVID-19 was 9.3% among dialysis patients and 9.2% among KTx recipients over a 9-month period in Istanbul. Twelve KTx recipients and three dialysis patients were asymptomatic (
p
= 0.12). Most of the symptomatic patients in both the dialysis and KTx groups had a mild respiratory illness. Only two patients, one in each group, experienced a severe disease course, and only one hemodialysis patient had a critical illness that required mechanical ventilation. In the entire cohort, one hemodialysis patient with multiple comorbidities died.
Conclusion
: While most cases are asymptomatic or have a mild disease course, pediatric patients undergoing dialysis and a kidney transplant are at increased risk for COVID-19.
What is Known:
• In adult population, both dialysis patients and kidney transplant recipients are at increased risk for severe illness of COVID-19 and have higher mortality rate.
• Children with kidney transplantation are not at increased risk for COVID-19 and most have mild disease course.
• Data on children on dialysis are scarce.
What is New:
• Pediatric patients undergoing dialysis and kidney transplantation have an increased risk for COVID-19.
• Most patients undergoing renal replacement therapy either on dialysis or transplanted develop asymptomatic or mild COVID-19 disease with a favorable outcome.
Background
Compared with the general population, the immune response to COVID-19 mRNA vaccines is lower in adult kidney transplant recipients (KTRs). However, data is limited for pediatric KTRs. In ...this study, we aimed to assess humoral and cellular immune responses to the COVID-19 mRNA vaccine in pediatric KTRs.
Methods
This multicenter, prospective, case–control study included 63 KTRs (37 male, aged 12–21 years), 19 dialysis patients, and 19 controls. Humoral (anti-SARS-CoV2 IgG, neutralizing Ab (nAb)) and cellular (interferon-gamma release assay (IGRA)) immune responses were assessed at least one month after two doses of BNT162b2 mRNA vaccine.
Results
Among COVID-19 naïve KTRs (
n
= 46), 76.1% tested positive for anti-SARS-CoV-2 IgG, 54.3% for nAb, and 63% for IGRA. Serum levels of anti-SARS-CoV-2 IgG and nAb activity were significantly lower in KTRs compared to dialysis and control groups (
p
< 0.05 for all). Seropositivity in KTRs was independently associated with shorter transplant duration (
p
= 0.005), and higher eGFR (
p
= 0.007). IGRA titer was significantly lower than dialysis patients (
p
= 0.009). Twenty (43.4%) KTRs were positive for all immune parameters. Only four of 11 seronegative KTRs were IGRA-positive. COVID-19 recovered KTRs had significantly higher anti-SARS-CoV-2 IgG and nAb activity levels than COVID-19 naïve KTRs (
p
= 0.018 and
p
= 0.007, respectively).
Conclusions
The humoral and cellular immune responses to SARS-CoV-2 mRNA BNT162b2 vaccine are lower in pediatric KTRs compared to dialysis patients. Further prospective studies are required to demonstrate the clinical efficacy of the mRNA vaccine in KTRs.
This prospective study was registered in ClinicalTrials.gov (NCT05465863, registered retrospectively at 20.07.2022).
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
.
Histopathological changes in the kidney in type 1 diabetes mellitus (T1DM) begin before detection of microalbuminuria. Therefore, there is interest in finding a better biomarker for the early ...detection of diabetic kidney injury. The aim of this present study was to determine whether urinary indicators of fibrosis are detectable early in the development of T1DM in children and if they may predict progressive renal injury.
Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) and transforming growth factor-β1 (TGF-β1) were assessed in 33 patients with T1DM with normal renal functions and in 24 healthy controls. Microalbuminuria was not present in the patient group with the exception of three patients. The results were adjusted to urine creatinine (Cr) and the differences between patients and controls were evaluated. These measurements were repeated after one year and the results were compared with the first year results.
Urine MMP2/Cr, MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-β1/Cr were not different between the patient and control groups (p>0.05). There were also no significant differences between the first and second year results for these biomarkers (p>0.05). None of these parameters were correlated with hemoglobin A1c, body mass index and duration of T1DM. Interestingly, all parameters were negatively correlated to age of onset of T1DM (p<0.05).
Our findings suggest that urinary biomarkers of fibrosis do not show an increase in diabetic children without microalbuminuria. The results also indicate that the risk of early fibrosis may increase as age of onset of T1DM decreases.
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