Clinical features and genetic analysis of 15 Chinese children with dent disease.

OBJECTIVE:  The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians' awareness of and attention to this disease. METHODS:  We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. RESULTS:  All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). CONCLUSION:  Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.

Congenital chloride diarrhoea in a Chinese infant with a compound heterozygous SLC26A3 mutation.

INTRODUCTION: Congenital chloride diarrhoea (CCD) is an autosomal recessive condition that causes secretory diarrhoea and potentially deadly electrolyte imbalances in infants because of solute carrier family 26 member 3 (SLC26A3) gene mutations. CASE PRESENTATION: A 7-month-old Chinese infant with a history of maternal polyhydramnios presented with frequent watery diarrhoea, severe dehydration, hypokalaemia, hyponatraemia, failure to thrive, metabolic alkalosis, hyperreninaemia, and hyperaldosteronaemia. Genetic testing revealed a compound heterozygous SLC26A3 gene mutation in this patient (c.269_270dup and c.2006 C > A). Therapy was administered in the form of oral sodium and potassium chloride supplements, which decreased stool frequency. CONCLUSIONS: CCD should be considered when an infant presents with prolonged diarrhoea during infancy, particularly in the context of maternal polyhydramnios and dilated foetal bowel loops.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

Systemic lupus erythematosus combined with Wilson's disease: a case report and literature review.

BACKGROUND: Systemic lupus erythematosus (SLE) and Wilson's disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose. CASE REPORT: We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery. CONCLUSIONS: SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

A novel mutation of the RPGRIP1L gene in a Chinese boy with Joubert syndrome with oculorenal involvement.

BACKGROUND: Joubert syndrome (JS) is a rare genetically heterogeneous primary ciliopathy characterized by a pathognomonic cerebellar and brainstem malformation, the "molar tooth sign", and variable organ involvement (such as eye, kidney, liver, and skeleton). Here, we present a case of JS in a Chinese boy. CASE PRESENTATION: An 11-year-old Chinese boy presented with neonatal asphyxiation and hypoxia, strabismus, subsequent developmental delay, ataxia and end-stage kidney disease (ESKD). Routine blood tests showed severe anemia, increasing blood urea nitrogen and creatinine, elevated parathyroid hormone, hypocalcemia, hypokalemia and metabolic acidosis. Urine tests showed mild proteinuria. Ultrasound showed two small kidneys. Brain magnetic resonance imaging (MRI) showed dysplasia of the cerebellar vermis and extension of the upper cerebellar feet with the "molar tooth sign". Genetic analysis showed novel compound heterozygous mutations in the RPGRIP1L gene [p.L447fs*7(p.Leu447fsTer7) and p.G908V (p.Gly908Val)]. CONCLUSION: In the present study, we identified novel compound heterozygous mutations in the RPGRIP1L gene in a Chinese boy. The clinical and genetic findings of this study will expand the understanding of JS.

Urinary epidermal growth factor predicts complete remission of proteinuria in Chinese children with IgA nephropathy.

BACKGROUND: This study investigated the association between urinary epidermal growth factor (EGF) and complete remission (CR) of proteinuria in children with IgA nephropathy (IgAN). METHODS: We included 108 patients from the Registry of IgA Nephropathy in Chinese Children. The urinary EGF at the baseline and follow-up were measured and normalized by urine creatinine (expressed as uEGF/Cr). The person-specific uEGF/Cr slopes were estimated using linear mixed-effects models for the subset of patients with longitudinal data of uEGF/Cr. Cox models were used to analyze the associations of baseline uEGF/Cr and uEGF/Cr slope with CR of proteinuria. RESULTS: Patients with high baseline uEGF/Cr were more likely to achieve CR of proteinuria (adjusted HR 2.24, 95% CI: 1.05-4.79). The addition of high baseline uEGF/Cr on the traditional parameters significantly improved the model fit for predicting CR of proteinuria. In the subset of patients with longitudinal data of uEGF/Cr, high uEGF/Cr slope was associated with a higher likelihood of CR of proteinuria (adjusted HR 4.03, 95% CI: 1.02-15.88). CONCLUSIONS: Urinary EGF may be a useful noninvasive biomarker for predicting and monitoring CR of proteinuria in children with IgAN. IMPACT: High levels of baseline uEGF/Cr (>21.45 ng/mg) could serve as an independent predictor for CR of proteinuria. The addition of baseline uEGF/Cr on the traditional clinical pathological parameters significantly improved the fitting ability for the prediction of CR of proteinuria. Longitudinal data of uEGF/Cr were also independently associated with CR of proteinuria. Our study provides evidence that urinary EGF may be a useful noninvasive biomarker in the prediction of CR of proteinuria as well as monitoring therapeutic response, thus guiding treatment strategies in clinical practice for children with IgAN.

Clinical features and enzyme replacement therapy in 10 children with Fabry disease.

Objective: To summarize the clinical features, diagnosis and enzyme replacement therapy(ERT) of Fabry disease (FD) in children. Methods: The clinical data, laboratory tests, genetic variations and treatment of 10 FD children diagnosed in Shandong Provincial Hospital from September 2020 to June 2022 were retrospectively analyzed. Results: Among the 10 cases from 6 families, 7 patients were boys of 4 to 13 years of age, and 3 were girls of 12 to 15 years of age. There were 7 symptomatic patients, including 6 boys and 1 girl. All 7 patients presented with acral neuralgia. Five patients had little or no sweating. Five patients presented with cutaneous angiokeratoma. Two patients had abdominal pain. One patient developed joint symptoms. Four patients had corneal opacity. One patient had hearing loss; one patient had short stature. One patient had mild proteinuria and 1 patient had dysplasia of the right kidney with decreased eGFR (55.28 ml/min.1.73 m2). The left ventricular mass index was slightly elevated in 1 patient. Three patients had mild obstructive ventilatory dysfunction; a small amount of effusion in the intestinal space of the lower abdomen or mild fatty liver was found in 2 patients. Partial empty sella turcica in 1 patient. A total of 6 GLA gene variants were detected in 10 children, among which C.1059_1061delGAT (p.met353del) was a newly discovered mutation. Five children received ERT, of which 4 were treated with agalsidase beta and 1 was treated with agalsidase alpha. Only 1 patient had anaphylaxis. Lyso-GL-3 levels decreased significantly in the first 3 months of ERT initiation and remained relatively stable thereafter in 3 patients. The Lyso-GL-3 level was decreased, but renal impairment continued to progress in 1 patient treated with agalsidase alpha. Conclusion: The clinical manifestations of FD in childhood are diverse, and it is necessary to make a definite diagnosis by combining family history, enzyme activity, biomarkers, gene testing and other indicators. Pedigree screening and high-risk population screening are helpful for early identification, early diagnosis and early treatment. No serious adverse reactions were found during the short-term treatment with agalsidase alpha and beta.

Clinical features of children with anti-CFH autoantibody-associated hemolytic uremic syndrome: a report of 8 cases.

OBJECTIVE: To explore the clinical characteristics, treatment protocol and prognosis of children with anti-complement factor H (CFH) autoantibody (Ab)-associated hemolytic uremic syndrome (HUS). METHODS: Clinical data of 8 patients with anti-CFH Ab-associated HUS who were admitted to Shandong Provincial Hospital from January 2011 to December 2020 were collected retrospectively. RESULTS: The age at disease onset ranged between 5.83 and 13.5 years, with a male: female ratio of 1.67:1. The time of onset was distributed from May to June and November to December. Digestive and upper respiratory tract infections were common prodromal infections. Positivity for anti-CFH Ab and reduced C3 levels were observed among all patients. Heterozygous mutation of the CHFR5 gene (c.669del A) and homozygous loss of the CFHR1 gene [loss2(EXON:2-6)] were found in two patients. All patients received early treatment with plasma exchange and corticosteroid therapy. Six patients were given immunosuppressive agents (cyclophosphamide and/or mycophenolate mofetil) for persistent proteinuria. The follow-up period was 12-114 months. Four of 8 patients achieved complete remission, 3 achieved partial remission, and 1 died. Relapse occurred in two patients. CONCLUSION: Children with anti-CFH Ab-associated HUS were mainly school-aged and predominantly male, with onset times of summer and winter. Digestive and upper respiratory tract infections were common prodromal infections. Plasma exchange combined with methylprednisolone pulse therapy in the acute phase and cyclophosphamide or mycophenolate mofetil treatment for maintenance can be utilized in children with anti-CFH Ab-associated HUS if eculizumab is not available.

CXCL16/ERK1/2 pathway regulates human podocytes growth, migration, apoptosis and epithelial mesenchymal transition.

Primary nephrotic syndrome (PNS) is the commonest glomerular disease affecting children. Previous studies have confirmed that CXC motif chemokine ligand 16 (CXCL16) is involved in the pathogenesis of PNS. However, the exact mechanisms underlying the pathogenesis of PNS remain to be elucidated. Thus, the present study aimed to elucidate the role of CXCL16 in PNS. It was found that the expression of CXCL16 and extracellular signal­regulated kinases 1 and 2 (ERK1/2) were significantly increased in clinical PNS renal tissues using reverse transcription­quantitative PCR, western blot analysis and immunohistochemistry. Lentivirus overexpression or short hairpin RNA vector was used to induce the overexpression or knockdown of CXCL16 in podocytes, respectively. Overexpression of CXCL16 in podocytes could decrease the cell proliferation and increase the migration and apoptosis, whereas CXCL16 knockdown increased cell proliferation and decreased cell migration and apoptosis. Results of the present study further demonstrated that ERK2 protein expression was regulated by CXCL16. The knockdown of ERK2 expression reversed the effects of CXCL16 on the proliferation, apoptosis, migration and epithelial mesenchymal transition (EMT) of podocytes. Collectively, the findings of the present study highlighted that the CXCL16/ERK1/2 pathway regulates the growth, migration, apoptosis and EMT of human podocytes.

The Clinical and Pathological Features of Children With Microscopic Polyangiitis.

Objective: The aim of this study was to explore the clinical features, pathological characteristics, and the prognosis of children with microscopic polyangiitis (MPA). Methods: Ten children with MPA that were hospitalized in our hospital were included in this study. The children's pre-diagnosis status, clinical manifestations, renal pathology, treatment, and prognosis data were analyzed retrospectively. Results: All 10 cases included female patients with a median age of 8.9 years old at the time of diagnosis. MPO-ANCA antibody was positive in all cases, combined with a positive anti-GBM antibody in two cases. Nine cases had primary AAV and one had antithyroid drug (ATD)-associated MPA (secondary to methimazole). Renal involvement was found in all 10 patients, lung impairment was present in eight cases, and anemia was present in nine patients. Renal biopsies were performed in all 10 patients. Segmental focal or global glomerular necrosis was observed in 70% of the patients (7/10). The treatment mainly included steroid use combined with Cyclophosphamide and Mycophenolate. The follow-up s of the patients revealed normal renal function in eight patients and progression to end-stage renal disease (ESRD) in two patients. Conclusions: Female predisposition and positive MPO-ANCA antibody were prominent in children with MPA. The patients' kidneys and lungs were the most frequently involved organs. Corticosteroid combined with immunosuppressive therapy was recommended for the treatment of MPA. Early diagnosis, prompt aggressive treatment, and regular follow-ups are also very important factors associated with a good prognosis.

oxLDL promotes podocyte migration by regulating CXCL16, ADAM10 and ACTN4.

Nephrotic syndrome (NS) is one of the most common causes of chronic kidney disease in the pediatric population. Hyperlipidemia is one of the main features of NS. The present study investigated the role of CXC motif chemokine ligand 16 (CXCL16) and ADAM metallopeptidase domain 10 (ADAM10) in oxidized low­density lipoprotein (oxLDL)­stimualted podocytes and the underlying mechanisms. CXCL16 and ADAM10 expression levels in oxLDL­treated podocytes were measured via reverse transcription­quantitative PCR and western blotting. Cell migration assays were conducted to assess the migration of oxLDL­treated podocytes. CXCL16 or ADAM10 overexpression and knockdown assays were conducted. The results indicated that oxLDL stimulation increased ADAM10 and CXCL16 expression levels, and enhanced podocyte migration compared with the control group. Moreover, CXCL16 and ADAM10 overexpression significantly increased podocyte migration and the expression of actinin­α4 (ACTN4) compared with the control groups. By contrast, CXCL16 and ADAM10 knockdown significantly reduced podocyte migration and the expression of ACTN4 compared with the control groups. The results suggested that oxLDL promoted podocyte migration by regulating CXCL16 and ADAM10 expression, as well as by modulating the actin cytoskeleton. Therefore, CXCL16 and ADAM10 may serve as novel therapeutic targets for primary nephrotic syndrome in children.

Parthenolide ameliorates tweak-induced podocytes injury.

Parthenolide (PTL) is a natural product from the shoots of Tanacetum parthenium, which has immunomodulatory effects in multiply type of diseases. This study aimed to explore the effect and the underlying mechanism of PTL on the anti-apoptotic and anti- inflammatory ability of tweak-induced podocytes. Conditionally immortalized mouse podocytes were incubated with Tumor necrosis factor-like weak inducer of apoptosis (Tweak, 100 ng/ml), PTL(10 µM) or Tweak + PTL for 12 h, 24 and 48 h, respectively. Podocytes viability was detected by CCK-8 assay. Tweak and Cxcl16 expression were evaluated by western blot and immunofluorescence assay. Dil-oxLDL stain was detected by immunofluorescence analysis. Intracellular Total Cholesterol (TC) content was measured through TC detection Kit. These results demonstrated that the podocytes cells viability was gradually decreased after treatment with different concentrations of Tweak (0, 50, 100, 150). Tweak and Cxcl16 protein expression in mouse podocytes treated with tweak were remarkably elevated and were found to have higher intracellular lipid accumulation compared with the control group, whereas co-administration with PTL, tweak and Cxcl16 expression as well as the intracellular lipid accumulation were notablely decreased in tweak-induced podocytes. Therefore, our conclusion was that tweak and Cxcl16 were involved in the regulation of tweak-induced podocytes injury. Meanwhile, the anti-apoptotic and anti-inflammatory effect of PTL may be correlated with the tweak and Cxcl16 expression decreased.

Presurgical Concerns of Primary Family Caregivers of Children With Cerebral Palsy.

BACKGROUND: Primary family caregivers (PFCs) of children with cerebral palsy have many worries and concerns when their children face orthopedic surgery. Levels of PFC stress about the upcoming surgery is related to the child's level of gross motor function as well as the support they receive from medical professionals. PURPOSE: The purposes of the present study were to (1) explore the levels of concern about orthopedic surgery; and (2) explore the predictive factors associated with concerns about orthopedic surgery among PFCs of children with cerebral palsy during the preoperative period. METHODS: A cross-sectional, correlational study was conducted. Primary family caregivers were assessed preoperatively using the Single-event Multilevel Surgery Scale, Social Support Scale, Gross Motor Function Classification System-Expanded and Revised, and background information form. Primary family caregivers were recruited from the outpatient department of orthopedic surgery and pediatric rehabilitation of a medical center in northern Taiwan. Data were analyzed by descriptive analysis, Pearson product-moment correlation, and multiple regression analysis. RESULTS: A total of 63 eligible subjects were enrolled in this study. Primary family caregivers had moderate levels of concern and mild-to-moderate levels of social support. The higher severity of motor function impairment in children with cerebral palsy, prior caregiving by PFCs for another family member, and PFCs' lower level of social support from healthcare providers were associated with higher levels of PFC concern. CONCLUSIONS: Concerns about orthopedic surgery is an overlooked issue that needs more attention from healthcare providers. This study determined that PFCs who perceived a lack of social support from their healthcare providers and those with children who had limited gross motor function were more concerned and anxious about their children's upcoming orthopedic surgery. Health professionals should provide adequate health education and counseling to help PFCs of children with cerebral palsy in the decision-making process prior to orthopedic surgery.

The effect of recombinant stromal cell-derived factor-1 treatment on hypoxic-ischemic brain injury in neonatal mice.

BACKGROUND: Stromal cell-derived factor-1 (SDF-1) plays a critical role in adult brain injury repair including neurogenesis and vasculogenesis. However, the effects of recombinant SDF-1(rSDF-1) treatment on hypoxic-ischemic (HI) brain injury in neonatal mice are not clear. MATERIALS AND METHODS: Seven-day-old (P7) C57BL/6J mice were divided into sham group, control group, and rSDF-1 group. Mice brains were collected to determine histopathological damage and the expression level of SDF-1, caspase-3, and Ki67 on P8, P10, P14, and P21. Passive avoidance and elevated plus-maze tests were also assessed on P20 and P21. RESULTS: Compared with control group, rSDF-1 treatment increased the weight ratio of left and right brain hemisphere (p < 0.05), reduced the number of electric foot shocks (p < 0.05) and the percentage of time spent in the open arms (p < 0.05), meanwhile, increased the retention latency (p < 0.05) and the percentage of time spent in the enclosed arms (p < 0.05) on P20 and P21. High expression of Ki67 and low expression of caspase-3 were also observed. DISCUSSION: This study showed that rSDF-1 treatment effectively alleviated brain injury shown by reducing in caspase-3 expression and increasing in Ki67 expression. Moreover, rSDF-1 treatment significantly improved behavioral performances in juvenile mice after HI.

[Effects of pseudolaric acid B on apoptosis of bladder cancer cell 5637].

OBJECTIVE: To investigate the apoptosis of bladder cancer cell 5637 induced by pseudolaric acid B in vitro and its mechanism. METHOD: The cell proliferation was detected by MTT assay;the cell cycle was measured by flow cytometry; the cell apoptosis was observed by flow cytometry with Annexin V-FITC/PI double staining; the expressions of survivin protein and caspase-3 protein were detected by Western blot assay. RESULT: It showed that pseudolaric acid B remarkably induced apoptosis of 5637 cell line. Moreover, pseudolaric acid B suppressed survivin and up-regulated caspase-3 expression. CONCLUSION: Pseudolaric acid B inhibits the proliferation and induces the apoptosis of 5637 cells. The molecular mechanism of pseudolaric acid B inducing the apoptosis of 5637 cells may be associated with its action of down-regulating the expression of survivin, and up-regulating the expression of caspase-3.

Gestational diabetes mellitus in women of single gravidity in Tianjin City, China.

OBJECTIVE: The aim of this study was to investigate the prevalence of gestational diabetes mellitus (GDM) and risk factors for the development of GDM in pregnant women in Tianjin, China, where the prevalence of GDM is still unknown. STUDY DESIGN AND METHODS: A total of 9,471 pregnant women living in the six urban districts of Tianjin, China, took part in the initial screening between December 1998 and December 1999. The screening test consisted of a 50-g 1-h glucose test. Women with a reading > or =7.8 mmol/l at the initial screening were invited to undergo a 75-g 2-h oral glucose tolerance test (OGTT). GDM was confirmed using the World Health Organization's diagnostic criteria. RESULTS: At the initial screening test, 888 women had a glucose reading of > or =7.8 mmol/l. A total of 701 (79%) women took a subsequent OGTT. Of these, 174 women were confirmed to have GDM (154 with impaired glucose tolerance [IGT] and 20 with diabetes). The prevalence of GDM was 2.31% (2.03% for IGT and 0.28% for diabetes), adjusting for serum glucose levels at the initial screening test. Independent predictors for GDM were maternal age, stature, prepregnancy BMI, weight gain in pregnancy before screening, diabetes in first-degree relatives, and habitual cigarette smoking during pregnancy. Women who smoked or had a short stature are more likely to develop GDM than their counterparts. CONCLUSIONS: The prevalence of GDM in pregnant women in the city of Tianjin, China, was 2.31%. Short stature and smoking in pregnancy were additional risk factors for GDM.