Search

Abstract Background Congenital anomalies of the kidney and urinary tract (CAKUT) are prevalent birth defects. Although pathogenic CAKUT genes are known, they are insufficient to reveal the causes for all patients. Our previous studies indicated GEN1 as a pathogenic gene of CAKUT in mice, and this study further investigated the correlation between GEN1 and human CAKUT. Methods In this study, DNA from 910 individuals with CAKUT was collected; 26 GEN1 rare variants were identified, and two GEN1 (missense) variants in a non-CAKUT group were found. Mainly due to the stability results of the predicted mutant on the website, in vitro, 10 variants (eight CAKUT, two non-CAKUT) were selected to verify mutant protein stability. In addition, mainly based on the division of the mutation site located in the functional region of the GEN1 protein, 8 variants (six CAKUT, two non-CAKUT) were selected to verify enzymatic hydrolysis, and the splice variant GEN1 (c.1071 + 3(IVS10) A > G) was selected to verify shear ability. Based on the results of in vitro experiments and higher frequency, three sites with the most significant functional change were selected to build mouse models. Results Protein stability changed in six variants in the CAKUT group. Based on electrophoretic mobility shift assay of eight variants (six CAKUT, two non-CAKUT), the enzymatic hydrolysis and DNA-binding abilities of mutant proteins were impaired in the CAKUT group. The most serious functional damage was observed in the Gen1 variant that produced a truncated protein. A mini-gene splicing assay showed that the variant GEN1 (c.1071 + 3(IVS10) A > G) in the CAKUT group significantly affected splicing function. An abnormal exon10 was detected in the mini-gene splicing assay. Point-mutant mouse strains were constructed (Gen1: c.1068 + 3 A > G, p.R400X, and p.T105R) based on the variant frequency in the CAKUT group and functional impairment in vitro study and CAKUT phenotypes were replicated in each. Conclusion Overall, our findings indicated GEN1 as a risk factor for human CAKUT.

Abstract Even after decades of research, pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and responses to conventional treatments remain mostly poor. Subclassification of PDAC into distinct biological subtypes has been proposed by various groups to further improve patient outcome and reduce unnecessary side effects. Recently, an immunohistochemistry (IHC)‐based subtyping method using cytokeratin‐81 (KRT81) and hepatocyte nuclear factor 1A (HNF1A) could recapitulate some of the previously established molecular subtyping methods, while providing significant prognostic and, to a limited degree, also predictive information. We refined the KRT81/HNF1A subtyping method to classify PDAC into three distinct biological subtypes. The prognostic value of the IHC‐based method was investigated in two primary resected cohorts, which include 269 and 286 patients, respectively. In the second cohort, we also assessed the predictive effect for response to erlotinib + gemcitabine. In both PDAC cohorts, the new HNF1A‐positive subtype was associated with the best survival, the KRT81‐positive subtype with the worst, and the double‐negative with an intermediate survival (p

Abstract Background Galloway-Mowat syndrome (GAMOS) is a group of rare hereditary diseases by the combination of early onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies caused by WDR73, LAGE3, OSGEP, TP53RK, TPRKB, GON7, WDR4 or NUP133 mutations. Case presentation We present the clinical and genetic features of a two-year-old boy with early nephrotic syndrome, microcephaly, growth retardation hypotonia and hypothyroidism. Genetic testing showed the presence of a canonical-splice mutation in the LAGE3 gene (NM_006014: c.188 + 1C > T). A total of nine female members of the family carried the variant. Seven male members died prematurely, and three of them suffered from nephrotic syndrome, which is consistent with the x-linked gene map of the disease. The overall symptoms of the disease due to the LAGE3 mutation were mild compared to other pathogenic genes. Conclusion As far as we know, this is the largest family case of GAMOS2 caused by LAGE3 mutation found so far. We also compared other subtypes of GAMOS. Due to the heterogeneity of the renal phenotype, regular proteinuria screening is recommended for all patients diagnosed with GAMOS.

Abstract Background In children, focal segmental glomerulosclerosis (FSGS) is the main cause of steroid resistant nephrotic syndrome (SRNS). To identify specific candidates and the mechanism of steroid resistance, we examined the formalin-fixed paraffin embedded (FFPE) renal tissue protein profiles via liquid chromatography tandem mass spectrometry (LC-MS/MS). Methods Renal biopsies from seven steroid-sensitive (SS) and eleven steroid-resistant (SR) children FSGS patients were obtained. We examined the formalin-fixed paraffin embedded (FFPE) renal tissue protein profiles via liquid chromatography tandem mass spectrometry (LC-MS/MS). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and Gene Ontology (GO) analysis, as well as the construction of protein-protein interaction (PPI) network were performed. Two proteins were further valiadated by immunohistochemistry staining in FSGS patients and mice models. Results In total, we quantified more than 4000 proteins, of which 325 were found to be differentially expressed proteins (DEPs) between the SS and SR group (foldchange ≥2, P

Phlorizin, as a flavonoid from a wide range of sources, is gradually becoming known for its biological activity. Phlorizin can exert antioxidant effects by regulating the IL-1β/IKB-α/NF-KB signaling pathway. At the same time, it exerts its antibacterial activity by reducing intracellular DNA agglutination, reducing intracellular protein and energy synthesis, and destroying intracellular metabolism. In addition, phlorizin also has various pharmacological effects such as antiviral, antidiabetic, antitumor, and hepatoprotective effects. Based on domestic and foreign research reports, this article reviews the plant sources, extraction, and biological activities of phlorizin, providing a reference for improving the clinical application of phlorizin.

Summary: Nephronophthisis-like nephropathy-1 (NPHPL1) is a rare ciliopathy, caused by mutations of XPNPEP3. Despite a well-described monogenic etiology, the pathogenesis of XPNPEP3 associated with mitochondrial and ciliary function remains elusive. Here, we identified novel compound heterozygous mutations in NPHPL1 patients with renal lesion only or with extra bone cysts together. Patient-derived lymphoblasts carrying c.634G>A and c.761G>T together exhibit elevated mitochondrial XPNPEP3 levels via the reduction of mRNA degradation, leading to mitochondrial dysfunction in both urine tubular epithelial cells and lymphoblasts from patient. Mitochondrial XPNPEP3 was co-immunoprecipitated with respiratory chain complex I and was required for the stability and activity of complex I. Deletion of Xpnpep3 in mice resulted in lower activity of complex I, elongated primary cilium, and predisposition to tubular dilation and fibrosis under stress. Our findings provide valuable insights into the mitochondrial functions involved in the pathogenesis of NPHP.

Abstract Proteinuria, an indication of kidney disease, is caused by the malfunction of podocytes, which play a key role in maintaining glomerular filtration. Angiopoietin-like 3 (ANGPTL3) has been documented to have a cell-autonomous involvement in podocytes, and deletion of Angptl3 in podocytes reduced proteinuria in adriamycin-induced nephropathy. Here, we developed a monoclonal antibody (mAb) against ANGPTL3 to investigate its effects on podocyte injury in an ADR nephropathy mouse model and puromycin (PAN) induced podocyte damage in vitro. The mAb against the human ANGPTL3-FLD sequence (5E5F6) inhibited the binding of ANGPTL3-FLD to integrin β3. Treatment with the 5E5F6 mAb in ADR nephropathy mice mitigated proteinuria and led to a significant decline in podocyte apoptosis, reactive oxygen species (ROS) generation and mitochondrial fragmentation. In PAN-induced podocyte damage in vitro, the 5E5F6 mAb blocked the ANPGPLT3-mediated activation of integrin αvβ3 and Rac1, which regulated the mitochondrial homeostasis. Altogether, anti-ANGPLT3-FLD mAb attenuates proteinuria and podocyte lesions in ADR mice models, as well as PAN-induced podocyte damage, in part through regulating mitochondrial functions. Our study provides a therapeutic approach for targeting ANGPTL3 in proteinuric kidney disease.

IntroductionThe pathogenic mechanisms of diabetic nephropathy (DN) include podocyte injury, inflammatory responses and metabolic disorders. Although the antagonism of Angiopoietin-like protein 3 (ANGPTL3) can alleviate proteinuria symptoms by inhibiting the activation of integrin αvβ3 on the surface of podocytes, it can not impede other pathological processes, such as inflammatory responses and metabolic dysfunction of glucolipid. Interleukin-22 (IL-22) is considered to be a pivotal molecule involved in suppressing inflammatory responses, initiating regenerative repair, and regulating glucolipid metabolism.MethodsGenes encoding the mIL22IgG2aFc and two chains of anti-ANGPTL3 antibody and bifunctional protein were synthesized. Then, the DN mice were treated with intraperitoneal injection of normal saline, anti-ANGPTL3 (20 mg/kg), mIL22Fc (12 mg/kg) or anti-ANGPTL3 /IL22 (25.3 mg/kg) and irrigation of positive drug losartan (20mg/kg/d) twice a week for 8 weeks.ResultsIn this research, a novel bifunctional fusion protein (anti-ANGPTL3/IL22) formed by the fusion of IL-22 with the C-terminus of anti-ANGPTL3 antibody exhibited favorable stability and maintained the biological activity of anti-ANGPTL3 and IL-22, respectively. The fusion protein showed a more pronounced attenuation of proteinuria and improved dysfunction of glucolipid metabolism compared with mIL22Fc or anti-ANGPTL3. Our results also indicated that anti-ANGPTL3/IL22 intervention significantly alleviated renal fibrosis via inhibiting the expression of the inflammatory response-related protein nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) p65 and NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Moreover, transcriptome analysis revealed the downregulation of signaling pathways associated with injury and dysfunction of the renal parenchymal cell indicating the possible protective mechanisms of anti-ANGPTL3/IL22 in DN.ConclusionCollectively, anti-ANGPTL3/IL22 bifunctional fusion protein can be a promising novel therapeutic strategy for DN by reducing podocyte injury, ameliorating inflammatory response, and enhancing renal tissue recovery.

Abstract Background Pathogenic variants of PAX2 cause autosomal-dominant PAX2-related disorder, which includes variable phenotypes ranging from renal coloboma syndrome (RCS), congenital anomalies of the kidney and urinary tract (CAKUT) to nephrosis. Phenotypic variability makes it difficult to define the phenotypic spectrum associated with genotype. Methods We collected the phenotypes in patients enrolled in the China national multicenter registry who were diagnosed with pathogenic variant in PAX2 and reviewed all published cases with PAX2-related disorders. We conducted a phenotype-based cluster analysis by variant types and molecular modeling of the structural impact of missense variants. Results Twenty different PAX2 pathogenic variants were identified in 32 individuals (27 families) with a diagnosis of RCS (9), CAKUT (11) and nephrosis (12) from the Chinese cohort. Individuals with abnormal kidney structure (RCS or CAKUT group) tended to have likely/presumed gene disruptive (LGD) variants (Fisher test, p

BackgroundThe duration of initial corticosteroid therapy in newly diagnosed Idiopathic nephrotic syndrome (INS) is about 3 months. Our study was designed to test the feasibility of a shorter duration of corticosteroid therapy in newly diagnosed INS who show a quicker response.MethodsPatients who responded within 10 days (Group A) received 8 weeks of corticosteroid therapy as compared to 12–14 weeks of standard therapy in those who responded between >10 days to 28 days (Group B), and follow up for 52 weeks. The primary endpoint is time to first relapse after treatment completion. (NCT03878914, March 18, 2019)ResultsA total of 33 children with INS were enrolled and the follow-up data were analyzed. The clinical and laboratory characteristics of patients in both groups were similar. No significant difference was found in time to first relapse [65(14.5, 159) days for Group A vs. 28(17, 61.5) days for Group B, P = 0.371], the incidence of frequently relapsing nephrotic syndrome [6/18 (33.3%) vs. 5/10(50%), P = 0.644] or requirement for alternative immunosuppressant [4/18 (22.2%) vs. 1/10 (10%), P = 0.769]. Group A received similar corticosteroid dose compare with Group B (3511 ± 2421 mg/m2 vs. 4117 ± 2556 mg/m2, P = 0.524). Frequency and severity of corticosteroid-related complications was similar in both groups.ConclusionsThe time to first relapse and the number of relapses per patient were comparable between the two groups. However, more patients in Group A relapsed and the mean total dose of prednisolone for the study period was very similar between the two groups.

Adverse intrauterine and early postnatal environment cause reduced nephron endowment and subsequent hypertension, chronic kidney disease (CKD). Exploring modifiable approaches is particularly important to alleviate the global burden of CKD. Enhanced glomerular progenitor cell apoptosis is a major contributor to renal developmental programming. The differentially expressed protein perlecan, which we previously identified using proteomics, is an important extracellular matrix glycoprotein, and its domain V (endorepellin) can inhibit apoptosis through a paracrine form. In explanted mice embryonic metanephros, we found that endorepellin can rescue glomeruli-deficit phenotype resulting from malnutrition, and this protective effect was also verified in vivo using a renal developmental programming model which was given a low-protein diet during pregnancy. We further demonstrated that endorepellin significantly inhibited glomerular progenitor cell apoptosis which activates ERK1/2 phosphorylation. Our results show that endorepellin rescues the nephron number reduction in renal developmental programming, possibly through the inhibition of progenitor cell apoptosis via the ERK1/2 pathway.

Background: Gen1 mutation can cause various phenotypes of congenital anomaly of the kidney and urinary tract (CAKUT). An intrauterine low-protein isocaloric diet can also cause CAKUT phenotypes in offspring. However, single factors such as gene mutation or abnormal environmental factor during pregnancy can only explain part of the pathogenesis of CAKUT. Objectives: A low-protein isocaloric diet was fed to Gen1-mutant mice throughout pregnancy to establish a Gen1-mutant mouse model exposed to a low-protein isocaloric intrauterine environment. The mice were divided into 4 groups: normal (22%) protein diet (ND) + wild-type mice (CON group), ND + Gen1PB/+ mice (Gen1PB/+ group), low (6%)-protein isocaloric diet (LD) + wild-type mice (LD group), and the LD + Gen1PB/+ groups. Methods: The experimental design included observing proportion and distribution of CAKUT phenotypes of neonatal mice; evaluating the number of ureteric buds (UBs) on embryonic day (E) 11.5, the location of UBs on E11.5, and length of the common nephric duct (CND); isolating embryonic kidneys on E11.5 from the Gen1PB/+ group and culturing embryonic kidneys in medium containing 10% serum or serum-free medium to observe the branching of UBs; and detecting the p-PLCγ, p-Akt, and p-ERK1/2 in UBs and CND on E11.5, as well as the apoptosis and proliferation of tissues by immunofluorescence staining. Results: We found that the incidence of CAKUT in offspring of Gen1PB/+ mice under an intrauterine low-protein isocaloric diet environment was significantly increased, and a duplicated collecting system was the dominant phenotype of CAKUT. During the early stage of metanephric development, ectopic protrusion of UBs may appear and lower locations of UBs in Gen1PB/+ mice under an intrauterine low-protein isocaloric diet environment and the number of UB branches in the serum-free culture condition significantly decreased. Further examination revealed that p-PLCγ signaling and tissue apoptosis were abnormal in UBs and the CND at the early stage of kidney development. Conclusions: The aforementioned findings suggest that an intrauterine low-protein isocaloric diet can aggravate the occurrence of CAKUT in Gen1-mutant mice, which might affect key steps in the metanephric development, such as the protrusion of UBs, which might be related to mediate UBs and CND apoptosis through p-PLCγ signaling.

Abstract Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.

Background: Assessment of renal lesions and deficiency accurately remains critical in the diagnosis of congenital anomalies of the kidneys and urinary tracts (CAKUT) in children. Advanced imaging such as Magnetic resonance Imaging (MRI) and Diffusion weighted Imaging (DWI) allows structural and functional insufficiency to be detected. Currently, radiomics machine learning models are being explored as full-automated diagnostic tools. We aimed to develop a machine learning integrated radiomics model to predict renal anomalies and deficiency in children.Methods: A retrospective study of 280 children with MRI/DWI were enrolled between 2018 and 202 at a children’s hospital. A total of 1,037 radiomics features were extracted from the DWI images of each participant, which were divided into training set and test set (8:2 split). Using 5-fold cross-validated method, multiple machine learning algorithms were employed to predict renal lesions and deficiency when compared with the radiologist’s diagnosis based on DWI, 99mTc-labeled dimercaptosuccinic acid (DMSA) SPECT cortical renal scintigraphy or 99mTc-labeled diethylenetriamine pentaacetate (DTPA) renal scan.Results: For detecting the kidney lesions, the LASSO + Random Forest algorithm outperformed other classifiers with an accuracy of 0.750 (95% confidence interval, 0.734–0.766) and area under the curve (AUC) of 0.765 (95% confidence interval, 0.700–0.831). The performance of classifiers did not show a significant difference (p > 0.05) in detecting bilateral or unilateral kidney lesions by DWI scanning. The classifiers performed significantly better in bilateral kidney deficit than in unilateral kidney deficit (p < 0.05). We next built prediction models for renal deficiency using the radiomics signature and clinical features compared to renal scintigraphy. The ensemble model had a high-test accuracy of 80.9% ± 4.2% and a sensitivity of 91.7% ± 7.1% with a moderate calibration.Conclusion: An ensemble model integrated with DWI-radiomic and clinical features can be utilized to predict renal lesions and deficiency in children with CAKUT.

Basilar trunk artery aneurysm (BTAA) has an overall low incidence in intracranial aneurysm, but its rupture is associated with high morbidity and mortality in older people. Situs inversus totalis (SIT) is a rare congenital abnormality characterized by visceral rotation and vascular abnormalities. It has been described in several uncommonly clinical cases, along with middle cerebral artery aneurysms and large carotid cavernous aneurysms. However, the association between interventional embolization for BTAA and SIT has not been reported. We described the angiography findings and interventional treatment of the association of BTAA with SIT.

Inherited kidney diseases are the fifth most common cause of end-stage renal disease (ESRD). Mitochondrial dysfunction plays a vital role in the progression of inherited kidney diseases, while mitochondrial-transfer RNA (mt-tRNA) variants and their pathogenic contributions to kidney disease remain largely unclear. In this study, we identified the pathogenic mt-tRNAPhe 616T>C mutation in 3 families and documented that m.616T>C showed a high pathogenic threshold, with both heteroplasmy and homoplasmy leading to isolated chronic kidney disease and hyperuricemia without hematuria, proteinuria, or renal cyst formation. Moreover, 1 proband with homoplamic m.616T>C presented ESRD as a child. No symptoms of nervous system evolvement were observed in these families. Lymphoblast cells bearing m.616T>C exhibited swollen mitochondria, underwent active mitophagy, and showed respiratory deficiency, leading to reduced mitochondrial ATP production, diminished membrane potential, and overproduction of mitochondrial ROS. Pathogenic m.616T>C abolished a highly conserved base pair (A31-U39) in the anticodon stem-loop which altered the structure of mt-tRNAPhe, as confirmed by a decreased melting temperature and slower electrophoretic mobility of the mutant tRNA. Furthermore, the unstable structure of mt-tRNAPhe contributed to a shortage of steady-state mt-tRNAPhe and enhanced aminoacylation efficiency, which resulted in impaired mitochondrial RNA translation and a significant decrease in mtDNA–encoded polypeptides. Collectively, these findings provide potentially new insights into the pathogenesis underlying inherited kidney disease caused by mitochondrial variants.

BackgroundCongenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N6-methyladenosine (m6A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m6A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m6A methylation in CAKUT.MethodsUsing m6A-mRNA epitranscriptomic microarray, we investigated the m6A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group).ResultsA total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m6A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m6A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m6A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison.ConclusionThe current results highlight the pathogenesis of m6A methylation in obstructive and reflux uropathy.

BackgroundGenetic kidney disease is a major cause of morbidity and mortality in neonates and end-stage renal disease (ESRD) in children and adolescents. Genetic diagnosis provides key information for early identification of congenital kidney disease and reproductive risk counseling. Preimplantation genetic testing for monogenic disease (PGT-M) as a reproductive technology helps prospective parents to prevent passing on disease-causing mutations to their offspring.Materials and MethodsA retrospective cohort of couples counseled on PGT who had a risk to given birth to a child with genetic kidney disease or had a history of prenatal fetal kidney and urinary system development abnormalities from 2011 to 2021. Through a combination of simultaneously screening for aneuploidy and monogenic kidney disease, we achieved reproductive genetic intervention.ResultsA total of 64 couples counseled on PGT for monogenic kidney disease in a single reproductive center during the past 10 years, of whom 38 different genetic kidney diseases were identified. The most frequent indications for referral were autosomal recessive disease (54.7%), then autosomal dominant disease (29.7%), and X-linked disease (15.6%). Polycystic kidney disease was the most common diseases counted for 34.4%. After oocyte-retrieval in all of 64 females, a total of 339 embryos were diagnosed and 63 embryos were transferred in succession. Among 61 cycles of frozen-embryo transfer (FET), ongoing pregnancy/live birth rate (OP/LBR) reached 57.38%. The cumulative OP/LBR in our cohort for the 64 couples was 54.69%. In addition, we have carried out expanded carrier screening (ECS) in all the in vitro fertilization (IVF) couples performed PGT covering 7,311 individuals. The carrier frequency of the candidate genes for monogenic kidney diseases accounted for 12.19%.ConclusionOverall, the customization PGT-M plan in our IVF center is pivotal to decreasing the morbidity and implementing reproductive genetic intervention of genetic kidney disease.

ObjectiveTo evaluate the value of ultrasound screening for congenital anomalies of the kidney and urinary tract (CAKUT) during the early postnatal period.MethodsThis is a prospective study that enrolled all neonates born from August 2019 to July 2020 at one medical center. Postnatal ultrasound screening was conducted in all neonates at 1, 3, and 6 months old, respectively. Information on antenatal detection and pregnancy was collected. We performed logistic regression analyses and established a predictive model to assess the potential risk factors of abnormal ultrasound screening results.ResultsPostnatal ultrasound scanning in 4,877 infants identified 268 cases (5.5%) of anomalies of kidney and urinary tract by primary screening and 92 cases (1.9%) by tertiary screening. A specific diagnosis was identified in 47 cases within the 6-month screening and follow-up program. Logistic regression revealed that preterm birth, oligohydramnios, antenatal ultrasound screening anomalies, and gestational hypothyroidism were independent risk factors for the early detection of CAKUT by postnatal ultrasound screening. The above factors were adopted to develop a predictive model that showed good calibration in predicting ultrasound findings of CAKUT. Decision curve analysis demonstrated good clinical utility.ConclusionsPostnatal ultrasound screening should be conducted in infants with risk factors associated with CAKUT. Further study on prenatal and fetal factors could help establish the predictive model for the early detection of CAKUT.

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects children, but this disease is significantly rarer in patients who are older than 15 years. In this disease, any organ can be involved. The skeleton, skin and lung are commonly affected, and isolated hypothalamic-pituitary (HP) involvement is relatively rare. Here we report a 17-year-old adolescent with isolated HP-LCH of enlarged pituitary stalk presented with central diabetes insipidus (CDI). Case presentation A 17-year-old male adolescent with polydipsia and polyuria accompanied with elevated serum sodium level and low urine osmolality for 3 weeks was referred to our hospital. After admission, hormonal evaluation showed that his growth hormone (GH) was slightly elevated, and serum osmolality and glucose were normal. The fluid deprivation-vasopressin test demonstrated CDI. Imaging examination showed an obvious thickening of the pituitary stalk. Lymphocytic hypophysitis, sarcoidosis and granulation tissue lesions were suspected. After oral 1-deamino-8-Darginine vasopressin (DDAVP) and prednisone were administered for 2 months, symptoms were relieved, and he discontinued taking the drugs by himself. On reexamination, imaging revealed changes in the size and shape of the pituitary stalk, with thickened nodules. Then, a diagnostic biopsy of the pituitary stalk lesion was performed. Immunohistochemistry confirmed the definitive diagnosis of LCH. The clinical symptoms subsided with oral hormone replacements. Conclusion CDI is a rare symptom in children and adolescents. Most of the causes are idiopathic, while others are caused by central nervous system (CNS) disorders. Meanwhile, lymphocytic hypophysitis, germinoma, LCH and other CNS disorders can all present as thickening of the pituitary stalk, diffuse enlargement of the pituitary gland, and weakening of high signal intensity in the neurohypophysis on magnetic resonance imaging (MRI). The differential diagnosis among these diseases depends on immunohistochemistry evidence.

Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched.Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively.Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The “recurrent variants” included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection.Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.

Objective: To analyse the clinical manifestations, aetiology, prognosis, and risk factors of fungal peritonitis (FP) in children on peritoneal dialysis (PD).Methods: Among 322 children undergoing PD at Children's Hospital of Fudan University, between January 2001 and December 2019, FP cases were retrospectively analysed and compared with those of bacterial peritonitis (BP) to analyse the risk factors of FP.Results: A total of 124 cases of peritonitis were treated, including 11 FP cases in 11 children (0.0019 episodes/patient*month) and 113 BP cases in 64 children (0.02 episodes/patient*month). Among the 11 FP cases, 7 cases (63.64%) were caused by Candida and Candida parapsilosis (5/7) was the most common pathogen of Candida. All FP patients were converted to haemodialysis (HD) and did not resume PD during follow-up. Two patients (18.2%) died after 6 months of HD due to heart failure, 2 patients underwent kidney transplant after 2 years of infection, and the other 7 patients were still on HD. The univariate analysis showed the usage rate of antibiotics in the month before the onset of peritonitis was higher (45.45 vs. 15.93%) and the mean serum albumin was lower (31.4 vs. 34.4 g/L) in the FP group when compared with BP group (P < 0.05), while multivariate analysis showed that serum albumin ≤ 30 g/L was an independent risk factor for FP (odds ratio 4.896, 95% confidence interval 1.335–17.961).Conclusion: FP is a rare complication of PD in children, but it is associated with high technique failure. Attention should be paid to hypoproteinaemia and antibiotic use in children on PD.

Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.

Abstract Background Angiopoietin-like-3 (Angptl3) knockout is known for its protective effects on podocyte injury and proteinuria in the early stage of adriamycin (ADR) nephropathy. The current study re-evaluated the renoprotective effect of Angptl3 knockout in chronic ADR nephropathy and attempted to explore the mechanism underlying the effect associated with Angptl3 knockout in glomerulosclerosis. Methods B6; 129S5 mice were injected with ADR to induce nephropathy. Kidney structure and serum and urine parameters were observed during long-term follow-up. Cultured primary mouse podocytes were exposed to ADR and analyzed for the expression of some relative proteins. Podocyte loss was analyzed in both in vivo and in vitro experiments. Results Angptl3 knockout attenuated proteinuria and hypoproteinemia, protected renal structure and function, and improved the survival of mice over the whole process of ADR nephropathy. Furthermore, Angptl3 knockout reduced the numbers of the detached and apoptotic cells in the renal tissue and alleviated podocyte loss in mice with ADR chronic nephropathy, thereby, delaying the glomerulosclerosis formation. Additional results in vitro showed that Angptl3 knockout attenuated ADR-induced primary podocyte loss, including podocyte detachment and apoptosis. Conclusion In addition to serving a renoprotective role in the early stage of ADR nephropathy, Angptl3 knockout contributed to disease amelioration throughout the ADR nephropathy process. Angptl3 knockout effectively delayed glomerulosclerosis formation by attenuating podocyte loss through rescuing podocytes from detachment and apoptosis. Angptl3 antagonists or inhibitors might have therapeutic potential in the occurrence and progression of nephropathy.

Abstract Background Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disease characterized by the combination of glomerulopathy with early-onset nephrotic syndrome and microcephaly with central nervous system anomalies. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogenous group of disorders. Recently, it has been reported that mutations in KEOPS-encoding genes, including the OSGEP gene, were responsible for GAMOS. Results Overall, 6 patients from 5 different Taiwanese families were included in our study; the patients had an identical OSGEP gene mutation (c.740G > A transition) and all exhibited a uniform clinical phenotype with early-onset nephrotic syndrome, craniofacial and skeletal dysmorphism, primary microcephaly with pachygyria, and death before 2 years of age. We reviewed their clinical manifestations, the prenatal and postnatal presentations and ultrasound findings, results of imaging studies, associated anomalies, and outcome on follow-up. All individuals were found to have an “aged face” comprising peculiar facial dysmorphisms. Arachnodactyly or camptodactyly were noted in all patients. Neurological findings consisted of microcephaly, hypotonia, developmental delay, and seizures. Brain imaging studies all showed pachygyria and hypomyelination. All patients developed early-onset nephrotic syndrome. The proteinuria was steroid-resistant and eventually resulted in renal function impairment. Prenatal ultrasound findings included microcephaly, intrauterine growth restriction, and oligohydramnios. Fetal MRI in 2 patients confirmed the gyral and myelin abnormalities. Conclusions Our study suggests that a careful review of the facial features can provide useful clues for an early and accurate diagnosis. Prenatal ultrasound findings, fetal MRI, genetic counseling, and mutation analysis may be useful for an early prenatal diagnosis.

Abstract Background Psoriasis is a chronic inflammatory dermatosis with complex genetic basis supported by family investigation. Renal involvement in psoriasis is sparsely studied and its pathogenesis is still unclear. Methods and Results We describe the case of a 7‐year‐old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. His mother had a long history of psoriasis without abnormal urinalysis records. The case showed non‐nephrotic range proteinuria, microscopic hematuria without any other abnormal results including renal function, complement cascade, and ultrasound. Renal pathological demonstrated the diagnosis of C3 glomerulonephritis (C3GN) showing mesangial proliferative glomerulonephritis with C3 staining only, effacement of podocyte process and intramembranous electron dense deposit by electric microscopy. Parent‐child trio WES performed to screening the common variants of psoriasis susceptibility locus and also the rare variants associated with C3GN. We identified a missense single nucleotide polymorphism of CARD14 (*607211, rs34367357, p.Val585Ile) carried by the proband and his mother. Meta‐analysis proved the association of rs34367357 and psoriasis (p = 0.006, OR = 1.23). A hemizygouse mutation of CLCN5 (*300008, c.1904A＞G,p.Asn635Ser) was identified for diagnosis of Dent disease (*300009). Conclusion The case highlights the genetic study is necessary to facilitate disease differentiation in new onset of nephropathy with psoriasis in children.

Abstract Background Mutations in COQ8B (*615567) as a defect of coenzyme Q10 (CoQ10) cause steroid resistant nephrotic syndrome (SRNS). Methods To define the clinical course and prognosis of COQ8B nephropathy, we retrospectively assessed the genotype and phenotype in patients with COQ8B mutations from Chinese Children Genetic Kidney Disease Database. We performed the comparing study of renal outcome following CoQ10 treatment and renal transplantation between early genetic detection and delayed genetic detection group. Results We identified 20 (5.8%) patients with biallelic mutations of COQ8B screening for patients with SRNS, non‐nephrotic proteinuria, or chronic kidney disease (CKD) of unknown origin. Patients with COQ8B mutations showed a largely renal‐limited phenotype presenting with proteinuria and/or advanced CKD at the time of diagnosis. Renal biopsy uniformly showed focal segmental glomerulosclerosis. Proteinuria was decreased, whereas the renal function was preserved in five patients following CoQ10 administration combined with angiotensin‐converting enzyme (ACE) inhibitor. The renal survival analysis disclosed a significantly better outcome in early genetic detection group than in delayed genetic detection group (Kaplan–Meier plot and log rank test, p = .037). Seven patients underwent deceased donor renal transplantation without recurrence of proteinuria or graft failure. Blood pressure showed decreased significantly during 6 to 12 months post transplantation. Conclusions COQ8B mutations are one of the most common causes of adolescent‐onset proteinuria and/or CKD of unknown etiology in the Chinese children. Early detection of COQ8B nephropathy following CoQ10 supplementation combined with ACE inhibitor could slow the progression of renal dysfunction. Renal transplantation in patients with COQ8B nephropathy showed no recurrence of proteinuria.

Abstract Background Triple-negative breast cancers (TNBCs) are a group of heterogeneous diseases with various morphology, prognosis, and treatment response. Therefore, it is important to identify valuable biomarkers to predict the therapeutic response and prognosis for TNBCs. Tumor-infiltrating lymphocytes (TILs) may have predictive value to pathological complete response (pCR) in neoadjuvant treated TNBCs. However, absence of standardized methodologies for TILs measurement has limited its evaluation and application in practice. In 2014, the International TILs Working Group formulated the recommendations of pathologic evaluation for TILs in breast cancers. Methods To evaluate the predictive value of TILs scored by methods recommended by International TILs Working Group 2014, we performed a retrospective study of TILs in 166 core needle biopsy specimens of primary invasive TNBCs with neoadjuvant chemotherapy (NAC) in a Chinese population. Intratumoral TILs (iTILs) and stromal TILs (sTILs) were scored respectively. The associations between TILs and pCR were analyzed. Results Both sTILs (p = 0.0001) and iTILs (P = 0.001) were associated with pCR in univariate logistic regression analysis. Multivariate logistic regression analysis indicated that both sTILs (P = 0.006) and iTILs (P = 0.04) were independent predictors for pCR. Receiver operating characteristics (ROC) curve analysis was used to identify the optimal thresholds of TILs. TNBCs with more than 20% sTILs (P = 0.001) or with more than 10% iTILs (P = 0.003) were associated with higher pCR rates in univariate analysis. Multivariate analysis showed that a 20% threshold of sTILs (P = 0.005) was an independent predictive factor for pCR. Conclusions Our study indicated that TILs scored by recommendations of International TILs Working Group 2014 in pre-NAC core needle biopsy specimens was significantly correlated with pCR in TNBCs, higher TILs scores predicting higher pCR rate. Both sTILs and iTILs were independent predictors for pCR in TNBCs. A 20% threshold for sTILs may be feasible to predict pCR to NAC in TNBCs.

Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

BACKGROUND: The illegal use of melamine in powdered baby formula resulted in a widespread outbreak of melamine-associated pediatric urolithiasis and kidney damage in China in 2008. We conducted this study because more needs to be known about the long-term effects of melamine-associated urolithiasis and kidney damage. OBJECTIVES: To determine the prognosis and long-term implications of chronic kidney damage in children with urolithiasis resulting from melamine consumption. DESIGN: Prospective cohort study. SETTING: Children's Hospital of Fudan University. PATIENTS AND METHODS: Children six years of age or older with a history of having consumed melamine-contaminated milk powder were voluntarily screened. We measured urinary microprotein profiles [microalbumin (ALBU), immunoglobulin G (IgG), and N-acetyl-β-D-glucosidase (NAG)] and creatinine (CR) results at 6 and 18 months in children with melamine-associated urolithiasis. This study was conducted from September 17 to October 15, 2008. MAIN OUTCOME MEASURES: Changes in urinary microprotein profiles. RESULTS: Of 8335 children screened, 102 children (1.22%) were diagnosed with melamine-associated urolithiasis. Follow-up rates at 6 and 18 months were 91.4% (96/105) and 89.2% (91/102), respectively. Eighteen months later, 90.3% patients had spontaneously passed a stone. The incidence rates of proteinuria and microscopic hematuria at 6 months were significantly higher than at 18 months (P=.029 and P=.017, respectively). The proportion of patients with abnormal ALBU/CR, IgG/CR and NAG/CR at 6 months (27.6%, 17.1% and 21.1%, respectively) was significantly higher than at 18 months (6.4%, 5.1% and 12.8%, respectively). The high concentration of melamine consumed was the primary factor correlated with the high microprotein levels. Approximately 90% melamine-associated urolithiasis cases can be resolved within 18 months by non-surgical therapy. CONCLUSION: The long-term presence of stones associated with a previous exposure to melanine can cause chronic kidney glomerular and tubular injuries. Passing these stones as soon as possible can reduce kidney injury and accelerate recovery. LIMITATIONS: We could not control for possible selection bias due to more visits to our hospital or visits to our hospital after diagnosis at other hospitals, which might have increased the rate of diagnosis.

Sweet potato (Ipomoea batatas (L.) Lam.) is a logical candidate crop to suppress invasive plants, but additional information is needed to support its potential application as a suppressive ground cover. The current study utilized a de Wit replacement series incorporating five ratios of sweet potato grown in the field in combination with one of three invasive plants (Ageratum conyzoides L., Bidens pilosa L., and Galinsoga parviflora Cav.) in replicated 9 m2 plots. Stem length, total biomass, and leaf area were higher for monoculture-grown sweet potato than these parameters for any of the invasive plants grown in monoculture. In mixed culture, the plant height, branch, leaf, inflorescence, seed, and biomass of all invasive plants were suppressed by sweet potato. The relative yield parameter indicated that intraspecific competition was greater than interspecific competition for sweet potato, while the reverse was true for invasive species. The net photosynthetic rate was higher for sweet potato than for B. pilosa and G. parviflora but not A. conyzoides. Superoxide dismutase and peroxidase activities of each of the three invasive plants were reduced in mixture with sweet potato. Our results demonstrated that these three invasive plants were significantly suppressed by sweet potato competition due to the rapid growth and phenotypic plasticity of sweet potato.