The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Risk factors and renal outcomes of AKI in children with secondary steroid-resistant nephrotic syndrome.

BACKGROUND: Acute kidney injury (AKI) is increasingly prevalent in children with nephrotic syndrome (NS). It is associated with adverse outcomes in NS, especially steroid-resistant nephrotic syndrome (SRNS). The incidence, risk factors and outcomes of AKI in secondary SRNS remain undefined. The main objectives of this study were to determine the risk factors and prognosis of AKI in hospitalized children with secondary SRNS. MATERIAL AND METHODS: This retrospective study was conducted from January 2014 to December 2019, involving 172 hospitalizations with secondary SRNS admitted to the First Affiliated Hospital of Sun Yat-sen University. AKI was defined and classified in accordance with the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines. RESULTS: AKI was found in 67 (39.0%) of 172 hospitalizations with secondary SRNS. Average age of onset in our group is 4.4 (3.1, 6.7) years with AKI and 3.7 (1.8, 5.6) years without AKI. Urea nitrogen level is 5.9 (4.1, 10.0) mmol/L with AKI and 5.1 (3.7, 7.0) mmol/L. Uric acid level is 446.0 (340.0, 567.0) umol/L with AKI and 401.0 (303.0, 496.0) umol/L. 24-h urinary protein level is 4.14 (2.9, 6.5) g with AKI and 2.5 (1.3, 5.3) without AKI. Multivariate logistic regression revealed that infection (OR = 5.287; 95% confidence interval, 2.349 to 11.899; p < 0.001), age at onset (OR = 1.180; 95% confidence interval, 1.032 to 1.349; p = 0.015) and uric acid level (OR = 1.003; 95% confidence interval, 1.000 to 1.006; p = 0.031) were significantly associated with the development of AKI in children with secondary SRNS. Among 72 children with secondary SRNS, six went to end-stage kidney disease (ESKD). Children in the AKI group were more likely to progress to ESKD compared with children in the non-AKI group (p = 0.017) with a median follow-up of 48.5months. CONCLUSION: AKI occurred in 39.0% of total hospitalizations associated with secondary SRNS. Risk factors including infection, age of onset, and uric acid level are associated with AKI in children with secondary SRNS. Furthermore, AKI was identified as a risk factor for the progression of secondary SRNS to ESKD.

Hyperuricemia is associated with the progression of IgA nephropathy in children.

BACKGROUND: The objective of the study was to explore the potential biomarkers and risk factors in children with immunoglobulin A nephropathy (IgAN). METHODS: Untargeted metabolomics analysis was performed on children with IgAN before and after treatment. Subsequently, a retrospective study involving the past 15 years and a follow-up study were performed to verify the role of hyperuricemia in IgAN children. RESULTS: Serum metabolomics analyses showed that levels of serum xanthosine were closely related to the outcome of IgAN, and KEGG analyses showed that differential metabolites were significantly enriched in purine metabolism. Furthermore, retrospectively analyses of 252 children with IgAN showed that hyperuricemia was associated with poorer renal outcome. Logistic regression analysis showed that BMI, serum creatinine, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. Kaplan-Meier analysis revealed that kidney progression-free survival in IgAN children with hyperuricemia was lower than that without hyperuricemia, especially in females. CONCLUSIONS: We first performed a dynamic metabolomics study to reveal that hyperuricemia is closely related to the progression of IgAN in children. Then retrospective and follow-up studies confirmed that hyperuricemia is an important risk factor for poor renal outcomes. We need to pay more attention to the hyperuricemia in children with IgAN. IMPACT: We first performed a dynamic metabolomics study to reveal that hyperuricemia was closely related to the progression of IgAN in children. Retrospective analyses in past 15 years confirmed that IgAN children with hyperuricemia had poorer renal function and worse renal pathology. The BMI, Scr, eGFR, Lee's grade III, and crescents were risk factors of hyperuricemia in children with IgAN. The long-term follow-up study showed that hyperuricemia was an important risk factor for poor renal outcome in children with IgAN. We need to pay more attention to hyperuricemia in children with IgAN, especially in females.

Serum levels and significance of soluble B-cell maturation antigen in childhood-onset systemic lupus erythematosus with renal involvement.

OBJECTIVE: The aim of this study was to investigate serum levels of soluble B-cell maturation antigen (sBCMA) in childhood-onset systemic lupus erythematous (cSLE) patients with renal involvement, and to elucidate their association with clinical characteristics. METHODS: 116 cases of cSLE patients with renal involvement (84 females and 32 males; median age 11.6 (10.1, 12.9) years) hospitalized in Department of Pediatric Nephrology and Rheumatology, the First Affiliated Hospital, Sun Yat-sen University and 31 healthy controls (HCs) were enrolled. Serum concentrations of sBCMA were determined using enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory information of cSLE patients were retrospectively analyzed. RESULTS: Serum sBCMA levels were significantly increased in primary cSLE when compared with treated cSLE patients and HCs, whereas there was no significant difference between treated cSLE patients and HCs. Patients with high disease activity displayed higher serum sBCMA levels compared with those with no or mild to moderate disease activity. Positive correlation was observed between serum sBCMA levels and systemic lupus erythematosus disease activity index-2K (SLEDAI-2K), antinuclear antibody titers, anti-double-stranded DNA titers, erythrocyte sedimentation rate, and immunoglobulin G levels, while sBCMA levels were negatively correlated with blood white blood cell count, hemoglobin, platelet count, complement C3 and C4 levels. Serum sBCMA levels decreased as disease ameliorated after treatments among 11 cases with follow-up examinations. CONCLUSIONS: In cSLE patients with renal involvement, serum sBCMA levels correlated significantly with disease activity, immunological, and hematological parameters, but not with renal parameters. Our results suggest the potential and significance of serum sBCMA as a biomarker in cSLE patients.

Mitochondrial micropeptide MOXI promotes fibrotic gene transcription by translocation to the nucleus and bridging N-acetyltransferase 14 with transcription factor c-Jun.

Progressive fibrosis is a hallmark of chronic kidney disease, but we lack effective treatments to halt this destructive process. Micropeptides (peptides of no more than 100 amino acids) encoded by small open reading frames represent a new class of eukaryotic regulators. Here, we describe that the micropeptide regulator of ß-oxidation (MOXI) regulates kidney fibrosis. MOXI expression was found to be up-regulated in human fibrotic kidney disease, and this correlated with the degree of fibrosis and loss of kidney function. MOXI was expressed in the cytoplasm and mitochondria of cultured tubular epithelial cells and translocated to the nucleus upon Transforming Growth Factor-ß1 stimulation. Deletion of Moxi protected mice against fibrosis and inflammation in the folic acid and unilateral ureteral obstruction models. As a potential molecular therapy, treatment with an antisense MOXI oligonucleotide effectively knocked-down MOXI expression and protected against kidney fibrosis in both models. Bimolecular fluorescence complementation identified the enzyme N-acetyltransferase 14 (Nat14) and transcription factor c-Jun as MOXI binding partners. The MOXI/Nat14/c-Jun complex enhances basal and Transforming Growth Factor-ß1 induced collagen I gene promoter activity. Phosphorylation at T49 is required for MOXI nuclear localization and for complex formation with Nat14 and c-Jun. Furthermore, mice with a MoxiT49A point mutation were protected in the models of kidney fibrosis. Thus, our studies demonstrate a key role for the micropeptide MOXI in kidney fibrosis and identify a new function of MOXI in forming a transcriptional complex with Nat14 and c-Jun.

Dyslipidemia may be a risk factor for progression in children with IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is often chronically progressive and commonly accompanied by dyslipidemia. However, the intrinsic relationship between dyslipidemia and IgAN remains to be elucidated. This study aimed to investigate the impact of different types of dyslipidemia on clinical and pathological characteristics in children with IgAN. METHODS: In our retrospective cohort study from January 2006 to January 2021, 276 children with IgAN were ultimately included in the baseline analysis, and 169 were included in the follow-up analysis. The clinical and pathological features of different types of dyslipidemia and their effect on kidney prognosis were analyzed. RESULTS: Children in the dyslipidemia group had more severe clinical characteristics (higher blood urea nitrogen, serum uric acid, and 24-h proteinuria; higher proportion of hypertension; and lower serum albumin and estimated glomerular filtration rate) and pathological changes (higher proportion of Lee grades IV-V and E1, S1, and C2 in MEST-C). Furthermore, the clinical and pathological characteristics were worse in the mixed hyperlipidemia group. Multivariate logistic analysis showed that hypertension, steroid treatment, lower serum albumin, severe proteinuria, and segmental glomerulosclerosis were independent risk factors for dyslipidemia in children with IgAN. The Kaplan-Meier analysis revealed that the probability of kidney survival in children with dyslipidemia was lower than that in those without dyslipidemia, with a median follow-up of 5.9 years. CONCLUSIONS: Children with IgAN and dyslipidemia, especially mixed hyperlipidemia, are prone to more severe clinical and pathological changes. Our study provides further insight into dyslipidemia as a potential risk factor in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information.

Association Between Macrophage Migration Inhibitory Factor -173 G>C Gene Polymorphism and Childhood Idiopathic Nephrotic Syndrome: A Meta-Analysis.

Background: Studies have identified that MIF -173 G>C gene polymorphism is associated with idiopathic nephrotic syndrome (INS) susceptibility and steroid resistance, but the results remain inconclusive. Methods: We searched PubMed, Embase, and Web of Science for relevant studies published before 31 March 2021. Pooled data were reported as odds ratio (OR) with 95% confidence interval (CI). Noteworthiness of significant OR was estimated by the false positive report probability (FPRP) test. Trial sequential analysis (TSA) was used to control type I and type II errors. Results: We selected seven case-control studies that included 1,026 INS children (362 were steroid-resistant NS and 564 were steroid-sensitive NS) and 870 controls. The results showed that MIF -173 G>C polymorphism was significantly associated with INS susceptibility in allelic, heterozygous and dominant genetic models (C vs. G: OR = 1.325, 95% CI: 1.011-1.738; GC vs. GG: OR = 1.540, 95% CI: 1.249-1.899; CC + GC vs. GG: OR = 1.507, 95% CI: 1.231-1.845), and FPRP test and TSA indicated that the associations were true in heterozygous and dominant models. The pooled results also revealed that MIF -173 G>C polymorphism was significantly associated with steroid resistance in allelic, homozygous and recessive models (C vs. G: OR = 1.707, 95% CI: 1.013-2.876; CC vs. GG: OR = 4.789, 95% CI: 2.109-10.877; CC vs. GC + GG: OR = 4.188, 95% CI: 1.831-9.578), but FPRP test indicated that all these associations were not noteworthy. Furthermore, TSA revealed that the non-significant associations between MIF -173 G>C polymorphism and steroid resistance in heterozygous and dominant models were potential false negative. Conclusions: This meta-analysis could draw a firm conclusion that MIF -173 G>C polymorphism was significantly associated with increased INS risk in heterozygous and dominant genetic models. MIF -173 G>C polymorphism was not likely to affect steroid responsiveness, but more studies were needed to confirm.

Long-Term Outcome of Secondary Steroid-Resistant Nephrotic Syndrome in Chinese Children.

INTRODUCTION: Secondary steroid-resistant nephrotic syndrome (SRNS) refers to the condition when patients with initial steroid-sensitive nephrotic syndrome develop steroid resistance in subsequent relapses. Long-term outcomes of secondary SRNS in children are uncertain. METHODS: This was a single-center retrospective study of 56 children with secondary SRNS between 2006 and 2016. The survival curve was estimated using the Kaplan-Meier method. Independent risk factors for end-stage renal disease (ESRD) were determined using Cox proportional hazards model. RESULTS: The median time from nephrotic syndrome onset to secondary SRNS was 7.8 months. Biopsy results at diagnosis secondary SRNS showed that 64.3% of cases were minimal change disease (MCD). No remission was observed in seven (12.5%) patients within the first year. The mean follow-up time was 7.8 ± 3.2 years. Eight patients were clinically cured, one died before ESRD, 10 reached ESRD, and 75.0% (3 of 4) of patients recurred post-transplantation. The 10-year ESRD-free survival rate was 85.8%. No response to intensified immunosuppression (IIS) in the first year was the independent predictor for ESRD. Repeat biopsies were performed in 20 cases, revealing that the reclassification from MCD to mesangial hypercellularity and focal segmental glomerulosclerosis (FSGS) in two when secondary steroid resistance appeared, from MCD and mesangial hypercellularity to FSGS in seven who developed multidrug resistance, and from FSGS to MCD and mesangial hypercellularity in two with favorable outcomes. CONCLUSIONS: The long-term outcome in children with secondary SRNS was heterogeneous, and no response to IIS in the first year was the independent predictor for ESRD. In patients with repeat biopsy, changes in histological appearance to FSGS were associated with multidrug resistance.

Clinicopathological Analysis of 34 Cases of Primary Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Chinese Children.

Background: This study aimed to summarize the clinicopathological features and prognostic risk factors of primary antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in children. Methods: Clinical and prognostic data for children admitted to our center with AAV between September 2003 and September 2020 were studied retrospectively. The incidence and risk factors of end-stage renal disease (ESRD) were calculated and analyzed. Results: Thirty-four children were enrolled; 28 were female, with a median onset age of 10 years. Except for one case negative for ANCA, the other 33 patients were diagnosed with microscopic polyangiitis (MPA). The most frequently involved organ was the kidney (100.0%), followed by the lungs (58.8%) and heart (50.0%). Twenty children (58.8%) progressed to ESRD with a median course of 3 months, and they were more likely to present respiratory and cardiovascular system involvement than were the non-ESRD group (P < 0.05). Patients in the ESRD group also had a higher serum creatinine level, 24-h protein excretion, Pediatric Vasculitis Activity Score (PVAS), and a lower level of estimated glomerular filtration rate (eGFR), hemoglobin, and complement C3 than had those in the non-ESRD group (P < 0.05). The main pathological manifestations were crescentic and sclerotic classes in the ESRD group and focal class in the non-ESRD group. After 6 months of induction therapy, 90.0% of cases achieved complete or partial remission. The multivariate logistic regression model showed that baseline eGFR < 60 ml/min/1.73 m2 was an independent risk factor for progressing to ESRD (OR = 0.016, 95% CI = 0.001~0.412, P = 0.012). Conclusions: AAV in children usually occurs in teenage girls, and the most commonly involved organ is the kidney, of which hematuria is the most common symptom, followed by proteinuria, abnormal renal function (eGFR < 90 ml/min/1.73 m2), etc. The primary type of AAV is MPA. Nearly 60% of patients progressed to ESRD with a median course of 3 months. Baseline eGFR < 60 ml/min/1.73 m2 is an independent risk factor for ESRD progression in AAV children.

Analysis of 10 Pediatric Nephrotic Syndrome Cases With Complications of Cerebral Sinovenous Thrombosis.

Background: To analyze the clinical characteristics of nephrotic syndrome (NS) with complications of cerebral sinovenous thrombosis (CSVT) in children. Method: Clinical, radiographic, laboratory, and treatment data obtained from 10 confirmed cases of NS with complications of CSVT were analyzed. All patients were followed up for at least 18 months. CSVT was diagnosed by cerebral computed tomography (CT) and/or magnetic resonance imaging (MRI) with or without magnetic resonance venography (MRV) of the cerebral vessels. Results: Among 10 cases reported, 4 were steroid-sensitive NS with frequent relapse, 5 were steroid-resistant (three of them had renal biopsies showing two minimal change disease and one IgA nephropathy), and 1 was steroid-sensitive with one relapse. Common clinical manifestations were headache or ophthalmodynia complicated by vomiting, dizziness, convulsion, and coma. Neuropathologic signs were positive in some cases. Papilledema appeared in only one case with winding of vein. Cerebrospinal fluid was examined in three cases with elevated pressure but normal cytological and biochemical results. D dimer and fibrinogen levels were elevated while prothrombin time and activated partial thromboplastin time were shortened. Five out of seven cases who had performed cranial CT were suspicious for cerebral thrombosis. Nine cases had cranial MRI with abnormal signs in seven cases. All of the cases received MRV, confirming the diagnosis of CVST. Conclusion: Clinical manifestations of NS with CSVT are not specific but varied. Therefore, CSVT should be considered once nervous manifestations present. MRV is a better method in the diagnosis of CSVT.

Anatomical variations of the aortic arch branches in a sample of Chinese cadavers: embryological basis and literature review.

OBJECTIVES: The aim of this study is to determine the incidence and explore the types of aortic arch branch variations found in our cadavers. METHODS: The types and incidence of aortic branch variations in 120 cadavers were analysed after careful dissection. RESULTS: One hundred and six of 120 cadavers had normal aortic arch branches and gave rise to usual branches, namely the brachiocephalic trunk, the left common carotid artery and the left subclavian artery. The remaining 14 cadavers had 2 basic types of branch variations, thus accounting for an incidence of 11.67%. A total of 9 aortic arches emitted 4 branches; the brachiocephalic trunk, the left common carotid artery, the left vertebral artery and the left subclavian artery (incidence 7.5%). The second subgroup of 5 cadavers also emitted 4 aortic branches: the right common carotid artery, the left common carotid artery, the left subclavian artery and the right subclavian artery (incidence 4.16%). In this group, the right subclavian artery sprung as a distal branch of the aortic arch (descending), thus making a vascular ring that takes a superoposterior course round the back of the trachea and the oesophagus to reach the right side. There was a single cadaver, different from the other 4 aortic branches of the second group which had a common origin for the common carotid arteries, while the left subclavian artery and distally placed right subclavian artery were present. We did not observe any Kommerell's aortic diverticula. CONCLUSIONS: The variations of aortic arch branching are complex and diverse due to varied possible alterations in the embryological processes. There is an imperative need for further research on these variations to elucidate the possible relationships with clinical diagnostic or surgical events.