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    Clinical Study

  • Wang Yin, Yu Binfeng, Chen Liangliang, Wang Yaomin, Xu Ying, Zhu Yilin, Chen Jianghua, Han Fei
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    Objective To evaluate the efficacy and safety of rituximab in the treatment of adult primary focal segmental glomerulosclerosis (FSGS). Methods Adult FSGS patients treated with rituximab in the First Affiliated Hospital of Zhejiang University College of Medicine were retrospectively enrolled. One or two doses of rituximab (375 mg/m2) were used aiming to achieve B cell depletion (defined as<5 B cells per microliter in peripheral blood) and the interval between the two doses was 2 weeks. The evaluated major outcomes were remission and relapse of nephropathy, and the secondary outcome measures were adverse events and renal outcomes. Results A total of 14 patients (9 males) were enrolled, among whom 7 cases were steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS), 6 cases were steroid-resistant nephrotic syndrome (SRNS) and one patient was new onset FSGS with contraindication to steroid. After treatment with rituximab, 7 patients with SDNS/FRNS achieved complete remission. At 6 months, the daily oral steroid dose reduced significantly compared with the baseline [(33.3±5.2) mg/d vs (6.7±6.6) mg/d, P<0.01]; while one patient still received tacrolimus 1.0 mg/d, the other 6 patients stopped using immunosuppressants; and the total number of relapse/total follow-up months decreased from 0.257 times/month to 0.058 times/month after the use of rituximab. For the other 6 SRNS patients and one patient with contraindication to steroid, three SRNS patients achieved partial remission and one patient with contraindication to steroid achieved complete remission at 34.50(20.25, 95.25) days after use of rituximab, and the other 3 SRNS patients failed to achieve remission, of whom one patient developed end stage renal disease at 23 months. Conclusions Rituximab may reduce the risk of relapse and help steroid or immunosuppressant-tapering in adult steroid-dependent/frequently relapsing idiopathic FSGS. However, it is not effective in SRNS patients.

  • Guo Wencong, Dong Bingzi, Zhang Ruixiao, Liu Zhiying, Xin Qing, Shi Xiaomeng, Han Yue, Lang Yanhua, Zhao Xiangzhong, Cai Yan, You Qingqing, Sun Yan, Du Huasheng, Shao Leping
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    Objective To analyze the gene variants in patients with primary distal renal tubular acidosis (dRTA), and explore the correlation between the genotype and phenotype. Methods The Sanger direct sequencing or whole-exome sequencing was used to identify causal variants and the variation pathogenicity was evaluated according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines in 44 dRTA patients (37 families) diagnosed in the Affiliated Qingdao Municipal Hospital of Qingdao University and the Affiliated Hospital of Qingdao University from April 2010 to September 2020. The clinical features of the patients were summarized, and the correlation between the genotype and phenotype was investigated. Results Seven variants of SLC4A1 gene, 17 variants of ATP6V0A4 gene, and 15 variants of ATP6V1B1 gene were identified in 44 patients with dRTA, and of which 11 variants were new ones. According to ACMG guidelines, the pathogenic, likely pathogenic, benign variants among the 39 variants were 22, 16 and 1, respectively. Nine patients were autosomal dominant hereditary dRTA caused by SLC4A1 gene mutation, 4 patients with autosomal recessive hereditary dRTA complicated with Southeast Asian ovalocytosis and anemia were caused by SLC4A1 gene mutation, and 14 patients caused by ATP6V0A4 gene mutation and 8 patients caused by ATP6V1B1 gene mutation were autosomal recessive hereditary dRTA; Two children with dRTA were found to carry one monoallelic defect in ATP6V1B1, and no causal gene mutation was identified in 7 patients. One patient showed incomplete dRTA, and the other 43 patients showed complete dRTA. The prevalence of sensory neural hearing loss caused by ATP6V0A4 and ATP6V1B1 mutation were 2/14 and 6/10 respectively. The frequency of chronic kidney disease in adults, children and infants were 4/4, 2/4, and 1/36, separately. After the drug treatment based on potassium citrate and sodium citrate, the growth and development (28/40) and electrolyte disturbance (41/44) of most patients were significantly improved. Conclusions The present study has identified 39 variants of SLC4A1, ATP6V0A4 and ATP6V1B1 genes in 44 patients with dRTA, including 11 novel ones. There is a close relationship between genotype and phenotype in dRTA patients and most patients' conditions were improved after proper treatment. This study enriches the human gene mutation database and provides valuable references for diagnosis, treatment and genetic counseling in patients with dRTA.

  • Huang Yajun, Gu Yue, Zhang Wenwen, Gao Mei, Sheng Yijia, Ren Yingying, Yan Lei, Shao Fengmin
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    Objective To analyze the influencing factors of death in patients with acute respiratory distress syndrome (ARDS) combined with acute kidney injury (AKI) in intensive care unit (ICU) after continuous renal replacement therapy (CRRT). Methods The demographic and clinical data of ICU patients with ARDS combined with AKI after CRRT at Henan Provincial People's Hospital from January 1, 2018 to December 31, 2018 were collected. According to the final treatment results of this hospitalization, the patients were divided into death group and survival group. Survival was defined as the improved patient's condition and hospital discharge. Death was defined as the patient's death during the ICU hospitalization or confirmed death after abandoning treatment and automatically being discharged from the hospital in the follow-up. The basic clinical characteristics and CRRT status between the two groups were compared. Multivariate logistic regression method was used to analyze the influencing factors of death in patients. Results A total of 132 patients were enrolled, of which 90 patients (68.2%) died, with 84 males (63.6%) and median age of 59(45, 73) years. Compared with the survival group, the death group had higher age, proportion of malignant tumors, sequential organ failure assessment (SOFA) score, number of organ dysfunction and proportion of positive balance of fluid accumulation at 72 hours, longer time from entering ICU to CRRT, and lower mean arterial pressure (minimum value) and oxygenation index (all P<0.05). Multivariate logistic regression analysis results showed that the age≥60 years old (OR=4.382, 95%CI 1.543-12.440, P=0.006), large number of organ dysfunction (OR=1.863, 95%CI 1.109-3.130, P=0.019), high SOFA score (OR=1.231, 95%CI 1.067-1.420, P=0.004) and long time from ICU admission to CRRT (OR=1.224, 95%CI 1.033~1.451, P=0.020) were independent influencing factors of death in patients with ARDS combined with AKI after CRRT, and high oxygenation index (OR=0.992, 95%CI 0.986-0.998, P=0.010) was an independent protective factor for patients' prognosis. Conclusions The mortality of patients with ARDS combined with AKI after CRRT is still high. The age≥60 years old, large number of organ dysfunction, high SOFA score and long time from ICU admission to CRRT are independent influencing factors for death, and high oxygenation index is an independent protective factor for prognosis in patients with ARDS combined with AKI after CRRT.

  • Chen Xiaojie, Xu Ricong, Hu Haofei, Song Haiying, Wan Qijun
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    Objective To investigate the relationship between hemoglobin levels and renal prognosis in patients with IgA nephropathy (IgAN). Methods The clinical data and pathological examination results of IgAN patients diagnosed by renal biopsy at the Second People's Hospital of Shenzhen from February 25, 2010 to September 9, 2020 were retrospectively collected and analyzed. The patients were divided into anemic group and non-anemic group according to the anemia diagnostic criteria (The hemoglobin levels were<120 g/L and<110 g/L in males and females respectively at sea level area). Endpoint event was defined as a decrease in estimated glomerular filtration rate (eGFR) of>50% from baseline and/or progression to stage 5 chronic kidney disease [eGFR<15 ml·min-1·(1.73 m2)-1]. Cox regression analysis was used to analyze the factors affecting the poor renal prognosis. The relationship between hemoglobin and renal function prognosis was analyzed by smoothing curve fitting and threshold effect. Kaplan-Meier survival curve was used to compare and analyze the difference of renal survival rate between the anemic and non-anemic IgAN patients. Results A total of 1 263 IgAN patients were included in this study, 255(20.19%) patients were in the anemia group and 1 008 (79.81%) patients were in the non-anemia group. The anemia group had lower body mass index, baseline eGFR, serum albumin, and triglyceride than those in the non-anemia group (all P<0.05). The proportion of females, 24 h urinary protein content, and the proportion of renal tubule atrophy/interstitial fibrosis, segmental sclerosis and crescents in the anemia group were higher than those in the non-anemia group (all P<0.05). Multivariate Cox regression analysis showed that low hemoglobin was an independent influencing factor for renal endpoint event (HR=0.25, 95%CI 0.07-0.90, P=0.022). Smoothing curve fitting analysis and threshold effect analysis showed that a curving relationship was detected between hemoglobin and relative risk of renal endpoint event. As hemoglobin increased, there was a protective effect on renal function when hemoglobin level was lower than 147 g/L (β=0.96, 95%CI 0.94-0.99, P=0.008). Kaplan-Meier survival curve analysis suggested that patients with anemia had a lower cumulative renal survival rate than that of patients without anemia (Log-rank test χ2=10.106, P=0.002). Conclusions Low hemoglobin is an independent influencing factor for poor prognosis of renal function in IgAN patients. Cumulative renal survival rate is lower in IgAN patients with anemia than that of patients without anemia.

  • Basic Study

  • Dai Jie, Li Chenyu, Guan Chen, Yang Chengyu, Wang Lin, Zhang Yue, Zhou Bin, Zhao Long, Jiang Wei, Liu Hang, Zhen Li, Li Lin, Li Haina, Xu Yan
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    Objective To explore the effect and involved mechanism of naringenin on acute kidney injury (AKI) induced by ischemia-reperfusion (IR). Methods The IR-AKI rat model was constructed using the classic bilateral renal pedicle clamping method, then renal function and pathological change were assessed, as well as inflammation-associated genes were detected by quantitative real-time PCR. The hub genes were selected through differential gene analysis and protein-protein interaction network analysis, and their transcription factors were predicted, which constructed a protein library together. The proteins binding to naringenin were selected by reverse molecular docking analysis and further their binding patterns were predicted to explore the mechanism of naringenin. Finally, the results of bioinformatics were verified by experimental methods. Results Compared with the AKI group, the kidney pathology of the rats in the naringenin pretreatment group was significantly improved, and the renal tubular injury score was reduced (P<0.01); meanwhile the serum creatinine level and the mRNA expression of the kidney injury molecule 1 (KIM-1) were significantly decreased (both P<0.05). Compared to sham group, IR-AKI increased the level of nuclear factor κB (NF-κB), tumor necrosis factor-α and interleukin-1β (all P<0.05), which reversed by naringenin indicated that naringenin inhibited inflammation in IR-AKI. Differential gene analysis was performed on the GSE98622 data set, and 359 differential genes were obtained. In reverse molecular docking, the proteins with smallest binding energy including NFKBIA, BCL3, NFKB2 and RELA were considered to be related to the preventive effect of naringenin, which were mainly enriched in NF-κB-related inflammation pathways. Domain functional analysis of NF-κB-related genes showed that naringenin could stably bind to its key domain. According to quantitative real-time PCR results, naringenin increased BCL3 level after AKI (P<0.05), and further decreased the expression level of RELA and NFKB2 (both P<0.05). Conclusion Naringenin protects IR-AKI by alleviating inflammation, and its mechanism is related to increasing BCL3 and thereby inhibiting the NF-κB pathway.

  • Ran Maoxia, Kang Ting, Zhu Tingting, Lin Jiaru, He Tao, Ou Santao
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    Objective To observe the expression of hypoxia-inducible factor 1 alpha (HIF-1α) signaling pathway in the aorta of chronic kidney disease (CKD) rats with vascular calcification and to explore the role of this pathway in aortic calcification of CKD. Methods Forty 8-week-old male SD rats were randomly divided into control group (CON group, n=15) and CKD with aortic calcification group (CKD+AC group, n=25). The rats were sacrificed at the end of 4th, 6th and 8th week respectively and urine, blood, aorta and kidney samples were collected. The level of serum HIF-1α was tested by ELISA. The pathology changes of kidney were observed by HE staining. The aortic calcification was evaluated by alizarin red staining and calcium content detection. Immunohistochemistry and real-time PCR were applied to detect the protein and mRNA expression of alpha-smooth muscle actin (α-SMA), Runt-related transcription factor 2 (Runx2), HIF-1α, vascular endothelial growth factor A (VEGFA) and Notch1 in the aorta. Results Compared with CON group, serum urea, creatinine, cystatin C, phosphorus, calcium-phosphorus product and 24-h urine protein were significantly higher in CKD+AC group (all P<0.05). Serum HIF-1α levels were higher at 4th and 8th week in CKD+AC group than that in CON group (both P<0.05). There was no significant calcium deposit in the aorta of the CON group at all time points, and calcium deposits were seen in the aorta of the CKD+AC rats at each time point, which gradually increased with time. Compared with CON group, the expressions of aortic α-SMA protein and mRNA were significantly decreased in CKD+AC group at each time point, however the protein and mRNA expressions of Runx2, HIF-1α, VEGFA and Notch1 in the aorta of CKD+AC group rats were markedly increased at each time point (all P<0.05). Correlation analysis showed that the aortic calcium content was positively correlated with serum HIF-1α (r=0.706, P<0.001) and the protein expressions of HIF-1α (r=0.852, P<0.001), VEGFA (r=0.747, P<0.001) and Notch1 (r=0.813, P<0.001) in aorta. Conclusion The HIF-1α-VEGFA-Notch1 signaling pathway is activated during aortic calcification in CKD rats, suggesting that this signaling pathway might be involved in the vascular calcification in CKD, and serum HIF-1α is expected to be one of serum markers for CKD vascular calcification.

  • Wang Xiaojian, Li Rongshan, Tian Wei, Zheng Gang, Bi Hong, Wang Yanhong, Dong Lina, Guo Songjia, Lu Xiao, Zhou Xiaoshuang
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    Objective To explore the mechanism of highly expressed primary cilia in tibial growth plate chondrocytes accelerating chondrocytes differentiation in young rats with chronic renal failure (CRF). Methods Forty male 4-week-old SD rats weighing (98±3) g were randomly divided into control group (intragastric administration with distilled water, n=20) and CRF group (intragastric administration with adenine suspension 150 mg·kg-1·d-1, n=20). All the young rats were sacrificed after continuous gavage for 6 weeks. The length of the growth plate was measured with histological sections. Immunofluorescence (IF) was used to detect the expression rate of primary cilia and the level of β-catenin, the key protein of Wnt/β-catenin signaling pathway in tibial growth plate chondrocytes. Chondrocytes isolated from growth plate in two groups were cultured in vitro to P3 generation, and the expression rate of primary cilia in chondrocytes, the levels of Indian hedgehog (IHH) and glycogen synthase kinase 3β (GSK3β) were detected by IF. Co-immunoprecipitation was used to detect the relationship between IHH and GSK3β. Results Compared with the control group, the relative length of the growth plate was shorter in histological sections [(0.51±0.11) vs (1.00±0.08), t=16.11, P<0.001], the expression rate of primary cilia was higher [(26.3±5.5)% vs (7.6±1.9)%, t=14.37, P<0.001], and the level of β-catenin increased [(7.1±2.0) scores vs (3.6±1.0) scores, t=7.10, P<0.001] in CRF group. In vitro, the expression rate of primary cilia was higher in CRF group chondrocytes [(31.4±8.2)% vs (12.5±3.1)%, t=9.64, P<0.001] than that in control group. The level of IHH in CRF group increased than that in control group [(1 360±270) vs (310±84), t=16.61, P<0.001]. There was no significant difference in GSK3β level of chondrocytes between the two groups [(850±195) vs (780±140), t=1.30, P=0.200]. There was a direct interaction between IHH and GSK3β in CRF group chondrocytes. Conclusions The expression levels of primary cilia and related protein IHH increase in tibial growth plate chondrocytes of CRF young rats. The IHH protein plays a direct interaction with GSK3β protein, Wnt/β-catenin signaling pathway antagonist, which leads to the activation of Wnt/β-catenin signaling pathway and final accelerated differentiation of chondrocytes. The rapid differentiation of chondrocytes causes the closing trend of growth plate.

  • Short Original Article

  • Yin Yan, Cai Xiaowen, Chen Yuanhan, Xie Jianteng, Ning Zhifang, Jian Jinlian, Chen Qi, Liang Xinling, Ye Zhiming
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  • Case Report

  • Lin Liuping, Wang Han, Qin Xinfang, Tian Jia, Chen Fangru, Bi Huixin
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  • Review

  • Chen Xinyun, Yin Qinghua, Fu Ping
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  • Zhang Yuxia, Tang Rining, Liu Bicheng
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