Objective:Through the investigation of the pathogenicity of COL4A4 heterozygous splicing mutations and the genotype-phenotype correlation in autosomal dominant Alport syndrome (ADAS), to better understand the impact of COL4A4 heterozygous splicing mutations on ADAS. Methods:The study was a case series analysis. Patients from 5 ADAS families with COL4A4 heterozygous splicing mutations detected by whole exome sequencing were recruited by three hospitals. In vivo transcriptional analysis and/or in vitro minigene splicing assay were conducted to determine the splicing patterns and assess the pathogenicity of COL4A4 heterozygous splicing mutations. Results:In the five ADAS pedigrees carrying COL4A4 heterozygous splicing mutations, four novel ADAS splicing patterns were described. In pedigree 1-4, most patients presented with continuous hematuria or/and microalbuminuria. Otherwise,the proband in pedigree 4 presented with macroalbuminuria and the proband in pedigree 1 had progressed to chronic kidney disease stage 2 at the age of 70 years old. In pedigree 5, all patients developed end-stage renal disease between 28 and 41 years old. c.735+3A>G detected in pedigree 1 and pedigree 2 and c.694-1G>C detected in pedigree 3 both led to exon 12 skipping in COL4A4, resulting in 42 nucleotides in-frame deletion (c.694_735del). c.2056+3A>G detected in pedigree 4 led to COL4A4 exon 26 skipping, which caused in-frame deletion of 69 nucleotides (c.1988_2056del). c.2716+5G>T detected in pedigree 5 led to a 360 nucleotides large in-frame deletion, including 100 bp sequence at the 3'end of exon 29,the whole sequence of exon 30 and 89 bp sequence at the 5'end of exon 31 (c.2446_2805del). Conclusions:Renal prognosis differs significantly for patients with small in-frame deletions versus large in-frame deletion splicing abnormalities. Determination of the pathogenicity and the splicing patterns of COL4A4 heterozygous splicing mutations using in vivo and in vitro transcriptional analysis may provide renal prognostic information.

Objectives:To analyze the clinical features of microscopic polyangiitis (MPA), and observe the clinical outcomes of different pathological types.Methods:The clinical data of 61 patients with MPA in Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2010 to December 2019 were analyzed retrospectively. According to age, the patients were divided into ≥ 60 years old group (46 cases) and<60 years old group (15 cases). According to the initial serum creatinine, the patients were divided into ≥ 500 μmol/L group (18 cases) and<500 μmol/L group (43 cases). The basic data and laboratory examination results of the patients were recorded, and the disease activity was evaluated by Birmingham systemic vasculitis activity score (BVAS). Twenty-three patients with complete pathological data were pathologically classified and followed up to assess their clinical outcomes. The progression to end-stage renal disease (ESRD) or death was defined as the endpoint.Results:Ferritin in ≥60 years old group was significantly higher than that in<60 years old group: 452 (289, 792) μg/L vs. 210 (119, 451) μg/L, and there was statistical difference ( P<0.05). The fever rate, hemoglobin and platelets in creatinine ≥ 500 μmol/L group were significantly lower than those in creatinine<500 μmol/L group: 3/18 vs. 48.8% (21/43), 77.5 (62.8, 86.0) g/L vs. 85.0 (77.0, 104.0) g/L and 192 (147, 234) × 10 9/L vs. 257 (208, 365) × 10 9/L, the gastrointestinal involvement and BVAS in creatinine ≥ 500 μmol/L group were significantly higher than those in creatinine<500 μmol/L group: 16/18 vs. 25.6% (11/43) and 20.0 (16.0, 23.3) scores vs. 15.0 (12.0, 19.0) scores, and there were statistical differences ( P<0.05 or<0.01). Pearson correlation analysis result showed that BVAS was positively correlated with creatinine ( r = 0.42, P<0.01), negatively correlated with hemoglobin ( r = -0.42, P<0.01), but it had no correlation with erythrocyte sedimentation rate and platelets ( r = 0.05 and 0.04, P>0.05). Among the 23 patients with completed the clinical outcome statistics, endpoint events occurred in 5 of 6 patients with crescent renal pathology, and in 7 of 12 patients with severe renal interstitial injury. Kaplan-Meier survival curve analysis result showed that the average survival time in ESRD MPA patients was significantly shorter than that in non ESRD MPA patients (41.2 months vs. 63.5 months), and there was statistical difference ( χ2 = 0.48, P = 0.028). Conclusions:The clinical manifestations of elderly MPA patients are similar to those of young MPA patients. Creatinine≥500 μmol/L or anemia at initial onset indicate higher vasculitis activity in MPA. The prognosis of MPA patients with pathological manifestations of crescent or severe interstitial injury is poor, and the survival rate of ESRD is lower than that of non ESRD patients.

Objective:To investigate the role of survival motor neuron ( SMN) gene knockout in mice with cisplatin-induced acute kidney injury (AKI). Methods:A mouse model (C57BL/6) of cisplatin-induced AKI was constructed. Twenty male wild type (WT) and SMN+/- mice weighing 22-24 g were randomly divided into four groups: WT mice with saline injection group (WT vehicle, n=5), SMN+/- mice with saline injection group ( SMN+/- vehicle, n=5), WT mice with cisplatin injection group (WT cisplatin, n=5) and SMN+/- mice with cisplatin injection group ( SMN+/- cisplatin, n=5). Mice were injected intraperitoneally with 20 mg/kg cisplatin or 0.9% saline. 72 hours later, the mice were sacrificed, and serum and kidney tissues were collected. The real time PCR and Western blotting were used to measure the expression levels of SMN mRNA and protein. The sarcosine oxidation and urease method were used to measure serum creatinine (Scr) and blood urea nitrogen (BUN) levels. Renal pathologic changes were observed by PAS staining. TUNEL immunofluorescence assay was used to detect the level of apoptosis. Western blotting and immunohistochemistry were used to detect the protein expression levels of apoptosis index poly (ADP-ribose) polymerase (PARP) and endoplasmic reticulum stress index CHOP. Results:Compared with WT mice, SMN mRNA and protein expression levels were lower in SMN+/- mice, and the expression level of SMN mRNA and protein was further decreased after intraperitoneal cisplatin injection (all P<0.05). Compared with WT mice with saline injection group, WT mice with cisplatin injection group had higher levels of Scr, BUN, tubular damage scores, TUNEL positive cell numbers, PARP and CHOP, while the expression levels of above indexes in the SMN+/- mice with cisplatin injection group were higher than those in the WT mice with cisplatin injection group (all P<0.05). Conclusions:SMN gene knockout can aggravate renal pathological damage and apoptosis of renal tubular epithelial cell in cisplatin-induced AKI mice. SMN may be a potential therapeutic target of AKI.

Background::Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis, correct anemia, and maintain hemoglobin levels. This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections (Recombinant Human Erythropoietin injection, rHuEPO) when maintaining hemoglobin (Hb) levels within the target range (10.0-12.0 g/dL) for the treatment of renal anemia.Methods::Ninety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients ( n = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group ( n = 56) and a twice or three times per week intravenous epoetin alfa group ( n = 39) for 28 weeks, who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease (CKD) and were undergoing hemodialysis or hemofiltration with ESA-naive (erythropoiesis stimulating agent-naive). The primary efficacy profile was the mean Hb level (the non-inferiority margin was -1.0 g/dL, week 21-28); the secondary efficacy profiles were the Hb increase rate (week 0-4), the target Hb achievement cumulative rate and time, the change trends of the Hb levels, and the target Hb maintenance ratio. Adverse events (AEs) were observed and compared, and the efficacy and safety were analyzed between the two treatment groups. Additionally, the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period. SAS? software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results::The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group, respectively; the difference of the lower limits of the 95% confidence intervals (CI) between the two groups was 0.1 g/dL (>-1.0 g/dL), and non-inferiority was proven; the Hb levels started to increase in the first four weeks at a similar increase rate; no obvious differences were observed between the groups in the target Hb achievement cumulative rates, and the Hb levels as well as the target Hb level maintenance rate changed over time. The incidence of AEs was 62.5% in the darbepoetin alfa group and 76.9% in the epoetin alfa group. All the adverse events observed in the study were those commonly associated with hemodialysis.Conclusion::Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well, which makes it not inferior to epoetin alfa intravenously twice or three times per week. Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.

Background::This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis.Method::This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS ? software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results::Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis.Conclusion::The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.

Background::Erythropoietin is a glycoprotein that mainly regulates erythropoiesis. In patients with chronic renal failure with anemia, darbepoetin alfa can stimulate erythropoiesis, correct anemia, and maintain hemoglobin levels. This study was designed to demonstrate the efficacy and safety of darbepoetin alfa injections as being not inferior to epoetin alfa injections (Recombinant Human Erythropoietin injection, rHuEPO) when maintaining hemoglobin (Hb) levels within the target range (10.0-12.0 g/dL) for the treatment of renal anemia.Methods::Ninety-five patients were enrolled in this study from April 15, 2013 to April 10, 2014 at 25 sites. In this study, patients ( n = 95) aged 18-70 years were randomized into a once per week intravenous darbepoetin alfa group ( n = 56) and a twice or three times per week intravenous epoetin alfa group ( n = 39) for 28 weeks, who had anemia with hemoglobin levels between 6 g/dL and 10 g/dL due to chronic kidney disease (CKD) and were undergoing hemodialysis or hemofiltration with ESA-naive (erythropoiesis stimulating agent-naive). The primary efficacy profile was the mean Hb level (the non-inferiority margin was -1.0 g/dL, week 21-28); the secondary efficacy profiles were the Hb increase rate (week 0-4), the target Hb achievement cumulative rate and time, the change trends of the Hb levels, and the target Hb maintenance ratio. Adverse events (AEs) were observed and compared, and the efficacy and safety were analyzed between the two treatment groups. Additionally, the frequencies of dose adjustments between the darbepoetin alfa and epoetin alfa groups were compared during the treatment period. SAS? software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results::The mean Hb level was 11.3 g/dL in the darbepoetin alfa group and 10.7 g/dL in the epoetin alfa group, respectively; the difference of the lower limits of the 95% confidence intervals (CI) between the two groups was 0.1 g/dL (>-1.0 g/dL), and non-inferiority was proven; the Hb levels started to increase in the first four weeks at a similar increase rate; no obvious differences were observed between the groups in the target Hb achievement cumulative rates, and the Hb levels as well as the target Hb level maintenance rate changed over time. The incidence of AEs was 62.5% in the darbepoetin alfa group and 76.9% in the epoetin alfa group. All the adverse events observed in the study were those commonly associated with hemodialysis.Conclusion::Darbepoetin alfa intravenously once per week can effectively increase Hb levels and maintain the target Hb levels well, which makes it not inferior to epoetin alfa intravenously twice or three times per week. Darbepoetin alfa shows an efficacy and safety comparable to epoetin alfa for the treatment of renal anemia.

Background::This study was to explore the clinical efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection (recombinant human erythropoietin injection, rHuEPO) for the treatment of anemia associated with chronic kidney failure in Chinese patients undergoing hemodialysis.Method::This study was a multicenter, randomized, open-label, intergroup parallel control phase III noninferiority trial from April 19, 2013 to September 9, 2014 at 25 sites. In this study, the members of the darbepoetin alfa group underwent intravenous administration once per week or once every two weeks. The members of the control drug epoetin alfa group underwent intravenous administration two or three times per week. All subjects underwent epoetin alfa administration during the 8-week baseline period. After that, subjects were randomly assigned to the darbepoetin alfa group or epoetin alfa group. The noninferiority in the changes of the average Hb concentrations from the baseline to the end of the evaluation period (noninferiority threshold: -1.0 g/dl) was tested between the two treatments. The time-dependent hemoglobin (Hb) concentration and the maintenance rate of the target Hb concentration (the proportion of subjects with Hb concentrations between 10.0 and 12.0 g/dl) were also evaluated. Iron metabolism, including changes in the serum iron, total iron-binding capacity, ferritin, transferrin saturation, and comparisons of the dose adjustments between the two groups during the treatment period were analyzed further. Adverse events (AEs) were also observed and compared, and the safety was analyzed between the two treatment groups. The conversion rate switching from epoetin alfa to darbepoetin alfa was also discussed. SAS ? software version 9.2 was used to perform all statistical analyses. Descriptive statistics were used for all efficacy, safety, and demographic variable analyses, including for the primary efficacy indicators. Results::Four hundred and sixty-six patients were enrolled in this study, and ultimately 384 cases were analyzed for safety, including 267 cases in the darbepoetin alfa group and 117 cases in the epoetin alfa group. There were 211 cases in the per-protocol set, including 152 cases in the darbepoetin alfa group and 59 cases in the epoetin alfa group. The changes in the average Hb concentrations from the baseline to the end of the evaluation period were -0.07 and -0.15 g/dl in the darbepoetin alfa group and epoetin alfa group respectively. The difference between the two groups was 0.08 g/dl (95% confidence interval [CI]: -0.22 to 0.39), and the lower limit of the 95% CI was -0.22 > -1.0 g/dl. The average Hb concentrations of the two groups were 10.88-11.43 g/dl (darbepoetin alfa) and 10.91-11.38 g/dl (epoetin alfa) during the study period of Weeks 0-28, with the maintenance rates of the target Hb concentration ranging within 71%-87% and 78%-95% in the darbepoetin alfa group and epoetin alfa group respectively. During the period of comparison between the two groups, the incidence of AEs in the darbepoetin alfa group was 61.42%, while in the epoetin alfa group it was 56.41%. All of the adverse events and reactions in the study were those commonly associated with hemodialysis.Conclusion::The overall efficacy and safety of darbepoetin alfa for the treatment of Chinese renal anemia patients undergoing hemodialysis are consistent with those of epoetin alfa.

Objective:To investigate the clinical practice of chronic kidney disease-mineral and bone disorder (CKD-MBD) in maintenance hemodialysis patients in Shanghai, and to better understand the changes of clinical practice for CKD-MBD.Methods:Sixty-four hospitals with qualified dialysis center in Shanghai were selected for questionnaire survey as of March 2019. The survey questionnaire included the number of hemodialysis and peritoneal dialysis patients, the implementation of CKD-MBD guidelines, the learning of CKD-MBD guidelines, the detection and distribution of CKD-MBD biochemical indicators, the treatment of hyperphosphatemia, the treatment of secondary heperparathyroidism (SHPT) and renal bone disease, and the concentration of calcium ion in dialysate. The results were compared with previous survey data in 2011.Results:There were sixty-three hospitals included in this study, with 10 168 maintenance hemodialysis patients and 4 610 maintenance peritoneal dialysis patients in Shanghai. 84.1%(53/63) hospitals implemented the guidelines smoothly, which increased by 28.5% compared with the rate (55.6%) of 2011. The successful implementation rates for guidelines in secondary and tertiary hospitals were 83.3%(25/30) and 84.8%(28/33) , which increased by 44.0% and 11.7% respectively (39.3% of secondary hospitals and 73.1% of tertiary hospitals in 2011). All hospitals carried out the detection for serum calcium and phosphorus. The rate for parathyroid hormone (PTH), total alkaline phosphatase (AKP), bone specific alkaline phosphatase (BAP), 25-hydroxy vitamin D[25(OH)D], and other bone metabolism-related biomarkers were 98.4%(62/63), 90.5%(57/63), 19.0%(12/63), 90.5%(57/63) and 42.9%(27/63), respectively; coronary artery CT, lumbar lateral X-ray plain, echocardiography, bone mineral density, and vascular ultrasound were carried out in 68.3%(43/63), 74.6%(47/63), 100.0%(63/63), 68.3%(43/63)and 69.8%(44/63), respectively. Compared with 2011, the proportion of detection for PTH, AKP, BAP, 25(OH)D, coronary artery CT, lumbar lateral film and echocardiography increased by 2.1%, 1.6%, 0.5%, 47.9%, 14.6%, 20.9% and 1.9%, respectively. The proportion of patients with serum phosphorus ranging in 0.80-1.45 mmol/L(KDIGO guideline), serum phosphorus ranging in 0.80-1.78 mmol/L(KDOQI guideline), calcium ranging in 2.10-2.54 mmol/L, and PTH ranging in 150-600 ng/L were 37.0%(3 323/8 969), 50.7%(4 571/9 018), 60.2%(5 568/9 244) and 33.2%(3 018/9 087). Compared with 2011(39.6%, 53.5% and 34.1%), the proportion of patients with ideal serum phosphorus (0.80-1.78 mmol/L) and calcium (2.10-2.54 mmol/L) levels increased by 11.1% and 6.7% respectively, and the proportion with PTH 150-300 ng/L decreased by 0.9%. The proportion of hospitals for using non-calcium phosphate binders (lanthanum carbonate from 1.9% to 87.3% and sevelamer carbonate from 14.8% to 63.5%) and surgical treatment (from 38.9% to 68.3%) for SHPT dramatically increased.Conclusions:Through the availability of medicine increases, and nephrologists gain deeper understanding in management and treatment of CKD-MBD, the detection rate for CKD-MBD indicators and the eligible rate have significantly improved compared with those in 2011. However, the comprehensive management of CKD-MBD in Shanghai still faces great challenges. It is still necessary to further improve eligible rate for serum phosphorus and iPTH, so as to provide more evidences and management strategies for integrated management of end-stage renal disease and prevention of abnormal calcium and phosphorus metabolism in patients.

Vascular access is the lifeline of hemodialysis patients. There are great differences in the establishment and use of vascular access in different countries and regions around the world. We believe that on the basis of good evaluation and planning, it is recommended that hemodialysis patients choose native arteriovenous fistula first. In view of the new progress of vascular access views domestic and international at home and abroad in recent years, we organized experts to recommend the establishment and maintenance of arteriovenous fistula (AVF) for the Chinese population, including preoperative evaluation and planning of the establishment of AVF, AVF surgery, perioperative drug intervention measures and postoperative maintenance, and put forward suggestions for future research directions. The recommendations in this consensus are general and clinicians need to make treatment decisions based on the actual situation.

Vascular access is the lifeline of hemodialysis patients. There are great differences in the establishment and use of vascular access in different countries and regions around the world. We believe that on the basis of good evaluation and planning, it is recommended that hemodialysis patients choose native arteriovenous fistula first. In view of the new progress of vascular access views domestic and international at home and abroad in recent years, we organized experts to recommend the establishment and maintenance of arteriovenous fistula (AVF) for the Chinese population, including preoperative evaluation and planning of the establishment of AVF, AVF surgery, perioperative drug intervention measures and postoperative maintenance, and put forward suggestions for future research directions. The recommendations in this consensus are general and clinicians need to make treatment decisions based on the actual situation.