Tissue inhibitor metalloproteinase-2 (TIMP-2) • IGF-binding protein 7 (IGFBP7) for the prediction of acute kidney injury following cardiac surgery.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinases-2 • insulin-like growth factor-binding protein 7 (TIMP-2•IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2•IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2•IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. METHODS: In the prospective cohort study, blood and urine samples were collected 6-12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. RESULTS: A total of 557 patients were enrolled, 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland clinical score, and simplified renal index than those without AKI. Urinary TIMP-2•IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2•IGFBP7 value of 0.265 (ng/ml)2/1,000. The TIMP-2•IGFBP7 values, simplified renal index (SRI) Score and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint, the percentage of patients who reached the composite end-point in the TIMP-2•IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/ml)2/1,000 group. CONCLUSIONS: Postoperative implementation of TIMP-2•IGFBP7 improved prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/ml))2/1,000 for the prediction of CSA-AKI among all AKI patients.

Dysregulation of ferroptosis may participate in the mitigating effect of CoCl2 on contrast-induced nephropathy / La desregulación de ferroptosis puede participar en el efecto mitigador de CoCl2 en la nefropatía inducida por contraste

Background: Contrast agents can directly or indirectly induce renal tubular ischemia and hypoxic damage. Given that cobalt chloride (CoCl2) can protect renal tubules, the protective effect and potential mechanism of action of CoCl2 on contrast-induced nephropathy (CIN) warrant investigation. Methods: A CIN mouse model was established to determine the protective effect of CoCl2 on renal injury in vivo. Then, TMT-based proteomics was performed to determine the differentially expressed proteins (DEPs), following which, enrichment analyses of gene ontology and the KEGG pathway were performed. In vitro, a CIN model was constructed with renal tubular epithelial cells (HK-2) to determine the effect of CoCl2 on potential targets and the role of the key protein identified from the in vivo experiments. Results: CoCl2 treatment decreased the levels of BUN and serum creatinine (sCr), while increasing the levels of urea and creatinine (Cr) in the urine of mice after CIN injury. Damage to the renal tubules in the CoCl2 treatment group was significantly less than in the CIN model group. We identified 79 DEPs after treating the in vivo model with CoCl2, and frequently observed ferroptosis-related GO and KEGG pathway terms. Of these, Hp (haptoglobin) was selected and found to have a strong renoprotective effect, even though its expression level in kidney tissue decreased after CoCl2 treatment. In HK-2 cells, overexpression of Hp reduced the ferroptosis caused by erastin, while knocking down Hp negated the attenuation effect of CoCl2 on HK-2 cell ferroptosis. Conclusion: CoCl2 attenuated kidney damage in the CIN model, and this effect was associated with the decrease in ferroptosis mediated by Hp.(AU)

Antecedentes: Los agentes de contraste pueden inducir isquemia tubular renal y daño hipóxico de manera directa o indirecta. Dado que el cloruro de cobalto (CoCl2) puede proteger los túbulos renales, el efecto protector y el mecanismo de acción potencial de CoCl2 en la nefropatía inducida por contraste (NIC) merecen ser investigados. Métodos: Se estableció un modelo de NIC en ratones para determinar el efecto protector de CoCl2 en la nefropatía in vivo. Seguidamente, se realizó un análisis proteómico por TMT para determinar las proteínas diferencialmente expresadas (DEP) y, a continuación, un análisis de enriquecimiento de ontología genética y vía KEGG. In vitro, se construyó un modelo NIC en células epiteliales de túbulos renales (HK-2) para determinar el efecto de CoCl2 en los objetivos potenciales y el rol de la proteína clave identificada en los experimentos in vivo. Resultados: El tratamiento con CoCl2 redujo los niveles de BUN y de creatinina sérica e incrementó, a la vez, los de urea y creatinina en la orina de los ratones, tras la lesión NIC. El daño a los túbulos renales en el grupo de tratamiento con CoCl2 fue significativamente menor que en el grupo de modelo NIC. Identificamos 79 DEP tras el tratamiento en el modelo in vivo con CoCl2 y observamos con frecuencia ontología genética relacionada con ferroptosis y términos de vías KEGG. De ellos, se seleccionó la haptoglobina (Hp) y se encontró que tenía un fuerte efecto renoprotector, aun cuando su nivel de expresión en el tejido renal se redujo tras el tratamiento con CoCl2. En las células HK-2, la sobreexpresión de Hp redujo la ferroptosis causada por erastina, a pesar de que el descenso de Hp negó el efecto atenuador de CoCl2 en la ferroptosis de las células HK-2. Conclusión: El CoCl2 atenuó el daño renal en el modelo NIC y se asoció este efecto al descenso de ferroptosis mediada por Hp.(AU)

SMN haploinsufficiency promotes ischemia/ reperfusion-induced AKI-to-CKD transition by endoplasmic reticulum stress activation.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are interconnected syndromes that represent a global public health challenge. Here, we identified a specific role of survival of motor neuron (SMN) in ischemia/reperfusion (I/R)-induced kidney injury and progression of CKD. SMN was an essential protein in all cell type and was reported to play important roles in multiple fundamental cellular homeostatic pathways. However, the function of SMN in experimental models of I/R-induced kidney fibrosis has not extensively studied. Genetic ablation of SMN or small interfering RNA-base knockdown of SMN expression aggravated the tubular injury and interstitial fibrosis. Administration of scAAV9-CB-SMN or epithelial cell overexpression of SMN reduced I/R-induced kidney dysfunction and attenuated AKI-to-CKD transition, indicating that SMN is vital for the preservation and recovery of tubular phenotype. Our data showed that the endoplasmic reticulum stress (ERS) induced by I/R was persistent and became progressively more severe in the kidney without SMN. On the contrary, overexpression of SMN prevented against I/R-induced ERS and tubular cell damage. In summary, our data collectively substantiate a critical role of SMN in regulating the ERS activation and phenotype of AKI-to-CKD transition that may contribute to renal pathology during injury and repair.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Efficacy and Safety of Mizoribine for the Treatment of Refractory Nephrotic Syndrome: Protocol for a Multicenter, Controlled, Open-label, Randomized Controlled Trial.

BACKGROUND: Nephrotic syndrome that is resistant to steroid therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease. Immunosuppressants are used to treat RNS; however, prolonged use may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy, which has few adverse effects, but data on its long-term use in patients with RNS are unavailable. OBJECTIVE: We propose a trial to examine the efficacy and safety of MZR compared with cyclophosphamide (CYC) in Chinese adult patients with RNS. METHODS: This is a multicenter, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study has been reviewed and approved by the Medical Ethics Committees of all 34 medical centers that are participating. Patients with RNS consent to participation, and are enrolled and randomized to an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants are assessed for adverse effects, and laboratory results are collected at 8 visits during the treatment phase (weeks 4, 8, 12, 16, 20, 32, 44, and 52 [exit visit]). Participants are able to withdraw voluntarily, and investigators are required to remove patients when there are safety concerns or deviations from the protocol. RESULTS: The study started in November 2014 and was completed in March 2019. A total of 239 participants from 34 hospitals in China have been enrolled. Data analysis has been completed. The results are being finalized by the Center for Drug Evaluation. CONCLUSIONS: This study examines the safety and efficacy of MZR as a long-term treatment approach for Chinese adults with RNS. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT02257697; https://clinicaltrials.gov/ct2/show/NCT02257697. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/46101.

ASH2L Controls Ureteric Bud Morphogenesis through the Regulation of RET/GFRA1 Signaling Activity in a Mouse Model.

SIGNIFICANCE STATEMENT: Causes of congenital anomalies of the kidney and urinary tract (CAKUT) remain unclear. The authors investigated whether and how inactivation of Ash2l -which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide histone H3 lysine K4 (H3K4) methylation-might contribute to CAKUT. In a mouse model, inactivation of Ash2l in the ureteric bud (UB) lineage led to CAKUT-like phenotypes. Removal of ASH2L led to deficient H3K4 trimethylation, which slowed cell proliferation at the UB tip, delaying budding and impairing branching morphogenesis. The absence of ASH2L also downregulated the expression of Ret , Gfra1 , and Wnt11 genes involved in RET/GFRA1 signaling. These findings identify ASH2L-mediated H3K4 methylation as an upstream epigenetic regulator of signaling crucial for UB morphogenesis and indicate that deficiency or dysregulation of these processes may lead to CAKUT. BACKGROUND: Ureteric bud (UB) induction and branching morphogenesis are fundamental to the establishment of the renal architecture and are key determinants of nephron number. Defective UB morphogenesis could give rise to a spectrum of malformations associated with congenital anomalies of the kidney and urinary tract (CAKUT). Signaling involving glial cell line-derived neurotrophic factor and its receptor rearranged during transfection (RET) and coreceptor GFRA1 seems to be particularly important in UB development. Recent epigenome profiling studies have uncovered dynamic changes of histone H3 lysine K4 (H3K4) methylation during metanephros development, and dysregulated H3K4 methylation has been associated with a syndromic human CAKUT. METHODS: To investigate whether and how inactivation of Ash2l , which encodes a subunit of the COMPASS methyltransferase responsible for genome-wide H3K4 methylation, might contribute to CAKUT, we inactivated Ash2l specifically from the UB lineage in C57BL/6 mice and examined the effects on genome-wide H3K4 methylation and metanephros development. Genes and epigenome changes potentially involved in these effects were screened using RNA-seq combined with Cleavage Under Targets and Tagmentation sequencing. RESULTS: UB-specific inactivation of Ash2l caused CAKUT-like phenotypes mainly involving renal dysplasia at birth, which were associated with deficient H3K4 trimethylation. Ash2l inactivation slowed proliferation of cells at the UB tip, delaying budding and impairing UB branching morphogenesis. These effects were associated with downregulation of Ret , Gfra1 , and Wnt11 , which participate in RET/GFRA1 signaling. CONCLUSIONS: These experiments identify ASH2L-dependent H3K4 methylation in the UB lineage as an upstream epigenetic regulator of RET/GFRA1 signaling in UB morphogenesis, which, if deficient, may lead to CAKUT.

Hemoperfusion in Maintenance Hemodialysis Patients.

The accumulation of protein-bound uremic toxins and medium-large molecule toxins in maintenance hemodialysis (MHD) patients is one of the causes of long-term dialysis-related complications. Hemoperfusion can remove these uremic toxins and reduce the complications of MHD patients. Upon a review of the Chinese and international literature, combined with practical experience of clinical diagnosis and treatment, the Shanghai Medical Association Society of Nephrology reached a consensus on the clinical applications of hemoperfusion in MHD patients. This consensus included four aspects: selection of appropriate patients, treatment frequency, treatment methods, and adverse reactions and precautions and provided guidelines for the rational and standardized treatment of hemoperfusion in MHD patients.

Randomized Control Study on Hemoperfusion Combined with Hemodialysis versus Standard Hemodialysis: Effects on Middle-Molecular-Weight Toxins and Uremic Pruritus.

INTRODUCTION: Classic hemodialysis schedules present inadequate middle-molecular-weight toxin clearance due to limitations of membrane-based separation processes. Accumulation of uremic retention solutes may result in specific symptoms (e.g., pruritus) and may affect clinical outcome and patient's quality of life. Hemoperfusion (HP) is a blood purification modality based on adsorption that can overcome such limitations, and thus, it may be interesting to test the efficacy of at least one session per week of HP combined with hemodialysis. This is a randomized, open-label trial, controlled, multicenter clinical study to investigate the effect of long-term HP combined with hemodialysis on middle-molecular-weight toxins and uremic pruritus in maintenance hemodialysis (MHD) patients. METHODS: 438 MHD patients from 37 HD centers in China with end-stage kidney disease (63.9% males, mean age 51 years) suffering from chronic intractable pruritus were enrolled in the study. Eligible patients were randomized into four groups: low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), HP + LFHD, and HP + HFHD at a 1:1:1:1 ratio. Beta-2 microglobulin (ß2M) and parathyroid hormone (PTH) were measured at baseline, 3-6, and 12 months. At the same time points, the pruritus score was evaluated. The primary outcome was the reduction of ß2M and PTH, while the secondary outcome was the reduction of the pruritus score. RESULTS: In the two groups HP + LFHD and HP + HFHD, there was a significant decrease of ß2M and PTH levels after 12 months compared to the control groups. No significant differences were noted between HP + LFHD and HP + HFHD. Pruritus score reduction was 63% in the HP + LFHD group and 51% in the HP + HFHD group, respectively. CONCLUSION: The long-term HP + HD can reduce ß2M and PTH levels and improve pruritus in MHD patients independently on the use of high- or low-flux dialyzers, showing that the results are linked to the effect of adsorption.

Efficacy and safety of darbepoetin alfa injection replacing epoetin alfa injection for the treatment of renal anemia in Chinese hemodialysis patients: A randomized, open-label, parallel-group, noninferiority phase III trial.

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.

Identification and functional characterization of the first deep intronic GLA mutation (IVS4+1326C>T) causing renal variant of Fabry disease.

BACKGROUND: Fabry disease (FD, OMIM #301500) is an X-linked lysosomal disorder caused by the deficiency of α-galactosidase A (α-GalA), encoded by the GLA gene. Among more than 1100 reported GLA mutations, few were deep intronic mutations which have been linked to classic and cardiac variants of FD. METHODS AND RESULTS: We report a novel hemizygous deep intronic GLA mutation (IVS4+1326C>T) in a 33-year-old Chinese man with a mild α-GalA deficiency phenotype involving isolated proteinuria and predominant globotriaosylceramide deposits in podocytes. IVS4+1326C>T, which appears to be the first deep intronic GLA mutation associated with renal variant of FD, was identified by Sanger sequencing the entire GLA genomic DNA sequence of the patient's peripheral mononuclear blood lymphocytes (PBMCs). Further sequencing of cDNA from PBMCs of the patient revealed a minor full-length GLA transcript accounting for about 25% of total GLA transcript, along with two major aberrantly spliced GLA transcripts encoding mutant forms of α-GalA with little enzyme activity characterized by in vitro α-GalA overexpression system in the HEK293T cells. Thus, the combined clinical phenotype, genetic analysis and functional studies verified the pathogenicity of IVS4+1326C>T. CONCLUSIONS: The identification of IVS4+1326C>T establishes a link between deep intronic GLA mutation and the renal variant of FD, which extends the mutation spectrum in GLA gene and justifies further study of how IVS4+1326C>T and potentially other deep intronic GLA mutations contribute to Fabry podocytopathy through aberrant splicing. Future studies should also assess the true incidence of IVS4+1326C>T in patients with different variants of FD, which may improve early genetic diagnosis to allow timely treatment that can prevent disease progression and improve survival.

Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure: A randomized, open-label, parallel-group, non-inferiority Phase III trail.

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.

Astragaloside IV Alleviates Intestinal Barrier Dysfunction via the AKT-GSK3ß-ß-Catenin Pathway in Peritoneal Dialysis.

Background and aims: Long-term peritoneal dialysis (PD) causes intestinal dysfunction, including constipation, diarrhea, or enteric peritonitis. However, the etiology and pathogenesis of these complications are still unclear and there are no specific drugs available in the clinic. This study aims to determine whether Astragaloside IV (AS IV) has therapeutic value on PD-induced intestinal epithelial barrier dysfunction in vivo and in vitro. Methods: We established two different long-term PD treatment mice models by intraperitoneally injecting 4.25% dextrose-containing peritoneal dialysis fluid (PDF) in uremia mice and normal mice, which were served as controls. In addition, PDF was applied to T84 cells in vitro. The therapeutic effects of AS IV on PD-induced intestinal dysfunction were then examined by histopathological staining, transmission electron microscopy, western blotting, and reverse transcription polymerase chain reaction. The protein levels of protein kinase B (AKT), glycogen synthase kinase 3ß (GSK-3ß) and ß-catenin were examined after administration of AS IV. Results: In the present study, AS IV maintained the intestinal crypt, microvilli and desmosome structures in an orderly arrangement and improved intestinal epithelial permeability with the up-regulation of tight junction proteins in vivo. Furthermore, AS IV protected T84 cells from PD-induced damage by improving cell viability, promoting wound healing, and increasing the expression of tight junction proteins. Additionally, AS IV treatment significantly increased the levels of phosphorylation of AKT, inhibited the activity GSK-3ß, and ultimately resulted in the nuclear translocation and accumulation of ß-catenin. Conclusion: These findings provide novel insight into the AS IV-mediated protection of the intestinal epithelial barrier from damage via the AKT-GSK3ß-ß-catenin signal axis during peritoneal dialysis.

Burden of kidney disease among patients with peritoneal dialysis versus conventional in-centre haemodialysis: A randomised, non-inferiority trial.

BACKGROUND: Little is known about the impact of haemodialysis (HD) and peritoneal dialysis (PD) on health-related quality of life (HRQoL). We compared HRQoL between conventional in-centre HD and home-based PD in 1082 newly diagnosed kidney failure patients. METHODS: This was an open-label, randomised, non-inferiority trial of adult patients with a diagnosis of end-stage kidney disease (estimated glomerular filtration rate ≤ 15 mL/min/1.73 m2) requiring maintenance dialysis from 36 sites in China randomised 1:1 to receive PD or conventional in-centre HD. The primary outcome was the 'Burden of Kidney Disease' assessed using the Kidney Disease Quality of Life-Short Form (KDQoL-SF) survey over 48 weeks and the main secondary outcomes were the remaining scales of KDQoL-SF and all-cause mortality. The effect of PD versus HD on the primary outcome was compared by their geometric mean (GM) ratio, and non-inferiority was defined by the lower bound of a one-sided 95% confidence interval (CI) >0.9. RESULTS: A total of 725 subjects completed the trial per protocol (395 PD and 330 HD, mean age 49.8 (standard deviation (SD) 14.4) years, 41.4% women). For the primary outcome, the mean (SD) change in 'Burden of Kidney Disease' over 48 weeks was 2.61 (1.27) in PD group and 2.58 (1.35) in HD group, and the GM ratio (95% CI) was 1.059 (0.908-1.234), exceeding the limit for non-inferiority. For the secondary outcomes, the PD and HD groups were similar in all scales. There were 17 and 31 deaths in PD and HD groups, respectively. Patients receiving PD had more adverse events, adverse event leading to hospitalisation and serious adverse events compared to those allocated to HD, but adverse events leading to death and discontinuation of the trial were not different between PD and HD. CONCLUSIONS: In this trial, PD may be non-inferior to HD on the 'Burden of Kidney Disease' among Chinese kidney failure patients who are of younger age and have lower comorbidity after 48 weeks' follow-up.

Efficacy and safety of intravenous paricalcitol treatment in Chinese hemodialysis patients: a real-world database analysis.

BACKGROUND: The aim of this retrospective observational study based on real-world data was to evaluate the efficacy and safety profile of paricalcitol in Chinese hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT) in routine clinical practice. METHODS: From the Better Life for Future database, a total of 668 Chinese hemodialysis patients from 104 dialysis centers between January 2015 and May 2019 were included in the analysis set. Intact parathyroid hormone (iPTH), total serum calcium (Ca), phosphate (P), dosage of intravenous (IV) paricalcitol (Zemplar®) were analyzed and discussed via retrospective analysis of the database during the treatment. RESULTS: Patients were divided into five groups according to the duration of follow-up. Median iPTH levels decreased from 1,183 pg/mL at baseline to 676 pg/mL at the final visit, or 30.88% (P<0.0001). A total of 56.14% of patients had a ≥30% decrease and 29.34% of patients had a ≥50% decrease in iPTH level. Serum Ca levels shown significantly increased in the group of Month 12-24 (P=0.0479). Serum phosphate levels remained stable in all follow-up groups. The average dose of paricalcitol was 20±9 µg/week. The total dose of paricalcitol and baseline iPTH were negatively correlated with the decrease in iPTH levels. CONCLUSIONS: This is the first national retrospective real-world observational study since intravenous paricalcitol is available in China since 2014. This study demonstrates the use of paricalcitol as an effective and well-tolerated treatment for the control of PTH during its use in routine practice.

A novel role of BK potassium channel activity in preventing the development of kidney fibrosis.

Kidney fibrosis is a common characteristic of chronic kidney disease and while the large conductance voltage and calcium-activated potassium channel (BK) is widely expressed in kidneys, its role in kidney fibrosis is unknown. To evaluate this, we found that BK protein expression was decreased in the fibrotic kidneys. Accompanying this was increased fibrotic marker protein expression of fibronectin, vimentin and α-smooth muscle actin and increased mRNA expressions of fibronectin, α-smooth muscle actin, collagen III and collagen I. These changes occurred in the unilateral ureteral obstruction and folic acid models of fibrosis and were more pronounced in BK knockout than in wild-type mice. Activation of BK activity by chemical NS1619 or BMS191011 channel openers attenuated kidney fibrosis in these two models while protecting kidney function in wild-type mice. BK deficiency up-regulated transforming growth factor-ß (TGF-ß)/transcription factor Smad2/3 signaling in the fibrotic kidney, whereas activation of BK activity inhibited this signaling pathway both in vivo and in vitro. BK channel activation increased the degradation of TGF-ß receptors induced by TGF-ß1 in vivo and in vitro. Furthermore, in cell lines HK-2, NRK49, and NRK-52E, BK channel activation by NS1619 led to increased caveolae formation and facilitated localization of TGF-ß receptors in the microdomains of lipid rafts. Thus, our data demonstrated that BK activation has an anti-fibrotic effect on kidney fibrosis by inhibiting the TGF-ß signaling pathway through accelerating TGF-ß receptor degradation via the caveolae route. Hence, our study provides innovative insight into BK as a potential therapeutic target for the treatment of kidney fibrosis.

Expert consensus on the establishment and maintenance of native arteriovenous fistula.

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.

Cost-effectiveness analysis of hemodialysis plus hemoperfusion versus hemodialysis alone in adult patients with end-stage renal disease in China.

BACKGROUND: This study evaluates the cost-effectiveness of hemodialysis (HD) plus hemoperfusion (HP) with HD alone in adult patients with end-stage renal disease (ESRD) in China. METHODS: A Markov model was constructed to assess the cost-effectiveness of interventions over a lifetime horizon. Model parameters were informed by the HD/HP trial, the first randomized, open-label multicenter trial comparing survival outcomes and incidence of cardiovascular disease (CVD) for HD + HP versus HD alone, and supplemented by published literature and expert opinion. The primary outcome was the incremental cost-effectiveness ratio (ICER) with respect to quality adjusted life-years (QALY). The robustness of the results was examined in extensive sensitivity analyses. Analyses were conducted from a healthcare perspective. Costs were reported in both Chinese Renminbi (RMB) and US Dollars (USD) in 2019 values. RESULTS: The base case ICER of HD + HP is RMB 174,486 (USD 25,251) per QALY, which is lower than the RMB 212,676 (USD 30,778) willingness-to-pay threshold of three times Gross Domestic Product. This conclusion is sensitive to the mortality for patients with no severe CVD events, the incidence of CVD events, and the cost of HP and HD. At a willingness-to-pay threshold of RMB 212,676 (USD 30,778) per QALY gained, the probability that HD + HP is cost-effective is 58%. CONCLUSIONS: Our results indicate a potential for HD + HP to be cost-effective for patients with ESRD. Further evidence on the longer-term impact of HD + HP on CVD event rates and mortality unrelated to CVD is needed to robustly demonstrate the cost-effectiveness of HD + HP. TRIAL REGISTRATION: The HD/HP trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IOR-16009332).

Dysfunction of Cullin 3 RING E3 ubiquitin ligase causes vasoconstriction and increased sodium reabsorption in diabetes.

Impaired endothelium-mediated vasodilation and/or increased sensitivity to vasoconstrictors lead to vascular smooth muscle cell (VSMC) dysfunction in individuals with diabetes. Diabetic nephropathy is associated with a considerably higher risk of cardiovascular disease and death than their nondiabetic counterparts. We studied the activity of Cullin 3 RING ubiquitin ligase (CRL3) and its substrates in mice using an intraperitoneal injection of streptozotocin (STZ) and db/db mice. The levels of CRL3 adaptors, including Kelch-like 2/3 (KLHL2/3) and Rho-related BTB domain-containing protein 1, were significantly decreased in the aortic tissues and heart of the STZ group, whereas the levels of Cullin 3 (CUL3) and its neddylated derivatives were substantially increased. Decreased KLHL3 expression and significantly increased expression of NEDD8 conjugates were observed in the kidneys of db/db mice. The neddylation inhibitor MLN4924 decreased the degradation of KLHL2/KLHL3 under high-glucose conditions with/without insulin, and transfection with KLHL2 promoted the degradation of its substrates with-no-lysine (WNK) kinases. Increased abundance of WNK3, RhoA/ROCK activity and phosphodiesterase 5 enhanced the sensibility to vasoconstrictors and impaired vasodilation. Moreover, WNK3 localized in VSMCs undergoing cell division, and high-glucose medium increased WNK3 signaling in VSMCs undergoing mitosis, which might explain the increased thickness of aortic tissues in subjects with diabetes. Increases in WNK4 abundance resulted in increased sodium reabsorption in the distal renal tubules. Thus, KLHL2/RhoBTB1/KLHL3 inactivation in the aortic tissues and kidney is a result of excessive activation of neddylation in hyperglycemia and hyperinsulinemia, which affects vascular tone and sodium reabsorption.

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study).

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. METHODS/DESIGN: This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. DISCUSSION: Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20-35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02936375 . Registered on October 18, 2016.

Leflunomide plus low-dose prednisone in patients with progressive IgA nephropathy: a multicenter, prospective, randomized, open-labeled, and controlled trial.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide, and the optimal approach to its treatment remains a significant challenge. METHODS: We did a prospective, randomized, open-labeled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment, and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF + prednisone group) or conventionally accepted-dose prednisone [prednisone(alone) group] Our primary outcome was 24-h urine protein excretion (UPE) and secondary outcomes were serum albumin (sALB), serum creatinine (Scr), and eGFR. Safety was evaluated in all patients who received the trial medications. RESULTS: One hundred and eight patients [59 in LEF + prednisone group, 49 in prednisone (alone) group]were enrolled and finished their treatment and follow-up periods. There is no significant difference in the baseline level between the two groups. Compared with baseline, both groups showed a significant decrease in 24-h UPE (p < 0.01) and increase in sALB (p < 0.01), with stable Scr and eGFR throughout the 12-month treatment period. What's more, these effects were sustained through the 12-month follow-up period. However, there was no difference in 24-h UPE, sALB, Scr, and eGFR between the two groups (p > 0.05). At 12 months, a difference in overall response rate, relapsing rate, and incidence of adverse events between the two groups was not significant. CONCLUSIONS: The efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in the treatment of progressive IgAN are comparable.