Molecular mechanism of renal lipid accumulation in diabetic kidney disease.

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Tauroursodeoxycholic acid ameliorates renal injury induced by COL4A3 mutation.

COL4A3/A4/A5 mutations have been identified as critical causes of Alport syndrome and other genetic chronic kidney diseases. However, the underlying pathogenesis remains unclear, and specific treatments are lacking. Here, we constructed a transgenic Alport syndrome mouse model by generating a mutation (Col4a3 p.G799R) identified previously from one large Alport syndrome family into mice. We observed that the mutation caused a pathological decrease in intracellular and secreted collagen IV α3α4α5 heterotrimers. The mutant collagen IV α3 chains abnormally accumulated in the endoplasmic reticulum and exhibited defective secretion, leading to persistent endoplasmic reticulum stress in vivo and in vitro. RNA-seq analysis revealed that the MyD88/p38 MAPK pathway plays key roles in mediating subsequent inflammation and apoptosis signaling activation. Treatment with tauroursodeoxycholic acid, a chemical chaperone drug that functions as an endoplasmic reticulum stress inhibitor, effectively suppressed endoplasmic reticulum stress, promoted secretion of the α3 chains, and inhibited the activation of the MyD88/p38 MAPK pathway. Tauroursodeoxycholic acid treatment significantly improved kidney function in vivo. These results partly clarified the pathogenesis of kidney injuries associated with Alport syndrome, especially in glomeruli, and suggested that tauroursodeoxycholic acid might be useful for the early clinical treatment of Alport syndrome.

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis.

SIGNIFICANCE STATEMENT: Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR ß 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. METHODS: We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. RESULTS: Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. CONCLUSIONS: We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.

Adult-Onset Focal Segmental Glomerulosclerosis With Steroid-Dependent Nephrotic Syndrome Caused by a Novel TBC1D8B Variant: A Case Report and Literature Review.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with a variety of potential causes, including rare variants of podocyte-related genes. Recently, it has been found that variants in the TBC1D8B gene on the X chromosome can lead to early-onset focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome by affecting endocytosis and recycling of nephrin. Here, we report a 19-year-old Chinese patient with nephrotic syndrome and normal kidney function. He had a complete remission of nephrotic syndrome after full-dose prednisone and cyclosporine treatment. Unfortunately, a relapse of nephrotic syndrome occurred during prednisone tapering. Focal segmental glomerulosclerosis was proven by a kidney biopsy, and a hemizygous pathogenic variant located in the TBC (Tre-2-Bub2-Cdc16) domain of TBC1D8B was detected by whole-exome sequencing. By comparing our case with reports of other patients with TBC1D8B variants, we suggest possible genotype-phenotype correlations. To our knowledge, this is the first report identifying a pathogenetic variant in the TBC domain of TBC1D8B in an adult-onset focal segmental glomerulosclerosis patient with steroid-dependent NS. With this report, we broaden the clinical and genetic spectrum of X-linked genetic FSGS.

Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis.

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS. METHODS: This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases. RESULTS: Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic. CONCLUSIONS: Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.

The magnitude of neurocognitive impairment is overestimated in depression: the role of motivation, debilitating momentary influences, and the overreliance on mean differences.

BACKGROUND: Meta-analyses agree that depression is characterized by neurocognitive dysfunctions relative to nonclinical controls. These deficits allegedly stem from impairments in functionally corresponding brain areas. Increasingly, studies suggest that some performance deficits are in part caused by negative task-taking attitudes such as poor motivation or the presence of distracting symptoms. A pilot study confirmed that these factors mediate neurocognitive deficits in depression. The validity of these results is however questionable given they were based solely on self-report measures. The present study addresses this caveat by having examiners assess influences during a neurocognitive examination, which were concurrently tested for their predictive value on performance. METHODS: Thirty-three patients with depression and 36 healthy controls were assessed on a battery of neurocognitive tests. The examiner completed the Impact on Performance Scale, a questionnaire evaluating mediating influences that may impact performance. RESULTS: On average, patients performed worse than controls at a large effect size. When the total score of the Impact on Performance Scale was accounted for by mediation analysis and analyses of covariance, group differences were reduced to a medium effect size. A total of 30% of patients showed impairments of at least one standard deviation below the mean. CONCLUSIONS: This study confirms that neurocognitive impairment in depression is likely overestimated; future studies should consider fair test-taking conditions. We advise researchers to report percentages of patients showing performance deficits rather than relying solely on overall group differences. This prevents fostering the impression that the majority of patients exert deficits, when in fact deficits are only true for a subgroup.

Particulate matter of air pollution may increase risk of kidney failure in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by deposition of galactose-deficient IgA1 (Gd-IgA1) in glomerular mesangium associated with mucosal immune disorders. Since environmental pollution has been associated with the progression of chronic kidney disease in the general population, we specifically investigated the influence of exposure to fine particulate matter less than 2.5 µm in diameter (PM2.5) on IgAN progression. Patients with biopsy-proven primary IgAN were recruited from seven Chinese kidney centers. PM2.5 exposure from 1998 to 2016 was derived from satellite aerosol optical depth data and a total of 1,979 patients with IgAN, including 994 males were enrolled. The PM2.5 exposure levels for patients from different provinces varied but, in general, the PM2.5 exposure levels among patients from the north were higher than those among patients from the south. The severity of PM2.5 exposure in different regions was correlated with regional kidney failure burden. In addition, each 10 µg/m3 increase in annual average concentration of PM2.5 exposure before study entry (Hazard Ratio, 1.14; 95% confidence interval, 1.06-1.22) or time-varying PM2.5 exposure after study entry (1.10; 1.01-1.18) were associated with increased kidney failure risk after adjustment for age, gender, estimated glomerular filtration rate, urine protein, uric acid, hemoglobin, mean arterial pressure, Oxford classification, glucocorticoid and renin-angiotensin system blocker therapy. The associations were robust when the time period, risk factors of cardiovascular diseases or city size were further adjusted on the basis of the above model. Thus, our results suggest that PM2.5 is an independent risk factor for kidney failure in patients with IgAN, but these findings will require validation in more diverse populations and other geographic regions.

Roxadustat Does Not Affect Platelet Production, Activation, and Thrombosis Formation.

Objective: Roxadustat is a new medication for the treatment of renal anemia. EPO (erythropoietin)-the current treatment standard-has been reported to enhance platelet activation and production. However, to date, the effect of roxadustat on platelets is unclear. To address this deficiency, herein, we have evaluated the effect of roxadustat on platelet production and function. Approach and Results: We performed several mouse platelet functional assays in the presence/absence of in vitro and in vivo roxadustat treatment. Both healthy and 5/6 nephrectomized mice were utilized. The effect of roxadustat on platelet function of healthy volunteers and chronic kidney disease patients was also evaluated. For platelet production, megakaryocyte maturation and proplatelet formation were assayed in vitro. Peripheral platelet and bone marrow megakaryocyte counts were also determined. We found that roxadustat could not stimulate washed platelets directly, and platelet aggregation, spreading, clot retraction, and P-selectin/JON/A exposure were similar with or without in vitro or in vivo roxadustat treatment among both healthy and 5/6 nephrectomized mice. In vivo mouse thrombosis models were additionally performed, and no differences were detected between the vehicle and roxadustat treatment groups. EPO, which was considered a positive control in the present study, promoted platelet function and production as reported previously. Megakaryocyte maturation and proplatelet formation were also not significantly different between control mice and those treated with roxadustat. After receiving roxadustat for 14 days, no difference in the peripheral platelet count was observed in the mice. Conclusions: Administration of roxadustat has no significant impact on platelet production and function.

A drug-free nanozyme for mitigating oxidative stress and inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an incurable disease of the gastrointestinal tract with a lack of effective therapeutic strategies. The proinflammatory microenvironment plays a significant role in both amplifying and sustaining inflammation during IBD progression. Herein, biocompatible drug-free ceria nanoparticles (CeNP-PEG) with regenerable scavenging activities against multiple reactive oxygen species (ROS) were developed. CeNP-PEG exerted therapeutic effect in dextran sulfate sodium (DSS)-induced colitis murine model, evidenced by corrected the disease activity index, restrained colon length shortening, improved intestinal permeability and restored the colonic epithelium disruption. CeNP-PEG ameliorated the proinflammatory microenvironment by persistently scavenging ROS, down-regulating the levels of multiple proinflammatory cytokines, restraining the proinflammatory profile of macrophages and Th1/Th17 response. The underlying mechanism may involve restraining the co-activation of NF-κB and JAK2/STAT3 pathways. In summary, this work demonstrates an effective strategy for IBD treatment by ameliorating the self-perpetuating proinflammatory microenvironment, which offers a new avenue in the treatment of inflammation-related diseases.

Impact of fluid overload on blood pressure variability in patients on peritoneal dialysis.

Fluid overload is a common complication in patients who are on continuous ambulatory peritoneal dialysis (CAPD). Blood pressure is the traditional indicator of fluid status in these patients. However, it has poor sensitivity. Blood pressure variability (BPV) can detect fluctuations in blood pressure sooner and more accurately and be useful for the assessment of fluid volume in hemodialysis patient. However, there are limited relevant studies involving patients on CAPD. This retrospective study included 175 patients on CAPD who underwent regular assessment of the peritoneal dialysis adequacy at 2-3-month intervals at our center from January 2018 to December 2020. The overhydration (OH) value was measured using a body composition monitor. Blood pressure measurements obtained in each visit over one-year follow-up were used to determine each patient's BPV under peritoneal dialysis. The patients were divided into the normal volume (OH ≤2 L), mild volume overload (OH 2-4 L), and severe volume overload groups (OH ≥4 L). There was no significant between-group difference in the mean blood pressure (p > 0.05). However, the systolic and diastolic BPV values were significantly higher in the severe volume overload group than in the other groups (p < 0.05). Further correlation and regression analysis showed volume overload severity and BPV existed positive association, and BPV was also significantly associated with PD volume related indexes, including diabetes mellitus, blood parathyroid hormone levels, Kt/V and subjective global assessment scores in the volume overloaded group (p < 0.05). All these results suggested BPV may be a useful indicator for fluid status in PD patients.

Anemia is associated with severe illness in COVID-19: A retrospective cohort study.

Anemia commonly aggravates the severity of respiratory diseases, whereas thus far, few studies have elucidated the impact of anemia on coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the clinical characteristics of patients with anemia, and to further explore the relationship between anemia and the severity of COVID-19. In this single-center, retrospective, observational study, a total of 222 confirmed patients admitted to Wuhan Ninth Hospital from 1 December 2019 to 20 March 2020 were recruited, including 79 patients with anemia and 143 patients without anemia. Clinical characteristics, laboratory findings, disease progression and prognosis were collected and analyzed. Risk factors associated with the severe illness in COVID-19 were established by univariable and multivariable logistic regression models. In our cohort, compared to patients without anemia, patients with anemia were more likely to have one or more comorbidities and severe COVID-19 illness. More patients demonstrated elevated levels of C-reactive protein (CRP), procalcitonin (PCT) and creatinine in anemia group. Levels of erythrocyte sedimentation rate, D-dimer, myoglobin, T-pro brain natriuretic peptide (T-pro-BNP) and urea nitrogen in patients with anemia were significantly higher than those without. In addition, the proportion of patients with dyspnea, elevated CRP, and PCT was positively associated with the severity of anemia. The odd ratio of anemia related to the severe condition of COVID-19 was 3.47 (95% confidence interval [CI]: 1.02-11.75; P = .046) and 3.77 (95% CI: 1.33-10.71; P = .013) after adjustment for baseline date and laboratory indices, respectively. Anemia is an independent risk factor associated with the severe illness of COVID-19, and healthcare professionals should be more sensitive to the hemoglobin levels of COVID-19 patients on admission. Awareness of anemia as a risk factor for COVID-19 was of great significance.

Impaired test performance yet spared neurocognitive functioning in individuals with obsessive-compulsive disorder: the role of performance mediators.

INTRODUCTION: Although most studies report neurocognitive deficits in patients with obsessive-compulsive disorder (OCD), important exceptions exist, highlighting the possible role of mediators (e.g., poor motivation). This study investigated neurocognitive functioning and potential influences affecting performance in OCD. METHODS: Forty-three participants (13 OCD patients, 30 healthy controls) were assessed using a battery of neurocognitive tests. During the assessment, the examiner completed the Impact on Performance Scale (IPS) which measures variables that may impact neurocognitive performance. RESULTS: Pooled neurocognitive performance was lower in OCD patients versus healthy controls at a moderate effect size. Patients performed more poorly on the IPS, particularly the Well-Being During Assessment subscale. Performance differences across the two groups were attenuated to a non-significant small-to-medium effect when the IPS was entered as a covariate. A total of 34% of patients showed scores greater than one standard deviation below the mean compared to 9.63% in healthy individuals. Yet, when a conservative impairment criterion (≥2 standard deviations below the mean) was applied, less than 10% of patients displayed deficits. CONCLUSIONS: Neurocognitive impairment in OCD is likely exaggerated. In addition to considering important mediators researchers should report the percentage of participants displaying performance deficits rather than mean group differences alone; the latter obscures the high percentage of patients without impairment and thus may unduly foster stigma in this population.

A validation study of UCSD-Mayo risk score in predicting hospital-acquired acute kidney injury in COVID-19 patients.

INTRODUCTION: Acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients is associated with poor prognosis. Early prediction and intervention of AKI are vital for improving clinical outcome of COVID-19 patients. As lack of tools for early AKI detection in COVID-19 patients, this study aimed to validate the USCD-Mayo risk score in predicting hospital-acquired AKI in an extended multi-center COVID-19 cohort. METHODS: Five hundred seventy-two COVID-19 patients from Wuhan Tongji Hospital Guanggu Branch, Wuhan Leishenshan Hospital, and Wuhan No. Ninth Hospital was enrolled for this study. Patients who developed AKI or reached an outcome of recovery or death during the study period were included. Predictors were evaluated according to data extracted from medical records. RESULTS: Of all patients, a total of 44 (8%) developed AKI. The UCSD-Mayo risk score achieved excellent discrimination in predicting AKI with the C-statistic of 0.88 (95%CI: 0.84-0.91). Next, we determined the UCSD-Mayo risk score had good overall performance (Nagelkerke R2 = 0.32) and calibration in our cohort. Further analysis showed that the UCSD-Mayo risk score performed well in subgroups defined by gender, age, and several chronic comorbidities. However, the discrimination of the UCSD-Mayo risk score in ICU patients and patients with mechanical ventilation was not good which might be resulted from different risk factors of these patients. CONCLUSIONS: We validated the performance of UCSD-Mayo risk score in predicting hospital-acquired AKI in COVID-19 patients was excellent except for patients from ICU or patients with mechanical ventilation.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection.

BACKGROUND: This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. METHODS: In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. RESULTS: In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14-1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. CONCLUSION: The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.

A regulatory role for CD72 expression on B cells and increased soluble CD72 in primary Sjogren's syndrome.

BACKGROUND: CD72, a co-receptor of B cell receptor (BCR), has been reported to have both positive and negative effects on B cell functions in several immunological diseases. The B cell plays an important role in the pathogenesis of primary Sjogren's syndrome (pSS). However, whether CD72 is involved in the process remains unknown. This study aimed to observe the possible role of CD72 in the pathogenesis of pSS. RESULTS: A total of 60 cases who fulfilled the American-European Consensus Group (AECG) criteria for the diagnosis of pSS and 61 gender and age-matched healthy controls were recruited in this study. The percentage of CD72+ B cells was 85.31 ± 8.37% in pSS patients and 76.91 ± 8.50% in healthy controls(p < 0.001). The percentage of CD72+ B cells was correlated to serum IgG levels in patients [ß = 0.018(0.001-0.036), p = 0.034]. The level of serum soluble CD72 was significantly higher in pSS patients than the one in healthy controls (0.41 (0.29) vs 0.07 (0.08) ng/mL, p < 0.001). CONCLUSIONS: The percentage of CD72+ B cells was upregulated in pSS patients and was correlated to the serum IgG level, which revealed the hyperactivity of B cells in this disease. The serum soluble CD72 level was also increased in pSS patients. These results indicated a potential role of CD72 in the pathogenesis of pSS.

New risk score for predicting steroid resistance in patients with focal segmental glomerulosclerosis or minimal change disease.

BACKGROUND: Glucocorticosteroid is used for patients with primary nephrotic syndrome. This study aims to identify and validate that biomarkers can be used to predict steroid resistance. METHODS: Our study contained two stages, discovery and validation stage. In discovery stage, we enrolled 51 minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS) patients treated with full dose steroid. Five urinary biomarkers including ß2-microglobulin (ß2-MG) and α1-microglobulin (α1-MG) were tested and candidates' biomarkers were selected based on their associations with steroid response. In validation stage, candidates' biomarkers were validated in two prospectively enrolled cohorts. Validation cohort A included 157 FSGS/MCD patients. Validation cohort B included 59 membranous nephropathy (MN) patients. Patients were classified into response group (RG) or non-response group (NRG) based on their responses to steroid treatment. RESULTS: In discovery stage, higher urinary ß2-MG was independently associated with response to corticosteroid treatment in MCD/FSGS patients [OR = 1.89, 95% CI 1.02-3.53] after adjusted by age and gender. In validation cohort A, patients in NRG had a significant higher urinary ß2-MG [Ln (ß2-MG/uCr): 4.6 ± 1.7 vs 3.2 ± 1.5] compared to patients in RG. We then developed a 3-variable risk score in predicting steroid resistance in FSGS/MCD patients based on the best predictive model including Ln(ß2-MG/uCr) [OR = 1.76, 95% CI 1.30-2.37], age [OR = 1.005, 95% CI 0.98-1.03] and pathology [MCD vs FSGS, OR = 0.20, 95% CI 0.09-0.46]. The area under the ROC curves of the risk score in predicting steroid response was 0.80 (95% CI 0.65-0.85). However, no such association was found in MN patients. CONCLUSIONS: Our study identified a 3-variable risk score in predicting steroid resistance in patients with FSGS or MCD.

Glomerular Transcriptome Profiles in Focal Glomerulosclerosis: New Genes and Pathways for Steroid Resistance.

BACKGROUND: Patients with focal segmental glomerulosclerosis (FSGS) characterized by steroid-resistant nephrotic syndrome (SRNS) are prone to progress to ESRD. Mechanism for the FSGS patients' response to steroid treatment is still unknown and currently, it is impossible to predict the steroid resistance before treatment of patients with FSGS. METHODS: To identify biomarkers and potential therapeutic targets of FSGS patients with SRNS, patients diagnosed as kidney biopsy-proven FSGS and nephrotic syndrome (NS) were prospectively enrolled. They were divided into 2 groups, steroid-sensitive NS and SRNS based on their treatment response. Cortical regions were selected from biopsied renal tissues, and glomeruli were isolated under an inverted microscope. RNA was prepared from the isolated glomeruli and further used for microarray analysis. Followed by multiple analyses, the top 6 highest and lowest, and a selected panel of differentially expressed genes obtained and their related pathways were validated via real-time PCR, western blot, and measurement of reactive oxygen species (ROS). RESULTS: In SRNS group, we discovered that the most significant up-regulated pathway was primarily related to cellular amino acid and derivative metabolic process. Meanwhile, the most significant down-regulated pathway was primarily involved in anatomical structure morphogenesis. Moreover, we found NADPH oxidase 4 (NOX4), one of the key regulators of renal ROS, at a much higher level in SRNS both at transcriptomic and proteomic levels. We also found the levels of ROS, p-p38 MAPK and matrix metalloproteinase (MMP)-2, which were all regulated by NOX4, were also higher in glomeruli isolated from SRNS patients. At last, we detected stimulated by retinoic acid gene 6 homolog (STRA6), a cell surface receptor formerly known as a gene preventing podocytes from over-proliferative lesion induced by HIV infection and was up-regulated by retinoic acid, expressed at a much higher level in SRNS kidneys. CONCLUSION: We found 2 potential mechanisms underline the SRNS, NOX4/ROS/P38 MAPK/MMP-2 pathway and STRA6. Our findings provided new insights into the steroid resistance.

Acute Kidney Disease Increases the Risk of Post-Kidney Biopsy Bleeding Complications.

INTRODUCTION: Kidney biopsy, providing the insightful information for most kidney diseases, is an invasive diagnostic tool with certain risks ranging from the least severe macroscopic hematuria to the most severe life-threatening bleeding necessitating renal artery embolization. We aimed to compare the postbiopsy bleeding complications between 2 common methods and to further explore the risk factors of bleeding complications in patients using the negative pressure suction puncture (NPS) method. METHODS: We retrospectively collected the data from percutaneous native kidney biopsies in 2016. The clinical, laboratory tests, pathological findings, and the occurrence of bleeding complications following kidney biopsy were analyzed. The kidney biopsy was performed in our center by experienced nephrologists with 2 different methods, namely, NPS method and real-time ultrasound-guided needle (RTU) method. We compared rates of complications between 2 methods and evaluated univariate and multivariate association of risk factors with bleeding complications in the NPS group. RESULTS: 626 kidney biopsies were performed between January 2016 and December 2016. There were 83.2% (521/626) participants in the NPS group and 16.8% (105/626) in the RTU group. There were more participants in the RTU group needing >1 needle pass during biopsy than those in the NPS group (61.0 vs. 14.7%, p < 0.001). Acute kidney disease (AKD) occurred before the procedure of kidney biopsy accounted for 13.8% (72/521) in the NPS group and 1.9% (2/105) in the RTU group. The renal pathological findings revealed higher number of glomeruli in the NPS group than in the RTU group (26.8 ± 13.0 vs. 17.2 ± 8.6, p < 0.001). The incidence of bleeding complications in the NPS group was lower than that in the RTU group (9.2 vs. 21.9%, p < 0.01). Logistic multivariate regression showed that AKD was independently associated with bleeding complications after kidney biopsy in the NPS group. CONCLUSION: Regarding the bleeding risk, there was noninferiority of NPS over RTU. AKD contributes to higher risks of bleeding complications after kidney biopsy.

Serum pre-albumin is prognostic for all-cause mortality in patients with community-acquired and post-operative acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a critical clinical syndrome characterised by a rapid decrease in renal filtration, with the accumulation of products of metabolism such as creatinine and urea. In recent years, the incidence of AKI has increased not only in critically ill hospitalised patients but also in community patients. Also, the prognosis of AKI is poor and treatment is limited in these populations. The increasing incidence and poor prognosis may be the reasons why more investigators are involved in epidemiological and risk factor analysis of AKI. AIMS: To investigate the effects of these risk factors on outcomes in both community-acquired and hospitalised AKI populations to provide certain guidance for clinics and to explore the prognostic value of prealbumin on all-cause mortality in patients with community-acquired and post-operative AKI. METHODS: From 2000 to 2010, 477 patients diagnosed with AKI and treated in the Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University, were enrolled in the community-acquired AKI (CA-AKI) group and 138 patients diagnosed with AKI after an operation were enrolled in the post-operative AKI (PO-AKI) group. Data were collected at AKI onset and 1 year after discharge and analysed retrospectively. RESULTS: Compared with PO-AKI patients, more patients in CA-AKI group had chronic kidney disease, obesity and hyperlipidaemia, and fewer patients had cerebrovascular disease (CVD), anaemia, shock or arrhythmia. Risks for CA-AKI were atherosclerosis, CVD, arrhythmia, multiple organ dysfunction syndrome and usage of vasoactive agents, and risks for PO-AKI were elderly, arrhythmia and requirement of renal replacement therapy. A higher level of serum PA was associated with a better outcome in the CA-AKI group (hazard ratio 0.92, 95% confidence interval 0.85-0.996) and PO-AKI group (hazard ratio 0.91, 95% confidence interval 0.84-0.99). In the CA-AKI group, the cumulative survival rate of patients with a normal PA level (PA >20 mg/dL) was higher than that among patients with a lower PA (PA ≤20 mg/dL; 95.4% vs 88.3%, P = 0.031). Similarly, in the PO-AKI group, a normal PA level was associated with a higher survival rate (74.1% vs 47.6%, P = 0.019). CONCLUSION: Serum PA may serve as a prognostic marker for CA-AKI and PO-AKI, and further research is warranted to confirm this finding.

GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.