Integrative ATAC-seq and RNA-seq analysis associated with diabetic nephropathy and identification of novel targets for treatment by dapagliflozin.

Dapagliflozin (DAPA) are clinically effective in improving diabetic nephropathy (DN). However, whether and how chromatin accessibility changed by DN responds to DAPA treatment is unclear. Therefore, we performed ATAC-seq, RNA-seq, and weighted gene correlation network analysis to identify the chromatin accessibility, the messenger RNA (mRNA) expression, and the correlation between clinical phenotypes and mRNA expression using kidney from three mouse groups: db/m mice (Controls), db/db mice (case group), and those treated with DAPA (treatment group). RNA-Seq and ATAC-seq conjoint analysis revealed many overlapping pathways and networks suggesting that the transcriptional changes of DN and DAPA intervention largely occured dependently on chromatin remodeling. Specifically, the results showed that some key signal transduction pathways, such as immune dysfunction, glucolipid metabolism, oxidative stress and xenobiotic and endobiotic metabolism, were repeatedly enriched in the analysis of the RNA-seq data alone, as well as combined analysis with ATAC-seq data. Furthermore, we identified some candidate genes (UDP glucuronosyltransferase 1 family, Dock2, Tbc1d10c, etc.) and transcriptional regulators (KLF6 and GFI1) that might be associated with DN and DAPA restoration. These reversed genes and regulators confirmed that pathways related to immune response and metabolism pathways were critically involved in DN progression.

Tubular basement membrane deposits after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Extraglomerular immune complex deposition is rare and only a few membranous nephropathy cases with tubular basement membrane deposits have been reported following allogeneic hematopoietic stem cell transplantation. CASE PRESENTATION: We reported a 56-year-old man with increased serum creatinine after allogeneic hematopoietic stem cell transplantation who underwent a renal biopsy. Tubular interstitial nephritis was identified on light microscope. The unique histologic features were diffuse tubular basement membrane immune complex deposition detected by both immunofluorescence and electron microscopy, while the glomerular involvement was inconspicuous. The differential diagnosis from other forms of tubular basement membrane deposition is discussed. CONCLUSION: Diffuse granular tubular basement membrane immune complex deposition with minimal glomerular involvement is also a manifestation of renal complication in hematopoietic stem cell transplantation recipient. However, the exact mechanism and target antigen remains unknown.

Renal histopathological lesions after liver transplantation: What can we find besides calcineurin inhibitor-induced nephrotoxicity?

BACKGROUND: Chronic kidney disease (CKD) is a common complication after liver transplantation and is traditionally considered to be secondary to calcineurin inhibitors (CNIs). However, several studies have reported that the etiology of CKD after liver transplantation is broad and may only be assessed accurately by renal biopsy. The current study aimed to explore the usefulness of renal biopsies in managing CKD after liver transplantation in daily clinical practice. METHOD: This retrospective analysis enrolled all post-liver transplantation patients who had a renal biopsy in a single center from July 2018 to February 2021. RESULTS: Fourteen renal biopsies were retrieved for review from 14 patients at a median of 35.7 (minimum-maximum: 2.80-134.73) months following liver transplantation. The male-to-female ratio was 13:1 (age range, 31-75 years). The histomorphological alterations were varied. The predominant glomerular histomorphological changes included focal segmental glomerular sclerosis (FSGS) (n = 4), diabetic glomerulopathy (n = 4), and membranoproliferative glomerulonephritis (n = 4). Thirteen (92.9%) patients had renal arteriolar sclerosis. Immune complex nephritis was present in six patients, of whom only two had abnormal serum immunological indicators. Despite interstitial fibrosis and tubular atrophy being present in all the patients, only six (42.9%) presented with severe interstitial injury. No major renal biopsy-related complications occurred. After a mean follow-up of 11.8 months (range: 1.2-29.8), three patients progressed to end-stage renal disease (ESRD). CONCLUSION: The etiology of CKD after liver transplantation might be more complex than originally thought and should not be diagnosed simply as calcineurin inhibitors(CNI)-related nephropathy. Renal biopsy plays a potentially important role in the diagnosis and treatment of CKD after liver transplantation and might not be fully substituted by urine or blood tests. It may help avoid unnecessary changes to the immunosuppressants and inadequate treatment of primary diseases.

NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation.

BACKGROUND/AIMS: The NOD-like receptor, pyrin domain containing-3 (NLRP3) inflammasome is involved in the progression of chronic kidney disease in several rodent models. Here, we investigated whether a specific inhibitor of NLRP3 inflammasome, MCC950, can attenuate cisplatin-induced renal fibrosis. MATERIALS: Renal fibrosis was induced via a series of three injections of cisplatin to male C57BL/6 mice (7.5 mg/kg body weight). Activation of NLRP3 inflammasome was detected by immunoblotting, real-time PCR, and immunofluorescence. To validate the protective effect of NLRP3 inflammasome inhibition, MCC950(20 mg/kg body weight) was daily injected into multiple-cisplatin-treated mice intraperitoneally for 14 days, starting from 4 weeks after the first dose of cisplatin. NLRP3-/- mice were used to confirm the role of NLRP3 inflammasome in cisplatin-induced renal fibrosis. RESULTS: Mice were euthanized at 6 weeks after the first dose of cisplatin treatment. In multiple-cisplatin-induced murine model, renal fibrosis was accompanied by the activation of NLRP3 inflammasome. MCC950, the specific inhibitor of NLRP3 inflammasome, reduced cisplatin-induced renal dysfunction, tubular damage, interstitial collagen deposit, and the expression of profibrotic parameters. NLRP3 inhibition might protect against cisplatin-induced renal fibrosis through the alleviation of oxidative stress and inflammation. Furthermore, inhibition of NLRP3 inflammasome activation by deleting NLRP3 gene halted the progression of cisplatin-induced renal fibrosis. CONCLUSION: Inhibition of NLRP3 inflammasome attenuates renal fibrosis due to repeated cisplatin injections, and might be identified as a potential target for attenuating cisplatin-induced chronic kidney disease.

The key candidate genes in tubulointerstitial injury of chronic kidney diseases patients as determined by bioinformatic analysis.

Pathologic changes such as renal tubular atrophy and interstitial fibrosis are common in chronic kidney disease (CKD), which in turn, leads to loss of renal function. The aims of present study were to screen critical genes with tubulointerstitial lesion in CKD by weighted gene correlation network analysis (WGCNA). Gene expression data including 169 tubulointerstitial samples of CKD and 21 controls downloaded from Gene Expression Omnibus (GEO) database. Totally 294 differentially expressed genes (DEGs) were screened, including 180 upregulated and 114 downregulated genes. Meanwhile, 90 expression data of tubulointerstitial samples combined with clinic information were applied to explore the potential mechanisms of tubulointerstitial lesion. As a consequence, the blue, brown and yellow modules which included the most DEGs compared to the other modules and exhibited strongly association with eGFR, were significantly enriched in several signalling pathways that have been reported involved in pathogenesis of CKD. Furthermore, it was found that the four genes (PLG, ITGB2, CTSS and CCL5) was one of the DEGs which also be identified as hub genes according to Kwithin. Finally, the Nephroseq online tool showed that the tubulointerstitial expression levels of PLG significantly positively correlated with the estimated glomerular filtration rate (eGFR), while ITGB2, CTSS and CCL5 connected negatively to the eGFR of CKD patients. Taken together, WGCNA is an efficient approach to system biology. By this procedure, the present study enhanced the understanding of the transcriptome status of CKD and might shed a light on the further investigation on the mechanisms of renal tubulointerstitial injury in CKD. SIGNIFICANCE OF STUDY: Traditional molecular biology can only explain the local part of the biological system, and difficult to make comprehensive exploration of the whole biological system in the chronic kidney disease (CKD). In this study, we gave an explicit elucidation of dysregulated protein coding genes by the analysis of microarray datasets in GEO database. We have presented a novel approach using weighted gene correlation network analysis (WGCNA) to explore the DEGs which implicated in CKD process. In this study, we conducted WGCNA to explore the potential mechanisms of renal tubular damage, and provided novel biomarkers associated with the molecular mechanisms underlying renal tubulointerstitial injury in CKD.

Investigation of the Mechanism Underlying Calcium Dobesilate-Mediated Improvement of Endothelial Dysfunction and Inflammation Caused by High Glucose.

BACKGROUND/AIMS: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. Recent studies have demonstrated that CaD exerts protective effects against diabetic nephropathy. The aim of this study was to elucidate the molecular and cellular mechanisms underlying the protective effects of CaD. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured with different D-glucose concentrations to determine the effects of high glucose on HUVEC gene expression. HUVECs were also incubated with CaD (25 µM, 50 µM, and 100 µM) for 3 days to determine the effects of CaD on HUVEC viability. db/db mice were treated with CaD. 2-[(Aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1) blocked the nuclear factor-κB (NF-κB) pathway in HUVECs. A pentraxin 3 (PTX3) small interfering RNA (siRNA) intervention experiment was performed in the cells. An adenovirus-encapsulated PTX3 siRNA intervention experiment was performed in db/db mice. Western blot and real-time PCR analyses were used to detect PTX3, p-IKBa/IKBa (I-kappa-B-alpha), and p-eNOS/eNOS (endothelial nitric oxide synthase) expression in mice and HUVECs. Hematoxylin-eosin (HE) staining and periodic acid-Schiff (PAS) staining were used to observe renal tissue damage in mice. PTX3 expression was observed by immunohistochemical staining. RESULTS: CaD downregulated the expression of PTX3 and p-IKBa/IKBa and upregulated the expression of p-eNOS/eNOS in vitro. When TPCA-1 was used, high glucose induced high PTX3 expression, and the expression of p-eNOS/eNOS increased. After PTX3 gene silencing, the expression of p-eNOS/eNOS also increased. In vivo, CaD reduced the expression of PTX3 and p-IKBa/IKBa in the kidneys of db/db mice and increased the expression of p-eNOS/eNOS. After PTX3 gene silencing, the urine protein and renal function of db/db mice were ameliorated, the glomerular extracellular matrix was decreased, and the expression of p-eNOS/eNOS was increased. CONCLUSIONS: Our results suggested that CaD may inhibit the expression of PTX3 by altering the IKK/IKB/NF-κB pathway, thereby improving endothelial dysfunction in HUVECs. PTX3 may be a potential therapeutic target for DKD.

Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function.

BACKGROUND/AIMS: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. However, no effective treatments for this disease are available. Calcium dobesilate (CaD) is widely used to treat diabetic retinopathy. DKD and retinopathy often co-exist and have similar mechanisms of pathogenesis. The aim of the present study was to elucidate the safety and efficacy of CaD in the treatment of DKD. METHODS: In the prospective randomised controlled study, 100 DKD from Type 2 diabetes mellitus (DM) patients with a urinary albumin/ creatinine ratio (ACR) ≥30 mg/g and urinary protein level between 150 mg/24 h and 2 g/24 h with GFR> 90ml/min were enrolled. The patients were randomly divided into the treatment group (500 mg of CaD, administered orally, 3 times per day) and the control group. DKD patients were treated for 3 months. In the case control study, DM patients without proteinuria and healthy individuals were also enrolled. Clinical data and related biochemical parameters were collected. Endothelial function markers (VEGF, ET-1, eNOS, NO) and inflammatory markers (MCP-1, ICAM, PTX3) were detected by ELISA. RESULTS: In the prospective randomised controlled study, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased after three months of treatment with CaD in the patients with DKD, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, ET-1) were significantly reduced compared to pre-treatment levels, NO was signifcantly increased post treatment. In the case control study, we found that PTX3, MCP-1, ICAM, VEGF and ET-1 levels were positively correlated with urinary albumin in DKD patients, while the NO level was negatively correlated. Logistic regression analysis showed that PTX3, NO and HbAlc were influential factors in DKD. After patients with DKD were treated with CaD for three months, the 24 h urinary albumin and 24 h urinary protein levels significantly decreased, but the cystatin C-based glomerular filtration rate (GFR) remained unchanged. In addition, the levels of inflammatory markers (PTX3, MCP-1, hsCRP, ICAM) and endothelial dysfunction markers (VEGF, NO, ET-1) were significantly reduced compared to pre-treatment levels. CONCLUSION: CaD can be safely and effectively used to treatdiabetic nephropathy.

High urinary excretion of kidney injury molecule-1 predicts adverse outcomes in acute kidney injury: a case control study.

BACKGROUND: Acute kidney injury (AKI) is a common clinical syndrome with poor prognosis. The insensitivity and non-specificity of traditional markers of renal dysfunction prevent timely estimation of the severity of renal injury, and the administration of possible therapeutic agents. Urinary kidney injury molecule-1 (uKIM-1) is a marker of epithelial injury of renal tubules. Different uKIM-1 levels are associated with various degrees of renal injury. This study sought to evaluate uKIM-1 as a predictor of renal prognosis by analyzing uKIM-1 levels in patients with AKI. METHODS: A total of 258 patients were screened, 201 patients were enrolled in the study, and 17 patients were lost to follow up. Therefore, 184 AKI patients were included in this study and were classified into transient AKI and renal AKI groups according to short-term renal function recovery (48 h). Changes in renal function were observed for one year during regular follow up, and risk factors that affected renal prognosis were analyzed. RESULTS: The uKIM-1 level in the renal AKI group was significantly higher than that in the transient AKI group. The receiver operating characteristic area under the curve (ROC-AUC) of uKIM-1 for the diagnosis of renal AKI was 0.691, and its sensitivity and specificity were 66.3 % and 64.7 %, respectively. The uKIM-1 level at AKI occurrence was significantly higher in the group with deterioration in renal function than in the group with stable renal function. Thus, uKIM-1 level is a prognostic factor for poor renal prognosis. ROC curve analysis demonstrated that the AUC for the prediction of renal function progression on the basis of uKIM-1 levels in patients with renal AKI and AKI was 0.680 and 0.703, respectively; the sensitivity was 78.6 % and 78.4 %, respectively; and the specificity was 57.9 % and 60.8 %, respectively. uKIM-1 > 2.37 ng/mg in patients with AKI positively correlated with poor renal prognosis. CONCLUSIONS: uKIM-1 levels sensitively predict the renal prognosis of patients with AKI, and they may be used as early screening indicators for poor renal prognosis.

Long-term kidney survival analyses in IgA nephropathy patients under steroids therapy: a case control study.

BACKGROUND: Corticosteroids are preferred to treat patients with active IgA nephropathy (IgAN), and beneficial effects from the short-term use of corticosteroids have been confirmed. However, a large number of patients will progress to end-stage renal disease after a long time follow-up. This study aimed to evaluate kidney disease progression and risk factors on kidney survival in IgAN patients receiving steroids treatment. METHODS: Two hundred biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for a median period of 63.33 months. Risk factors on kidney survival were retrospectively investigated by the Cox proportional hazards model. RESULTS: Of the two hundred patients, twenty patients showed progression of renal impairment at the end of follow-up. The median and interquartile range values for initial serum creatinine were 89.2 and 68.08-121.35 µmol/L, respectively. Multivariate Cox regression analyses revealed that relapse, non-remission, time-averaged eGFR (TA-eGFR), and time-averaged serum albumin (TA-ALB) were independently associated with the kidney progression. Those with TA-ALB levels <35 g/L and TA-eGFR levels <60 mL/min/1.73 m(2) were less likely to recover from kidney progression. Patients were more likely to show kidney function deterioration, when they had non-remission or relapse after corticosteroids treatment. CONCLUSION: This study demonstrated that relapse, non-remission, TA-eGFR, and TA-ALB could serve as independent predictors of long term prognosis of IgAN patients receiving corticosteroid therapy.

Time-averaged albumin predicts the long-term prognosis of IgA nephropathy patients who achieved remission.

BACKGROUND: Primary IgA nephropathy (IgAN) is the most common form of idiopathic glomerulonephritis worldwide. Although most patients are able to achieve remission with the current therapy, a large number of patients will still progress to end-stage renal disease. This study aimed to evaluate kidney disease progression and the risk factors for progression in IgAN patients who achieved remission. METHODS: Patients from a prospective database with IgAN were included in this study. All the subjects had achieved a complete remission (CR) or partial remission (PR) following 6 months of therapy. Renal survival and the relationship between the clinical parameters and composite renal outcomes were assessed. RESULTS: The study comprised 878 IgAN patients recruited between January 2005 and December 2010. Overall, 632 patients were enrolled in this study. The data from the 369 patients who achieved remission were analyzed; the mean follow-up time was 49 months. The median serum creatinine (SCr) concentration at baseline was 91.3 µmol/L, and the time-averaged creatinine (TA-SCr) was 91.8 µmol/L. The mean serum albumin (ALB) level at baseline was 39.4 g/L, and the time-averaged serum albumin (TA-ALB) was 42.1 g/L. Multivariate Cox regression analyses revealed that the TA-ALB and TA-SCr levels were independently associated with the composite renal outcome. The patients with a TA-SCr value > 120 µmol/L and a TA-ALB level < 38 g/L were less likely to recover from renal progression. CONCLUSION: The strong predictive relationship of low TA-ALB and high TA-SCr levels with progression observed in this study suggests that TA-ALB may serve as a marker of the long-term renal prognosis of IgAN patients who have achieved remission.

Astragalosides IV inhibits high glucose-induced cell apoptosis through HGF activation in cultured human tubular epithelial cells.

Astragaloside IV (ASI) in Radix Astragali is believed to be the active component. The study aims to investigate whether ASI inhibits tubular epithelial cells apoptosis induced by high glucose and its mechanisms. Tubular epithelial cells in this paper were isolated from human kidney. The cells apoptosis was detected by TUNEL and caspase 3 assay. The protein levels of HGF and TGF-ß1 were measured by ELISA. The phospho-p38 production, ERK and JNK were determined by Western blot. ASI could inhibit cells apoptosis induced by high glucose (25 mmol/L) in dose-dependent and time-dependent manners. ASI also inhibited high glucose-induced expression of TGF-ß1 and activation of p38 MAPK pathway at the protein level. Furthermore, ASI increased HGF production in human tubular epithelial cells. The ASI inhibition of tubular epithelial cells apoptosis and reduction of TGF-ß1 expression induced by high glucose may represent a new treatment for diabetic kidney injury. The mechanism underlying this inhibitory effect may be related to the inhibition of p38 MAPK signaling pathway activation and HGF overproduction.

Efficacy and safety of Yiqi Peiyuan granules for improving the short-term prognosis of patients with acute kidney injury: A multicenter, double-blind, placebo-controlled, randomized trial.

BACKGROUND: Yiqi Peiyuan (YQPY) prescription, a composite prescription of traditional Chinese medicine, has been used to prevent or delay the continued deterioration of renal function after acute kidney injury (AKI) in some institutions and has shown considerable efficacy. OBJECTIVE: This is the first randomized controlled trial to assess efficacy and safety of YQPY for improving short-term prognosis in adult patients with AKI. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: This is a prospective, double-blind, multicenter, randomized, and placebo-controlled clinical trial. A total of 144 enrolled participants were randomly allocated to two groups according to a randomization schedule. Participants, caregivers and investigators assessing the outcomes were blinded to group assignment. Patients in the YQPY group received 36 g YQPY granules twice a day for 28 days. Patients in the placebo group received a placebo in the same dose as the YQPY granules. MAIN OUTCOME MEASURES: The primary outcome was the change in the estimated glomerular filtration rate (eGFR) between baseline and after 4 and 24 weeks of treatment. The secondary outcomes were the change of serum creatinine (Scr) level between baseline and after treatment, and the incidence of endpoint events, defined as eGFR increasing by more than 25% above baseline, eGFR >75 mL/min per 1.73 m2 or the composite endpoint, which was defined as the sum of patients meeting either of the above criteria. RESULTS: Data from a total of 114 patients (59 in the YQPY group and 55 in the control group) were analyzed. The mean changes in eGFR and Scr in weeks 4 and 24 had no difference between the two groups. In further subgroup analysis (22 in the YQPY group and 31 in the control group), the mean change in eGFR after treatment for 4 weeks was 27.39 mL/min per 1.73 m2 in the YQPY group and 5.78 mL/min per 1.73 m2 in the placebo group, and the mean difference between groups was 21.61 mL/min per 1.73 m2 (P < 0.001). Thirteen (59.1%) patients in the YQPY group and 5 (16.1%) in the placebo group reached the composite endpoints (P = 0.002). During the intervention, 2 and 4 severe adverse events were reported in the YQPY and placebo groups, respectively. CONCLUSION: The YQPY granules can effectively improve the renal function of patients 4 weeks after the onset of AKI, indicating that it has good efficacy for improving short-term renal outcomes in patients with AKI. The YQPY granules may be a promising therapy for adults with AKI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100051723. Please cite this article as: Wu JJ, Zhang TY, Qi YH, Zhu MY, Fang Y, Qi CJ, Cao LO, Lu JF, Lu BH, Tang LM, Shen JX, Mou S. Efficacy and safety of Yiqi Peiyuan granules for improving the short-term prognosis of patients with acute kidney injury: a multicenter, double-blind, placebo-controlled, randomized trial. J Integr Med. 2024; 22(3): 279-285.

Activation of lipophagy is required for RAB7 to regulate ferroptosis in sepsis-induced acute kidney injury.

Sepsis-induced acute kidney injury (S-AKI) is the most common type of acute kidney injury (AKI), accompanied by elevated morbidity and mortality rates. This study investigated the mechanism by which lipid droplets (LDs) degraded via autophagy (lipophagy)required for RAB7 regulated ferroptosis in the pathogenesis of S-AKI. Here, we constructed the S-AKI model in vitro and in vivo to elucidate the potential relationship of lipophagy and ferroptosis, and we first confirmed that the activation of lipophagy promoted renal tubular epithelial cell ferroptosis and renal damage in S-AKI. The results showed that lipopolysaccharide (LPS) induced a marked increase in lipid peroxidation and ferroptosis, which were rescued by ferrstain-1 (Fer-1), an inhibitor of ferroptosis. In addition, LPS induced the remarkable activation of RAB7-mediated lipophagy. Importantly, silencing RAB7 alleviated LPS-induced lipid peroxidation and ferroptosis. Thus, the present study demonstrated the potential significant role of ferroptosis and lipophagy in sepsis-induced AKI, and contributed to better understanding of the pathogenesis and treatment targets of AKI.

DDRGK1-mediated ER-phagy attenuates acute kidney injury through ER-stress and apoptosis.

Acute kidney injury (AKI) constitutes a prevalent clinical syndrome characterized by elevated morbidity and mortality rates, emerging as a significant public health issue. This study investigates the interplay between endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and ER-associated degradation (ER-phagy) in the pathogenesis of AKI. We employed four distinct murine models of AKI-induced by contrast media, ischemia-reperfusion injury, cisplatin, and folic acid-to elucidate the relationship between ER-phagy, ER stress, and apoptosis. Our findings reveal a marked decrease in ER-phagy coinciding with an accumulation of damaged ER, elevated ER stress, and increased apoptosis across all AKI models. Importantly, overexpression of DDRGK1 in HK-2 cells enhanced ER-phagy levels, ameliorating contrast-induced ER stress and apoptosis. These findings unveil a novel protective mechanism in AKI, wherein DDRGK1-UFL1-mediated ER-phagy mitigates ER stress and apoptosis in renal tubular epithelial cells. Our results thereby contribute to understanding the molecular underpinnings of AKI and offer potential therapeutic targets for its treatment.

The presence of exudative thickening of Bowman's capsule predict poor prognosis in diabetic kidney disease.

BACKGROUND: The relationship between Bowman's capsule thickening and progression of diabetic kidney disease (DKD) remains uncertain. METHODS: Renal biopsy specimens from 145 DKD patients and 20 control subjects were evaluated for Bowman's capsule thickness. Immunohistochemical staining assessed col4α2, laminin ß1, and albumin expression. In a discovery cohort of 111 DKD patients with eGFR ≥ 30 ml/min/1.73 m2, thickening was classified as fibrotic or exudative. The composite endpoint included CKD stage 5, dialysis initiation, and renal disease-related death. Prognosis was analyzed using Kaplan-Meier and Cox regression analyses. Two validation cohorts were included. RESULTS: Three types of thickening were observed: fibrotic, exudative, and periglomerular fibrosis. Parietal epithelial cell matrix protein accumulation contributed to fibrotic thickening, while albumin was present in exudative thickening. Bowman's capsule was significantly thicker in DKD patients (5.74 ± 2.09 µm) compared to controls (3.38 ± 0.43 µm, P < 0.01). In discovery cohort, the group of exudative thickning had a poorer prognosis(median time 20 months vs 57 months, P = 0.000). Cox multivariate analysis revealed that exudative thickening of Bowman's capsule were associated with a poor prognosis. The validation cohorts confirmed the result. CONCLUSIONS: Various mechanisms contribute to Bowman's capsule thickening in DKD. The proportion of exudative thickening may serve as a valuable prognostic indicator for DKD patients.

Predicting mortality in microscopic polyangiitis with renal involvement: a survival analysis based on 64 patients.

BACKGROUND: To determine predictors of survival in patients with microscopic polyangiitis (MPA). METHODS: A cohort of 64 patients who met the Chapel Hill criteria for MPA with renal involvement participated in the study. All subjects received cytotoxic drugs. All of the diagnoses were biopsy proven. RESULTS: We retrospectively studied 64 patients (median age, 59 years; male/female ratio, 1.6:1). The mean follow-up was 38 months; 34 (53.13%) patients died or acquired end-stage renal disease. According to univariate analysis, a preliminary prognostic value was attributed to serum creatinine (Scr) > 459 µmol/L (p < 0.001); erythrocyte sedimentation rate (ESR) > 99 mm/h (p < 0.001); serum albumin < 30 g/L (p < 0.001); and hemoglobin < 84 g/L (p < 0.001). Logistic regression analysis showed that Scr level (ß = 1.02, p = 0.0002) and ESR (ß = 1.02, p = 0.0002) at baseline were associated with poor prognosis, and Cox regression analysis further confirmed this result [Scr: ß = 1.004, 95% confidence interval (CI): 1.002-1.006, p < 0.001; ESR: ß = 1.018, 95% CI: 1.000-1.037, p = 0.046]. The receiver operating characteristic curve showed that Scr and ESR were predictors of MPA patient prognosis, their areas under the curves were 0.95 and 0.80, their sensitivities were 94.1% and 92.3%, and their specificities were 94% and 70%, respectively. CONCLUSION: Despite the small number of patients in this study, the prevalence of renal vasculitis was high in patients with MPA. The level of Scr and ESR may be a useful clinical biomarker for monitoring prognosis.

[Analysis of associated factors for remission and relapse in proliferative and membranous lupus nephritis patients: a 4-year follow-up study].

OBJECTIVE: To explore the related factors of remission and relapse in lupus nephritis (LN) patients. METHODS: A retrospective study was conducted for proliferation and membrane LN patients diagnosed from 2003 to 2010. Their clinical, laboratory and pathological parameters were collected. According to the response to treatment, they were divided into 3 groups of complete remission (CR), partial remission (PR) and no response (NR). Those in remission were divided into 2 groups of relapsing and non-relapsing during maintenance period. Associated factors for remission and relapse were analyzed. RESULTS: (1) Among a total of 105 patients, there were 99 females and 6 males with an average follow-up period of (51 ± 30) months. Eighty-six patients achieved remission after 6-month treatment. (2) The outcomes were CR (n = 36), PR (n = 50) and NR (n = 19). Proteinuria in PR group was higher than that in CR group (4.7 (3.1-7.6) vs 1.7 (1.4-3.8), P < 0.01) while proteinuria of CR group was lower than that of NR group (1.7 (1.4-3.8) vs 3.0 (2.3-5.9), P < 0.01). Serum albumin level of CR group was significantly higher than those of PR (30.6 (27.8-34.6) vs 22.4 (19.3-29.4), P < 0.01) and NR groups (30.6 (27.8-34.6) vs 23.1 (18.9-28.6), P < 0.01). Serum creatinine was significantly higher in NR group than those of CR (128.9 (69.9-184.3) vs 58.1 (53.0-70.9), P < 0.01) and PR group (128.9 (69.9-184.3) vs 67.5 (53.5-129.1), P < 0.05). Acute index (AI) and chronic index (CI) were lower in CR group than those of PR and NR groups. (3) A total of 86 cases achieved remission (CR/PR) while 20 cases (23.3%) had relapse. During the maintenance period, the relapse rate was higher in the group on prednisone alone than those on combined therapy of prednisone plus immunosuppressant (P < 0.05). Sixty patients (90.9%) in non-relapse group and 12 cases (60.0%) in recurrence group had good compliance. CONCLUSIONS: Initial proteinuria, serum creatinine, serum albumin, estimated glomerular filtration rate and AI were related with remission of induction period. Prednisone-alone therapy is an independent risk factor for relapse during maintenance period. Poor compliance of patients may be one of the risk factors for relapse during maintenance period. It may be useful to maintain sustained remission and reduce relapse in LN patients by improving their compliance and using steroids plus immunosuppressant during maintenance period.

Mitophagy alleviates cisplatin-induced renal tubular epithelial cell ferroptosis through ROS/HO-1/GPX4 axis.

Cisplatin is widely recommended in combination for the treatment of tumors, thus inevitably increasing the incidence of cisplatin-induced acute kidney injury. Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis. Ferroptosis, a new modality of programmed cell death, is characterized by iron-dependent phospholipid peroxidation and oxidative membrane damage. However, the role of mitophagy in ferroptosis in kidney disease is unclear. Here, we investigated the mechanism underlying both BNIP3-mediated and PINK1-PARK2-mediated mitophagy-induced attenuation of ferroptosis in cisplatin-induced acute kidney injury. The results showed that cisplatin induced mitochondrial injury, ROS release, intracellular iron accumulation, lipid peroxidation and ferroptosis in the kidney, which were aggravated in Bnip3 knockout, Pink1 knockout or Park2 knockout cisplatin-treated mice. Ferrstatin-1, a synthetic antioxidative ferroptosis inhibitor, rescued iron accumulation, lipid peroxidation and ferroptosis caused by inhibition of mitophagy. Thus, the present study elucidated a novel mechanism by which both BNIP3-mediated and PINK1-PARK2-mediated mitophagy protects against cisplatin-induced renal tubular epithelial cell ferroptosis through the ROS/HO1/GPX4 axis.

Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerulonephritis, and a major cause of end-stage renal disease; however, its pathogenesis requires elucidation. Here, a hub gene, FABP1, and signaling pathway, PPARα, were selected as key in IgAN pathogenesis by combined weighted gene correlation network analysis of clinical traits and identification of differentially expressed genes from three datasets. FABP1 and PPARα levels were lower in IgAN than control kidney, and linearly positively correlated with one another, while FABP1 levels were negatively correlated with urinary albumin-to-creatinine ratio, and GPX4 levels were significantly decreased in IgAN. In human mesangial cells (HMCs), PPARα and FABP1 levels were significantly decreased after Gd-IgA1 stimulation and mitochondria appeared structurally damaged, while reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, and glutathione and GPX4 decreased, relative to controls. GPX4 levels were decreased, and those of ACSL4 increased on siPPARα and siFABP1 siRNA treatment. In PPARα lentivirus-transfected HMCs stimulated by Gd-IgA1, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPARα and GPX4, increased; and damaged mitochondria reduced. Hence, PPARα pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

C4d as a Screening Tool and an Independent Predictor of Clinical Outcomes in Lupus Nephritis and IgA Nephropathy.

BACKGROUND: As an indispensable marker of complement cascades activation, C4d was confirmed of its crucial role in the pathogenesis of both lupus nephritis (LN) and IgA nephropathy (IgAN). While the studies directly comparing the diagnostic value, and outcomes predicting function of C4d between LN and IgAN are still absent. METHODS: A cohort of 120 LN patients, 120 IgAN patients who were diagnosed by renal biopsy between January 2015 and December 2017 and 24 healthy age matched controls were prospectively analyzed. The patients were followed till December 2020. The outcomes were adverse disease treatment response (disease relapse) and kidney disease progression event (decline of estimated glomerular filtration rate by more than 20% or end-stage kidney disease). The renal C4d deposition proportion and pattern were compared between IgAN and LN patients. In addition, the relationship between renal C4d deposition and disease subtypes, disease relapse as well as disease progression for LN and IgAN patients were also analyzed. RESULTS: The LN, IgAN patients and healthy controls were well matched in ages. The follow-up period was 38.5 (30.3-60.8) months for LN patients and 45.0 (30.5-57.0) months for IgAN patients. 78 patients (65.0%) with LN had renal C4d deposition, compared with only 39 IgAN patients (32.5%) with C4d deposition in renal tissues (P < 0.001). The LN patients shared different renal C4d distribution patterns with IgAN patients. Compared with IgAN patients, the C4d deposition in LN patients was significantly more in renal glomerulus (P < 0.001) and less in renal tubules (P = 0.003). For disease subtypes, renal C4d deposition was especially strong in class V membranous LN and IgAN with tubulointerstitial fibrosis (T1/T2) lesions. Renal C4d deposition was independently correlated with the disease relapse of LN patients (HR = 1.007, P = 0.040), and acted as an independent predictor of disease progression during the follow-up period for IgAN patients (HR = 1.821, P = 0.040). CONCLUSIONS: Renal C4d distribution proportion and pattern differed between LN and IgAN patients. The presence of C4d in renal tissue acted as an independent predictor of relapse for LN patients and disease progression for IgAN patients.