Clinical characteristics and outcome of double-seropositive patients with anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies.

OBJECTIVE: To explore the clinical characteristics of double-seropositive patients (DPPs) with anti-glomerular basement membrane (Anti-GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We collected patients with both ANCA and anti-GBM positive glomerulonephritis who were hospitalized in the Department of Nephrology at the First Affiliated Hospital of Nanjing Medical University from January 2010 to August 2022. Retrospective analysis of the baseline clinical characteristics of patients and follow-up to explore relevant factors affecting renal and patient survival. RESULTS: A total of 386 patients, including 69 ANCA negative anti-GBM glomerulonephritis patients, 296 anti-GBM negative ANCA associated vasculitis (AAV) patients, and 21 DPPs were enrolled in this study. Among the 21 DPPs aged 68.0 years (59.5, 74.0), there were 11 males and 10 females. The median serum creatinine at diagnosis was 629.0 (343.85, 788.75) µmol/L, and the median eGFR (CKD-EPI) was 7.58 (4.74, 13.77) mL/min. Fifteen cases (71.4 %) underwent initial RRT. After a follow-up of 40.0 (11.0, 73.0) months, 13 out of 21 DPPs (61.9 %) received maintenance RRT, while 49 out of 69 (71.0 %) ANCA negative anti-GBM-GN patients and 124 out of 296 (41.9 %) anti-GBM negative AAV patients received maintenance RRT (P < 0.001). Kaplan-Meier survival analysis showed that DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients (P = 0.001). Among the 21 patients with DPPs, renal survival was significantly better in patients with better initial renal function, including those who did not receive initial RRT (P = 0.003), with lower serum creatinine levels (Cr < 629.0 µmol/L, P = 0.004) and higher eGFR levels (eGFR ≥ 7.60 ml/min, P = 0.005) than those with poor initial renal function. At the end of follow-up, 14 out of 21 DPPs (66.7 %) survived. Survival analysis showed no significant difference among patients in DPPs group, ANCA negative anti-GBM-GN group, and anti-GBM negative AAV group. CONCLUSIONS: DPPs and ANCA negative anti-GBM-GN patients were more likely to progress to ESRD than anti-GBM negative AAV patients. In DPPs, the poor renal function at diagnosis might be a risk factor associated with poor renal survival.

Quantification of urinary podocyte-derived migrasomes for the diagnosis of kidney disease.

Migrasomes represent a recently uncovered category of extracellular microvesicles, spanning a diameter range of 500 to 3000 nm. They are emitted by migrating cells and harbour a diverse array of RNAs and proteins. Migrasomes can be readily identified in bodily fluids like serum and urine, rendering them a valuable non-invasive source for disease diagnosis through liquid biopsy. In this investigation, we introduce a streamlined and effective approach for the capture and quantitative assessment of migrasomes, employing wheat germ agglutinin (WGA)-coated magnetic beads and flow cytometry (referred to as WBFC). Subsequently, we examined the levels of migrasomes in the urine of kidney disease (KD) patients with podocyte injury and healthy volunteers using WBFC. The outcomes unveiled a substantial increase in urinary podocyte-derived migrasome concentrations among individuals with KD with podocyte injury compared to the healthy counterparts. Notably, the urinary podocyte-derived migrasomes were found to express an abundant quantity of phospholipase A2 receptor (PLA2R) proteins. The presence of PLA2R proteins in these migrasomes holds promise for serving as a natural antigen for the quantification of autoantibodies against PLA2R in the serum of patients afflicted by membranous nephropathy. Consequently, our study not only pioneers a novel technique for the isolation and quantification of migrasomes but also underscores the potential of urinary migrasomes as a promising biomarker for the early diagnosis of KD with podocyte injury.

High sodium intake and fluid overhydration predict cardiac structural and functional impairments in chronic kidney disease.

Background: High sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their effects on cardiac dysfunction remain unclear. Aims: The study aimed to explore the impact of salt and volume overload on cardiac alterations in non-dialysis CKD. Methods: In all, 409 patients with CKD stages 1-4 (G1-G4) were enrolled. Daily salt intake (DSI) was estimated by 24-h urinary sodium excretion. Volume status was evaluated by the ratio of extracellular water (ECW) to total body water (TBW) measured by body composition monitor. Recruited patients were categorized into four groups according to DSI (6 g/day) and median ECW/TBW (0.439). Echocardiographic and body composition parameters and clinical indicators were compared. Associations between echocardiographic findings and basic characteristics were performed by Spearman's correlations. Univariate and multivariate binary logistic regression analysis were used to determine the associations between DSI and ECW/TBW in the study groups and the incidence of left ventricular hypertrophy (LVH) and elevated left ventricular filling pressure (ELVFP). In addition, the subgroup effects of DSI and ECW/TBW on cardiac abnormalities were estimated using Cox regression. Results: Of the enrolled patients with CKD, the median urinary protein was 0.94 (0.28-3.14) g/d and estimated glomerular filtration rate (eGFR) was 92.05 (IQR: 64.52-110.99) mL/min/1.73 m2. The distributions of CKD stages G1-G4 in the four groups was significantly different (p = 0.020). Furthermore, compared to group 1 (low DSI and low ECW/TBW), group 4 (high DSI and high ECW/TBW) showed a 2.396-fold (95%CI: 1.171-4.902; p = 0.017) excess risk of LVH and/or ELVFP incidence after adjusting for important CKD and cardiovascular disease risk factors. Moreover, combined with eGFR, DSI and ECW/TBW could identify patients with higher cardiac dysfunction risk estimates with an AUC of 0.704 (sensitivity: 75.2%, specificity: 61.0%). The specificity increased to 85.7% in those with nephrotic proteinuria (AUC = 0.713). The magnitude of these associations was consistent across subgroups analyses. Conclusion: The combination of high DSI (>6 g/d) and high ECW/TBW (>0.439) independently predicted a greater risk of LVH or ELVFP incidence in non-dialysis CKD patients. Moreover, the inclusion of eGFR and proteinuria improved the risk stratification ability of DSI and ECW/TBW in cardiac impairments in CKD.

Fibrinogen-albumin ratio predicts treatment response in phospholipase A2 receptor-associated membranous nephropathy with nephrotic syndrome.

BACKGROUND: The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN. METHODS: 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman's correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission. RESULTS: In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766. CONCLUSIONS: FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

25(OH)D level and vascular lesion scores in kidney histopathology as risk-stratification tool for predicting renal progression in people with type 2 diabetes.

AIM: To evaluate the potential of the combined individual vascular histopathological lesion and serum 25-hydroxy vitamin D [25(OH)D] level as predictors of outcomes in patients with diabetes and chronic kidney disease. METHODS: A total of 190 patients with type 2 diabetes and kidney disease stages 1-4 were retrospectively included. Kaplan-Meier analysis and the log-rank test were performed to assess renal survival differences. And the time-dependent receiver operating characteristic analyses were used to characterize the predictive accuracy. Hazard ratios for vascular lesion scores and 25(OH)D levels with renal outcomes were estimated using Cox proportional hazards regression models with follow-up time. RESULTS: Over a median follow-up of 23.78 (12.61, 37.14) months, 71 patients (37.4 %) experienced the renal outcomes. Enrolled patients with more severe vascular lesions had worse kidney function, heavier proteinuria, lower serum 25(OH)D levels, and higher prevalence of composite kidney outcomes. Baseline serum 25(OH)D was a significant independent risk factor for vascular lesion scores. The effect of serum 25(OH)D level on kidney prognosis was more pronounced in males and those with more exacerbated vascular lesions (score 2). The severity of vascular lesions and serum 25(OH)D levels were associated with unfavorable kidney outcomes. Accordingly, further time-dependent receiver operating characteristic curves confirmed that combined 25(OH)D level and vascular lesion score had a stable and reliable performance in renal outcomes prediction at short and long-term follow-up times. CONCLUSIONS: 25(OH)D level and vascular lesion scores in kidney histopathology could serve as a useful risk-stratification tool for predicting renal progression in patients with type 2 diabetes.

Utilization of the corticomedullary difference in magnetic resonance imaging-derived apparent diffusion coefficient for noninvasive assessment of chronic kidney disease in type 2 diabetes.

BACKGROUNDS: Accumulating data demonstrated that the cortico-medullary difference in apparent diffusion coefficient (ΔADC) of diffusion-weighted magnetic resonance imaging (DWI) was a better correlation with kidney fibrosis, tubular atrophy progression, and a predictor of kidney function evolution in chronic kidney disease (CKD). OBJECTIVES: We aimed to assess the value of ΔADC in evaluating disease severity, differential diagnosis, and the prognostic risk stratification for patients with type 2 diabetes (T2D) and CKD. METHODS: Total 119 patients with T2D and CKD who underwent renal MRI were prospectively enrolled. Of them, 89 patients had performed kidney biopsy for pathological examination, including 38 patients with biopsy-proven diabetic kidney disease (DKD) and 51 patients with biopsy-proven non-diabetic kidney disease (NDKD) and Mix (DKD + NDKD). Clinicopathological characteristics were compared according to different ΔADC levels. Moreover, univariate and multivariate-linear regression analyses were performed to explore whether ΔADC was independently associated with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR). The diagnostic performance of ΔADC for discriminating DKD from NDKD + Mix was evaluated by receiver operating characteristic (ROC) analysis. In addition, an individual's 2- or 5-year risk probability of progressing to end-stage kidney disease (ESKD) was calculated by the kidney failure risk equation (KFRE). The effect of ΔADC on prognostic risk stratification was assessed. Additionally, net reclassification improvement (NRI) was used to evaluate the model performance. RESULTS: All enrolled patients had a median ΔADC level of 86 (IQR 28, 155) × 10-6 mm2/s. ΔADC significantly decreased across the increasing staging of CKD (P < 0.001). Moreover, those with pathological-confirmed DKD has a significantly lower level of ΔADC than those with NDKD and Mix (P < 0.001). It showed that ΔADC was independently associated with eGFR (ß = 1.058, 95% CI = [1.002,1.118], P = 0.042) and UACR (ß = -3.862, 95% CI = [-7.360, -0.365], P = 0.031) at multivariate linear regression analyses. Besides, ΔADC achieved an AUC of 0.707 (71% sensitivity and 75% specificity) and AUC of 0.823 (94% sensitivity and 67% specificity) for discriminating DKD from NDKD + Mix and higher ESKD risk categories (≥50% at 5 years; ≥10% at 2 years) from lower risk categories (<50% at 5 years; <10% at 2 years). Accordingly, the optimal cutoff value of ΔADC for higher ESKD risk categories was 66 × 10-6 mm2/s, and the group with the low-cutoff level of ΔADC group was associated with 1.232 -fold (95% CI 1.086, 1.398) likelihood of higher ESKD risk categories as compared to the high-cutoff level of ΔADC group in the fully-adjusted model. Reclassification analyses confirmed that the final adjusted model improved NRI. CONCLUSIONS: ΔADC was strongly associated with eGFR and UACR in patients with T2D and CKD. More importantly, baseline ΔADC was predictive of higher ESKD risk, independently of significant clinical confounding. Specifically, ΔADC <78 × 10-6 mm2/s and <66 × 10-6 mm2/s would help to identify T2D patients with the diagnosis of DKD and higher ESKD risk categories, respectively.

Association of Mitochondrial Pyruvate Carrier with the Clinical and Histological Features in Lupus Nephritis.

Background: Mounting evidence suggests that mitochondrial dysfunction contributes to lupus nephritis (LN) pathogenesis. Mitochondrial pyruvate carrier 1 (MPC1) and mitochondrial pyruvate carrier 2 (MPC2) mediating pyruvate transport from the cytoplasm to the mitochondrial matrix, determines the cell survival and cellular energy supply. Here, we aimed to investigate the association of mitochondrial pyruvate carrier expression with the clinical and histological features in LN. Methods: Patients with biopsy-proven proliferative LN (class III and class IV, n=18) and membranous LN (class V, n=18) were included. Expression of MPC1 and MPC2 were examined by immunohistochemistry. MPC protein levels in the two groups were evaluated by the Student's t-test. Correlation analysis between MPC levels and clinicopathological features was performed by Spearman's rank correlation. Results: Both MPC1 and MPC2 were exclusively expressed in renal tubules of enrolled LN. Significantly lower MPC1 and MPC2 were observed in patients with proliferative LN compared to membranous LN. In addition, the MPC1 and MPC2 were negatively correlated with SLEDAI-2K score, renal function, and renal pathology activity index. Conclusion: Both MPC1 and MPC2 were localized in renal tubules, and decreased MPC content was more pronounced in proliferative LN than membranous LN. MPC levels were significantly correlated with renal functions and renal pathology activity.

Decoding the Intercellular Cross-Talking Between Immune Cells and Renal Innate Cells in Diabetic Kidney Disease by Bioinformatics.

Aim: Diabetic kidney disease (DKD) continues to be devastating complication of diabetes mellitus. Immune response and inflammatory reaction play essential roles in the progression of DKD. But the specific mechanism of immune cells, and their act on renal innate cells remains unclear. This article focused on immune cells and their communication with renal innate cells to provide bioinformatic evidence for further understanding the immune mechanism in DKD. Methods: Data were analyzed to evaluate the differentially expressed genes (DEGs) and their pathways in DKD patients and mice. Gene set enrichment analysis (GSEA) was used to explore the immune inflammation-related pathways. CIBERSORT was applied to evaluate the distribution of inflammatory cells in different states. Cell-type DEGs and their enrichment pathways were further explored in podocytes, proximal tubule cells and injured tubule cells. Cellchat was used to reveal the cellular communication between immune cells and renal innate cells in DKD. Results: GO and KEGG analysis showed that DEGs were mainly enriched in immune inflammation-related pathways. Monocytes, M2 macrophages and T cells were significantly increased in DKD samples, especially in renal tubule. ScRNA datasets showed that the immune cells number in DKD were significantly increased. Cell-type DEGs were involved in kidney growth and development. In DKD, the interaction numbers and strength between immune cells and innate cells were significantly increased. VISTANT, SPP1 and IGF signal flow were increased in DKD. SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1-Igf1r receptor ligand pairs were enhanced in DKD, which mediated the communication between immune-inflammatory cells and innate cells. Conclusion: Our study explored the pathogenesis of renal injury promoted by immunoinflammatory in DKD. VISTANT, SPP1, and IGF signaling pathways and SPP1-CD44, NRG1-ERBB4, NAMPT-INSR, and Igf1- Igf1r receptor ligand pairs might occupy essential place in the occurrence and progress of DKD.

Therapeutic effects and mechanism of human amnion-derived mesenchymal stem cells on hypercoagulability in a uremic calciphylaxis patient.

Calciphylaxis is a rare cutaneous vascular disease that manifests with intolerable pains, non-healing skin wounds, histologically characterized by calcification, fibrointimal hyperplasia, and microvessel thrombosis. Currently, there are no standardized guidelines for this disease. Recent studies have recognized a high prevalence of thrombophilias and hypercoagulable conditions in calciphylaxis patients. Here, we report a case of uremic calciphylaxis patient whom was refractory to conventional treatments and then received a salvage strategy with intravenous and local hAMSC application. In order to investigate the therapeutic mechanism of hAMSCs from the novel perspective of hypercoagulability, coagulation-related indicators, wound status, quality of life and skin biopsy were followed up. Polymerase chain reaction (PCR) was performed to determine the distribution of hAMSCs in multiple tissues including lung, kidney and muscle after infusion of hAMSCs for 24 h, 1 week and 1 month in mice aiming to investigate whether hAMSCs retain locally active roles after intravenous administration. Improvement of hypercoagulable condition involving correction of platelet, D-dimer and plasminogen levels, skin regeneration and pain alleviation were revealed after hAMSC administration over one-year period. Skin biopsy pathology suggested regenerative tissues after 1 month hAMSC application and full epidermal regeneration after 20 months hAMSC treatment. PCR analysis indicated that hAMSCs were homing in lung, kidney and muscle tissues of mice even until tail vein injection of hAMSCs for 1 month. We propose that hypercoagulability is a promising therapeutic target of calciphylaxis patients, which can be effectively improved by hAMSC treatment.

Serum 25-hydroxyvitamin D as a predictive biomarker of clinical outcomes in patients with primary membranous nephropathy.

Background: Primary membranous nephropathy (PMN) is an immune-related disease with increased morbidity and the most common cause of adult nephrotic syndrome (NS). The serum 25-hydroxyvitamin D [25(OH)D)], a biomarker of vitamin D (VD) status, tends to decline in patients with kidney disease. However, the relationship between 25(OH)D and PMN is still unclear. Therefore, this study aims to clarify the association between 25(OH)D and disease severity and therapy response of PMN. Methods: A total of 490 participants diagnosed with PMN by biopsy from January 2017 to April 2022 were recruited at the First Affiliated Hospital of Nanjing Medical University. The correlations between baseline 25(OH)D and manifestations of nephrotic syndrome (NS) or seropositivity of anti-PLA2R Ab were confirmed by univariate and multivariate logistic analyses. Spearman's correlations were used to examine the associations between baseline 25(OH)D and other clinical parameters. In the follow-up cohort, Kaplan-Meier analysis was used to assess remission outcomes among groups with low, medium, and high levels of 25(OH)D. Furthermore, the independent risk factors for non-remission (NR) were explored by COX regression analysis. Results: At baseline, 25(OH)D was negatively related to 24-h urinary protein and serum anti-PLA2R Ab. The lower level of baseline 25(OH)D was associated with an increased risk for the incidence of NS in PMN (model 2, OR 6.8, 95% CI 4.4, 10.7, P < 0.001) and seropositivity of anti-PLA2R Ab (model 2, OR 2.4, 95% CI 1.6, 3.7, P < 0.001). Furthermore, the lower level of 25(OH)D during follow-up was demonstrated as an independent risk factor for NR even after adjusting age, gender, MBP, 24 h UP, serum anti-PLA2R Ab, serum albumin, and serum C3 [25(OH)D (39.2-62.3 nmol/L): HR 4.90, 95% CI 1.02, 23.53 P = 0.047; 25(OH)D < 39.2 nmol/L: HR 17.52, 95% CI 4.04, 76.03 P < 0.001); vs. 25(OH)D ≥ 62.3 nmol/L]. The Kaplan-Meier survival analysis also demonstrated that the higher level of follow-up 25(OH)D had a higher possibility of remission than the lower one (log-rank test, P < 0.001). Conclusion: Baseline 25(OH)D was significantly correlated with nephrotic proteinuria and seropositivity of anti-PLA2R Ab in PMN. As an independent risk factor for NR, a low level of 25(OH)D during follow-up might serve as a prognostic tool for sensitively identifying cases with a high probability of poor treatment response.

Triglyceride-glucose index is associated with the risk of chronic kidney disease progression in type 2 diabetes.

OBJECTIVE: The study aimed to investigate the association of TyG index with chronic kidney disease (CKD) progression in type 2 diabetes mellitus (T2DM). METHODS: A total of 179 T2DM patients with CKD were retrospectively included. CKD progression was defined as a doubling of baseline serum creatinine or onset of end-stage kidney disease (ESKD). Internal validation was performed by the Kidney Failure Risk Equation (KFRE) model and Net reclassification improvement (NRI). RESULTS: The optimal cut-off value of the TyG index was 9.17. The cumulative incidence of kidney outcomes was significantly higher in the high-TyG group (v.s low-TyG group, P = 0.019). In addition, the high-TyG index was associated with a greater risk of CKD progression (HR 1.794, 95% CI 1.026-3.137, P = 0.040). And reclassification analyses confirmed the final adjusted model improved NRI (61.90% v.s model 2, 43.80% v.s model 1). The further RCS curves presented an inverted S-shaped relationship between the TyG index and the risk of CKD progression. Internal validation verified that a higher TyG index was associated with 2.10-fold increased odds of 2-year ESKD risk >10% (95% CI 1.82-8.21). Moreover, subgroup analysis suggested that the association was more pronounced in those at relatively early CKD stages (higher than stage 2) and with no medication history of oral hypoglycemic agents. CONCLUSION: An elevated TyG index was associated with a higher risk of CKD progression in T2DM patients. Our findings suggested that timely targeting insulin sensitivity at the early stages of T2DM might be associated with declined future risk of CKD development.

Mitochondrial dynamics in vascular remodeling and target-organ damage.

Vascular remodeling is the pathological basis for the development of many cardiovascular diseases. The mechanisms underlying endothelial cell dysfunction, smooth muscle cell phenotypic switching, fibroblast activation, and inflammatory macrophage differentiation during vascular remodeling remain elusive. Mitochondria are highly dynamic organelles. Recent studies showed that mitochondrial fusion and fission play crucial roles in vascular remodeling and that the delicate balance of fusion-fission may be more important than individual processes. In addition, vascular remodeling may also lead to target-organ damage by interfering with the blood supply to major body organs such as the heart, brain, and kidney. The protective effect of mitochondrial dynamics modulators on target-organs has been demonstrated in numerous studies, but whether they can be used for the treatment of related cardiovascular diseases needs to be verified in future clinical studies. Herein, we summarize recent advances regarding mitochondrial dynamics in multiple cells involved in vascular remodeling and associated target-organ damage.

The thickness of glomerular basement membrane predicts complete remission in primary membranous nephropathy.

Objective: Glomerular basement membrane (GBM) thickening is a typical and essential histopathological characteristic for the diagnosis of primary membranous nephropathy (PMN). The present study aimed to explore the relationship between GBM thickness and treatment response in PMN patients.Methods: A total of 128 patients with nephrotic syndrome concurrent with PMN were studied. The highest GBM thickness was measured from at least five glomerular capillary loops using an electron microscope, and the mean value was obtained. Patients were categorized into three groups according to the tertiles of GBM thickness as follows: Group 1 (GBM thickness ≤ 1100 nm, n = 48), Group 2 (1100 nm < GBM thickness ≤ 1300 nm, n = 40), Group 3 (GBM thickness >1300 nm, n = 40). Clinicopathological features and treatment response were compared among the three groups. The associations of GBM thickness with complete remission (CR) were assessed by Cox proportional hazard analyses and a cubic spline curve.Results: During a median follow-up period of 25.80 months, 69 (53.9%) patients achieved CR. Kaplan-Meier analysis showed that the non-CR probability was significantly higher in the highest tertile of GBM thickness (p˂0.001). Univariate Cox proportional hazard analysis indicated that GBM thickness was associated with CR (HR per SD 0.617, 95% CI [0.471-0.809], p˂0.001). After adjusting for age, duration of PMN, estimated glomerular filtration rate (eGFR), urinary protein excretion, grade of C3 deposition, and titer of serum anti-phospholipase A2 receptor (PLA2R) antibody, GBM thickness remained an independent predictor of CR (HR per SD 0.580, 95% CI [0.436-0.772], p˂0.001). Further multivariable-adjusted restricted cubic spline analysis confirmed a significant reverse linear association between GBM thickness and CR (p for nonlinear = 0.1261).Conclusions: GBM thickness is an independent risk factor of CR. PMN patients with an increased level of GBM thickening at diagnosis have a lower probability of achieving CR.

Efficacy and safety of rituximab for primary nephrotic syndrome with acute kidney injury: A two-center prospective cohort study.

The purpose of this study was to investigate the efficacy and safety of a low-dose Rituximab (RTX) regimen driven by peripheral blood B lymphocyte count in the treatment of adult patients with nephrotic syndrome (NS) complicated with acute kidney disease (AKI). We conducted a prospective single-arm study to evaluate the effect of B cells-driven RTX regimen. Patients with NS (MCD, FSGS, MN, IgAN) complicated with AKI fulfilling the inclusion criteria were eligible for this study. Patients were followed up at intervals of 2 months. Student's t-test and Chi-squared test were used to analyze normally distributed continuous variables and non-normally distributed continuous variables, respectively. From August 2018 to January 2022, 23 patients met the inclusion criteria and agreed to participate in the study. 3, 9, and 11 patients were AKI stage 1, 2, and 3, respectively. From baseline to the latest follow-up, 20 patients had complete and partial recovery of renal function. Accompanied by depletion of B cells, significant reduction of urinary protein excretion, serum total cholesterol, and the number of relapses were observed during the 12 months after the first RTX infusion as compared with during the 12 months before RTX injection. The number of patients who maintained steroids and immunosuppressive medications also remarkably decreased. This study indicates that the targets-driven treatment of low-dose RTX can achieve a high remission rate and alleviate the loss of kidney function in treating NS with AKI. The long-term efficacy, side effects, and therapeutic economics of RTX are reasonable.

The association of RNA-binding protein Human antigen R with kidney clinicopathologic features and renal outcomes in patients with diabetic nephropathy.

AIMS: RNA-binding protein Human antigen R (HuR) is closely related to diabetic nephropathy (DN) pathogenesis. However, the capacity of histological HuR level as a biomarker for DN progression remains unclear. METHODS: A total of 147 patients with type 2 diabetes mellitus who had biopsy-proven DN were enrolled. Renal outcomes were defined by doubling serum creatinine level or progression to end-stage renal disease (ESRD). A nomogram was built to predict renal outcomes based on Cox proportional hazards regression. RESULTS: The median follow-up period was 31 months, during which 71 (48.30 %) patients confronted DN progression. Pearson's correlation indicated that histological HuR increased along with DN pathological class rising (r = 0.776, p < 0.001). Notably, multivariate Cox regression analysis showed that elevated HuR was associated with a greater risk of DN progression (HR 2.431, 95 %CI: 1.275-4.634, p = 0.007) beyond 6 months after renal biopsy. Patients in the higher HuR expression group had lower cumulative renal survival rates beyond the first 6 months. Simultaneously, a well-performed nomogram including HuR classification, was developed to predict the individual progression risk (C-index 0.828). CONCLUSIONS: Our findings demonstrated that the histologic HuR expression was an independent risk factor for kidney progression beyond 6 months after renal biopsy in DN.

Clinicopathological characteristics and outcome predictors of anti-glomerular basement membrane glomerulonephritis.

OBJECTIVE: To explore the clinicopathological features of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (anti-GBM-GN) and the prognostic values of clinical and laboratory indicators at diagnosis on renal and patient survival. METHODS: A total of 76 patients (34 males and 42 females) with anti-GBM-GN who were hospitalized in the First Affiliated Hospital of Nanjing Medical University between January 2010 and June 2021 were included in this study. The baseline clinical features, histopathological data from renal biopsies, and predictors of renal and patient survival were retrospectively analyzed. RESULTS: Among the 76 patients, the median serum creatinine at diagnosis was 618.0 (350.98, 888.25) µmol/L and the median estimated glomerular filtration rate (eGFR) was 6.62 (4.39, 14.41) mL/min. Of these 76 patients, 55 (72.4%) received initial kidney replacement therapy (KRT) and 39 (51.3%) received plasma exchange or double-filtered plasmapheresis (DFPP). During a median follow-up duration of 28.5 (6.0, 71.8) months, 53 (69.7%) patients progressed to kidney failure with replacement therapy (KFRT) and received maintenance dialysis. Initial KRT (HR = 3.48, 95% CI = 1.22-9.97, p = 0.020) was a significant risk factor for renal survival. During the follow-up, 49 (64.5%) of 76 patients survived. Age (≥60 years, HR = 4.13, 95% CI = 1.65-10.38, p = 0.003) and initial KRT (HR = 2.87, 95% CI = 1.01-8.14, p = 0.047) were predictive of patient survival. CONCLUSIONS: Among patients with anti-GBM-GN, initial KRT at presentation was predictive of KFRT while older age and initial KRT were associated with higher all-cause mortality.

Clinicopathological features and individualized treatment of kidney involvement in B-cell lymphoproliferative disorder.

Background: Due to the various clinical and pathological manifestations of kidney involvement in lymphoproliferative disorder (LPD), the whole spectrum of kidney disease in LPD is still unclear, and data on kidney prognosis is scarce. Methods: We retrospectively reviewed the renal pathology profiles from January 2010 to December 2021, and 28 patients with B-cell LPD combined with intact renal biopsy data were included. Results: There were 20 men and eight women aging 41 to 79 years at the time of renal biopsy (median age 62 years). According to hematological diagnosis, patients were classified into four groups: chronic lymphocytic leukemia (CLL) (group1, n=7), Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) (group 2, n=8; WM, n=6; LPL, n=2), Other non-Hodgkin's lymphomas (NHL) (group3, n=7; diffuse large B-cell lymphoma (DLBCL), n=2; mucosa-associated lymphoid tissue (MALT) lymphoma, n=4; Low grade B-cell lymphoma, n=1), and monoclonal gammopathy of undetermined significance/monoclonal gammopathy of renal significance (MGUS/MGRS) (group 4, n=6). Median serum creatinine (Scr) level was 129 (range,59-956) umol/L. Eight patients (29%) were presented with acute kidney injury (AKI), and five patients (18%) required hemodialysis upon admission. Twenty-three patients (82%) presented with proteinuria (median protein excretion, 2.14 g/d), 11(39%) of whom had the nephrotic syndrome. Interstitial malignant infiltration was the most frequent renal lesion (n=6). Eight patients underwent immunohistochemistry of renal tissues, of which three patients (CLL, n=1; LPL, n=1; WM, n=1) had confirmed lymphoma infiltrates, and the infiltrating cells in the remaining five patients (CLL, n=1; MALT lymphoma, n=2; MGUS, n=2) were considered unrelated to lymphoma. The most common glomerular diseases were renal amyloidosis (n=4) and membranous nephropathy (n=4). Only 20 patients were treated, 13 of whom were treated with rituximab separately or in combination. The median follow-up time was 11 months. Of these, six had achieved hematological response, complete response in five cases. Eight had achieved renal response. At the end-of-study visit, four patients died and two progressed to end stage kidney disease (ESKD). Conclusion: In conclusion, the clinicopathological spectrum of renal involvement in BLPD is diverse. Renal biopsy and immunohistochemistry are required for early diagnosis and prognostic assessment.

Association of Serum 25 (OH) Vitamin D With Chronic Kidney Disease Progression in Type 2 Diabetes.

Objectives: Growing evidence demonstrated that vitamin D levels had been linked to type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in light of various extraskeletal effects. Therefore, the present study aimed to evaluate the association of 25-hydroxyvitamin D [25(OH)D] level with the clinicopathological features and CKD progression in T2DM. Methods: A total of 182 patients with T2DM with CKD stages 1 through 4 (G1-G4) were retrospectively included. Identification of the serum 25(OH)D level associated with CKD progression was executed by Kaplan-Meier survival analysis and Cox proportional hazards models. We further performed sensitivity analyses with a time-weighted average (TWA) of the serum 25(OH)D level in 75 participants to reinforce the findings. Results: The median serum 25(OH)D level was 26 (IQR, 14; 39) nmol/L in the study participants. Median follow-up time was 42 months, during which 70 (38%) patients confronted CKD progression. Cumulative kidney outcomes were significantly higher in the lowest tertile of the serum 25(OH)D level in Kaplan-Meier analyses (P < 0.001). Consistently, the analyses of Cox proportional hazards regression models indicated a significantly greater risk for CKD progression in the lowest tertile of the serum 25(OH)D level compared with the highest tertile of the serum 25(OH)D level (P = 0.03). These relationships remained robust with further sensitivity analysis of data with TWA of the serum 25(OH)D level, showing an independent association between lower TWA of the serum 25(OH)D level and an unfavorable renal outcome in patients with T2DM with CKD. Conclusions: Our findings demonstrated that patients with T2DM with a decreased 25(OH)D level had deteriorated renal function. Both lower levels of baseline and TWA of serum 25(OH)D were associated with an increased risk of CKD progression in patients with T2DM, which suggested that the long-term maintenance of optimal vitamin D levels from early in life might be associated with reduced future risk of CKD development in T2DM.

Podocyte Injury in Diabetic Kidney Disease: A Focus on Mitochondrial Dysfunction.

Podocytes are a crucial cellular component in maintaining the glomerular filtration barrier, and their injury is the major determinant in the development of albuminuria and diabetic kidney disease (DKD). Podocytes are rich in mitochondria and heavily dependent on them for energy to maintain normal functions. Emerging evidence suggests that mitochondrial dysfunction is a key driver in the pathogenesis of podocyte injury in DKD. Impairment of mitochondrial function results in an energy crisis, oxidative stress, inflammation, and cell death. In this review, we summarize the recent advances in the molecular mechanisms that cause mitochondrial damage and illustrate the impact of mitochondrial injury on podocytes. The related mitochondrial pathways involved in podocyte injury in DKD include mitochondrial dynamics and mitophagy, mitochondrial biogenesis, mitochondrial oxidative phosphorylation and oxidative stress, and mitochondrial protein quality control. Furthermore, we discuss the role of mitochondria-associated membranes (MAMs) formation, which is intimately linked with mitochondrial function in podocytes. Finally, we examine the experimental evidence exploring the targeting of podocyte mitochondrial function for treating DKD and conclude with a discussion of potential directions for future research in the field of mitochondrial dysfunction in podocytes in DKD.

Impact of Overhydration on Left Ventricular Hypertrophy in Patients With Chronic Kidney Disease.

Objective: Volume overload is a frequent feature related to left ventricular hypertrophy (LVH) in dialysis patients, but its influence on patients with chronic kidney disease (CKD) not on dialysis has not been accurately uncovered. This article was to examine the relationship between overhydration (OH) and LVH in patients with CKD not yet on dialysis. Methods: A total of 302 patients with CKD stages 1-4 were included. Participants were divided into different subgroups according to occurring LVH or not, and OH tertiles. Clinical and laboratory parameters were compared among groups. Spearman correlation analyses were adopted to explore the relationships of echocardiographic findings with the clinical and laboratory characteristics. Binary logistic regression models were performed to estimate the odds ratios (ORs) for the associations between OH and LVH. Restricted cubic splines were implemented to assess the possible non-linear relationship between OH and LVH. LVH was defined as left ventricular mass index (LVMI) >115 g/m2 in men and >95 g/m2 in women. Results: Of the enrolled patients with CKD, the mean age was 45.03 ± 15.14 years old, 165 (54.6%) cases were men, and 65 (21.5%) cases had LVH. Spearman correlation analyses revealed that OH was positively correlated with LVMI (r = 0.263, P < 0.001). After adjustment for age, gender, diabetes, body mass index (BMI), systolic blood pressure (SBP), hemoglobin, serum albumin, estimated glomerular filtration rate (eGFR), and logarithmic transformation of urinary sodium and urinary protein, multivariate logistic regression analyses demonstrated that both the middle and highest tertile of OH was associated with increased odds of LVH [OR: 3.082 (1.170-8.114), P = 0.023; OR: 4.481 (1.332-15.078), P = 0.015, respectively], in comparison to the lowest tierce. Restricted cubic spline analyses were employed to investigate the relationship between OH and LVH, which unfolded a significant non-linear association (P for non-linear = 0.0363). Furthermore, patients were divided into two groups according to CKD stages. The multivariate logistic regression analyses uncovered that increased odds of LVH were observed in the middle and the highest tertile of OH [OR: 3.908 (0.975-15.670), P = 0.054; OR: 6.347 (1.257-32.054), P = 0.025, respectively] in patients with stages 1-2. Conclusion: These findings suggest that a higher level of OH was associated with a higher occurrence of LVH in patients with CKD not on dialysis, especially in patients with CKD stages 1-2.