Complement C3a/C3aR and C5a/C5aR deposits accelerate the progression of advanced IgA nephropathy to end-stage renal disease.

IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732-0.935; P = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079-9.363; P = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a (P = 0.010), C3aR (P = 0.005), C5a (P = 0.015), and C5aR (P < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.

Identification and validation of biomarkers in membranous nephropathy and pan-cancer analysis.

Background: Membranous nephropathy (MN) is an autoimmune disease and represents the most prevalent type of renal pathology in adult patients afflicted with nephrotic syndrome. Despite substantial evidence suggesting a possible link between MN and cancer, the precise underlying mechanisms remain elusive. Methods: In this study, we acquired and integrated two MN datasets (comprising a single-cell dataset and a bulk RNA-seq dataset) from the Gene Expression Omnibus database for differential expression gene (DEG) analysis, hub genes were obtained by LASSO and random forest algorithms, the diagnostic ability of hub genes was assessed using ROC curves, and the degree of immune cell infiltration was evaluated using the ssGSEA function. Concurrently, we gathered pan-cancer-related genes from the TCGA and GTEx databases, to analyze the expression, mutation status, drug sensitivity and prognosis of hub genes in pan-cancer. Results: We conducted intersections between the set of 318 senescence-related genes and the 366 DEGs, resulting in the identification of 13 senescence-related DEGs. Afterwards, we meticulously analyzed these genes using the LASSO and random forest algorithms, which ultimately led to the discovery of six hub genes through intersection (PIK3R1, CCND1, TERF2IP, SLC25A4, CAPN2, and TXN). ROC curves suggest that these hub genes have good recognition of MN. After performing correlation analysis, examining immune infiltration, and conducting a comprehensive pan-cancer investigation, we validated these six hub genes through immunohistochemical analysis using human renal biopsy tissues. The pan-cancer analysis notably accentuates the robust association between these hub genes and the prognoses of individuals afflicted by diverse cancer types, further underscoring the importance of mutations within these hub genes across various cancers. Conclusion: This evidence indicates that these genes could potentially play a pivotal role as a critical link connecting MN and cancer. As a result, they may hold promise as valuable targets for intervention in cases of both MN and cancer.

Unraveling the interplay of ferroptosis and immune dysregulation in diabetic kidney disease: a comprehensive molecular analysis.

BACKGROUND: Diabetic kidney disease (DKD) is a primary microvascular complication of diabetes with limited therapeutic effects. Delving into the pathogenic mechanisms of DKD and identifying new therapeutic targets is crucial. Emerging studies reveal the implication of ferroptosis and immune dysregulation in the pathogenesis of DKD, however, the precise relationship between them remains not fully elucidated. Investigating their interplay is pivotal to unraveling the pathogenesis of diabetic kidney disease, offering insights crucial for targeted interventions and improved patient outcomes. METHODS: Integrated analysis, Consensus clustering, Machine learning including Generalized Linear Models (GLM), RandomForest (RF), Support Vector Machine (SVM) and Extreme Gradient Boosting (xGB), Artificial neural network (ANN) methods of DKD glomerular mRNA sequencing were performed to screen DKD-related ferroptosis genes.CIBERSORT, ESTIMATE and ssGSEA algorithm were used to assess the infiltration of immune cells between DKD and control groups and in two distinct ferroptosis phenotypes. The ferroptosis hub genes were verified in patients with DKD and in the db/db spontaneous type 2 diabetes mouse model via immunohistochemical and Western blotting analyses in mouse podocyte MPC5 and mesangial SV40-MES-13 cells under high-glucose (HG) conditions. RESULTS: We obtained 16 differentially expressed ferroptosis related genes and patients with DKD were clustered into two subgroups by consensus clustering. Five ferroptosis genes (DUSP1,ZFP36,PDK4,CD44 and RGS4) were identified to construct a diagnostic model with a good diagnosis performance in external validation. Analysis of immune infiltration revealed immune heterogeneity between DKD patients and controls.Moreover, a notable differentiation in immune landscape, comprised of Immune cells, ESTIMATE Score, Immune Score and Stromal Score was observed between two FRG clusters. GSVA analysis indicated that autophagy, apoptosis and complement activation can participate in the regulation of ferroptosis phenotypes. Experiment results showed that ZFP36 was significantly overexpressed in both tissue and cells while CD44 was on the contrary.Meanwhile,spearman analysis showed both ZFP36 and CD44 has a strong correlation with different immune cells,especially macrophage. CONCLUSION: The regulation of the immune landscape in DKD is significantly influenced by the focal point on ferroptosis. Newly identified ferroptosis markers, CD44 and ZFP36, are poised to play essential roles through their interactions with macrophages, adding substantial value to this regulatory landscape.

Unraveling DDIT4 in the VDR-mTOR pathway: a novel target for drug discovery in diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) necessitates innovative therapeutic strategies. This study delves into the role of DNA damage-inducing transcription factor 4 (DDIT4) within the VDR-mTOR pathway, aiming to identify a novel target for DKD drug discovery. Methods: Transcriptome data from the Gene Expression Omnibus Database were analyzed to assess the expression of mTOR and VDR expression in human renal tissues. Clinical samples from DKD patients and minimal change disease (MCD) controls were examined, and a DKD animal model using 20-week-old db/db mice was established. DDIT4 plasmid transfection was employed to modulate the VDR-mTOR pathway, with its components evaluated using immunohistochemistry, real-time quantitative PCR (qRT-PCR), Western blotting, and enzyme-linked immunosorbent assay (ELISA). Results: Changes in the expression of the VDR-mTOR pathway were observed in both DKD patients and the animal model. Overexpression of DDIT4 increased VDR expression and decreased levels of mTOR, p70s6k, and 4E-BP1. Furthermore, DDIT4 treatment regulated autophagy by upregulating LC3I expression and downregulating LC3II expression. Notably, DDIT4 alleviated oxidative stress by reducing the levels of lipid peroxidation product MDA, while simultaneously increasing the levels of superoxide dismutase (SOD) and glutathione (GSH), underscoring the role of DDIT4 in the pathological process of DKD and its potential as a therapeutic target. Conclusion: Unraveling DDIT4's involvement in the VDR-mTOR pathway provides insights for innovative DKD drug discovery, emphasizing its potential as a therapeutic target for future interventions.

Prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy: a retrospective study of 420 biopsy-proven cases.

BACKGROUND: This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN). METHODS: Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed. RESULTS: Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (p < .05). Serum anti-PLA2R antibody testing on 280 HBV-MN patients revealed a total positive rate of 44.6%, with the seronegative group showing a significantly higher rate (62.6%) compared to the seropositive group (32.1%) (p < .01). The anti-PLA2R antibody-positive group displayed higher levels of urine protein (p < .05), serum cholesterol (p < .01), and IgG4 subtypes (p < .05) compared to the negative group. Additionally, the positive group had significantly lower levels of serum albumin and IgG than the negative group (p < .01). CONCLUSIONS: This comprehensive study reveals a significantly higher prevalence of seronegative HBV-MN than previously thought. The blood creatinine values and incidence of liver function abnormalities was higher in the serology-positive group than in the serology-negative group. Notably, the seronegative group displayed a higher positive rate of anti-PLA2R antibodies compared to the seropositive group, indicating distinctive clinical and immunopathologic features.

Membranous nephropathy with systemic light-chain amyloidosis of remission after rituximab therapy: A case report.

BACKGROUND: About 70%-80% of patients with primary membranous nephropathy (MN) have phospholipase A2 receptor (PLA2R) in renal tissue. Systemic light-chain (AL) amyloidosis is the most common type of amyloidosis. MN complicated with amyloidosis is rare. CASE SUMMARY: A 48-year-old Chinese male presented with nephrotic syndrome, positive serum PLA2R antibody, and positive serum and urine IgG-lambda type M-protein, with a normal ratio of serum-free light-chain level. The patient was diagnosed with MN accompanied by AL amyloidosis. He was treated with rituximab with glucocorticoids and CyBorD regimen of chemotherapy. After 21 mo of follow-up, the patient achieved complete remission regarding nephrotic syndrome without adverse effects of chemotherapy. CONCLUSION: We report a case of PLA2R-related MN complicated with primary AL amyloidosis only with renal involvement and successfully treated with rituximab, glucocorticoids and chemotherapy.

Clinical characteristics of membranous nephropathy with spontaneous remission: An analysis of 24 patients / Características clínicas de la nefropatía membranosa con remisión espontánea: análisis de 24 pacientes

Purpose To investigate the prognosis of patients with spontaneous remission (SR) of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN).Patients and methods Patients diagnosed with MN were recruited after examining their renal biopsy in the Renal Department of China-Japan Friendship Hospital between January 2015 and September 2021. Among them, 24 patients with SR were included in this study and follow-up. Results Twenty-four patients diagnosed with SR of PLA2R-associated MN were recruited; 11 were male, and 13 were female, with a mean age of 49.5±14.5 years (range, 30–77 years). The initial 24-hour urinary total protein and serum albumin levels were 0.29±0.14g/d and 37.5±4.4g/L, respectively, and the initial serum creatinine was 65.0±15.8μmol/L. During the follow-up of 33.9±19.1 months (range, 6–73 months), 22 (91.7%) patients maintained remission; however, one patient had impaired renal function due to acute coronary syndrome and coronary angiography findings, and one patient experienced a repeated relapse caused by respiratory tract infection, at 50 and 70 months. A systematic review of the relevant literature was conducted, and records of patients with SR of PLA2R-associated MN were retrieved from 16 case reports or case series with a total of 97 cases. ConclusionsMost patients with SR of MN had a promising long-term prognosis, with only a few cases of relapse. (AU)

Objetivo Investigar el pronóstico de los pacientes con remisión espontánea en la nefropatía membranosa (MN, por sus siglas en inglés) asociada al receptor fosfolipasa A2 (PLA2R). Pacientes y métodos Pacientes con MN diagnosticados por biopsia renal en el Departamento Renal del China-Japan Friendship Hospital entre enero de 2015 y septiembre de 2021. Entre ellos, 24 pacientes con remisión espontánea fueron reclutados y seguidos. Resultados Se reclutaron 24 pacientes con MN en remisión espontánea asociada a PLA2R; 11 varones y 13 mujeres, con una edad media de 49,5±14,5 años (rango: 30-77 años) en el momento del diagnóstico. La proteína total y la albúmina sérica en orina de 24h iniciales fueron de 0,29±0,14 y 37,5±4,4g/l, respectivamente; la creatinina sérica inicial fue de 65,0±15,8μmol/l. Durante el seguimiento de 33,9±19,1 (rango: 6-73) meses, 22 pacientes (91,7%) mantienen la remisión. Un paciente presentó insuficiencia renal por síndrome coronario agudo y angiografía coronaria. Otro paciente tuvo una recaída causada por una infección del tracto respiratorio 2 veces, a los 50 y 70 meses. Se realizó una revisión sistemática de la literatura. Los pacientes con MN asociada con PLA2R en remisión espontánea se recuperaron en 16 informes o series de casos, de 97 casos en total. ConclusionesLa mayoría de los pacientes con MN en remisión espontánea tuvieron un pronóstico prometedor a largo plazo, mientras que solo unos pocos casos tuvieron recaída. (AU)

Efficacy and safety of low-dose rituximab as induction therapy for antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: a Chinese case series.

BACKGROUND: Rituximab (RTX) is a standard therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the most frequently used dose may lead to severe adverse effects (SAEs). We explored the efficacy and safety of low-dose RTX in Chinese patients with AAV. METHODS: A total of 22 Chinese patients diagnosed with AAV with renal involvement, including 8 treated with low-dose RTX (400 mg of RTX total over 4 weeks) and 14 treated with cyclophosphamide (CYC), were evaluated. The baseline clinical and pathological data and laboratory parameters during follow-up at months 1, 3, 6, and 12 were collected retrospectively. RESULTS: The baseline data showed no significant differences between the two groups. The median peripheral CD19+ cell counts in the RTX group decreased from 315.0/µL to 1.5/µL at 2 weeks, and to 2.5/µL at 1 month after the first dose. The median SCr level decreased from 267.8 µmol/L before treatment to 151.45 µmol/L at 1 month, 132.75 µmol/L at 3 months, 123.2 µmol/L at 6 months, and 151.9 µmol/L at 12 months in RTX-treated patients. The improvements in renal function, proteinuria, and ANCA titre were not significantly different between the two groups. The SAE rate was significantly lower in the RTX group (one SAE of pneumonia) compared with the CYC group. CONCLUSIONS: This is the first report that low-dose RTX could be effective for the treatment of Chinese patients with AAV with renal involvement.

Utility of shear wave-based ultrasound elastography in chronic kidney disease and related pathological quantitative analysis.

OBJECTIVES: The purpose of this study was to investigate the effects of tissue fibrosis and microvessel density on shear wave-based ultrasound elastography (SWUE) of chronic kidney disease (CKD). In addition, we were looking to see whether SWUE could predict stage of CKD, correlating with the histology on kidney biopsy. METHODS: Renal tissue sections from 54 patients diagnosed with suspected CKD were subjected to immunohistochemistry (CD31 and CD34), and the degree of tissue fibrosis was assessed using Masson staining. Before renal puncture, both kidneys were examined using SWUE. Comparative analysis was used to assess the correlation between SWUE and microvessel density, and between SWUE and the degree of fibrosis. RESULTS: Fibrosis area according to Masson staining (p < 0.05) and integrated optical density (IOD) (p < 0.05) were positively correlated with CKD stage. The percentage of positive area (PPA) and IOD for CD31 and CD34 were not correlated with CKD stage (p > 0.05). When stage 1 CKD was removed, PPA and IOD for CD34 were negatively correlated with CKD stage (p < 0.05). Masson staining fibrosis area and IOD were not correlated with SWUE (p > 0.05), PPA and IOD for CD31 and CD34 were not correlated with SWUE (p > 0.05) and, finally, no correlation between SWUE and CKD stage was found (p > 0.05). CONCLUSION: The diagnostic value of SWUE for CKD staging was very low. The utility of SWUE in CKD was affected by many factors and its diagnostic value was limited. KEY POINTS: • There was no correlation between SWUE and the degree of fibrosis, or between SWUE and microvessel density among patients with CKD. • There was no correlation between SWUE and CKD stage and the diagnostic value of SWUE for CKD staging was very low. • The utility of SWUE in CKD is affected by many factors and its value was limited.

Clinical characteristics of membranous nephropathy with spontaneous remission: An analysis of 24 patients.

PURPOSE: To investigate the prognosis of patients with spontaneous remission (SR) of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN). PATIENTS AND METHODS: Patients diagnosed with MN were recruited after examining their renal biopsy in the Renal Department of China-Japan Friendship Hospital between January 2015 and September 2021. Among them, 24 patients with SR were included in this study and follow-up. RESULTS: Twenty-four patients diagnosed with SR of PLA2R-associated MN were recruited; 11 were male, and 13 were female, with a mean age of 49.5±14.5 years (range, 30-77 years). The initial 24-hour urinary total protein and serum albumin levels were 0.29±0.14g/d and 37.5±4.4g/L, respectively, and the initial serum creatinine was 65.0±15.8µmol/L. During the follow-up of 33.9±19.1 months (range, 6-73 months), 22 (91.7%) patients maintained remission; however, one patient had impaired renal function due to acute coronary syndrome and coronary angiography findings, and one patient experienced a repeated relapse caused by respiratory tract infection, at 50 and 70 months. A systematic review of the relevant literature was conducted, and records of patients with SR of PLA2R-associated MN were retrieved from 16 case reports or case series with a total of 97 cases. CONCLUSIONS: Most patients with SR of MN had a promising long-term prognosis, with only a few cases of relapse.

Retroperitoneal laparoscopic renal biopsy: an 8 year experience at a single centre.

PURPOSE: To present our experience and outcome of consecutive laparoscopic renal biopsy (LRB) in a series of Chinese patients over an 8 year period. METHODS: Between January 1, 2013, and December 31, 2020, 104 patients (M/F 71/33, age 43.6 ± 16.0 years) were enrolled. All patients underwent LRB for various indications, e.g., dialysis dependence (33.7%), serum levels of creatinine ≥ 442 µmol/L (20.2%), morbid obesity (18.3%), uncontrolled severe hypertension (14.4%), aberrant renal anatomy (5.8%), solitary kidney (2.9%), deaf-mutes (2.9%), failed percutaneous biopsy (1.0%) and patient choice (1.0%). The kidney was approached via the laparoscopic retroperitoneal route using a three-port technique. Then, 16-gauge true-cut needle biopsy was performed and haemostasis was achieved by compression. Topical collagen mesh was used if necessary. RESULTS: Renal tissue was obtained in all cases. The operative time and amount of blood loss were significantly (P < 0.05) lower in 2017-2020 than 2013-2016 [42.6 ± 1.5 min and 9.6 ± 0.7 mL, respectively (n = 61) vs. 51.2 ± 1.3 min and 14.4 ± 0.9 mL, respectively (n = 43)], while the hospital stay was not significantly different between the two periods. The rate of tissue adequacy and median number of glomeruli were significantly higher in 2017-2020 than 2013-2016 [100% and 52 (IQR 24-94), respectively vs. 93% and 35 (IQR 6-98), respectively). Two postoperative complications occurred in the first 4 years: disseminated intravascular coagulation (DIC) during the operation and injury at the hilum of the kidney (n = 1 each). The renal pathological diagnoses were also complex: 70.2% of the cases were independent pathological types, including IgA nephropathy (IgAN) (13.5%), Henoch-Schönlein purpura nephritis (HSPN) (2.9%), focal segmental glomerulosclerosis (FSGS) (9.6%), membranous glomerulonephritis (MN) (1.9%), lupus nephritis (LN) (3.8%), crescentic glomerulonephritis (CreGN) (7.7%), diabetic nephropathy (DN) (10.6%), tubulointerstitial nephritis (TIN) (11.5%) and malignant hypertensive nephropathy (MHTN) (8.7%). However, the rates of combinations of two and three pathological types were 25.0% and 4.8%, respectively. CONCLUSION: Retroperitoneal LRB is a safe, reliable, minimally invasive alternative for patients in whom PRB in not feasible. As a helpful supplement to PRB, it may be necessary to use this technique more often in the future.

Lung cancer patients with nephropathy as the first manifestation: Literature review and clinical study report.

Background: To investigate the relationship between membranous nephropathy (MN) and lung cancer. Methods: To report patients with lung cancer detected by follow-up after the diagnosis of MN by renal biopsy in China-Japan Friendship Hospital from January 2010 to December 2019, and to study the prognosis of lung cancer-associated MN and have a review of the literature. Results: Lung cancer was detected in six patients followed for 1-27 months (median 8 months) after the diagnosis of MN: including four cases of lung adenocarcinoma, one case of carcinoma in situ, and one case of small cell lung cancer with multiple metastases. Five cases were in remission after surgical resection, and one case was remitted after chemotherapy. Six patients were negative for serum anti-PLA2R antibodies, and glomerular IgG subclass deposition detected by immunofluorescence was positive for IgG1 and IgG2. Glomerular PLA2R, THSD7A, and NELL-1 stainings were assessed in all six patients; one patient was positive for glomerular PLA2R staining, two patients were positive for glomerular THSD7A staining, and all patients were negative for NELL-1 staining. A literature review of the relationship between MN and lung cancer was performed: seven articles about cancer-associated MN were searched, reporting 32 cases of MN associated with lung cancer, among which 14 cases had nephropathy as the first manifestation and only five patients had remission of MN after treatment of lung cancer. Conclusions: A few lung cancer patients have nephropathy as the first clinical manifestation, and MN can also be remitted after treatment of lung cancer.

Complement Deposition Predicts Worsening Kidney Function and Underlines the Clinical Significance of the 2010 Renal Pathology Society Classification of Diabetic Nephropathy.

Objectives: Converging evidence points towards a role of the complement system in the pathogenesis of diabetic nephropathy (DN). The classification system of diabetic kidney lesions devised by the Renal Pathology Society (RPS) in 2010 are based on the pathogenic process of DN. Therefore, we investigated the correlation between glomerular C3 deposits and RPS DN classification and the combined deleterious effects thereof on kidney function. Methods: The study analyzed data from 217 diabetic patients who underwent renal biopsy between 2010 and 2021 and were found to have DN as the only glomerular disease. C3 deposition was considered positive if the glomerular C3 immunofluorescence intensity was at the trace or ≥1+ level. We divided DN into five glomerular lesion classes and separately evaluated the degree of interstitial and vascular involvement. The primary outcome was the composite of a ≥50% decline from the initial estimated glomerular filtration rate, end-stage renal disease, and death. Results: None of the patients were classified into class I, and few were classified into classes IIa (7.8%) and IV (9.2%). Most patients were classified as IIb (30.9%) and III (52.1%). C3 deposition was detected in 53.9% of patients. Multivariate logistic regression analysis showed that DN class was significantly correlated with C3 deposits [odds ratio, 1.59; 95% confidence interval (CI), 1.08-2.36; p = 0.02). During a median follow-up of 22 months, 123 (56.7%) patients reached the composite outcome. The endpoints occurred more frequently in patients with C3 deposition (69.2 vs. 42%) compared with those without C3 deposition. Patients with C3 deposition in either class IIb [hazards ratio (HR), 3.9 (95% CI, 1.14-13.17) vs. 2.46 (95% CI, 0.68-8.89)] or III [HR, 4.98 (95% CI, 1.53-16.23) vs. 2.63 (95% CI, 0.77-9.0)] had a higher risk of adverse kidney outcomes than those without C3 deposition. The prognostic accuracy of the combination of DN class and C3 deposits at 1 and 3 years was higher than that for DN class only. Conclusions: Complement deposition together with DN class predicts more rapid deterioration of kidney function in DN, which underlines the clinical significance of the DN phenotype according to the RPS classification.

Activation of Complement Pathways in Kidney Tissue May Mediate Tubulointerstitial Injury in Diabetic Nephropathy.

Introduction: Key genes involved in tubulointerstitial injury may influence the development and progression of diabetic nephropathy (DN). We investigated whether complement-related genes are linked to the mechanism underlying tubulointerstitial injury in DN. Methods: We analyzed the microarray data of 17 tubulointerstitial tissue samples from DN patients and 21 normal controls from the Gene Expression Omnibus. A gene co-expression network was constructed, and genes were divided into modules by weighted gene co-expression network analysis (WGCNA). We also investigated the association of C3 and C1q deposits in kidney tissues with a composite outcome of end-stage renal disease or a 50% reduction in the estimated glomerular filtration rate (eGFR) in DN patients. Finally, we performed immunohistochemical analyses of C3, C1q, C5b-9, mannose-binding lectin (MBL), and factor B in kidney tissues. Results: Nine co-expression modules were constructed using 12,075 genes from the 38 human tubulointerstitial tissue samples. Black module with more genes was positively correlated with tubulointerstitial injury in DN. C3, one of the top 10 genes in tubulointerstitial injury, was verified in an independent dataset; C3 was significantly overexpressed in tubulointerstitial tissue from patients with DN compared to the normal controls. The mRNA level of C3 in renal tubulointerstitium was negatively correlated with eGFR in DN patients (r = -0.75; p = 0.001). Analysis of the follow-up data of 54 DN patients demonstrated that codeposits of C3 and C1q in kidney tissues were independently associated with the renal outcome in DN (hazard ratio, 2.3, 95% confidence interval, 1.01-5.2, p < 0.05). Immunohistochemical analysis showed that patients with higher C1q, C3, C5b-9, MBL, or factor B expression in renal tubulointerstitium were more likely to progress to kidney failure. Conclusion: Local complement activation of the classical, lectin and alternative pathways appears linked to tubulointerstitial injury and disease progression in DN.

Anti-neutrophil cytoplasmic antibody seropositivity in young adults aged up to 35 years: kidney histopathological findings and patient outcomes.

OBJECTIVE: To investigate the clinical features, pathological renal findings, and outcomes in young adults with anti-neutrophil cytoplasmic antibody (ANCA) seropositivity. METHODS: Adults aged ≤35 years, with ANCA seropositivity, who underwent renal biopsy and received treatment comprising a combination of corticosteroids and cyclophosphamide between January 2004 and May 2018, were retrospectively enrolled. RESULTS: Thirteen patients with ANCA seropositivity were included, all of whom presented with kidney disease at diagnosis: 10 (76.9%) with ANCA-associated pauci-immune glomerulonephritis, one with ANCA-associated crescentic glomerulonephritis with immune complex deposition, one with immunoglobulin A nephropathy, and one with membranous nephropathy. The median serum creatinine level was 183.2 µmol/l (range, 55.0-1024.0 µmol/l). Respiratory symptoms (9/13 [69.2%]) and nonspecific gastrointestinal symptoms (5/13 [38.5%]) were the most common extrarenal manifestations. Remission was achieved in 10 (91%) of 11 ANCA-associated nephritis cases, and median interval from diagnosis to relapse was 30 months (range, 9-63 months). Cumulative relapse-free survival rates at 1 and 5 years were 100% and 88.9%, respectively. Overall, 1-year and 5-year renal survival rates were 80.8% and 58.9%, respectively. CONCLUSION: Renal histopathology varied in young adults with ANCA seropositivity. Although relapse rates in this young adult population were generally low, long-term renal survival rates remain unsatisfactory.

Activation of complement C1q and C3 in glomeruli might accelerate the progression of diabetic nephropathy: Evidence from transcriptomic data and renal histopathology.

AIMS/INTRODUCTION: It is not unclear whether the complement system is involved in the pathogenesis of diabetic nephropathy (DN). We explored the role of the complement system in glomeruli from patients with DN using integrated transcriptomic bioinformatics analysis and renal histopathology. MATERIALS AND METHODS: Four datasets (GSE30528, GSE104948, GSE96804 and GSE99339) from the Gene Expression Omnibus database were integrated. We used a protein-protein interaction network and the Molecular Complex Detection App to obtain hub genes. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out to identify significant pathways. We also investigated the associations of C1q and C3 deposition on renal histopathology with clinical data, pathological parameters and renal survival in DN patients. RESULTS: We identified 47 up- and 48 downregulated genes associated with DN. C3, C1QB and C1QA were found to be complement-related hub genes. The gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses identified complement activation and humoral immune response as the significant oncology terms, with C1QB and C3 positioned at the center of the pathway. Regarding renal histopathology, patients with both C1q and C3 deposition had more severe glomerular classes. Multivariate Cox proportional hazards regression showed that the deposition of glomerular C1q and C3 was an independent risk factor for kidney failure. Patients with high C1q, C3 or C4d expression in glomeruli were more likely to progress to kidney failure, whereas glomerular mannose-binding lectin was rare. CONCLUSIONS: Complement activation is involved in the development of DN, and activation of the classical complement pathway in glomeruli might accelerate disease progression.

IgA Nephropathy with Macroproteinuria and a GFR of 20-30 ml/min/1.73 m2 May Still Benefit from RAS Inhibition.

Introduction: There has been controversy about renin-angiotensin system (RAS) inhibition in IgAN patients with advanced (stage 4) chronic kidney disease (CKD). Therefore, we investigated the effect of RAS blockade in these patients. Methods: Renal specimens of 50 IgAN patients who underwent renal biopsy during stage 4 CKD between 2010 and 2020, were stained using immunohistochemistry to detect the expression of RAS receptors (AT1R, AT2R, MasR, and MrgD). The primary endpoint was a composite of end-stage renal disease (ESRD) and death. Main baseline information and the administration of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) were collected. Results: During a median follow-up time of 25.5 months, 21 (42.0%) patients reached ESRD and none died. Six patients had a baseline eGFR of 15-20 ml/min/1.73m2, and reached ESRD with a median renal survival time of 7.0 (range 6.0-23.0) months. Among patients with a baseline eGFR of 20-30 ml/min/1.73m2, the percentage of patients using ACEI/ARB in progressive group was much lower than that in stable group (33.3% vs. 62.1%, P = 0.045), together with a shorter renal survival time in progressive group (26.0 vs. 30.5 months, P = 0.033). Macroproteinuria (24 h - UP ≥ 2.5 g) was also associated with a shorter renal survival time, as well as a significant decline in eGFR of stable group (24.4 vs. 26.4 ml/min/1.73 m2, P = 0.026). Lower eGFR [hazards ratio (HR), 0.829, 95% confidence interval (CI), 0.724-0.950; P = 0.007] and use of ACEI/ARB (HR, 0.356, 95% CI, 0.133-0.953; P = 0.040) were predictive of time to ESRD in this stage. No differences were found in the expression of AT1R, AT2R, MasR, and MrgD of renal tissues at the time of biopsy between stable and progressive groups. Conclusion: Contingent on monitoring serum creatinine and potassium levels, IgAN with macroproteinuria and a GFR of 20-30 ml/min/1.73m2 may still benefits from intrarenal RAS inhibition.

Acute kidney injuries induced by thrombotic microangiopathy following severe hemorrhage in puerperants: a case series and literature review.

BACKGROUND: Acute kidney injury in puerperants is generally caused by acute tubular necrosis and occasionally by thrombotic microangiopathy (TMA) following post-partum hemorrhage. However, TMA leads to worse clinical outcomes and is rarely reported in the literature. Therefore, this study aimed to evaluate the pathological mechanism behind the development of TMA in puerperants to improve the diagnosis and treatment of this condition. METHODS: Three patients diagnosed with severe postpartum hemorrhage and TMA from 2014 to 2017 at a nephrology center were retrospectively investigated. RESULTS: All patients had severe hemorrhage during delivery with a mean blood loss, 4.0 L (range, 2.7-5.0 L). AKI developed rapidly in these patients and was treated with hemodialysis. Following treatment, the mean volume of packed red blood cells was 2.3 L (range, 1.2-3.6 L), and the mean volume of resuscitation fluid was 3.7 L (range, 3.5-4.0 L). All patients had renal biopsy specimens with typical TMA and ATN changes on light microscopy. Two patients required a hysterectomy while another two patients received respiratory support. Only one patient received plasma exchange. None of the patients had recovered normal kidney function by the final follow-up (26-61 months), with two patients having stage 3 chronic kidney disease, and one patient having an end-stage renal disease requiring maintenance hemodialysis. CONCLUSION: Severe postpartum hemorrhage could lead to TMA, in addition to the common finding of ATN. Renal histology revealed that poor renal outcomes could be attributed to TMA coexisting with ATN. The potential mechanism was ischemia-reperfusion, which was followed by endothelial cell injury and activation of the alternative complement pathway.

The relationship between neutrophil-lymphocyte ratio and early renal fibrosis and renal prognosis in patients with lupus nephritis.

OBJECTIVE: To explore the relationship between neutrophil-lymphocyte ratio (NLR) and early renal fibrosis and renal prognosis in patients with lupus nephritis. METHODS: A total of 186 patients with lupus nephritis admitted to our hospital were enrolled and grouped according to the standard of "NLR=3.175". There were 90 patients in the higher NLR group and 96 patients in the lower NLR group. The correlation and independent relationship between NLR/estimated glomerular filtration rate (eGFR) and pathological indicators were explored by comparing the differences of physiological indicators between the two groups. The correlation between NLR/eGFR and renal insufficiency and renal prognosis were explored. RESULTS: The higher NLR group showed increased levels of hs-CRP, white blood cells, neutrophils, platelets, PLR values, eGFR, D-dimer, crescent compared with the lower NLR group, while lymphocyte count in the higher NLR group was lower than that in the lower NLR group. Platelets, neutrophils, white blood cells, serum anhydride, serum C4 and vascular cellulose had positive correlations with NLR. eGFR, age, systolic blood pressure, diastolic blood pressure, neutrophils, leukocytes, NLR, blood uric acid, triglycerides, crescent ratio, endothelial hyperplasia, spherical sclerosis ratio, intraglomerular leukocyte infiltration, platinum loop, microthrombus, nuclear fragmentation, interstitial inflammatory cell infiltration, renal tubular atrophy, interstitial fibrosis, and mesangial cell showed negative correlation with matrix hyperplasia, arteriolar wall thickening and pathological activity scores, but showed positive correlation with hemoglobin and low-density lipoprotein. CONCLUSION: NLR affects some important renal functions to a certain extent and is not the only risk factor for renal prognosis in patients with LN.