[Renal leukocyte chemokine type 2 amyloidosis: a clinicopathological analysis of fifteen cases].

Objective: To investigate the clinicopathological features of renal leukocyte chemokine type 2 amyloidosis (ALECT2). Methods: The prevalence, clinical characteristics, renal histopathological features, and renal outcome of 15 patients with ALECT2 by kidney biopsy were collected in the Department of Kidney Pathology, Shanxi Medical University Second Hospital, Taiyuan, China from January 1993 to December 2023. Immunohistochemistry and mass spectrometry for amyloid proteins were carried out. Results: Fifteen patients with ALECT2 were included in the study, representing 12.93% (15/116) of the renal biopsy-proven amyloidosis cases. There were 5 males and 10 females. The median age at diagnosis was 61 years. All patients had various degrees of proteinuria; 7 patients had nephrotic syndrome; 3 patients had renal insufficiency; 7 patients had microscopic hematuria. Renal biopsy showed that strongly orangophilic amyloid proteins distributed mainly in the renal cortical interstitium, vascular walls, the glomerular mesangium and/or glomerular basement membrane. Eight cases were diagnosed with ALECT2 alone and 7 cases combined with other renal diseases, including 4 cases with membranous nephropathy, 2 cases with IgA nephropathy, and 1 case with subacute tubular interstitial nephropathy. ALECT2 patients with concurrent renal disease showed a higher proteinuria level than those without (3.48 g/24 h versus 4.58 g/24 h). All patients were corroborated by immunohistochemistry to exhibit the specific location of LECT2 in the amyloid fibrils. Mass spectrometry analysis revealed LECT2 polypeptide in 9 patients. Except two patients with worsening renal function, the others showed stable renal function during the mean follow-up period of 12.5 months. Conclusions: ALECT2 is the second common type of renal amyloidosis in our center. The majority of ALECT2 patients show concurrent renal diseases, with a high rate of membranous nephropathy. Amyloid deposits distribute mainly in the cortical interstitium of the kidney, the glomerular mesangium and vascular walls. Mass spectrometry is the most sensitive and specific method for detecting LECT2 amyloidosis.

[Idiopathic membranous nephropathy with focal segmental sclerosis].

AIM: To evaluate the clinical and pathological features and prognosis of idiopathic membranous nephropathy (IMN) with focal segmental sclerosis (FSGS) in a group of Russian patients. MATERIALS AND METHODS: 101 patients with morphologically verified IMN were enrolled in our single-center cohort retrospective study. The patients were divided into IMN group and IMN+FSGS group. The primary and secondary outcomes were analyzed in 59 patients, which had follow-up data for period more than 6 months. RESULTS: At the time of renal biopsy the median age was 46.0 (33.0; 55.0) years and the median follow-up was 6.8 (4.0; 15.6) months. Secondary FSGS was revealed in 15 (14.9%) patients with IMN. The IMN and IMN+FSGS groups did not differ in gender, age of onset IMN and age of renal biopsy. In the IMN+FSGS group proteinuria was higher and estimated glomerular filtration rate was lower than that in the IMN group (p<0.05). The systolic arterial pressure and creatinine levels in the IMN+FSGS group were slightly higher than in the IMN group, but the difference was not significant. Anti-PLA2R positivity was similar in both groups. Chronic kidney disease (CKD) progression was observed in 10/52 (19.2%) and 5/7 (71.4%) patients in IMN and IMN+FSGS groups, respectively. In a multivariate Cox regression model, age of renal biopsy (odds ratio - OR 1.12, 95% confidence interval - CI 1.03-1.22; р=0.07), FSGS (OR 0.05, 95% CI 0.01-0.34; р=0.002) и response to initial course of immunosuppression (OR 0.33, 95% CI 0.12-0.95; р=0.039) were associated with the CKD progression. CONCLUSION: In patients with IMN secondary FSGS is associated with a greater severity of proteinuria and a decrease in estimated glomerular filtration rate, and is also an independent factor of the CKD progression.

Expansion of T follicular helper cells is associated with disease progression in rat experimental membranous nephropathy model.

BACKGROUND: T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses, but the functional role of Tfh cells in the pathogenesis of idiopathic membranous nephropathy (IMN) remains unclear. OBJECTIVES: This study aimed to establish a rat experimental membranous nephropathy model, investigate the phenotypic characteristics of Tfh cells, and analyze a clinically significant correlation between Tfh cells. MATERIAL AND METHODS: Passive Heymann nephritis (PHN) rats were induced by immunizing Sprague Dawley rats with anti-Fx1A serum. The frequency of Tfh and B cell subsets was analyzed with flow cytometry (FC). The serum concentration of interleukin-21 (IL-21), the relative mRNA expression levels of IL-21 and B cell lymphoma 6 (Bcl-6) in spleen mononuclear cells (MNCs), and the kidney infiltration of CD4+ T cells and IL-21 were assessed. The potential correlations among these measures were analyzed. RESULTS: In comparison with the control group, significantly increased percentages of Tfh cells, inducible T cell co-stimulator-positive (ICOS+) Tfh cells, and mRNA expression of Bcl-6 were detected in the spleen of PHN rats. Elevated IL-21 expression was detected in the serum and kidneys. Remarkably, the percentage of splenic ICOS+ Tfh cells was positively correlated with 24 h urine protein concentrations (r = 0.676, p = 0.011) in PHN rats. CONCLUSION: These data indicate that ICOS+ Tfh cells contribute to development of IMN, and they might be potential therapeutic targets for IMN.

Membranous nephropathy with Kimura's disease: A case report and review of literature.

Kimura's disease (KD) is a chronic inflammatory disorder characterized by nontender lymphadenopathy involving the head and neck region. Renal involvement in KD is rare, especially in children. We report a 12-year-old boy who had been previously treated for classical KD and had presented with anasarca and oliguria after 4 years. There were no swellings or lymphadenopathy. The kidney biopsy revealed membranous nephropathy. Remission was achieved with oral prednisolone and tacrolimus therapy. This patient highlights the need to regularly monitor patients with KD for the evolution of renal diseases, even if lymphadenopathy regresses. Serial monitoring for eosinophilia, inflammatory markers, and urine examination is needed to help identify subclinical disease early and prompt initiation of specific therapy.

Astragaloside IV relieves passive heymann nephritis and podocyte injury by suppressing the TRAF6/NF-κb axis.

The pathogenesis of membranous nephropathy (MN) involves podocyte injury that is attributed to inflammatory responses induced by local immune deposits. Astragaloside IV (AS-IV) is known for its robust anti-inflammatory properties. Here, we investigated the effects of AS-IV on passive Heymann nephritis (PHN) rats and TNF-α-induced podocytes to determine the underlying molecular mechanisms of MN. Serum biochemical parameters, 24-h urine protein excretion and renal histopathology were evaluated in PHN and control rats. The expression of tumor necrosis factor receptor associated factor 6 (TRAF6), the phosphorylation of nuclear factor kappa B (p-NF-κB), the expression of associated proinflammatory cytokines (TNF-α, IL-6 and IL-1ß) and the ubiquitination of TRAF6 were measured in PHN rats and TNF-α-induced podocytes. We detected a marked increase in mRNA expression of TNF-α, IL-6 and IL-1ß and in the protein abundance of p-NF-κB and TRAF6 within the renal tissues of PHN rats and TNF-α-induced podocytes. Conversely, there was a reduction in the K48-linked ubiquitination of TRAF6. Additionally, AS-IV was effective in ameliorating serum creatinine, proteinuria, and renal histopathology in PHN rats. This effect was concomitant with the suppression of NF-κB pathway activation and decreased expression of TNF-α, IL-6, IL-1ß and TRAF6. AS-IV decreased TRAF6 levels by promoting K48-linked ubiquitin conjugation to TRAF6, which triggered ubiquitin-mediated degradation. In summary, AS-IV averted renal impairment in PHN rats and TNF-α-induced podocytes, likely by modulating the inflammatory response through the TRAF6/NF-κB axis. Targeting TRAF6 holds therapeutic promise for managing MN.

Rhodojaponin VI ameliorates podocyte injury related with MDM2/Notch1 pathway in rat experimental membranous nephropathy.

AIM: Rhodojaponin VI (R-VI) is the key compound of Rhododendron molle G. Don (Ericaceae) (RM) with effective clinical application in rheumatoid arthritis and chronic glomerulonephritis. In our study, we tried to explore the effect of R-VI on the rat model of membranous nephropathy. METHODS: The rat model of passive heymann nephritis (PHN) was established by injecting sheep anti-rat Fx1A serum at a single dose through the tail. The rats were orally administered R-VI (0.02 mg/kg) or FK506 (1 mg/kg) 1 day before PHN induction, which was kept for 4 weeks. Urine and blood samples as well as kidney tissue were collected for analysis. C5b-9-induced human podocyte cell (HPC) was employed for experiments in vitro. RESULTS: R-VI could alleviate glomerulonephritis progression and podocyte injury in PHN rats, as indicated by the decreased proteinuria and the elevated level of albumin, accompanied with reduced immune deposits, reversed podocyte injury in the kidneys. Furthermore, R-VI suppressed murine double minute 2 (MDM2) expression without the alteration in the protein level of p53 and decreased Notch1 expression independent of Numb regulation. Pre-treatment with R-VI in C5b-9-induced HPC blocked MDM2/Notch1 signalling pathway. CONCLUSION: Thus, R-VI ameliorates podocyte injury in rats with PHN, which was probably related with MDM2/Notch1 signalling pathway.

Establishing a differential diagnosis model between primary membranous nephropathy and non-primary membranous nephropathy by machine learning algorithms.

CONTEXT: Four algorithms with relatively balanced complexity and accuracy in deep learning classification algorithm were selected for differential diagnosis of primary membranous nephropathy (PMN). OBJECTIVE: This study explored the most suitable classification algorithm for PMN identification, and to provide data reference for PMN diagnosis research. METHODS: A total of 500 patients were referred to Luo-he Central Hospital from 2019 to 2021. All patients were diagnosed with primary glomerular disease confirmed by renal biopsy, contained 322 cases of PMN, the 178 cases of non-PMN. Using the decision tree, random forest, support vector machine, and extreme gradient boosting (Xgboost) to establish a differential diagnosis model for PMN and non-PMN. Based on the true positive rate, true negative rate, false-positive rate, false-negative rate, accuracy, feature work area under the curve (AUC) of subjects, the best performance of the model was chosen. RESULTS: The efficiency of the Xgboost model based on the above evaluation indicators was the highest, which the diagnosis of PMN of the sensitivity and specificity, respectively 92% and 96%. CONCLUSIONS: The differential diagnosis model for PMN was established successfully and the efficiency performance of the Xgboost model was the best. It could be used for the clinical diagnosis of PMN.

Membranous nephropathy (MN) without obvious causes is called primary MN (PMN), This study utilized deep learning classification algorithms for differential diagnosis of PMN and explored the most suitable classification algorithm for PMN recognition, provided data reference for PMN diagnosis research.

Changes in the spectrum of biopsy-proven renal diseases over 11 years: a single-center study in China.

BACKGROUND: There have been some shifts in the frequency and distribution of biopsy-proven renal diseases in China over recent years. The aim of the study was to investigate the changing spectrum of renal diseases from the view of kidney biopsy data in a single center of China. METHODS AND RESULTS: A total of 10,996 cases of native renal biopsies from patients aged ≥15 years old in Huashan Hospital, Fudan University, between 2008 and 2018 were analyzed retrospectively. The results showed that primary glomerular nephropathy (PGN) remained the most common biopsy-proven renal disease (69.42% of total), with IgA nephropathy (IgAN) accounting for 44.40% of PGN, membranous nephropathy (MN) for 28.55%, minimal change disease (MCD) for 13.26% and focal segmental glomerulosclerosis (FSGS) for 8.00%. During the study period, the proportion of MN in PGN appeared an increasing tendency, while that of IgAN and MCD remained stable and that of FSGS showed a decline. Secondary glomerular nephropathy (SGN) constituted 21.54% of total cases, among which the leading two diseases were lupus nephritis (LN) and Henoch-Schonlein purpura nephritis (HSN) which accounted for 41.08% and 19.11% respectively. CONCLUSIONS: The 11-year retrospective study revealed that PGN was the predominant histologic diagnosis among patients undergoing renal biopsy and the most frequent type of PGN remained to be IgAN, followed by MN which increased dramatically.

Mannose-Binding Lectin Deposition in Membranous Nephropathy and Differentiation of Primary from Secondary Forms.

The differentiation between primary and secondary forms of membranous nephropathy (MN) is a cornerstone that is necessary for adequate decision making regarding the treatment options and behavior of each specific case. Kidney biopsy and antibody results can be controversial, and a unique biomarker has still not been found. BACKGROUND AND OBJECTIVES: We investigated the lack of mannose-binding lectin (MBL) deposition in patients with secondary MNs (sMNs) with the presence of IgG4 deposition in relation to the presence of MBL deposition in patients with primary MNs (pMNs). We also established a connection between the stage of MN and MBL deposition. MATERIALS AND METHODS: Materials from 72 renal biopsies with proven MN were used for immunohistochemistry staining (IHC) for the phospholipase A2 receptor (PLA2R), immunoglobulin subtype IgG4, and MBL. Patients were separated into one of the following three groups: primary MN (pMN), idiopathic MN (iMN), and secondary MN (sMN). Serum antibodies for PLA2R and thrombospondin type-I-domain-containing 7A (THSD7A) were also used for the precise evaluation of the type of MN, as well as for detecting positivity for PLA2R using IHC. Which stage of MN was present in relation to the deposition of MBL was evaluated. RESULTS: In total, 50 patients were positive for IgG4, 34 with pMN, 12 with iMN, and 4 with sMN. A total of 20 patients were positive for MBL, 14 with pMN and 6 with iMN; no MBL deposits were found in patients with sMN. MBL positivity was predominantly present in the first two stages of MN, with a gradual reduction in the later stages. CONCLUSIONS: The activation of the lectin-complement pathway occurs in the early stages of the disease and is associated with the deposition of IgG4; IgG4 deposition is present in sMN, but there is no MBL deposition. IgG4 cannot be used for the differentiation of primary from secondary MNs, but the lack of MBL can be used as a marker for sMN in the early stages of the disease.

Membranous-like glomerulopathy with masked monotypic IgG deposits: A single center case series.

BACKGROUND: Membranous-like glomerulopathy with masked monoclonal IgG deposits (MGMID) is a newly recognized condition predominantly observed in young females, and its understanding in the pediatric population remains limited. MATERIALS AND METHODS: Four cases of MGMID are reported, including three pediatric patients. RESULTS: All patients were female, with ages ranging from 12 to 26 years. None of the patients had malignancies. They presented with kidney dysfunction, proteinuria, or hematuria. Kidney biopsies of all cases exhibited a membranous pattern of injury with monoclonal IgG-κ restriction, "unmasked" by pronase digestion. Pediatric cases were treated conservatively, while the adult case underwent immunosuppressive treatment. All patients had favorable outcomes, and none reached end stage kidney disease (ESKD). CONCLUSION: MGMID can affect both adult and pediatric patients. Further studies are needed to fully characterize its risk factors, optimal therapy, and outcomes.

[Diagnostic significance of C4d in membranous nephropathy]. / Importancia diagnóstica del C4d en la nefropatía membranosa.

INTRODUCTION: Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome in adults (20-30%). Light microscopy shows thickening of glomerular basement membrane with appearance of spikes. These histological findings are not evident in early forms, in which case the granular deposition pattern of IgG and/or C3 in the basement membrane by immunofluorescence (IF) constitutes the diagnostic tool that allows to differentiate it from minimal change disease (MCD). Complement system plays a key role in the pathophysiology of MN. C4d is a degradation product and a marker of the complement system activation. C4d labelling by immunohistochemical (HI) technique can help in the differential diagnosis between both glomerulopathies NM and MCD when the material for IF is insufficient and light microscopy is normal. Our objective was to explore the discrimination power of C4d to differentiate between MN and MCD in renal biopsy material. METHODS: Paraffin-embedded samples were recovered from renal biopsies with a diagnosis of MN and MCD performed between 1/1/2008 and 4/1/2019. IH staining was performed by immunoperoxidase technique using a rabbit anti-human C4d polyclonal antibody. RESULTS: In all cases with MN (n = 27, 15 males) with a median age of 63 (range: 18-87) years, C4d deposits were detected. In 21 cases with MCD (12 males) with a median age of 51 (range: 18-87) years, the C4d marking was negative in every samples. CONCLUSION: The results indicate that the marking of the renal biopsy with C4d is a useful tool for the differential diagnosis between NM and MCD.

Introducción: La nefropatía membranosa (NM) es la causa más frecuente de síndrome nefrótico primario en adultos (20-30%). En la microscopia óptica se observa engrosamiento de membrana basal glomerular con aparición de espigas. Estos hallazgos histológicos no son evidentes en formas tempranas, en cuyo caso el patrón de depósito granular de IgG y/o C3 en la membrana basal por inmunofluorescencia (IF) permite diferenciarla de enfermedad por cambios mínimos (ECM). El sistema del complemento juega un papel central en la fisiopatología de la NM. C4d es producto de degradación y un marcador de la activación del complemento. La marcación con C4d en muestras de biopsias renales, por técnica de inmunohistoquímica (IH) puede colaborar en el diagnóstico diferencial entre ambas glomerulopatías. Nuestro objetivo fue explorar el poder de discriminación del C4d para diferenciar NM de ECM en material de biopsias renales. Métodos: Se recuperaron muestras en parafina de biopsias renales con diagnóstico de NM y ECM realizados entre 1/1/2008 y 1/4/2019. Se realizaron tinciones de IH por técnica de inmunoperoxidasa con C4d usando un anticuerpo policlonal antihumano de conejo. Resultados: En todos los casos con NM (n = 27, 15 hombres) con mediana de edad de 63 (rango: 18-86) años se detectaron depósitos de C4d. En los 21 casos con ECM (12 hombres) con mediana de edad de 51 (rango: 18-87) años la marcación de C4d fue negativa. Conclusión: Los resultados indican que la marcación de la biopsia renal con C4d es una herramienta útil para el diagnóstico diferencial entre NM y ECM.

Glomerulus-Targeted ROS-Responsive Polymeric Nanoparticles for Effective Membranous Nephropathy Therapy.

Membranous nephropathy (MN) is a common immune-mediated glomerular disease that requires the development of safe and highly effective therapies. Celastrol (CLT) has shown promise as a therapeutic molecule candidate, but its clinical use is currently limited due to off-target toxicity. Given that excess levels of reactive oxygen species (ROS) contributing to podocyte damage is a key driver of MN progression to end-stage renal disease, we rationally designed ROS-responsive cationic polymeric nanoparticles (PPS-CPNs) with a well-defined particle size and surface charge by employing poly(propylene sulfide)-polyethylene glycol (PPS-PEG) and poly(propylene sulfide)-polyethylenimine (PPS-PEI) to selectively deliver CLT to the damaged glomerulus for MN therapy. Experimental results show that PPS-CPNs successfully crossed the fenestrated endothelium, accumulated in the glomerular basement membrane (GBM), and were internalized by podocytes where rapid drug release was triggered by the overproduction of ROS, thereby outperforming nonresponsive CLT nanotherapy to alleviate subepithelial immune deposits, podocyte foot process effacement, and GBM expansion in a rat MN model. Moreover, the ROS-responsive CLT nanotherapy was associated with significantly lower toxicity to major organs than free CLT. These results suggest that encapsulating CLT into PPS-CPNs can improve efficacy and reduce toxicity as a promising treatment option for MN.

Diagnosis of membranous nephropathy with Anti-GBM glomerulonephritis: a case series report.

BACKGROUND: The concomitant occurrence of membranous nephropathy and anti-glomerular basement (anti-GBM) disease has been previously described but is extremely rare. However, delayed recognition or misdiagnosis leads to delayed treatment, resulting in worse renal and patient outcomes. CASE PRESENTATION: We present 3 patients with rapidly progressive glomerulonephritis (RPGN), anti-GBM and serum-positive M-type phospholipase A2 receptor (anti-PLA2R) antibody. Renal biopsies revealed PLA2R-associated membranous nephropathy with anti-GBM glomerulonephritis. We analyzed the clinical and pathological characteristics and discussed that the correct diagnosis of membranous nephropathy with anti-GBM should rely on a combination of renal biopsy findings and serological testing. Despite aggressive treatment, one patient received maintenance hemodialysis, one patient progressed to CKD 3 stage, and the other patient died of cerebral infarction. CONCLUSION: The simultaneous occurrence of membranous nephropathy and anti-GBM disease is extremely rare. The correct diagnosis of membranous nephropathy with anti-GBM relies on a combination of renal biopsy findings and serological testing. Early diagnosis is needed to improve the renal dysfunction.

Aggressive treatment may be needed for idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions.

OBJECTIVE: The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. METHODS: This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. RESULTS: A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) µmol/L vs. 72.0 (58.7, 84.9) µmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. CONCLUSION: Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.

Podocyte Pathogenic Bone Morphogenetic Protein-2 Pathway and Immune Cell Behaviors in Primary Membranous Nephropathy.

Primary membranous nephropathy (PMN) is one of the leading causes of end-stage renal disease, and the most frequent cause of massive proteinuria in nondiabetic adults, resulting in fatal complications. However, the underlying pathomechanisms of PMN remain largely unclear. Here, single-cell RNA sequencing is employed to analyze kidney biopsies from eleven PMN patients and seven healthy subjects. Profiling 44 060 cells from patients allowed us to characterize the cellular composition and cell-type-specific gene expression in the PMN kidney. The complement-induced BMP2/pSMAD1/COL4 pathway is identified as the pathogenic pathway in podocytes, bridging two key events, i.e., complement system activation and glomerular basement membrane thickening in PMN. Augmented infiltration and activation of myeloid leukocytes and B lymphocytes are found, profiling delicate crosstalk of immune cells in PMN kidneys. Overall, these results provide valuable insights into the roles of podocytes and immune cells in PMN, and comprehensive resources toward the complete understanding of PMN pathophysiology.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

A Dynamic Prediction Model for Renal Progression in Primary Membranous Nephropathy.

Objective: This study aimed to build and validate a practical web-based dynamic prediction model for predicting renal progression in patients with primary membranous nephropathy (PMN). Method: A total of 359 PMN patients from The First Affiliated Hospital of Fujian Medical University and 102 patients with PMN from The Second Hospital of Longyan between January 2018 to December 2023 were included in the derivation and validation cohorts, respectively. Renal progression was delineated as a decrease in eGFR of 30% or more from the baseline measurement at biopsy or the onset of End-Stage Renal Disease (ESRD). Multivariable Cox regression analysis was employed to identify independent prognostic factors. A web-based dynamic prediction model for renal progression was built and validated, and the performance was assessed using. An analysis of the receiver operating characteristic and the decision curve analysis. Results: In the derivation cohort, 66 (18.3%) patients experienced renal progression during the follow-up period (37.60 ± 7.95 months). The final prediction rule for renal progression included hyperuricemia (HR=2.20, 95%CI 1.26 to 3.86), proteinuria (HR=2.16, 95%CI 1.47 to 3.18), significantly lower serum albumin (HR=2.34, 95%CI 1.51 to 3.68) and eGFR (HR=1.96, 95%CI 1.47 to 2.61), older age (HR=1.85, 95%CI 1.28 to 2.61), and higher sPLA2R-ab levels (HR=2.08, 95%CI 1.43 to 3.18). Scores for each variable were calculated using the regression coefficients in the Cox model. The developed web-based dynamic prediction model, available online at http://imnpredictmodel1.shinyapps.io/dynnomapp, showed good discrimination (C-statistic = 0.72) and calibration (Brier score, P = 0.155) in the validation cohort. Conclusion: We developed a web-based dynamic prediction model that can predict renal progression in patients with PMN. It may serve as a helpful tool for clinicians to identify high-risk PMN patients and tailor appropriate treatment and surveillance strategies.

Prevalence and prognosis of malignancy in THSD7A-associated membranous nephropathy: a systematic literature review and clinical case study.

BACKGROUND: This study aims to investigate the incidence and prognosis of malignancy in individuals with thrombospondin type-1 domain-containing 7A (THSD7A)-associated membranous nephropathy (MN). METHODS: First, we performed a systematic literature review of prevalence of malignancy in THSD7A-associated MN. Then, we conducted a retrospective analysis of 454 patients diagnosed with MN through renal biopsy at our hospital between January 2016 and December 2020. We assessed the presence of serum anti-THSD7A antibodies and performed immunohistochemical staining of renal tissue for THSD7A. Subsequently, we followed patients with THSD7A-associated MN for a minimum of 3-5 years, collecting their clinical, pathological characteristics, and prognosis. Additionally, we conducted a literature review on patients with THSD7A-associated MN in conjunction with malignancy. RESULTS: We identified a total of nine articles containing comprehensive data on THSD7A-associated MN and malignancy. Among 235 patients with THSD7A-positive MN, 36 individuals had concurrent malignancies, resulting in a malignancy prevalence of 13.3% (95% CI: 8.9-17.7%). In our center, we followed up with 15 patients diagnosed with THSD7A-associated MN and observed three cases of concomitant tumors: two cases of lung adenocarcinoma and one case of small cell lung cancer with multiple metastases. The prevalence of malignancy in our cohort was 20%. Notably, we detected positive THSD7A staining in both renal and lung cancer tissues in one patient with small cell lung cancer. CONCLUSIONS: Patients with THSD7A-associated MN should undergo vigilant follow-up assessments, with a particular focus on actively seeking potential tumorigenic lesions to prevent misdiagnosis or oversight.

Tubular expression of Toll-like receptor 9 in lupus and primary membranous nephropathy.

INTRODUCTION: Toll-like- receptors (TLR) control important aspects of innate and adaptive immune responses. Renal cells are among the non-immune cells that express (TLR). Therefore, their activation might be implicated in renal tubulo-interstitial injury. AIM: The study aimed to compare TLR9 expression in patients with primary membranous nephropathy (MN) to patients with lupus membranous nephropathy. METHODS: Kidney sections from 10 Lupus nephritis (LN) patients and ten patients with primary MN were analyzed by immunohistochemistry using anti-human TLR9 antibody. RESULTS: Results showed that TLR9 expression was weak and exclusively tubular in primary MN patients' biopsies. There was a significant difference between LN patients' biopsies and primary MN patients' biopsies. TLR9 expression was more diffused in LN patients' specimen than in those with primary MN. CONCLUSION: This study focuses on molecular level pathogenesis of MN. The data suggest that the receptors TLR9 may play role in tubulointerstitial injury in the pathogenesis of LN but not primary membranous nephropathy.

Clinical implications of serum anti-PLA2R levels and glomerular PLA2R deposits in primary membranous nephropathy.

Introduction. The clinical implications of serum anti-PLA2R with glomerular PLA2R deposits in primary membranous nephropathy (PMN) is scarcely reported. Hence the study was designed to demonstrate the prevalence of serum anti-PLA2R levels and PLA2R staining in glomeruli in PMN and the clinical implications of the two parameters. Objectives. Investigate the prevalence of anti PLA2R positivity in PMN. Ascertain correlation between serum anti-PLA2R levels and glomerular staining for PLA2R with clinical and lab parameters in PMN. Patients and Methods. Fifty PMN patients during the period from October 2017 to December 2018 were included. Labs were done and eGFR was calculated as per MDRD 6. Anti-PLA2R titres were done in all patients. Titres more than 20 RU/ml were considered positive. Glomerular staining for PLA2R was graded on fresh frozen tissue by immunofluorescence technique. Results. Anti-PLA2R antibody positivity and glomerular PLA2R deposition was observed in 42% (21/50) and 86% (43/50) patients respectively. 79.3% (23/29) had positive glomerular PLA2R deposition with negative serum anti PLA2R. Positive correlation were observed between serum PLA2R antibody and serum creatinine (p = 0.0001) and urine protein-creatinine ratio levels with tissue PLA2R staining grades (p = 0.04). Negative association was found between serum albumin (p = 0.026) and tissue PLA2R staining grades. Conclusion. Serum anti-PLA2R wasn't a sensitive marker of primary membranous nephropathy in our study group emphasising the need to consider a compendium of serological markers for diagnosis of primary membranous nephropathy and to rely more on glomerular deposition of PLA2R as a better clinical indicator for PMN.