Primary Glomerular Disease Research Articles

#3979 DIGITAL SPATIAL PROFILING CAN BE USED TO STUDY GLOMERULAR ENDOTHELIAL CELLS IN IGA NEPHROPATHY

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide; approximately 30% of cases progress to kidney failure 10-20 years from diagnosis. Five histopathological kidney lesions independently predict a poor prognosis in IgAN (MEST-C score) [1]. Published case series highlight the ‘endocapillary hypercellularity’ (E1) lesion as potentially reversible with systemic immunosuppression, improving clinical outcomes [2]. Delineating differences in the transcriptomes of glomerular endothelial cells (GEnCs) associated with and without E1 (E0) may highlight avenues for safer therapeutic strategies, given the overt risks associated with systemic immunosuppression in IgAN. GEnC transcriptomes have never been profiled in diseased kidneys before. Here we used digital spatial profiling (DSP) to achieve this. Method DSP was performed on a Nanostring GeoMx platform. Single 5μm sections were collected from four formalin fixed paraffin embedded (FFPE) kidney biopsies with E1 and five with E0. Following deparaffinization and antigen retrieval, the tissue was incubated with a whole transcriptome atlas probe set. GEnCs were stained for CD31 (red) and macrophages (which associate with E1[3]) with CD68 (yellow) with conjugated antibodies. Glomeruli were selected as regions of interests (ROIs), and a custom JavaScript function was used to mask over GEnCs and macrophages (segmentation), which were selected as areas of illumination (AOIs) (Fig 1). Photocleaved nucleotide barcodes were sequenced using an Illumina sequencer. Single cell enrichment was assessed using the SpatialDecon algorithm, differential gene expression was explored using a linear mixed effects model, and pathway analysis was performed using Reactome. Results The custom written JavaScript function allowed good segmentation on GEnCs and macrophages (Fig 1). Single cell deconvolution performed using the human kidney cell atlas as a reference showed significant enrichment of GEnCs relative to neighbouring cell types (Fig 2). Exploration of differential gene expressions using a linear mixed effects model found an up-regulation of TRIM23, IL27RA, TMEM139, P14K2B and PSMD9, after P value adjustment, among GEnCs associated with macrophages in glomerular capillary loops compared to those in the absence of macrophages (Fig 3). Pathway analysis based on differential gene expression performed using Reactome revealed that the complement cascade and regulators of the complement cascade were enhanced in GEnCs associated with macrophages (Fig 4). Conclusion This pilot study found DSP on the GeoMx to be effective at enriching GEnC transcript signals from neighbouring cell types in FFPE tissue. This preliminary data also shows that GEnCs associated with macrophages may display a more inflammatory phenotype, which may be related to up-regulation in complement activity and may account for the progressive phenotype associated with E1 in IgAN. With several trials investigating complement system targeting therapeutics in IgAN, validation of these findings might highlight a cohort of patients with IgAN most likely to benefit from treatment.

#4353 HEALTH-RELATED QUALITY OF LIFE IN ADULTS WITH PRIMARY GLOMERULAR DISEASES IN INDIA

Abstract Background and Aims Glomerular diseases pose a substantial burden on the healthcare system. While the medical and economic burden of glomerular diseases is well established, the data on the health-related quality of life impact is scant. Method We used the PROMIS 29 v2.1 (Patient-Reported Outcomes Measurement Information System) tool to assess HRQOL impact of primary glomerular diseases in adult Indian patients [1], under the domains: physical function, anxiety, fatigue, depression, sleep disturbance, ability to participate in social roles and activities and pain interference in daily activities. The questionnaire was administered in English and Hindi. Patient responses were then used to calculate T-scores with a mean of 50 and an SD of 10 with the score having positive correlation with the quantum of the outcome measured. Results 141 adult patients were recruited (39 minimal change disease/ focal segmental glomerulosclerosis, 36 membranous nephropathy, 56 IgA nephropathy, 9 membrano-proliferative glomerulonephritis). Mean T-scores across domains were as follows: physical function- 48.2 (46.8-49.6), fatigue- 49.2 (47.5-51), anxiety- 52.3 (50.6-53.9), sleep impairment- 43.5 (41.9-45.1), depression- 50.7 (49-52.4), ability to participate in social roles and activities- 55 (53.3-56.7), hindrance in daily activities due to pain 51.2 (49.7-52.8). Better physical function was associated with higher eGFR (T-score of 44 at eGFR<45 ml/min/1.73m2 and 49.8 at eGFR>45 ml/min/1.73m2, p<0.001), lower BMI (42.4 in obese vs 48.6 in non-obese, p = 0.02), and male sex (50.2 vs 44.5 in females, p<0.001). Fatigue was associated with eGFR<45 ml/min/1.73m2 (52.2 vs 48.1 at eGFR>45 ml/min/1.73m2, p = 0.04), and female sex (53.2 vs 47.1 in males, p<0.001). Worse anxiety was seen in females (55.8 vs 50.4 in males, p = 0.002) and patients with eGFR<45 ml/min/1.73m2 (55.4 vs 51.1 at eGFR>45 ml/min/1.73m2, p = 0.02). Sleep impairment was seen in patients having a history of steroid usage in the last 2 months (45.8 vs 42.1, p = 0.02), females (45.8 vs 42.3, p = 0.04), and patients with eGFR<45 ml/min/1.73m2 (46.2 vs 42.5 at eGFR>45 ml/min/1.73m2, p = 0.04). Pain interference was higher in females (55.9 vs 48.8 in males, p<0.001) and patients with eGFR<45 ml/min/1.73m2 (54 vs 50.2 at eGFR>45 ml/min/1.73m2, p = 0.03). eGFR>45 ml/min/1.73m2 (56.4 vs 51.4 at eGFR<45 ml/min/1.73m2, p = 0.008) was associated with better involvement in social roles. Depression was associated with female sex (54.2 vs 48.9 in males, p = 0.003). Degree of proteinuria, serum albumin, duration of disease, immunosuppressive drug use, age, patient-reported edema, and socio-economic status were not associated with a significant decrease in HRQOL. Multivariable linear regression models were evaluated for all domains. Physical function was negatively associated with eGFR<45ml/min/1.73m2 (β = -5.46), female sex (β = -5.16), and obesity (β = -6.36). Fatigue was associated with eGFR<45ml/min/1.73m2 (β = 3.89), female sex (β = 5.76), and obesity (β = 9.62). Worse anxiety was associated with eGFR<45ml/min/1.73m2 (β = 3.82) and female sex (β = 4.97). Sleep impairment was associated with eGFR<45ml/min/1.73m2 (β = 3.46) and female sex (β = 3.24). Pain interference was associated with eGFR<45ml/min/1.73m2 (β = 3.39) and female sex (β = 7.19) Ability to participate in social roles and activities was negatively associated with eGFR<45ml/min/1.73m2 (β = -4.86) and female sex (β = −3). Depression was associated with obesity (β = 6.16) and female sex (β = 5.22). Conclusion Glomerular diseases adversely impact the quality of life. Female sex, lower renal function (eGFR), higher BMI and history of recent steroid use correlated with higher morbidity.

#5012 THE EFFECT OF GLOMERULAR C3 DEPOSITION ON RENAL OUTCOME IN PATIENTS WITH MEMBRANOUS NEPHROPATHY: DATA OF THE TSN-GOLD STUDY

Abstract Background and Aims We aimed to evaluate the effect of glomerular C3 deposits on clinical and laboratory findings and outcome in patients with idiopathic membranous nephropathy (MN) included in the Primary Glomerular Diseases Study of Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD). Method The data of 1595 patients with MN in the database has been evaluated. 114 patients were excluded due to lack of data about C3 staining, 54 patients due to secondary MN and 523 due to lack of data about the follow-up. Patients with glomerular C3 deposits were compared with those with no C3 staining. Results Glomerular C3 deposits were detected in kidney biopsy specimens of 601 patients of the 888 patients analysed. The demographic data, clinical and laboratory findings at the time of diagnosis of C3 (+) and C3 (-) groups are presented in Table 1. They were similar except serum albumin level that was lower in C3 (+) group. Subepithelial deposits and interstitial fibrosis was more prominent, IgG, Kappa and Lambda staining more intense, positivity for C1q and IgA was more frequent in C3 (+) group (Table 2). The study groups were similar regarding remission rates after the first imuunosuppressive treatment (p = 0.582). 155 patients (25.8%) had partial, 152 (25.3%) had complete remission while no remission was detected in 92 patients (15.3%) in C3 (+) group. 69 patients (24.0%) had partial and 81 patients (28.2%) had complete remission; 40 patients (13.9%) had no remission in C3 (-) group. The relapse rates were 17.6% and 19.9% in C3 (+) and C3 (-) groups (p = 0.360). The percentage of patients who died or needed renal replacement therapy (RRT) were higher C3 (+) group (p = 0.013) (Figure 1). Conclusion Need for RRT and mortality is higher in patients with C3 deposition showing the importance of C3 deposition in the prognosis of MN. More prominent interstitial fibrosis may be related with the worse outcome.

#4970 SINGLE-CELL RNA SEQUENCING REVEALS THE MOLECULAR CHARACTERISTIC OF IGA-MCD

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerular disease in children and adolescents worldwide, and is one of the major causes of end-stage renal disease in China. Minimal change disease(MCD) is the most common pathological type of nephrotic syndrome in children. In some rare cases, the renal pathology of these patient has IgA deposits in the mesangial regionns and diffuse fusion of podocyte foot process,which is called IgA-MCD. Previous studies have analyzed the characteristics of IgA-MCD from the aspects of clinical manifestations, pathological features, therapeutic response and prognosis, but the molecular mechanism of its occurrence and development has not been clarified. For the first time, single-cell transcriptome sequencing technology was used to compare IgA-MCD, IgAN and MCD, in order to describe the unique molecular characteristics of IgA-MCD and elucidate the molecular mechanism related to clinical manifestations. It lays the foundation for formulating more appropriate treatment plan and improving prognosis. Method Renal fine-needle puncture tissues were collected from 3 children with IgAN, 4 children with MCD, and 1 child with IgA-MCD in Children's Hospital of Chongqing Medical University, and adjacent normal tissues were collected from 1 child with renal tumor as control group. Children in the three disease groups had clinical manifestations of nephrotic syndrome, and nephrotic-level proteinuria at the time of sampling. High-throughput, unbiased single-cell transcriptome sequencing was performed on the above renal tissue samples, and the sequencing results were systematically compared and analyzed. Results By analyzing single-cell sequencing data, we systematically described single-cell transcriptome cell maps of renal tissues form children with nephrotic-level albuminuria with different pathologic types (IgAN, MCD, IgA-MCD). Twelve cell types, such as mesenchymal cells and podocytes, were defined by classical marker genes. By comparing the constituent ratio of renal cells and PC analysis of cell subsets in the control group and the three disease groups, it was found that IgA-MCD was closer to MCD. By comparing the differential genes of the three disease groups with those of the control group, we found that the number of differential genes in IgAN’s podocytes was significantly higher than that in the other two groups. Compared with the control group, HMGCS2 was significantly up-regulated in IgA-MCD, and cellular energy metabolism was enhanced. Through pairwise comparison among the three disease groups, it was found that there was no significant difference in genes in podocytes between IgA-MCD and MCD. Compared with IgAN, CXCL12 gene expression in IgA-MCD is significantly up-regulated, and CXCL12 can recruit immune cells and lead to cell damage. Conclusion The overall transcription profile of IgA-MCD is more similar to that of MCD. CXCL12 was specifically highly expressed in the podocytes of IgA-MCD, which may be used as a marker molecule for functional changes of IgA-MCD podocyte. IgA-MCD mesenchymal cells were significantly different from those in the other two disease groups. The significant up-regulation of CD81 may be a molecular signal that leads to the activation, proliferation, and secretion of more extracellular matrix of IgAN-MCD glomerular mesenchymal cells.We analyzed the associations and differences among IgAN, MCD and IgA-MCD at the single-cell transcriptome level, which provided a new perspective and insight for the follow-up study of the pathogenesis of the diseases.

#4052 IMMUNOSUPPRESSIVE TREATMENT RESULTS IN PATIENTS WITH PRIMARY IGA NEPHROPATHY IN TURKIYE: A NATIONWIDE STUDY

Abstract Background and Aims IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis in Turkey, as well as all over the world. Along with the frequent occurrence, deleterious renal outcome odds make treatment approaches important. Additionally, for high-risk individuals immunosuppressive treatment (IST) is recommended. However, studies to date revealed conflicting results regarding IST. Therefore, we aimed to investigate IST results among IgAN patients which is the leading primary glomerulonephritis in Turkiye. Method The data of 1656 IgAN patients in the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD) were analyzed. A total of 506 primary IgAN patients (63.4% male, mean age 38.9±12.5 years) were included and divided into two groups according to treatment protocols as isolated corticosteroid (69.6%) and combined IST (30.4%) groups. The median follow-up duration was 24 (3-218) months. Results Remission (66.6% partial remission, 33.4% complete remission) was achieved in 70.6% of patients. Systolic and diastolic blood pressures, urea, creatinine, and proteinuria levels were lower, and eGFR levels were higher in responsive patients (Table 1). There was no difference between the treatment groups in terms of remission rates (p = 0.147) and remission types’ rates (p = 0.279). Remission rates were different between treatment subgroups. However, there was no difference between the treatment subgroups according to the remission types (p = 0.132) (Table 2). Complete remission was lower in the S1 and T1 categories (p = 0.003 and 0.039, respectively). The serious infection was higher in the combined IST group (17.1% vs 2.9%). The outcome data of 229 individuals was evaluated, 40 of 229 (17.5%) developed ESRD and 8 were dead. In the multivariate analysis, eGFR (OR 1.007, 95%CI 1.001-1.013, p = 0.020), proteinuria (OR 1.000, p = 0.009), MEST-C S1 (OR 1.912, 95%CI 1.216-3.005, p = 0.005), MEST-C T2 (OR 0.226, 95%CI 0.102-0.501, p = < 0.001) were found to be significant regarding remission. Conclusion IST provides remission in high-risk IgAN patients but was associated with serious adverse events. The fact that the remission rates were similar between the treatment groups and that the complete remission rate was low in chronic changes supports the necessity of determining the treatment choice according to patient characteristics.

THE RELATIONSHIP BETWEEN ARTERIAL STIFFNESS, SUBCLINICAL HEART FAILURE, CARDIAC FIBROSIS AND RENAL FUNCTION IN CHRONIC KIDNEY DISEASE, IGA NEPHROPATHY

Objective: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Arterial stiffness may predict cardiovascular (CV) mortality and morbidity in chronic kidney disease (CKD). Heart failure is very common in advanced CKD stages. Onset of myocardial fibrosis may be a pathophysiological alteration in CKD patients with heart failure. Design and method: In our cross-sectional study, we examined 90 patients who cared for IgAN in our clinic. Arterial stiffness was determined by measuring carotis-femoral pulse wave velocity (cfPWV) using the ShygmoCor device. N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and carboxy-terminal telopeptide of collagen type I (CITP) were measured using ELISA kits. Renal function was detected by the estimated glomerular filtration rate (eGFR-CKD-EPI). Furthermore, a routine echocardiography examination was performed. Results: Of the 90 patients included in the study, 50 were male, with a mean age of 54.9 ± 14.4 years. Patients were divided into two groups based on eGFR (CKD 1-2 and CKD 3-5). There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. The number of patients with combined biomarker positivity (NT-proBNP and CITP) was also significantly higher in the CKD3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), but the systolic blood pressure was not. eGFR and hemoglobin level showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP by Spearman's correlation. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. Conclusions: A possible mechanism for the development of heart failure in CKD patients may be an elevation of central aortic systolic pressure. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

Safety of SGLT2 inhibitors in patients with different glomerular diseases treated with immunosuppressive therapies.

Despite the known effects of sodium-glucose-cotransporter 2 (SGLT2) inhibitors in halting chronic kidney disease (CKD) progression and decreasing mortality from renal and cardiovascular causes, their use in patients with primary and secondary glomerular diseases maintained on immunosuppressive therapies (IST) has not yet been established. In this open-label, uncontrolled study, SGLT2 inhibitors were prescribed to patients with glomerular diseases maintained on IST to assess the safety of their use. Nine out of 17 patients had no diabetes. During a mean of 7.3months follow-up duration, the incidence rate of urinary tract infection (UTI) was 1.6 per 100 person-months. The UTI episodes were successfully treated with antibiotic therapy without the need to discontinue SGLT2 inhibitors. There were no cases of acute kidney injury (AKI), ketoacidosis, amputation, or Fournier gangrene. Moreover, markers of kidney damage such as mean serum creatinine (decreased from 1.7 to 1.37mg/dl) and mean proteinuria (urinary albumin-to-creatinine ratio decreased from 2669 to 858mg/g) improved throughout the follow-up period. SGLT2i are safe to use in patients with glomerular diseases on IST.

A Cross-Sectional Study on Histological Pattern of Primary Glomerular Diseases among Adult Patients

Background and Aims: Primary glomerulonephritis (GN) is the major cause for end-stage renal disease (ESRD) and considered to contribute in 52% cases. Kidney biopsy is an essential tool in nephrologists' clinical practice for determining diagnosis, prognosis, and therapy of a variety of glomerular conditions. The purpose of the present study was to determine the primary glomerular diseases histopathological pattern among adult patients. Patients and Methods: A total of 94 suspected primary glomerular disease (GD) patients were investigated in this cross-sectional study conducted in the Nephrology Unit of Medicine department of Mayo Hospital, Lahore from 21st January 2021 to 20th February 2022. Individual’s demographic details, diagnostic tests, clinical presentation, kidney biopsy indications, and post-biopsy complications were recorded on pre-designed questionnaire/pro-forma. Data analysis was done using SPSS version 27. Results: Out of 94 patients, about 76 (80.9%) patients had primary glomerular disease diagnosed on native kidney biopsies. The overall mean age was 38.4± 6.2 years. Out of 94 primary glomerular disease patients, there were 48 (51.1%) male and 46 (48.9%) females. The incidence of nephrotic syndrome and unexplained renal parameters elevations were 47.4% (n=36) and 31.6% (n=24) respectively. The prevalence of Primary focal segmental glomerulosclerosis (FSGS), membrano-proliferative glomerulonephritis (MPGN), minimal change disease, and IgA nephropathy was 30.3% (n=23), 25% (n=19), 17.1% (n=13), and 6.6% (n=5) respectively. Kidney biopsy post-complications were found in 8 (10.5%) cases. Conclusion: The present study observed that MPGN and FSDS were the most prime causes for primary glomerular disease. The most prevalent indication of kidney biopsy was nephrotic syndrome. Keywords: Glomerular disease, kidney biopsy, histopathological pattern, adult patients

Cyclic neutropenia and concomitant IgA nephropathy: a case report

BackgroundIgA nephropathy (IgAN) is universally recognized as one of the most common primary glomerular diseases in all ages. Cyclic neutropenia (CN) is a rare haematologic disorder that is associated with mutations of the ELANE gene. The co-occurrence of IgAN and CN is extremely rare. This is the first case report of a patient with IgAN and genetically confirmed CN.Case presentationWe report a case of a 10-year-old boy who presented with recurrent viral upper respiratory tract infections accompanied by several episodes of febrile neutropenia, haematuria, proteinuria and acute kidney injury. Upon first admission, his physical examination was unremarkable. His kidney function was impaired, whereas his urine microscopy showed evidence of macroscopic haematuria and proteinuria. Further workup showed elevated IgA. The renal histology was consistent with mesangial and endocapillary hypercellularity with mild crescentic lesions, while immunofluorescence microscopy showed IgA-positive staining, which was characteristic of IgAN. Moreover, genetic testing confirmed the clinical diagnosis of CN, therefore Granulocyte colony-stimulating factor (G-CSF) was initiated to stabilize the neutrophil count. Regarding proteinuria control, the patient was initially treated with an Angiotensin-converting-enzyme inhibitor for approximately 28 months. However, due to progressive proteinuria (> 1 g/24 h), Corticosteroids (CS) were added for a period of 6 months according to the revised 2021 KDIGO guidelines with favorable outcome.ConclusionsPatients with CN are more susceptible to recurrent viral infections, which can trigger IgAN attacks. In our case CS induced remarkable proteinuria remission. The use of G-CSF contributed to the resolution of severe neutropenic episodes, viral infections and concomitant AKI episodes, contributing to better prognosis of IgAN. Further studies are mandatory to determine whether there is a genetical predisposition for IgAN in children with CN.

Effects of modified Huangqi Chifeng decoction on the IL-17 signaling pathway in an IgA nephropathy rat model.

Immunoglobulin A nephropathy (IgAN) is an immune-related primary glomerular disease prevalent worldwide, with complicated clinical manifestations and an unclear pathogenesis. IgAN is the main cause of chronic renal failure and places a significant burden on patients and society. The modified Huangqi Chifeng decoction (MHCD) is an effective prescription for the clinical treatment of IgAN while its specific mechanism remains to be further elucidated. Based on the findings of previous network pharmacology-related method-based studies, this study aimed to further explore the mechanism of action of MHCD for IgAN treatment. IgAN rat model was established by bovine serum protein+carbon tetrachloride+lipopolysaccharide. After successful modeling, the rats in the original model group were divided into 5 group: model group, telmisartan group, and MHCD high-, medium- and low-dose groups by random number table (n=10 respectively). The corresponding drugs were applied for 8 weeks, and the experiment lasted for 21 weeks. At the end of the experiment, 24h urine protein quantification, serum biochemistry and IL-6 and IL-17A levels were measured. The pathological changes of kidney were observed by light microscope, immunofluorescence microscope and the changes of glomerular ultrastructure were observed by transmission electron microscope. The expression levels of IL-17 signaling pathway related proteins (HSP90, MMP9, NF-κB P65 and p-NF-κB P65) were detected by Western Blot and immunohistochemistry. Telmisartan and MHCD treatment can reduce the 24h urinary protein level and improved blood stasis states of IgAN rats, alleviate the renal pathological injury, decrease the serum levels of IL-6, IL-17A and the expression levels of HSP90, MMP9 and p-NF-κB P65 related proteins in IL-17 signaling pathway. MHCD can down-regulate the expression of IL-17 signaling pathway-related factors in IgAN model rats, improve the state of blood stasis, and alleviate the pathological damage of kidney in rats.

Alport syndrome misdiagnosed with IgA nephropathy from familial history: a case report and brief review

BackgroundAlport syndrome is a rare inherited disease resulting from a primary disorder of the glomerular basement membrane. This disease results from mutations in genes encoding alpha chains of type IV collagen. In the differential diagnosis of this disease, IgA nephropathy is the most common primary glomerular disease with gross or microscopic hematuria.Case presentationA 50-year-old woman was presented with microscopic hematuria and proteinuria of under one gram. Due to the diagnosis of IgA nephropathy in family members, she was treated and followed up for 4 years as a possible case of IgA nephropathy. Eye examination and audiometry were normal. She underwent renal biopsy with an exacerbation of proteinuria. There was no finding in favor of IgA nephropathy in the histological examination, but the findings of electron microscopy and family history favored Alport syndrome.ConclusionsThis case demonstrates the importance of accurate history and electron microscopy in the complete histological evaluation and diagnosis of glomerular disease. Although in most cases the two can be differentiated based on clinical manifestations, laboratory findings, and histopathological examination, sometimes the association of these two diseases in the families involved or the lack of accurate history and complete histological examinations can complicate the diagnosis.

Activation of CD3 + TIM3 + T cells contributes to excessive inflammatory response during glucocorticoid treatment

Glucocorticoids (GCs) are widely used to treat autoimmune and inflammatory diseases, but recent research has challenged the notion that GCs are universally anti-inflammatory. In this study, we investigated the effects of long-term GC exposure on circulating T cells in a retrospective cohort of 5,476 patients with primary glomerular diseases. Our results revealed that GCs altered the composition pattern of circulating leukocytes and the correlation between circulating lymphocytes and serum cytokines in response to infections, as well as the subsets of CD4 + T cells. Specifically, GCs promoted the loss of CD4 + T cells and increased the proportions of CD3 + TIM3 + T cells in response to infections, which correlated with the expression of serum inflammatory cytokines, such as IFNG and IL-10. Using animal models of cecal ligation and puncture, we demonstrated that long-term GC exposure exacerbated apoptosis of CD4 + T cells and cytokine storm during sepsis, which was mechanistically linked to the increase of CD3 + TIM3 + T cells. Notably, we found that CD3 + TIM3 + T cells expressed high levels of multiple cytokine genes during infections, suggesting a potent role of TIM3 in the regulation of T cell biology. In vitro studies further showed that engagement of anti-TIM3 treatment enhanced the inflammatory activity of CD3 + T cells. Our findings suggest a causal relationship between chronic exposure to GCs and an excessive inflammatory response mediated by T cells during infections, which is, at least partly, driven by dysregulation of CD3 + TIM3 + T cells.

Renal failure and pleural effusion; a diagnostic challenge

Sjögren’s syndrome is a chronic inflammatory disorder mostly involving the exocrine glands. Extraglandular disease may occur in up to one quarter of patients. Kidney involvement is rare, more often manifested by tubular dysfunction secondary to tubulointerstitial nephritis. Primary glomerular disease is uncommon. The authors present the case of a 73-year-old woman with xerostomia and positivity for anti-Ro and anti-La antibodies admitted for acute kidney injury and exudative pleural effusion. Biopsy of salivary glands was compatible with Sjögren’s syndrome. Extraglandular involvement was also confirmed by renal and pleural deposition of AA-amyloid. The patient was started on prednisolone followed by azathioprine with rapid improvement of lung disease. However, due to progressing renal disease and clinical deterioration, prognosis was guarded and the patient died. We describe a case of secondary amyloidosis with systemic involvement and infrequent clinical manifestations, briefly reviewing the key aspects of Sjögren’s syndrome and AA-amyloidosis.

KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression.

Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease.

Primary glomerular disease

This is a review of the clinical features, pathogenesis, investigation and management of glomerulonephritis (GN). GN can occur as a primary isolated renal disease, as a manifestation of systemic diseases such as vasculitis or lupus, or secondary to drugs, infections or tumours. It is an important cause of morbidity and mortality and a potentially preventable cause of end-stage renal disease; early diagnosis is vital to allow timely referral to specialist units where renal biopsy can be performed. Proteinuria and/or haematuria are typical findings. Pathogenesis involves immune cells and inflammatory mediators, with intrinsic glomerular cells, especially podocytes, also being important in glomerular injury and the responses to it. I present brief outlines of schemes for appropriate investigations when GN is suspected, and guidelines for referral strategies to investigate proteinuria and haematuria, and manage common forms of GN. When nephrotic syndrome (NS) is present, it can lead to major morbidity and potential mortality even if excretory renal function is well preserved. NS should be managed, irrespective of the cause, with diuretics, antiproteinuric agents, cholesterol-lowering agents and sometimes anticoagulants. Treatment with corticosteroids, with or without other immunosuppressive agents, is effective in many forms of GN, but adverse effects are problematic. More selective forms of immunotherapy are increasingly used as understanding of the pathogenesis of GN improves but there is a continuing need for better collaboration on clinical trials so that the evidence base can be improved.

Seasonal variations in renal biopsy numbers and primary glomerular disease features based on the Japan renal biopsy registry

We analyzed the seasonal variations in the number of renal biopsies and clinical characteristics of primary glomerular disease in Japan using the Japan Renal Biopsy Registry (J-RBR). We retrospectively collected clinical and pathological data of patients with primary glomerular disease who were registered in the J-RBR between 2007 and 2018. Immunoglobulin A nephropathy (IgAN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and postinfectious acute glomerulonephritis (PIAGN) constituted the four major glomerular disorders included in this study (total, 13,989; IgAN, 9121; MCNS, 2298; MN, 2447; and PIAGN, 123). The number of patients with IgAN or MCNS was higher during summer. However, no overt seasonal variations were observed in patients with MN or PIAGN. Subgroup analyses suggested that in the patients with IgAN, more renal biopsies of severe cases were performed during winter, probably owing to age and blood pressure. Furthermore, more renal biopsies of severe cases were performed during spring and winter in patients with MCNS even after adjusting for the abovementioned host factors. This study suggests that seasonal factors influence the decision to perform renal biopsy as well as the pathogenesis of primary glomerular disease. Thus, our findings may provide important insights regarding the pathophysiology of primary glomerular disease.

Long-term glucocorticoid exposure persistently impairs CD4+ T cell biology by epigenetically modulating the mTORC1 pathway

Conventional glucocorticoid (GC) treatment has a long-term influence on T-cell immunity, resulting in an increased risk of opportunistic infection after drug withdrawal. The underlying mechanisms remain ambiguous. This study demonstrated that long-term GC treatment induced persistent lymphopenia in patients with primary glomerular disease. GCs continuously suppressed the proportion of CD4+ T cells even after the daily dose was tapered down to the physiologic equivalences, leading to a significant decline of the CD4/CD8 ratio. Meanwhile, GCs impaired CD4+ T cell biology, leading to enhanced apoptotic cell death, reduced proliferative capacity, downregulated pro-inflammatory genes, and upregulated immunoregulatory genes. Specifically, GCs altered FOXP3 expression pattern in CD4+ T cells and favored their acquisition of an active T regulatory (Treg) cell phenotype with enhanced IL-10 production upon stimulation. Mechanistically, GCs tampered with the transcriptional regulation of mechanistic target of rapamycin complex 1 (mTORC1) pathway, resulting in an inhibitory impact on the signaling activity. Targeting mTORC1 signaling by siRNAs could sufficiently modify the viability of GC-exposed CD4+ T cells. By high-throughput sequencing of genome-wide DNA methylation and mRNA, we further uncovered a causal relationship between the altered DNA methylation level and transcription activity in a subset of mTORC1 pathway genes in long-term GC exposure. Taken together, this study reveals a novel regulation of mTORC1 signaling, which might dominate the long-term influence of GC on CD4+ T cell biology in a dose-independent manner.

Clinical efficacy of supplementing qi dispelling wind and activating blood circulation method in the treatment of IgA nephropathy: A meta-analysis.

IgA nephropathy (IgAN) is a common primary glomerular disease, and supplementing qi dispelling wind and activating blood is commonly used as a treatment method in Chinese medicine. However, the existing studies have small sample sizes. This study aimed to use a meta-analysis to explore the clinical efficacy of this method and to systematically introduce this effective treatment. We searched for randomized controlled trial studies on supplementing qi dispelling wind and activating blood circulation methods for IgAN indexed in the China National Knowledge Infrastructure, Wanfang Data, Chongqing VIP, SinoMed, PubMed, EMBASE, and Web of Science databases, which were interrogated from database inception to January 2022. Combining the inclusion and exclusion criteria to screen the literature, we included a total of 15 eligible studies; the quality of the included studies was evaluated using the risk of bias assessment tool of the Cochrane System Revies Manual 5.4. The outcome indexes were extracted, and a meta-analysis was performed using Review Manager 5.4 software. Fifteen articles were included in this review. A meta-analysis of the results led to the conclusion that supplementing qi dispelling wind and activating blood circulation prescription has beneficial effects on the total effective rate [odds ratios = 3.95, 95% confidence interval (CI) 2.76-5.67], and can reduce 24-hour urinary protein quantity (mean deviation = -0.35, 95% CI -0.54 to -0.16) and serum creatinine (mean deviation = -15.41,95% CI -28.39 to -2.44) without impact normal level of alanine transaminase, hemoglobin, and serum albumin. Supplementing qi dispelling wind and activating blood can significantly improve renal function and reduce 24-hour urinary protein quantity levels in patients with IgAN compared to the use of non-Chinese medicine treatment. This finding provides a rationale for using this method in the clinical treatment of IgAN.

TYRO3 agonist as therapy for glomerular disease.

Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts antiapoptotic and antiinflammatory effects to confer protection against podocyte loss. Among the 3 TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. Therefore, we posited that the agonistic PS/TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonists as an optimal therapeutic approach to glomerular disease. Among the small-molecule TYRO3 agonistic compounds screened, compound 10 (C-10) showed a selective activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 were lost in Tyro3-knockout mice, indicating that C-10 is a selective agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.

Patterns of Glomerular Disease at a Large Urban Public Hospital in South Africa- Impact of HIV Infection

Abstract Introduction Glomerular disease is an important cause of renal failure. We sought to describe the patterns of glomerular disease in patients undergoing native kidney biopsy at a large urban public hospital in South Africa during the period 2001–2010. Methods We retrospectively reviewed all native kidney biopsies undertaken during the study period. We further characterised and compared clinical, laboratory and demographic data between glomerular pathologies. Results The majority of patients undergoing biopsy were young (median age 34 years) and of Black African descent (83%). Proteinuria was the most common indication for biopsy. Secondary glomerular disease was more common than primary glomerular disease. HIV-associated glomerular diseases were the most common secondary glomerulopathies Focal segmental glomerulosclerosis (FSGS) was the most frequent primary glomerulopathy. Minimal change nephropathy (MCN) was more frequent in younger patients and membranous nephropathy (MN) more common in older patients. Renal function was poorer in FSGS and membranoproliferative glomerular disease. Conclusions HIV is an important contributor to the high rates of secondary glomerular disease. Primary glomerulopathy demonstrates geographic variation in South Africa with FSGS being dominant in Johannesburg. Although clinical parameters may suggest underlying glomerulopathy, an accurate diagnosis to facilitate directed treatment and prevent progression to renal failure requires a renal biopsy.