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Frontiers in Immunology 2021We aimed to validate three IgAN risk models proposed by an international collaborative study and another CKD risk model generated by an extended CKD cohort with our... (Comparative Study)
Comparative Study
We aimed to validate three IgAN risk models proposed by an international collaborative study and another CKD risk model generated by an extended CKD cohort with our multicenter Chinese IgAN cohort. Biopsy-proven IgAN patients with an eGFR ≥15 ml/min/1.73 m at baseline and a minimum follow-up of 6 months were enrolled. The primary outcomes were a composite outcome (50% decline in eGFR or ESRD) and ESRD. The performance of those models was assessed using discrimination, calibration, and reclassification. A total of 2,300 eligible cases were enrolled. Of them, 288 (12.5%) patients reached composite outcome and 214 (9.3%) patients reached ESRD during a median follow-up period of 30 months. Using the composite outcome for analysis, the Clinical, Limited, Full, and CKD models had relatively good performance with similar C statistics (0.81, 0.81, 0.82, and 0.82, respectively). While using ESRD as the end point, the four prediction models had better performance (all C statistics > 0.9). Furthermore, subgroup analysis showed that the models containing clinical and pathological variables (Full model and Limited model) had better discriminatory abilities than the models including only clinical indicators (Clinical model and CKD model) in low-risk patients characterized by higher baseline eGFR (≥60 ml/min/1.73 m). In conclusion, we validated recently reported IgAN and CKD risk models in our Chinese IgAN cohort. Compared to pure clinical models, adding pathological variables will increase performance in predicting ESRD in low-risk IgAN patients with baseline eGFR ≥60 ml/min/1.73 m.
Topics: Adult; Cohort Studies; Creatinine; Disease Progression; Female; Follow-Up Studies; Glomerular Mesangium; Glomerulonephritis, IGA; Glucocorticoids; Hospitals, Teaching; Humans; Immunoglobulin A; Kidney Failure, Chronic; Male; Microscopy, Fluorescence; Middle Aged; Models, Theoretical; Multicenter Studies as Topic; Prognosis; Proteinuria; ROC Curve; Renin-Angiotensin System; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 34721428
DOI: 10.3389/fimmu.2021.753901 -
Renal Failure Nov 2020Glomerular IgG deposition in patients with IgA nephropathy (IgAN) has been shown to be associated with poor renal survival; however, most published studies to date are...
BACKGROUND
Glomerular IgG deposition in patients with IgA nephropathy (IgAN) has been shown to be associated with poor renal survival; however, most published studies to date are too small-scale and inconsistent to provide guidance for clinical practice.
METHODS
Based on renal biopsy findings, 742 patients were divided into the following groups: (i) IgA deposition alone (IgA) vs IgA + IgG deposition (IgA + IgG) and (ii) IgG co-deposition confined to the mesangium vs mesangium + capillary loops (CLs). The clinicopathological variables at biopsy and renal outcome were assessed.
RESULTS
Of the 742 patients, 182 had IgG co-deposition and 51 had IgG deposits in the mesangium + CLs. Patients with IgG co-deposition were associated with severe clinical and pathological lesions, especially those with a location of IgG deposits in the mesangium +CLs. Kaplan-Meier analysis revealed that a lower renal cumulative survival rate was present in both patients with IgG co-deposition and those with a location of IgG deposits in the mesangium + CLs (all < 0.05). Moreover, patients with a higher intensity of glomerular IgG deposits or C3 deposits or C1q deposits were also associated with a lower survival rate. A multivariate Cox regression model identified the location of IgG deposits in the mesangium + CLs as an independent risk factor for poor prognosis (, 2.11; 95% CI: 1.06-4.18; = 0.005).
CONCLUSIONS
Glomerular IgG co-deposition and the location of glomerular IgG deposits in the mesangium + CLs were both associated with adverse renal outcomes, but only the location of glomerular IgG deposits in the CLs was an independent risk factor for poor prognosis in IgAN.
Topics: Adult; Biopsy; Female; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin G; Kaplan-Meier Estimate; Kidney Glomerulus; Male; Middle Aged; Prognosis; Proportional Hazards Models; Retrospective Studies
PubMed: 32869693
DOI: 10.1080/0886022X.2020.1811120 -
Indian Journal of Nephrology 2022C4d is a biomarker of the complement cascade and has a primary role in the diagnosis of antibody-mediated rejection in solid organ transplantation. The present study was...
INTRODUCTION
C4d is a biomarker of the complement cascade and has a primary role in the diagnosis of antibody-mediated rejection in solid organ transplantation. The present study was undertaken to investigate the role of C4d in the diagnosis and prognosis of native renal diseases.
METHODS
An observational cross-sectional study was conducted in the Department of Pathology from September 2017 to September 2019. In this study, we applied C4d staining by immunohistochemistry in 51 native renal biopsies. Semiquantitative scoring was done on the basis of intensity of C4d staining along the glomerular capillary wall (0-3) and mesangium (0-3), tubules (0-3), and arteries (0-3). These individual scores were added to get the total C4d score (0-12) which was correlated with chronicity index, serum urea and creatinine levels. Glomerular C4d score was correlated with 24 h urinary protein as well as with immunofluorescence deposition of immunoglobulins and complements.
RESULTS
We found a linear positive correlation ( < 0.05) between the total C4d score and serum creatinine; tubular C4d score and serum creatinine; and glomerular C4d score along capillary wall and 24 h urinary protein. A positive correlation ( < 0.05) was found between glomerular C4d score along the capillary wall with immunofluorescence deposits of immunoglobulins and complements, suggesting the efficacy of C4d as a surrogate marker in the diagnosis of native renal diseases.
CONCLUSIONS
C4d deposition is associated with a poor prognosis in renal diseases and an accelerated deterioration of renal function. It also plays a role as a surrogate marker in diagnosis of native renal diseases.
PubMed: 35603116
DOI: 10.4103/ijn.IJN_251_20 -
Journal of the American Society of... Sep 2019
Topics: Glomerular Mesangium; Kidney Glomerulus; Male; Mesangial Cells
PubMed: 31471498
DOI: 10.1681/ASN.2019070724 -
Journal of the American Society of... Sep 2022The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear...
The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications. One, which uses novel serial section electron microscopy, reveals a shorter capillary pathway between the basins of the afferent and efferent arterioles. Such a pathway, when patent, may short-circuit the multitude of capillaries in the glomerular tuft. Notably, this shorter capillary route is enclosed within the glomerular mesangium. The second study used anti-Thy1.1-induced mesangiolysis and intravital microscopy to unequivocally establish the long-suspected contractile function of mesangial cells, which have the ability to change the geometry and curvature of glomerular capillaries. These studies led me to hypothesize the existence of a glomerular perfusion rheostat, in which the shorter path periodically fluctuates between being more and less patent. This action reduces or increases blood flow through the entire glomerular capillary tuft. A corollary is that the GFR is a net product of balance between the states of capillary perfusion, and that deviations from the balanced state would increase or decrease GFR. Taken together, these studies may pave the way to a more profound understanding of glomerular microcirculation under basal conditions and in progression of glomerulopathies.
Topics: Microcirculation; Kidney Glomerulus; Glomerular Mesangium; Arterioles; Kidney Tubules
PubMed: 35853715
DOI: 10.1681/ASN.2022030354 -
Molecules (Basel, Switzerland) Oct 2022Diabetes mellitus (DM) is a group of metabolic disorders, the characteristics of which include chronic hyperglycemia owing to defects in insulin function, insulin... (Review)
Review
Diabetes mellitus (DM) is a group of metabolic disorders, the characteristics of which include chronic hyperglycemia owing to defects in insulin function, insulin secretion, or both. Inflammation plays a crucial role in DM pathogenesis and innate immunity in the development of microvascular complications of diabetes. In addition, hyperglycemia and DM mediate a proinflammatory microenvironment that can result in various microvascular complications, including diabetic nephropathy (DNP), diabetic neuropathy (DN), and diabetic retinopathy (DR). DNP is a major cause of end-stage renal disease. DNP can lead to albuminuria, decreased filtration, mesangium expansion, thickening of the basement membrane, and eventually renal failure. Furthermore, inflammatory cells can accumulate in the interstitium and glomeruli to deteriorate DNP. DN is another most prevalent microvascular complication of DM and the main cause of high mortality, disability, and a poor quality of life. DNs have a wide range of clinical manifestations because of the types of fiber dysfunctions and complex structures of the peripheral nervous system. DR is also a microvascular and multifactorial disease, as well as a major cause of visual impairment globally. Pathogenesis of DR is yet to be fully revealed, however, numerous studies have already confirmed the role of inflammation in the onset and advancement of DR. Despite evidence, and better knowledge regarding the pathogenesis of these microvascular complications of diabetes, there is still a deficiency of effective therapies. Bioactive compounds are mainly derived from plants, and these molecules have promising therapeutic potential. In this review, evidence and molecular mechanisms regarding the role of inflammation in various microvascular complications of diabetes including DNP, DN, and DR, have been summarized. The therapeutic potential of several bioactive compounds derived from plants in the treatment of these microvascular complications of diabetes has also been discussed.
Topics: Humans; Diabetes Mellitus, Type 2; Quality of Life; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Inflammation; Anti-Inflammatory Agents; Hyperglycemia
PubMed: 36364178
DOI: 10.3390/molecules27217352 -
Kidney International Reports Mar 2023Dysregulation of alternative complement pathway underlies the pathogenesis of both C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA). In this study, we...
INTRODUCTION
Dysregulation of alternative complement pathway underlies the pathogenesis of both C3 glomerulopathy (C3G) and thrombotic microangiopathy (TMA). In this study, we describe both disease entities occurring in 5 patients.
METHODS
We identified 114 patients at our institution from 2007 to 2016 with C3G in native kidney biopsies and those with concurrent TMA were included.
RESULTS
The median age at diagnosis was 58 years (range: 28-69); all were male. Median serum creatinine and proteinuria at presentation were 2.3 mg/dl and 2089 mg/d, respectively. Three cases presented with TMA-predominant phenotype and 2 with C3G-predominant phenotype. Immunofluorescence (IF) showed bright C3 staining in mesangium and/or capillary walls. Electron microscopy showed marked subendothelial expansion by fluffy material in the capillary loops without associated deposits. However, capillary wall deposits were present in other loops in 4 cases. Mesangial deposits were present in all cases. Four cases showed low C3, of which 2 showed low C4. Complement evaluation in 3 cases showed pathogenic CFH mutation in 1 case, and multiple variant of unknown significance along with factor B autoantibody and C4 nephritic factor in 1 case. One patient negative for complement abnormalities had a monoclonal gammopathy. Three cases were treated with steroids and/or immunosuppressants. One case progressed to end-stage renal disease (ESRD) at 38.3 months; the remaining showed median serum creatinine and proteinuria of 2.5 mg/dl and 1169 mg/d, respectively at median follow-up of 17.5 months.
CONCLUSION
Overlap of C3G and TMA is rare and can clinically present as C3G-predominant or TMA-predominant phenotype. The significance of concurrent C3G/TMA findings on long-term renal survival remains to be explored.
PubMed: 36938079
DOI: 10.1016/j.ekir.2022.12.009 -
The Journal of Pathology Jun 2021IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune...
IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Albuminuria; Animals; Complement C3; Disease Models, Animal; Glomerulonephritis; Glomerulonephritis, IGA; Hematuria; Humans; Immunoglobulin A; Immunoglobulin G; Kidney; Kidney Glomerulus; Male; Mesangial Cells; Rats; Rats, Wistar; Recombinant Proteins
PubMed: 33660264
DOI: 10.1002/path.5658 -
Scientific Reports May 2023To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer...
To explore the feasibility of mesangium or membrane anatomy theory in thoracolaparoscopic radical esophagectomy for esophageal cancer, 98 patients with esophageal cancer were enrolled including 45 patients in the mesoesophageal esophagectomy group and 53 patients in the non-mesoesophageal esophagectomy group. Thoracolaparoscopic radical esophagecotmy was technically successful in all patients. Compared the non-mesoesophageal group, the mesoesophageal group had significantly (P < 0.05) shorter surgical duration (211.9 ± 42.0 min vs. 282.0 ± 44.5 min), less blood loss during the procedure (68.9 ± 45.9 ml vs. 167.0 ± 91.4 ml), more harvested lymph nodes (25.9 ± 6.3 vs. 21.8 ± 7.3), shorter hospital stay after surgery (10.5 ± 2.5 d vs. 12.5 ± 4.2 d), shorter fasting time or quicker postoperative feeding time (7.3 ± 1.2 d vs. 9.5 ± 3.9 d), and quicker removal of the thoracic drainage tube after surgery (7.7 ± 2.0 d vs. 9.2 ± 4.1 d). The overall incidence of postoperative complications was 46.7% (21/45) in the mesoesophageal group, which was significantly (P = 0.02) fewer than that (69.8% or 37/53) of the non-mesoesophageal group (P = 0.020). During follow-up 20.6 ± 4.3 or 20.8 ± 3.4 months after esophagectomy, liver metastasis occurred in 1 case and lung metastasis in 1 in the mesoesophageal group, whereas liver metastasis occurred in 2 cases, mediastinal metastasis in 2, and anastomotic recurrence in 1 in the non-mesoesophageal group. The mesoesophageal group had significantly better physical function (81.9 ± 7.3 vs. 78.3 ± 7.6), social function (65.1 ± 7.1 vs. 56.2 ± 18.2), global health status (65.3 ± 10.1 vs. 58.7 ± 12.4), and pain improvement (29.5 ± 9.5 vs. 35.6 ± 10.6). The overall survival rate was 82.2% (37/45) in the mesoesophageal group and 71.7% (38/53) in the non-mesoesophageal group (P = 0.26). The disease-free survival rate was 77.8% (35/45) for the mesoesophageal group and 62.3% (33/53) for the non-mesoesophageal group (P = 0.13). In conclusion:, the mesangium or membrane anatomy theory can be used safely and effectively to guide thoracolaparoscopic radical esophagectomy for esophageal cancer, with advantages of shorter surgical time, less bleeding, more lymph node harvest, fewer complications, and faster postoperative recovery.
Topics: Humans; Esophagectomy; Lymph Node Excision; Esophageal Neoplasms; Lymph Nodes; Postoperative Complications; Retrospective Studies
PubMed: 37253750
DOI: 10.1038/s41598-023-35513-w -
CEN Case Reports Nov 2020Nintedanib, a triple tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor...
Nintedanib, a triple tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has been used in idiopathic pulmonary fibrosis and adenocarcinoma in advanced non-small cell lung cancer. Although vascular endothelial growth factor inhibitors have been reported to cause endothelial injury and glomerular microangiopathy, nintedanib-induced glomerular microangiopathy has not been reported. A 68-year-old man with a history of primary aldosteronism, idiopathic pulmonary fibrosis, and pleomorphic carcinoma of the lung developed proteinuria and leg edema after nintedanib initiation. Kidney biopsy revealed prominent endothelial and mesangial injury. Proteinuria improved after nintedanib withdrawal. To the best of our knowledge, this is the second case report of nintedanib-induced glomerular microangiopathy. Although the incidence of nephropathy among patients receiving nintedanib is unknown at this moment, we recommend monitoring urinary protein excretion and blood pressure in patients receiving nintedanib and performing kidney biopsy to determine any histopathological change.
Topics: Aged; Carcinoma; Endothelium, Vascular; Glomerular Mesangium; Humans; Hyperaldosteronism; Idiopathic Pulmonary Fibrosis; Indoles; Kidney; Kidney Diseases; Lung Neoplasms; Male; Protein Kinase Inhibitors; Proteinuria; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Thrombotic Microangiopathies; Withholding Treatment
PubMed: 32279192
DOI: 10.1007/s13730-020-00474-w