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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 -
BMC Nephrology Oct 2021Galactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the...
BACKGROUND
Galactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the glomerular mesangium. Several studies showed that glomerular IgG deposition in IgAN is an important cause of mesangial proliferation and glomerular damage. This study aims to determine the association of the positivity of IgG and the intensity of IgG staining with a poor renal prognosis.
METHODS
A total of 943 IgAN patients were included in the study. Glomerular IgG staining negative and positive patients were compared using Oxford classification scores, histopathological evaluations, proteinuria, eGFR, albumin, blood pressures. IgG positive patients were classified as (+), (++), (+++) based on their staining intensity, and the association with the prognostic criteria was also evaluated.
RESULTS
81% (n = 764) of the patients were detected as IgG negative, while 19% (n = 179) were positive. Age, gender, body mass index, blood pressure, proteinuria, eGFR, uric acid values were similar in IgG positive and negative patients who underwent biopsy (p > 0.05). Intensity of glomerular IgG positivity was not found to be associated with diastolic and systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p > 0.05 for all, r = - 0.084, r = - 0.102, r = - 0.006, r = 0.062, r = 0.014, r = - 0.044, r = - 0.061, r = - 0.066, r = 0.150, respectively). There was no difference for histopathological findings between IgG (+), IgG (++), IgG (+++) groups (for all, p > 0.05).
CONCLUSION
Glomerular IgG negativity and positivity detected by routine IFM in IgAN patients is not associated with poor renal prognostic risk factors.
Topics: Adult; Cross-Sectional Studies; Female; Glomerulonephritis, IGA; Humans; Immunoglobulin G; Kidney Glomerulus; Male; Middle Aged; Prognosis; Retrospective Studies; Staining and Labeling
PubMed: 34711174
DOI: 10.1186/s12882-021-02560-2 -
Clinical Journal of the American... Dec 2021IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in...
BACKGROUND AND OBJECTIVES
IgA nephropathy is the most common primary GN worldwide. Previous research demonstrated that collectin11, an initiator of the complement lectin pathway, was involved in both AKI and chronic tubulointerstitial fibrosis. Here, we investigated the potential role of collectin11 in the pathogenesis of IgA nephropathy.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
The deposition of collectin11 and other complement proteins was detected in glomeruli of 60 participants with IgA nephropathy by immunofluorescence. , human mesangial cells were treated with IgA1-containing immune complexes derived from participants with IgA nephropathy. Then, the expression of collectin11 in mesangial cells was examined by quantitative RT-PCR and immunofluorescence. The codeposition of collectin11 with IgA1 or C3 on mesangial cells was detected by immunofluorescence and proximity ligation assays.
RESULTS
In total, 37% of participants with IgA nephropathy (22 of 60) showed codeposition of collectin11 with IgA in the glomerular mesangium. Using an injury model of mesangial cells, we demonstrated that IgA1-immune complexes derived from participants with IgA nephropathy increased the secretion of collectin11 in mesangial cells with the subsequent deposition of collectin11 on the cell surface the interaction with deposited IgA1-immune complexes. , we found that collectin11 bound to IgA1-immune complexes in a dose-dependent but calcium-independent manner. Furthermore, deposited collectin11 initiated the activation of complement and accelerated the deposition of C3 on mesangial cells.
CONCLUSIONS
-produced collectin11 by mesangial cells might play an essential role in kidney injury in a subset of patients with IgA nephropathy through the induction of complement activation.
Topics: Humans; Glomerulonephritis, IGA; Antigen-Antibody Complex; Immunoglobulin A; Glomerular Mesangium; Complement Activation; Complement System Proteins
PubMed: 34615657
DOI: 10.2215/CJN.04300321 -
Case Reports in Nephrology and Dialysis 2021Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a...
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a progressive nature and can eventually lead to end-stage kidney failure. It can occur as a potential side effect of treatment with tumor necrosis factor alpha antagonist that has been used for numerous chronic inflammatory conditions, such as Crohn's disease. In this study, the case of a 33-year-old man with renal dysfunction, nephrotic proteinuria, and erythrocyturia is described. He had had a history of Crohn's disease for 8 years and had been treated with adalimumab for the past 7 years. The diagnosis of IgAN was confirmed by kidney biopsy. After discontinuance of adalimumab and the induction of corticosteroid therapy, he made a remarkable recovery. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was normal with no proteinuria and only mild erythrocyturia.
PubMed: 34595210
DOI: 10.1159/000515585 -
Journal of Clinical Medicine Sep 2021Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal...
Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulonephritis characterized by diffuse deposits of IgM in the glomerular mesangium. However, its renal prognosis remains unknown. We compared renal outcomes of IgMN patients with those of patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or mesangial proliferative glomerulonephritis (MsPGN) from a prospective observational cohort, with 1791 patients undergoing native kidney biopsy in eight hospitals affiliated with The Catholic University of Korea between December 2014 and October 2020. IgMN had more mesangial proliferation and matrix expansion than MsPGN and more tubular atrophy and interstitial fibrosis than MCD. IgMN patients had decreased eGFR than MCD patients in the earlier follow-up. However, there was no significant difference in urine protein or eGFR among all patients at the last follow-up. When IgMN was divided into three subtypes, patients with FSGS-like IgMN tended to have lower eGFR than those with MCD-like or MsPGN-like IgMN but higher proteinuria than MsPGN-like IgMN without showing a significant difference. The presence of hypertension at the time of kidney biopsy predicted ≥20% decline of eGFR over two years in IgMN patients. Our data indicate that IgMN would have a clinical course and renal prognosis similar to MCD, FSGS, and MsPGN.
PubMed: 34575298
DOI: 10.3390/jcm10184191 -
Biomedicines Aug 2021Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high...
Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients' serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic and mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.
PubMed: 34572299
DOI: 10.3390/biomedicines9091112 -
Frontiers in Medicine 2021Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant...
Podocyte foot process effacement is a key histologic finding in proteinuric kidney disease. We previously showed that 3-week old CD2AP-deficient mice have significant proteinuria, glomerular hypertrophy and mesangial expansion. The goal of this study is to use morphometry to establish the temporal sequence of podocyte foot process effacement, glomerular volume expansion and albuminuria in mice by measuring these parameters at the 2-week time point. Wild-type mice age 14 ± 1 days with the Cd2ap gene (WT, = 5) and mice deficient for Cd2ap ( KO, = 5) were generated. Kidneys were harvested and fixed in 2.5% glutaraldehyde and processed for examination by light and electron microscopy. An average of 415.2 (range 268-716) grid points were counted for all the glomeruli, and quantification of glomerular volume from each kidney. Urine was collected the day prior to sacrifice for urine albumin-to-creatinine ratio (ACR) measurements. There was no difference in albuminuria [median (range) mg/g] between WT [212.2 (177.6-388.4) mg/g] vs. KO mice [203.3 (164.7-910.2) mg/g], = 0.89; or glomerular volume 68,307[10,931] vs. 66,844[13,022] μm, = 0.92. The volume densities of glomerular components of the podocyte, capillary lumen and mesangium were not different for the two groups, = 0.14, 0.14 and 0.17 respectively. However, foot process width was increased in KO 1128[286] vs. WT [374 ± 42] nm, = 0.02. Here we show that while 2-week old WT and KO mice have similar levels of albuminuria, glomerular and mesangial volume, KO mice have more extensive podocyte foot process effacement. The data suggests that podocyte injury is the initiating event leading to mesangial expansion and albuminuria in this model.
PubMed: 34568396
DOI: 10.3389/fmed.2021.745319 -
American Journal of Physiology. Renal... Nov 2021Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E,...
Following our previous reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN) (Kriz W, Löwen J, Federico G, van den Born J, Gröne E, Gröne HJ. 312: F1101-F1111, 2017; Löwen J, Gröne E, Gröne HJ, Kriz W. 317: F399-F410, 2019), we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulointerstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerged from two defects: ) increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium and ) a defect of glomerular vessels consisting of increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of accumulated worn-out GBM material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule (BC) to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally intact podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulotubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myofibroblasts resulting in interstitial fibrosis. Based on analysis of 918 human biopsies, essential derangement in diabetic nephropathy consists of accumulation of worn-out glomerular basement membrane in the mesangium that may advance to global sclerosis. The most frequent pathway to nephron dropout starts with the penetration of glomerular capillaries into Bowman's capsule (BC), delivering an exudate into BC that spreads around the entire glomerular circumference and via the glomerulotubular junction onto the tubule, resulting in glomerular sclerosis and chronic tubulointerstitial damage.
Topics: Biopsy; Bowman Capsule; Capillaries; Capillary Permeability; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Fibrosis; Glomerular Basement Membrane; Glomerulonephritis; Humans; Microscopy, Electron, Transmission; Neovascularization, Pathologic; Nephrons; Podocytes
PubMed: 34541901
DOI: 10.1152/ajprenal.00669.2020 -
Journal of the American Society of... Oct 2021IgA nephropathy (IgAN) is the most common primary GN worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger...
BACKGROUND
IgA nephropathy (IgAN) is the most common primary GN worldwide. Circulating immune complexes form that are prone to deposition in the mesangium, where they trigger glomerular inflammation. A growing body of evidence suggests that dysregulated expression of microRNAs in IgAN may play a significant role in establishing the disease phenotype.
METHODS
We generated single miR-23b-3p(miR-23b) knockout mice using CRISPR-Cas9.
RESULTS
In humans, miR-23b levels are downregulated in kidney biopsies and sera of patients with IgAN, and serum miR-23b levels are negatively correlated with serum IgA1 levels. We show that miR-23b mice develop an IgAN-like phenotype of mesangial IgA and C3 deposition associated with development of albuminuria, hypertension, an elevated serum creatinine, and dysregulated mucosal IgA synthesis. Dysregulation of IgA production is likely mediated by the loss of miR-23b-mediated suppression of activation-induced cytidine deaminase in mucosal B cells. In addition, we show that loss of miR-23b increases the susceptibility of the kidney to progressive fibrosis through loss of regulation of expression of gremlin 2 and IgA accumulation through downregulation of the transferrin receptor.
CONCLUSIONS
Our findings suggest an indispensable role for miR-23b in kidney disease, and in particular, IgAN. miR-23b may in the future offer a novel therapeutic target for the treatment of IgAN.
Topics: Animals; B-Lymphocytes; Bone Morphogenetic Proteins; Cells, Cultured; Complement C3; Cytidine Deaminase; Cytokines; Down-Regulation; Enzyme Activation; Female; Fibrosis; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Hypertension; Immunoglobulin A; Intestinal Mucosa; Male; Mice; Mice, Knockout; MicroRNAs; Phenotype; Receptors, Transferrin; Signal Transduction
PubMed: 34479967
DOI: 10.1681/ASN.2021010133 -
Archivos Argentinos de Pediatria Aug 2021Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulopathy characterized by diffuse global mesangial deposits of IgM. We retrospectively studied the clinical...
Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulopathy characterized by diffuse global mesangial deposits of IgM. We retrospectively studied the clinical and histopathological characteristics of the patients with IgMN seen in our service. Of 241 renal biopsies, 21 corresponded to IgMN (8.7 %). One patient was excluded due to associated systemic disease and 2 due to follow-up less than 1 year, 18 were included (14 girls, median age 3.08 years). Fourteen manifested with nephrotic syndrome (NS) and the remaining with proteinuria (isolated or associated with hematuria). On Nefropatía por inmunoglobulina M: características histopatológicas y clínicas. Serie de casos Immunoglobulin M nephropathy: histopathological and clinical characteristics. Case series light microscopy, 13 had hyperplasia with mesangial expansion and 5 had focal and segmental sclerosis. Of the patients with NS, 7 were steroid-resistant, 4 steroid-dependent, and 3 frequent relapsers. All patients with NS and 1 with proteinuria-hematuria received immunosuppressants; the 18 patients also received antiproteinuric drugs. After 5.2 years (2-17.5) of follow-up, 6 patients developed chronic kidney disease.
Topics: Child, Preschool; Female; Hematuria; Humans; Immunoglobulin M; Nephrotic Syndrome; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies
PubMed: 34309313
DOI: 10.5546/aap.2021.e335