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1.
Int Immunopharmacol ; 91: 107282, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33370682

ABSTRACT

BACKGROUND: There are few studies describing the prevalence and immune features of people with subclinical mesangial immunoglobulin A (IgA) deposition in the Chinese population. We sought to investigate the prevalence of mesangial IgA deposition among kidney donors and the immune characteristics of donors with mesangial IgA deposition. METHODS: Fifty blood-related living donors with zero-hour allograft biopsies obtained at Peking University First Hospital were enrolled. Galactose-deficient IgA1 (Gd-IgA1) in glomerular deposits was examined by double immunofluorescent staining using the specific monoclonal antibody KM55. Plasma IgA, IgA1, Gd-IgA1 and antibodies directed against Gd-IgA1 were measured using enzyme-linked immunosorbent assay. RESULTS: Thirteen of 50 (26%) donors had mesangial IgA deposition, which was confirmed by both immunofluorescence and electron microscopy. The levels of plasma IgA, IgA1 and Gd-IgA1 were all increased in donors with IgA deposition compared with those without IgA deposition (mean ± SD, 3.54 ± 0.505 versus 2.356 ± 0.265 mg/ml, p = 0.049; 3.003 ± 0.4048 versus 2.356 ± 0.265 mg/ml, p = 0.057; and 4.719 ± 0.4357 versus 3.356 ± 0.4707 ug/ml, p = 0.0440, respectively). Colocalized IgA1 and Gd-IgA1 indicated that there were galactose-deficient IgA1 deposits in the glomerular mesangium. While donors with IgA deposition showed lower levels of IgG anti-glycan antibodies than patients with IgA nephropathy (37.71 ± 8.886 versus 78.86 ± 5.155 units/ml, p = 0.001). CONCLUSIONS: The immune features of donors with IgA deposition, including IgA1 and Gd-IgA1 deposition, were similar to those of patients with IgA nephropathy, but donors with IgA deposition had lower levels of antiglycan antibodies, which may explain the subclinical status of IgA deposition in donors. Mesangial IgA deposition was common in the Chinese blood related donors cohort, further large study with both living and cadaveric donor kidneys was still needed to confirm these findings.


Subject(s)
Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Immunoglobulin A/analysis , Kidney Transplantation , Living Donors , Polysaccharides/immunology , Adult , Autoantibodies/blood , Beijing/epidemiology , Case-Control Studies , Female , Glomerulonephritis, IGA/blood , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/epidemiology , Humans , Male , Middle Aged , Prevalence
2.
Theranostics ; 10(25): 11462-11478, 2020.
Article in English | MEDLINE | ID: mdl-33052226

ABSTRACT

Infections have been considered to play a critical role in the pathogenesis of IgA nephropathy (IgAN) because synpharyngitic hematuria is a common feature in IgAN. However, how infections participate in this process is still debated. More recent studies have also revealed that the alteration of the gut microbiome exerts a profound effect on host immune responses, contributing to the etiology or progression of autoimmunity. Considering IgA as the first line of defense against bacterial and viral antigens, this review evaluates the relationships among intestinal infections, gut microbiome, and IgA for a better understanding of the pathogenesis of IgAN. Moreover, as a prototype of IgA immunity, we provide detailed clarification of IgAN pathogenesis to shed light on other diseases in which IgA plays a role. Finally, we discuss potential therapies focusing on microbes and mucosal immune responses in IgAN.


Subject(s)
Gastrointestinal Microbiome/immunology , Glomerulonephritis, IGA/immunology , Immunity, Mucosal , Immunotherapy/methods , Infections/immunology , Animals , Complement Activation/immunology , Disease Models, Animal , Glomerular Mesangium/immunology , Glomerular Mesangium/pathology , Glomerulonephritis, IGA/microbiology , Glomerulonephritis, IGA/pathology , Glomerulonephritis, IGA/therapy , Humans , Immunoglobulin A/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology
3.
Ren Fail ; 42(1): 629-637, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32660366

ABSTRACT

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a clinical and pathological syndrome with heterogenous manifestation and progression. Complement activation is involved in the disease. However, the clinical significance of C4 deposition in IgAN is obscure. METHODS: A multicenter retrospective study was conducted in biopsy-proven IgAN patients. Based on mesangial C4 deposition, patients were divided into two groups. The baseline clinical data and immunopathological phenotypes were compared. The composite endpoint was defined as eGFR decline greater than 50%, doubling of baseline serum creatinine, the occurrence of end-stage renal disease (ESRD). RESULTS: A total of 642 IgAN patients were recruited, with 41 patients showing mesangial C4 deposition. The mesangial C4 positive group showed lower serum albumin, higher proteinuria, and a higher rate of IgG, IgM, and C1q mesangial deposition. After a median follow-up of 43.18 months, 81 (12.62%) patients achieved the composite endpoint. The multivariate Cox regression models identified glomerular C4 deposition (hazard ratios [HR] = 3.22, 95% confidence intervals [CI] = 1.51-6.87, p < 0.01), global sclerosis (G1 vs. G0, HR = 1.90, 95%CI = 1.02-3.52, p = 0.04; G2 vs. G0, HR = 3.72, 95%CI = 1.98-7.00, p < 0.01), male (HR = 1.80, 95%CI = 1.10-2.97, p = 0.02), serum creatinine (HR = 1.01, 95%CI = 1.00-1.01, p < 0.01), triglyceride (HR = 1.17, 95%CI = 1.01-1.35, p = 0.04), proteinuria (HR = 1.07, 95%CI = 1.01-1.13, p = 0.02), serum C3 level (HR = 0.05, 95%CI = 0.01-0.25, p < 0.01), and serum C4 level (HR = 99.59, 95%CI = 8.69-1140.89, p < 0.01) as independent risk factors for poor renal outcomes. CONCLUSIONS: Glomerular mesangial C4 deposition and global sclerosis are independent predictors for poor prognosis in IgAN patients.


Subject(s)
Complement C4/metabolism , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Glomerulonephritis, IGA/pathology , Adult , China , Creatinine/blood , Disease Progression , Female , Glomerular Filtration Rate , Glomerulonephritis, IGA/blood , Humans , Kaplan-Meier Estimate , Kidney Failure, Chronic/etiology , Male , Prognosis , Proportional Hazards Models , Proteinuria/etiology , Retrospective Studies , Risk Factors
4.
Pediatr Nephrol ; 35(5): 843-850, 2020 05.
Article in English | MEDLINE | ID: mdl-31932958

ABSTRACT

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schönlein purpura are common glomerular disorders in children sharing the same histopathologic pattern of IgA deposits within the mesangium, even if their physiopathology may be different. Repeated exposure to pathogens induces the production of abnormal IgA1. The immune complex deposition in the renal mesangium in IgAN or potentially in small vessels in Henoch-Schönlein purpura induces complement activation via the alternative and lectin pathways. Recent studies suggest that levels of membrane attack complex (MAC) in the urine might be a useful indicator of renal injury. Because of the emerging availability of therapies that selectively block complement activation, the aim of the present study is to investigate whether MAC immunostaining might be a useful marker of IgA-mediated renal injury. METHODS: We conducted immunohistochemistry analysis of the MAC on renal biopsies from 67 pediatric patients with IgAN and Henoch-Schönlein purpura. We classified their renal biopsies according to the Oxford classification, retrieved symptoms, biological parameters, treatment, and follow-up. RESULTS: We found MAC expression was significantly related to impaired renal function and patients whose clinical course required therapy. MAC deposits tend to be more abundant in patients with decreased glomerular filtration rate (p = 0.02), patients with proteinuria > 0.750 g/day/1.73 m2, and with nephrotic syndrome. No correlation with histological alterations was observed. CONCLUSIONS: We conclude that MAC deposition could be a useful additional indicator of renal injury in patients with IgAN and Henoch-Schönlein purpura, independent of other indicators.


Subject(s)
Complement Membrane Attack Complex/analysis , Glomerular Mesangium/pathology , Glomerulonephritis, IGA/diagnosis , IgA Vasculitis/diagnosis , Immunosuppressive Agents/therapeutic use , Adolescent , Biomarkers/analysis , Biopsy , Child , Child, Preschool , Complement Membrane Attack Complex/immunology , Complement Pathway, Alternative/drug effects , Complement Pathway, Alternative/immunology , Complement Pathway, Mannose-Binding Lectin/drug effects , Complement Pathway, Mannose-Binding Lectin/immunology , Feasibility Studies , Female , Follow-Up Studies , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/immunology , Glomerulonephritis, IGA/pathology , Humans , IgA Vasculitis/drug therapy , IgA Vasculitis/immunology , IgA Vasculitis/pathology , Immunoglobulin A/immunology , Immunosuppressive Agents/pharmacology , Male , Prognosis , Retrospective Studies , Treatment Outcome
5.
J Autoimmun ; 105: 102309, 2019 12.
Article in English | MEDLINE | ID: mdl-31402200

ABSTRACT

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and a major cause of chronic kidney disease and failure. IgAN is driven by an autoimmune reaction against galactose-deficient IgA1 that results in the generation of autoantibodies and large IgG-IgA immune complexes. Immune complexes accumulate in the glomerular mesangium causing chronic inflammation and renal scarring. A significant proportion of IgAN patients develop end-stage kidney disease and require dialysis or transplantation. Currently, there are no approved specific therapies that can ameliorate the systemic autoimmune reaction in IgAN and no biomarkers that can predict renal inflammation and scarring. In this study, we used shotgun LC-MS/MS proteomics to compare small volumes of urine from healthy subjects and IgAN patients. We identified multiple urine proteins with unknown renal or IgAN function. Our attention was captured by the increase of phosphatidylethanolamine binding protein-4 (PEBP4) in IgAN urine. The function of PEBP4 in IgAN or renal disease is unknown. Increased levels of urine and serum PEBP4 were subsequently validated in different cohorts of IgAN patients and PEBP4 was linked to declining kidney function in IgAN. Strong PEBP4 staining was sporadically seen in IgAN kidney biopsies, colocalising with IgA in glomeruli and in the lumen of kidney tubules. In a small number of IgAN biopsies, PEBP4 colocalised with IgA and CD19 while the increased excretion of PEBP4 in IgAN urine was accompanied by increased excretion of classic B-cell factors BAFF, BCMA and TACI as well as IgA and IgG. PEBP4 is a new IgAN-related protein with unknown function and a likely renal disease marker in urine and serum.


Subject(s)
B-Lymphocytes/immunology , Glomerulonephritis, IGA/immunology , Immunoglobulin A/immunology , Kidney/immunology , Phosphatidylethanolamine Binding Protein/immunology , Adult , Antigen-Antibody Complex/immunology , Autoantibodies/immunology , B-Lymphocytes/metabolism , Biomarkers/metabolism , Biopsy , Case-Control Studies , Female , Galactose/immunology , Galactose/metabolism , Glomerular Mesangium/immunology , Glomerular Mesangium/metabolism , Glomerulonephritis, IGA/metabolism , Humans , Kidney/metabolism , Kidney Failure, Chronic/immunology , Kidney Failure, Chronic/metabolism , Male
6.
BMC Nephrol ; 20(1): 25, 2019 01 25.
Article in English | MEDLINE | ID: mdl-30683055

ABSTRACT

BACKGROUND: Anti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy. We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months. CASE PRESENTATION: A 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years. Serum creatinine level was normal at that time. The first renal biopsy was performed. Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus. Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium. Therefore, the diagnosis was IgA nephropathy. Eight months later, the patient's serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/gCr). The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL. Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy. At 4 weeks after admission, the second renal biopsy was performed. Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli. IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition. Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed. Renal function was not restored despite treatment, but alveolar hemorrhage was prevented. CONCLUSIONS: We report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy. This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course.


Subject(s)
Anti-Glomerular Basement Membrane Disease/complications , Glomerulonephritis, IGA/complications , Anti-Glomerular Basement Membrane Disease/therapy , Autoantibodies/blood , Biopsy , Combined Modality Therapy , Complement C3/analysis , Female , Glomerular Mesangium/chemistry , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/therapy , Glomerulonephritis, Membranoproliferative/complications , Humans , Immunoglobulin A/analysis , Immunoglobulin G/analysis , Methylprednisolone/therapeutic use , Middle Aged , Plasma Exchange , Renal Dialysis
7.
Cell Mol Immunol ; 16(9): 735-745, 2019 09.
Article in English | MEDLINE | ID: mdl-29568121

ABSTRACT

Mesangial proliferative glomerulonephritis (MsPGN) is an inflammatory disease, but both the nature of disease progression and its regulation remain unclear. In the present study, we monitored the course of anti-Thy1 nephritis from days 1 to 5 and established gene expression profiles at each time point using microarrays to explore the development of inflammation. According to the gene expression profiles, macrophage infiltration (triggered by CCL2 activation) was evident on day 1 and enhanced inflammation over the next few days. We screened for genes with expression levels similar to CCL2 and found that the upregulation of the circadian gene albumin D-site-binding protein (DBP) was involved in CCL2 activation in mesangial cells. More importantly, CCL2 expression showed oscillatory changes similar to DBP, and DBP induced peak CCL2 expression at 16:00 a clock on day 1 in the anti-Thy1 nephritis model. We knocked down DBP through transfection with a small interfering RNA (siRNA) and used RNA sequencing to identify the DBP-regulated TNF-α-CCL2 pathway. We performed chromatin immunoprecipitation sequencing (ChIP-Seq) and the dual luciferase assay to show that DBP bound to the TRIM55 promoter, regulating gene expression and in turn controlling the TNF-α-CCL2 pathway. In conclusion, DBP-regulated circadian CCL2 expression by the TRIM55-TNF pathway in injured mesangial cells at an early stage, which promoted macrophage recruitment and in turn triggered infiltration and inflammation in a model of anti-Thy1 nephritis.


Subject(s)
Chemokine CCL2/metabolism , Circadian Rhythm , DNA-Binding Proteins/metabolism , Gene Expression Regulation , Isoantibodies/immunology , Nephritis/immunology , Thy-1 Antigens/immunology , Transcription Factors/metabolism , Animals , Chemokine CCL2/genetics , DNA-Binding Proteins/genetics , Glomerular Mesangium/immunology , Glomerular Mesangium/metabolism , Macrophages/immunology , Macrophages/metabolism , Nephritis/metabolism , Nephritis/pathology , Rats , Rats, Sprague-Dawley , Transcription Factors/genetics
8.
Clin Exp Nephrol ; 23(3): 371-379, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30293216

ABSTRACT

BACKGROUND: Glomerular immunoglobulin G deposition in patients with immunoglobulin A nephropathy (IgAN) has been shown to be associated with adverse renal outcomes. Clinical significance of mesangial immunoglobulin M (IgM) deposition in these patients remains to be proven. METHODS: One hundred patients who had a diagnosis of IgAN between 2001 and 2017 were enrolled. Patients were divided into two groups based on mesangial IgM deposition status. Groups were compared for demographic, clinical, and pathologic variables at baseline and in follow-up. Cox regression analysis was performed to evaluate the effect of mesangial IgM positivity on renal survival. RESULTS: IgM-positive group included 51% of participants. Baseline demographic and clinical parameters were not significantly different between groups. Mesangial IgM deposition was significantly associated with a higher segmental sclerosis score (p = 0.008). At last visit, median serum creatinine was higher (p = 0.021) and eGFR was lower (p = 0.006) in IgM-positive group. Nineteen (19%) of all patients reached the combined primary outcome which includes doubling in serum creatinine or evolution to ESRD. Cumulative renal survival was lower (p = 0.001) and resistant disease was more frequent in IgM-positive group (p = 0.026). Renal survival at 15 years was 94.2% and 59.7% in IgM-negative and IgM-positive groups, respectively (p = 0.006). Time-averaged proteinuria (HR 2.9; 95% CI 1.9-4.5; p < 0.001) and mesangial IgM deposition (HR, 13.2; 95% CI 1.9-93.1; p = 0.01) were found to be independent predictors of unfavorable renal outcomes. CONCLUSIONS: In conclusion, we demonstrated that mesangial IgM deposition independently associated with worse renal outcomes in patients with IgA nephropathy.


Subject(s)
Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Immunoglobulin M/metabolism , Adult , Creatinine/blood , Disease Progression , Female , Glomerular Filtration Rate , Glomerulonephritis, IGA/complications , Humans , Kidney Failure, Chronic/etiology , Male , Middle Aged , Proportional Hazards Models
9.
Pediatr Nephrol ; 34(8): 1311-1323, 2019 08.
Article in English | MEDLINE | ID: mdl-29948306

ABSTRACT

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40-80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.


Subject(s)
Complement C3 Nephritic Factor/immunology , Complement C3/immunology , Complement Pathway, Alternative/genetics , Glomerulonephritis, Membranoproliferative/immunology , Complement C3/genetics , Complement C3-C5 Convertases, Alternative Pathway/immunology , Complement Factor B/immunology , Complement Factor H/immunology , Glomerular Basement Membrane/immunology , Glomerular Basement Membrane/pathology , Glomerular Mesangium/immunology , Glomerular Mesangium/pathology , Glomerulonephritis, Membranoproliferative/genetics , Glomerulonephritis, Membranoproliferative/pathology , Humans
10.
Medicine (Baltimore) ; 97(52): e13799, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30593167

ABSTRACT

RATIONALE: Acute renal failure developing over a short period of time with evidence of glomerular disease by urine sediment microscopy characterizes the clinical syndrome of rapidly progressive glomerulonephritis (RPGN), of which the most common causes are ANCA-associated glomerulonephritis (GN), immune-complex mediated GN and anti-GBM disease. PATIENT CONCERNS: This was a middle-aged gentleman who presented with acute renal failure and a positive PR3-ANCA. DIAGNOSIS: Renal biopsy showed an unusual combination of PR3-ANCA GN with focal crescents, monoclonal immunoglobulin deposition disease (MIDD) and mesangial IgA deposition on renal biopsy. INTERVENTIONS: Serum and urine protein electrophoresis (UPEP) and immunofixation showed no detectable monoclonal paraprotein; bone marrow biopsy was negative for plasma cell neoplasia. He received high dose steroids and rituximab. OUTCOMES: The patient did not respond to treatment and progressed to end-stage renal failure within 2 months after presentation. LESSONS: To our knowledge, the simultaneous occurrence of MIDD, PR3-ANCA and mesangial IgA has not been reported. This case highlights not only the diagnostic but also the therapeutic challenges that such a complex case presentation poses to clinicians, where the culprit may not always be what would seem most obvious (such as ANCA in a patient with RPGN) but may, in fact, be an underlying and unsuspected disease, or possibly a combination of both.


Subject(s)
Acute Kidney Injury/immunology , Anti-Glomerular Basement Membrane Disease/immunology , Antibodies, Antineutrophil Cytoplasmic/immunology , Glomerulonephritis/immunology , Myeloblastin/immunology , Paraproteinemias/immunology , Disease Progression , Glomerular Mesangium/immunology , Humans , Male , Middle Aged
11.
Nephrology (Carlton) ; 23 Suppl 2: 4-9, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29968406

ABSTRACT

Post-transplant immunoglobulin A (IgA) nephropathy (IgAN) in the allograft is the major cause of allograft loss. Using a protocol biopsy, latent mesangial IgA deposition (IgAD) can be detected in the allograft. Latent IgAD is distinguished from IgAN by the absence of urinary abnormalities, although IgA is observed in the mesangium. However, the pathophysiology and most appropriate treatment strategy for latent mesangial IgAD in the allograft remain to be fully determined. Importantly, it is unknown whether all cases of post-transplant asymptomatic IgAD progress to symptomatic IgAN; indeed, IgA deposits disappear in some cases. The differences in allograft prognosis between asymptomatic IgAD and IgAN have also not been determined. Non-invasive methods of diagnosis of IgAD in the allograft using serological and pathological biomarkers are being developed. Possible serum biomarkers include serum galactose-deficient IgA1 (Gd-IgA1), Gd-IgA1-specific IgG and Gd-IgA1-specific IgA, and its immune complexes. Immunofluorescence analysis using Gd-IgA1 monoclonal antibody may provide a pathological biomarker. These serological and pathological biomarkers may be suitable for the characterization of the stage of IgAD. However, there is insufficient information regarding whether serological and pathological biomarkers can predict the progression of asymptomatic IgAD to symptomatic IgAN. We propose that the pathogenesis of IgAN can be defined through the clinical study of IgAD in the allograft using protocol biopsies conducted by nephrologists involved in clinical kidney transplantation.


Subject(s)
Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Immunoglobulin A/immunology , Kidney Transplantation/adverse effects , Allografts , Biomarkers/blood , Biopsy , Fluorescent Antibody Technique , Glomerular Mesangium/pathology , Glomerulonephritis, IGA/blood , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/therapy , Graft Survival , Humans , Immunoglobulin A/blood , Predictive Value of Tests , Treatment Outcome
12.
BMC Gastroenterol ; 18(1): 64, 2018 May 16.
Article in English | MEDLINE | ID: mdl-29769033

ABSTRACT

BACKGROUND: A relationship between IgA nephropathy (IgAN) and celiac disease (CD) has been reported. We show the pathogenetic link for the first time. CASE PRESENTATION: A 39-year-old man with cystic fibrosis (CF) and CF-related diabetes started to present gross hematuria, back pain and headache. At admission, laboratory analysis showed increase in serum creatinine of 1.5 mg/dl, together with hematuria and mild proteinuria (1 g/24 h). He underwent a renal biopsy to investigate the cause of hematuria and renal failure. Biopsy was consistent with IgAN. In view of patient reported dyspepsia, an upper gastrointestinal endoscopy with duodenal biopsies was undertaken and was normal. We looked for mucosal deposits of tTG-2 in the duodenum and the renal mesangium. tTG-2 deposits were found both in the duodenum and in renal biopsies, where they topographically replicated mesangial IgA deposits. After one year on a continued gluten containing diet, the patient developed a Marsh 2 type duodenal pathology. CONCLUSIONS: Our findings suggest a connection between CD and IgAN in terms of an immune-mediated gluten-induced pathogenesis even in the absence of villous atrophy and serum celiac autoantibodies.


Subject(s)
Autoantibodies/blood , Celiac Disease/complications , Celiac Disease/immunology , Duodenum/immunology , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/etiology , Glomerulonephritis, IGA/immunology , Transglutaminases/immunology , Adult , Humans , Intestinal Mucosa/immunology , Male
13.
BMC Nephrol ; 19(1): 82, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29625558

ABSTRACT

BACKGROUND: C1q nephropathy (C1qN) was first described as glomerular disease characterized by predominant meangial C1q deposits in patients with proteinuria and no evidence of systemic lupus erythematosus. Several studies, however, revealed the clinical heterogeneity of C1qN, showing some cases with normal urinalysis. To confirm the existence of cases with predominant mesangial C1q deposits and negative or mild proteinuria and/or hematuria, we investigated renal graft biopsy specimens showing negative to mild proteinuria (less than or equal to 1+ by dip stick test) and/or hematuria. METHODS: Eligible participants were kidney transplant cases who corresponded to the criteria for C1qN and were followed more than 10 years. Their medical records were reviewed to determine the age at detection of predominant mesangial C1q deposits, gender, original renal disease and reason for renal graft biopsy, blood pressure, degree of proteinuria and hematuria, and serum creatinine levels. RESULTS: From 414 cases in adults and children, five pediatric patients (the male to female ratio, 1:1.5) were eligible. At the time when predominant mesangial C1q deposits were detected, 2 cases presented with mild proteinuria without hematuria, but the other 3 cases showed normal urinalysis. Light microscopy revealed minor glomerular abnormality in all the cases. Immunofluorescent study showed predominant mesangial C1q deposits with IgG, IgM and C3 in all cases. All selected specimens presented electron dense-depos in the mesangium. Ten years later from the detection, 2 cases continued to be normal urinalysis and 3 cases had mild proteinuria without hematuria. During this follow-up period, no cases presented with persistent proteinuria and/or hematuria greater than or equal to 2+ by dip stick test. And no cases developed systemic lupus erythematosus. Follow-up renal graft biopsies were performed once in 2 cases 8 years later from the detection. They showed minor glomerular abnormalities. C1q deposit disappeared in one case. In another case, immunofluorescent study was not examined. CONCLUSIONS: This long-term observational study on transplanted kidneys confirms the existence of cases with predominant but silent C1q deposits in the mesangium who have negative or mild proteinuria.


Subject(s)
Complement C1q/analysis , Glomerular Mesangium/immunology , Glomerular Mesangium/pathology , Kidney Diseases/immunology , Kidney Diseases/pathology , Kidney Transplantation/adverse effects , Adolescent , Adult , Biopsy , Child , Child, Preschool , Female , Follow-Up Studies , Hematuria/pathology , Humans , Longitudinal Studies , Male , Postoperative Complications/immunology , Postoperative Complications/pathology , Proteinuria/pathology , Urinalysis , Young Adult
14.
Cell Physiol Biochem ; 45(6): 2161-2173, 2018.
Article in English | MEDLINE | ID: mdl-29544224

ABSTRACT

BACKGROUND/AIMS: Healing of mesangioproliferative glomerulonephritis involves degradation of excess extracellular matrix, resolution of hypercellularity by apoptosis and phagocytosis of apoptotic cells. Integrin receptors participate in the regulation of phagocytosis. In mice deficient for alpha8 integrin (Itga8-/-) healing of glomerulonephritis is delayed. As Itga8 is abundant in mesangial cells (MC) which are non-professional phagocytes, we hypothesized that Itga8 facilitates phagocytosis of apoptotic cells and matrix components by MC. METHODS: MC were isolated from wild type (WT) and Itga8-/- mice. Latex beads were coated with matrix components. Apoptosis was induced by cisplatin in macrophages and in DiI-stained MC. After coincubation of latex beads or apoptotic cells with MC, the phagocytosis rate was detected in WT and Itga8-/- MC via fluorescence microscopy and FACS analysis. RESULTS: Itga8-/- MC showed reduced phagocytosis of matrix-coated beads and apoptotic cells compared to WT MC. Reduction of stress fibers was observed in Itga8-/- compared to WT MC. Inhibition of cytoskeletal reorganization by inhibition of Rac1 or ROCK during phagocytosis significantly decreased the rate of phagocytosis by WT MC but not by Itga8-/- MC. CONCLUSION: The expression of Itga8 facilitates phagocytosis in MC, likely mediated by Itga8-cytoskeleton interactions. An impairment of MC phagocytosis might thus contribute to a delayed glomerular regeneration in Itga8-/- mice.


Subject(s)
Glomerular Mesangium/cytology , Integrin alpha Chains/genetics , Mesangial Cells/immunology , Phagocytosis , Animals , Apoptosis , Cells, Cultured , Gene Deletion , Gene Expression , Glomerular Mesangium/immunology , Glomerular Mesangium/metabolism , HEK293 Cells , Humans , Integrin alpha Chains/immunology , Mesangial Cells/metabolism , Mice , RAW 264.7 Cells , Rats, Sprague-Dawley
15.
Clin J Am Soc Nephrol ; 13(2): 258-264, 2018 02 07.
Article in English | MEDLINE | ID: mdl-29146701

ABSTRACT

BACKGROUND AND OBJECTIVES: The prognostic value of mesangial C4d deposits in IgA nephropathy has been analyzed in patients with reduced GFR but has not been analyzed in those with normal kidney function. The main objective of the study was to analyze the prognostic value of C4d deposits and association with response to treatment in patients with IgA nephropathy and normal GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 190 patients with idiopathic IgA nephropathy diagnosed by kidney biopsy between 1988 and 2005. The patients had GFR≥80 ml/min per 1.73 m2 at the time of diagnosis, and they had a paraffin-embedded kidney biopsy with eight glomeruli available. RESULTS: In total, 170 (89%) and 20 (11%) patients were >18 and <18 years old, respectively; median (interquartile range) follow-up was 15 (12-22) years. Mesangial C4d deposit prevalence was 20% (38 of 190). At diagnosis, C4d-positive versus -negative patients had higher protein-to-creatinine ratio (median [interquartile range]: 1.94 g/g [0.9-3.1] versus 1.45 g/g [0.9-2.2]; P=0.04). During follow-up, C4d-positive patients showed a higher number of nephritic flares (median [range]: 1.4 [0-5] versus 0.9 [0-2]; P=0.04), had a higher protein-to-creatinine ratio (median [interquartile range]: 1.32 g/g [0.7-1.7] versus 0.89 g/g [0.1-1.3]; P<0.01), were more prone to receive repeated treatment with corticosteroids (45% versus 24%; P<0.01), and showed a larger reduction in eGFR (-1.6 versus -0.8 ml/min per 1.73 m2 per year; P=0.04). Furthermore, the presence of mesangial C4d deposits was an independent predictor of long-term kidney survival. CONCLUSIONS: C4d deposits may be one of the earliest poor prognostic variables available for patients with idiopathic IgA nephropathy and normal kidney function at the time of diagnosis. However, Cd4 deposits alone are not associated with the response to angiotensin blockers or corticosteroid treatment.


Subject(s)
Complement C4b/analysis , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Peptide Fragments/analysis , Adolescent , Adult , Biomarkers/analysis , Biopsy , Disease Progression , Female , Glomerular Filtration Rate , Glomerular Mesangium/drug effects , Glomerular Mesangium/pathology , Glomerular Mesangium/physiopathology , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/pathology , Glomerulonephritis, IGA/physiopathology , Humans , Immunohistochemistry , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome , Young Adult
17.
Pathol Int ; 66(8): 453-9, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27439692

ABSTRACT

The Oxford classification (OC) of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as predictors of outcome. We aimed to validate the OC and to investigate the clinical significance of extracapillary hypercellularity and IgG immunostaining. We examined the renal outcome at December 31, 2014, of 121 adult patients with biopsy proven primary IgAN between 2003 and 2013. The primary endpoint was doubling of serum creatinine or renal replacement therapy initiation. The mean observation period was 59.7 months. Thirty-one percent of the patients presented with a grade of extracapillary hypercellularity. In comparison with the group with no crescents, they had higher grade of inflammation, lower eGFR and increased proteinuria. There were no differences between the IgA and IgA&IgG immunostaining groups regarding the disease progression risk factors. Mean kidney survival time for the entire cohort was 10.6 (9.1, 12.0) years. In the Cox regression model, the independent predictors of decreased renal survival were eGFR at time of biopsy, S1 and the presence of crescents. Our study showed that extracapillary proliferation and S1 had the greatest importance in establishing the renal prognosis of patients with IgAN.


Subject(s)
Glomerular Mesangium/immunology , Glomerulonephritis, IGA/classification , Glomerulonephritis, IGA/pathology , Adult , Cohort Studies , Female , Fluorescent Antibody Technique , Glomerular Filtration Rate , Glomerular Mesangium/pathology , Glomerulonephritis, IGA/immunology , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Male , Middle Aged , Retrospective Studies
18.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 47(3): 337-41, 2016 May.
Article in Chinese | MEDLINE | ID: mdl-27468476

ABSTRACT

OBJECTIVE: To explore the underlying mechanism of "Gubentongluo Formula" in treatment of IgA nephropathy (IgAN). METHODS: After the IgAN model was successfully induced at week 12, the Kunming mice were randomly divided into three groups: normal control group (n = 15), IgAN group (n = 15) and Traditional Chinese Medicine (TCM) group. The mice in normal control and IgAN group were intragastriclly administrated with normal saline for 8 weeks; meanwhile, the mice in TCM group were intragastriclly administrated with "Gubentongluo Formula" 1.35 mL/ (g · d). The levels of 24 h urine protein were determined at Week 0, 12 and 20. At week 20, the changes of renal pathology were detected; the mRNA expressions of transforming growth factor-ß (TGF-ß) and small mothers against decapentaplegic (Smad) 3 in Peyer's patches (PPs) were detected by fuorescent quantitative reverse transcription-polymerase chain reaction; the protein expressions of TGF-ß and Smad 3 in PPs were detected by immunohistochemistry technique; the levels of (IgA + B)/B lymphocytes in PPs were determined by flow cytometry. RESULTS: Compared with those results of normal control group, the levels of 24 h urine protein, IgA deposition in glomerular mesangial area, and expressions of protein and mRNA of TGF-ß and Smad3 in IgAN group were significantly increased (P < 0.01). Besides, the levels of (IgA+B)/B lymphocytes were significantly elevated in IgAN group (P < 0.01). All these indicators were improved in TCM group. Compared with IgAN group, the differences were statistically significant (P < 0.01). Compared with those results of control group, the levels of (IgA + B)/B lymphocytes showed no significant difference in TCM group (P > 0.05), but other indicators showed significant differences (P < 0.01). CONCLUSION: "Gubentongluo Formula" could effectively improve proteinuria and suppress IgA deposition in glomerular mesangial area in IgAN mice, due to affect IgA class switch recombination of B lymphocytes in PPs through regulating TGF-ß/Smad3 pathway.


Subject(s)
B-Lymphocytes/drug effects , Drugs, Chinese Herbal/pharmacology , Glomerulonephritis, IGA/drug therapy , Immunoglobulin Class Switching/drug effects , Peyer's Patches/drug effects , Animals , Glomerular Mesangium/drug effects , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/immunology , Immunoglobulin A/immunology , Immunohistochemistry , Mice , RNA, Messenger , Random Allocation , Smad3 Protein/metabolism , Transforming Growth Factor beta1/metabolism
19.
PLoS One ; 11(4): e0152315, 2016.
Article in English | MEDLINE | ID: mdl-27055155

ABSTRACT

Diabetic nephropathy (DN) is one of the most severe complications of diabetes and remains the largest cause of end-stage renal disease in the Western world. Treatment options are limited and novel therapies that effectively slow disease progression are warranted. Previous work suggested that treatment with CTLA4-Ig (abatacept), a molecule that binds and blocks B7-1 and is licensed for the treatment of rheumatoid arthritis, could ameliorate DN. This study was designed to assess whether B7-1 signalling constitutes a promising therapeutic pathway for DN. Mice injected with streptozotocin (STZ) were treated with abatacept and glycemia and renal function were assessed. No differences were found in diabetes progression, albumin excretion rates or albumin/creatine ratios, while mesangial expansion was unaltered at endpoint. Except for increased renal CCL5, treatment did not affect a panel of gene expression endpoints reflecting early fibrotic changes, inflammation and kidney injury. Finally, abatacept treatment effectively reduced the accumulation of activated CD4+ T cells in the kidney, suggesting that renal T cell inflammation is not a driving factor in the pathology of the STZ model. In conjunction with the recent data discounting the expression of B7-1 on podocytes, our present data do not support a role for abatacept in DN treatment.


Subject(s)
Abatacept/pharmacology , CD4-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Experimental/immunology , Diabetic Nephropathies/immunology , Glomerular Mesangium/immunology , Podocytes/immunology , Animals , B7-1 Antigen/immunology , CD4-Positive T-Lymphocytes/pathology , Chemokine CCL5/immunology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/drug therapy , Diabetic Nephropathies/pathology , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Glomerular Mesangium/pathology , Lymphocyte Activation , Mice , Podocytes/pathology
20.
G Ital Nefrol ; 33(2)2016.
Article in Italian | MEDLINE | ID: mdl-27067220

ABSTRACT

Tumor necrosis factor (TNF) inhibitors are widely used for the treatment of various rheumatic diseases. These agents may lead to development of systemic autoimmune diseases and renal complications. We report a patient with psoriatic arthritis and renal failure treated with two TNF inhibitors (Etanercept and then Adalimumab). After this treatment he developed proteinuria with nephrotic syndrome. A renal biopsy was performed highlighting GN with mesangial IgA deposits. Then he developed p-ANCA positivity. Following that, etanercept and adalimumab were stopped and a treatment by corticosteroids was initiated, but renal function decreased. Currently the patient is treated by haemodialysis. In our patient, the pathogenic role for anti-TNF therapy is suggested by the close temporal relationship with development of glomerular disease and by the improvement in proteinuria after drug withdrawal. However, the patient was treated once more with TNF agents, so he developed end stage renal disease.


Subject(s)
Antibodies, Antineutrophil Cytoplasmic/immunology , Antirheumatic Agents/adverse effects , Arthritis, Psoriatic/drug therapy , Glomerulonephritis, IGA/chemically induced , Glomerulonephritis, IGA/diagnosis , Immunoglobulin A/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab/adverse effects , Antirheumatic Agents/administration & dosage , Biomarkers/blood , Etanercept/adverse effects , Glomerular Mesangium/immunology , Glomerulonephritis, IGA/drug therapy , Glomerulonephritis, IGA/immunology , Humans , Kidney Failure, Chronic/chemically induced , Kidney Failure, Chronic/diagnosis , Male , Methylprednisolone/administration & dosage , Middle Aged , Treatment Outcome
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