Primary IgA Nephropathy Research Articles

Characterization of IgA Deposition in the Kidney of Patients with IgA Nephropathy and Minimal Change.

Approximately 5% of patients with IgA nephropathy (IgAN) exhibit mild mesangial lesions with acute onset nephrotic syndrome and diffuse foot process effacement representative of minimal change disease (MCD). It is not clear whether these unusual cases of IgAN with MCD (IgAN-MCD) are variant types of IgAN or coincidental deposition of IgA in patients with MCD. In a retrospective multicenter cohort study of 18 hospitals in Korea, we analyzed 46 patients with IgAN-MCD. Patients with endocapillary proliferation, segmental sclerosis, and crescent were excluded, and the clinical features and prognosis of IgAN-MCD were compared with those of pure MCD. In addition, we performed galactose-deficient IgA1 (KM55) staining to characterize IgAN-MCD. Among the 21,697 patients with glomerulonephritis enrolled in the database, 46 patients (0.21%) were diagnosed with IgAN-MCD, and 1610 patients (7.4%) with pure MCD. The 46 patients with IgAN-MCD accounted for 0.6% of primary IgAN patients (n = 7584). There was no difference in prognosis between patients with IgAN-MCD and those with only MCD. IgA and KM55 showed double positivity in all patients with IgAN-MCD (n = 4) or primary IgAN (n = 5) under double immunofluorescent staining. However, in four patients with lupus nephritis, mesangial IgA was deposited, but galactose-deficient-IgA1 (Gd-IgA1) was not. These findings suggest that IgAN-MCD is a dual glomerulopathy in which MCD was superimposed on possibly indolent IgAN. We confirmed by KM55 staining that IgAN-MCD is true IgAN, enabling better characterizations of the disease. Furthermore, IgAN-MCD shows a good prognosis when treated according to the usual MCD treatment modality.

Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy

In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn’s disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.

The analysis of treatment of Immunoglobulin A-nephropathy

An evaluation of the effectiveness of immunosuppressive therapy (IST) and tonsillectomy (TE) in patients with IgA nephropathy (IgAN). A retrospective cohort of the study included cases with biopsy proven primary IgAN (n=367, age 3412 years, men 55%). We used demographic and clinical and morphological parameters at the time of biopsy. Median followup period was 26 (10; 61) months. Outcomes were remission (complete or partial) and the progression of IgAN (defined as the start of dialysis or a decrease in glomerular filtration rate 50% from baseline). All patients received treatment with renin angiotensin system blockers. Evaluation of the effectiveness of therapy was carried out using propensity score (PS) methods matching, conventional double robust regression models with PS as independent covariate, and inverse probability weighting. Following patient subgroups were used for comparative analyses: with IST (n=176) and without IST (n=191); with TE (n=63) and without TE (n=304); without IST and without TE (IST-TE-; n=162); with TE and without IST (IST-TE+; n=29); with IST and without TE (IST+TE-; n=142); with IST and with TE (IST+ TE+; n=34). All PS methods used gave close estimates of the comparative effectiveness of treatment in different subgroups: 1) patients on monotherapy with corticosteroids (CS) and combination of CS with other immunosuppressants did not have significant differences in probabilities of IgAN progression (hazard ratio 0.919; 95% CI 0.3332.950) and remission (odds ratio 0.919; 95% CI 0.3792.344) and were further combined into a group of IST; 2) IST was significantly associated with the lower risk of disease progression and increased odds ratio for remission; 3) the positive effects of IST were limited to cases with proteinuria 2 g/24 h; 4) the likelihood of IgAN remission and progression did not differ significantly between TE+ and TE-, IST-TE+ and IST-TE- groups. There were no cases of disease progression in the IST+TE+ group. The cumulative renal survival was higher in the IST+TE+ group compared to IST+ TE- group (p=0.010), while the probability of remission did not differ. IST was associated with a lower risk of IgAN progression and increased probability of remission, while these effects of IST were limited to patients with proteinuria 2 g/24 h. TE in combination with IST is associated with an additional reduction in the risk of disease progression.

External Validation of the International IgA Nephropathy Prediction Tool.

The International IgA Nephropathy Network recently developed and externally validated two models to predict the risk of progression of IgA nephropathy: full models without and with race. This study sought to externally validate the International IgA Nephropathy Prediction Tool in a large, independent, and contemporary cohort in China. We included 1373 patients with biopsy-confirmed primary IgA nephropathy from The First Affiliated Hospital of Zhengzhou University from January 2012 to May 2018 and calculated predicted risks for each patient. The outcomes of interest were a 50% decline in eGFR or kidney failure. We assessed the performance of both models using discrimination (concordance statistics and Kaplan-Meier curves between subgroups), calibration (calibration plots), reclassification (net reclassification improvement and integrated discrimination improvement), and clinical utility (decision curve analysis). The median follow-up was 29 months (interquartile range, 21-43 months; range, 1-95 months), and 186 (14%) patients reached the kidney outcomes of interest. Both models showed excellent discrimination (concordance statistics >0.85 and well separated survival curves). Overall, the full model without race generally underestimated the risk of primary outcome, whereas the full model with race was well calibrated for predicting 5-year risk. Compared with the full model without race, the full model with race had significant improvement in reclassification, as assessed by the net reclassification improvement (0.49; 95% confidence interval, 0.41 to 0.59) and integrated discrimination improvement (0.06; 95% confidence interval, 0.04 to 0.08). Decision curve analysis showed that both full models had a higher net benefit than default strategies, and the model with race performed better. In this study, both full models demonstrated remarkable discrimination, acceptable calibration, and satisfactory clinical utility. The relatively short follow-up time may have limited the validation of these models.

Reduced Recurrence of Primary IgA Nephropathy in Kidney Transplant Recipients Receiving Everolimus With Corticosteroid: A Retrospective, Single-Center Study of 135 Transplant Patients

BackgroundLong-term kidney allograft survival remains a major clinical challenge. Recurrent glomerulonephritis disease, including recurrence of IgA nephropathy (IgAN), is a significant barrier to long-term kidney allograft survival. We performed a retrospective, observational study to evaluate the role of everolimus (EVR) in the risk of recurrent IgAN. MethodsThe study included data from 135 patients aged ≥16 years with biopsy-proven IgAN on native kidneys who underwent a kidney transplant (KT) between December 2002 and December 2018. ResultsPatients who underwent de novo KT received mycophenolate mofetil (MMF) (n = 107) or EVR (n = 28). The mean recipient age in the MMF and EVR groups was 44.9 ± 13.7 and 41.1 ± 10.1, respectively. The median (interquartile range) follow-up period was 90.9 (64.9-115.3) and 21.2 (11.4-30.6) months, respectively (< .0001). All patients received continuous corticosteroid and tacrolimus therapy. The death-censored graft survival rate after KT and the recurrence-free survival rate did not differ significantly between the groups. Univariate and multivariate Cox regression analyses identified EVR for de novo KT as an independent predictive factor for recurrence-free survival (P = .024). ConclusionsOur findings suggest that EVR-based regimens with tacrolimus and corticosteroid therapy for de novo KT reduce the recurrence of IgAN compared with MMF-based regimens with tacrolimus and corticosteroid therapy.

Progress in Pathogenesis of Immunoglobin A Nephropathy.

The understanding of the pathogenesis of any disease is the key to effective and specific treatment of the disease. immunoglobulin A (IgA) nephropathy is an autoimmune disease of the kidney. Oxford MEST classification is commonly used to stratify patients according to the severity of the disease. Patients with IgA nephropathy seem to produce anti-GalNAc antibodies against a particularly defective IgA1. This immune complex deposits in the kidneys, leading to a type 3 hypersensitivity reaction which ultimately damages the kidneys. People of a certain genetic background and who experience upregulation of certain defective receptors seem to develop primary IgA nephropathy. Secondary IgA nephropathy could be due to dysbiosis of the microbiota in the gut, compromised gut immunity or other gut pathologies, pulmonary function abnormalities, or amyloidosis. Overproduction of IgA due to plasma cell dyscrasia or reduced clearance of IgA due to liver abnormalities could also be potential causes. Genes that predispose individuals to IgA nephropathy and intestinal abnormalities, such as Celiac disease, seem to overlap and these people tend to have a poorer prognosis and need to be placed on more intensive treatment regimens. IgA Vasculitis seems to be a systemic form of IgA nephropathy, whereby IgA deposits systemically and leads to multiple disease manifestations. Patients in high-risk groups could also be prophylactically screened for the disease and closely monitored by immunohistochemical methods such as an enzyme-linked immunosorbent assay (ELISA) or identified by genetic testing. Currently, the major treatment regimens involve supportive therapy or immunosuppressive therapy which has major side effects. More specific treatment methods such as monoclonal antibodies, immunoglobulin replacement therapy, or low-antigen-content diet could also be looked into as potential treatment options. Stem cell replacement, by way of bone marrow transplant and tonsillectomy, has been suggested as a treatment option in patients with indications.

P0412VALUE OF INTERNATIONAL RISK-PREDICTION TOOL IN IGA NEPHROAPTHY : A SINGLE CENTRE STUDY

Abstract Background and Aims A new International Risk-Prediction Tool in IgA Nephropathy developed was recently developed to help predict disease progression over a 5-7 year period1. We tested use of this Risk-Prediction Calculator in patients diagnosed with IgA Nephropathy to stratify the risk and predict outcomes during follow up. Method All adult patients (aged ≥18years) with biopsy proven IgA Nephropathy diagnosed between 2011 and 2016 at Manchester University NHS Foundation Trust were included in the study. Exclusion criteria included patients with secondary causes, prior exposure to immunosuppression, or presentation eGFR of less that 15ml/min. Demographic, clinical phenotypic &amp; renal histological characteristics (MEST score) at baseline were used to calculate the individual risk scores. These risk scores were compared with outcomes seen during subsequent follow up. Primary outcome was a composite of first ESRD or reduction in eGFR to below 50% of value at biopsy. Patients were censored at last follow visit for primary outcome or death. Renal outcomes were analysed using Kaplan Meier survival plots of subgroups based on predicted risk (&amp;lt;16th percentile, 16-50th percentile, 50-84th percentile or &amp;gt;84th percentile). Results 121 patients were included in the analyses. 45 other patients were excluded based on exclusion criteria. 84 patients (69%) were males, mean age was 42±16 years, eGFR was 63±34ml/min and uPCR was 151±42mg/mmol. Mean follow up was 51.4±28 months. 87% were on RAS inhibition at or within 6 weeks of kidney biopsy diagnosis. During the follow up period 23 patients (19%) developed the primary outcome. Outcomes were significantly worse in patients with higher risk-prediction scores (Fig 1 log rank p&amp;lt;0.01). Conclusion This single centre study confirms that the International IgA Nephropathy Risk-Prediction Model for kidney outcomes can be a valuable tool for prognostication in Primary IgA Nephropathy in routine clinical practice.

P0136COMPARISON OF SECONDARY IGA NEPHROPATHY OF ANKYLOSING SPONDYLITIS AND PRIMARY IGA NEPHROPATHY IN CLINICAL AND PATHOLOGICAL FEATURES

Abstract Background and Aims Renal involvement is one of the most common extra-articular complications caused by ankylosing spondylitis (AS). The main pathological manifestation is secondary IgA nephropathy(SIgAN) in Chinese AS patients. The difference between SIgAN and primary IgAN (PIgAN) remains unclear due to the lack of cases. Therefore, the aim of this retrospective study was to compare the clinical and pathological features of SIgAN of AS (SIgAN-AS) and PIgAN, to detect the pathogenesis of SIgAN Method Clinical characteristics and pathological data were collected in patients who were diagnosed with IgAN by renal biopsy in our hospital from Jan 2008 to Oct 2018. Patients with SIgAN-AS were recruited by the ratio 1:5 of patients with primary IgAN as the control group in the study. Fifteen patients with SIgAN-AS and Seventy-five patients with PIgAN were enrolled in this retrospective study. Results There were 15 cases in AS group, including 13 male and 2 female. The cohort of 75 patients with PIgAN included 34 male and 41 female. There were more males in AS group 13/15 (86.7%) vs 37/75(49.3%) ,P &amp;lt; 0.05. Compared with PIgAN patients, SIgAN-AS patients had higher incidences of hematuria( 13/15(86.7%)vs 44/75 (58.7%) , P &amp;lt; 0.05), lower levels of 24-hour urinary protein(0.85±0.68 vs 1.57±1.54g, P &amp;lt; 0.05), but higher levels of eGFR (CKD-MDRD formula) (117.60±37.33 vs 85.35±31.36, P &amp;lt; 0.05),eGFR (CKD-EPI formula) (128.01±41.58 vs 92.75±36.09, P &amp;lt; 0.05), Albumin (44.67±3.48 vs 41.09±7.07 g/L, P &amp;lt; 0.05) ESR (43.20 ±33.94 vs 18.79±16.26mm/h, P &amp;lt; 0.001) , and CRP (21.19±30.61 vs 2.11±4.58mg/L, P &amp;lt; 0.001) . From the perspective of renal pathology of PIgAN, SIgA-AS patients had fewer incidences of renal tubular atrophy / interstitial fibrosis of nephropathy (P &amp;lt;0.05). The immunohistostaining analysis showed higher incidences of dominant deposits of single IgA in mesangial cell area (P &amp;lt; 0.05). Conclusion Patients with SIgAN-AS is more common in male and display a milder progression than those with primary IgAN. Majority of the SIgAN-AS can be improved with early intervention.

P0228THE NEFIGARD TRIAL: THE EFFECT OF NEFECON® (BUDESONIDE) IN PATIENTS WITH PRIMARY IGA NEPHROPATHY AT RISK OF DEVELOPING END-STAGE RENAL DISEASE

Abstract Background and Aims Since the first description of IgA nephropathy (IgAN) over 50 years ago, it has been recognised that the mucosal immune system plays a crucial role in the pathogenesis of this common global cause of kidney failure. Recently, particular attention has focussed on the importance of the gut-associated lymphoid tissue (GALT) as the potential source of the poorly O-galactosylated IgA1 that triggers the formation of nephritogenic immune complexes in IgAN. Pathway analysis based on a large meta-analysis of genome wide association studies identified the intestinal immune network for IgA production as the most enriched KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway in IgAN. Furthermore, separate studies have shown that the IgA in glomerular IgA deposits is indistinguishable from mucosal IgA. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. After 9 months’ treatment, urine protein–creatinine ratio (UPCR) was reduced by 29.3% in the NEFECON® 16 mg group compared with the placebo group. Estimated glomerular filtration rate (eGFR) dropped 4.7 ml/min/1.73 m2 in the placebo group with no deterioration seen in the NEFECON® 16 mg group. Incidence of patients reporting adverse events was similar in all groups. These data led to the design of the NefIgArd study which aims to assess the efficacy, safety, and tolerability of NEFECON® 16 mg in patients with IgAN at risk of end-stage renal disease. Method The NefIgArd study is a randomised, double-blind, placebo-controlled Phase 3 trial, with two parts – PART A a 15–35-day screening period, 9-month treatment and 3-month follow-up period; and PART B a 12-month no-treatment follow-up period (Figure). The study is recruiting across 146 nephrology clinics in 19 countries. Patients must be at least 18 years old with biopsy-confirmed primary IgAN and persistent proteinuria &amp;gt;1 g/24 h and eGFR between 35 and 90 ml/min per 1.73 m2 (CKD-EPI) despite optimised renin–angiotensin system blockade. Patients are randomised on a 1:1 ratio to NEFECON® 16 mg/day or placebo. Consistent with the Kidney Health Initiative White Paper “Proteinuria Reduction as a Surrogate End Point in Trials of IgA Nephropathy” published in early 2019, the primary outcome of Part A is to assess the effect of NEFECON® 16 mg on 24 h UPCR at 9 months compared with placebo. The Part B primary outcome is based on data presented at the NKF/FDA/EMA workshop in March 2018 that supported eGFR slope as an endpoint for full approval and will assess the effect of NEFECON® 16 mg on a 2-year eGFR-based endpoint compared with placebo. In comparison with other studies that are recruiting, we believe that the relatively short period required to provide validation of the surrogacy of proteinuria reduction will significantly reduce the risks of non-protocol treatments and loss of patients from the study that could dilute the true treatment effect of NEFECON®. Results As of 1 January 2020, 207 patients have been randomised, and Part A is expected to complete in Q4 2020, with Part B completing in 2022. To ensure the NefIgArd study results are fully translatable to the global IgAN population, NefIgArd will also open in China in 2020. Conclusion The NefIgArd study builds on the experience of the NEFIGAN trial, the largest commercially sponsored study ever completed in IgAN. The design of the NefIgArd study has used state-of-the-art data to evaluate kidney outcomes, using proteinuria as a reasonably likely surrogate of the effect of NEFECON® on long-term kidney outcomes and confirming long-term renoprotection using an NKF/FDA/EMA-suggested eGFR-based endpoint as a basis for full approval.

P0490IS THE SEVERITY OF GLOMERULAR IGG STAINING IN PATIENT WITH IGA NEPHROPATHY USEFUL FOR PREDICTING POOR RENAL PROGNOSIS? THE DATA FROM TSN-GOLD WORKING GROUP

Abstract Background and Aims In IgA nephropathy (IgAN), which is characterized by mesangial IgA accumulation, there is the formation of circulating autoantibodies against galactose deficient IgA1s (Gd-IgA1). IgG / Gd-IgA1 immunocomplexes accumulate in the glomerular mesangium and play a role in the pathogenesis of IgAN. Recent studies have suggested a relationship between glomerular IgG deposition and the severity of glomerular inflammation. However, detection of the presence and severity of IgG in routine immunofluorescence microscopy (IFM) may fail. This study aims to investigate whether IgG positivity detected by IFM is associated with poor renal prognostic indicators and whether renal prognosis can be predicted according to IgG positivity. Method 4399 patients who were enrolled between May 2009-June 2019 in database of Turkish Society of Nephrology, Glomerular Diseases Working Group (TSN-GOLD) including 44 centers were evaluated. After exclusion criteria, 994 primary IgAN patients were included in the study. Glomerular IgG negative and positive patients were compared by means of Oxford classification scores, histopathological evaluations, proteinuria, creatinine, albumin, blood pressures. IgG positive patients were divided into subgroups according to the grade of the IFM positivity. The relationship between IgG positivity and poor prognosis criteria were evaluated. Results Demographic and biochemical findings of glomerular IgG positive and negative patients at the time of biopsy are shown in Table 1. No difference was found between the groups. There was no difference in the demographic and biochemical findings at the time of biopsy in IgG subgroup analyses (Table 2). There was no difference between the histopathological and Oxford MEST scores of the subgroups. Glomerular IgG positivity was not associated with diastolic blood pressure, systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p&amp;gt; 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). Conclusion Glomerular IgG positivity detected by routine IFM in IgAN is not associated with poor renal prognostic indicators. It is difficult to predict renal prognosis by looking at the severity of IgG positivity at the baseline evaluation.

The precise long-term outcomes of adult IgA nephropathy by mail questionnaires: Better renal survival compared to earlier cohort studies

The estimated 20-year renal survival rate of immunoglobulin A (IgA) nephropathy is approx. 60%, but it is difficult to determine the 'big picture' for IgA nephropathy because a biopsy is essential for its diagnosis. Here we attempted to determine the longer and more precise renal prognosis of IgA nephropathy. We examined 310 patients with primary IgA nephropathy. Using the patients' clinical records and histological reports from our hospital and other clinics, we surveyed their renal prognoses and treatments within 1 year post-biopsy, and we sent questionnaires to the patients who had stopped visiting any hospital. We set renal death as the primary endpoint and analyzed factors related to renal death. The total patient cohort was 267: 159 males, 108 females; average age at biopsy, 37.7 years; average estimated glomerular filtration rate (eGFR), 69.7 mL/min/1.73m2; urinary protein, 1.3 g/day. The mean follow-up duration was prolonged to 13.8±8.9 years (vs. 9.2±8.5 years using only medical records). The 10- and 20-year follow-up rates were 61.7% and 27.3%. The 10-, 20-year renal survival rates were 83.6% and 72.5%. Lower eGFR, hypertension, and smoking were revealed as factors independently related to renal death. To study survival of relatively benign diseases such as IgA nephropathy, longer survival rate was affected by many censoring cases. The results regarding the long-term renal prognoses of IgA nephropathy patients (including those with a mild phenotype) obtained by our analysis of a questionnaire sent to the patients provided more precise and longer-term prognoses compared to earlier studies.

Spatiotemporal trends and prognosis of end-stage renal disease patients with biopsy-proven immunoglobulin Anephropathy in France from 2010 to 2014.

BackgroundAlthough end-stage renal disease (ESRD) is frequently used as an outcome marker for primary immunoglobulin A nephropathy (IgAN), the clinical course after reaching ESRD is not well documented. This study examined patients’ characteristics and survival in ESRD-related biopsy-proven IgAN in France.MethodsFrench Renal Epidemiology and Information Network Registry data from 2010 to 2014 were used to analyse patients’ survival and outcome in incident ESRD patients >16 years of age with biopsy-proven primary IgAN, in comparison with other primary and secondary glomerulonephritis (GN), adult polycystic kidney disease (ADPKD) or diabetes. Multivariable survival analysis was adjusted for age, sex, time on dialysis and comorbidities.ResultsAmong 17 138 incident dialysis patients with ESRD, IgAN (242.8/10 000 dialysis initiation) represents the most common GN related to ESRD during 2010. IgAN patients were the youngest, and had the fewest comorbidities and the highest use of peritoneal dialysis (PD) (17%). In comparison with the haemodialysis group, hazard ratios for death were not different in the preemptive transplantation group [0.46, 95% confidence interval (CI) 0.17–1.28] and in the PD group (0.77, 95% CI 0.44–1.33). Mortality rates in IgAN patients with preemptive transplantation and in those receiving dialysis waiting for transplantation were 2.9% (95% CI 0.0–5.6) and 6.7% (95% CI 0.9–12.3). Mortality rates of ADPKD patients receiving dialysis waiting for transplantation were higher (18%, 95% CI 3.1–30.6).ConclusionIgAN has the best prognosis among primary and secondary GN. IgAN patients receiving dialysis waiting transplantation seem to have a more favourable prognosis than ADPKD patients, who usually comprise the reference population. The underlying reasons for the difference in access treatment modalities should be investigated to improve survival with respect to renal disease.

Fecal microbiota characteristics of Chinese patients with primary IgA nephropathy: a cross-sectional study

BackgroundGrowing evidence has shown that the gut-renal connection and gut microbiota dysbiosis play a critical role in immunoglobulin A nephropathy (IgAN). However, the fecal microbiome profile in Chinese patients with IgAN remains unknown. A cross-sectional study was designed for the first time to investigate the fecal microbiota compositions in patients with primary IgAN in China and to evaluate the relationship between the fecal microbiome and IgAN clinical presentation.MethodsFecal samples were collected from 17 IgAN patients and 18 age-, sex-, and body mass index-matched healthy controls, and bacterial DNA was extracted for 16S ribosomal RNA gene sequencing targeting the V3-V4 region.ResultsFecal samples from the IgAN patients and healthy controls showed differences in gut microbiota community richness and compositions. Compared to the healthy controls, IgAN patients at the phylum level had an increased abundance of Fusobacteria, but a decreased abundance of Synergistetes. The significantly increased genera in the IgAN group were Escherichia-Shigella, Hungatella, and Eggerthella, all of which possess pathogenic potential. Furthermore, the genus Escherichia-Shigella was negatively associated with the estimated glomerular filtration rate (eGFR) but was positively associated with the urinary albumin-to-creatinine ratio (uACR). However, the genus rectale_group was present in the IgAN group with a low abundance and was negatively associated with the uACR. Functional analysis disclosed that infection-related pathways were enriched in the IgAN group.ConclusionsWe demonstrate that gut microbiota dysbiosis occurs in patients with IgAN, and that changes in gut bacterial populations are closely related to IgAN clinical features, suggesting that certain specific gut microbiota may be a potential therapeutic target for IgAN.

Initial serum creatinine concentration affects clinical outcomes in patients with IgA nephropathy treated with mycophenolate mofetil combined with low-dose prednisone.

Indicators for predicting the efficacy of mycophenolate mofetil (MMF) have so far remained elusive. The present study aimed to identify predictive indicators of the efficacy of MMF combined with low-dose prednisone in patients with IgA nephropathy. A total of 598 patients presenting with primary IgA nephropathy at our center were screened. Patients were followed up for 18 months, where the end-point was defined as complete clinical remission. Cox proportional hazards models were performed for analyzing the initial serum creatinine (SCr) concentration to predict incomplete clinical remission. In total, 7 of 71 patients (9.86%) were in complete clinical remission at the final visit. Logistic regression indicated that the hazard ratio (HR) for quartile 4 was significantly higher than the HR for quartile 1 (quartile 4 vs. quartile 1: HR, 2.51; 95% CI, 1.20-5.21; P=0.01). Additional adjustment for the confounding variables, including age, sex, systolic BP, diastolic BP, proteinuria, uric acid, serum triglyceride, hemoglobin, serum albumin, serum total cholesterol and The Oxford classification of the models, did not reduce the HRs for the association between the initial SCr concentration and risk of incomplete clinical remission (quartile 4 vs. quartile 1: HR, 7.27; 95% CI, 1.21-43.63; P=0.03). Each unit increase in the initial SCr concentration was associated with a 67 and 194% increase in the risk of incomplete clinical remission based on model 1 (95% CI, 1.02-2.73; P=0.04) and model 2 (95% CI, 1.01-8.60; P=0.048), respectively. In conclusion, in the present cohort of patients with IgA nephropathy treated with MMF plus low-dose prednisone, the initial SCr concentration was an independent risk factor for incomplete clinical remission.

Relationship between serum C3/C4 ratio and prognosis of immunoglobulin A nephropathy based on propensity score matching.

BackgroundAberrant activation of the complement system plays an important role in the pathogenesis and development of immunoglobulin A nephropathy (IgAN). The relationship between serum complement and the clinical-histopathological features and outcomes of IgAN is controversial. This retrospective study aimed to examine the relationship between the complement 3/4 (C3/C4) ratio and the clinicopathologic changes and prognosis of patients with IgAN.MethodsA total of 397 patients with primary IgAN from January 2007 to December 2012 at the Chinese People's Liberation Army General Hospital were included in this study. The correlation test and Chi-square test or one-way analysis of variance test were performed to evaluate the relationship between the C3/C4 ratio and other clinical-pathological factors. Propensity score matching and a multivariate Cox regression model were used to calculate the risk factors of renal outcome.ResultsThe median follow-up period was 75 months. During the follow-up period, 62 patients (15.6%) developed into the end-stage renal disease (ESRD). The C3/C4 ratio at baseline was associated with the level of serum creatinine (SCr), 24 h urinary protein excretion (24 h Upre), global glomerular sclerosis, and tubulointerstitial lesion. The level of SCr and 24 h Upre and the degree of chronic kidney injury were statistically different among groups defined by different C3/C4 ratio levels. The survival rates of patients among groups with different C3/C4 ratio levels were different. After propensity score matching, eighty-eight pairs of patients were successfully matched, and the C3/C4 ratio was an influencing factor for the patients’ outcome (hazard ratio 0.587, 95% confidence interval 0.329–0.880). Patients with a C3/C4 ratio <3.6 had a poorer outcome compared with the others (P = 0.002).ConclusionsIgAN patients with decreased C3/C4 ratio displayed significantly more severe clinical symptoms and chronic renal injury than patients with higher ratios. A low C3/C4 ratio could be a risk factor for patients developing to ESRD.

Clinical Profile, Histopathological Features and Outcome of IgA Nephropathy in a Tertiary Care Hospital in India.

IgA nephropathy (IgAN) is reported to be more common in Asians and is considered to be a very progressive disease with worse outcome. The present study encompasses a cohort of biopsy-proven IgAN in a tertiary care hospital to characterize the initial clinical presentation, Oxford classification profile and one year follow up of patients with clinical and biochemical investigations. All renal biopsies with a diagnosis of primary IgAN were included. In all biopsies with ≥8 viable glomeruli, the MEST-C scores were analyzed, according to the Oxford criteria. Demographic and clinical data included age, gender, presence of hypertension, presence of hematuria and edema. Baseline investigations include urine protein semiquantitative, spot urine protein creatinine ratio, 24-h urinary protein, serum creatinine, and serum albumin. All the details of the use of antiproteinuric drugs and immunosuppressive drugs were recorded. Total 48 renal biopsies (21.62%) were diagnosed as primary IgAN. Thirty-seven (77.08%) had renal dysfunction on initial presentation out of which 31 (64.5%) patients had subnephrotic range proteinuria (SNRP). MEST-C lesions distribution were interpreted in 39 patients. 42.85% of patients with nephrotic range proteinuria (NRP) and 55.55% of patients with SNRP had renal deterioration during follow up period while 28.57% patients with NRP and 41.66% patients with SNRP had reached end-stage renal disease (ESRD). Our study population of IgAN has a unique clinical profile with hypertension, microscopic hematuria and subnephrotic proteinuria as the predominant clinical presentation. In spite of low MEST-C score in our study cohort, the disease has an aggressive course with 47.91% of patients with renal function deterioration and about one third follow up patients approaching ESRD during the study period.

Immunoglobulin A-nephropathy in Russian population: clinical and morphological presentation and long-term prognosis

AIM. The analysis of incidence, clinical and morphological manifestations, and the prognosis of IgA nephropathy in the Russian population.PATIENTS AND METHODS. Six hundred cases with primary IgA nephropathy (IgAN) from 1999 to 2019 were enrolled in the single-center retrospective study. Demographic and clinical parameters, morphrology data, and the treatment were analyzed. Three hundred forty seven patients were included in follow-up study. The following outcomes were evaluated: the occurrence of complete (PR) or partial remission (CR), death from all causes, the need for renal replacement therapy (RRT). The composite endpoint (RRT or eGFR decrease ≥ 50 % from the time of biopsy) was used to evaluate the risk of IgAN progression and associated factors.RESULTS. The period-average incidence of IgAN cases was 20.5 % of all indication biopsies and 31.7 % of primary immune glomerulopathies (with gradual increase to 41,5 % in last 5 years). At the time of the kidney biopsy, the proteinuria was 2.20 (1.10; 4.40) g/24h, eGFR – 69 ± 32 ml / min / 1.73 m2. Proportions of cases with arterial hypertension and with eGFR &lt;60 ml / min / 1.73 m2 were 75 % and 36 %, respectively. The prevalence of histological changes in accordance with the MEST-C classification was as follows: M1 – 40.5 %, E1 -22.9 %, S1-70.2 %, T1-22 %, T2 – 9 %, C1-16.7 %, C2 – 4.4 %. Combined deposits of IgA and IgM (71.1 % of cases) were more frequent compared to IgA and IgG (9,6 %). In the followup period (27 (11; 61) month), 6 deaths from all causes were registered (1.7 %). The 10-year cumulative renal survival was 75 % (by dialysis) and 55 % (by composite endpoint). PR registered in 26 % of cases, CR – 24 %. PR / CR was more frequent in patients who received immunosuppression compared with patients on renin-angiotensin system blockers only (60 % vs. 40 %, p = 0.001). In multivariable Cox regression the independent factors associated with the risk of IgAN progression were: male gender, a younger age, higher blood pressure and hematuria, lower eGFR, interstitial fibrosis/ tubular atrophy (≥50 %), peritubular capillaritis and the presence of any crescents. Compared to the cohorts of other ethnic or geographical affiliation, analyzed IgAN cases were found to have more severe clinical and morphological presentations and faster progression rate.CONCLUSION. While being the most common glomerulopathy, IgAN in the Russian population has more pronounced clinical and morphological presentations and an unfavorable prognosis.

BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF‑κB signaling pathway in glomerular mesangial cells.

The aim of the present study was to investigate the involvement of B cell-activating factor (BAFF) in the pathogenesis of IgA nephropathy by activating the tumor necrosis factor receptor-associated factor 6 (TRAF6)/NF-κB signaling pathway in glomerular mesangial cells. For the clinical analysis, blood, urine and kidney tissue samples were collected from 58 patients diagnosed with primary IgA nephropathy by renal biopsy. For the in vitro study, glomerular mesangial cells were divided into five groups: Control (con)-short hairpin RNA (shRNA) (control group); con-shRNA + BAFF (20 ng/ml); con-shRNA + BAFF + BAFF-RFc chimera protein (500 µg/ml); TRAF6-shRNA; and TRAF6-shRNA + BAFF (20 ng/ml). For the in vivo experiments, 60 Sprague-Dawley rats were randomly divided into four groups: Con-small interfering RNA (siRNA) (control group); con-siRNA + IgA (IgA nephropathy group), BAFF-RFc chimera protein (2 µg/ml) + IgA, and TRAF6-siRNA (0.2 µM) + IgA. Reverse transcription-quantitative PCR was performed to evaluate the mRNA expression levels of TRAF6, connective tissue growth factor (CTGF), fibronectin (FN) and NF-κBP65. Western blot analysis was used to detect the protein expression levels of TRAF6, FN, CTGF and phosphorylated-NF-κBP65 in glomerular mesangial cells and kidney tissues. The results revealed that plasma BAFF levels were positively correlated with the severity of pathological damage in patients with IgA nephropathy. In vitro, BAFF induced the mRNA and protein expression of TRAF6, CTGF, FN and NF-κBP65 in glomerular mesangial cells. After the BAFF-RFc chimera protein was added to inhibit the binding of BAFF and BAFF-receptor (-R), this effect was reduced. In vivo, inhibition of the effects of BAFF via injection with the BAFF-R Fc chimera protein reduced kidney damage in rats suffering from IgA nephropathy. The effect on the expression of signaling pathway-associated proteins was also alleviated. In conclusion, BAFF enhanced the expression of fibroblast factors in the kidneys by activating the TRAF6/NF-κB signaling pathway.

Secondary IgA Nephropathy Shares the Same Immune Features With Primary IgA Nephropathy

IntroductionGalactose-deficient IgA1 (Gd-IgA1) and related IgA/IgG immune complexes have been identified as the key drivers in the pathogenesis of IgA nephropathy (IgAN). However, their roles in the development of secondary IgAN are still unknown.MethodsIn this study, we measured the plasma Gd-IgA1 level, IgA/IgG complex, and Gd-IgA1 glomerular deposits in 100 patients with various kinds of secondary IgAN. Plasma Gd-IgA1 was measured using a lectin-based enzyme-linked immunosorbent assay, and Gd-IgA1 in glomerular deposits was examined by double immunofluorescent staining using its specific monoclonal antibody KM55.ResultsPatients with secondary IgAN presented with higher plasma Gd-IgA1 levels compared to healthy controls (median, 354.61 U/ml; interquartile range [IQR], 323.93, 395.57 U/ml vs. median, 303.17 U/ml; IQR, 282.24, 337.92 U/ml, P < 0.001) or patients with other kidney diseases (median, 314.61 U/ml; IQR, 278.97, 343.55 U/ml, P < 0.001). A similar trend was observed in plasma IgA/IgG immune complexes or IgA1. There were no differences between secondary and primary IgAN in plasma Gd-IgA1 levels (median, 378.54 U/ml; IQR, 315.96, 398.33 U/ml, P = 0.700) and IgA1-IgG complex levels (median, 18.76 U/ml; IQR, 14.51, 22.83 U/ml vs. median, 19.11 U/ml; IQR, 13.21, 22.37 U/ml, P = 0.888). Co-localized IgA1 and Gd-IgA1 of both secondary and primary IgAN indicated that they both share the feature of Gd-IgA1 deposits on the glomerular mesangium.ConclusionOur study strongly suggests that secondary IgAN shares a similar galactose-deficient IgA1-oriented pathogenesis with primary IgAN.

Clinical, pathological characteristics and outcomes of immunoglobulin A nephropathy patients with different ages.

To determine the clinical and pathological differences in immunoglobulin A (IgA) nephropathy (IgAN) with different ages, and to determine whether age is a risk factor for progression of IgAN. This was a single centre retrospective cohort study. Patients with biopsy-diagnosed primary IgAN were stratified into three groups: young-aged (14-29 years), middle-aged (30-49 years) and older-age (≥50 years). The primary outcome was end-stage renal disease (estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2 , dialysis or renal transplantation) or doubling of the baseline serum creatinine. A total of 981 patients were enrolled, including 65 (6.6%) patients in older-age group, 517 (52.7%) in middle-aged group and 399 (40.7%) in young-aged group. The older-age group had significantly higher levels of serum IgA, cholesterol, triglycerides and creatinine, and a reduced eGFR. In contrast to the young adults who had a higher percentage of crescent formation in glomeruli, the older-aged patients had more severe chronic pathological changes including global glomerulosclerosis and vascular lesions (p < .01). The cumulative renal survival in the older-age group was slightly shorter than that in the young adult or middle-aged group, but not achieving significant (p > .05). The 3- and 5-year renal survival rates were similar among the three groups. A multivariate Cox regression analysis showed that age was not an independent predictor of an unfavourable prognosis. The IgAN patients with aged 50 years or older had different clinical pathological changes as compared with younger patients. However, aging was not found as an independently predictor of renal progression of IgAN. Prolonged follow up is necessary to confirm this trend.