Therapy For IgA Nephropathy Research Articles

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

Comparative Efficacy and Safety of New Therapies for IgA Nephropathy: A Systematic Review and Network Meta-Analysis

Comparative Efficacy and Safety of New Therapies for IgA Nephropathy: A Systematic Review and Network Meta-Analysis

Correlation of Urinary Soluble CD163 Levels With Disease Activity and Treatment Response in IgA Nephropathy

BackgroundThe TESTING trial demonstrated that corticosteroids reduce the risk of kidney failure in IgA nephropathy (IgAN) patients but increase the risk of serious adverse events. Reliable noninvasive biomarkers are needed to identify patients who would benefit most from corticosteroid therapy. Previous studies suggest glomerular macrophage infiltration is associated with the response to immunosuppressive therapy in IgAN and urinary soluble CD163(u-sCD163, a marker of M2c macrophage) is correlated with clinical remission in vasculitis. This study aims to investigate the association between u-sCD163 and response of steroids therapy in IgAN. MethodsWe measured u-sCD163 in patients from a large IgAN cohort including China participants of the TESTING trial. The correlation of baseline or serial u-sCD163 and their response of corticosteroids therapy or kidney outcomes were investigated. ResultsIn cross-sectional analysis, u-sCD163 levels correlated with kidney macrophage infiltration, especially in crescentic areas, and with active lesions. Subgroup analysis of the TESTING cohort showed higher levels u-sCD163 were associated with greater benefits from corticosteroids therapy in proteinuria remission [OR, 35.56 (95% CI, 7.62-292.34) vs 3.94 (95% CI, 1.39-12.93), p for interaction 0.036]. Corticosteroids therapy significantly reduced u-sCD163 levels at 6th month compared to placebo group [79% (IQR 58%,91%) vs 37% (-11%,58%), P<0.001]. There was no difference in the suppressive effects on u-sCD163 by either dosage of corticosteroids (full and reduced-dose). The suppression of u-sCD163 was significantly associated with a reduced risk of kidney progression events (adjusted HR 0.52,95% CI 0.30 to 0.93, P=0.027). ConclusionsU-sCD163 is a reliable noninvasive biomarker associated with active pathological lesions in IgAN and can guide glucocorticoid therapy.

Effect of tonsillectomy combined with steroid pulse therapy upon IgA nephropathy depending on proteinuria status at diagnosis: a nationwide multicenter cohort study in Japan.

The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan. Between 2002 and 2004, 632 IgAN patients with ≥ 0.5g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99g/day; n = 264), moderate (1.00-1.99g/day, n = 216), or severe (≥ 2.00g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy. The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively). TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

#1365 Clinical efficacy of tonsillectomy combined with steroid pulse therapy in IgA nephropathy

Abstract Background and Aims IgA nephropathy is the most common primary glomerulonephritis in the Asia–Pacific region, including Japan, and often leads to dialysis initiation. The etiology of IgA nephropathy remains unclear; however, focal infections such as chronic tonsillitis are proposed. Although tonsillectomy should not be performed for Caucasian IgA nephropathy patients, some Japanese studies reported that the combination of steroid pulse therapy with tonsillectomy (TSP) was more effective than steroid pulse therapy alone for the remission of urinary findings. However, the immunosuppressive treatment regimens vary among studies, and treatment effect of combination therapy in preventing renal functional decline is unclear. This study aimed to compare the efficacy of steroid pulse therapy alone versus TSP in improving the remission rate of urinary findings and preventing renal functional decline. Method This retrospective observational study included 116 patients diagnosed with IgA nephropathy based on renal biopsy and treated between January 1, 2010 and December 31, 2020 in Gifu University Hospital. TSP group underwent tonsillectomy received 0.5 g/day of methylprednisolone intravenously for 3 consecutive days at 1-3 weeks. TSP and steroid pulse therapy alone group had 83 and 33 patients, respectively. Of these, 25 patients per group were matched using propensity score matching based on clinicopathologic factors including age, urinary protein level, estimated glomerular filtration rate (eGFR), and the risk classification for progression to end-stage renal disease. The remission rate of urinary findings and the change in eGFR one year after treatment initiation were compared between the two groups. Remission of urinary findings was defined as a urinary protein level of &amp;lt;150 mg/day and &amp;lt;5 erythrocytes/high-power field in the urine sediment. Results The TSP and steroid pulse therapy alone groups did not significantly differ in baseline characteristics including median age (interquartile range) (58 [47–63] and 56 [49–68] years, respectively), female sex (9 and 7, respectively), mean eGFR (60 ± 20 and 63 ± 21 mL/min/1.73 m2, respectively), median urinary protein level (764 [440–1,472] and 990 [425–1,872] mg/day, respectively) (p &amp;gt; 0.05 for all). The remission rate of urinary findings was significantly higher in the TSP group than in the steroid pulse therapy alone group (72% vs. 20%; p &amp;lt; 0.001, χ2 test). Albeit statistically nonsignificant, the decline in eGFR was smaller in the TSP group than that in the steroid pulse therapy alone group (−1.5 ± 8.1 vs −3.7 ± 10.5 mL/min/1.73 m2, p = 0.416; t test). No severe side effect was observed in both treatment groups. Conclusion The higher remission rate of urinary findings observed in the TSP group compared to the steroid pulse alone group suggested that the addition of tonsillectomy to steroid pulse therapy was a clinically effective treatment for IgA nephropathy. Albeit not significant, the TSP group tended to have a smaller decline in eGFR reduction at one-year follow-up, indicating the need for further studies with long-term observation.

Therapy of IgA nephropathy: time for a paradigm change.

Immunoglobulin A nephropathy (IgAN) often has a poor outcome, with many patients reaching kidney failure within their lifetime. Therefore, the primary goal for the treatment of IgAN should be to reduce nephron loss from the moment of diagnosis. To achieve this, IgAN must be recognized and treated as both a chronic kidney disease and an immunological disease. Agents that have received US Food and Drug Administration and European Medicines Agency approval for the treatment of IgAN include modified-release/targeted-release formulation budesonide (Nefecon) and sparsentan, a selective dual endothelin-A and angiotensin II receptor type 1 antagonist. Other agents, including selective endothelin receptor antagonists, selective or combined APRIL and BAFF antagonists, and a vast array of complement inhibitors are being investigated for the treatment of IgAN. Furthermore, treatment combinations are also being studied, including sodium-glucose cotransporter-2 inhibitors with endothelin receptor antagonists. Due to the complexity of IgAN, combination treatment, rather than a single-agent approach, may provide maximum benefit. With the number of treatments for IgAN likely to increase, combinations allowing safe and effective treatment to halt progression to kidney failure seem within grasp. While trials evaluating combinations are ongoing, more are needed to pave the way for a comprehensive IgAN treatment strategy. Furthermore, an approach to IgAN treatment in which agents are combined early to achieve rapid induction of remission and prevent unnecessary and irreversible nephron loss is required. Following remission, treatments may be adjusted and stripped back as necessary in the maintenance phase with close monitoring. This review discusses the current status of IgAN treatment and explores future strategies to improve outcomes for patients with IgAN.

MMF as Immunosuppressive Therapy in IgA Nephropathy

Introduction: IgA Nephropathy (IgAN) is the most common cause of primary glomerulonephritis in developed countries. Treatment with ACEI/ARB has strong evidence in managing IgAN. If there is evidence of progression, immunosuppression is recommended. KDIGO guidelines do not advise Mycophenolate Mofetil’s (MMF) use in non-Chinese population currently. Methods: In this study, we reviewed immunosuppression with MMF retrospectively in IgAN patients managed at the Sussex Kidney Unit (SKU) – Brighton – United Kingdom. This was assessed using the primary measures of renal survival without requiring renal replacement therapy (RRT) and proteinuria reduction to &gt;50% of the diagnosis baseline. Twenty-five patients diagnosed with IgAN between 2011 and 2020 and had been treated with MMF were retrospectively reviewed. Data was collected until January 2023, including laboratory results, histopathology, clinic letters, and medication. For those on RRT, data was collected up until the start of RRT. Results: Twenty- Five patients were reviewed; 24 were white Caucasians, and 1 was ethnically Asian. MMF was used in all 25 patients. Three patients were treated with MMF alone and 17 in combination with steroids. Five patients had prednisolone and cyclophosphamide for three months, followed by MMF maintenance. The average treatment duration was 2 years, and the average dose was 1g BD. Five patients progressed to end-stage renal disease (ESRD), and 3 had renal transplants. Twenty patients maintained renal survival; the mean eGFR at diagnosis was 45.6+/-34.1 and, at the time of review, was 56.1+/-26.6. Of the 17 patients who presented with AKI, 5 recovered to normal renal function, 5 had end-stage renal disease (ESRD), 4 had improvements, and 3 showed a decrease in eGFR. Overall, 70.6% of AKI patients recovered to normal or CKD levels. Eighty % of the patients had renal survival without RRT during the review. Twenty patients achieved more than 50% reduction of proteinuria, with five patients having proteinuria less than 0.3 g/24 hours and nine patients less than 0.5 g/24 hours. Comparison between the proteinuria at diagnosis and at the assessment time was significant (P&lt;0.001). Conclusions: Mycophenolate mofetil effectively maintained renal survival and improved proteinuria in IgA nephropathy patients indicated for immunosuppression. The treatment was well tolerated by all patients.

IgA nephropathy pathogenesis and therapy: Review &amp; updates

IgA nephropathy (IgAN) is the most frequent type of primary glomerulonephritis since the first type was described more than four decades ago. It is the prevalent cause of primary glomerular disease that causes end-stage renal disease. In most patients with IgAN, hematuria is the most common reported symptom, particularly in those with a preceding upper respiratory tract infection. Although the pathogenesis of IgAN is usually multifactorial, autoimmune complex formation and inflammatory processes are the most widely recognized pathogenic mechanisms. Multiple approaches have been trialed as a therapy for IgAN, including tonsillectomy, steroids, other immune-suppressive therapy in different regimens, and kidney transplantation. PubMed, Google, Google Scholar, Scopus, and EMBASE were searched by the authors using different texts, keywords, and phrases. A non-systemic clinical review is intended to review the available data and clinical updates about the possible mechanism(s) of IgAN pathogenesis and treatments. IgAN has a heterogeneous pattern worldwide, making it difficult to understand its pathogenesis and treatment. Proteinuria is the best guide to follow up on the IgAN progression and treatment response. Steroids are the cornerstone of IgAN therapy; however, other immune-suppressive and immune-modulative agents are used with a variable response rate. Kidney transplantation is highly advisable for IgAN patients, although the recurrence rate is high. Finally, IgAN management requires collaborative work between patients and their treating physicians for safe long-term outcomes.

Pathological Changes After Methylprednisolone (MP) Pulse Therapy in IgA Nephropathy

Pathological Changes After Methylprednisolone (MP) Pulse Therapy in IgA Nephropathy

Immunosuppressive therapy for IgA nephropathy in children

Immunosuppressive therapy for IgA nephropathy in children

The effectiveness and safety of corticosteroid therapy for IgA nephropathy with crescents: a prospective, randomized, controlled study

BackgroundPozzi protocol (methylprednisolone intravenous infusion in 1st-3rd-5th months and oral steroid for 6 months) has been thought to be the classic therapy for IgA nephropathy (IgAN) patients with proteinuria> 1.0 g/24 h. There is no consensus on the treatments for IgAN with active pathological changes, especially for IgAN patients with crescents proportion < 50%. This study aimed to evaluate the effectiveness and safety of the treatment protocol of methylprednisolone intravenous infusion at the 1st-2nd-3rd months for IgAN patients with crescents.MethodsIn this prospective, randomized, controlled, non-blind study, 68 IgAN patients with crescents proportion < 50% were divided into the 1–2-3 group receiving 0.25 g/d methylprednisolone intravenously for 3 consecutive days in the 1st-2nd-3rd months, and oral prednisone 0.5 mg/kg/d on consecutive days for 6 months and the 1–3-5 group with the same intravenous methylprednisolone treatment in the 1st-3rd-5th months, and the same oral prednisone. The primary outcome measure was remission of proteinuria (complete or partial); while the secondary outcome measures were deterioration of renal function (evidenced by a 50% rise from baseline serum creatinine levels, or a 25% decline from baseline eGFR levels).ResultsThere was no significant difference in incidence of crescents (median 14.66% vs. 11.45%, p = 0.143) between the 1–2-3 and 1–3-5 groups. From month 1 to month 6, there was a decreasing trend in the levels of urine protein and serum creatinine and an increasing trend in eGFR in both groups. The mean period of remission in the 1–2-3 group seemed shorter. Overall, there were 55 (80.89%) patients meeting remission. The rates of remission in the 1–2-3 group and 1–3-5 group were 85.3 and 76.47%, respectively (P = 0.644). The 1–2-3 group had lower creatinine and higher eGFR than the 1–3-5 group, but the difference was not significant. The complication rate was 11.11 and 15.79% in the two groups, respectively. There was no significant difference in the complications between groups.ConclusionsBoth the 1st-3rd-5th and 1st-2nd-3rd protocols can effectively alleviate proteinuria and protect renal function in IgAN patients with crescents but the 1st-2nd-3rd protocol seemed to have better effectiveness.Trial registrationClinicalTrials.gov, Identifier: NCT02160132, Registered June 10, 2014.

Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients with IgA Nephropathy.

The lack of a tool for predicting the response to immunosuppressive therapy in IgA nephropathy (IgAN) limits patient-specific risk stratification and early treatment decision making. Models for predicting response to immunosuppression in IgAN that can be applied at the time of kidney biopsy are needed. This prospective cohort study involved 621 Chinese patients with IgAN who were at high risk for disease progression and had persistent proteinuria ≥1 g/d, despite 3 months of optimized supportive care with renin-angiotensin system inhibitors. Participants received immunosuppressive therapy for a median of 18 months. We used immunochemistry to identify macrophage and lymphocyte infiltrates in biopsy specimens and digital image analysis to quantify them. The outcome was response to immunosuppression, defined as complete or partial remission within 12 months of immunosuppression. Kidney infiltration of CD68 + and CD206 + macrophages increased in patients with IgAN. Having higher levels of glomerular CD206 + macrophage infiltration was associated with a 40-fold increased probability of response to immunosuppression in adjusted analysis compared with having lower levels. Patients with a higher intensity of glomerular CD68 + infiltrates had a 13-fold increase in probability of responding to immunosuppression. Intensity of glomerular CD206 + and CD68 + macrophage infiltration predicted the response to immunosuppression (area under the curve [AUC], 0.84; 95% CI, 0.81 to 0.88). The AUC increased to 0.87 (95% CI, 0.84 to 0.91) in a model combining the infiltration score of CD206 + and CD68 + infiltrates with the MEST-C score and clinical data at biopsy. Intensity of glomerular macrophage infiltration predicted response to immunosuppressive therapy in patients with IgAN who were at high risk of progression, and may help physicians identify patients who will benefit from such treatment.

Long-term outcomes of IgA nephropathy patients with less than 25% crescents and mild proteinuria.

Whether immunosuppressive therapy in IgA nephropathy (IgAN) patients with lessthan25% crescents (C1) and mild proteinuria can improve the renal outcome is still unclear. We recruited 140 IgAN patients with C1 and proteinuria < 1g/24h who received supportive care (n = 52) or steroid-based immunosuppressive therapy (n = 88) in Xijing Hospital from July 2008 to December 2016. The primary outcome was the rate of renal function decline. The median of proteinuria was 575.5mg/24h, the fraction of crescents was 7% (5%, 12%) and follow-up time was 69.1months. The rate of renal function decline [0.5 (- 1.5, 3.2) vs - 0.7 (- 3.5, 0.5) ml/min per 1.73 m2 per year; P = 0.01] was slower in steroid-based immunosuppressive therapy group than supportive care group. Multivariate linear regression analyses showed steroid-based immunosuppressive therapy significantly slowed down the rate of renal function decline (β = - 0.220, 95% CI - 3.804 to - 0.449, P = 0.013) after adjusting age, sex, MAP, proteinuria, eGFR, M1, E1, S1, T1-2, the fraction of crescents and RASB. In the matched cohort, the rate of renal function decline was also slower in steroid-based immunosuppressive therapy group. The incidence of adverse events was similar between the two groups. Steroid-based immunosuppressive therapy may slow down the rate of renal function decline of IgAN patients with C1 and proteinuria ≤ 1g/24h.

The predictive value of Oxford MEST-C classification to immunosuppressive therapy of IgA nephropathy.

To analyze the efficacy of immunosuppressive therapy in IgA nephropathy and investigate the value of all clinicopathologic indicators. One hundred and one eligible IgA nephropathy patients were retrospectively studied. All the patients received immunosuppressive treatment and were then grouped according to the treatment outcome. The endpoint was a composite outcome (halving eGFR, end-stage renal disease (ESRD) or death due to kidney disease). The outcomes of immunosuppressive therapy were evaluated, and the factors influencing the outcomes of immunosuppressive therapy were analyzed by logistics regression. The independent significance of clinicopathologic indicators on renal outcome was then analyzed by multivariable Cox regression. Multivariate logistic regression analysis showed that S1 and M1 were the risk factors for the immunosuppressive treatment effect in IgAN patients, and eGFR was the protective factor for the immunosuppressive treatment effect in IgAN patients. Kaplan-Meier analysis revealed that outcomes of immunosuppressive therapy were significantly associated with poor renal outcomes. Multiple Cox regression analysis further confirmed that M1, T2, and the initial level of eGFR were independent predictive factors for poor renal outcomes. M, S scores and initial eGFR are independent predictors of outcomes of immunosuppressive therapy. Only M, T scores can effectively predict poor renal outcomes after immunosuppressive therapy. Nonetheless, stable eGFR and low proteinuria can protect renal outcomes.

Hydroxychloroquine in IgA nephropathy: a systematic review

Background Hydroxychloroquine (HCQ) has recently been reported to be a promising and safe anti-proteinuric agent for IgA nephropathy (IgAN) patients. In the present systematic review, we aimed to summarize the evidence concerning the benefits and risks of HCQ therapy in IgAN. Methods Electronic databases were searched for randomized, cohort, or case-control studies with IgAN biopsy-proven patients comparing the effects of HCQ with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or immunosuppression on proteinuria reduction. Results Five studies, one randomized and three observational, involving a total of 504 patients, were eligible for inclusion. Overall, there was a tendency of HCQ treatment to reduce proteinuria. In the studies where the control arm was supportive therapy, HCQ significantly reduced proteinuria at 6 months. However, in the studies that compared HCQ to immunosuppressive therapy, we found no difference in proteinuria reduction. HCQ had no impact on eGFR. Conclusion HCQ seems to be an efficient alternative therapy for patients with IgAN who insufficiently respond to conventional therapy. However, ethnically diverse randomized controlled studies with long-term follow-up are needed.

The prognostic effect of immunosuppressive therapy in IgA nephropathy with stage 3 or 4 chronic kidney disease

Background It is debated whether patients with IgAN with heavy proteinuria and decreased eGFR benefit from aggressive treatment consisting of corticosteroids alone or combined with immunosuppressive agents. Methods A retrospective study was performed between January 2008 and December 2016 on patients with IgAN who had urinary protein excretion > 1.0 g/d and an eGFR between 15 and 59 mL/min/1.73 m2. These patients were assigned to receive supportive care alone or supportive care plus immunosuppressive therapy. The primary outcome was defined as the first occurrence of a 50% decrease in eGFR or the development of ESKD. Results All 208 included patients were followed for a median of 43 months, and 92 (44%) patients experienced the primary outcome. Cumulative kidney survival was better in the immunosuppression group than in the supportive care group (p < .001). The median annual rate of eGFR decline in the immunosuppression group was −2.0 (−7.3 to 4.2), compared with −8.4 (–18.9 to −4.1) mL/min/1.73 m2 in the supportive care group (p < .001). In multivariate Cox regression analyses, immunosuppressive therapy was associated with a lower risk of progression to ESKD, independent of age, sex, eGFR, proteinuria, MAP, kidney histologic findings and the use of RASi agents (HR = 0.335; 95% CI 0.209–0.601). Among the adverse events, infection requiring hospitalization occurred at similar rates in both groups (p = .471). Conclusion Immunosuppressive therapy attenuated the rate of eGFR decline and was associated with a favorable kidney outcome in IgAN patients with heavy proteinuria and decreased eGFR, and the side effects were tolerable.

The effect of endocapillary hypercellularity lesions on the renal prognosis and response to immunosuppressive therapy in IgA nephropathy

In this retrospective cohort study, we aim to evaluate the effect of endocapillary hypercellularity (E) lesions on the renal prognosis and response to immunosuppressive therapy, especially diffuse endocapillary hypercellularity lesion in IgA nephropathy (IgAN). A total of 365 patients with IgAN and E lesions and 31 patients with diffuse E lesions and over 12-month follow-up period were included in this study. We performed an 1∶1 propensity score to identify controls with matched clinical and pathological features from 769 IgAN patients without E lesions. The end-point was defined as a 30% decrease in estimated glomerular filtration rate (eGFR) or end-stage kidney disease. The kidney survival of the two groups was compared by Kaplan-Meier analysis. During median follow-up period of 41 months, kidney survival rates in patients with E lesions were 96.0% at 1 year, 83.6% at 3 years, 67.7% at 5 years; while they were 96.9% at 1 year, 83.6% at 3 years, and 68.7% at 5 years in patients without E lesions (P=0.265).The HR of immunosuppressive therapy was 1.038 (95%CI 0.749-1.440) and 1.113 (95%CI 0.770-1.609) in patients not receiving immunosuppressive therapy (P=0.781). (2) During median follow-up period of 52.5 months, the kidney survival rates in patients with diffuse E-lesion were 100.0% at 1 year, 96.2% at 3 years, 74.5% at 5 years; while they were 96.2% at 1 year, 82.3% at 3 years, and 63.7% at 5 years in patients without E-lesion (P=0.158). The HR of immunosuppressive therapy was 0.625 (95%CI 0.213-1.839) and 0.447 (95%CI 0.028-7.191) in patients not receiving immunosuppressive therapy (P=0.825). E lesion or diffuse E lesion may not be associated with prognosis or response to immunosuppressive therapy.

Differential expression of peptides serves as an indicator of IgA nephropathy in pediatric patients.

Peptide profiles change significantly with aging and peptide biomarkers discovered in adult patients may not be suitable for the evaluation of pediatric patients. The present study was designed to explore alterations in the serum peptidome profile of pediatric patients with IgA nephropathy (IgAN). A total of 17 children diagnosed with IgAN were recruited as the experimental group, 11 sex-matched healthy children were recruited as a healthy control group and 18 sex-matched children with other glomerular diseases were recruited as a disease control group. Serum peptides of each subject were enriched and analyzed by liquid chromatography with tandem mass spectrometry and the subsequently identified IgAN-specific peptides were evaluated using Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Subsequently, the function of the IgAN-specific peptides was predicted via sequence comparison with other known functional bioactive peptides. A total of 123 peptides with a fold change >2 (P<0.05) and 48 peptides with a fold change >5 (P<0.05) were identified to be differentially expressed between the pediatric IgAN group and the two other groups. Consequently, two putative peptides that may have bioactive effects in the pathogenesis of IgAN in pediatric patients were identified. The serum peptidome profile of pediatric patients with IgAN was significantly different from the disease control group and the healthy control group. These differentially expressed peptides may serve as biomarkers for the minimally invasive diagnosis of pediatric patients with IgAN. Additionally, the potential bioactive peptides specifically expressed in pediatric IgAN patients that were identified in this study may lay a foundation for exploring new therapies for IgAN, such as the creation of novel peptide drugs.

SUN-036 SPLEEN TYROSINE KINASE (SYK) INHIBITION IN IGA NEPHROPATHY: A GLOBAL, PHASE II, RANDOMISED PLACEBO-CONTROLLED TRIAL OF FOSTAMATINIB

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, causing chronic kidney disease and end-stage renal disease. Pre-clinical data implicates SYK in the pathogenesis of IgAN (Kim MJ et al J Immunol 2012, McAdoo et al JASN 2014). We hypothesize that SYK inhibition with fostamatinib may represent a novel therapeutic opportunity. This ascending-dose study (NCT02112838) enrolled patients from 20 renal centers in Asia, Europe and USA with a recent diagnostic biopsy showing IgAN with mesangial and/or endocapillary hypercellularity at diagnosis. All patients previously received a maximum tolerated dose of renin-angiotensin-aldosterone system (RAAS) blockade for ≥12 weeks during the run-in period. At screening, the inclusion criteria were intended to be sPCR >442mg/g (50 mg/mmol) and >884 mg/g for USA only, and eGFR >30 ml/min/1.73 sqm were randomised to 3 groups: placebo BID (n=25), fostamatinib 100mg BID (n=26) or fostamatinib 150mg BID (n=25) orally for 24 weeks. Because of rate of recruitment, some patients with lower sPCR and eGFR were recruited following assessment with medical monitor. At end of study, patients were offered an optional repeat kidney biopsy. Of the 76 patients enrolled, the median age was 40.5 years; 67%, 30%, and 2% were white, Asian, and African-American, respectively; mean (range) disease duration was 3.0 yrs (0.1 to 25 yr). Baseline sPCR and eGFR are shown in Table 1; baseline median mesangial cellularity score, % glomeruli showing endocapillary hypercellularity and segmental sclerosis, and % tubular atrophy/interstitial fibrosis [continuous data for Oxford Classification criteria] were 0.6 (0–2), 0 (0-37%), 15.6 (0-54%), and 30 (0-60), respectively. Both doses of fostamatinib reduced proteinuria (sPCR) compared to baseline, although the differences were not significant (Table 1). In a pre-specified subgroup analysis of patients with baseline sPCR ≥1000mg/g, there was a dose dependent reduction in sPCR, which did not reach significance (Figure 1). There were no significant changes in eGFR during the study. Serial renal biopsies samples were available from a limited number of patients. Analysis of serial renal biopsies showed no significant changes in median Oxford classification scores. There was no increase in infectious episodes in either treatment group. Eight serious adverse events occurred in 6 patients. Six patients discontinued due to an AE. There were 7 fostamatinib-treated patients who had >50% higher sPCR at week 24 compared to baseline. Immunohistochemical analysis of macrophages and SYK in the renal biopsies is in progress. Table 1Kidney function and proteinuria Median (range)GroupsPlacebo (n=25)100 mg (n=26)150 mg (n=25)eGFR (ml/min/1.73 sq m) baseline51 (25,104)50 (20,109)35 (18,103)eGFR (ml/min/1.73 sq m) 24 weeks51 (21, 115)51 (25,120)37 (13, 93)sPCR (mg/g) baseline1272 (525, 9938)1828 (387, 16259)1878 (664, 4076)sPCR (mg/g) 24 weeks1034 (78, 13819)842 (97, 9803)1299 (309, 4661) Open table in a new tab This is the first clinical trial of a new class of medication (SYK inhibitor) in patients with kidney disease. The results suggest that further investigation of fostamatinib as a novel therapy for IgAN is warranted in patients with >1g proteinuria/day (presented on behalf of SIGN clinical trial collaboration group).

Half a century of IgA nephropathy: achievements, frustrations and challenges

IgA nephropathy is the most common glomerulonephritis worldwide. This disease has a tremendous economic impact because renal replacement therapy is expensive and hard-to-reach. It also represents a social problem because children and young adults in their second and third decades of life are affected by the IgA nephropathy, and it is the most active period of human life with highest work productivity. Many retrospective studies have shown that 40% of biopsy-proven IgA nephropathy patients develop end-stage kidney disease in 20 years after their biopsy disease. &#x0D; The biomarker research in IgA nephropathy has experienced a major splash in recent years with great number of scientific reports. Individual biomarkers often lack sensitivity and specificity with impairment of disease specificity as a consequence. The review describes a novel approach based on a panel of biomarkers for pathogenic process of IgA nephropathy. Integration of genetic, clinical, and bioinformatics data sets could optimize the specific value of each biomarker in a multimarker panel. This is a inspirational and promising approach for precision medicine and personalized therapy in IgA nephropathy. &#x0D; Half a century into the original description of IgA nephropathy, there is still no specific therapy for this condition Although the scarcity in treatment advances could be related to the disease’s complex pathogenesis. The evolution of different therapeutic approaches is reviewed over time and resulted in the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Glomerulonephritis that presently is being updated, and provide collation of recent data on various forms of immunosuppressive agents. Existing approaches to treatment of IgA nephropathy are described with focus primarily on innovative therapeutic strategies currently being evaluated in IgA nephropathy that were not discussed in the 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guidelines.