The role of immunosuppression in IgA nephropathy (IgAN) is controversial. In the Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) Trial, 162 patients with IgAN and proteinuria >0.75 g/d after 6 months of optimized supportive care were randomized into two groups: continued supportive care or additional immunosuppression (GFR≥60 ml/min per 1.73 m2: 6-month corticosteroid monotherapy; GFR=30–59 ml/min per 1.73 m2: cyclophosphamide for 3 months followed by azathioprine plus oral prednisolone). Coprimary end points were full clinical remission and GFR loss ≥15 ml/min per 1.73 m2 during the 3-year trial phase. In this secondary intention to treat analysis, we separately analyzed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; P=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% versus 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. In conclusion, only corticosteroid monotherapy induced disease remission in a minority of patients who had IgAN with relatively well preserved GFR and persistent proteinuria. Neither immunosuppressive regimen prevented GFR loss, and both associated with substantial adverse events.
IgA nephropathy is the most common primary glomerular disease worldwide. In the United States, IgA nephropathy is second only to focal segmental glomerulosclero
Human glomerular diseases can be caused by several different diseases, many of which include mesangial expansion and/or proliferation followed by glomerulosclerosis. However, molecular mechanisms underlying the pathologic mesangial changes remain poorly understood. Here, we investigated the role of the mammalian target of rapamycin complex 1 (mTORC1)–S6 kinase pathway in mesangial expansion and/or proliferation by ablating an upstream negative regulator, tuberous sclerosis complex 1 (TSC1), using tamoxifen-induced Foxd1-Cre mice [Foxd1ER(+) TSC1 mice]. Foxd1ER(+) TSC1 mice showed mesangial expansion with increased production of collagen IV, collagen I, and α–smooth muscle actin in glomeruli, but did not exhibit significant mesangial proliferation or albuminuria. Furthermore, rapamycin treatment of Foxd1ER(+) TSC1 mice suppressed mesangial expansion. Among biopsy specimens from patients with glomerular diseases, analysis of phosphorylated ribosomal protein S6 revealed mesangial cell mTORC1 activation in IgA nephropathy and in lupus mesangial proliferative nephritis but not in the early phase of diabetic nephropathy. In summary, mesangial cell mTORC1 activation can cause mesangial expansion and has clinical relevance for human glomerular diseases. This report also confirms that the tamoxifen-induced mesangium-specific Cre-loxP system is useful for studies designed to clarify the role of the mesangium in glomerular diseases in adults.
IgA nephropathy (IgAN) is the most common primary glomerulonephritis characterized by human mesangial cells (HMC) proliferation and extracellular matrix expansion associated with immune deposits consisting of galactose-deficient IgA1. However, how IgA1 contributes to IgAN has yet to be completely elucidated. In this study, the expression profile of chemokines was more altered in IgA1-treated HMC than in the control group. CCL20 was significantly higher either in the serum of IgAN patients or in IgA1-treated HMC. Further experiments demonstrated that CCR6, the only receptor of CCL20, was highly expressed in activated T cells. Intracellular staining assay and cytokine expression profile implied that CCR6+ T cells produced high IL-17 levels. Transwell experiment immunohistochemistry and immunofluorescence experiments extensively demonstrated that CCL20 could recruit inflammatory Th17 cells to the kidneys. These phenomena caused a series of immune inflammatory responses and further damaged the kidneys. Therefore, HMC stimulated by IgA1 could produce CCL20 and consequently recruit inflammatory Th17 cells to the kidneys to induce further lesion in IgA nephropathy.
Tonsillectomy has been applied for recurrent immunoglobulin (Ig)A nephropathy (IgAN) in kidney transplantation recipients, but allograft histologic changes after this treatment remain unclear.
Complement activation has a deep pathogenic influence in IgA nephropathy (IgAN). C3a and C5a, small cleavage fragments generated by complement activation, are key mediators of inflammation. Th
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis i
Author summary O-glycosylation is a common type of post-translational modification of proteins; specific abnormalities in the mechanism of O-glycosylation have been implicated in cancer, inflammatory and blood diseases. However, the molecular basis of abnormal O-glycosylation in these complex disorders is not known. We studied the genetic basis of defective O-glycosylation of serum immunoglobulin A1 (IgA1), that represents the key pathogenic defect in IgA nephropathy, the most common form of primary glomerulonephritis worldwide. We report our results of the first genome-wide association study for this trait using serum assays in 2,633 individuals of European and East-Asian ancestry. In our genome scan, we observed two significant signals with large effects, on chromosomes 7p21.3 and Xq24, jointly explaining about 7% of trait variability. These signals implicate two genes that encode molecular partners essential for enzymatic O-glycosylation of IgA1 and mucins, and represent potential new targets for therapy.
There were few related studies aiming to severe IgA nephropathy (IgAN) which could progress rapidly to end stage renal disease (ESRD) within ten years. To find valuable clinical or pathological factors and promising precautions is essential. A single center case–control study was performed. Fifty ESRD patients with the primary cause of IgAN and a short renal survival time of less than ten years after diagnose were enrolled in the case group. One hundred IgAN patients with a renal survival time of more than ten years were enrolled in the control group. IgA Oxford classification scores, clinical data at baseline and during the follow-up were collected. Multivariate logistic regression was used to investigate factors associated with the development of ESRD. There were significant differences in baseline clinical data between these two groups, as well as the constituent ratio of Oxford MEST-score. Distinct differences were observed in time-average uric acid(TA-UA), time-average hemoglobin(TA-Hb), time-average albumin(TA-Alb), time-average total cholesterol(TA-TC) and time-average urinary protein(TA-P) during the follow-up. In multivariate logistic models, IgA Oxford score M1(OR = 5.10, P = 0.018) and eGFR(OR = 0.97, P = 0.039) at biopsy, TA-UA (OR = 2.06, P = 0.026) and TA-Hb (OR = 0.53, P = 0.022) during the follow-up were identified independent factors for developing ESRD. IgAN patients with pathological assessment of M1, low baseline eGFR, TA-Hb and high TA-UA were more likely to progress to ESRD, and should be paid more attention. Appropriate regulations of UA, Hb and urine protein after diagnose may be a promising treatment.
IgA nephropathy (IgAN) is a common chronic glomerular disease that, in most patients, slowly progresses to ESRD. The immune and autoimmune responses that characterize IgAN indicate a potential benefit for corticosteroids. The 2012 Kidney Disease Improving Global Outcome (KDIGO) guidelines suggest giving corticosteroids to patients with rather preserved renal function (GFR>50 ml/min per 1.73 m2) and persistent proteinuria >1 g/d, despite 3–6 months of optimized supportive care with renin-angiotensin system blockers. However, the evidence supporting this guideline was considered of low quality. More recent results from large cohort studies and randomized, controlled trials have provided conflicting messages about the benefits of corticosteroid treatment over supportive care alone, mostly involving optimized renin-angiotensin system blockade, which might generate further uncertainty in the therapeutic choice. Overall, these results indicate that corticosteroids are a powerful tool for treating patients with IgAN; however, treatment success is not universal and mostly occurs in patients who are highly proteinuric with early CKD. In patients with advanced CKD, the side effects of corticosteroids increase, and the renal protection decreases. This brief review aimed at integrating the findings of these recently published reports to provide balanced advice for clinicians as well as suggestions for future trials.
IgA nephropathy (IgAN) is characterized by infections followed by episodic gross hematuria. Deficiency of mannose-binding lectin (MBL) is associated with recurrent infection in many diseases, but controversy exists regarding the role of MBL in IgAN. Here, we measured MBL2 variants and MBL levels in 749 patients with IgAN and 489 healthy controls. Overall, 5.2% (39 of 749) of patients with IgAN had MBL deficiency (MBL levels <100 ng/ml), among whom LYPB/LYPB and LXPA/LYPB were the predominant MBL2 haplotypes (82%; 32 of 39). We found a nonlinear association between MBL levels and renal outcome in IgAN. Patients with IgAN and MBL deficiency had a higher incidence of prodromic infections and gross hematuria than those with sufficient MBL levels (100–3540 ng/ml). Moreover, MBL deficiency independently associated with poor renal outcome in IgAN after multiple adjustments (hazard ratio, 5.18; 95% confidence interval, 2.50 to 10.72; P<0.001). Patients with high MBL levels (>3540 ng/ml) had more severe proteinuria and a higher proportion of crescents, although the association with IgAN progression did not reach statistical significance after adjustments. In conclusion, MBL deficiency and MBL excess may both have deleterious effects on IgAN progression, which suggests that MBL contributes to IgAN pathogenesis through multiple mechanisms.
IgA nephropathy (IgAN), the most common GN worldwide, is characterized by circulating galactose-deficient IgA (gd-IgA) that forms immune complexes. The immune complexes are deposited in the glomerular mesangium, leading to inflammation and loss of renal function, but the complete pathophysiology of the disease is not understood. Using an integrated global transcriptomic and proteomic profiling approach, we investigated the role of the mesangium in the onset and progression of IgAN. Global gene expression was investigated by microarray analysis of the glomerular compartment of renal biopsy specimens from patients with IgAN (n=19) and controls (n=22). Using curated glomerular cell type–specific genes from the published literature, we found differential expression of a much higher percentage of mesangial cell–positive standard genes than podocyte-positive standard genes in IgAN. Principal coordinate analysis of expression data revealed clear separation of patient and control samples on the basis of mesangial but not podocyte cell–positive standard genes. Additionally, patient clinical parameters (serum creatinine values and eGFRs) significantly correlated with Z scores derived from the expression profile of mesangial cell–positive standard genes. Among patients grouped according to Oxford MEST score, patients with segmental glomerulosclerosis had a significantly higher mesangial cell–positive standard gene Z score than patients without segmental glomerulosclerosis. By investigating mesangial cell proteomics and glomerular transcriptomics, we identified 22 common pathways induced in mesangial cells by gd-IgA, most of which mediate inflammation. The genes, proteins, and corresponding pathways identified provide novel insights into the pathophysiologic mechanisms leading to IgAN.
The Oxford Classification of IgA nephropathy (IgAN) is the most widely accepted system for assessing histologic findings in IgAN. A new publication refines this classification by adding a crescent score, reassessing the segmental sclerosis score, and contextualizing the clinical relevance of the histologic lesions.
Evidence-Based Complementary and Alternative Medicine (eCAM) is an international peer-reviewed, Open Access journal that seeks to understand the sources and to encourage rigorous research in this new, yet ancient world of complementary and alternative medicine.
One disease or many? IgA nephropathy (IgAN) is well identified by dominant IgA glomerular deposits; however, this immunohistologic entity can be an asymptomatic chance finding or present with an extremely variable course. The variable clinical and histologic expressions are likely to be the result of genetic and environmental factors modulating common pathogenetic and progression mechanisms.
Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a pr
IgA nephropathy is the most common progressive glomerular disease to end stage renal failure worldwide. Calcineurin inhibitors (CNIs) is a selective immunosuppressant widely used in organ transplantation. The efficacy and safety of calcineurin inhibitors for the treatment of IgA nephropathy remain uncertain. We performed a systematic literature search using the PubMed, Embase, Science Citation Index, Ovid evidence-based medicine, Chinese Biomedical Literature (CBM) and Chinese science and technology periodicals (CNKI, VIP, and Wan Fang) for randomized, controlled trials of CNIs therapy of IgA nephropathy. Complete remission rate (CR) was defined as proteinuria less than 0.5 or 0.3 g/d. Partial remission rate (PR) was defined as proteinuria reduced to at least half of the baseline measurement and an absolute value of >0.5 or 0.3 g/d. Seven relevant trials were conducted with 374 patients enrolled. CNIs plus medium/low-dose steroid had a higher CR (RR = 2.51 [95% CI,1.25 to 5.04], P = 0.02) compared to therapy with steroid alone or placebo, but were not significant on PR (RR = 0.87 [95% CI,0.32 to 2.38]; P = 0.78). Also, significant alterations were observed in proteinuria (weighted mean difference, −0.46 g/d,[95% CI:-0.55 to −0.24], P < 0.01) with no differences were found in serum creatinine (SCr) (weighted mean difference, 0.57,95% CI:-4.05 to 5.19; P = 0.78) and estimated glomerular filtration rate (eGFR) (weighted mean difference, 1.13,95% CI:-4.05 to 6.32; P = 0.34) level between the two groups. CNI therapy was associated with an increased risk for adverse events (RR = 2.21,95% CI:1.52 to 3.21, P < 0.01), such as gastrointestinal and neurological symptoms or hirsutism. CNIs might provide renal protection in patients with IgAN, but at an increased risk of adverse events. Reliably defining the efficacy and safety of CNIs in IgAN requires a high-quality trial with a large sample size.
Publication date: December 2016 Source:Medical Hypotheses, Volume 97 Author(s): Elham Sadat Mirfazeli, Sayed-Amir Marashi, Shiva Kalantari IgA nephropathy is one of the most common forms of primary glomerulonephritis worldwide leading to end-stage renal disease. Proliferation of mesangial cells, i.e., the multifunctional cells located in the intracapillary region of glomeruli, after IgA- dominant immune deposition is the major histologic feature in IgA nephropathy. In spite of several studies on molecular basis of proliferation in these cells, specific pathways responsible for regulation of proliferation are still to be discovered. In this study, we predicted a specific signaling pathway started from transferrin receptor (TFRC), a specific IgA1 receptor on mesangial cells, toward a set of proliferation-related proteins. The final constructed subnetwork was presented after filtration and evaluation. The results suggest that estrogen receptor (ESR1) as a hub protein in the significant subnetwork has an important role in the mesangial cell proliferation and is a potential target for IgA nephropathy therapy. In conclusion, this study suggests a novel hypothesis for the mechanism of pathogenesis in IgA nephropathy and is a reasonable start point for the future experimental studies on mesangial proliferation process in this disease.
<span class="paragraphSection">The most common primary glomerular disease globally is IgA nephropathy (IgAN). It is often a slowly progressive disease, and ∼40% of patients will progress to kidney failure. Due to a lack of large clinical trial networks and a lack of surrogate markers of treatment efficacy, there are relatively few large multicenter clinical trials in IgAN. Given that both the pathogenesis and progression of IgAN are linked to defects in mucosal immune regulation and inflammation, use of immunosuppression to prevent kidney failure is well founded. However, recent clinical trials have supported improvement in disease parameters, but this has not always translated to parallel amelioration in longer-term outcome. In this review we summarize the most current clinical research examining the efficacy of immunosuppression in IgAN.</span>
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