Pathophysiology Of IgA Nephropathy Research Articles

#177 Assessment and comparison of physician gaps related to clinical knowledge of IgA nephropathy

Abstract Background and Aims Understanding physician gaps related to IgA nephropathy (IgAN) can inform development of tools to improve physician knowledge and competence related to both diagnosis and treatment. Additionally, comparisons among specialists (nephrologists) and generalists (primary care physicians, PCPs) can segment educational needs for combined or customized education to close identified gaps. Method A survey instrument of 25 multiple choice, knowledge- and case-based questions allowed participants to assess their clinical knowledge related to IgAN. The survey was available online to physicians without monetary compensation or charge. Respondent confidentiality was maintained and responses were de-identified and aggregated prior to analyses. Initial data collection occurred from March 16, 2023 to May 19, 2023. Results In total, 98 nephrologists and 57 PCPs completed the full assessment within the data collection period. Conclusion This assessment of physicians’ clinical knowledge yielded important insights into gaps related to IgAN. Both nephrologists and PCPs need education on pathophysiology of IgAN and emerging treatment pathways, role of proteinuria and risk correlations to ESRD with IgAN, clinical use of the International IgAN Prediction Tool, and KDIGO recommendations for managing IgAN. PCPs need additional education on basic IgAN prevalence as well as clinical strategies for diagnosis. Further studies are planned to assess the effect of medical education on decreasing these clinical practice gaps.

Indirect Markers of Intestinal Damage in IgA Nephropathy

Introduction: Presence of subclinical intestinal inflammation has repeatedly been shown in IgA nephropathy (IgAN) and the degree of histological inflammation has correlated with abnormal urinary findings. There is lack of noninvasive biomarkers evaluating the presence of subclinical intestinal damage in IgAN. We conducted this study hypothesizing that selected biomarkers regarded as indirect markers of intestinal damage could be elevated in IgAN. Methods: Eighty-five primary IgAN patients (median age 55 years, 54% men) participated in this single-center study in Tampere, Finland. None had end-stage kidney disease or previously diagnosed enteropathies. Celiac disease was excluded with serum transglutaminase 2 antibody (TG2Ab) and endomysial antibody tests and inflammatory bowel disease with fecal calprotectin. Intestinal damage was evaluated from sera with analyses of intestinal fatty-acid binding protein (I-FABP), soluble cluster of differentiation molecule 14 (sCD14), and lipopolysaccharide binding protein. Fourteen people suffering from dyspepsia and 15 healthy people served as controls. Results: I-FABP levels among IgAN patients were higher than in the healthy controls (median 830 pg/mL vs. 289 pg/mL, p < 0.001). Also, sCD14 was increased in IgAN patients compared to dyspepsia controls. Although TG2Ab levels were within the normal range among IgAN patients, they were higher than in the healthy controls (median 1.3 U/mL vs. 0.6 U/mL, p < 0.001). Conclusions: Elevated serum levels of I-FABP were present in primary IgAN patients without known enteropathies. Serum I-FABP may indicate the presence of subclinical intestinal damage. These findings encourage further investigation into the role of the intestine in the pathophysiology of IgAN.

Treatment of IgA Nephropathy: A Rapidly Evolving Field.

The pivotal event in the pathophysiology of IgA nephropathy is the binding of circulating IgA-containing immune complexes to mesangial cells, with secondary glomerular and tubulointerstitial inflammation and fibrosis. The paramount difficulty in the management of IgA nephropathy is the heterogeneity in its clinical presentation and prognosis, requiring an individualized treatment approach. Goal-directed supportive care remains the bedrock of therapy for all patients, regardless of risk of progression. Sodium-glucose transporter 2 inhibitors and sparsentan should be integral to contemporary supportive care, particularly in patients with chronic kidney damage. Pending the development of reliable biomarkers, it remains a challenge to identify patients prone to progression due to active disease and most likely to derive a net benefit from immunosuppression. The use of clinical parameters, including the degree of proteinuria, the presence of persistent microscopic hematuria, and the rate of eGFR loss, combined with the mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents score, is currently the best approach. Systemic glucocorticoids are indicated in high-risk patients, but the beneficial effects wane after withdrawal and come at the price of substantial treatment-associated toxicity. Therapies with direct effect on disease pathogenesis are increasingly becoming available. While targeted-release budesonide has garnered the most attention, anti-B-cell strategies and selective complement inhibition will most likely prove their added value. We propose a comprehensive approach that tackles the different targets in the pathophysiology of IgA nephropathy according to their relevance in the individual patient.

MO243: Intestinal Fatty-Acid Binding Protein: A Potential Biomarker of Enterocyte Damage in IGA Nephropathy?

Abstract BACKGROUND AND AIMS An abundance of inflammatory cells has been found in duodena of IgA nephropathy (IgAN) patients [1, 2]. The degree of intestinal inflammation was shown to correlate with the amount of proteinuria and haematuria in IgAN [3]. Serum intestinal fatty-acid-binding protein (I-FABP) has shown to correlate with the degree of enterocyte damage in untreated coeliac disease (CD) patients [4]. The median level of I-FABP in untreated CD patients was 785 pg/mL and 173 pg/mL in healthy controls [5]. We conducted this study hypothesizing that I-FABP would be elevated in IgAN as a potential biomarker for the presence of subclinical enterocyte damage and intestinal inflammation. CD was excluded with coeliac autoantibody tests. METHOD This study was carried out at the Tampere University Hospital and Tampere University, Finland. Altogether 85 IgAN patients participated (median age 55 years, 54% males). None of the patients had progressed to end-stage kidney disease, nor had they a diagnosed enteropathy. Fifteen healthy controls (median age 57 years, 47% males) were participants from our previous CD studies. Coeliac autoantibodies were determined from the serum samples by measuring IgA class endomysial antibodies (EmA) and transglutaminase antibodies (tTGAb). EmA was determined by an in-house indirect immunofluorescence method using human umbilical cord as substrate. A serum dilution of 1: ≥ 5 was considered positive. tTGAb levels were determined with EliA Celikey assay (ThermoFisher Scientific, Waltham, MA, USA, cut-off for positivity 7.0 U/mL). The serum levels of I-FABP were determined with a commercially available ELISA kit (Hycult Biotech, Uden, The Netherlands, detection limit 47 pg/mL). Current kidney function was available in 68 IgAN patients (80%), and eGFR &amp;gt;60 mL/min/1.73 m2 was regarded as preserved kidney function. RESULTS I-FABP levels among IgAN patients (median 830 pg/mL, IQR 475–1378) were higher (P &amp;lt; .001) compared with healthy controls (289 pg/mL, IQR 199–568). A total of 57% of the IgAN patients from whom the data on current kidney function were available had preserved kidney function. Also, I-FABP levels in IgAN patients with preserved kidney function (650 pg/mL, IQR 419–880) were higher compared with healthy controls (P .006). tTGAb levels in IgAN patients (1.3, 0.8–1.9 U/mL) were higher (P &amp;lt;.001) compared with healthy controls (0.6, 0.3–0.7 U/mL). One IgAN patient had a borderline elevated tTGAb of 7.1 U/mL. No one had an elevated EmA test result. I-FABP and tTGAb levels had no correlation (rS 0.182, P = .051). CONCLUSION The clear difference in the levels of I-FABP in IgAN patients with preserved kidney function compared with healthy controls was of utmost interest. Elevated I-FABP may represent enterocyte injury and intestinal inflammation present in IgAN. Even though CD was excluded serologically, also the tTGAb levels were higher among IgAN patients. These findings spur us in search for an intestinal process in the pathophysiology of IgAN.

The Contribution of Complement to the Pathogenesis of IgA Nephropathy: Are Complement-Targeted Therapies Moving from Rare Disorders to More Common Diseases?

Primary IgA nephropathy (IgAN) is a leading cause of chronic kidney disease and kidney failure for which there is no disease-specific treatment. However, this could change, since novel therapeutic approaches are currently being assessed in clinical trials, including complement-targeting therapies. An improved understanding of the role of the lectin and the alternative pathway of complement in the pathophysiology of IgAN has led to the development of these treatment strategies. Recently, in a phase 2 trial, treatment with a blocking antibody against mannose-binding protein-associated serine protease 2 (MASP-2, a crucial enzyme of the lectin pathway) was suggested to have a potential benefit for IgAN. Now in a phase 3 study, this MASP-2 inhibitor for the treatment of IgAN could mark the start of a new era of complement therapeutics where common diseases can be treated with these drugs. The clinical development of complement inhibitors requires a better understanding by physicians of the biology of complement, the pathogenic role of complement in IgAN, and complement-targeted therapies. The purpose of this review is to provide an overview of the role of complement in IgAN, including the recent discovery of new mechanisms of complement activation and opportunities for complement inhibitors as the treatment of IgAN.

O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

Plasma Galactose-Deficient IgA1 and C3 and CKD Progression in IgA Nephropathy.

Increased circulating galactose-deficient IgA1 and subsequently complement activation both play important roles in the pathophysiology of IgA nephropathy. However, their relationship to disease severity and progression remains unclear. We assessed 1210 participants in a cohort study of biopsy-proven IgA nephropathy at Peking University First Hospital. Plasma concentrations of galactose-deficient IgA1 and complement component C3 were measured at the time of biopsy. We tested associations of galactose-deficient IgA1 and galactose-deficient IgA1/C3 ratio with CKD progression event, defined as ESKD or 50% decline in eGFR, using Cox proportional hazards models and restricted cubic splines. After a median follow-up of 43 months (interquartile range, 24-76 months), 172 (14%) participants reached the CKD progression event. The association of galactose-deficient IgA1 levels and CKD progression event showed a nonlinear relationship. The risk of CKD progression events was greater with higher plasma galactose-deficient IgA1 levels but reached a plateau when galactose-deficient IgA1>325 U/ml, whereas the risk of CKD progression events monotonically increased with higher galactose-deficient IgA1/C3 ratio. After adjustment for traditional risk factors (demographics, eGFR, proteinuria, hypertension, Oxford pathologic score, and corticosteroids/immunosuppressive therapy), higher levels of galactose-deficient IgA1/C3 ratio were independently associated with CKD progression event (per natural log-transformed [galactose-deficient IgA1/C3], hazard ratio, 2.03; 95% confidence interval [95% CI], 1.25 to 3.29; P=0.004). In reference to the first quartile of the galactose-deficient IgA1/C3 ratio, hazard ratios were 1.71 (95% CI, 1.01 to 2.89) for the second quartile, 1.55 (95% CI, 0.91 to 2.63) for the third quartile, and 2.17 (95% CI, 1.33 to 3.56) for the fourth quartile. In IgA nephropathy, plasma galactose-deficient IgA1/C3 ratio was associated with CKD progression event independent of clinical and biopsy characteristics.

Pathophysiology of IgA Nephropathy.

Immunoglobulin (Ig)A nephropathy is the most prevalent primary chronic glomerular disease in the world. Studies of molecular and cellular interactions involved in the pathogenesis of IgA nephropathy have revealed several inherent abnormalities in the production and subsequent handling of IgA1. In patients with this disease, altered glycan structures in the unique hinge region of the heavy chains of IgA1 molecules lead to the exposure of antigenic determinants, which are recognized by naturally occurring antiglycan antibodies of the IgG and/or IgA1 isotype. In addition, due to a homing abnormality there is a gradual shift of mucosal IgA1 producing lymphoplasma cells from mucosal lymphoid tissue to bone marrow resulting in excess production of mucosal-type IgA1 in the systemic circulation. As a result, nephritogenic immune complexes form in the circulation and deposit in the glomerular mesangium. Deposited immune complexes induce proliferation of resident mesangial cells with increased production of extracellular matrix proteins. A number of inflammatory cytokines produced by the mesangial cells damage the filtration barrier resulting in hematuria and proteinuria ultimately leading to progressive renal damage.

Immunoglobulin A nephropathy: a pathophysiology view.

IgA nephropathy is one of the leading causes of primary glomerulonephritis worldwide and an important etiology of renal disease in young adults. IgA nephropathy is considered an immune complex-mediated disease. This review article summarizes recent evidence on the pathophysiology of IgA nephropathy. Current studies indicate an ordered sequence of multi-hits as fundamental to disease occurrence. Altered glycan structures in the hinge region of the heavy chains of IgA1 molecules act as auto-antigens, potentially triggering the production of glycan-specific autoantibodies. Recognition of novel epitopes by IgA and IgG antibodies leads to the formation of immune complexes galactose deficient-IgA1/anti-glycan IgG or IgA. Immune complexes of IgA combined with FcαRI/CD89 have also been implicated in disease exacerbation. These nephritogenic immune complexes are formed in the circulation and deposited in renal mesangium. Deposited immune complexes ultimately induce glomerular injury, through the release of pro-inflammatory cytokines, secretion of chemokines and the resultant migration of macrophages into the kidney. The TfR1/CD71 receptor has a pivotal role in mesangial cells. New signaling intracellular mechanisms have also been described. The knowledge of the whole pathophysiology of this disease could provide the rational bases for developing novel approaches for diagnosis, for monitoring disease activity, and for disease-specific treatment.

Tonsillectomy and IgA Nephropathy Recurrence After Kidney Transplantation.

[Background and purpose] The pathophysiology of IgA nephropathy (IgAN) remains poorly understood, although it frequently recurs after kidney transplantation, and its recurrence has been reported to depend on some factors. We studied a retrospective single-center analysis of renal transplant recipients with IgAN as the cause of end-stage renal failure to examine factors that may affect IgAN recurrence after kidney transplantation and the preventative and therapeutic effects of tonsillectomy on IgAN recurrence. [Material and method] From January 1987 to December 2012, 126 kidney transplantations were performed at Ryuku University Hospital, among which 14 cases (10 men; and 4 women) were identified with IgAN as their primary disease. Their mean age at transplantation was 38.1 ± 8.4 years.Donor types were as follows: 2 cadaveric, and 12 living (10 related; 2 unrelated). Tonsillectomy was performed for 8 cases; 2 were for therapeutic purposes for IgAN recurrence, and 6 were to prevent IgAN recurrence. IgAN recurrence diagnosis was based on light microscopic findings showing mesangioproliferative changes and mesangial IgA deposition on the basis of immunofluorescence analysis. [Result] Among the 14 patients, 2 cases were identified as IgAN recurrence based on episode biopsies. Both the recurrent cases had living related kidney donors. One patient with recurrent transplant IgAN progressed to graft failure 2.0 years after tonsillectomy, whereas the other subsequently retained renal function for 7.0 years. No pathological IgAN recurrence was found in 6 preventative tonsillectomy cases and in 2 cadaveric transplants that did not undergo tonsillectomy. Among 6 preventative tonsillectomy patients, 5 had improved urinary findings (protein urine and/or microscopic hematuria) after tonsillectomy. The 10 years living kidney donor graft survival rate of the IgAN group was lower than that of the non IgAN group (50 % vs. 88 %; P< 0.05). [Conclusion] Our data suggest that IgAN recurs more frequently after living related kidney transplantation than with cadaveric and living unrelated donor transplantation. Furthermore, no pathological IgAN recurrence was found after preventative tonsillectomy, and it was found that tonsillectomy could improve urinary findings. Thus, tonsillectomy has preventive and/or therapeutic effects for IgAN recurrence after kidney transplantation.

Increased number of Th22 cells and correlation with Th17 cells in peripheral blood of patients with IgA nephropathy

T-helper (Th) 22 and Th17 cells are involved in the pathogenesis of autoimmune diseases. However, the role of Th22 and correlation with Th17 cells in the pathophysiology of IgA nephropathy (IgAN) remain unknown. In our study, Th22 and Th17 cells in peripheral blood of IgAN patients, non-IgA mesangial proliferative glomerulonephritis (non-IgA MsPGN) patients, and healthy controls were measured by flow cytometry. The concentration of plasma interleukin-22 (IL-22) was examined by enzyme linked immunosorbent assay (ELISA). The results showed that Th22 cells, Th17 cells, and plasma IL-22 were significantly elevated in IgAN patients compared with non-IgA MsPGN patients and healthy controls. Th22 cells showed a positive correlation with the levels of plasma IL-22 in IgAN patients. Moreover, a significantly positive correlation between Th22 cells and Th17 in IgAN patients was observed. Furthermore, IgAN patients with proteinuria showed a higher percentage of Th22 cells than IgAN patients without proteinuria. Our data demonstrated that IgAN had increased frequencies of peripheral Th22, Th17 cells and plasma IL-22, indicating that Th22 along with Th17 cells are involved in the immune responses of IgAN.

The Significance of Foot Process Effacement in Immunoglobulin A Nephropathy: Clinicopathologic Study of 161 Cases with Light, Immunofluorescence and Electron Microscopic Studies

IGA nephropathy (IGAN) is the most common glomerular disease worldwide. Patients may present with hematuria and non-nephrotic (NNRP) or uncommonly nephrotic range proteinuria (NRP). To the authors' knowledge, correlation of podocyte foot process effacement (FPE) with subclasses of IGAN and proteinuria (PT) has not been studied. Retrospectively, 161 cases of IGAN with light, immunofluorescence, and electron microscopy (EM) were reviewed and classified according to Haas classification. EM was available in 110 out of 161 (67%) cases. FPE was evaluated as mild, <30%; moderate, 30–70%; and severe, >70% and was correlated with class and the level of PT. Out of 161 cases, 101 were males and 60 were females with M:F ratio of 1.71:1. In 72 cases, race was known as follows: white, 63 (88%); black, 6 (8%); Hispanic, 2 (3%); Asian, 1 (1%). Clinical history was available in 94 cases: PT 39 cases (42%), PT+hematuria 33 cases (35%), hematuria 15 cases (16%), and renal failure in 7 cases (7%). In 88 cases with FPE, PT was nephrotic in 21 and non-nephrotic in 29 cases. FPE is common in IGAN. No correlation between FPE and IGAN subclass (p=.42) or proteinuria group and IGAN subclass (p=.10) is present. Whether FPE is simply a reflection of other pathologic mechanisms and its significance in the pathophysiology of IGAN requires further investigation.

Expression of microRNAs in the urinary sediment of patients with IgA nephropathy.

Background: Micro-RNAs (miRNAs) regulate one-third of all protein-coding genes and are fundamental in the pathophysiology of a wide range of diseases. We studied the expression of several miRNA species (miR-200 family, miR-205 and miR-192) in the urinary sediment of patients with IgA nephropathy (IgAN). Methods: We studied 43 patients with biopsy-proven IgAN. Urinary expression of miRNAs was determined and compared to that from 13 healthy controls. Results: The levels of urinary miR-200a, miR-200b and miR-429, but not miR-200c, miR-141, miR-205, or miR-192, were down-regulated in patients with IgAN. Proteinuria significantly correlated with urinary expression of miR-200a (r = −0.483, P < 0.001), miR-200b (r = −0.448, P = 0.001) and miR-429 (r = −0.466, P = 0.001). Baseline renal function significantly correlated with urinary expression of miR-200b (r = 0.512, P < 0.001) and miR-429 (r = 0.425, P = 0.005). Urinary gene expression of ZEB2 inversely correlated with miR-200b (r = −0.321, P = 0.017); and vimentin expression inversely correlated with that of miR-200a (r = −0.360, P = 0.007), miR-200b (r = −0.416, P = 0.002) and miR-429 (r = −0.375, P = 0.005). After 33.4 ± 12.6 months, the rate of renal function decline significantly correlated with urinary expression of miR-200b (r = 0.316, P = 0.034). Conclusions: Urinary expression of miR-200a, miR-200b and miR-429 were down-regulated in patients with IgAN, and the degree of reduction correlated with disease severity and rate of progression. The results suggested that these miRNA species might play important roles in the pathophysiology of IgAN. Further studies are needed to clarify the role of urinary miRNA repression as a non-invasive marker of IgAN.

Expression of MicroRNAs in the Urinary Sediment of Patients with IgA Nephropathy

Background:Micro-RNAs (miRNAs) regulate one-third of all protein-coding genes and are fundamental in the pathophysiology of a wide range of diseases. We studied the expression of several miRNA species (miR-200 family, miR-205 and miR-192) in the urinary sediment of patients with IgA nephropathy (IgAN).Methods:We studied 43 patients with biopsy-proven IgAN. Urinary expression of miRNAs was determined and compared to that from 13 healthy controls.Results:The levels of urinary miR-200a, miR-200b and miR-429, but not miR-200c, miR-141, miR-205, or miR-192, were down-regulated in patients with IgAN. Proteinuria significantly correlated with urinary expression of miR-200a (r= −0.483,P&lt; 0.001), miR-200b (r= −0.448,P= 0.001) and miR-429 (r= −0.466,P= 0.001). Baseline renal function significantly correlated with urinary expression of miR-200b (r= 0.512,P&lt; 0.001) and miR-429 (r= 0.425, P = 0.005). Urinary gene expression of ZEB2 inversely correlated with miR-200b (r= −0.321,P= 0.017); and vimentin expression inversely correlated with that of miR-200a (r= −0.360,P= 0.007), miR-200b (r= −0.416,P= 0.002) and miR-429 (r= −0.375,P= 0.005). After 33.4 ± 12.6 months, the rate of renal function decline significantly correlated with urinary expression of miR-200b (r= 0.316,P= 0.034).Conclusions:Urinary expression of miR-200a, miR-200b and miR-429 were down-regulated in patients with IgAN, and the degree of reduction correlated with disease severity and rate of progression. The results suggested that these miRNA species might play important roles in the pathophysiology of IgAN. Further studies are needed to clarify the role of urinary miRNA repression as a non-invasive marker of IgAN.

Intra-renal and urinary RNA expression of podcyte-associated molecules in patients with IgA nephropathy

Background Podocyte injury probably plays important roles in the pathogenesis of IgA nephropathy (IgAN). We studied intra-renal and urinary messenger RNA (mRNA) expression of podocyte-associated molecules in patients with IgAN. Methods We studied 43 consecutive patients with biopsy-proven IgAN. Intra-renal and urinary expression of mRNAs was determined and compared to that of 20 patients with nephrectomy for kidney cancer and 12 normal subjects. Results Intra-renal mRNA expression levels of nephrin, podocin and synaptopodin were significantly lower in patients with IgAN than that of controls. In contrast, their urinary mRNA expression levels were similar. Intra-renal gene expression of nephrin inversely correlated with proteinuria (r = –0.620, P < 0.001), GFR (r = 0.538, P < 0.001), and the degree of tubulointerstitial scarring (r = –0.423, P = 0.013). After followed for an average of 33.4 ? 12.6 months, intra-renal nephrin expression significantly correlated with the rate of GFR decline (r = 0.324, P = 0.041). Conclusions Intra-renal mRNA expression of podocyte associated molecules was down-regulated in patients with IgAN, and the degree of down- regulation of nephrin correlated with disease severity and the rate of progression. Our result supports the hypothesis that podocyte injury is an important component in the pathophysiology of IgAN.

The role of fish oil/omega-3 fatty acids in the treatment of IgA nephropathy

Beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) have been reported in recent epidemiologic studies and randomized clinical trials in a variety of cardiovascular and autoimmune diseases. Fish and marine oils are the most abundant and convenient sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major n-3 fatty acids that serve as substrates for cyclooxygenase and lipoxygenase pathways leading to less potent inflammatory mediators than those produced through the n-6 PUFA substrate, arachidonic acid. N-3 PUFA can also suppress inflammatory and/or immunologic responses through eicosanoid-independent mechanisms. Although the pathophysiology of IgA nephropathy is incompletely understood, it is likely that n-3 PUFA prevents renal disease progression by interfering with a number of effector pathways triggered by mesangial immune-complex deposition. In addition, potential targets of n-3 PUFA relevant to renal disease progression could be similar to those involved in preventing the development and progression of cardiovascular disease by lowering blood pressure, reducing serum lipid levels, decreasing vascular resistance, or preventing thrombosis. In IgA nephropathy, efficacy of n-3 PUFA contained in fish oil supplements has been tested with varying results. The largest randomized clinical trial performed by our collaborative group provided strong evidence that treatment for 2 years with a daily dose of 1.8 g of EPA and 1.2 g of DHA slowed the progression of renal disease in high-risk patients. These benefits persisted after 6.4 years of follow up. With safety, composition, and dosing convenience in mind, we can recommend two products that are available as pharmaceutical-grade fish-oil concentrates, Omacor (Pronova Biocare, Oslo, Norway) and Coromega (European Reference Botanical Laboratories, Carlsbad, CA).

Increased Production of Macrophage Migration Inhibitory Factor by T Cells in Patients with IgA Nephropathy

Background/Aim: Several studies have demonstrated an upregulation of macrophage migration inhibitory factor (MIF) synthesis in experimental glomerulonephritis. To our best knowledge, no investigation of MIF production by T cells from patients with IgA nephropathy (IgAN) has been reported so far. MIF is one of the immunoregulatory cytokines involved in T-cell activation and delayed-type hypersensitivity. In this study, we examined MIF production of T cells from patients with IgAN to investigate the contribution of the cells to elevated serum MIF content and to its pathologic characteristics. Methods: We measured MIF production by T cells from the peripheral blood of 20 healthy controls and 20 patients with IgAN before and approximately 10 days after the beginning of steroid therapy. The disease controls included 20 patients with minimal-change nephrotic syndrome (MCNS) before therapy. MIF concentrations in the supernatants of T-cell cultures were measured with a specific enzyme-linked immunosorbent assay (ELISA). We also investigated the relationship between MIF levels and disease activity. Results: The mean level for MIF in patients with IgAN was significantly elevated compared with that of healthy controls and also higher than that of patients with MCNS. When T cells were stimulated by concanavalin A, MIF production by T cells of patients with IgAN was more enhanced than in control subjects or patients with MCNS. We also investigated the relationship between MIF levels and pathological features in IgAN patients. Our findings reveal that MIF levels correlated with the grade of glomerular crescent formation and immunofluorescent C3 deposits in the glomeruli. Moreover, MIF overproduction was significantly related to the acute exacerbation stage of IgAN patients. Elevated MIF levels during the acute phase or exacerbations were found to be decreased during spontaneous or steroid therapy-induced remission in all IgAN patients examined. Conclusions: We provide data indicating that a T-cell population isolated by negative selection from peripheral blood mononuclear cells shows increased in vitro production of MIF in IgAN, and a reduction in that production when patients are treated with corticosteroids. In this paper, we describe the hypothetical role of MIF in the pathophysiology of IgAN.

RATIONALES FOR TREATING IgA NEPHROPATHIES

An outline is given of the pathophysiology of IgA nephropathy (IgA) in order to emphasize the role of eicosanoids, angiotensin II, and reactive oxygen species. ACE inhibitors and early corticosteroid usage are prime therapies. Tonsillectomy is to be considered, certainly for individual cases. It is logical that other components of a cocktail could be (i) thromboxane antagonists, (ii) leukotriene antagonists, or (iii) PAF an tagonist. In theory there should be benefit from antioxidants. Fish oils have not come up to expectation. PDGF aptamers look promising for the prevention of mesangial cell proliferation. Heparins are not used in the way that they could be. Various other agents could help reduce decline.

Results of a survey of the relationship between palatine tonsil and IgA nephropathy

To investigate the relationship between palatine tonsil and IgA nephropathy, a survey was performed by questionnaire to 154 non-ENT medical doctors who had reported case of IgA nephropathy. The questionnaire was sent in February 1997, and answers were obtained within one month from 93 doctors (79 internal physicians, 12 pediatricians and 2 pathologists); a 60.4% response rate. A total of 72.0% of doctors answered that renal pathology was the most important prognostic factor for IgA nephropathy. A total of 73.1% of doctors thought that the administration of corticosteroid was the most effective therapy for IgA nephropathy, whereas only one doctor answered that tonsillectomy was most effective. Urine protein was the most useful factor for the estimation of the treatment, according to 37.6% of doctors. The majority of doctors who replied to the questionnaire thought that palatine tonsil seemed to be involved in the pathophysiology of IgA nephropathy in less than half of patients with IgA nephropathy. In addition, they answered that the rate of patients with IgA nephropathy to whom tonsillectomy was effective was also less than 50%. The tonsillar provocation test was rarely performed for the diagnosis of tonsillar focal infection in IgA nephropathy. Furthermore, 51.6% doctors answered that urine protein was the most important factor in any estimation of the provocation test.

Measurement of Plasma and Urinary Adrenomedullin in Patients with IgA Nephropathy

In this study, we measured plasma and urinary adrenomedullin (AM) concentrations in 47 patients with IgA nephropathy. Controls were 39 healthy volunteers. Plasma and urinary AM values were measured by specific radioimmunoassay. The plasma AM concentrations were higher, and the urinary AM levels were lower in patients with IgA nephropathy than in healthy volunteers. Plasma AM concentrations showed a positive correlation with serum creatinine and blood urea nitrogen, whereas urinary AM levels correlated negatively with serum creatinine and blood urea nitrogen. The plasma AM concentrations showed a positive correlation with fractional excretions of sodium and potassium. Renal biopsy specimens of patients without renal failure were scored for activity (percentage of glomeruli demonstrating cellular crescent formation, degree of mesangial proliferation and interstitial infiltration; total score = 9). Urinary AM levels were shown to be lower in the group with a high activity (score 3–9) as compared with the group with a low activity (score 0–2) based on renal biopsy. Thus, urinary levels of AM are affected by the degree of the activity in IgA nephropathy, and AM may participate in the pathophysiology of IgA nephropathy.