A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy

Tested was the hypothesis that high-dose omega (omega)-3 fatty acids will be more effective than low-dose omega-3 fatty acids in preserving renal function in patients with severe IgA nephropathy in a randomized, open-label, parallel-group clinical trial. Patients were assigned to receive either high-dose fatty acids (EPA 3.76 g and DHA 2.94 g) or low-dose fatty acids (EPA 1.88 g and DHA 1.47 g), both given daily in a highly purified ethyl ester concentrate (Omacor). Patients were treated for a minimum of 2 yr in the absence of a treatment failure or until study closure (January 2000). Seventy-three patients were enrolled in the trial with two ranges of elevated serum creatinine (SC): 63 patients (86%) with a range of 1.5 to 2.9 mg/dl and 10 patients (14%) with a range of 3.0 to 4.9 mg/dl. The primary end point, within-patient rates of change in SC (2-yr minimum), showed an annualized median increase in SC of 0.08 mg/dl per yr in the low-dose group and 0.10 mg/dl per yr in the high-dose group (P: = 0.51). Patients in the lower entry SC range had lower SC slopes (P: = 0.02) and less end-stage renal disease (ESRD) (P: < 0.001) compared with those in the higher entry SC range. No patient died, and 18 patients developed ESRD: 10 in the low-dose group and 8 in the high-dose group (P: = 0.56). SC slopes were significantly lower, and survival free of ESRD was significantly higher (both, P: = 0.04) in the 63 Omacor-treated patients compared with the 22 placebo-treated patients from our previously reported clinical trial in which both groups had a similar level of renal impairment. Patient compliance was excellent, and no serious adverse events were noted. Low-dose and high-dose omega-3 fatty acids were similar in slowing the rate of renal function loss in high-risk patients with IgA nephropathy, particularly those with moderately advanced disease.     

鱼油治疗IgA肾病的Meta分析

目的 采用Meta分析的方法评价鱼油治疗IgA肾病的疗效,为临床实践提供理论依据。 方法 计算机检索Cochrane 图书馆、PubMed、EMBASE、中国知网等数据库。文献检索起止时间均从建库至2009年9月,收集鱼油治疗IgA肾病的随机对照试验（RCT）,提取资料后使用Revman 软件5.0进行数据分析。 结果 共纳入6个研究,包括258例对象。Meta分析结果显示,与对照组比较,鱼油组蛋白尿水平下降,差异有统计学意义[SMD=-0.27,95%CI（-0.52~-0.03）,P=0.03];鱼油组肾小球滤过率（GFR）下降,差异有统计学意义[SMD=0.30,95%CI（0.05~0.55）,P=0.02]。 结论 鱼油虽可以降低IgA肾病患者的蛋白尿,但并不能维持肾功能稳定。     

鱼油治疗IgA肾病的Meta分析

目的 采用Meta分析的方法评价鱼油治疗IgA肾病的疗效,为临床实践提供理论依据.方法 计算机检索Cochrane图书馆、PubMed、EMBASE、中国知网等数据库.文献检索起止时间均从建库至2009年9月,收集鱼油治疗IgA肾病的随机对照试验(RCT),提取资料后使用Revman软件5.0进行数据分析.结果 共纳入6个研究,包括258例对象.Meta分析结果显示,与对照组比较,鱼油组蛋白尿水平下降,差异有统计学意义[SMD=-0.27,95%CI(-0.52～-0.03),P=0.03];鱼油组肾小球滤过率(GFR)下降,差异有统计学意义[SMD=0.30,95%CI(0.05～0.55),P=0.02].结论 鱼油虽可以降低IgA肾病患者的蛋白尿,但并不能维持肾功能稳定.     

鱼油治疗IgA肾病的Meta分析

目的 采用Meta分析的方法评价鱼油治疗IgA肾病的疗效,为临床实践提供理论依据.方法 计算机检索Cochrane图书馆、PubMed、EMBASE、中国知网等数据库.文献检索起止时间均从建库至2009年9月,收集鱼油治疗IgA肾病的随机对照试验(RCT),提取资料后使用Revman软件5.0进行数据分析.结果 共纳入6个研究,包括258例对象.Meta分析结果显示,与对照组比较,鱼油组蛋白尿水平下降,差异有统计学意义[SMD=-0.27,95%CI(-0.52～-0.03),P=0.03];鱼油组肾小球滤过率(GFR)下降,差异有统计学意义[SMD=0.30,95%CI(0.05～0.55),P=0.02].结论 鱼油虽可以降低IgA肾病患者的蛋白尿,但并不能维持肾功能稳定.     

Chronic effects of omega-3 fatty acids (fish oil) in a rat 5/6 renal ablation model

It has been proposed that fish oil dietary supplementation in the chronic rat 5/6 renal ablation model may be either protective or toxic. These conflicting hypotheses were tested in rats who underwent renal ablation or sham surgery. Twenty rats received sham surgery, and 40 received 5/6 renal ablation. All rats were fed a regular laboratory diet up to 1 week postsurgery. At that time, one half of the renal ablation group was provided with an isocaloric diet supplemented with 24% MaxEPA (fish oil), 1% safflower oil, and antioxidants. The renal ablation rats developed hypertension, albuminuria, gammaglobulinuria, and a decline in glomerular filtration rate, which was less in the fish oil group compared with that in the regular laboratory diet group at 10 and 20 wk postsurgery. The fish oil renal ablation rats had significantly less glomerulosclerosis than did the regular laboratory diet renal ablation animals, and no more glomerular fibrin deposition than did the sham controls. The renal ablation regular laboratory diet rats had a significant dyslipidemia at 20 wk which was prevented in the fish oil renal ablation cohort. The fish oil renal ablation rats also demonstrated a significant decline in renal tissue arachidonic acid incorporation and a concomitant increase in eicosapentaenoic acid and docosahexaenoic acid incorporation. The mortality of the renal ablation group was greater than that of the sham controls but not significantly different for the fish oil or the regular laboratory diet groups. These results support the hypothesis that the fish oil diet containing specific antioxidant, vitamin E, and essential fatty acid supplementation is protective in the rat remnant nephron model and prevents the evolution of glomerulosclerosis with associated renal functional impairment, while preserving glomerular filtration.     

Treatment of severe IgA nephropathy with omega-3 fatty acids: the effect of a "very low dose" regimen

BACKGROUND: The effect of a "very low dose" of purified omega-3 fatty acids (PFA) in the progression of severe IgA nephropathy (IgAN) was tested, in a randomized, prospective, controlled trial. METHODS: Fourteen patients were assigned to receive a "very low dose" of PFA (0.85 g EPA and 0.57 g PHA) and 14 patients were treated symptomatically and used as controls. Both groups were similar in terms of serum creatinine (Scr) and glomerular filtration rate (GFR) at baseline. Patients were treated for 4 years. The primary end-points were an increase of 50% or more in Scr or a decrease of 50% or more in GFR at the end of the study. RESULTS: During treatment, 1 patient (7%) in the PFA group and 6 (43%) in the control group had an increase of 50% or more in their Scr (p<0.01). Also, 1 patient (7%) in the PFA group and 7 (50%) in the control group had a decrease of 50% or more in GFR (p<0.007). The mean annual change in Scr was 0.2 mg/dL in the PFA group and 1.0 mg/dL in the control group (p<0.01). The mean annual change in GFR was -1.4 mL/min in the PFA group and -3.0 mL/min in the control group (p <0.001). One patient in the PFA group (7%) and 6 patients in the control group (43%) (p<0.01) developed end-stage renal disease during the period of observation. CONCLUSIONS: A "very low dose" of PFA is also effective in slowing renal progression in high-risk patients with IgAN and particularly those with advanced renal disease.     

Effect of 12-month therapy with omega-3 polyunsaturated acids on glomerular filtration response to dopamine in IgA nephropathy

BACKGROUND: Omega-3 polyunsaturated acids therapy is efficient in primary IgA nephropathy. It is unknown whether doses of omega-3 smaller than those given previously are still effective. The aim of the study was to examine the effect of omega-3 therapy on renal vascular function in relation to proteinuria and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). METHODS: 20 IgA patients aged 36.5 +/- 10.77 with creatinine clearance (Cr(cl)) 105.71 +/- 27.3 ml/min and proteinuria 3.31 +/- 2.01 g/24 h were given orally 810 mg EPA and 540 mg DHA daily for 12 months. Before and at the end of the study, 24-hour proteinuria, serum homocysteine, and Cr(cl) were measured. At the same time, renal vascular function was estimated as dopamine-induced glomerular filtration response (DIR). DIR was measured as: two 120-min lasting Cr(cl) (before and during 2 microg/kg b.w./min i.v. dopamine). RESULTS: The results obtained during follow-up were as follows (baseline vs. after therapy): DIR 14.9 +/- 16.4 vs. 30.3 +/- 14.3% (p < 0.01); urine protein 2.31 +/- 2.01 vs. 1.31 +/- 1.37 g/24 h (p < 0.01); (Cr(cl)) 105.71 +/- 27.3 vs. 103.9 +/- 20.9 ml/min (n.s.); NAG 8.3 +/- 1.8 vs. 6.0 +/- 1.2 U/g(creat) (p < 0.01), and homocysteine 16.2 +/- 3.15 vs. 13.8 +/- 2.6 micromol/l (p < 0.05). The only correlation found was linear correlation between basal DIR and DIR change (r = -0.570; p < 0.010) and basal NAG (r = -0.460; p < 0.50). CONCLUSIONS: Omega-3 supplementation is associated with the improvement of both renal vascular function and tubule function.     

The role of integrins in IgA nephropathy

Summary: The complicated network of immune reactions leading to mesangial cell activation and glomerular sclerosis in IgA nephropathy (IgAN) involves interactions between infiltrating cells, mesangial cells and mesangial matrix which are mediated by adhesion molecules. Integrin expression on mesangial cells in culture has recently been described. In the present work we investigated whether integrin expression on cultured human mesangial cells (MC) and mesangial matrix production could be modulated by mesangial matrix components, or by other proteins which may come into contact with MC during pathologic conditions, such as fibrinogen and von Willebrand factor. Moreover, we evaluated the effects induced by polymeric IgA or aggregated IgA or mixed IgA/IgG aggregates on integrin expression. To elucidate a possible role for abnormally glycosylated IgA, we tested IgA pretreated with various enzymes specific for carbohydrate residue components of the side carbohydrate chains of IgA molecules. We found that cultured mesangial cells, highly express the αv β3 integrin receptor for vitronectin and to a lesser extent the α3 β1 receptor for fibronectin and collagens. Among these integrins, αv β3 is modulated by matrix components and particularly enhanced when cells are incubated with proteins which can be abnormally present in the mesangial area, such as fibrinogen, collagen I and von Willebrand factor. IgA and aggregated IgA can modify integrin expression, inducing a decrease in α3 β1 and an increase in αv expression. Moreover, sugars can affect these interactions, since desialylated IgA enhance the expression of integrin β3 chain on cultured mesangial cells and sialic acid per se strongly inhibits it. Conversely, other sugars, represented in the carbohydrate chains of IgA₁ including mannose and N-acetylgalactosamine, were found to enhance αv expression. Our data suggest that the interactions of native polymeric IgA, IgA or IgA/IgG aggregates, as well as IgA with altered glycosylation may result in structural rearrangement of mesangial integrins, possibly reflecting on mesangial matrix composition.     

The role of secretory IgA and complement in IgA nephropathy

IgA nephropathy (IgAN) is characterized by glomerular deposition of IgA, often together with complement components. This deposited IgA is mainly polymeric in nature. Although early studies suggested a role for local complement activation in the development of glomerular injury in IgAN, recent attention has focused on the involvement of the lectin pathway of complement activation in the progression of renal disease in IgAN. In addition, we have found that glomerular secretory IgA deposition may be one of the initiators of local complement activation in the kidney. In the present review we discuss recent developments in this area and provide a model of how mucosal immunity and renal inflammation may be interconnected.     

Pathogenic role of the IgA molecule in IgA nephropathy

SUMMARY: Deposits of IgA together with complement in different body tissues support the hypothesis that IgA can trigger inflammatory mechanisms. IgA nephropathy (IgAN) is characterized by predominant mesangial IgA₁ deposits of a polymeric nature. So far, the mechanism of polymeric IgA₁ deposition in the kidney mesangium is poorly understood in IgAN. the exact pathophysiological sequel preceding renal fibrosis following the mesangial deposition of IgA immune complexes remains speculative. Recent in vitro studies revealed that binding of IgA to mesangial cells led to increased expression of growth factors, cytokines, and integrins. the release of these proinflammatory factors is likely to enhance inflammatory injury. In addition, the local renin-angiotensin system present in renal tissues also contributes to renal fibrosis through the activation of transforming growth factor-β. the question of whether polymeric IgA isolated from patients with IgAN exerted any upregulatory effect on the synthesis of macrophage migration inhibitory factor (MIF) and components of the renin-angiotensin system in human mesangial cells was explored. the in vitro studies revealed that polymeric IgA from IgAN patients upregulated the gene expression of renin and MIF in human mesangial cells in a dose-dependent manner. These findings further support the notion that glomerular deposition of IgA is not only a pathological epiphenomenon of IgAN, but that polymeric IgA exerts a pathophysiologic effect on the mesangial cells leading to renal fibrosis.     

The IgA nephropathy treatment dilemma

Although IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, our understanding of the pathogenesis of this complex disease remains limited. IgA nephropathy may appear with a variety of clinical presentations, a number of different clinical and histopathologic risk factors for progressive renal disease, and a very variable course over time. Thus, it is not surprising that a single therapeutic treatment plan has not been established. Many of the studies dealing with IgAN are retrospective, lack statistical significance, or have confounding designs, which hinder their general acceptance. Nevertheless, a number of well-designed studies have been performed. This paper reviews currently available therapeutic options for IgAN. It attempts to address several important questions: Why do we treat patients with IgAN? How do we decide which patients should be treated? What are the general treatment guidelines for all IgAN patients? What is the role of specific therapy such as fish oils, tonsillectomy, and immunosuppression in the treatment of patient with IgAN? It also addresses several on-going trials and goals for future therapeutic studies for IgAN patients.     

The role of IgA and IgG immune complexes in IgA nephropathy

The presence of circulating immune complexes in 54 patients with IgA nephropathy has been studied by two different techniques. 64% of the patients had IgG immune complexes and 37% had IgA immune complexes, both determined with the Raji cell assay, and 48% of patients had IgA immune complexes with the anti-IgA inhibition binding assay (anti-IgA Inh BA). In sequential sera from individual patients, immune complexes remained persistently positive or negative in more than 50% of the cases being intermittently in the rest. The immune complexes detected by the Raji cell assay were mostly of 7-13S in size, while those detected by anti-IgA Inh BA were bigger. There was a good correlation between the serum levels of polymeric IgA and the presence of IgA complexes (Raji cell assay). A certain correlation (p less than 0.05) was found between these IgA immune complexes and the clinical activity assessed by the hematuria. A similar correlation (p less than 0.05) was found with specific polymeric IgA immune complexes studied by a method recently described. No relationship was observed between the presence of any HLA antigens and the existence of circulating immune complexes. These results support the contention that IgA immune complexes, especially those composed of polymeric IgA, may have a role in the pathogenesis of IgA nephropathy. Moreover, the high serum levels of polymeric IgA observed in these patients could contribute to the slow clearance and long persistence in the circulation of IgA immune complexes with their subsequent deposition at the glomerular mesangium.     

Effects of omega-3 fatty acids on acute necrotizing pancreatitis in rats

The aim of this study was to investigate the influence of omega-3 fatty acids (omega3FA) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. The induction of ANP resulted in significant increases in mortality rate, intestinal permeability, bacterial infection in pancreas and extrapancreatic organs, and serum activity of urea and amylase, alanine transferase (ALT), interleukin (IL)-6, tumor necrotizing factor-alpha (TNF-alpha), lactate dehydrogenase (LDH) in bronchoalveolar lavage (BAL) fluid, tissue activity of myeloperoxidase (MPO) and malondialdehyde (MDA) in the pancreas and lung, and a considerable decrease of concentrations of calcium, protein and albumin. The use of omega3FA reduced mortality, phenol sulfophthalein excretion in urine, bacterial infection in pancreas, liver, spleen, MPO and MDA levels in pancreatic and lung tissue, LDH level in BAL fluid and serum IL-6 and TNF-alpha values. Serum triglyceride increased only in the omega3FA groups. Serum amylase, ALT, calcium, urea, protein, IL-1, and degree of pancreatic damage indicated no difference between the pancreatitis groups. Increased intestinal permeability and cytokine levels, and free radical damage play an important role during the course of acute pancreatitis. The treatment with omega3FA improves these effects. omega3FA may be useful in the treatment during ANP in rats. Therefore, it can be beneficial in patients with pancreatitis.     

Plasma fatty acid composition in continuous ambulatory peritoneal dialysis patients: an increased omega-6/omega-3 ratio and deficiency of essential fatty acids

Patients with end-stage renal disease, including those treated with peritoneal dialysis, have a high risk for death, particularly from cardiovascular causes. Plasma fatty acid (FA) composition is used as an indicator of disease risk, because its alteration has been related to metabolic disease and cardiovascular disease. For this purpose, we have measured plasma FA composition in continuous ambulatory peritoneal dialysis (CAPD) patients and compared them with those of healthy subjects. This study was performed on 51 (21 M, 30 F) CAPD patients at least 6 months under dialysis, aged 20-75 years (mean 47.81 ± 11.8 years) and 45 (25 M, 20 F) healthy control subjects aged 20-60 years (mean 38.62 ± 12.9 years). Plasma 10-cis-pentadecanoic acid, 10-cis-heptadecanoic acid, heneicosanoic acid, tricosanoic acid, nervonic acid, saturated fatty acid, and monounsaturated FA levels and delta 9 desaturase activity were significantly higher whereas linoleic acid, linolenic acid, 11,14-eicosedienoic acid, arachidonic acid, docosahexaenoic acid, and omega-3 FA levels were significantly lower in the CAPD group than those in the healthy group. Our results show that there are FA abnormalities and especially a depletion in essential FA levels and a high level of omega-6/omega-3 ratio in CAPD patients, the underlying mechanism of which is not known and needs to be investigated. Therefore, we believe that essential FA supplementation should be encouraged for CAPD patients.     

The pathogenic role of IgA1 O-linked glycosylation in the pathogenesis of IgA nephropathy

Numerous abnormalities of the IgA immune system have been reported in IgAN but the most consistent finding remains aberrant IgA1 O-linked glycosylation of the IgA1 hinge region. The defect comprises reduced galactosylation of O-linked N-acetylgalactosamine residues with or without changes in the terminal sialylation of the O-linked sugars. Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. There is evidence that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a pro-inflammatory phenotype; they secrete cytokines, chemokines, growth factors and extracellular matrix components promoting glomerular inflammation and glomerulosclerosis. Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites and the association of aberrant IgA1 galactosylation with low affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may in fact be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities they deposit in the mesangium and trigger glomerular inflammation. This review will discuss the evidence for the role of IgA1 O-glycosylation in the pathogenesis of IgAN and propose an explanation for the presence of aberrantly O-glycosylated IgA1 in the circulation of patients with IgAN.