Role of IgA receptors in the pathogenesis of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end-stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd-IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcαRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment.

Gluten exacerbates IgA nephropathy in humanized mice through gliadin-CD89 interaction.

IgA1 complexes containing deglycosylated IgA1, IgG autoantibodies, and a soluble form of the IgA receptor (sCD89), are hallmarks of IgA nephropathy (IgAN). Food antigens, notably gluten, are associated with increased mucosal response and IgAN onset, but their implication in the pathology remains unknown. Here, an IgAN mouse model expressing human IgA1 and CD89 was used to examine the role of gluten in IgAN. Mice were given a gluten-free diet for three generations to produce gluten sensitivity, and then challenged for 30 days with a gluten diet. A gluten-free diet resulted in a decrease of mesangial IgA1 deposits, transferrin 1 receptor, and transglutaminase 2 expression, as well as hematuria. Mice on a gluten-free diet lacked IgA1-sCD89 complexes in serum and kidney eluates. Disease severity depended on gluten and CD89, as shown by reappearance of IgAN features in mice on a gluten diet and by direct binding of the gluten-subcomponent gliadin to sCD89. A gluten diet exacerbated intestinal IgA1 secretion, inflammation, and villous atrophy, and increased serum IgA1 anti-gliadin antibodies, which correlated with proteinuria in mice and patients. Moreover, early treatment of humanized mice with a gluten-free diet prevented mesangial IgA1 deposits and hematuria. Thus, gliadin-CD89 interaction may aggravate IgAN development through induction of IgA1-sCD89 complex formation and a mucosal immune response. Hence, early-stage treatment with a gluten-free diet could be beneficial to prevent disease.

Dietary Perilla seed oil supplement increases plasma omega-3 polyunsaturated fatty acids and ameliorates immunoglobulin A nephropathy in high immunoglobulin A strain of ddY mice.

BACKGROUND/AIMS: The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in the treatment of immunoglobulin A nephropathy (IgAN) have been reported. Perilla frutescens (Linn.) Britton var. frutescens is grown in Eastern Asia and its seed (perilla seed) is rich in α-linolenic acid, an n-3 PUFA. We investigated the antinephritic effects of perilla seed oil in a mouse model of IgAN. METHODS: Ten-week-old high IgA ddY mice were fed diets containing either perilla seed oil (PS group) or corn oil (C group, control). After 20 weeks, we compared body weight, blood pressure, serum creatinine levels, IgA levels, fatty acid composition, urinary protein excretion, mesangial matrix expansion, and glomerular transforming growth factor-ß1 mRNA expression between groups. RESULTS: Serum n-3 PUFA levels were higher in the PS group than the C group (p<0.001). Blood urea nitrogen levels were lower (p=0.0246) and urinary protein excretion was reduced (p=0.0198) in the PS group. Mesangial matrix expansion (p=0.0063) and glomerular transforming growth factor-ß1 mRNA expression (p=0.0291) were suppressed in the PS group. No significant differences between groups were found in body weight, blood pressure, serum IgA, and creatinine levels. CONCLUSIONS: Dietary perilla seed oil supplement could suppress the progression of IgAN.

Idiopathic hypercalciuria preceding IgA nephritis in a child with recurrent hematuria.

A 5-year-old boy was investigated after an episode of gross hematuria of non-glomerular origin and was found to have idiopathic hypercalciuria. Despite normalization of calciuria he had recurrent attacks of gross hematuria. Since SDS-PAGE analysis of urinary proteins indicated a glomerular origin of hematuria, a renal biopsy was performed and revealed IgA nephropathy. We believe that association of hypercalciuria and IgA nephropathy is by chance, since both are frequently found in children with hematuria. Also, we recommend all children with well-controlled hypercalciuria who experience further attacks of gross hematuria be evaluated for glomerular disease.

Tumoral calcinosis after an injection of recombinant human erythropoietin in a dialysis patient.

Tumoral calcinosis is a rare form of soft tissue calcifications, initially described as an idiopathic condition, which could occur in uremic patients. Despite its distinct clinical and morphologic presentations, the underlying pathogenesis is unknown. We present a dialysis patient who developed tumoral calcinosis over the right shoulder after receiving a misplaced injection of human recombinant erythropoietin probably into the periarticular tissue. This case serves as an example highlighting the importance of periarticular inflammatory reaction in precipitating the development of the lesion in predisposed patients.

The emerging role of omega-3 polyunsaturated fatty acids in the management of patients with IgA nephropathy.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis in the world, affects mostly young adults, and shows a widely variable clinical course with many patients developing progressive renal disease, culminating in terminal renal failure in 20% to 40% of those afflicted. Until recently, no treatment options have been available for IgAN. Although a cure for the disease remains elusive, drugs that slow disease progression are becoming available, including omega-3 (n-3) fatty acids. The largest long-term clinical trial evaluating n-3 fatty acids in high-risk patients with IgAN showed that early and prolonged treatment with n-3 fatty acids retards renal progression. The rationale for using these fats involves potential mechanisms that reduce renal inflammation and glomerulosclerosis, hallmarks of progressive disease.

Use of fish oil to treat patients with immunoglobulin a nephropathy.

This review describes the use of fish oil in the treatment of patients with immunoglobulin (Ig) A nephropathy. IgA nephropathy is the most common glomerular disease worldwide. It has a variable course and leads to end-stage renal disease in a substantial number of cases. Among the 4 published randomized clinical trials that tested the efficacy of fish-oil treatment of IgA nephropathy, 2 reported beneficial effects on renal function and 2 showed negative results. In the largest trial conducted by my collaborative study group, convincing evidence was provided for protection against progressive renal disease after daily treatment for 2 y with fish oil providing 1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid-the 2 major n-3 polyunsaturated fatty acids in fish oil. Oral prednisone has also been advocated, especially in the treatment of children with IgA nephropathy. Two randomized trials are currently underway in the United States to resolve the discrepancy of results in previous fish-oil trials and to determine whether corticosteroids or fish oil is the better treatment of patients at risk for developing progressive disease; results of these studies are not yet available.

Polyunsaturated fatty acids and renal disease.

An upregulation of arachidonate metabolism often accompanies renal pathophysiologic states. The resulting eicosanoids contribute to, or modify, the underlying process. Recent investigations suggest that platelet-neutrophil interactions, as well as alterations in the expression of the inducible isoform of cyclooxygenase, play a critical role in mediating changes in arachidonate metabolism in renal inflammation. The importance of arachidonate to renal pathophysiology has been highlighted by prior investigations which have demonstrated a beneficial effect of dietary polyunsaturated fatty acid (PUFA) modulation in a variety of models of experimental renal disease. More recent work has established that this beneficial effect may depend upon alterations in both lipid mediator generation as well as changes in cell function. In light of the benefits of dietary PUFA modulation in models of experimental renal disease, there have been numerous recent clinical trials of dietary (n-3) PUFA supplementation in patients with a variety of renal disorders. These clinical trials suggest that such therapy may be an important addition to the clinical armamentarium, especially in the treatment of IgA nephropathy.

A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group.

BACKGROUND: The n-3 fatty acids in fish oil affect eicosanoid and cytokine production and therefore have the potential to alter renal hemodynamics and inflammation. The effects of fish oil could prevent immunologic renal injury in patients with IgA nephropathy. METHODS: In a multicenter, placebo-controlled, randomized trial we tested the efficacy of fish oil in patients with IgA nephropathy who had persistent proteinuria. The daily dose of fish oil was 12 g; the placebo was a similar dose of olive oil. Serum creatinine concentrations, elevated in 68 percent of the patients at base line, and creatinine clearance were measured for two years. The primary end point was an increase of 50 percent or more in the serum creatinine concentration at the end of the study. RESULTS: Fifty-five patients were assigned to receive fish oil, and 51 to receive placebo. According to Kaplan-Meier estimation, 3 patients (6 percent) in the fish-oil group and 14 (33 percent) in the placebo group had increases of 50 percent or more in their serum creatinine concentrations during treatment (P = 0.002). The annual median changes in the serum creatinine concentrations were 0.03 mg per deciliter (2.7 mumol per liter) in the fish-oil group and 0.14 mg per deciliter (12.4 mumol per liter) in the placebo group. Proteinuria was slightly reduced and hypertension was controlled to a comparable degree in both groups. The cumulative percentage of patients who died or had end-stage renal disease was 40 percent in the placebo group after four years and 10 percent in the fish-oil group (P = 0.006). No patient discontinued fish-oil treatment because of adverse effects. CONCLUSIONS: In patients with IgA nephropathy, treatment with fish oil for two years retards the rate at which renal function is lost.

Low-antigen-content diet in the treatment of patients with IgA nephropathy.

Since dietary macromolecular antigens can be involved in the pathogenesis of IgA nephropathy (IgAN), the effect of a low-antigen-content diet was evaluated in 21 patients (10 women, 11 men, mean age 27.7 +/- 10 years) with immunohistochemical findings of active IgAN. The diet was followed for a 14-24-week period (mean 18.8 +/- 6); in all cases the effects of the treatment were evaluated by clinical and serological parameters, and in 11 patients also by repeat renal biopsy. After dietetic therapy a significant reduction of urinary proteins was recorded (P < 0.001); in particular, heavy proteinuria (> 1 g/day), present in 12 cases during the 6 months preceding the treatment, was markedly reduced or disappeared in 11. At post-treatment control biopsy mesangial and parietal deposits of immunoglobulins, complement C5 fraction and fibrinogen were significantly reduced. The improvement of the objective parameters such as heavy proteinuria, a strong predictor of a poor prognosis, and of immunohistochemical alterations indicate that a low-antigen diet can positively affect patients with IgAN. These results could be ascribed to a reduction of nephritogenic food antigen input and to a putative functional restoration of the mononuclear phagocytic system.

Effects of a gluten-free diet in primary IgA nephropathy.

In an uncontrolled study a gluten-free diet was given to 29 patients affected by primary IgA nephropathy (IgAGN). All of them followed the diet for 6 months, 23 patients for 1 year and 9 for 2 to 4 years. Mean levels of IgA containing circulating immune complexes (IgAIC), detected by a specific conglutinin assay and by measuring IgA content in 2.5% polyethylene glycol precipitates, on an unrestricted diet, significantly decreased after 6 months of gluten-free diet (p less than 0.01) and remained reduced during the follow-up. A decrease in IgAIC levels was evident in 85.7% of the cases with basal positive data, with complete normalization in 64.3% of them. IgA to gluten antigens (ethanol- or saline-soluble gliadin, glutenin and the lectin fraction termed glyc-gli) as well as to heterologous bovine and egg albumins were found to be significantly increased on an unrestricted diet in the group of 14 IgAGN patients with basal positive IgAIC. The mean levels of IgA to most dietary antigens significantly decreased after 6 months to 1 year of a gluten-free diet. A decrease in IgA to ethanol-soluble gliadin was evident in 81.8% of the cases with basal positive data, with complete normalization in 63.6%. A subgroup of 27.5% of IgAGN patients showed positive IgAIC values associated with increased IgA values to a variety of dietary antigens. A gluten-free diet induced in 75% of the cases a parallel improvement in these abnormal immunological data. Mean proteinuria values were found to be significantly decreased after 6 months of the diet and a reduction was also observed in microscopic hematuria. However, mean blood creatinine levels showed a significant increase after the gluten-free diet. The data of this study indicate that a gluten-free diet can modify some immunological abnormalities in a group of IgAGN patients, reducing levels of IgAIC and IgA to dietary antigens. The clinical course does not seem to be favorably influenced, since a relentless progression towards renal failure was observed.

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial.

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.