IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells

BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.     

Sequential study of the IgA system in relapsing IgA nephropathy

Cellular and immunochemical parameters of the IgA system were studied in 15 subjects with IgA nephropathy (IgAN) and 15 agematched controls. In IgAN remission no abnormalities of the IgA system were detectable by the methods used. In IgAN relapse, [macroscopic hematuria associated with upper respiratory tract infection (URTI) (N = 6)] there were rises in IgA-bearing B-lymphocytes (three of six), T helper/suppressor cell ratio (six of six) and pokeweed mitogen-induced IgA production (four of six). Total serum and salivary IgA were unchanged. Serum IgA profile (HPLC-ELISA) showed increases in polymer IgA (three of six). No such changes were found during URTI in controls. These findings support the view that an exaggerated IgA response to mucosal antigen challenge initiates glomerular damage and hematuria in IgAN.     

Circulating immune complexes in regularly dialyzed patients with chronic renal failure

The prevalence of circulating immune complexes (CIC) was investigated using the C1q binding assay (C1q BA) and the conglutinin binding assay (Kg BA) in 200 patients undergoing maintenance hemodialysis. Increased C1q binding was found in 45% (87 of 194) of the patients, and the modified Kg BA gave elevated values in 31% (20 of 65). The prevalence of CIC was similar in American and Swiss patients, and in patients undergoing hemodialysis, self-dialysis or peritoneal dialysis. In patients with 'nonimmunological' renal diseases, CIC were detected with similar frequency. No change in CIC was noted during hemodialysis in 6 additional patients tested. The abnormality was not related to age, sex, duration of dialysis, hepatitis B antigenemia, bacterial infections, or transfusions. Anti-DNA antibodies were absent in all subjects tested and the results of the C1q BA were not changed by DNase digestion of eight sera with high C1q binding. Rheumatoid factor activity (RF) was detected in approximately one-fifth of the patients, and there was a direct correlation between positive C1q binding and RF. There was no correlation between CIC and lymphocytotoxic antibodies. This study demonstrated a high prevalence of CIC in dialyzed uremic patients and established its relationship to other immunological abnormalities.     

‘Renal hypersensitivity’ to inulin and IgA nephropathy

Hypersensitivity to inulin (polyfructan) is a rare event; two cases of food allergy and some patients presenting with allergy and hypersensitivity after inulin infusion have been reported. An 11-year-old boy suffering from severe immunoglobulin (Ig)A nephropathy (IgAN) experienced both anaphylactic reaction and concomitant relapse of his nephropathy following inulin infusion, used for measuring glomerular filtration rate (GFR) 2 years after the appearance of his initial symptoms. Pruritus, wheezing and cough were observed during a first renal function test; results of prick and intradermal tests were negative for inulin. The patient presented with pallor, asthenia and oliguria when a second inulin infusion was performed under dexchlorpheniramine, leading to the immediate cessation of the infusion. He was readmitted 2 days later because of fatigue and nausea related to acute renal failure. A drug-induced acute interstitial nephritis was first suspected. However, due to the presence of macroscopic haematuria and proteinuria, a renal biopsy was performed and showed acute proliferative relapse of IgAN. The underlying mechanism of inulin hypersensitivity is not well known. We can hypothesize that inulin had activated the innate immune system. Inulin may, thus, have been the initiating event of the renal relapse, acting like an infection, in a patient with IgA-mediated immunological dysregulation.     

Characterization of a large Lebanese family segregating IgA nephropathy.

BACKGROUND: Familial aggregation of IgA nephropathy (IgAN) suggests that genetic factors contribute to the development of this trait. Because clinical manifestations in IgAN families are often limited to episodic haematuria, large kindreds tractable to linkage analysis have been difficult to identify. METHODS: We identified a large Lebanese-Druze kindred ascertained via an index case with biopsy-documented IgAN. We performed systematic screening of 38 family members and tested linkage to reported IgAN loci. RESULTS: Screening of this family identified 16 affected individuals, including 2 individuals with biopsy-documented IgAN and 14 with chronic renal failure or abnormal urinalyses on at least three separate occasions. This kindred spanned five generations and contained five consanguineous unions. Multigenerational inheritance suggested that autosomal dominant inheritance was most likely. Phenotypic manifestations among affected individuals varied from isolated haematuria to advanced renal failure necessitating transplantation; one instance of IgAN recurrence after transplantation was also documented. Older age was associated with greater severity of disease and higher incidence of renal failure. Parametric and non-parametric analyses with 33 microsatellite markers did not reveal any evidence of linkage to reported IgAN loci on chromosomes 6q22-23, 2q36 and 4q22-31. CONCLUSIONS: We describe one of the largest multigenerational IgAN kindreds reported to date. The high incidence of renal failure among older generations suggests a significant risk of progression to renal failure. We found no evidence of linkage to known loci, suggesting that familial IgAN encompasses multiple subtypes that will require distinction based on genetic or biomarker data.     

Hepatitis B virus-associated membraneous nephropathy: clinical features, immunological profiles and outcome

To evaluate the clinical features, immunological profiles and the prognosis of hepatitis B virus-associated membraneous nephropathy (HBVMN), 34 patients (25 boys and 9 girls) were studied from April 1981 to November 1987. With Fab fragments of monoclonal antibodies, hepatitis B e antigen (HBeAg) was detected in the glomerular deposits from 30 cases (88.2%) and in the sera from 32 cases (94.1%). These results suggest that HBeAg plays an important role in the development of HBVMN. In addition, clinical trials of 32 cases demonstrate a relatively poor response to the steroid therapy with persistent heavy proteinuria (32.4%) or a high frequent relapse rate (38.2%); only 1 case (3.1%) had early response. In 4 cases follow-up renal biopsy was performed, progressive sclerosis with interstitial fibrosis being noted in each instance. The stage of membraneous nephropathy examined under the light microscope, had progressed from stage I or II to stage III. One had impaired renal function. Therefore, HBVMN does not always take a benign course. In the immunological profiles, significant hypocomplementemia with low C3, C4 and properdin factor B levels were found during the initial 6 months after the onset of disease. Hepatitis B surface antigen (HBsAg) circulating immune complexes (CIC) were also significantly higher. However, the levels of HBsAg CIC did not correlate with the degree of proteinuria or hematuria. In patients with persistent HBaAg carriage, serum HBeAg status alone did not correlate with remission rate, and remission occurred usually before the HBeAg seroconversion to anti-HBe. These results suggest that factors other than HBeAg play important roles in HBVMN.     

Improvement of immune-complex nephritis associated with hepatitis B surface antigen excess

A case of hypocomplementemic membranoproliferative glomerulonephritis was studied during remission of nephrosis induced by high doses of corticosteroids. Hepatitis B surface antigen (HBsAg) and immune complexes were detected in serum and glomeruli. Anti-hepatitis-B surface antibody, undetectable in serum by conventional radioimmunoassays was identified in circulating immune complexes (CIC). On two occasions, improvement in renal function coincided paradoxically with an extreme increase in serum HBsAg levels as well as with marked elevation of CIC. We suggest that, as previously observed in animal models of glomerulonephritis, extreme antigen excess may inhibit glomerular deposition of immune complexes.     

Streptococcal M protein enhances TGF-beta production and increases surface IgA-positive B cells in vitro in IgA nephropathy.

BACKGROUND: High serum levels and enhanced in vitro production of IgA are observed in more than half of patients with IgA nephropathy (IgAN); and transforming forming growth factor-beta (TGF-beta) is certain IgA class switching factor. On the other hand, macroscopic haematuria appears frequently with upper respiratory infection as tonsillitis in IgAN. METHODS: We compared the lymphocytic response to in-vitro stimulation by group A streptococcal M proteins of apparent virulence factor between IgAN, non-proliferative glomerulonephritis (NPGN), and normal subjects. M proteins were extracted from group A streptococcal strain type 5 and type 12 determined serologically. RESULTS: M protein-induced proliferation of lymphocytes from IgAN was higher than in NPGN but not in healthy control subjects. Flow cytometric analysis indicated that stimulation by M protein extracts derived from type 5 streptococci (M5) increased surface IgA-positive B cells in IgAN, but did not activate the production of soluble IgA. We also showed that M5 induced significant increases in TGF-beta, in culture supernatants of lymphocytes from patients with IgAN. CONCLUSION: Our results suggest that Streptococcal infection may play an important role in the pathogenesis of IgAN by stimulating IgA production through TGF-beta synthesis.     

Studies of circulating immune complexes and lymphocyte subpopulations in childhood IgM mesangial nephropathy

T cell subsets, serum immunoglobulin (IgM) level, IgM-bearing lymphocytes, and circulating immune complexes (CIC) were studied in 12 children who suffered from IgM mesangial nephropathy (IgMN) during the acute nephrotic phase, in remission and relapse. Frequent relapses were observed in 11 cases, and 1 was partially responsive to steroid treatment. IgMN was diagnosed by the consistent pattern of IgM deposition by all four FITC-labelled antihuman IgM antibodies from rabbits and goats supplied by four different companies and by the 100% positivity of electron-dense mesangial deposits in an identical localization and distribution pattern of kidney biopsy specimen. CIC were detected by the 3.5% polyethylene glycol method. In sera from 12 patients IgM CIC were detected in 8 cases during the acute nephrotic phase. High levels of C3 CIC and C4 CIC were also found in these cases during the acute nephrotic phase. The CIC were undetectable in remission. Only 3 cases were detectable at low levels of IgM CIC during the second relapse. High serum IgM levels and IgM-bearing lymphocytes were noted in these patients. The patients also had a significant increase of OKT8 cells and a decrease in the OKT4/OKT8 ratio during the acute phase and in relapse. Taken together, the immunopathologic and clinical features suggest that IgMN is a disease entity with a chiefly classical pathway activation of complement components. The correlation between the changes of T cell subsets and the disease activity in IgMN suggests that this may serve as a therapeutic and prognostic guide.     

Polymorphism in IgA nephropathy

Summary: IgA nephropathy (IgAN) is polyphormic in its clinical manifestation, course and prognosis. Patients with isolated IgA deposit in glomeruli tend to have a high incidence of macroscopic haematuria and carry a better prognosis. In contrast, patients with deposits of IgA and IgG and IgM have a higher incidence of nephrotic syndrome and hypertension. In parallel, patients with IgA and IgG and IgM tend to have more glomerulosclerosis and tubulointestitial lesions. Recently, the angiotensin converting enzyme (ACE) gene polymorphism and its association in disease risk provided interesting exploration leading us to speculate about a possible mechanism to explain the variation in the rate of progression of IgAN; although, the results are still controversial. The variability of plasma ACE concentration has been shown to be associated with an insertion/deletion polymorphism. The frequencies of ACE genotype in 177 Chinese patients with IgAN has been observed. We found that patients with IgAN showed a higher frequency of DD genotype than normal population. In contrast to the previous reports, we did not find any association between ACE genotype and the rate of progression of IgAN. As different genotypes of IL-1 receptor antagonist (IL-1 ra) are also responsible for the circulating levels of IL-1 ra, the polymorphism of IL-1 ra gene has been analyzed in 100 IgAN patients. There was no significant difference in the frequency of IL1RN*2 allele between normal subjects and IgAN. However, patients with recurrent macroscopic haematuria showed a higher carriage rate of IL1RN*2. Hereditable factors, in combination with a number of recognized environmental risk factors, are important determinants of the pathogenesis and natural history of IgAN. The notion that the gene polymorphism might be responsible for the clinical features and progression of IgAN is both intriguing and provocative. The lessons from previous multiple small size studies have produced conflicting results illustrating the need for observation of large numbers of cases in further studies to verify these observed associations.     

A clinicopathological study of adult Japanese IgA nephropathy patients: Early stage cases and cases with exacerbation

Summary: Most cases of adult type IgA nephropathy (IgAN) have an insidious onset and asymptomatic course. However, some patients reveal recurrent macroscopic haematuria following episodes of respiratory or urinary tract infections. In order to clarify the correlation between clinical features and histological alterations or prognosis, 42 cases of early stage IgAN and 40 cases with acute exacerbation episodes were investigated and compared with a control group. Early stage cases were defined as having had a renal biopsy within 1 year after the first detection of urinary abnormalities, and had normal urinary findings within the 12 months before the first detection of urinary abnormalities. Acute exacerbation cases were defined as macroscopic haematuria or worsening of urinary abnormalities after acute infectious episodes and undergoing a renal biopsy within 120 days after the onset of these episodes. the early stage cases had better renal function and lower systolic and diastolic blood pressure than that of control group. They also showed milder changes in mesangial cell proliferation, mesangial matrix increase, totally sclerotic glomeruli, and tubulo-interstitial changes. However, it is important to note that glomerular and interstitial sclerotic changes were observed even in early stage cases. Endothelial detachment was noticed more frequently in the early stage cases. Acute exacerbation cases revealed lesions of endocapillary proliferation, mesangiolysis and endothelial detachment more frequently, although these changes were segmental in each glomerulus. There was no statistical difference in disease prognosis between cases with and without acute exacerbation. These data indicated that there are characteristic histological changes in early stage cases and acute exacerbation cases of IgAN.     

Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.

BACKGROUND: In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN. METHODS: Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP-IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-beta 1 by cultured mesangial cells was also examined. RESULTS: IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-beta 1 production in a time- and dose-dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating cells with neutralizing antibody against MIF. CONCLUSIONS: Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1 expression in an experimental model of IgAN.     

An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy.

BACKGROUND: Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. METHODS: A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n = 21) and patients with IgAN (n = 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. RESULTS: Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. CONCLUSIONS: Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.     

The pathogenetic potential of environmental antigens in IgA nephropathy

Patients with IgA nephropathy (IgAN) can be considered high responders for IgA production; data which indicate a generalized hyperreactivity of the immune system include autoantibody production, increased response to viral vaccination, and high titers of antibodies to various common respiratory and gastrointestinal microbes. From clinical and experimental observations, two types of antigen seem to be most involved in the pathogenesis of IgAN, ie, environmental respiratory or gastrointestinal infectious agents and dietary antigens. A role played by microbes has been suggested because macroscopic hematuria shortly follows a pharyngitis or a gastrointestinal disturbance. Antibodies to a wide spectrum of viral and bacterial infectious agents have been detected in sera from patients with IgAN. The possible role of dietary antigens has been demonstrated experimentally in animal models. In human IgAN, antibodies to various dietary antigens have been detected in sera; antibodies have also been found in IgA immune complexes and renal eluates. In human IgAN, a significant decrease in serum levels of IgA-containing circulating immune complexes after a gluten-free diet has been observed. The present experience accounts for 27 IgAN patients followed for 6 months to 3 years on a gluten-free diet. A decrease in serum levels of IgA-containing circulating immune complexes was observed in 64% of the patients whose initial levels were high during a period of unrestricted diet. Patients with basal high levels also had significantly high levels of IgA antibodies to dietary antigens, including bovine serum albumin, ovalbumin, and various gluten fractions. After 1 year of gluten-free diet the levels significantly decreased. A disappearance of antigliadin IgA, observed in 80% of the cases, was paralleled by a decrease in titers of the other antibodies to dietary components. These data support the hypothesis that in patients with IgAN, gluten may act as a toxic lectin, increasing the permeability of the intestinal mucosa to various dietary antigens.     

Long-term follow-up of patients with IgA nephropathy treated with prednisolone and cyclophosphamide therapy

BACKGROUND: Analyses of selected cases suggest that immunosuppressive treatment could reduce proteinuria and delay the progression of immunoglobulin A nephropathy (IgAN). The aim of this study was to examine the long-term effectiveness of this therapy on the clinical course of IgAN. We also examined the relationship between the efficacy of the treatment and the suppression of the serum immunoglobulin level. METHODS: Eighteen patients who were observed for more than 2 years after prednisolone and cyclophosphamide therapy were enrolled in this study. Their clinical and laboratory characteristics were recorded for 2-18 years (mean 7.8 +/- 5.7 years). RESULTS: Of the 18 patients, 13 had remission of proteinuria. We observed the subsequent development of proteinuria in four patients. Fourteen patients had remission of hematuria, with five patients experiencing subsequent relapse of hematuria. The mean time from the treatment to the relapse of proteinuria or hematuria was 5.8 years. Serum immunoglobulins were suppressed by the combination therapy. Serum IgG and IgM recovered 6 months after the treatment, whilst the suppression of serum IgA lasted for 4 years. We found a positive correlation between the serum IgA level and the degree of proteinuria. CONCLUSION: This study indicates that long-term follow-up is essential in order to prove the long-term benefit of immunosuppressive therapy in patients with IgAN. Careful monitoring of the serum IgA level may be useful in the follow-up of patients with IgAN, especially when they are treated with immunosuppressive agents.     

Tonsillectomy and IgA nephritis

IgA nephritis (IgAN) is an autoimmune disease characterized by deposits of IgA in the glomerular mesangium. Clinically, the disease may be punctuated by episodes of macroscopic haematuria often associated with pharingotonsillitis or may be oligosyntomatic with microscopic haematuria and mild proteinuria. The natural course of IgAN may be indolent and benign; however, some 30-50% of patients may progress to end-stage renal disease when follow-up is extended to ≥20 years. In patients with IgAN, circulating IgA1 molecules have an aberrant structure of O-glycans in the hinge region, which is characterized by abbreviated glycans composed of N-acetylgalactosamine, with or without sialic acid. These aberrant IgA1 trigger the production of autoantibodies, with formation of immune complexes that deposit in the mesangium causing inflammation and production of extracellular matrix. A number of experimental and clinical data outlined a possible pathogenetic role of tonsillitis. As a consequence, tonsillectomy has been frequently performed in Japan. Observational studies, made in patients with normal renal function and mild proteinuria, reported that tonsillectomy could reduce the episodes of macrohaematuria as well as the entity of microhaematuria and proteinuria. However, the available studies had short-term follow-up and could not asses the role of tonsillectomy in protecting from renal function deterioration. In a longitudinal retrospective study, Isseki et al. compared the outcome of tonsillectomized patients with IgAN with that of IgAN patients who did not receive tonsillectomy. Tonsillectomized patients had a higher number of remissions and a better slope of glomerular filtration rate in comparison with controls. These data are interesting and suggest that tonsillectomy may prevent renal dysfunction in patients with IgAN and normal renal function. However, the retrospective nature of the study and the presence of some confounding factors require further investigations to confirm these promising data.     

The effect of triple therapy on rapidly progressive type of Henoch-Schönlein nephritis

Twelve patients with Henoch-Schönlein purpura, aged 6–14 years (mean 10.3 years), presenting with rapidly progressive glomerulonephritis (RPGN) were investigated prospectively. Analysis of the initial clinical features revealed: oedema (8 patients), hypertension (7 patients), gross haematuria (11 patients), oliguria (5 patients) and a decreased glomerular filtration rate (GFR) (<40 ml/min per 1.73 m², 8 patients). Renal biopsies were available in 9 patients and revealed focal necrotising and a fibroepithelial type of crescentic glomerulonephritis (with 60%–90% crescent formation). The remaining 3 patients fulfilled the clinical criteria of RPGN. Two patients who were in the acute stage required peritoneal dialysis for a period of 2 weeks. The treatment protocol in all patients consisted of intravenous pulse methylprednisolone (3 days), oral cyclophosphamide (2 months), oral dipyridamole (6 months) and oral prednisolone (3 months). At the end of triple therapy, GFR returned to normal in all but 1 patient. During a follow-up period of 9–39 months, 7 patients achieved complete remission, while 4 patients showed partial remission, 3 of whom had persistent proteinuria and haematuria and 1 microscopic haematuria only. One patient had persistent nephropathy with decreased GFR and macroscopic haematuria and nephrotic-range proteinuria. His renal biopsy, performed 30 months after the onset of the disease, showed chronic diffuse sclerosing glomerulonephritis and intratubular severe IgA deposition. Although our patient group was small, this type of intensive treatment appears to be effective; further studies are needed.     

Clinicopathological features of paediatric renal biopsies in Shanghai over a 31 year period

Aim: To identify the variations in paediatric renal biopsy pathology and clinicopathological features during the past 31 years. Methods: A retrospective analysis of paediatric renal biopsies performed at a single institution in Shanghai from January 1979 to December 2009 was conducted. Results: The major pathologies included minor glomerular abnormalities (MGA, 26.1%), IgA nephropathy (IgAN, 17%) and mesangial proliferative glomerulonephritis (MsPGN) without IgA deposition (11.3%). The major clinical presentations included nephrotic syndrome (NS, 39.4%), haematuria with proteinuria (24.4%) and persistent microscopic haematuria (15.1%). MGA accounted for 46.9% of the cases in NS. IgAN and HSN accounted for 24% and 28.9% of patients with concomitant haematuria and proteinuria, and thin basement membrane nephropathy accounted for 51.2% of cases with persistent microscopic haematuria. The frequency of IgAN (78.6%) was much higher than that of TBMN (29.0%) in patients with persistent microscopic haematuria with abnormal urinary albumin. Conclusion: Minor glomerular abnormalities and IgAN were the major renal diseases in our study population, and the focus of our paediatric nephrologists. The high proportion of TBMN suggested that there should be limited use of renal biopsy for patients with persistent microscopic haematuria and renal biopsy should be performed in the presence of proteinuria or abnormal levels of urinary albumin.     

Possible pathogenic role of IgE in Henoch-Schönlein purpura

The incidences of clinical and biological markers of atopy were investigated in 16 children with IgA nephropathy (IgAN) (group A) and in 22 with Henoch-Schönlein purpura nephritis (HSPN) (group B). The incidence of increased plasma IgE levels according to age-matched normal values was significantly higher in group B (17/22, 77%) than in group A (7/16, 44%) (P<0.05). Although not significant, the incidences of positive RAST tests and of a history of typical atopic symptoms were also higher in group B [10/22 (45%) and 11/22 (50%), respectively] than in group A [4/16 (25%) and 5/16 (31%), respectively]. Moreover, IgE deposits were demonstrated by a peroxidase/anti-peroxidase method on cutaneous Langerhans and mast cells in 4 of 6 patients with HSPN. Thus immunoallergy might account, in some cases, for the cutaneous, intestinal and pulmonary signs observed in HSPN, but not in IgAN. We postulate stimulation of IgE-sensitized mast cells by specific antigens in the presence of IgA circulating immune complexes (CIC), release of vasoactive substances, increased capillary permeability and perivascular deposition of IgA CIC.     

Immunological aspects of IgA nephropathy

Summary: IgA nephropathy (IgAN) is one of the most common primary renal diseases, and can be readily diagnosed by finding glomerular IgA deposits as either the dominant or codominant immunoglobulin on immunofluorescence microscopy. Despite some contradictory results about the nature and origin of IgA, it is generally accepted that the deposited IgA is polymeric and belongs to the IgA, subclass and systemic compartment is the source of circulating polymeric-IgA in IgAN. Because IgAN presents with asymptomatic microscopic haematuria or with episodic gross haematuria following upper respiratory and gastrointestinal disturbance, various environmental respiratory or gastrointestinal infectious agents and dietary antigens are suggested. Until now, however, it has not been possible to unequivocally identify specific antigens that are responsible for the formation of mesangial IgA deposits in patients with IgAN. Overproduction or delayed clearance of IgA as observed in patients and in animal models and in those processes, polyclonal stimulation of immunoglobulin production, with structural abnormalities of IgA, seems to play an important role. The mechanism responsible for the mesangial deposition of IgA is still unclear. The codeposition of IgA, C3 and properdin without Clq and C4 suggested a possible activation of the alternative pathway by IgA-containing immune complexes. To sum up, in IgAN the predominant antibody appears to be composed of polymeric-IgA₁ originating in the systemic compartment. The deposition of polymeric-IgA₁ in the mesangium and the activation of the alternative pathway of complement are probably crucial in the induction of the inflammatory lesions in the glomeruli and the development of haematuria in IgAN.