Andrew J. Woodroffe

No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis☆

It has been recently reported that in type 1 diabetes the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme gene is associated with the presence of diabetic nephropathy. Tissue angiotensin I-converting enzyme is determined by I/D polymorphism, and it has been speculated that in diabetes differences of local angiotensin II availability determine the risk of renal disease. Since angiotensin II is thought to play an important role in the evolution of renal disease in general, we tested whether genotype distribution of the I/D polymorphism is also different in patients with immunoglobulin A-glomerulonephritis (IgA-GN). Furthermore we compared IgA-GN patients with (1) stable renal function or (2) terminal renal failure to investigate a potential role of the I/D polymorphism in the renal prognosis. We examined 122 patients with biopsy-confirmed IgA-GN who had stable renal function and 82 dialysis-dependent or transplanted patients with biopsy-confirmed IgA-GN. Furthermore, in 134 healthy individuals used as controls we analyzed the DNA for normal distribution of genotypes and allele frequencies. The polymorphic region was amplified using polymerase chain reaction with specific primers. Alleles were detected on 2% agarose gels. Genotype distributions and allele frequencies were not significantly different between controls and patients with IgA-GN and stable renal function. Furthermore, no significant difference in genotype distribution was detected between patients with IgA-GN and stable renal function compared with patients with IgA-GN and end-stage renal failure, although a trend for a higher frequency of DD-homozygotes was noted in the latter group (P = 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular IgA deposits in clinically normal skin of patients with renal disease

&NA; Direct immunofluorescent tests for IgA deposits were done on biopsies of normal appearing skin from 49 patients with proven renal disease and 7 healthy individuals, in order to evaluate the method in the diagnosis of IgA nephropathy. Many of the 28 patients with IgA nephropathy had high levels of IgA deposition, often accompanied by notable deposits of IgM, Clq and fibrin, and less frequently by C3 and IgG, in small vessels of the superficial dermis. However, some of the 21 patients with other renal diseases had heavy deposits of IgA, limiting the usefulness of the test as a diagnostic aid.

Mesangial IgA nephritis

SummaryCurrent data suggest that mesangial IgA nephritis is mediated by the mesangial deposition of soluble antigen-IgA class antibody complexes from the circulation. It is likely that common infectious gut flora and dietary antigens contribute to the immune complex load. Defects in antigen exclusion at the mucosa, in the control of IgA production, and in immune complex clearance are postulated to account for each of the recognized clinical syndromes. As yet no effective treatment is available, and a detailed analysis of the mediation pathways will be required before prevention or therapy can be attempted.

IgA Antibodies to Dietary Antigens and Lectin-Binding IgA in Sera From Italian, Australian, and Japanese IgA Nephropathy Patients

We studied serum IgA as antibodies to dietary antigens (Ag), as lectin-binding molecules, and as conglutinin-binding immune complexes (IgAIC) in people from geographical areas in which IgA nephropathy (IgAGN) is particularly frequent. Sera from 63 Italian, 21 Australian, and 25 Japanese patients affected by IgAGN and 24 Italian, 20 Australian, and 40 Japanese healthy controls were studied. Increased values of IgAIC were detected in 42.8% of Italian patients, while only in 23.8% and 8% of Australian and Japanese patients, respectively. Mean values were significantly increased only in Italian patients (P less than 0.0001). Positive values of IgA antibodies against dietary Ag had variable prevalences, but again Italian patients showed the highest frequency, from 19% to 28.5% versus 0 to 38% in Australians and 0 to 16% in Japanese. Mean values of these antibodies were not significantly increased in any patient groups in comparison to the corresponding healthy populations. However, patients with elevated values of IgAIC had significantly higher serum concentrations of antibodies to alimentary components and a linear correlation was found between IgAIC and some IgA antibodies to food components. The relationship between these two series of data was particularly evident for Italian and Australian IgAGN patients. Moreover, the patients with positive data tended to have a cluster of increased levels of IgA antibodies against several alimentary Ag at the same time. A linear correlation was evident between values of IgA antibodies to gluten fractions and to heterologous albumins. None of these correlations was evident among healthy controls.(ABSTRACT TRUNCATED AT 250 WORDS)

IgA nephropathy--accumulated experience and current concepts.

&NA; Primary IgA nephropathy is the most common form of glomerulonephritis in Australia. The condition presents in a variety of ways, but commonly with synpharyngitic hematuria, most often in young men in the third and fourth decades. The course of the disease is indolent but there is progression to renal failure in up to one quarter of cases. Renal biopsy morphology is variable but the essential immunofluorescence finding is diffuse mesangial IgA staining of greater intensity but often in association with other immunoglobulins. C3 is usually also present. Mesangial cellularity is increased in some two‐thirds of cases, one third being of a minor focal or variable extent and one‐third diffuse. Focal segmental lesions, hyaline nodules and vascular changes are frequent. Crescents are also often present. The etiology of the disease is uncertain but has been linked with HLA antigens, elevated serum IgA levels, IgA polymers, immune complexes and impaired T cell function. Secondary forms of mesangial IgA deposition occur with mucosal defects, hyperglobulinemia or impaired hepatobiliary clearance, and these may offer some insight into the immunopathogenesis of the primary disease.

Fc-Specific Reticulo-Endothelial Clearance in Systemic Lupus Erythematosus and Glomerulonephritis

Fc-specific reticulo-endothelial (R-E) clearance was determined in control subjects (n = 11) and in patients with immune complex (IC) glomerulonephritis (n = 22) and systemic lupus erythematosus (SLE) nephritis (n = 10). Clearance (t1/2) depended on the removal of autologous erythrocytes labeled with 51chromium and sensitized with anti-D IgG by fixed splenic macrophages bearing receptors for the Fc portion of the IgG molecule. A significant difference in clearance rates was demonstrated between normal individuals with and without the HLA-B8, DR3 haplotype. Marked clearance defects were found in SLE (8/10), and t1/2 correlated with the levels of circulating IC. Delayed clearance was also observed in 6/11 patients with IgA nephropathy or Henoch-Schönlein purpura and in 4/11 patients with membranous nephropathy (MN). No correlation was found between circulating IC levels and t1/2 in these diseases. Clearance defects in these patients did not correlate with the presence of the HLA-B8, DR3 haplotype. This study demonstrates that some patients with IC glomerulonephritis have defective Fc-mediated clearance that does not appear to be secondary to IC blockade.

Therapeutic Options in IgA Nephropathy

IgA nephropathy (IgAN) is a common form of glomerulonephritis that leads to end-stage renal disease at variable rates in 20% to 30% of cases. A rational approach to therapy requires an understanding of pathogenetic mechanisms that are largely unknown. Several therapeutic approaches have been used, generally in uncontrolled trials, aimed at lowering levels of circulating immune complexes, affecting cellular immunity, or removing antigens through dietary restriction. Thus far, no clear-cut beneficial effects are evident. Alternative means of changing glomerular hemodynamics through prevention of harmful mediators await exploration.

STUDIES ON GLOMERULAR IMMUNE SOLUBILIZATION BY COMPLEMENT IN PATIENTS WITH IgA NEPHROPATHY

A study of the solubilization of glomerular immune deposits by serum or complement in patients with IgA nephropathy is described. Renal biopsy specimens were obtained from 15 patients with IgA nephropathy. These specimens were incubated with fresh and heated sera from healthy adults or with lyophilized complement components, i.e., C3 and C4, at 37°C for one hour in plastic tubes. The sections were then stained with fluorescein isothiocyanate (FITC)‐labelled anti‐human IgA antisera and examined by fluorescence microscopy. Normal sera showed a marked capacity to solubilize the glomerular immune deposits characteristic of IgA nephropathy. The solubilization capacity was reduced after inactivation and absorption of sera with anti‐human C3 antiserum. Lyophilized C3 or C4 did not show any ability to solubilize such deposits. It was concluded that the solubilization of glomerular immune deposits may require whole active (fresh) components of complement related to the alternative pathway. ACTA PATHOL. JPN.

Fractionation of serum IgA in patients with IgA nephropathy, alcoholic cirrhosis and systemic lupus erythematosus (SLE)

Deposits of IgA and C3 are found in renal biopsies from patients with IgA nephropathy, alcoholic cirrhosis and SLE. Many of these patients have raised serum IgA levels and it has been suggested that the glomerular deposits may be IgA aggregates rather than soluble immune complexes (IC). The molecular size of serum IgA was therefore determined in control subjects and in patients with these diseases using gel filtration (Sephadex G-200 and Sepharose CL-6B) and sucrose density gradient (10-60%) ultracentrifugation. The fractions were assayed for IgA, IgG, IgM and C3 by laser nephelometry and for IC by “solid phase Clq RIA. Patients with alcoholic cirrhosis and SLE had increased amounts of > 7S IgA and IC. There was no increase in polymeric IgA in the majority of patients with IgA nephropathy by 30% had IC. The data suggests that the serological and renal findings in these diseases result from IC rather than IgA aggregates.