Immunoglobulin A and renal diseases

Immunoglobulin A (IgA) is a dominant immunoglobulin of the mucosal surfaces, but it is also present in plasma. In men and in hominoid primates it occurs in two subclasses: IgA1 and IgA2. Circulating IgA is mostly IgA1 monomer, secretory IgA is mostly dimer or tetramer with varying content of IgA1 and IgA2 on individual mucosal surfaces. Its main physiological function is a defence of the mucosal surfaces against infection. It binds either specifically to bacterial antigens or through its O-linked glycosidic chains, it binds to the lectins of bacterial cells and thus protects mucosal surfaces against bacterial adhesion and infection. On each of its heavy chain, IgA1 has at least two N-glycosidically bound oligosaccharides and 3 to 5 O-linked side-chains. The occurrence of O-glycosidically bound glycans on other circulating immunoglobulins is rare. An aberrant composition of these glycans may be an antigenic determinant for naturally occurring circulating antibodies. The resulting IgA-containing immune complexes, which are deposited in the glomeruli, may be the cause of IgA nephropathy. IgA glomerular deposits are also frequently present in many other primary and systemic glomerulonephritides.     

New insights in the pathogenesis of IgA nephropathy

IgA nephropathy (N) or Berger's disease is the most common form of primary glomerulonephritis worldwide and one of the first cause of end-stage renal failure. The disease is characterized by the accumulation in mesangial areas of complexes containing polymeric IgA1. The mechanisms involved in the pathogenesis of IgAN is only now emerging. We discussed here three essential points: (i) the generation of abnormal IgA1 and formation of IgA1 complexes; (ii) the generation of mesangial injury mediated by interaction of IgA1 complexes with mesangial IgA1 receptors, and (iii) the progression of IgA-mediated mesangial injury towards renal failure. In summary, our data reveal that quantitative and structural changes of IgA1 play a key role on the onset of the disease due to functional abnormalities of two IgA receptors: the Fc alphaRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal IgA induces release of soluble CD89 soluble leading to the formation of circulating IgA complexes, which in turn may be trapped by CD71 that is overexpressed on mesangial cells in IgAN patients allowing formation of IgA1 deposits. The elucidation of IgA-receptor interactions may open new avenues for drug design and treatment of IgAN.     

Pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is initiated by glomerular deposition of polymeric IgA1(pIgA1). In IgAN pIgA production is reduced in the mucosal immune system, perhaps mediated by a mucosal gamma delta T cell defect, and mucosal IgA responses to immunisation are impaired. But pIgA1 production by the marrow is increased. Human pIgA1 has an O-glycosylated hinge region unique to circulating immunoglobulins and there is reduction of galactosyl residues in the hinge of serum IgA1 in IgAN and Henoch-Sch?nlein nephritis. This reduced galactosylation may be due to a functional defect in plasma cell beta 1,3-galactosyltransferase. Altered hinge region glycosylation may alter IgA1 structure, modifying interactions with matrix proteins, IgA receptors and complement, and therefore influence mesangial deposition and subsequent injury through mechanisms other than classical antigen-antibody reactions. IgA clearance through the hepatic asialoglycoprotein receptor or Fc alpha receptors on circulating white cells may also be impaired. The unique features of human IgA1 have prevented development of satisfactory animal models for the early stages of IgAN. It is likely that events after pIgA1 deposition which result in glomerular inflammation and scarring are not specific to IgAN but generic to many forms of glomerulonephritis.     

Cell biology of diabetic nephropathy: Roles of endothelial cells,tubulointerstitial cells and podocytes

Diabetic nephropathy is the major cause of end‐stage renal failure throughout the world in both developed and developing countries. Diabetes affects all cell types of the kidney, including endothelial cells, tubulointerstitial cells, podocytes and mesangial cells. During the past decade, the importance of podocyte injury in the formation and progression of diabetic nephropathy has been established and emphasized. However, recent findings provide additional perspectives on pathogenesis of diabetic nephropathy. Glomerular endothelial damage is already present in the normoalbuminuric stage of the disease when podocyte injury starts. Genetic targeting of mice that cause endothelial injury leads to accelerated diabetic nephropathy. Tubulointerstitial damage, previously considered to be a secondary effect of glomerular protein leakage, was shown to have a primary significance in the progression of diabetic nephropathy. Emerging evidence suggests that the glomerular filtration barrier and tubulointerstitial compartment is a composite, dynamic entity where any injury of one cell type spreads to other cell types, and leads to the dysfunction of the whole apparatus. Accumulation of novel knowledge would provide a better understanding of the pathogenesis of diabetic nephropathy, and might lead to a development of a new therapeutic strategy for the disease.     

Predictors of prognosis in IgA nephropathy

IgA nephropathy (nephropathy with mesangial IgA and IgG deposits, so-called Berger's disease) is the most common primary chronic glomerulonephritis worldwide, and was first described in 1968. Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. This disease, therefore, is considered to be an immune-complex-mediated glomerulonephritis although the antigenic agents are still obscure. Clinically, patients with IgA nephropathy show microscopic and macroscopic hematuria and/or proteinuria. Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia, and end-stage kidney disease is not as rare as originally thought. Since pathogenesis and radical treatment for IgA nephropathy are still not established, it is necessary to study them using various clinical findings.     

Celiac disease and HLA DQ in patients with IgA nephropathy

OBJECTIVES: Despite some reports on an association between celiac disease and IgA nephropathy, the evidence is still sparse. Celiac disease is strongly associated with the HLA DQ2 and DQ8 haplotypes, which might explain the potential risk of patients to contract various autoimmune conditions. In this study, we sought to establish how common celiac disease is in patients with IgA nephropathy, and whether the possible association can be explained by similar HLA DQ status. METHODS: A total of 223 consecutive adult patients with IgA nephropathy were studied; 95 cadaver organ transplant donors served as controls for HLA DQ analysis. The diagnosis of celiac disease was based on small bowel mucosal biopsy. All known celiac cases were recorded, and eligible patients (n = 168) underwent serological screening for celiac disease as well as HLA DQ2 and DQ8 analysis. Screening methods were serum endomysium and tissue transglutaminase antibodies; patients who tested positive underwent mucosal biopsy. RESULTS: Eight patients (3.6%, 95% CI = 1.6-7.0%) with IgA nephropathy were found to have celiac disease; three of them were identified by serological screening. All celiac cases had the HLA DQ2 or DQ8 haplotype, but these were not more common in patients with IgA nephropathy than in controls. As many as 14% of HLA DQ2 positive patients with IgA nephropathy had celiac disease. Gluten-free diet had no apparent influence on the course of nephropathy. CONCLUSIONS: Although there is no increase in celiac-type HLA DQ, patients with IgA nephropathy carry a risk of contracting celiac disease. It can be hypothesized that the increased intestinal permeability in IgA nephropathy may predispose genetically susceptible patients to celiac disease.     

Circulating anti-glomerular basement membrane antibodies in coeliac disease and epidermolysis bullosa acquisita

Abstract The demonstration of circulating anti-glomerular basement membrane (GBM) antibodies is almost diagnostic for anti-GBM disease and Goodpasture's syndrome. These antibodies are, however, occasionally present in SLE and diabetes, in association with IgA disease and membranous nephropathy and after transplantation in Alport's syndrome. In addition, we describe circulating anti-GBM antibodies in a research worker who handled GBM and in whom coeliec disease later developed, and in an individual with epidermolysis bullosa acquisita. Neither patient had impaired renal function nor an abnormal urinary sediment, suggesting either that these antibodies were of low affinity, or that additional factors are required for the pathogenesis of an aggressive glomerular lesion when circulating anti-GBM antibodies are present. In at least one of these individuals anti-GBM antibodies may have developed after the exposure of basement membrane collagen type IV to activated immunological mediators and cells. (Aust NZ J Med 1991; 21: 867–870.)     

Preliminary study on specificity of IgA released from lymphocytes by EB virus transformation in patients with IgA nephropathy

A study on the specificity of IgA in the supernatant of Epstein-Barr Virus (EBV) transformed lymphocytes obtained from patients with IgA nephropathy is described. Renal biopsy specimens were obtained from nine patients with IgA nephropathy and nine patients with other glomerular diseases. Mononuclear cells obtained from two patients with IgA nephropathy and two healthy adults were transformed with EBV and the supernatant of such transformed cell culture was applied to acid (pH 3.2)-treated renal sections obtained from the same and other patients with IgA nephropathy, as well as to those with other glomerular diseases. The sections were stained with FITC-labeled heavy chain-specific anti-human IgA antiserum and then examined with a fluorescent microscope. It was demonstrated that IgA in the supernatant specifically bound with the glomerular mesangial areas in patients with IgA nephropathy, while it did not bind with such areas in patients with other glomerular diseases. Although IgA in such samples bound with autologous renal tissues, about 50% bound with allogeneic renal specimens of IgA nephropathy. IgA in the supernatant of transformed lymphocytes from healthy adults was not bound with the glomerular mesangial areas of patients with IgA nephropathy and other glomerular diseases. It is concluded that IgA in the supernatant of lymphocytes by EB virus transformation is specific to the mesangial areas of IgA nephropathy and that some heterogeneity is seen among patients with this disease.     

Regulation of mesangial cell function by vasodilatory signaling molecules

Proliferation of mesangial cells and expansion of mesangial matrix is a hallmark of glomerular disease leading to end-stage renal failure and requiring renal replacement therapy. Independently from the type of injury, e.g. in glomerulonephritis or diabetic nephropathy, the response to injury is remarkably uniform. Chronic glomerular disease is frequently associated with increases in systemic blood pressure and altered intraglomerular hemodynamics. Furthermore, reduction of systemic blood pressure and inhibition of the vasoconstrictor peptide angiotensin II have been shown to delay end-stage renal failure in various types of human kidney disease. Since vasoconstrictors of mesangial cells and efferent glomerular arterioli, such as angiotensin II, are thought to be detrimental for the progression of chronic glomerular disease, we propose that vasodilatory factors which antagonize the effects of angiotensin II, might have beneficial effects during the course of progressive kidney disease. To support this concept we will summarize currently available data on the role of vasodilatory signaling molecules such as natriuretic peptides (ANP, BNP and CNP), nitric oxide (NO), the prostaglandines PGE2 and prostacycline, and the purine mediator adenosine in the regulation of mesangial function.     

The salt paradox and its possible implications in managing hypertensive diabetic patients

Diabetes mellitus is one of the leading causes of end-stage renal disease. The pathogenesis of diabetic nephropathy is still poorly understood, but glomerular injury has been ascribed, at least in part, to glomerular hyperfiltration, which occurs early in the course of diabetes mellitus. Therefore, a better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. In this review, we discuss the pathophysiology for the paradoxical relationship between dietary salt and glomerular filtration rate observed in early diabetes mellitus and possible implications in managing diabetic patients.     

Do IgA antigliadin and IgA antiendomysium antibodies show there is latent coeliac disease in primary IgA nephropathy?

The finding in primary IgA nephropathy of increased levels of IgA to food antigens and particularly to gliadin prompted the hypothesis that a subgroup of these patients may have latent coeliac disease. The observation that gliadin may experimentally induce IgA mesangial deposits supported this hypothesis. We evaluated specific immunological markers of coeliac disease (antiendomysium antibodies) which parallel histological changes of gluten sensitive enteropathy, and an IgA immunofluorescent test for antigliadin antibodies in 18 patients with IgA nephropathy, in 56 untreated coeliac disease patients, in 254 controls (58 healthy and 196 disease controls). Antiendomysium antibodies were positive in 89.28% of coeliac patients, but negative in all IgA nephropathies and controls. IgA immunofluorescent test for antigliadin antibodies, negative in all IgA nephropathy patients, was positive in 76.78% of coeliac patients and in 4.91% of controls. ELISA IgA antigliadin antibodies were negative in controls, but positive in 22.22% of IgA nephropathy patients and in 60.71% of coeliac patients. Our data would suggest that in most patients with IgA nephropathy there is no evidence of latent coeliac disease.     

Increase of IgA in pharyngeal washings from patients with IgA nephropathy

The levels of IgA and total proteins in pharyngeal washings were examined in patients with IgA nephropathy and other glomerular diseases in order to determine whether secretory IgA, IgA1 and IgA2 were increased in these patients. Thirty patients with IgA nephropathy, 21 patients with other glomerular diseases and 15 healthy adults were examined. The levels of IgA were quantitated by radial immunodiffusion and laser nephelometry. The levels of total proteins in pharyngeal washings were quantitated by Tonein-TP. It was demonstrated that the levels of IgA in pharyngeal washings were significantly increased in patients with IgA nephropathy compared to those with other glomerular diseases and healthy adults. The levels of total proteins in pharyngeal washings were increased in patients with IgA nephropathy, and the ratio of IgA and total proteins in the washings from patients with IgA nephropathy was not significantly different from those healthy adults. There was a significant correlation between the levels of IgA in pharyngeal washings and those of IgA in sera from patients with IgA nephropathy. The IgA observed in pharyngeal washings contained secretory components, IgA1 and IgA2, in patients with IgA nephropathy. It is suggested that the increase of IgA in the pharyngeal washings in parallel with the increase of total proteins might be associated with local inflammation.     

Progress in understanding the pathogenesis of IgA nephropathy: new perspectives for the near future?

Progress in understanding the pathogenesis of IgA nephropathy has shown that probably there is no a single IgA nephropathy with the same pathogenic mechanism, clinical course and response to therapy. The evidence currently available suggests the existence of at least two possible mechanisms of IgA deposition in the renal mesangium. In a small percentage of patients, mesangial deposition of IgA1 colocalizes with secretory component, indicating that the deposited IgA1 in glomeruli originates completely or partly in the mucose-associated lymphoid tissue. This deposition pattern has been associated with activation of complement by the lectin pathway and has been associated with a worse prognosis, although this last statement needs to be confirmed in long-term studies. The mechanisms responsible for secretory IgA deposition are not known. In the majority of patients with IgA nephropathy secretory component is not detectable in the mesangium. In these cases, the presence of elevated circulating levels of galactose-deficient IgA, produced by bone marrow plasma cells would be a predisposing factor but not sufficient to induce nephropathy. To produce kidney disease, galactose-deficient IgA1 must be deposited in the renal mesangium, and once there, either by interaction with specific receptors (CD71?), by direct activation of complement or by being the target of an IgG autoimmune response anti-IgA, induce activation, proliferation and increased mesangial matrix synthesis and eventually cell injury. In parallel, galactose-deficient IgA, through interaction with the RR Fc alpha/gamma, may activate circulating lymphocytes and monocytes and enhance their response to chemoattractants produced by the mesangial cell, causing, thus, the inflammatory infiltrate to initiate and maintain the interstitial injury. In the next few years, advances recently added to the knowledge of the pathogenesis of nephropathy IgA1 could provide new variables that allow walking in the direction of having a classification of patients based not only in clinical and morphological criteria but also having a greater pathogenic basis.     

IgA nephropathy in non-cirrhotic portal hypertension

Renal glomerular changes are a well recognised complication of cirrhosis and are frequently characterised by mesangial IgA deposition. We report a patient with non-cirrhotic portal hypertension who developed IgA nephropathy and a nephrotic syndrome with renal histological changes classically associated with cirrhosis. Splenectomy with resection of a splenic artery aneurysm resulted in remission of the nephrotic syndrome. This case illustrates the factors which contribute to the pathogenesis of IgA nephropathy in liver disease.     

Glomerulonephritis

The differential diagnosis of glomerulonephritis without systemic disease includes poststreptococcal glomerulonephritis, IgA nephropathy, rapidly progressive glomerulonephritis (RPGN), and membranoproliferative glomerulonephritis (MPGN). Glomerular inflammation is probably induced directly by a nephritogenic streptococcal protein in poststreptococcal glomerulonephritis, and by mesangial deposition of abnormally glycosylated IgA1-containing immune aggregates in IgA nephropathy. In crescentic RPGN the role of cellular rather than humoral immune mechanisms is now becoming clear. Many patients with MPGN have chronic hepatitis C infection. There is no effective disease-specific therapy for poststreptococcal glomerulonephritis or IgA nephropathy. RPGN benefits from high-dose steroids and cytotoxic drug therapy with the addition of plasma exchange in disease induced by antibody to glomerular basement membrane. Antiviral therapies reduce the severity of MPGN due to hepatitis C virus. However, various new therapies directed at specific cytokines, growth factors, fibrin deposition, and other mediators of injury are being developed, as well as more specific and less toxic forms of immunotherapy.     

Immunological comparison of patients with rheumatoid arthritis with and without nephropathy.

Serum immunoglobulins IgG, IgA, and IgM, serum complement components C3 and C4, circulating immune complexes, antinuclear antibodies, and rheumatoid factor were measured in 56 patients with rheumatoid arthritis (RA) and nephropathy (23 with mesangial glomerulopathy; 13 with membranous glomerulonephritis; and 20 with amyloidosis) and 35 patients with RA without nephropathy (controls). Renal immunofluorescence findings in patients with mesangial glomerulopathy were compared with the serologic data. There were no differences in the occurrence of rheumatoid factor, antinuclear antibodies, and circulating immune complexes and the concentrations of serum complement C3 and C4 between various RA nephropathy groups and controls. Serum IgA and IgM concentrations were significantly higher in patients with mesangial glomerulopathy and amyloidosis than in controls. In patients with mesangial glomerulopathy glomerular IgM, IgA, and C3 were the most prominent findings in immunofluorescence examination. The serum IgA concentration was significantly higher in those patients with mesangial glomerulopathy with mesangial IgA deposits than in those without (4.97 (SD 1.03) g/l v 2.07 (1.21) g/l). The highest serum IgA concentrations (5.08 (1.39) g/l) were seen in the four patients with IgA glomerulonephritis. The prevalence of IgA glomerulonephritis in the renal biopsy material of the patients with RA was 5%, which possibly differs little from that seen in the general population. The results suggest that circulating immune complexes may not have any major role in the pathogenesis of various nephropathy types in patients with RA, contrary to their role in most extra-articular manifestations of RA.     

IgA nephropathy. Use of modern laboratory methods and renal biopsy for diagnosis

IgA nephropathy is the most frequent primary glomerulonephritis worldwide. At its onset, the most common laboratory sign is isolated haematuria often accompanied with mild proteinuria (up to 1.5 g/24 h). The disease displays a progressive course with end-stage renal disease occurring in up to half of patients 20 years after onset. Diagnosis is established by immunofluorescent microscopy of a renal biopsy specimen. Discoveries in the past decade on the pathogenesis of IgA nephropathy together with complex evaluation of its clinical presentation enable to establish diagnosis with a satisfactory degree of probability even without biopsy. IgA nephropathy patients display increased or borderline serum IgA levels; increased serum levels of IgA fraction with degalactosylated O-linked side sugar chains; increased serum levels of anti-N-acetylgalactosamine antibodies; increased levels of circulating immune complexes composed of IgA1 complexed with IgG or IgA1; increased serum levels of circulating complexes composed of IgA and fibronectin; and frequent occurrence of the rheumatoid IgA factor. Clinical use of these still generally unavailable methods would reduce the renal biopsy indication in patients with isolated or predominant haematuria.     

IgA nephropathy associated with axial spondyloarthritis responding to treatment by etanercept: A case report

IntroductionImmunoglobulin A (IgA) nephropathy may be associated with spondyloarthritis (SpA). This association raises the possibility of a common pathogenesis. Tumor necrosis factor alpha (TNFα) blockers showed good efficiency in SpA and may be efficient in IgA nephropathy.Case reportA case of a 28-year-old man diagnosed with axial SpA is reported. The patient’s Bath ankylosing spondylitis disease activity index (BASDAI) was 7 and functional index (BASFI) 9. Laboratory investigations revealed: erythrocyte sedimentation rate (ESR) 38 mm/1st hour, C-reactive protein (CRP) 6 mg/L, serum creatinine 72 μmol/L with a clearance of 108 ml/min; proteinuria 1.55 g/24 h, leucocyturia at 60,000 cells/ml and haematuria 80,000 red cells/ml. The serum IgA level was normal (238.8 mg/dL). Salivary gland and subcutaneous fat biopsies were normal. The renal biopsy showed moderate focal interstitial fibrosis. The glomerular basement membranes were not thickened while the mesangium was slightly thickened. There was no vascular damage. Congo red staining was negative. By immunofluorescent microscopy, there were mesangial deposits of IgA mainly; leading to the diagnosis of IgA nephropathy. Infliximab was initially given with limited efficacy and the patient was switched to etanercept which was effective especially in the osteoarticular symptoms. Leucocyturia, haematuria and proteinuria decreased but did not disappear, and the renal function and blood pressure remained normal. After 2 years there remained a persistent efficacy and good profile of tolerance (BASDAI = 2.2, BASFI = 4, CRP = 2, ESR = 21, proteinurua = 0.5 g/24 h).ConclusionEtanercept may be a potentially effective option for treating IgA nephropathy associated with axial SpA.     

Immunofluorescence staining of renal biopsy samples in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus using monoclonal antibody to reduced glycated lysine

This is the first report on immunofluorescence staining of renal biopsy samples in human diabetic nephropathy (DN) using monoclonal antibodies to reduced glycated lysine. In order to detect the localization of glycated lysine in the mesangial matrix and/or the glomerular basement membrane (GBM), we examined immunofluorescence staining using antibodies against reduced glycated lysine in the glomeruli of 16 patients with DN and ten age-matched patients with diffuse mesangial proliferative glomerulonephritis without IgA deposition (DPGN) as controls. In the early stage of DN, immunofluorescence microscopy revealed the presence of intense staining for reduced glycated lysine in the GBM as well as in part of the tubular basement membrane, but not in the mesangial area. In contrast, immunofluorescence microscopy revealed less staining for glycated lysine in the GBM in the advanced stage of DN, and no reaction with any part of the renal tissue in patients with DPGN. It was concluded that detection of reduced glycated lysine in GBM in the early stage of DN might be associated with the initial pathogenesis of this disease.