Future directions in the treatment of IgA nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis yet its etiology remains uncertain. Recent data suggest a structural aberration of the IgA molecule in IgAN that may exert pathophysiologic effects on target cells, reduce clearance of IgA-immune complexes (IC), or favor mesangial IC trapping. Mesangial reactivity to immune complexes triggers off the release of cytokines and the alteration of prostaglandin and thromboxane A(2) production promoting mesangial cell proliferation. Angiotensin II-induced mesangial cells contraction with efferent arteriolar vasodilatation initiates glomerular injury and eventually lead to glomerulosclerosis following increased local production of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor (PDGF). This paper highlights the potential therapeutic strategies in the future. These strategies include: (i) decreasing the synthesis of IgA-IC; (ii) limiting the mesangial uptake of IgA-IC; (iii) antagonizing the effect of PDGF and TGF-beta to reduce mesangial proliferation and glomerulosclerosis; and (iv) reducing the noxious glomerular injury due to infiltrating neutrophils. The effective treatment of IgAN requires a better clarification of the pathogenesis of the nephropathy. Future therapeutic attempts to slow down the renal deterioration should target at prevention of mesangial IgA deposition and the amelioration of inflammatory injury induced by infiltrating neutrophils and the released cytokines.     

<Emphasis Type="Italic">Saccharomyces boulardii</Emphasis> prevents oral-poliovirus vaccine-induced IgA nephropathy in mice

Immunoglobulin A nephropathy (IgAN) is associated with mucosal IgA defect. Probiotics regulate specific and innate immunity. We evaluated the effect of Saccharomyces boulardii on experimental IgAN in mice. Four groups of BALB/c mice (eight for each) were formed. Group 1 was immunized by oral poliovirus vaccine (OPV) at 0, 14, and 28 days. Group 2 was also given S. boulardii in addition to OPV. Group 3 was given only S. boulardii, whereas group 4 received no treatment. At week 6, after urine and serum samples were obtained for urinalysis and serum creatinine and IgA measurements, all animals were sacrificed to get their kidneys for histopathological evaluation. Urinalysis and serum creatinine levels were normal in all groups. Serum IgA level was increased only in group 1. Whereas group 1 had mesangial proliferation, histology was normal in the other groups. Predominant IgA deposition was universal in group 1, whereas it was either not present or minimal in other groups. Three mice in group 1 also had C3 deposition, which was absent in other groups. Electron microscopy revealed mesangial proliferation, matrix expansion, focal glomerular basement membrane thickening and electron-dense deposits in group 1 only, whereas the other groups were normal. In conclusion, enteral S. boulardii prevented OPV-induced IgAN in mice.     

Mannose-binding lectin gene polymorphism associated with the patterns of glomerular immune deposition in IgA nephropathy

OBJECTIVE: To elucidate the genetic background underlying the diversity of mesangial immune deposition in IgA nephropathy (IgAN), we investigated the distribution of mannose-binding lectin (MBL) gene codon 54 polymorphism and serum MBL levels in IgAN patients. METHODS: Seventy-seven IgAN patients with glomerular IgA and C3 deposits (Group A) and 70 with glomerular IgA, IgG, IgM, C3 and Clq deposits (Group AGM) were included in the present study. Control group consisted of 140 normal adults. MBL genotypes were investigated by polymerase chain reaction and restriction fragment length polymorphism. Serum MBL levels with different genotypes were also assayed in some subjects. RESULTS: The variant allele (GAC) was markedly associated with Group AGM (OR = 1.95, 95% C.I.: 1.06-3.58). In both Group A and Group AGM, more patients carrying the variant allele had episodes of upper respiratory or gastrointestinal infections prior to onset or exacerbation of IgAN than wild homozygotes (GGC/GGC). In addition, a significant difference in serum MBL level was also observed between wild homozygotes and heterozygotes (GGC/GAC) (GGC/GGC > GGC/GAC) (p<0.0001) in all groups, while there was no difference for subjects with the same genotypes among the three groups (p > 0.05). Serum MBL levels of the rare variant homozygotes approached zero. CONCLUSIONS: Our findings provide evidence that the host defense molecule, MBL, may be involved in the formation of the diversity of glomerular immune deposition in IgAN. Genetic deficiency of MBL may partially account for abundant immune deposits in some IgAN patients.     

Clinico-pathological characterization of mesangial proliferative glomerulonephritis with predominant deposition of IgM

Background. IgM nephropathy (IgMN) was first described in 1978 but whether IgMN is a distinct entity has not yet been confirmed. We tried to clarify the characteristics of IgMN on the basis of clinical and histological findings of patients who were treated and investigated by us. Methods. We evaluated 90 patients (group A) with mesangial proliferative glomerulonephritis (MesPGN) who exhibited more dominant mesangial deposits of IgM than of IgG and IgA. To clarify the significance of the IgM mesangial deposits, we divided these patients into two subgroups: group A1 comprised 30 patients with diffuse and global mesangial IgM deposits and group A2 comprised the other 60 patients, with focal segmental mesangial IgM deposits. Ninety Mes-PGN patients without predominant IgM deposits, excluding those with IgA nephropathy were studied as controls (group B). Results. Group A had significantly higher levels of serum IgM than group B (P < 0.01). The mean values for glomerular filtration rate (GFR), serum albumin, and CH50 in group A were significantly lower than those in group B (P < 0.01). Proteinuria in group A was significantly more severe than in group B (P < 0.05). Group A had a significantly higher incidence of adhesion (P < 0.01) and duplication (P < 0.05) of capillary loops than group B. They also demonstrated a significantly higher incidence of glomerular deposition of C1q and/or C4,C3, and fibrinogen than group B (P < 0.01). Conclusion. These findings suggest that the mesangial deposition of IgM is useful for assessing glomerular damage or renal dysfunction in MesPGN patients, regardless of the amount of mesangial IgM deposits. Furthermore, MesPGN with predominant IgM deposition, which includes both diffuse global and focal segmental deposition of IgM, should be referred to as IgM nephropathy. Received: October 20, 1997 / Accepted: October 8, 1998     

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.     

Novel mechanisms of tubulointerstitial injury in IgA nephropathy: a new therapeutic paradigm in the prevention of progressive renal failure

IgA nephropathy (IgAN) runs a highly variable clinical course with frequent involvement of tubulointerstitial damage. Notably, renal progression correlates more closely with the severity of tubulointerstitial lesions than with the degree of glomerular lesions In IgAN. Mesangial IgA deposition induces local release of cytokines, complement, and angiotensin II leading to glomerular inflammation. It remains unclear how mesangial IgA deposition leads to tubulointerstitial injury in IgAN. Moreover, IgA deposits are rarely detected in renal interstitium in IgAN. We hypothesize that mediators released from mesangial cells triggered by IgA deposition leads to activation of proximal tubular epithelial cells. Our preliminary findings implicate a glomerulotubular cross talk with mediators released from the mesangium contributing to the pathogenesis of tubulointerstitial damage in IgAN. We have also found the expression of angiotensin II subtype-1 receptor or angiotensin II subtype-2 receptor in proximal tubular epithelial cells differs from that of mesangial cells. One potential therapeutic approach is to counterbalance the growth-stimulatory effects of angiotensin II through subtype-1 receptor in tubular epithelial cells by subtype-2 receptor-mediated apoptosis and growth inhibition. These novel findings may provide clinicians new therapeutic approach for selective blockade of the RAS in IgAN.     

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.     

Characteristics of immunoglobulin A nephropathy with mesangial immunoglobulin G and immunoglobulin M deposition

Aim: There are immunoglobulin (Ig)A nephropathy (IgAN) cases showing mesangial IgG and/or IgM deposition, however, their characteristics have remained unknown. Methods: Three hundred and eighty‐four IgAN patients were divided according to the existence of mesangial IgG and/or IgM deposition: IgA deposition only (A group, n = 77); IgA and IgM deposition (AM group, n = 114); IgA and IgG deposition (AG group, n = 36); and IgA, IgG and IgM deposition (AGM group, n = 157). Clinical and histological findings, and outcomes were examined and compared among these four groups. Results: At the time of renal biopsy, serum creatinine was significantly higher in the A and AM group, however, creatinine clearance did not differ among the four groups. The ratio of glomerular obsolescence was significantly higher in the AM group than in the A and AGM group, and the ratio of glomerular tuft adhesion was significantly higher in the AM, AG and AGM group than in the A group. However, the other clinical and histological findings, electron microscopic findings and renal survivals did not differ among the four groups. Proteinuria was independently associated with an increase in risk of doubling of creatinine (P = 0.005), however, IgG and IgM depositions were not by multivariate Cox regression. Conclusion: The presence of other Ig classes, besides IgA deposits, was found to be associated with glomerular obsolescence and tuft adhesions, however, without any effect on renal survival in IgAN.     

Structural features of IgA molecules which contribute to IgA nephropathy.

IgA nephropathy (IgAN) is characterised by the mesangial deposition of polymeric IgA1 (pIgA1). pIgA1 production is reduced in the mucosal immune system in IgAN and increased in the marrow; this switch may be secondary to a defect in gammadeltaT cell control of IgA production. However this does not explain the mechanism by which pIgA1 deposits in the mesangium. There is no direct evidence that classical immune complex deposition occurs in IgAN and alternative mechanisms resulting from physicochemical abnormalities of the IgA1 molecule, particular altered glycosylation, have been proposed. IgA1 has a distinctive hinge region which is a site for O-glycosylation. There is reduced terminal galactose on the hinge region O-glycans of circulating IgA1 in IgAN, perhaps due to a defect in B cell beta1,3 galactosyltransferase. A concomitant O-glycan defect in mesangial IgA1 has not yet been proven. Altered hinge O-glycosylation may have substantial impact on the quaternary structure of the IgA1 molecule influencing its capacity to interact with matrix proteins, IgA receptors on mesangial cells and leucocytes, and complement; it may therefore play a key role in the pathogenesis of mesangial deposition of IgA1 and subsequent glomerular injury in IgAN.     

TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy

BackgroundIgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis.MethodsForty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks.ResultsBSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice.ConclusionTNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.     

Clinico-pathological features and renal outcomes of primary IgA nephropathy with IgM deposition

Objective To investigate the clinico-pathological features and renal outcomes of primary IgA nephropathy (IgAN) with glomerular IgM deposition. Methods Primary IgAN diagnosed with biopsy from January 2006 to December 2011 were recruited. Patients were divided into groups according to IgM deposition (Group A) and without IgM deposition (Group B). In addition, Group A was subdivided into two groups based on the position of IgM deposits as the mesangium (Group A1) and both mesangium and capillary wall (Group A2). Renal outcomes were defined as end stage renal disease (ESRD) and/or the doubling of baseline serum creatinine. Clinico-pathological features were retrospectively compared. Kaplan-Meier was conducted for renal outcomes, and Cox regression model was used to analyze the prognostic value of IgM deposition and the position of IgM deposition in the progression of nephropathy in IgAN patients. Results 939 patients were enrolled with 422 (44.9%) having IgM deposition (Group A). Of the 422 patients, 382 patients were divided as Group A1, whereas 40 patients were noted as Group A2. Compared to Group B, hemoglobin, serum protein, albumin and serum IgG levels in group A were significantly lower, and the cholesterol and serum IgM levels were significantly higher (all P＜0.05). There was no significant difference in serum creatinine, estimated glomerular filtration rate (eGFR), urinary protein, blood pressure and uric acid between group A and B. In terms of pathological manifestations, patients in Group A exhibited more severe histological lesions including glomerular sclerosis, S1, M1 and interstitial inflammatory cell infiltration (all P＜0.05). Immunofluorescence showed that the proportion of IgG, C1q and Fg deposition in group A was significantly higher than that in group B (all P＜0.05). By Kaplan-Meier, cumulative renal survival rate has no significant difference between Group A and B (Log-rank test χ2=0.019, P=0.891). Univariate and multivariable Cox regression analysis showed that IgM deposition had no significant effect on the renal progression in IgAN patients. Subgroup analysis showed that patients in Group A2 exhibited higher urine protein, creatinine and blood pressure, and lower eGFR and serum albumin, also had worse histological lesions including M1, E1 and T1-2 of Oxford classification (all P＜0.05), Immunofluorescence showed that the proportion of IgG, C1q and Fg deposition in group A2 was significantly higher than that in group A1 (all P＜0.05). By Kaplan-Meier, renal survival rates calculated from outcomes were lower in Group A2 (Log-rank test χ2=18.207, P＜0.001). In addition, IgM deposited both in the mesangium and capillary wall was a risk factor for renal progression of IgAN patients with IgM deposition by a univariate Cox hazards regression mode and multivariable-adjusted Cox models (HR=3.621, 95%CI 1.924-6.814, P＜0.001; HR=2.309, 95%CI 1.176-4.533, P=0.015 respectively). Conclusions The IgAN patients with IgM deposition relatively had more severe clinico-pathological changes, especially those with IgM deposited both in the mesangium and capillary wall. In this study, IgM deposition was not found to be an independent risk factor for the prognosis of kidney in IgAN patients. However, IgM deposited both in the mesangium and capillary wall was an independent risk factor for renal prognosis in IgAN patients with IgM deposition.     

Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), characterized by predominant or exclusive deposition of IgA1 in glomerular mesangium, is the most common primary glomerulonephritis worldwide. At present, the treatment is always limited due to the incomplete understanding of the pathogenesis of IgAN. Mesangial deposited IgA1 is the common final pathway leading to glomerulonephritis and renal injury. IgA1 protease, a proteolytic enzyme with strict substrate specificity for human IgA1, may be an effective therapeutic candidate for IgAN by removing the mesangial deposited IgA1.     

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.     

Secondary IgA nephropathy presenting as nephrotic syndrome with glomerular crescentic changes and acute renal failure in a patient with autoimmune hepatitis

Patients with end-stage liver disease are prone to hemodynamic and immunologic renal injury, the latter at times manifesting as glomerulonephritis. Elevated serum immunoglobulin A (IgA) levels and mesangial IgG-IgA deposits are common in these patients, but are often clinically silent. We report a patient with autoimmune hepatitis and secondary IgA nephropathy (IgAN) who presented with nephrotic syndrome, acute renal failure (ARF), with 30% of the renal glomeruli having undergone crescentic change, and with IgA2 deposits in the glomerular mesangium. This article discusses secondary IgAN pathogenesis and its therapeutic management.     

Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease

IgA nephropathy (IgAN) is characterized by glomerular co-deposition of IgA and complement components. Earlier studies showed that IgA activates the alternative pathway of complement, whereas more recent data also indicate activation of the lectin pathway. The lectin pathway can be activated by binding of mannose-binding lectin (MBL) and ficolins to carbohydrate ligands, followed by activation of MBL-associated serine proteases and C4. This study examined the potential role of the lectin pathway in IgAN. Renal biopsies of patients with IgAN (n=60) showed mesangial deposition of IgA1 but not IgA2. Glomerular deposition of MBL was observed in 15 (25%) of 60 cases with IgAN and showed a mesangial pattern. All MBL-positive case, but none of the MBL-negative cases showed glomerular co-deposition of L-ficolin, MBL-associated serine proteases, and C4d. Glomerular deposition of MBL and L-ficolin was associated with more pronounced histologic damage, as evidenced by increased mesangial proliferation, extracapillary proliferation, glomerular sclerosis, and interstitial infiltration, as well as with significantly more proteinuria. Patients who had IgAN with or without glomerular MBL deposition did not show significant differences in serum levels of MBL, L-ficolin, or IgA or in the size distribution of circulating IgA. Furthermore, in vitro experiments showed clear binding of MBL to polymeric but not monomeric patient IgA, without a significant difference between both groups. Together, these findings strongly point to a role for the lectin pathway of complement in glomerular complement activation in IgAN and suggest a contribution for both MBL and L-ficolin in the progression of the disease.     

IgA肾病诊疗进展

IgA肾病是全球最常见的原发性肾小球肾炎,亚洲人群中发病率高于其他人种。IgA肾病是目前导致终末期肾病的重要原因之一。临床上以血尿为特点,常伴随蛋白尿、高血压。其病理表现主要为IgA免疫复合物在肾小球系膜区的沉积、系膜细胞增生、毛细血管内皮细胞增生等。其发病机制可能为血液循环中半乳糖缺乏的IgA1增多,在內外界环境刺激下,产生过多的、能沉积于肾小球系膜区的免疫复合物。目前,对IgA肾病的诊断主要依靠病理检查。治疗方面,以肾素-血管紧张素系统阻断剂、控制血压为基础,恰当联合免疫抑制剂、细胞毒性药物、鱼油等或能延缓IgA肾病的进展。本文的目的是对IgA肾病的诊疗现状进行总结和分析,为临床工作及进一步科研提供指导和参考。     

Studies on circulating immune complexes. II: Circulating immune complexes in primary IgA nephropathy and membranoproliferative glomerulonephritis

A study of circulating immune complexes (CIC) was undertaken in 25 patients with primary IgA nephropathy and 13 patients with membranoproliferative glomerulonephritis (MPGN). Clinically, the 25 patients with IgA nephropathy were divided into two groups: the latent type, characterized by chance proteinuria and/or hematuria; and the acute onset type, revealing acute nephritic syndrome. Both the IgG class of CIC (IgG-IC) and the IgA class of CIC (IgA-IC) were measured by conglutinin binding enzyme immunoassay (C-assay). IgG-IC were found to be positive in 32% of the patients with IgA nephropathy, and in 77% of those with MPGN. IgA-IC were positive in 72% of the patients with IgA nephropathy, and in 54% of those with MPGN. Concerning the acute onset type of IgA nephropathy, IgG-IC and IgA-IC were found in 71% and 86% of the patients, respectively, which was more frequent than in the latent type group. Simultaneous presence of IgA-IC and glomerular IgA deposits detected by an immunofluorescence study was noted in 75% of the patients with IgA nephropathy. On the other hand, 78% of the patients with MPGN revealed IgG-IC and glomerular IgG deposits simultaneously. Thus, IgG-IC and IgA-IC appear to play important roles in the pathogenesis of MPGN and IgA nephropathy, respectively.     

Glomerular apolipoprotein B deposition in glomerular diseases

In an attempt to elucidate the relationship between the progress of glomerular injury and abnormalities of lipid metabolism, we investigated glomerular deposition of apolipoprotein B (apo B) in renal biopsy specimens from 60 patients with glomerular diseases by indirect immunofluorescence using antihuman apo B-100 monoclonal antibody in comparison with clinical and histopathological findings. The patients were divided into 2 groups according to the intensity in staining of apo B in glomerulus (group A: negative or weakly positive; and group B: definitely positive). Staining of apo B in glomerulus was found in 37 patients (62%). The levels of serum total cholesterol, phospholipids, low density lipoprotein cholesterol and apo B in group B were significantly higher than in group A. The urinary protein excretion in group B was greater than that in group A. Group B was also shown to have a significantly decrease in renal function. Light microscopy revealed severe mesangial proliferation in patients with IgA nephropathy of group B. These findings suggested that glomerular apo B containing-lipoprotein deposition may play an important role in the progression of glomerular injury.     

Differential effects of circulating IgA isolated from patients with IgA nephropathy on superoxide and fibronectin production of mesangial cells.

BACKGROUND: IgA nephropathy (IgAN) is characterized by predominant deposition of IgA in the glomerular mesangium. Serum IgA is often elevated in patients with IgAN, and it has been postulated that it is responsible for the mesangial lesions. However, the direct effect of circulating IgA on mesangial cells is not clear. METHODS: We investigated the effects of sera and IgA which were isolated from patients with IgAN on thymidine uptake, superoxide and fibronectin production and fibronectin mRNA expression of cultured rat mesangial cells, and we compared the findings to the effects of IgA isolated from patients with non-IgA mesangial proliferative glomerulonephritis (MsPGN) and normal controls. IgA was isolated with affinity chromatography using cyanogen bromide activated Sepharose 4B coupled to sheep antihuman IgA antiserum. RESULTS: Our results demonstrated that both sera and IgA from patients with IgAN dose-dependently increased mitogenesis of mesangial cells as measured by (3)H-labeled thymidine uptake. The thymidine uptake by sera and IgA isolated from patients with IgAN was significantly higher than that of sera and IgA isolated from patients with MsPGN and normal controls. Sera and IgA from patients with IgAN significantly enhanced superoxide and fibronectin production and fibronectin mRNA expression of mesangial cells. The superoxide and fibronectin production was also significantly higher as compared with patients with MsPGN and normal controls. CONCLUSIONS: Our results indicate that circulating IgA isolated from patients with IgAN is different from that of patients with MsPGN and normal controls and may potentially induce oxidative injury and production of extracellular matrix of glomerular mesangial cells in IgAN.     

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.