Mesangial IgA Research Articles

Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Schönlein nephritis: association between CD71 expression and IgA deposits.

ABSTRACT. IgA nephropathy (IgA-N) that comprises Berger disease and Henoch-Schönlein Purpura (HSP) nephritis is defined by mesangial IgA deposits. Recently, this group has characterized a new receptor for IgA, the transferrin receptor (CD71), expressed on mesangial cells. To assess whether CD71 was involved in the pathogenesis of IgA-N, its expression was analyzed together with IgA deposits on 16 kidney biopsies from 16 patients with Berger disease (n = 4) or HSP (n = 12). These biopsies were compared with 17 kidney biopsies of a group of 15 patients (control group) with other glomerulonephritis, including systemic lupus erythematosus, poststreptococcal acute glomerulonephritis, membranoproliferative glomerulonephritis, steroid-sensitive minimal change nephrotic syndrome, steroid-resistant idiopathic nephrotic syndrome with focal and segmental glomerulosclerosis, and persistent and isolated proteinuria with minimal change on kidney biopsy. In this control group, IgA deposits could be observed in eight kidney biopsies of seven patients. These biopsies were also compared with normal kidney specimens (normal group). In normal kidney, it was found that CD71 was linearly expressed on tubular epithelium but was either not expressed or very dimly in glomeruli. In contrast, CD71 was strongly expressed in 105 of the 107 glomeruli of the kidney biopsies from the IgA-N group. For the control group, it was found that expression of CD71 in glomeruli was correlated to the presence of IgA deposits. Indeed, among the 87 glomeruli of nine kidney biopsies (eight patients) without IgA fixation, 78 exhibited no CD71 expression and nine exhibited a very dim one. On the other hand, all 49 glomeruli of the eight kidney biopsies (seven patients) in which IgA deposits were detected exhibited CD71 expression (P < 10(-4)). Performance of dual-labeling studies with confocal microscopy on kidney biopsies of IgA-N patients demonstrated that most of the IgA deposits co-localized with CD71. It was also demonstrated that the intensity of the expression of CD71 was not linked to the intensity of clinical or biologic findings but to the intensity of cellular proliferation in both IgA-N and control groups. These results show that mesangial CD71 expression is not specific to IgA-N. However, the association between IgA deposits and CD71 expression and their co-localization in the mesangium provide strong evidence that CD71 is a major IgA receptor on mesangial cells.

Incidental mesangial IgA deposition in minimal change nephrotic syndrome(MCNS)

The frequency of incidental mesangial IgA deposition and its clinicopathological features were investigated in patients with minimal change nephrotic syndrome(MCNS). Mesangial IgA deposition was present in 15/63 patients(23.8%), and co-deposition of IgA and C3 was present in 10/63 patients(15.9%). The serum IgA concentration was significantly higher in IgA(+) patients than in IgA(-) patients(341 +/- 79 mg/dl vs. 252 +/- 99 mg/dl, p = 0.034). The urinary red blood cell count tended to be higher in IgA(+) patients than in IgA(-) patients (12.8 +/- 24.9 vs. 5.0 +/- 7.9 counts/HPF, p = 0.58). Histologically, no significant differences were observed between IgA(+) and IgA(-) patients. After steroid treatment. 14 patients with mesangial IgA deposition showed complete remission and one patient had persistent proteinuria. The microhematuria also disappeared after steroid treatment in 13/15 patients (86.7%), although it reappeared in 6/13 patients(46%) during reduction of steroid administration. The present study indicated that the incidental mesangial IgA deposition was frequently observed in MCNS patients(23.8%). The phenomenon of mesangial IgA deposition was related to the higher concentration of serum IgA. However, no influence of mesangial IgA deposition in MCNS patients was found on the post-treatment amount of proteinuria, renal function and clinical outcome of MCNS.

Size-dependent binding of IgA to HepG2, U937, and human mesangial cells

IgA nephropathy (IgAN) is characterized by increased circulating IgA and mesangial IgA deposition. The mechanism of mesangial IgA deposition remains poorly understood in IgAN. In this report, we studied the binding characteristics of serum IgA from patients with IgAN and healthy controls to different cell types, including a liver-cell line (HepG2), a monocytic cell line (U937), and human mesangial cells (HMCs). Jacalin-bound proteins (JBPs) were purified from serum IgA by means of jacalin affinity chromatography. Total IgA concentrations were significantly higher in patients with IgAN than in controls (P <.001). JBPs were further separated by means of size exclusion chromatography, and six pooled fractions with molecular weight ranging from 50 to 1000 kD were obtained. The concentration of low-molecular-weight (LMW) IgA complexes (150-300 kD) and high-molecular-weight (HMW) IgA complexes (300-1000 kD) were significantly higher in patients than in healthy controls (P <.001 and.05, respectively). Cultured human mesangial cells bound more IgA of 300 to 610 kD in IgA isolated from patients with IgAN (P <.01). The binding of IgA (LMW and HMW) from patients with IgAN to HepG2 was significantly higher than that of IgA preparations from controls. U937 significantly bound more IgA of 150 to 825 kD in IgA isolated from patients with IgAN (P <.01). Different and distinct binding patterns were observed in the three cell types for IgA with different molecular weights. HMCs bound more HMW than LMW IgA. We noted preferential binding of LMW (150 to 300 kDa) and intermediate (350-710 kDa) IgA to HepG2 than of IgA complexes of more than 710 kDa. U937 mainly bound LMW and intermediate size IgA (150 to 710 kDa) with no binding of IgA with size greater than 710 kD. Our findings suggest that monocytes, hepatocytes, and mesangial cells have unique properties with regard to their binding to different forms of IgA. These characteristic properties may alter the catabolism of circulating IgA and, hence, predispose their deposition in the kidney mesangium in IgAN. (J Lab Clin Med 2002;140:398-406)

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 A₂ 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-β (TGF-β) 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-β 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.

Characteristics of polymeric lambda-IgA binding to leukocytes in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by predominant mesangial polymeric IgA1 (pIgA1) deposits, with increased plasma IgA1 levels. Plasma IgA levels are determined by the rate of IgA production, uptake by leukocytes, and removal by hepatocytes. Fc(alpha) receptor 1 (Fc(alpha)R1) is a candidate molecule for the regulation of IgA levels, but reports of its expression in leukocytes in IgAN are conflicting. Increased binding of endogenous IgA to circulating granulocytes and monocytes in IgAN was demonstrated in this study. Fc(alpha)R1 expression on leukocytes was increased, independently of plasma IgA levels. Fc(alpha)R1 was not saturated in leukocytes, because of internalization of IgA after uptake. Further binding of exogenous IgA isolated from individual subjects was observed with leukocytes from the same subjects. Compared with cells from control subjects, granulocytes but not monocytes from patients with IgAN exhibited a greater binding capacity for exogenous IgA, predominantly pIgA. To circumvent the possibility that endogenous IgA might alter Fc(alpha)R1 expression, granulocytes or monocytes derived from the HL-60 or U937 cell lines were used to explore the nature of IgA binding. A higher affinity for pIgA was demonstrated. Inhibition studies using unlabeled IgA, other serum proteins, or a specific Fc(alpha)R1-blocking antibody suggested binding mechanisms other than Fc(alpha)R1 for pIgA uptake by leukocytes. This study also suggested the migration and/or sequestration of "activated" leukocytes with predominant lambda-IgA in the mononuclear phagocytic system or inflammatory tissues, after the initial binding of lambda-pIgA. These immunologic abnormalities might contribute to the glomerulointerstitial injury in IgAN, in the presence of leukocytic infiltration.

Usage of T Cell Receptor Variable Segments of the Beta-Chain in IgA Nephropathy

Background: We previously reported that glomerulonephritis associated with Staphylococcus aureus infection (SAGN) showed an increased usage of T cell receptor Vβ 5.3 and 8 in peripheral lymphocytes and mesangial IgA and IgG depositions. To elucidate the immunological mechanisms and pathogenesis of IgA nephropathy, we analyzed the usage of TCR Vβ in both peripheral blood lymphocytes (PBLs) and renal infiltrating T cells from IgA-N patients. Methods: In 38 patients with IgA nephropathy and controls, the usage of TCR Vβ in PBLs were analyzed using monoclonal antibodies against Vβ 3.1, Vβ 5.1, Vβ 5.2 + 5.3, Vβ 5.3, Vβ 6.7, Vβ 8, Vβ 12.1, and Vβ 13.1 + 13.3 with three-color flow cytometry. Furthermore, we examined immunohistochemically renal biopsy specimens using antibodies against Vβ 5.3 and Vβ 8. Results: The percentages of DR+CD4+CD8– cells, CD45RO+CD4+ cells, and CD45RO+CD4+DR+ cells in PBLs from IgA nephropathy were significantly higher than controls. The percentages of TCR Vβ 5.3 positive cells and TCR Vβ 8 positive cells in PBLs from patients were 1.3 ± 0.1 and 3.1 ± 0.2%, and both were significantly higher than controls. The percentage of renal interstitial TCR Vβ 5.3 expression was significantly higher than that in PBLs. However, there was no significant difference between the TCR Vβ 8 expression in the interstitium and that in PBLs. Conclusions: TCR Vβ 5.3 and 8 usage and broad CD4+ T cell activation have occurred in IgA nephropathy. These changes were similar but weak compared with formerly reported SAGN.

Effects of tumor necrosis factor type 1 and 2 receptor deficiencies on anorexia, growth and IgA dysregulation in mice exposed to the trichothecene vomitoxin

Dietary exposure of mice to vomitoxin (VT), a trichothecene mycotoxin, causes anorexia and impaired growth as well as inducing elevated serum IgA and kidney mesangial IgA deposition in a manner analogous to human IgA nephropathy. Based on the observations that TNF-α is induced by in vitro and in vivo VT exposure, it was hypothesized that this cytokine plays a role in the nutritional and immunological effects of this toxin. To test this hypothesis, the effects of dietary VT on feed intake, weight gain, serum IgA levels and kidney mesangial IgA deposition in mice homozygous for targeted disruption of the two known TNF-α cell surface receptors, TNFR1(p55) or TNFR2(p75), were compared to effects in corresponding C57BL/6J wild-type (WT) mice with normal receptor function. The capacity of VT to cause feed refusal or impair weight gain over a 12-week feeding period was not impaired in TNFR1 knockout (KO) or TNFR2-KO as compared to WT mice. Both WT and TNFR-KO mice fed VT exhibited reduced ( P<0.05) feed conversion efficiency, but surprisingly, feed conversion efficiency was significantly higher ( P<0.05) in TNFR1-KO and TNFR2-KO fed either control or VT diets than in corresponding WT mice. By week 12, serum IgA concentrations in all three mouse groups fed VT were significantly higher than those for corresponding mice fed control diets ( P<0.05). Serum IgA levels in the VT-fed TNFR1-KO group were significantly less ( P<0.05) than those for the VT-fed WT mice at 4, 8 and 12 weeks, whereas no differences in this parameter were found between the TNFR2-KO and WT groups. Serum IgA immune complex concentrations were measured at wk 12 and found to follow an identical pattern to IgA. Kidneys taken from VT-fed TNFR2-KO and WT mice after 12 weeks had significantly increased mesangial IgA deposition as compared to controls. While slight increases in mesangial IgA were also observed in VT-fed TNFR1-KO mice, these levels were significantly less ( P<0.05) than that found in VT-fed TNFR2-KO and WT mice. Taken together, the data suggest that while VT-mediated anorexic and growth effects were largely independent of TNF-α, VT-induced dysregulation of IgA production was dependent, in part, on the interaction of TNF-α with TNFR1.

Serum IgA/C3 Ratio May Predict Diagnosis and Prognostic Grading in Patients with IgA Nephropathy

Recently, the authors reported that the ratio of serum IgA to C3 (serum IgA/C3 ratio) is a good marker to distinguish patients with IgA nephropathy from non-IgA nephropathy patients together with serum IgA levels using an international reference preparation (IFCC/CRM470). In this study, the authors investigated whether the serum IgA/C3 ratio might be an indicator of prognostic grading in patients with IgA nephropathy. Two hundred and thirteen patients with IgA nephropathy and 96 other glomerular diseases including diffuse or focal mesangial proliferative glomerulonephritis without mesangial IgA deposition (non-IgA PGN), membranous nephropathy and thin basement membrane syndrome were examined. The levels of serum IgA and C3 in these patients were adjusted by the specified formula to those using international standard serum (IFCC/CRM470) in this study. The results of this study showed the highest levels of IgA/C3 ratio in patients with IgA nephropathy. The serum IgA/C3 ratio appears to gradually increase according to the prognostic grading of this disease. Therefore, measurement of the serum IgA/C3 ratio may be useful for prediction of diagnosis and prognostic grading in patients with IgA nephropathy.

Impact of mesangial IgA deposits in 14th‐post operative‐day routine renal allograft biopsies

SUMMARY: Three hundred fourteen 14th‐postoperative‐day routine renal allograft biopsies were evaluated together with clinical data. Out of 314 biopsies, mesangial IgA deposits were positive in 122 biopsies (39%). According to Banff classification, the rate of acute rejection was significantly lower in mesangial IgA deposit‐positive (IgA(+)) patients (7.4%) than in mesangial IgA deposit‐negative (IgA(‐)) patients (19.7%) on the 14th postoperative day. Thereafter, rate of biopsy‐proven and clinical acute rejection was continuously lower for up to 12 months in IgA(+) patients than in IgA(‐) patients. The detection rate of mesangial IgA deposits was significantly higher in human leucocyte antigen (HLA)‐well‐matched (HLA mismatch number was &lt;3) patients than in HLA‐poorly matched (HLA mismatch number was ≥3) patients. In HLA‐well‐matched patients, the serum creatinine levels were significantly lower in IgA(+) patients than in IgA(‐) patients after 3 post‐transplant months and up to 1 post‐transplant year. Follow‐up (mean interval: 13 months) allograft biopsies were performed in 34 patients out of 122 IgA(+) patients. In the follow‐up biopsies, initially detected mesangial IgA deposits had disappeared in 22 patients (65%) out of 34 patients. Twelve patients (35%) still had mesangial IgA deposits, and all of them had clinical and pathological findings consistent with IgA nephropathy. Patients with continuous mesangial IgA deposits in the follow‐up biopsies had a better renal function at 1 year and a higher 5‐year graft survival rate compared with patients who lost the initially deposited IgA. The present study demonstrates that long‐lasting mesangial IgA deposits in renal transplants prevent allografts from acute rejection, which leads to better graft outcome.

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.

Live donor renal transplantation in patients with end‐stage renal failure due to IgA nephropathy: clinicopathological assessment

SUMMARY: The long‐term outcome was evaluated, in terms of recurrence and graft survival, after live donor renal transplantation in 90 grafts in 89 patients with biopsy‐proven IgA nephropathy (IgAN) as a primary diagnosis of end‐stage renal disease. Additionally, histological assessment including glomerular morphometry was performed in 19 grafts having recurrent IgAN. The 10‐year graft survival for IgAN patients was 66%, which was comparable with that of 84% for 107 reference recipients having other kinds of glomerulonephritis (GN) or 69% for 90 other recipients having non‐GN renal failure (P = 0.27). In 43 grafts, 54 event graft biopsies were performed, and mesangial IgA deposits were documented in 19 grafts. In eight grafts, lesions were accompanied by chronic rejection (CR). Ten‐year cumulative recurrence was 44%. In total, 10 grafts were lost: this was due to CR (n = 3) or acute rejection (n = 1) in 24 recurrence‐free recipients; CR (n = 2) or recurrence (n = 2) in 19 patients with recurrence; and patient death (n = 2) in 46 patients who did not have graft biopsy. No difference in 10‐year graft survival between the patients with and without recurrence (63%vs 74%; P = 0.98), or the proportion of related donors was found (68%vs 83%; P = 0.25). In the grafts with recurrence, renal histological damage was relatively mild and had no uniform pattern. The percentage of global and segmental sclerosis were 11.9% and 3.7%, respectively. Non‐sclerotic glomeruli were ischaemic or hypertrophied. Mesangium showed lysis or focal and mild expansion by matrix and cellular increase. Glomerular morphometry was performed in seven patients, in whom glomerular hypertrophy was found as demonstrated by increases of Bowman's and glomerular tuft areas (1.4 and 1.3 times the control, respectively) and concomitant decrease of total glomerular and mesangial cells per glomerular cross‐section (71.2% and 84.9% of the control, respectively). In conclusion, recurrence increased to 44% with longer follow up, but this did not limit the graft outcome. Recurrence was not affected by the types of live donor. Glomerular hypertrophy in the recurrent IgAN group suggests hyperfiltration.

Impact of mesangial IgA deposits in 14th‐postoperative‐day routine renal allograft biopsies

SUMMARY: Three hundred fourteen 14th‐postoperative‐day routine renal allograft biopsies were evaluated together with clinical data. Out of 314 biopsies, mesangial IgA deposits were positive in 122 biopsies (39%). According to Banff classification, the rate of acute rejection was significantly lower in mesangial IgA deposit‐positive (IgA(+)) patients (7.4%) than in mesangial IgA deposit‐negative (IgA(‐)) patients (19.7%) on the 14th postoperative day. Thereafter, rate of biopsy‐proven and clinical acute rejection was continuously lower for up to 12 months in IgA(+) patients than in IgA(‐) patients. the detection rate of mesangial IgA deposits was significantly higher in human leucocyte antigen (HLA)‐well‐matched (HLA mismatch number was &lt;3) patients than in HLA‐poorly matched (HLA mismatch number was &lt;3) patients. In HLA‐well‐matched patients, the serum creatinine levels were significantly lower in IgA(+) patients than in IgA(‐) patients after 3 post‐transplant months and up to 1 post‐transplant year. Follow‐up (mean interval: 13 months) allograft biopsies were performed in 34 patients out of 122 IgA(+) patients. In the follow‐up biopsies, initially detected mesangial IgA deposits had disappeared in 22 patients (65%) out of 34 patients. Twelve patients (35%) still had mesangial IgA deposits, and all of them had clinical and pathological findings consistent with IgA nephropathy. Patients with continuous mesangial IgA deposits in the follow‐up biopsies had a better renal function at 1 year and a higher 5‐year graft survival rate compared with patients who lost the initially deposited IgA. the present study demonstrates that long‐lasting mesangial IgA deposits in renal transplants prevent allografts from acute rejection, which leads to better graft outcome.

Role of transforming growth factor‐β/Smad signalling pathway in enhanced production of glomerular extracellular matrix in IgA nephropathy of high‐serum‐IgA ddY mice

SUMMARY: The high‐IgA inbred strain (HIGA) of ddY mice, an animal model of human IgA nephropathy, shows consistently high serum IgA levels, progressive mesangial sclerosis and IgA deposition, and elevated renal expression of transforming growth factor (TGF)‐β. In the present study the role of the TGF‐β/Smad signalling pathway in extracellular matrix (ECM) production was assessed in cultured mesangial cells derived from HIGA mice. the production of type I and type IV collagens in response to TGF‐β1, expression of Smad2, Smad4, Smad7, and Sp1 and p300, and phosphorylation of Smad2 by TGF‐β1 were assessed in cultured mesangial cells derived from HIGA mice at the age of 10 weeks by comparison with age‐matched C57BL/6 mice as controls. In addtion, the expression of p300 and type I and type IV collagens in renal tissues of HIGA mice at the age of 60 weeks was determined. the production of type I and type IV collagens by cultured mesangial cells in HIGA mice was markedly upregulated compared with that in C57BL/6 mice. Although protein expression levels of Smad2, Smad4, Smad7, and Sp1 in the mesangial cells were simiiar in the two mouse strains, upregulation of p300 was marked in HIGA mice. Expression of p300 in renal tissues of HIGA mice was also enhanced in HIGA mice when compared with C57BL/6 mice. In HIGA mice, p300 expression was upregulated in the mesangial cells both in vitro and in vivo. It appears that the upregulation of p300 may be related to glomerular sclerosis associated with IgA nephropathy in HIGA mice.

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.

Live donor renal transplantation in patients with end‐stage renal failure due to IgA nephropathy: clinicopathological assessment

SUMMARY: The long‐term outcome was evaluated, in terms of recurrence and graft survival, after live donor renal transplantation in 90 grafts in 89 patients with biopsy‐proven IgA nephropathy (IgAN) as a primary diagnosis of end‐stage renal disease. Additionally, histological assessment including glomerular morphometry was performed in 19 grafts having recurrent IgAN. the 10‐year graft survival for IgAN patients was 66%, which was comparable with that of 84% for 107 reference recipients having other kinds of glomerulonephritis (GN) or 69% for 90 other recipients having non‐GN renal failure (P=0.27). In 43 grafts, 54 event graft biopsies were performed, and mesangial IgA deposits were documented in 19 grafts. In eight grafts, lesions were accompanied by chronic rejection (CR). Ten‐year cumulative recurrence was 44%. In total, 10 grafts were lost: this was due to CR (n=3) or acute rejection (n=1) in 24 recurrence‐free recipients; CR (n=2) or recurrence (n=2) in 19 patients with recurrence; and patient death (n=2) in 46 patients who did not have graft biopsy. No difference in 10‐year graft survival between the patients with and without recurrence (63%vs 74%; P=0.98), or the proportion of related donors was found (68%vs 83%; P=0.25). In the grafts with recurrence, renal histological damage was relatively mild and had no uniform pattern. the percentage of global and segmental sclerosis were 11.9% and 3.7%, respectively. Non‐sclerotic glomeruli were ischaemic or hypertrophied. Mesangium showed lysis or focal and mild expansion by matrix and cellular increase. Glomerular morphometry was performed in seven patients, in whom glomerular hypertrophy was found as demonstrated by increases of Bowman's and glomerular tuft areas (1.4 and 1.3 times the control, respectively) and concomitant decrease of total glomerular and mesangial cells per glomerular cross‐section (71.2% and 84.9% of the control, respectively). In conclusion, recurrence increased to 44% with longer follow up, but this did not limit the graft outcome. Recurrence was not affected by the types of live donor. Glomerular hypertrophy in the recurrent IgAN group suggests hyperfiltration.

Dietary Fish Oil Suppresses Experimental Immunoglobulin A Nephropathy in Mice

Dietary fish oil (FO) supplementation reportedly retards the progression of renal disease in patients with immunoglobulin (Ig)A nephropathy (IgAN), the most common glomerulonephritis worldwide. Using an experimental mouse model in which early immunopathological hallmarks of IgAN are induced by the mycotoxin vomitoxin (VT), the ameliorative effects of FO ingestion on this disease were evaluated in two studies. In Study 1, the capacity of VT to induce IgAN was evaluated in mice fed for 12 wk AIN-76A diets containing 50 g/kg corn oil (CO), 50 g/kg CO plus 9 mg/kg tert butylhydroquinone (TBHQ), or 5 g/kg CO plus 45 g/kg menhaden FO that contained 200 mg/kg TBHQ. Serum IgA, serum IgA immune complexes and kidney mesangial IgA deposition were greater in mice fed VT + CO compared with the CO control group, whereas all three variables were significantly attenuated in mice fed VT + FO. Although TBHQ also had attenuating effects, these were significantly less than those for the VT + FO group. In Study 2, the effects of feeding modified AIN 93G diets containing either 70 g/kg CO or 10 g/kg CO plus 60 g/kg FO for 20 wk on VT-induced IgAN were compared. Again, consumption of FO attenuated all three immunopathological variables. In addition, spleen cell cultures from the VT + FO group produced markedly less IgA than those cultures from mice fed VT + CO. Taken together, the results suggested that diets containing FO may impair early immunopathogenesis in VT-induced IgAN and that this was not totally dependent on the presence of the antioxidant TBHQ.

Complications of IgA nephropathy in a non-insulin-dependent diabetes model, the Akita mouse.

The Akita mouse, which has a mutation (Cys96Tyr) in the insulin 2 gene (Ins2(Akita)), is a model for diabetes. The male Akita mouse has diabetes, while females develop mild diabetes. This study aimed to investigate renal complications in the Akita mouse model, which has been maintained in a heterozygous state Ins2(Akita) (+/-) with a C57BL/6 background (B6). Renal function (BUN, creatinine), serum IgA concentrations and histological changes in the kidneys were evaluated in diabetic and control mice in a B6 background. Five each of male and female mice per group (diabetes vs. control) were killed at 10, 20, 30 and 40 weeks of age. The influence of major histocompatibility antigens (MHC) on renal complications was tested using male diabetic mice in a C3H/He (C3H) background. When compared with controls, diabetic males, but not females, developed impaired renal function with elevation of serum IgA after 30 weeks of age. Diabetic glomerulosclerosis advanced with age in both sexes. Diffuse granular mesangial deposits of IgA were detected by immunofluorescence microscopy in diabetic males after 20 weeks. We tested whether the IgA-associated lesions were influenced by MHC using diabetic males in a C3H background. Similar degrees of diabetic glomerulosclerosis and glomerular IgA deposition were found in mice with C3H and B6 backgrounds. Akita mouse is a unique mouse model showing both mesangial sclerosis and IgA nephropathy.

Increased sialylation of polymeric lambda-IgA1 in patients with IgA nephropathy.

The mechanism of mesangial IgA deposition is poorly understood in IgA nephropathy (IgAN). Abnormal glycosylation of carbohydrate moieties in the hinge region of the IgA molecule has recently attracted much attention. In this report, we studied galactosylation and sialylation profiles in kappa- and lambda-IgA1 from patients with IgAN. Total serum IgA1 was isolated from patients with IgAN or healthy controls by jacalin-affinity chromatography. Six fractions of molecular weight (MW) 50-1,000 kDa were separated by fast protein liquid chromatography (FPLC). Four lectin-binding assays were used to study the sialylation and the presence of terminal galactose or N-acetylgalactosamine (GalNAc) in the O-linked carbohydrate moieties of kappa- or lambda-IgA1. Maackia amurensis agglutinin (MAA) and Sambucus nigra agglutinin (SNA) lectin recognize alpha(2,3)- and alpha(2,6)-linked sialic acid, respectively. Peanut agglutinin (PNA) and Helix aspersa (HA) lectin recognize terminal galactose and GalNAc, respectively. Reduced HA was demonstrated in macromolecular kappa or lambda-IgA1 (300-825 kDa) isolated from patients with IgAN (P < 0.05 compared with healthy controls). Lambda- but not kappa-IgA1 from patients with IgAN bound less to PNA (P < 0.05). The alpha(2,3)-linked sialic acid content in lambda- but not kappa-IgA1 of MW 150-610 kDa from patients was higher than that of controls (P < 0.005). The alpha(2,6)-linked sialic acid content in lambda-IgA1 (300-825 kDa) and kappa-IgA1 (150-610 kDa) from patients was also higher than that of controls. This unusual glycosylation and sialylation pattern of the lambda-IgA1 may have important implications for the pathogenesis of IgAN, as both the masking effect of sialic acid on galactose and the reduced galactosylation will hinder the clearance of macromolecular lambda-IgA1 by asialoglycoprotein receptor of hepatocytes. The negative charge from sialic acid may also favor mesangial deposition of macromolecular lambda-IgA1 in IgAN.

Expression of Fc α/μ Receptor by Human Mesangial Cells: A Candidate Receptor for Immune Complex Deposition in IgA Nephropathy

IgA nephropathy is characterized by the deposition of IgA immune complexes in the glomerular mesangium, but the mechanisms responsible for this are not well understood. Human mesangial cells (HMCs) can bind IgA but do not express known IgA receptors. We show here that primary HMCs express mRNA for a novel receptor, the Fc alpha/mu receptor (Fcα/μR), and that receptor expression is upregulated by IL-1. We also detected mRNA for a novel receptor variant in HMCs that may encode a soluble form of the receptor. Fcα/μR was expressed in a heterologous system which showed that the receptor was approximately 58 kDa in weight and was only minimally N-glycosylated. As predicted from the characteristics of the murine homologue, the expressed human Fcα/μR was able to bind IgA and IgM, but not IgG. These results suggest that Fcα/μR may be the receptor responsible for mesangial IgA deposition in IgA nephropathy.

Significance of incidental mesangial IgA deposition in minimal change nephrotic syndrome

Background: Incidental IgA deposition in glomerular mesangium exists in 10–20% of autopsy kidneys1, 2 or renal allograft donors.3 In the present study, we examined the clinicopathological features of incidental mesangial IgA deposition in renal biopsy from patients with minimal change nephrotic syndrome (MCNS) to understand the significance of mesangial IgA deposition in MCNS and pathogenesis of IgA nephropathy. Patients and Methods: From January 1994 to September 2000, 63 patients were diagnosed with MCNS by renal biopsy at Kidney Center, Tokyo Women’s Medical University. Mesangial IgA and C3 deposition was examined by immunofluorescence staining using frozen sections. The frequency of IgA and C3 deposition in MCNS and clinicopathological features of IgA-positive patients with MCNS were investigated. Results: The mesangial IgA deposition was present in 15 out of 63 patients (23.8%). Among these 15 patients, codeposition of C3 was present in 10 patients (66.7%) (Fig. 1). The serum IgA concentration was significantly higher in the IgA-positive patients than in the IgA-negative patients (309 ± 75 mg/dL versus 245 ± 106 mg/dL, P = 0.043) (Fig. 2). The urinary red blood cell count was higher in IgA-positive patients than in IgA-negative patients, although not significantly different (11.7 ± 12.7 counts/HPF versus 5.3 ± 4.0 counts/HPF, P = 0.067) (Fig. 3). Other clinical parameters (age, sex, amount of proteinuria, serum creatinine and creatinine clearance) were not significantly different. Histologically, no significant differences were observed between IgA-positive and IgA-negative patients in following parameters: grade of mesangial cell proliferation and mesangial matrix increase, extents of tubular atrophy and interstitial fibrosis and grade of vascular sclerosis. After steroid treatment, all 15 patients with mesangial IgA deposition had become complete remission, although three patients once relapsed proteinuria. The haematuria also disappeared after steroid treatment in these patients. Figure 1Open in figure viewerPowerPoint The frequency of mesangial IgA and C3 deposition in MCNS patients (n = 63). The mesangial IgA deposition was present in 15 out of 63 patients (23.8%). Among these 15 patients, codeposition of C3 was present in 10 patients (66.7%). Figure 2Open in figure viewerPowerPoint The serum IgA concentration of the MCNS patients with and without mesangial IgA deposition. The serum IgA concentration was significantly higher in IgA-positive patients (n = 15) than in IgA-negative patients (n = 48) (309 ± 75 mg/dL vs 245 ± 106 mg/dL, P = 0.043). Figure 3Open in figure viewerPowerPoint The urinary red blood cell counts of the MCNS patients with and without mesangial IgA deposition. The urinary red blood cell count was higher in IgA-positive patients (n = 15) than in IgA-negative patients (n = 48), although not significantly different (11.7 ± 12.7 counts/HPF vs 5.3 ± 4.0 counts/HPF, P = 0.067). Conclusion: The incidental mesangial IgA deposition was frequently observed in MCNS patients (15/60 patients, 23.8%). The phenomenon of mesangial IgA deposition in MCNS patients was related to higher serum IgA concentration and might cause slight haematuria. However, no influence of mesangial IgA deposition was found on the renal function and the clinical outcome of MCNS after treatment.