Recurrent mesangial IgA nephritis following renal transplantation

Recurrence of mesangial IgA deposits in renal allografts ofpatients whose original disease was primary IgA nephropathy(IgAN) has been studied. Forty-six patients with primary IgANreceived 51 renal allografts and have been followed for 3–183months. A prospective study of 11 patients (11 biopsies) anda retrospective analysis of 17 patients (16 biopsies; 2 nephrectomyspecimens) have been combined. Seventeen of the 29 allograftshad recurrent mesangial IgA deposits and of these three patientshave negative urinalysis, normal glomeruli by light microscopy,and stable renal function; six patients have microhaematu-ria,mesangial proliferative nephritis, but at present stable renalfunction; and five have mesangial proliferative glomerulonephritiswith microhaematuria, heavy proteinuria, hypertension, and progressiveallograft failure secondary to IgA disease alone, and one ofthese is now back on dialysis. Three other grafts with recurrentdeposits are failing because of transplant glomerulopathy orrejection. The only predictor identified for recurrence of mesangial IgAdeposits was length of time post-transplantation, with allografttissue being studied at 45.9±10.0 versus 15.3±4.8months (P = 0.008) post-transplantation in patients with andwithout recurrent deposits respectively. Cyclosporin A did notprevent recurrence. By virtue of a longer follow-up of patientspost-transplantation than all other reported series, these resultssuggest that with increasing time post-transplantation recurrenceof mesangial IgA disease will become increasingly importantas a cause of progressive allograft dysfunction and failureunless effective treatment is found for the primary disease.     

The pathogenetic significance of C5b-9 in IgA nephropathy

Renal biopsies from 20 patients with IgAN were retrospectivelystudied using monoclonal antibodies against T cells, monocytes/macrophages(MM), HLA-DR-related antigen and the C5b-9 neoantigen. GlomerularC5b-9 deposits were mainly found in the mesangial areas andshowed an association with IgA (P<0.005) and C3 deposits(P<0.001). Interstitial T cells and MM were highly correlatedwith the interstitial DR+ve cells (P<0.001 and P<0.0005respectively). Tubular C5b-9 deposition was observed on thetubular basement membranes and related to the numbers of interstitialT cells (P<0.005), MM (P<0.005) and DR+ve cells (P<0.01)as well as to the tubular DR expression (P <0.025). The severityof tubular atrophy and interstitial fibrosis showed a positivecorrelation with the interstitial T cells, MM and DR+ve cells,as well as with the intensity of tubular C5b-9 deposition (P<0.05and P<0.05 respectively). Plasma creatinine on presentationwas correlated with the numbers of interstitial T cells (P<0.05),MM (P<0.01), interstitial DR+ve cells (P<0.005), and tubularC5b-9 deposits (P<0.005). No correlation between glomerularT cells, MM, and C5b-9 deposits with plasma creatinine was seen.During follow-up, renal function deteriorated in those patientswith the more extensive tubular C5b-9 deposits In conclusion, glomerular C5b-9 deposition seems to be secondaryto the IgA and C3 deposition. In contrast, tubular C5b-9 isrelated to the numbers of interstitial T cells and MM. Activatedinterstitial mononuclear cells may lead to the tubular depositionof C5b-9, which eventually might contribute to the developmentof tubulointerstitial lesions (TIL) and renal function impairment     

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

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

Low-antigen-content diet in the treatment of patients with IgA nephropathy

Since dietary macromolecular antigens can be involved in thepathogenesis of IgA nephropathy (IgAN), the effect of a low-antigen-contentdiet was evaluated in 21 patients (10 women, 11 men, mean age27.7±10 years) with immunohistochemical findings of activeIgAN. The diet was followed for a 14–24-week period (mean18.8±6); in all cases the effects of the treatment wereevaluated by clinical and serological parameters, and in 11patients also by repeat renal biopsy. After dietetic therapy a significant reduction of urinary proteinswas recorded (P< 0.001); in particular, heavy proteinuria(>1 g/day), present in 12 cases during the 6 months precedingthe treatment, was markedly reduced or disappeared in 11. Atposttreatment control biopsy mesangial and parietal depositsof immunoglobulins, complement C₅, fraction and fibrinogen weresignificantly reduced. The improvement of the objective parameterssuch as heavy proteinuria, a strong predictor of a poor prognosis,and of immunohistochemical alterations indicate that a low-antigendiet can positively affect patients with IgAN. These resultscould be ascribed to a reduction of nephritogenic food antigeninput and to a putative functional restoration of the mononuclearphagocytic system.     

Soluble fibrin formation in the mesangial area of IgA nephropathy

Background Fibrin monomer and its derivatives in blood are found in an early stage of thrombosis. When they are produced in blood, they form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanisms of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted. Methods Nineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated. Results XFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P < 0.05). Furthermore, XFb, factor V, and SF depositions were markedly correlated with disease activity (P < 0.001 in each case). Conclusions These findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompanied by mesangial proliferation, in particular, in its early stage.     

Impact of recurrent disease and chronic allograft nephropathy on the long‐term allograft outcome in patients with IgA nephropathy

Although recurrent IgA nephropathy (IgAN) may lead to graft dysfunction after transplantation, donation from living related donor (LRD), with whom the risk of recurrence may be higher, is not a contraindication. Herein, we evaluated the natural history of allograft in recipients with IgAN and the risk factors influencing long‐term allograft outcome. Recurrence rate and graft survival were assessed retrospectively in 221 IgAN patients, including transplants from 139 LRDs (62.9%). Ten‐year cumulative rate for recurrent IgAN was 30.8%. The operation at younger age and donation from LRD were significant for the recurrence by multivariate analysis. Ten‐year graft survival was affected by recurrent IgAN (61.0% in recurrent IgAN group vs. 85.1% in nonrecurrent, P < 0.01). However, transplants from LRDs did not show poor graft survival when compared with those from other types of donors. In transplants from LRDs, the incidence of chronic allograft nephropathy (CAN) was lower than those in grafts from deceased donors (10.8% vs. 19.5%, P < 0.05). When CAN was considered in addition to recurrence, the variance of graft survival was affected significantly by the development of CAN than by the recurrence. These results suggest that the detection and adequate management of CAN could improve graft outcome in transplant recipients with IgAN.     

Differential expression of platelet-derived growth factor and transforming growth factor-β in relation to progression of IgA nephropathy

SUMMARY: The role of platelet-derived growth factor (PDGF) and transforming growth factor-β1 (TGF-β1) in relation to mesangial matrix expansion and progressive glomerulosclerosis in IgA nephropathy (IgAN) is not clearly defined. Expression of PDGF B, TGF-β1, and extracellular matrix proteins in glomeruli was assessed by immunohistochemistry in 42 biopsies with IgAN and six renal biopsies with no detectable abnormalities. the mRNA expression of PDGF B, TGF-β1, α1(IV) collagen, laminin B1 and fibronectin genes was further evaluated by in situ hybridization in 25 biopsies with IgAN and six controls. In IgAN, the intensity of immunostaining for PDGF B, type IV collagen, laminin and fibronectin, but not for TGF-β1, was increased in the mesangium compared with controls. the immunoreactivity of PDGF B was closely correlated with that of type IV collagen and laminin. the number of PDGF B mRNA-, α1(IV) collagen mRNA-, laminin B1 mRNA-, and TGF-β1 mRNA-expressing cells/glomerular section, but not the number of fibronectin mRNA-expressing cells, was increased in IgAN compared with controls. the number of PDGF B mRNA-expressing cells correlated significantly with the percentage of glomerulosclerosis. In the cellular lesions of focal segmental glomerulosclerosis (FSGS), expression of TGF-β1 protein and mRNA was markedly increased in visceral glomerular epithelial cells (GEC). These results suggest that PDGF B mainly overproduced by mesangial cells may cause mesangial matrix expansion, whereas TGF-β1 produced by GEC may be related to the formation of FSGS in IgAN. Thus, PDGF B and TGF-β1 may play differential roles in the pathogenesis of renal fibrosis and the progression of IgAN.     

The level of serum secretory IgA of patients with IgA nephropathy is elevated and associated with pathological phenotypes.

BACKGROUND: Mucosal infection associated episodic macroscopic haematuria is observed in many patients with IgA nephropathy (IgAN), however, the mechanism has not been elucidated. Recent study suggested that secretory IgA (SIgA) might play an important role in the pathogenesis of IgAN. The aim of this study is to investigate the level of serum SIgA and the deposition of SIgA in glomeruli in IgAN patients with different pathological phenotypes. METHODS: The levels of serum SIgA were detected in 57 patients with IgAN and 48 normal controls. The associations between the levels of SIgA and the pathological phenotypes of IgAN as well as clinical parameters were investigated. Frozen renal sections from 34 of the 57 patients without IgM deposition were immunofluorescence stained and examined by confocal microscopy to detect the co-deposition of IgA and secretory component (SC). The association between deposition of SIgA and the level of serum SIgA was analysed. RESULTS: The level of serum SIgA in patients with IgAN was significantly higher than that of normal controls. The level of serum SIgA in patients with focal proliferative sclerosing IgAN (fpsIgAN) was much higher than that in patients with mild mesangial proliferative IgAN (mIgAN) (P<0.001). The level of serum SIgA correlated with the level of serum creatinine (R=0.509, P<0.001), degree of proteinuria (R=0.643, P<0.001) and creatinine clearance (R= -0.454, P=0.002) in patients with IgAN. Significant co-deposition of SC and IgA were found in 11 of the 34 patients. Although the level of serum SIgA in patients with SC deposits was higher than those without SC deposits, the difference was not significant. CONCLUSIONS: It was concluded that mesangial IgA, at least partly, was originated from mucosal immune sites. The levels of serum SIgA were significantly increased in patients with IgAN and were closely associated with pathological phenotypes.     

Immunological studies of IgA nephropathy in blacks reveal elevations of serum IgA2 as well as IgA1

Although IgA nephropathy (IgAN) is recognized worldwide as themost common primary glomerulonephritis, the prevalence of thisdisease among American blacks is strikingly low despite thefrequency of other renal disorders. We have previously describedthe clinical features of 27 black patients enrolled in a multicentreIgAN database; in this paper we report several immunologicalparameters of the disease in this population. Quantificationof serum immunoglobulins revealed significantly higher concentrationsof total IgA, IgAl and IgA2 (P=0.0001, 0.002 and 0.005 respectively)in the patients, but no significant increases in IgG or IgM.Examination of immunoglobulin synthesis by peripheral bloodlymphocytes indicated relatively few differences in the secretionof immunoglobulins by patients compared to healthy Americanblacks. The spontaneous production of total IgA, IgA1, and IgA2in patients was depressed compared to the control subjects (P=0.02,0.04, 0.03,), yet the ratio of IgA1:IgA2 was normal. Stimulationwith poke-weed mitogen enhanced secretion of immunoglobulinin both subject groups. However, a significantly greater IgA1:IgA2ratio was noted in the patients (P=0.002). Circulating immunecomplexes containing C3 and IgA as well as C3 and IgM were elevatedin the patients (P=0.0006, 0.0003 and 0.02, respectively). Theseimmunological aberrancies did not correlate with clinical manifestationsof disease. These data suggest the immune abnormalities of blackIgAN patients are similar to, but not identical with, thoseof white patients.     

Correlation between glomerular morphology and renal haemodynamic response to amino-acid administration in patients with IgA nephropathy

RATIONALE.: To establish relationship, if any, between renal morphologyand renal haemodynamic response to amino acids. DESIGN AND METHODS.: We investigated the correlation between renal haemodynamic regulationand morphology in a group of 15 patients with primary IgA nephropathy(IgAN) (age 26±2 years, BMI 24.4±1, GFR 64±5ml/min, RPF 377±34 mI/mm, FF 0.17±0.02). Twelvenormal subjects (age 30±3 years, BMI 24±1, GFR82±6 ml/min, RPF421±42 ml/min, FF 0.19±0.02)were studied as controls. IgA patients were divided into twogroups according to the histological staging of glomerular lesions:group I (n=7) stage II, and group II (n=8) stage III–IV. RESULTS.: In the basal state GFR was similar in the two groups and averaged64±9 and 64±6 ml/mm respectively. In contrast,FF was significantly lower in group II(0.14±0.01) (P<0.05)in comparison to group I (0.21±0.03) and controls (0.19±0.02).In order to evaluate the renal functional reserve, all studygroups underwent to an intravenous amino-acid infusion designedto increase plasma amino acid levels twofold (total from 2096±145to 4301±221 µmol/l in IgA nephropathy patientsand from 2272±83 to 3844±238 µmol/l in controls).In response to amino-acid infusion, GFR rose significantly ingroup I (GFR 20±2% and RPF 37±4% versus basal)and controls (GFR 20±2% and RPF 20±3% versus basal)(both P<0.01 vs basal). In contrast, in patients with moresevere glomerular lesions (group II) neither GFR nor RPF rosesignificantly (GFR –1±4% and RPF –8±6%versus basal) (P NS versus basal, P<0.01 versus group I andcontrols). CONCLUSIONS.: The data show that in IgA nephropathy: severe forms of glomerularlesions are associated with a complex alteration of glomerularhaemodynamic regulation, characterized by lower basal FF andloss of haemodynamic response to hyperaminoacidaemia.     

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.     

Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil.

BACKGROUND: Transplantation offers an excellent option for patients with immunoglobulin-A nephropathy (IgAN) with severe renal dysfunction. However, IgAN frequently recurs in allografts treated with azathioprine. We examined the impact of mycophenolate mofetil immunosuppression on recurrence of IgAN. METHODS: We reviewed the charts of patients transplanted for IgAN at our institution in the cyclosporin era. Patients were excluded from further analysis if follow-up was <12 months or if immunosuppression at engraftment did not include azathioprine or mycophenolate mofetil. Laboratory data, medications and allograft biopsy findings were compiled. RESULTS: 152 kidney transplantations met the study criteria. At engraftment, 61 allografts were treated with azathioprine and 91 with mycophenolate mofetil. By 3 years post-transplant, IgAN developed in six of 60 (10.0%) azathioprine-treated allografts and five of 62 (8.1%) mycophenolate mofetil-treated allografts (P = 0.76). Overall, 13 azathioprine-treated and seven mycophenolate mofetil-treated allografts showed recurrence. As expected in this retrospective study, the duration of observation was longer in the azathioprine group. The interval between engraftment and diagnosis of recurrent disease was also longer. Survival of allografts with recurrent IgAN was similar in the two groups. Survival of allografts with recurrent IgAN was worse than for allografts without recurrence or allografts transplanted into patients with non-IgAN renal failure. Neither switching azathioprine to mycophenolate mofetil nor using an angiotensin-converting enzyme inhibitor or angiotensin-II type 1 receptor blocker ameliorated the clinical course after a biopsy documented recurrent IgAN. CONCLUSIONS: Mycophenolate mofetil, compared with azathioprine, did not lessen the recurrence of IgAN or its clinical impact.     

Treatment of severe IgA nephropathy in children

We treated ten children with severe IgA nephropathy (IgAN) [proteinuria > 1g/day, hypertension, renal insufficiency, segmental sclerosis, crescent formation and/or glomerular basement membrane (GBM) deposition of IgA] with prednisone and azathioprine for 1 year. Following the year of therapy, seven of the ten children underwent a repeat kidney biopsy. All biopsies were scored for activity (percentage of glomeruli demonstrating crescent formation, degree of mesangial proliferation and interstitial infiltrate; maximum score = 9) and chronicity (percentage of glomeruli demonstrating fibrous crescents, segmental sclerosis, global sclerosis, and degree of tubular atrophy and interstitial fibrosis; maximum score = 12). After 1 year of therapy, the protein excretion of all the children decreased significantly (P<0.01) from 4052±3190 mg/day to 1692±1634 mg/day. The activity score decreased significantly (P<0.01) from 4.35±0.94 prior to therapy to 2.28±0.75 after therapy while the chronicity score was unchanged (5.42±1.7 vs 5.85±2.0). The percentage of glomeruli demonstrating cellular crescents decreased (P<0.05) from 21.2±21.7% prior to therapy to 0.94±2.4% after therapy. Mesangial deposition of IgA persisted but GBM deposition of IgA was less prominent after therapy. During the follow-up period (mean 2.6 years, range 9 months–7.5 years), one child required brief retreatment for biopsy-confirmed recurrence of active disease, two children have developed renal insufficiency due to progressive scarring in the absence of inflammation, while the remaining seven are stable. We suggest that treatment with prednisone and azathioprine may be beneficial in children with severe IgAN and that a controlled clinical trial is warranted.     

Clinical remission and pathological progression after tonsillectomy in a renal transplant patient with recurrent IgA nephropathy

Abstract:  We discuss a renal transplant patient with recurrent IgA nephropathy (IgAN) before and after tonsillectomy. A 36-year-old man started on hemodialysis support in 1996 due to biopsy-proven IgAN, living related renal transplantation was then performed in 1997. Six years after transplantation, the patient presented with microhematuria and proteinuria. Graft biopsy for these urinary abnormalities showed recurrent IgAN. Tonsillectomy was subsequently performed in December 2003, proteinuria remitted 6 months after the tonsillectomy and microhematuria disappeared three years later. Protocol graft biopsy was subsequently performed twice, at 2 yr after the tonsillectomy (2005) and 4 yr after (2008). Comparing the findings of the pre-tonsillectomy biopsy and the two post-tonsillectomy biopsies, an increase in mesangial cells and matrix in 2005, and an expansion of the mesangial matrix and proliferation of mesangial interposition in 2008. In addition, global sclerosis of glomeruli increased over time, the area of tubulointerstitial damage has extended as well. While the tonsillectomy led to clinical remission of recurrent IgAN, the chronicity progressed on these protocol biopsies. This is the first report of the efficacy and the limitations of tonsillectomy in a case of recurrent IgAN in a transplant patient.     

Acute reversible renal failure with macroscopic haematuria in IgA nephropathy

Macroscopic haematuria is common in IgA nephropathy, but itssignificance and influence on prognosis remains uncertain. Wecompared the clinical and pathological features of 11 adultpatients with primary IgA nephropathy who had had a renal biopsyduring or shortly after a bleeding episode. Six patients developedtransient acute renal failure (ARF) (group 1) and five did not(group 2). Patients of group 1 had a higher percentage of tubularred-blood-cell (RBC) casts (P<0.05) and of glomerular crescents(P<0.001). However, crescents were focal and involved lessthan 50% of glomeruli. Acute tubular necrosis was only presentin patients of group 1, and ARF was attributed to the acutetubular changes rather than to the glomerular lesions. Despitea prolonged duration of ARF (mean: 38 days), further outcomedid not differ in patients of both groups. We suggest that acutetubular damage and/or tubular obstruction by RBC casts shouldbe considered in any patient who develops ARF soon after a haematuricepisode.     

Evaluation of Renal Clinicopathological Changes in IgA Nephropathy by Urinary Podocytes Excretion and Podocalyxin Expression

Objective: To explore the association of urinary podocyte excretion and renal expression of podocyte-specific marker podocalyxin (PCX) with clinicopathological changes in immunoglobulin A nephropathy (IgAN). Methods: Morning urine samples from IgAN patients and healthy controls were collected. The expression of glomerular PCX was quantified in 50 IgAN patients diagnosed by renal biopsy. IgAN was classified based on the Lee’s Grading system and scored according to the Katafuchi semiquantitative criteria. Morphological evaluation of podocyte was determined by electron microscopy. Results: The amount of urinary podocytes in the IgAN patients was significantly higher than that in the healthy controls (p < 0.01). Pairwise comparison among Lee’s grades of IgAN showed that the median of urinary podocytes in Lee’s I–II group was lower than that in Lee’s III, IV, and V groups (p < 0.05); group III lower than group V (p < 0.05). The positive rate of urinary podocytes was the highest in Lee’s IV and V groups (100%), and lowest in Lee’s I–II group (55%). Multiple comparison among groups of Lee’s grades of IgAN showed that the glomerular PCX expression in Lee’s I–II group was higher than that in Lee’s III, IV, and V groups (p < 0.05); groups III and IV higher than group V (p < 0.05). The amount of urinary podocytes in IgAN patients was negatively correlated with PCX expression (r = ?0.702, p < 0.01), but positively correlated with 24-h urinary protein (r = 0.465, p < 0.01) and glomerular (r = 0.233, p < 0.01) and renal tubular pathological scores (r = 0.307, p < 0.05). The glomerular PCX expression was negatively correlated with 24-h urinary protein (r = ?0.367, p < 0.05) and glomerular (r = ?0.560, p < 0.05) and tubular pathological scores (r = ?0.377, p < 0.05). Electron microscopy showed significant changes in podocytes of IgAN, especially in the foot process. Conclusion: The amount of urinary podocyte can reflect the loss of podocytes in renal tissue, which may be a marker of IgAN progression.     

Effect of aggregated immunoglobulin A1 from immunoglobulin A nephropathy patients on nephrin expression in podocytes

Aim: Abnormal immunoglobulin (Ig)A1 is considered to play a pivotal role in IgA nephropathy. We used mouse podocytes as the experimental model to investigate the effect of aggregated IgA1 (aIgA1) isolated from IgA nephropathy (IgAN) patients on nephrin expression in podocytes through direct and indirect pathways. Methods: Jacalin affinity chromatography and Sephacryl S‐200 molecular sieve chromatography were used to isolate IgA1 from blood of IgAN patients which was therefore became aIgA1. Podocytes were incubated with aIgA1 or special mesangial medium. Nephrin expression in podocytes was measured by real‐time polymerase chain reaction and western blot analysis. Results: Aggregated IgA1 from IgAN patients and healthy controls reduced nephrin expression in podocytes at mRNA and protein levels when compared with podocytes incubated with control medium (RPMI‐1640 with 0.5% foetal bovine serum) (P < 0.05). While medium from mesangial cells incubated with aIgA1 from IgAN inhibited nephrin expression in podocytes at mRNA and protein levels when compared with podocytes incubated with medium from mesangial cells with aIgA1 from healthy controls (P < 0.05). Conclusion: Our findings implicate that aIgA1 from IgAN patients could inhibit nephrin expression through direct and indirect pathways, although these mechanisms remain to be clarified.     

Detection of enteroviruses in renal biopsies from patients with immunoglobulin A nephropathy

Viruses have been suspected to be one of the causes of IgA nephropathy (IgAN). Recent studies have detected viruses in renal tissues of patients with IgAN. Enteroviruses have been reported as pathogenic agents in some renal diseases. We previously reported that group B coxsackieviruses cause pathological changes in experimentally infected mouse kidney. The aim of the present study was to examine the participation of enteroviruses in the pathogenesis of renal diseases including IgAN. Renal biopsies of ten patients with IgAN (group 1) and of 19 patients with non-IgAN renal disease(group 2) were analyzed by polymerase chain reaction (PCR) for the presence of enteroviral RNA. Positive PCR results were obtained for three patients (30%) of group 1. We confirmed by sequencing that the positive PCR products were derived from strains of enteroviruses. One of these three patients also had a positive result for lymphocytes from peripheral blood. In contrast, enteroviral RNA was detected in none of the 19 patients of group 2. The incidence of enteroviral RNA detection in patients of group 1 was higher than that in group 2 (P<0.05). Our findings suggest that enteroviral infection may have the possibility of becoming one of the factors involved in the mechanism of onset or evolution of IgAN.     

Activation of mRNA expression of collagen,collagenase and its inhibitor on renal biopsy specimens in patients with IgA nephropathy

Summary: In situ hybridization of mRNA for collagen IV, collagen VI, stromelysin (MMP-3) and TIMP1 was examined in renal biopsy specimens from patients with IgA nephropathy (IgAN) or diabetic nephropathy with various degrees of tissue damage. The majority of cells in the glomeruli expressed these mRNA almost simultaneously, but a few cells demonstrated positive expression for only one of these probes. There was a parallel relationship between the degree of tissue damage and that of mRNA expressions of these probes in patients with IgAN, while patients with diabetic nephropathy showed a reverse relationship between these two parameters. It is concluded that patients with mesangial proliferative glomerulonephritis expressed mRNA for collagen collagenase and its inhibitor in the glomeruli in parallel with the progress of tissue damage. In contrast, glomerular samples from patients with diabetic nephropathy showed that there was an inverse relationship between tissue damage and expression of mRNA. It is concluded that expression of collagen, collagenase and its inhibitor parallels the progression of glomerular changes in IgAN, but such parallel expression was not observed in patients with diabetic nephropathy.     

Abnormal glycosylation of serum IgG in patients with IgA nephropathy

Background We postulated that IgA nephropathy (IgAN) involved alterations of serum IgG. The present study was undertaken to elucidate changes in serum IgG oligosaccharide structure analysis and to assess the diagnostic usefulness of this analysis in IgAN. Methods The subjects were 28 children who were definitively diagnosed as having IgAN on the basis of renal biopsy and who had not received treatment for this disease; 27 healthy children; 15 untreated adults definitely diagnosed as having IgAN; 5 patients with other nephropathies; and 61 healthy adults. Oligosaccharide analyses of IgG were performed by reverse-phase high-performance liquid chromatography (HPLC) developed by Takahashi and colleagues. Results In both the children and the adults, the peak area ratio of isomers with two different galactosyl-N-acetylglucosamine (Gal-GlcNAc) binding sites was significantly lower in the presence of IgAN than in the healthy subjects (P < 0.05 in children and P < 0.001 in adults). The ratio of Gal-free oligosaccharides to Gal-positive oligosaccharides did not differ according to the presence or absence of IgAN in children or in adults. Conclusions The analysis of the oligosaccharide structure of serum IgG seems to be useful in diagnosing IgAN.