IgA-Dominant Postinfectious Glomerulonephritis: Not Peculiar to Staphylococcal Infection and Diabetic Patients

Background: IgA-dominant postinfectious glomerulonephritis (PIGN) is a unique form of PIGN. It has been linked to staphylococcal infection and underlying diabetic glomerulosclerosis. However, the significance of glomerular IgA-dominant deposition in PIGN remains unclear. Methods: We reported 10 patients with IgA-dominant PIGN encountered at a single center, each characterized by subepithelial humps. Their demographic, clinical, and renal biopsy findings were summarized and compared with the data of 32 patients with non-IgA-dominant PIGN. Results: The mean age was 57 years. An immunocompromised background was present in 70% of patients; only one patient had diabetes mellitus. The causative infectious agents included Staphylococcus (30%), Streptococcus (20%), and gram-negative organisms (50%). Decreased serum complement was present in 60%. Increased serum IgA was noted in 75%. The mean peak serum creatinine was 5.1?mg/dL, and 20% required acute dialysis. Diffuse endocapillary-proliferative glomerulonephritis was found in all cases, and three patients also had crescentic glomerulonephritis. Electron microscopy revealed large subepithelial hump-shaped deposits in all cases. At the last follow-up, one patient had died, five had achieved complete recovery, three had persistent renal insufficiency, and one was on chronic dialysis. Compared to patients with non-IgA-dominant PIGN, increased serum IgA was more commonly present in IgA-dominant group (p?=?0.007). There were no significant differences in other clinical parameters and outcome between the two groups. Conclusions: IgA-dominant PIGN resembles poststreptococcal glomerulonephritis in its histological spectrum and ultrastructural appearance. Increasing serum IgA may be involved in the pathogenesis of this form of PIGN. Our data suggested that IgA-dominant PIGN was not peculiar to staphylococcal infection and diabetic 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     

Differences in new-onset IgA nephropathy between young adults and the elderly

Background: The goal of this study was to define the clinical and histological differences in new-onset IgA nephropathy between young adults and the elderly. Methods: We retrospectively examined renal biopsy findings, clinical features at presentation and outcomes in 82 young adults (mean age 30.3 ± 10.2 years) and 17 elderly patients (mean age 71.9 ± 4.5 years) with IgA nephropathy whose renal biopsies were taken within 1 year from the onset of renal manifestations. Results: The elderly group more frequently had hypertension (p < 0.001), acute renal failure (p < 0.001), and nephrotic range proteinuria (p = 0.001) at presentation than the young adults group. On histology, a higher percentage of globally sclerotic glomeruli (p < 0.001) was present in the elderly group. In patients presenting with acute renal failure, the elderly group more frequently had an intercurrent disease (p = 0.02), mostly infection, and a higher mortality rate (p = 0.033). On histology, the young adults group had a higher percentage of glomeruli affected by crescents (p = 0.027); in contrast, the elderly group more commonly had acute tubular injury (p = 0.02). Conclusions: The elderly patients affected by IgA nephropathy had more severe renal manifestations at presentation (acute renal failure in 52.9% and nephrotic syndrome in 41.2% of patients). In cases of acute renal failure, the elderly patients had more predominant tubular rather than glomerular injury. Moreover, the considerable mortality rate (44.4%) might be associated with the intercurrent disease, mostly infection, which was more commonly present in the elderly patients.     

Cationic dextran induces mesangioproliferative nephritis in rats independent of glomerular IgA deposition

Background. Dextran-induced mesangioproliferative glomerulonephritis in mice and, as recently reported, in rats is used as a model of IgA nephropathy. The pathogenetic role of the glomerular IgA deposits in this model, however, is unclear since IgG is often deposited in parallel. Methods. Lewis rats were immunized with cationic DEAE-dextran. Following this, rats received 5 x /week i.v. injections of 3 mg DEAE-dextran each, from days 20 to 80 and were then followed until day 120. Results. Rats developed transient proteinuria (range 63-152 mg/24 h) and haematuria on day 80. Renal biopsies obtained at days 60, 80, 100 and 120 showed mild to severe mesangioproliferative changes at days 80 and 100 which did not persist at day 120. Electron-microscopy revealed mesangial immune deposits, signs of endothelial activation and vacuoles in mesangial cells and podocytes. Compared to normal, age-matched controls, in the nephritic rats significant (P<0.05) increases were noted for glomerular total celluarity, &agr;-smooth-muscle actin expression (a marker of activated mesangial cells), monocyte/macrophage counts, and matrix proteins. Using three different antibodies, no evidence of glomerular IgA deposition was detected at any timepoint. In contrast, glomerular IgG, IgM, C3 and occasional small C5b-9 deposits were present in nephritic rats. Circulating IgG but not IgA anti-dextran antibodies could be demonstrated in nephritic rats. Conclusions. The data confirm that mesangioproliferative glomerulonephritis can be induced in rats by immunization and chronic challenge with cationic dextran. Our data also show that in rats glomerular IgG deposition rather than IgA, appears to play an important pathogenetic role in this mesangioproliferative glomerulonephritis model.     

IgA nephropathy: association of C4d with clinical and histopathological findings and possible role of IgM

Abstract

Background: In patients with IgA nephropathy (IgAN) lectin and alternative pathways of the complement can be activated. Our aim was to analyze the association of glomerular and extraglomerular C4d staining—the representative of lectin pathway—with demographic, clinical and histopathological findings in primary IgAN patients. Design: Seventy-three patients were enrolled and after re-evaluation 37 of them were included in this study. Biopsies were analyzed for staining with anti-C4d primary monoclonal antibody by immunohistochemistry. Patients were classified as positive and negative groups based on their glomerular C4d deposition. Groups were compared for their baseline clinical and histopathological findings. Results: Sixteen (43.2%) of 37 patients were C4d-positive. Glomerular C4d-staining was associated with more severe proteinuria (2906?mg/day vs. 1091?mg/day; p?=?0.002), lower GFR (54.87?mL/min vs. 95?mL/min; p?=?0.023), higher blood pressure (p?=?0.022), more severe endocapillary hypercellularity (p?<?0.001) and more severe tubular atrophy (p?<?0.01). Mesangial IgM deposition was found to be associated with glomerular C4d staining and nephrotic range proteinuria. Conclusions: Glomerular C4d deposition was found to be associated with more unfavorable histopathological and clinical findings at the time of diagnosis. Association of mesangial IgM deposition with the activation of lectin pathway is a novel finding. Mesangial IgM deposition in our patients may reflect the genetic heterology of IgAN between diverse populations. However, since these data are about association, a cause-and-effect about IgM and IgAN cannot be proven solely with these findings.     

Abnormal IgA glycosylation in Henoch-Schonlein purpura restricted to patients with clinical nephritis

Background: Glomerular deposition of IgA1 is a common feature of Henoch-Schonlein purpura, and is indistinguishable from that seen in IgA nephropathy. Serum IgA1 is abnormally O-glycosylated in IgA nephropathy, and this may contribute to mesangial IgA1 deposition and the development of glomerular injury. This altered O-glycosylation of IgA1 can be detected by its increased binding to the lectin Vicia villosa. Methods: To investigate whether IgA1 is abnormally glycosylated in Henoch-Schonlein purpura, the binding of Vicia villosa lectin to serum IgA1 was studied in the following subject groups: IgA nephropathy; adults and children with Henoch-Schonlein purpura and nephritis; children with clinically diagnosed Henoch-Schonlein purpura but no renal involvement; adults and children with non-IgA associated glomerulonephritis; and matched controls. Results: The abnormality of lectin binding seen in IgA nephropathy was also found in both adults and children with Henoch-Schonlein purpura with nephritis. However the lectin binding of serum IgA1 from children with Henoch-Schonlein purpura lacking renal involvement did not differ from controls, and similarly no abnormality of lectin binding was seen in patients with non-IgA associated glomerulonephritis. Conclusions: These data indicate that the abnormality of IgA1 O-glycosylation seen in IgA nephropathy is also found in Henoch Schonlein purpura, but only in those subjects with renal involvement, while IgA1 O-glycosylation is normal in patients with other forms of renal disease. These findings lend strong support to a role for altered IgA1 O-glycosylation in the pathogenesis of IgA-associated glomerular disease.     

Characterization of kidney lesions in Indian adults: towards a renal biopsy registry

BACKGROUND: In the absence of a renal biopsy registry, there is a paucity of data on the renal disease pattern seen in India. This study reviews the changing pattern of renal disease seen at a single center over the last 30 yrs. METHODS: Histopathological data of 5415 adequate native kidney biopsies performed on consecutive adult Indian patients presenting to our hospital from 1986-2002 were analyzed. This pathological demography classified according to the modified World Health Organization (WHO) classification was compared to the earlier published cohort collected from 1971-1985 (n=2827) to ascertain the changing trends. RESULTS: The indications for renal biopsy were comparable between the cohorts and included nephrotic syndrome (65%), nephritic syndrome (13%) and chronic renal failure (10.2%). Primary glomerular disease accounted for 71% of all biopsies. Non-immunoglobulin A (IgA) mesangio proliferative glomerulonephritis as a group was the predominant pathology (20.2%), followed by idiopathic focal segmental glomerulosclerosis (FSGS) (17%), minimal change disease (MCD) (11.6%), membranous glomerulopathy (MN) (9.8%), IgA nephropathy (8.6%) and membranoproliferative glomerulonephritis (MPGN) (3.7%). Of the patients with secondary kidney diseases, lupus nephritis (6.5%), diabetic nephropathy (2.5%), interstitial nephropathy (2.5%) and benign nephrosclerosis (2.2%) were notable. During the 31 yrs of the study period, there was a steady increase in FSGS prevalence (p<0.001), MN (p<0.0001), and post infectious glomerulonephritis (PIGN) (p<0.001). A reduction in the frequency of MPGN (p<0.001) and MCD (p<0.001) was observed. CONCLUSIONS: This is the largest series of renal biopsy data from India; and therefore, could reflect the demographic picture of renal diseases in this country. It discusses evolving patterns over 30 yrs and highlights differences with the developed world. This report represents the basis for the future of a renal biopsy registry in India.     

Apoptosis and proliferation in childhood acute proliferative glomerulonephritis

Acute proliferative glomerulonephritis is characterized by glomerular hypercellularity that can be caused by many different etiologies and pathogenetic mechanisms. A balance between cell birth by mitosis and cell death by apoptosis is crucial. In this study, apoptosis and the regenerative activity (Ki67/apoptosis index) were investigated in acute proliferative glomerulonephritis. Thirty-five children with biopsy-proven acute proliferative glomerulonephritis and five controls with MCD were studied retrospectively. According to the clinical outcome, patients were divided into 2 groups: group 1 (n =21) were patients with normal renal functions at follow-up; group 2 (n =8) were patients with end-stage renal failure or those who died. Immunohistochemical staining of proliferating cells (Ki67) was done. In situ end labeling of DNA was used to evaluate apoptosis. Glomerular cell apoptosis was 45% in the patients with acute proliferative glomerulonephritis and 3% in controls ( p <0.001). Apoptotic cells were identified in the tubulointerstitial compartment with higher and heavier immunostaining in patients than controls (p =0.001). Tubular proliferative index (= tubular proliferation/tubular apoptosis ratio) was significantly higher in group 1 patients than in group 2 patients (2.03±2% versus 0.32±0.6%, p =0.002). Tubulointerstitial regenerative ratio (=tubular proliferation/interstitial proliferation ratio) was significantly higher in controls than in patients (3.4±1.9 versus 1.52±0.8, p =0.01). In addition, it was significantly increased in group 1 patients when compared with those in group 2 patients (1.89±0.8 versus 0.73±0.2, p =0.001). Since 17 patients presented with postinfectious proliferative glomerulonephritis, which is known to exhibit better course, we also evaluated those parameters in patients with postinfectious proliferative glomerulonephritis separately. We found statistically significant differences only in the tubulointerstitial regenerative ratio, which was higher in postinfectious cases when compared with those in other cases [1.60 interquartile range (IQR) 1.54 versus 1.22 IQR 1.26, respectively, p =0.003]. In conclusion, tubular proliferative index and tubulointerstitial regenerative ratio might be useful parameters for predicting final functional outcome in acute proliferative glomerulonephritis. Further studies, however, are still needed to clarify the importance of these histopathological parameters.     

The features in IgA-dominant infection-related glomerulonephritis distinct from IgA nephropathy: a single-center study

Background

IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN).

Methods

Thirteen patients with IgA-IRGN (IgA-IRGN group) and 122 with IgAN (IgAN group) were selected from 1788 patients who underwent kidney biopsy between 2000 and 2015 in Kitano Hospital. Data selected included clinical and serological parameters; light and electron microscope findings; immunofluorescence findings; and prognostic parameters like renal and overall survival and creatinine increase by >?50%. In addition, a 26-patient IgAN cohort (matching-IgAN), matching with IgA-IRGN group with respect to age, sex, estimated glomerular filtration rate (eGFR), and proteinuria was segregated for comparison.

Results

Compared to IgAN group, IgA-IRGN group were older, had lower hemoglobin, higher CRP, lower eGFR, heavier proteinuria, lower serum albumin, and higher serum IgG and IgA levels (p?<?0.05). Endocapillary hypercellularity, deposition of immune complexes along the glomerular capillary wall, and subendothelial and subepithelial electron dense deposits were more frequently observed (p?<?0.05); and they were more susceptible to renal dysfunction and poorer prognosis. After propensity score-matching, serum albumin was significantly lower in the IgA-IRGN group. Significantly subendothelial and subepithelial deposits were frequently observed in this group. Matching-IgAN group showed relatively advanced sclerotic lesions with more global sclerosis and fibrous crescent.

Conclusion

Local inflammation involved glomerular capillary wall in IgA-IRGN, in contrast to relatively chronic and sclerotic renal lesion in IgAN, might result in poorer prognosis in former, even under indistinguishable condition of deteriorated renal function and proteinuria.

     

Diagnostic Value of the Aminopeptidase N,N-Acetyl-β-D-Glucosaminidase and Dipeptidylpeptidase IV in Evaluating Tubular Dysfunction in Patients with Glomerulopathies

Aim. The aim of the present study was to investigate the value of the urine cell glycoprotein 1 (PC-1), aminopeptidase N (APN), N-acetyl-β-D-glucosaminidase (NAGA), and dipeptidylpeptidase IV (DPP IV) in the evaluation of tubular damage in patients with primary glomerulonephritis, diabetic nephropathy, and lupus nephritis. Subjects and Methods. PC-1, APN, NAGA, and DPP IV activities were determined in serum, urine, and lymphocytes of 178 subjects, including 10 patients with membranous nephropathy, 38 with IgA nephropathy, 29 with lupus nephritis, 51 with diabetic nephropathy, and 50 control subjects. Results. Urinary PC-1 excretion in IgA nephropathy group was significantly higher (p < 0.05) than in controls. Urinary NAGA excretion was markedly (p < 0.01) higher in membranous nephropathy group, and APN excretion in diabetic nephropathy group was significantly higher (p < 0.01) than in healthy controls. Urinary APN activity was significantly (p < 0.01) higher in both type 1 and type 2 diabetic patients with microalbuminuria, as well as urinary NAGA and DPP IV activities in type 2 diabetics with microalbuminuria (p < 0.01 and p < 0.05, respectively) compared to controls. Serum PC-1 and APN activities were significantly higher than the control level in membranous nephropathy group, as well as serum PC-1 and DPP IV activities in IgA nephropathy patients (p < 0.05). However, significantly lower serum DPP IV and APN activity was observed in type 2 diabetics with microalbuminuria compared to controls (p < 0.05). Conclusion. Damage of tubules in primary glomerulonephritis, lupus nephritis, and diabetic nephropathy is accompanied by a release of several tubular enzymes, with possible diagnostic and prognostic significance. Increased serum PC-1, APN, and DPP IV activities could be also of diagnostic significance.     

Serum and glomerular IgG in poststreptococcal glomerulonephritis are correlated

Among 75 patients hospitalized for poststreptococcal acute glomerulonephritis, 33 (44%) had an elevated serum level of IgG. The IgA level was elevated in 11 of 39 patients (28%). Paradoxically, of 20 biopsied patients with elevated IgG levels, IgG was absent from the glomerular deposits in 11, while of 23 with normal IgG levels, IgG was absent from the glomerular deposits in only 2 (P <0.001). Also, patients with an elevated level more frequently had antistreptolysin O titers ≥833 Todd units (P <0.001). Elevated IgG did not correlate with severity of disease, with age of the patient, or with the serum albumin or C3 level. There appears to be a subset of patients with elevated serum IgG levels who with high frequency have IgG absent from their glomerular deposits. Thus, failure to form antibody to a glomerular-bound protein produced by the nephritogenic streptococcus, widely assumed to be the origin of the IgG in the glomerular deposits, is in some way significantly associated with elevated serum levels of IgG and of antibody to streptolysin O. Received September 23, 1997; received in revised form October 23, 1997; accepted November 19, 1997     

Endothelin-1 and Endothelin A Receptor Immunoreactivity Is Increased in Patients with Diabetic Nephropathy

Background: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. Materials and methods: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. Results: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. Conclusion: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.     

Enhanced glomerular expression of caldesmon in IgA nephropathy and its suppression by glucocorticoid-heparin therapy

Background: Activation and consequent phenotypic modulation of mesangial cells is considered to play a crucial role in the process of glomerular disease progression. Caldesmon, a calmodulin and actin-binding protein, is a molecular marker of the phenotypic change in smooth muscle cells. Subjects and Methods: We studied whether the expression of caldesmon in mesangial cells was enhanced in the process of IgA nephropathy and whether it would be a marker of mesangial activation indicating prognostic significance in specific disease states. We performed immunohistochemical staining with anti-caldesmon and &agr;-smooth-muscle actin (&agr;-SMA) antibodies in 32 biopsy specimens from IgA nephropathy patients and analysed them quantitatively with a computer-aided manipulator. Results: The glomerular expression of caldesmon was enhanced in IgA nephropathy patients. We compared caldesmon expression with composite histological scores (cell score and matrix score), clinical parameters and expressions of &agr;-SMA. There was a statistically significant correlation between the caldesmon score and the histological scores (cell score and matrix score, P<0.001, P<0.01 respectively). Patients showing a high intensity of caldesmon expression (defined as caldesmon score ⩾35; H-group) had significantly higher urinary protein excretion than those showing a low intensity of caldesmon expression (defined as caldesmon score <35; L-group) 1.2±1.2 g/24 h vs 0.41±0.53 g/24 h, P<0.05). Caldesmon and &agr;-SMA expression had a statistically significant correlation (P<0.0001). Next, 13 patients were treated with glucocorticoid-heparin for 4-8 weeks and re-biopsies were performed. After the therapy, the caldesmon and &agr; SMA scores were significantly lower than those before the therapy (P<0.01). Discussion: These results suggest that the expression of caldesmon in glomeruli is associated with the progression of IgA nephropathy, and that glucocorticoid-heparin therapy may reverse the phenotype of mesangial cells during the disease process of glomerulonephritis.     

IgA Nephropathy Associated with Thin Basement Membrane with or without Inflammatory Disease: Getting a Different Prognosis?

Background. Thin basement membrane nephropathy (TBMN) patients with additional inflammatory diseases and IgA nephropathy (IgAN) have not been reported before. It was unclear that if the prognosis of these patients is better or worse than patients with IgAN and TBMN, or IgAN patients with normal glomerular basement membrane (GBM). Methods. We first reported five TBMN patients with additional inflammatory diseases and IgAN: three were with rheumatoid arthritis, and two had Crohn's disease. Clinical and laboratory features were analyzed between this group (group 3), IgAN patients with normal GBM (group 1), and patients with TBMN and IgAN (group 2). Results. Significant differences were observed in serum levels of IgG, IgA, and IgM between groups 1 and 3, p < 0.001, and between groups 2 and 3, p < 0.001. Glomerular filtration rate (GFR) in group 3 was significantly lower than that of groups 1 and 2, p < 0.01, respectively. Conclusion. The prognosis of these patients is worse than patients with IgAN and TBMN or IgAN patients with normal GBM. Serum immunoglobulin levels and GFR in these patients were different from patients with IgAN and TBMN, or IgAN patients with normal GBM.     

Central fibrous areas: changes in glomerular vascular pole lesions associated with age and disease

Purpose

Central fibrous areas (CFAs) are small, hyalinotic, monotonous nodular areas observed in glomerular vascular pole lesions. We attempted to clarify the relationship between CFA formation and age in healthy kidneys and in those affected by immunoglobulin A (IgA) nephropathy.

Methods

Zero-hour biopsy specimens from living renal donors (135 cases) and IgA nephropathy biopsy specimens (67 cases) were collected retrospectively. We observed each biopsy specimen and determined the total number of glomeruli, total level of glomerulosclerosis, number of observable glomerular vascular poles, number of glomeruli with CFAs, serum creatinine level, and estimated glomerular filtration rate (eGFR). Additionally, we calculated the glomerular sclerosis rate (GSR), vascular pole appearance rate (PAR), and CFA rate (CFAR) to evaluate the relationship between these factors and patient age.

Results

There was a significant negative correlation between patient age and eGFR for both the zero-hour (p?<?0.0001 in Spearman, p?=?0.0009 in multiple regression, the same hereafter) and IgA (p?=?0.0022, p?=?0.0001) groups. In the zero-hour group, we observed a significant positive correlation between patient age and GSR (p?=?0.0001, p?<?0.0001); however, there was no such correlation in the IgA group. In both groups, there was a significant positive correlation between patient age and CFAR (zero-hour group: p?=?0.0003, p?=?0.0091, IgA group; p?<?0.0001, p?=?0.0004). The slope of the regression line of the IgA group formula was also significantly higher than that of the zero-hour group formula (p?<?0.01).

Conclusion

These findings indicate that CFA may be a useful indicator of kidney aging, especially in patients with kidney disease caused by IgA nephropathy.

     

Differences in glomerular leukocyte infiltration between IgA nephropathy and membranoproliferative glomerulonephritis

Background: An important aspect in glomerular nephritic processes is the enhanced influx of leukocytes into the glomerulus. Methods: To investigate the mechanisms of intraglomerular leukocyte infiltration in IgA nephropathy (IgA-N) and membranoproliferative glomerulonephritis type I (MPGN-I), we immunohistochemically examined the intraglomerular expression of leukocyte function-associated antigen-1 (LFA-1, CD11a/CD18), macrophage-1 (Mac-1, CD11b/CD18) and intercellular adhesion molecule-1 (ICAM-1, CD54) together with glomerular deposition of C3c and fibrinogen. Results: In IgA-N (n=42), LFA-1⁺ cells were distributed mainly in glomeruli with intense expression of ICAM-1, and there was a positive correlation (P<0.001) between the number of LFA-1⁺ cells and the degree of ICAM-1 expression. Mac-1⁺ cells had no correlation with glomerular C3c deposition, but had a significant correlation with fibrinogen deposition (P<0.05). The number of LFA-1⁺ cells was significantly greater than of Mac-1⁺ cells (P<0.05). The number of LFA-1⁺ cells was strongly correlated with that of CD68⁺ cells (P<0.00001). In MPGN-I (n=43), on the contrary, Mac-1⁺ cells correlated only with C3c deposition (P<0.001), and they were observed mainly in peripheral loops of glomerular capillaries where C3c was deposited with a similar distribution. However, there was no relationship between LFA-1⁺ cells and ICAM-1 expression. The number of Mac-1⁺ cells was greater than that of LFA-1⁺ cells (P<0.0001), and most Mac-1⁺ cells were identical to CD15⁺ cells. Conclusion: These results indicate the possibility that different mechanisms may cause glomerular leukocyte infiltration in various forms of human glomerulonephritis. The LFA-1/ICCAM-1 pathway may play an important role in glomerular leukocyte infiltration in IgA-N, while the Mac-1/complement pathway may be important in MPGN-I. The former may promote mainly the infiltration of CD68⁺ cells, and the latter may promote that of CD15⁺ cells. In addition, Mac-1⁺ cells may act as fibrinogen and complement receptors in IgA-N and MPGN-I, respectively. Key words: adhesion molecules; complements; glomerular leukocytes infiltration; IgA nephropathy; membranoproliferative glomerulonephritis      

Pathogenetic and therapeutic approaches to IgA nephropathy using a spontaneous animal model,the ddY mouse

IgA nephropathy is the most common primary chronic glomerulonephritis in the world and was first described by Berger et al. (J Urol Nephrol 74:694–695;1968). Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. In advanced patients, global glomerular sclerosis, crescent formation and tubulo-interstitial fibrosis are marked in light microscopy. IgA nephropathy is generally considered to be an immune-complex mediated glomerulonephritis. Although more than 40 years have passed since this disease was firstly described, the pathogenesis/initiation factors of IgA nephropathy are still obscure. The objective of this review is to explain the pathogenesis and treatment based on our previous data of ddY mouse, a spontaneous animal model for IgA nephropathy.     

Para-capillary electron-dense deposits reduce glomerular filtration in patients with primary glomerular diseases

Background Electron-dense deposits are often found around glomerular capillary lumens in patients with glomerulonephritis, forming a portion of the blood-urine barrier (BUB). Methods Four hundred and four patients with primary glomerular diseases or donors for living-related kidney transplantation who underwent both percutaneous renal biopsy and renal clearance tests were included in the study. Sodium thiosulfate and paraamino hippurate double-clearance studies were performed with catheterized urinary collection. The filtration fraction (FF) was determined as follows: FF = sodium thiosulfate clearance/paraamino hippurate clearance (Cpah). Histomorphometric analyses were performed in 53 patients with overt para-capillary electron-dense deposits (PCEDD) by electron microscopic observations. Results Patients with membranous nephropathy and membranoproliferative glomerulonephritis showed significantly lower levels of FF than the donors for living-rebated kidney transplantation (normal controls). FF levels were significantly lower in patients with PCEDD than in those without (P < 0.001), while the levels of mean blood pressure and Cpah were comparable in the two groups. The PCEDD/BUB ratio demonstrated a significant negative correlation with FF (P < 0.0001; r² = 0.331). Patients with a ratio of 0.5 or more showed significantly lower FF levels than those with a ratio of 0.25 or less. Conclusions PCEDD significantly affected FF levels in patients with primary glomerular diseases. FF may not be an accurate indicator of intraglomerular blood pressure in patients with overt PCEDD.     

IgA nephropathy: lessons from an animal model, the ddY mouse

IgA nephropathy is the most common primary chronic glomerulonephritis, and was first described by J. Berger (Transplant Proc. 1969;1:939-944). Histopathologically, IgA nephropathy is characterized by expansion of glomerular mesangial matrix, with mesangial cell proliferation. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA, IgG and C3. Since pathogenesis of IgA nephropathy is still obscure, it is important to try to determine the initiation and progression of this disease using a suitable animal model. Several investigators, including Rifai's group (Rhode Island, USA) and Emancipator's group (Cleveland, Ohio, USA), reported various experimental animal models for this disease. In 1985, Imai et al first reported that the ddY strain of mouse can serve as a spontaneous animal model for IgA nephropathy. These mice show mild proteinuria without hematuria, and mesangioproliferative glomerulonephritis with severe glomerular IgA deposits in association with an increase of serum IgA level (Imai et al. Kidney Int. 1985;27:756-761). Electron-dense deposits are observed in the glomerular mesangial areas by electron microscopy. Furthermore, Muso's group succeeded in generating a mouse model of IgA nephropathy with a high incidence and early onset of glomerular IgA deposition (Miyawaki et al. Nephron. 1997;76:201-207). The selection procedure was successful in increasing the serum IgA level of the selected line. The selected ddY line (HIGA mice) showed only mild proteinuria (100-300 mg/dL) and did not show hematuria. These immunohistopathological findings in ddY mice resemble those in IgA nephropathy patients. The objectives of this review are to introduce the genetic background, Th1/Th2 polarization, expansion of extracellular matrices (ECMs) and treatment of IgA nephropathy of the ddY mouse. These findings from the ddY mouse appear to be useful in determining the pathogenesis and treatment of patients with IgA nephropathy.     

Association of IgA nephropathy with Clostridium difficile colitis

Immunoglobulin A (IgA) nephropathy, the most common cause of glomerulonephritis worldwide, is usually idiopathic in origin and renal limited. Secondary IgA nephropathy has been associated with systemic disease, including such gastrointestinal tract disturbances as celiac sprue and inflammatory bowel disease. We describe gross hematuria and reversible acute renal failure from IgA nephropathy in a patient with cephalosporin-induced Clostridium difficile colitis. In addition to mesangial IgA and C3 deposition, renal histological examination showed glomerular bleeding, intratubular red blood cell casts, and acute tubular necrosis. To the best of our knowledge, this is the first report of an association between IgA nephropathy and C difficile colitis.