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NDT Advance Access originally published online on August 25, 2006
Nephrology Dialysis Transplantation 2006 21(12):3466-3474; doi:10.1093/ndt/gfl455
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Histological differences in new-onset IgA nephropathy between children and adults

Yohei Ikezumi1, Toshiaki Suzuki1, Naofumi Imai2, Mitsuhiro Ueno2, Ichiei Narita2, Hiroshi Kawachi3, Fujio Shimizu3, David J. Nikolic-Paterson4,5 and Makoto Uchiyama1

1Department of Pediatrics, Niigata University Medical and Dental Hospital, 2Division of Clinical Nephrology and Rheumatology and 3Department of Cell Biology, Institute of Nephrology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan, 4Department of Nephrology and 5Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia

Correspondence and offprint requests to: Yohei Ikezumi, MD, PhD, Department of Pediatrics, Niigata University Medical and Dental Hospital, Asahimachi-dori, Niigata 951-8510, Japan. Email: ikezumi{at}med.niigata-u.ac.jp



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN.

Methods. Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 ± 3 years of age) and 38 adult (35 ± 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry.

Results. Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix.

Conclusions. This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.

Keywords: activated macrophage; childhood; glomerular hypercellularity; glomerular matrix; IgA nephropathy



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide, and in Japan [1,2]. Although all ages are affected, the disease most commonly affects people in their teens and twenties. In adult IgAN, 15–40% of the patients eventually progress to end-stage renal disease (ESRD) [1–7]. While early studies concluded that childhood IgAN was a benign disorder [8–10], more recent studies have reported only 70–80% renal survival at 20 years of age [11–14]. It is therefore evident that IgAN in childhood is not always benign, and the prognosis of paediatric IgAN is rather similar to that of adult IgAN. Thus, it is important to determine whether there are significant differences in renal pathology early in the course of adult vs childhood IgAN and whether such differences are associated with the severity of renal injury.

The most characteristic finding in IgAN by light microscopy is that of mesangial enlargement, caused by hypercellularity and/or an increase in matrix. However, mesangial enlargement in paediatric IgAN is mainly due to mesangial hypercellularity rather than an increase in matrix. Serial biopsy studies in paediatric IgAN have shown that mesangial hypercellularity is frequently present in the initial biopsy and that this usually disappears in follow-up biopsies. In contrast, studies have reported that mesangial matrix expansion is the predominant finding in adult IgAN [15,16]. These observations suggest that mesangial hypercellularity is characteristic of the early lesion in paediatric IgAN, while mesangial matrix expansion is a more chronic lesion and a feature of adult IgAN. However, a major limitation in the interpretation of such studies is that while it is relatively straightforward to study new onset IgAN in children (through the annual urine screening program in Japanese schools), it is very difficult to study new onset IgAN in adult. This is because the time of onset of renal abnormalities in adult IgAN is often uncertain and renal biopsies are usually delayed for several years after the first report of clinical symptoms. Thus, it has yet to be established whether adult onset IgAN may also begin with an initial phase of mesangial hypercellularity that subsequently progresses to mesangial matrix expansion.

A common feature of most types of glomerulonephritis, including IgAN, is the presence of macrophages and T cells within the glomerulus and/or interstitial compartments [17–20]. The intensity of the interstitial macrophage correlates with the degree of proteinuria and renal function at the time of biopsy; however, conflicting results have been obtained when correlating glomerular macrophages with these clinical parameters [18–20]. In addition, macrophage activation has been identified in paediatric IgAN on the basis of expression of MRP8/14 (S100A8/9) and sialoadhesin (Sn) [21,22]. Analysis of a group of different paediatric glomerular diseases, including IgAN, found that both glomerular and interstitial Sn+ macrophages correlated with the degree of proteinuria and histological damage [22]. However, the design of these 2 studies did not allow examination of whether activated macrophages correlate with proteinuria or renal function in IgAN.

The aim of this study was to compare findings in renal biopsies, in terms of histology and leucocyte infiltration, in recent onset IgAN in children and adults to determine whether the induction of disease is essentially similar in both patient groups, or if there is truly a different pathology in this early stage of the disease process. To achieve this, biopsy proven IgAN was examined in children and adults in whom renal abnormalities were first detected as part of a regular medical screening program.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
All patients in our hospital with a biopsy diagnosis of IgAN from 1998 to 2004 were reviewed. The same criteria were used in the decision to biopsy paediatric and adult patients: (i) continuous haematuria and proteinuria of ~0.5 g/day, or (ii) continuous macro-haematuria and proteinuria. An additional criterion for inclusion in the study was biopsy proven IgAN identified within 2 years of the first detection of urine abnormalities and no treatment during this period. Thirty-three children aged 5–15 years (10.7±3.1 years) and 38 adults aged 26–45 years (35.0±6.4 years) undergoing diagnostic renal biopsy at the Department of Pediatrics and Department of Medicine Niigata University Medical and Dental Hospital were examined. Patients gave informed consent for the use of renal biopsy tissue, in excess of that required for diagnostic purposes, to be used for research purposes. The diagnosis of IgAN was based upon the demonstration by direct immunofluorescence of IgA as the dominant or co-dominant immunoglobulin in a predominantly mesangial distribution and the lack of clinical or serological evidence for systemic lupus erythematosus, vasculitis or Henoch–Schönlein purpura.

Clinical parameters of the two groups are summarized in Table 1. All patients underwent the renal biopsy before commencing any treatment. Renal tissue from 5 paediatric patients (12.8±3.8 years old) with thin basement membrane disease (TBMD) or the uninvolved portion of adult renal carcinoma nephrectomies from 4 patients were used as minor abnormality tissue controls. Serum creatinine (sCr), creatinine clearance (CCr), haematuria and 24 h protein excretion were determined at the time of biopsy with assays performed by the Department of Biochemistry, Niigata University Medical and Dental Hospital. To evaluate the degree of haematuria, 10 ml of fresh urine was centrifuged at 350 g for 5 min and examined by microscope at high power field, and then scored between 0 and 4 according to the number of red blood cells in sediment as follows: 0 (0–5), 1 (6–20), 2 (21–50), 3 (51–100) and 4 (>100).


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  		Table 1. Comparison of clinical parameters

 
Quantification of histological damage in renal biopsies
For light microscopy, renal specimens were taken by standard needle biopsy methods, then fixed with Carnoy's solution, embedded in paraffin, and then 2 µm sections were stained with periodic acid-Schiff and periodic acid—methenamine silver. The specimens were reviewed and analysed by an independent anatomic pathologist who was blinded to both clinical data and the quantification of macrophage accumulation.

Sections were analysed for: glomerular cellularity, glomerular matrix expansion, the number of glomeruli with crescents (a layer more than 2 cells thick along Bowman's capsule) and/or adhesions (adhesion of glomerular tuft to parietal epithelial cells or directly to a denuded Bowman's capsule), and interstitial damage with fibrosis and/or tubular cell atrophy. The morphometric analysis was performed with a system composed of a microscope (Axioplan 2 imaiging, Carl Zeiss, Tokyo, Japan) attached to a colour CCD camera (AxioCam, Carl Zeiss) and a computer, using image analysis software SigmaScan Pro Ver. 5.0 (Systat Software Inc., Point Richmond, CA, USA). Imaging analysis consisted of the following steps: (i) capturing glomeruli on the PAS preparation at a magnification of 200x; (ii) tracing the outline of the glomerular tuft to obtain the total glomerular area; (iii) selecting the mesangial area automatically as colour thresholds of PAS positive area. Finally, the percentage area occupied by mesangial matrix was calculated from the ratio of the mesangial area to the glomerular area measured as earlier. The mean of glomerular mesangial matrix area in each specimen was regarded as representing the magnitude of mesangial matrix accumulation in each subject. The mesangial area including mesangial matrix and nuclei was also measured. The number of nuclei in the mesangial, endocapillary and extracapillary areas in each glomerulus was counted at the same time and expressed as mean number of glomerular nuclei per mm2. All cell counts were restricted to the glomerular tuft, with cells in crescents excluded. At least 12 (range 12–43, mean 19.5) glomeruli were examined in each patient and the average glomerular damage score calculated. Globally sclerosed glomeruli were not included in the analysis. The degree of interstitial damage was scored between 0 and 4 according to the area of the tubulointerstitium demonstrating fibrosis and/or tubular atrophy as follows: 0 (none), 1 (0–25%), 2 (25–50%), 3 (50–75%) and 4 (>75%). At least 12 consecutive high power fields were evaluated for each patient and expressed as mean ± SD.

Antibodies
Fluorescein isothiocyanate (FITC)-conjugated rabbit anti-human IgG, IgA, IgM, C3c, C4, C1q and fibrinogen sera (Dako Glostrup, Denmark) were used for routine immunofluorescence (IF) staining for determination of the diagnosis. Monoclonal antibodies used in this study were: HSn7D2, anti-human sialoadhesin (mouse IgG1; Serotec, Oxford, UK); Y1/82A, anti-CD68 labels human monocyte and macrophages (mouse IgG2b; BD Biosciences Pharmingen, San Diego, CA, USA); and Cris-7, anti-human CD3 labels human T lymphocytes (mouse IgG2a; Cymbus Biotechnology, Chandlers Ford, UK). Other antibodies used were: FITC-conjugated anti-mouse IgG1 (Southern Biotechnology Associates, Birmingham, AL, USA), FITC-conjugated anti-mouse IgG2a (Southern Biotechnology Associates); and tetramethyl-rhodamine isothiocyanate (TRITC)-conjugated goat anti-mouse IgG2b (Southern Biotechnology Associates).

Immunofluorescence
Tissue samples for immunofluorescence studies were snap-frozen in pre-cooled n-hexane and stored at –70°C. Glomerular deposition of IgG, IgA, IgM, C3c, C4, C1q and fibrinogen was assessed in 3 µm frozen sections by direct immunofluorescence. The intensity of immunofluorescence staining was evaluated on a semi-quantitative scale as follows: 0 (– negative), 1 (1+ positive), 2 (2+ strong positive without halation) and 3 (3+ strong positive with halation). Macrophages and T cells were detected by indirect immunofluorescence using monoclonal antibodies described above. The number of cells stained for CD68, Sn or CD3 antigens were counted in at least 12 glomeruli per patient. Interstitial cells stained for CD68, Sn or CD3 antigens were counted at least in 9 consecutive high-power fields (400x).

To examine whether Sn+ cells also expressed the CD68 antigen (a pan macrophage marker), two-colour immunofluorescence studies were performed on tissue sections using HSn7D2 (anti-Sn; mouse IgG1) and Y1/82A (anti-CD68; mouse IgG2b) as primary antibodies followed by incubation of sections with FITC-conjugated anti-mouse IgG1 and TRITC-conjugated goat anti-mouse IgG2b.

Statistical analyses
Comparisons were made between 2 groups by Mann–Whitney U-test (GraphPad 4.0, San Diego, CA) or Fisher's exact test. One-way ANOVA with POST-HOC analysis using the Tukey multiple comparison test was used for comparison of more than 3 groups. Correlation analysis for parametric data used the Pearson single correlation coefficient, while non-parametric data was analysed using the Spearman correlation coefficient. Data are shown as the mean ± 1 SD and P < 0.05 was considered to be significant.



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Comparison of clinical parameters
Most childhood cases of IgAN were detected via the annual urinary protein/haematuria screen in school children aged 6–15 years, while the other childhood cases were detected by chance urinary investigation. The children underwent renal biopsy about 1 year (1.1 ± 1.3 years) after detection of urine abnormalities (Table 1). Patients in adult IgAN group were selected from employees who have annual medical examinations at their workplaces, thus allowing detection of recent onset disease. All the adults also underwent renal biopsy about 1 year after detection of urine abnormalities (mean 0.76 ± 0.69 years), providing a comparable period between detection and biopsy in childhood and adult patients (Table 1). The last normal urinary examination was performed about 2 years before renal biopsy and there was no difference in the term between both groups. The degree of haematuria at the time of biopsy was more severe in paediatric IgAN compared to adult IgAN (Table 1). There was no difference in the degree of proteinuria between the two groups (Table 1). Only 1 paediatric and 4 adult IgAN patients had renal impairment at the time of biopsy. No paediatric patients presented with hypertension at biopsy or had a history of hypertension, while 5 patients in the adult group had hypertension at the time of biopsy and 2 patients had a history of hypertension although neither of them has received anti-hypertensive treatment until after the biopsy.

Renal histology
Prominent glomerular hypercellularity with mild matrix expansion was the most common finding in biopsies of early onset paediatric IgAN. In contrast, glomerular matrix expansion rather than hypercellularity was the most common finding in recent onset adult IgAN (Figure 1A and B). Quantification of these changes identified a significant increase in glomerular cellularity in paediatric vs adult IgAN, and conversely a significant increase in glomerular matrix in adult vs paediatric IgAN (Figure 2A and F). A more detailed assessment found that the number of cells in the mesangial area was significantly increased in paediatric IgAN, but not increased in adult IgAN (Figure 2B). There was no change in the number of endocapillary cells in either disease group; however, the number of extracapillary cells was significantly lower in adult IgAN group (Figure 2D). Furthermore, the number of glomeruli showing extracapillary changes (adhesions and/or crescents) and the degree of interstitial damage was significantly greater in adult vs paediatric IgAN (Figure 2G and H).


Figure 1
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  		Fig. 1. Representative light microscopic findings in glomeruli from (A) paediatric IgAN and (B) adult IgAN. There is significant mesangial cell proliferation and matrix expansion in both paediatric and adult IgAN. However, glomerular hypercellularity is the prominent finding in paediatric IgAN, whereas glomerular matrix expansion is the prominent finding in adult IgAN. Dual immunofluorescence staining in a case of paediatric IgAN is photographed to show (C) CD68+ cells (total macrophages) and (D) Sialoadhesin (Sn)-positive cells (activated macrophages) in the same section. Both glomerular and interstitial Sn+ activated macrophages can be seen.

 

Figure 2
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  		Fig. 2. Comparison of histological findings in paediatric and adult IgAN in terms of: (A) glomerular cellularity—total nuclei within the glomerular tuft, (B) cells in the mesangial area, (C) cells in the endocapillary area, (D) cells in the extracapillary area, (E) glomerular mesangial expansion (mesangial matrix plus cell nuclei), (F) glomerular mesangial expansion (matrix without nuclei), (G) extracapillary changes, and (H) degree of interstitial damage. Paediatric patients with thin basement membrane disease (TBMD; n = 5) and the normal portion from nephrectomy tissue taken from adult patients with renal tumor (n = 4) were used as the normal control. Analysis was performed by one-way ANOVA with post-hoc analysis with Tukey Multiple Comparison test (A–F) or by the Mann–Whitney U-test (G and H).

 
In paediatric IgAN, 41% of crescents were entirely cellular, while 59% of crescents showed some degree of fibrous organization. In contrast, only 16% of crescents in adult IgAN were cellular and 84% of crescents showed varying degrees of fibrous organization.

IF staining revealed that the degree of glomerular deposition of C3c and the frequency of patients positive for glomerular IgM were significantly higher in paediatric IgAN, whereas the degree of glomerular deposition of fibrinogen was higher in adult IgAN (Table 2). There was no difference in the degree of IgA, IgM or C1q deposition (Table 2), while no deposition of C4 was detected in any patient.


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  		Table 2. Immunofluorescence findings

 
Correlation between renal histology and clinical parameters
Glomerular hypercellularity is a prominent feature of paediatric IgAN and correlated with proteinuria, but not with renal function, in this group (Table 3). Furthermore, the number of cells in the mesangial area also correlated with proteinuria. In adult IgAN, glomerular hypercellularity and mesangial cellularity failed to correlate with proteinuria or renal function. However, glomerular matrix expansion—the prominent feature in adult IgAN—correlated with both proteinuria and renal function in this patient group (Table 3). Interstitial damage correlated with proteinuria and renal function in both groups, whereas extra-capillary changes correlated with proteinuria (but not renal function) in both IgAN groups. In addition, the degree of haematuria in paediatric IgAN correlated with extracapillary changes and interstitial damage (Table 3).


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  		Table 3. Correlation between histological findings and clinical data

 
Glomerular and interstitial inflammatory cells
A significant infiltrate of glomerular and interstitial CD68+ macrophages and CD3+ T cells was evident in both paediatric and adult IgAN (Figure 3). In addition, cells expressing the macrophage activation marker, Sn, were seen in both patient groups. Confirmation that Sn+ cells are a subset of the macrophage population was demonstrated by two-colour immunofluorescence staining (Figure 1C and D). Quantification of immunostaining showed the presence of a significantly greater number of all of the leukocyte populations in the glomerulus and the interstitium in adult vs paediatric IgAN, except for glomerular CD3+ T cells (Figure 3).


Figure 3
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  		Fig. 3. Comparison of immunostaining for leukocytes in paediatric and adult IgAN in terms of glomerular (A, C, E) and interstitial (B, D, F) staining of CD68+ total macrophages (A, B), Sn+ activated macrophages (C, D) and CD3+ T cells (E, F). Analysis was performed by one-way ANOVA with post-hoc analysis with Tukey Multiple Comparison test.

 
Correlation of leucocyte populations with clinical parameters and renal histology
Glomerular and interstitial infiltration of macrophages and T cells correlated with proteinuria in both paediatric and adult IgAN (Table 4). Interstitial but not glomerular leucocytes correlated with haematuria in paediatric IgAN (Table 4). Leucocytes did not correlate with renal function in paediatric IgAN, whereas a significant correlation was seen for interstitial leucocytes and glomerular Sn+ macrophages in adult IgAN (Table 4).


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  		Table 4. Correlation of leucocyte accumulation with clinical data and hisotological findings

 
Glomerular hypercellularity and mesangial hypercellularity, the prominent features of paediatric IgAN, correlated with glomerular macrophages and T cells in this patient group, but not in adult IgAN (Table 4). In contrast, glomerular matrix correlated with glomerular Sn+ macrophages only. Glomerular adhesions and crescents correlated with glomerular macrophages and the Sn+ macrophage subset in both IgAN groups. A highly significant correlation between interstitial leucocytes and interstitial damage was evident in both patient groups (Table 4).



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
This study has identified significant differences in the glomerular lesions seen in early onset IgAN in paediatric vs adult patients. Recent onset childhood IgAN exhibited prominent mesangial hypercellularity, whereas the onset of IgAN in adults featured prominent glomerular matrix expansion. The unique aspect of this study is the use of verifiable early onset IgAN biopsies in both paediatric and adult groups. This enables the conclusion to be drawn that there are distinct differences in the initial glomerular lesions in these two patient groups. These findings argue strongly against glomerular hypercellularity, particularly mesangial cell proliferation, being prominent in the initiation of adult IgAN which then converts to a pathology featuring marked glomerular matrix expansion. To further support this contention, mesangial proliferation correlated with proteinuria in paediatric, but not early onset adult, IgAN. In a similar vein, glomerular matrix correlated with proteinuria in adult, but not early onset paediatric IgAN. Although the individual cell types within the mesangial area were not identified, it can be inferred—because leucocytes were more numerous in adult vs paediatric IgAN and yet adult IgAN showed no significant increase in mesangial cellularity—that the significant mesangial hypercellularity seen in paediatric IgAN was largely due to increased numbers of mesangial cells.

While it is clear that there are distinct morphological changes in early onset paediatric and adult IgAN, the mechanism(s) causing this difference are not clear. One possibility is that the more intense fibrinogen deposition seen in adult IgAN acts to promote glomerular matrix expansion in these patients, although it is less clear whether the difference in C3c deposition may play a role in the development of these distinct pathologies [23]. Another possibility is that vascular hypertension or the leucocyte infiltrate present at the time of biopsy may affect the disease severity and pathological findings.

Significant glomerular infiltration by macrophages and T cells was detected in both paediatric and adult IgAN and this was found to correlate with the degree of proteinuria in both groups. A more impressive association was seen with interstitial macrophages and T cells which gave a highly significant correlation with the degree of proteinuria, renal function (in adult IgAN), and interstitial damage. These findings are consistent with previous studies in which interstitial macrophage and T cell infiltrates have been described in IgAN and shown to correlate with proteinuria and renal function, whereas detection of glomerular macrophage and T cell infiltrates and their relationship to clinical parameters has varied widely [17–22].

Function-based evidence that macrophages mediate renal injury has come from animal studies of glomerular diseases, in particular anti-GBM glomerulonephritis with little data available for models of IgAN [24]. Adoptive transfer studies have demonstrated that macrophages induce proteinuria and mesangial cell proliferation in acute rat anti-GBM glomerulonephritis [25], while macrophage depletion in established anti-GBM disease can suppress crescent formation and disease progression [26,27]. Activation of macrophages is a key step in the mediation of renal injury. Recent adoptive transfer studies in rat anti-GBM glomerulonephritis have shown that activation of macrophages by interferon-{gamma} enhances renal injury, while inhibition of macrophage activation via dexamethasone or blockade of the JNK or NF-{kappa}B signalling pathways results in suppression of macrophage-mediated renal injury [28,29].

We previously examined macrophage activation in a group of childhood proliferative glomerular diseases [22]. Macrophage activation was assessed by expression of Sn, a cell-surface receptor induced exclusively in macrophages in response to stimuli such as pro-inflammatory cytokines [30,31]. Sn+ activated macrophages were identified in both glomeruli and the interstitium in IgAN patients, but the group size was too small to compare this to clinical or histological parameters. In the current study, activated Sn+ macrophages were not found in normal human kidney or in paediatric thin membrane disease. However, significant numbers of Sn+ macrophages were seen in the glomerulus and interstitial in recent onset paediatric and adult IgAN. Since Sn is absent from blood monocytes, the expression of Sn in the kidney demonstrates that activation of the macrophage population occurs locally within the renal environment during early onset IgAN. Analysis of Sn+ cells in the glomerulus identified significant correlations with renal function and glomerular matrix that were not evident when analysing the total macrophage infiltrate. Furthermore, Sn+ macrophages—but not total CD68+ macrophages—correlated with glomerular matrix and renal function in adult, but not paediatric, IgAN. These results suggest that: (i) local activation of macrophages within the kidney contributes to the development of renal injury in early onset IgAN and (ii) the larger number of Sn+ activated macrophages seen in early onset adult IgAN may contribute to the characteristic glomerular matrix expansion seen in these patients.

There are a number of mechanisms by which glomerular macrophages may contribute to glomerular damage in early onset IgAN. Adoptive transfer studies in rat anti-GBM disease have clearly demonstrated that macrophages can induce mesangial cell proliferation and this may operate via macrophage production of mesangial cell mitogens PDGF-B and IL-1 [25,32]. Indeed, a study of paediatric IgAN found that glomerular macrophage recruitment correlated with mesangial expression of {alpha}-smooth muscle actin—a feature of mesangial cell proliferation that is associated with disease progression [33]. Another mechanism by which macrophages may contribute to glomerular lesions is through production of TGF-ß1, which stimulates glomerular matrix expansion [34]. Finally, Sn+ macrophages are known to be important in antigen presentation to T cells [35], and therefore may promote T cell-mediated renal injury.

Therapeutic options for IgAN that are applicable to all cases include symptomatic treatment and strategies to delay progression. However, immunosuppression is considered appropriate for selected cases only. Current immunosuppressive therapies for human glomerulonephritis are not uniformly effective in IgAN and are frequently associated with serious side effects. Immunosuppressive therapies are considered in cases of IgAN with persisted proteinuria [36]. Although no specific studies have addressed the role of steroids in IgAN, the results in the current study suggest that therapies targeting the initial accumulation of inflammatory cells—particularly activated macrophages—may prevent progression of histological damage.

In conclusion, this study has provided evidence that early onset adult IgAN follows a different pathological course to that seen in children. This difference in pathology is associated with differences in leucocyte infiltration and macrophage activation which are likely to play important roles in the pathogenesis of these 2 disease entities.



   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
This work was supported by Grant-Aids for Scientific Research (16790569 to Y.I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 9. 2.06
Accepted in revised form: 3. 7.06


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M. Haas, M. H. Rahman, R. A. Cohn, S. Fathallah-Shaykh, A. Ansari, and S. M. Bartosh
IgA Nephropathy in children and adults: comparison of histologic features and clinical outcomes
Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2537 - 2545.
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