Introduction
Immunoglobulin A nephropathy (IgAN) is the most prevalent form of primary chronic glomerulonephritis; 20–40% of IgAN patients progress to end-stage renal disease (ESRD) within 20 years from its onset [
1,
2]. Numerous studies have identified histological and clinical prognostic parameters. Most previous studies have reported that the histological grade, severe proteinuria, and a reduced renal function were strong predictors of progression. Some studies have suggested that hypertension, age, and gender were also prognostic factors. Histological classification for evaluating the disease severity and deciding therapeutic strategies is essential in the clinical management of IgAN [
3‐
5]. Recently, an international working group created the Oxford classification of IgAN [
6]. The Oxford classification, which was consensus-based, defined pathologic lesions with acceptable interobserver reproducibility and identified four prognostic pathologic features based on a rigorous statistical analysis (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis). However, the results of the validation studies remain controversial [
5], and most recently, a multicenter study proposed addition of crescents scores to the original Oxford/MEST classification [
7].
In our country, IgAN is often diagnosed in patients with a relatively early stage of the disease who show asymptomatic proteinuria with microhematuria or isolated microhematuria. In
the Clinical Practice Guidelines for IgA Nephropathy, treatments with renin–angiotensin system (RAS) inhibitors or corticosteroids were recommended to patients with sustained proteinuria of > 0.5 g/day [
8,
9]. Severe proteinuria (≥ 1 g/day) at the time of renal biopsy (RBx) is a well-known prognostic factor of IgAN [
10,
11]. On the other hand, in the Oxford cohort, patients had severe proteinuria (mean, 1.7 g/day) and the majority of patients were white race [
6]. The Special IgAN Study Group of the Progressive Renal Diseases (IgAN-SG) developed an evidence-based histological classification of IgAN that was suitable for predicting long-term renal outcome of IgAN in Japan, because the optimal threshold values and classifications could differ according to the patient background and the outcome definitions in different cohorts [
12]. This Japanese histological classification system demonstrated that pathological lesions that independently predicted the progression to ESRD were global sclerosis, segmental sclerosis, and fibrous crescents in IgAN patients who required dialysis within < 5 years after biopsy (early progressors) and cellular/fibrocellular crescents for those who required dialysis at 5–10 years after biopsy (late progressors). The classification included four histological grades, which identified the magnitude of the risk of progression to ESRD. This classification was validated by Sato et al. and was well-correlated with the long-term prognosis in their cohorts [
13]. In our previous study, however, 11 patients with a histological grade (HG) I, which indicates the lowest risk of progression to ESRD (percentage of glomeruli exhibiting cellular/fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents vs. total glomeruli < 25%) developed ESRD over the long-term follow-up period [
12]. The fact that these HG I progressed to ESRD indicated that there are limitations in predicting the prognosis of IgAN based on the histological variables at the initial diagnosis alone, and suggested the need to create better prognostic models.
To create better prognostic models, the special IgAN-SG at first established a predictive grading system for assessing the clinical severity based on the clinical variables associated with progression to ESRD. Furthermore, we defined a prognostic model for predicting the risk of dialysis induction by combining the grade of clinical severity with the histological grading system, and reported the prognostic model in clinical guides for IgAN [
9]. The essence of the model was referred by
the Clinical Practice Guidelines for IgA Nephropathy [
8]. However, details of the process of constructing the grading system have not been published yet. Therefore, in this special report, we described the process of constructing these grading systems, including the details of the statistical analyses.
The present special report provided the process of constructing the grading system for the risk of dialysis by combining the grade of clinical severity with the histological grading system [
12]. To the best of our knowledge, no grading system for IgAN has included both the clinical and histological grades (Table
5).
So far, several representative histological grading systems have been reported; however, there are some differences in included histological lesions among these reports (Table
8). Haas et al. [
15], Manno et al. [
16], and the Oxford classification in 2009 [
6] evaluated glomerular and tubulo-interstitial lesions. Likewise, recently reported the Oxford classification in 2016 [
7,
17] also evaluated glomeruar and tubulo-interstitial lesions. Katafuchi et. al. examined glomerular, tubulo-interstitial, and vascular lesions; then, they concluded that glomerular score more closely related to renal outcome than those according to total score including glomerular, tubulo-interstitial, and vascular lesions [
18]. On the other hand, Lee et al. constructed the refined HS Lee grading system focusing simply on glomerular lesions [
19], like as our histological classification system [
12]. As the reasons for constructing histological grading system using only glomerular lesions, Kawamura et al. discussed that global sclerosis had a high statistically significant association with interstitial fibrosis, and global sclerosis showed outstanding reproducibility in the Oxford classification [
12].
Table 8
Comparison of included histological lesions among histological grading systems
| × | × | × | × | × | × | |
| × | × | × | × | × | × | |
Oxford classification 2009 [ 6] | × | × | | × | | × | |
Oxford classification 2016 [ 7, 17] | × | × | | × | × | × | |
| × | | × | × | × | × | × |
| × | | × | × | × | | |
| | | × | × | × | | |
Interestingly, when the patients in HG I, which showed the best prognosis among the four HGs, were classified into three classes according to the three CGs, the ORs for the risk of progression to ESRD increased as the CG advanced (ORs of [HG I − CG I], [HG I − CG II] and [HG I − CG III] were 1 (Reference), 8.7 and 47.3, respectively.). Likewise, when the patients in HG III + HG IV, whose histological classification was associated with a poor prognosis [
12], were classified into three classes according to their CGs, the ORs increased as the CG advanced (ORs of [(HG III + HG IV) − CG I], [(HG III + HG IV) − CG II] and [(HG III + HG IV) − CG III] were 17.8, 14.2, and 130, respectively.). These results suggest that the combination of the CG and HG improved the accuracy in predicting the progression to ESRD, in comparison with either grade alone, in patients with IgAN. Furthermore, we defined four dialysis induction risk groups by grouping nine compartments into four groups based on the magnitude of ORs (Table
5). The logistic regression analysis revealed that the ORs for the risk of progression to ESRD significantly and progressively increased from the low-risk group to the super-high-risk group (Table
6). Of note, the patients in the super-high-risk group received various kinds of treatments, including corticosteroids (Table
7), suggesting that the extremely high OR of the super-high-risk group was not due to insufficient treatment.
Numerous studies have reported on the clinical and histological prognostic factors at the diagnosis of IgAN [
2‐
6,
12,
15‐
19]. Most of these previous studies reported that severe proteinuria, a reduced renal function, and histological grading predicted disease progression, while some studies suggested that hypertension at RBx, severe hematuria, age, and gender were also prognostic factors. In our cohort, the multivariate logistic analysis revealed that proteinuria and the eGFR were significant independent variables, whereas hypertension, severe hematuria, age, and gender were not independently associated with progression to ESRD.
Prior to this analysis, several studies have used ROC analyses to investigate combinations of prognostic variables that could improve the accuracy in predicting future disease progression. In the Nord-Trondelag Health Study, a CKD classification that combined albuminuria and the eGFR improved prediction of ESRD [
20]. Furthermore, in IgAN patients, the combination of proteinuria and the eGFR improved the accuracy in predicting the development of ESRD in comparison with either factor alone [
14]. Thus, it is suggested that the inclusion of both proteinuria and the eGFR in the prediction model of the present analysis may help to improve the accuracy in predicting the risk of future ESRD in IgAN patients.
The optimal threshold values and classification may differ according to the patient background and the definition of the outcome. We selected our threshold values based on the following reasons. First, Imai et al. reported that Japanese IgAN patients are often diagnosed at a relatively early stage when they show asymptomatic proteinuria with microhematuria or isolated microhematuria, which can be found in the annual urinary screening system (kenshin), and many Japanese nephrologists believe that IgAN patients with early stage or mild proteinuria respond readily to treatment with RAS inhibitors or corticosteroids, while those with severe proteinuria (> 1.0 g/day) and a reduced creatinine clearance < 70 ml/min are often resistant to these treatments [
21]. In addition, they also hypothesized that a therapeutic ‘golden period’ may exist when patients have moderate proteinuria < 1.0 g/day [
21]. Furthermore, some IgAN patients with even mild proteinuria (< 0.4 g/day) or early stage IgAN showed a progressive course [
22,
23]. Thus, we regarded sustained proteinuria at > 0.5 g/day as the level at which treatment should be initiated. Second, CKD is defined based on a GFR of 60 ml/min/1.73 m
2, and various clinical events are associated with a GFR of < 60 ml/min/1.73 m
2 for a period > 3 months—even in the absence of known structural alterations [
24]. Third, the combination of the threshold values of UPE 0.5 g/day and eGFR 60 ml/min/1.73 m
2 produced a suitable prognostic-predictive equation [threshold score (= -1.86) = 0.722 + 0.364 x UPE − 0.046 × eGFR] [
14]. Thus, we selected UPE 0.5 g/day and eGFR 60 ml/min/1.73 m
2 as the threshold values in the present analysis. Although these threshold values might not have been statistically optimal for the cohort of the present analysis, by dividing patients into three clinical grades using these values, the ORs for the risk of progression to ESRD were found to increase significantly from CG I to CG III (Table
4).
The
KDIGO 2012 Clinical Practice Guidelines, which are accepted worldwide, reported the prognostic classification of CKD [
24]. The classification consisted of 3 parameters (the cause of CKD, the category of GFR, and the category of albuminuria), and a GFR–albuminuria grid reflected the risk of CKD progression. Although the classification clearly showed that the risk of CKD progression increased with an advancement in the GFR and/or albuminuria categories, this classification system consisted of clinical parameters alone. In addition to the clinical prognostic parameters, various histological parameters are correlated with the renal prognosis in IgAN patients. However, the previous studies by us [
12] and others [
1] showed that nearly 10% of IgAN patients with the lowest histological grade or minor glomerular lesions progressed to ESRD. The discrepancies between the minor glomerular injury and progression to ESRD suggested that evaluating the prognosis of IgAN based on histological parameters alone is associated with some limitations. This led us to create better prognostic models that combined predictive clinical variables with the histological grades. Aside from our analysis, Barbour et al. recently reported that the risk prediction in IgAN could be significantly improved by adding the histological severity (Oxford MEST) to the clinical data (proteinuria) at RBx [
25], suggesting the validity of our strategy.
The present analysis is associated with several limitations. First, the present analysis evaluated prognostic clinical and histological parameters at RBx and constructed the grading system. However, we could not fully clarify the effects of each therapy on the renal outcome because of the limited sample size and design of a retrospective case–control study. Second, because the clinical data were only available at the time of RBx, and at the end of the follow-up period, the assessments of the clinical course were limited. Thus, a further long-term prospective study with a large sample size will be necessary to assess the therapeutic effects on the renal outcome, the validity and reliability of the present grading system in IgAN.
In summary, the combination of the clinical grade and the histological grade improved the accuracy with which the risk of progression to ESRD could be predicted in IgAN patients in comparison with the clinical grade or the histological grade alone. The results suggest that our grading system for predicting the long-term prognosis of IgAN may be useful for the management of individual patients with IgAN.
Acknowledgements
This analysis was supported in part by a Grant-in-Aid for Progressive Renal Diseases Research, from the Ministry of Health, Labour and Welfare of Japan. The multicenter retrospective case–control study was conducted in collaboration with the following 16 hospitals. Fukuoka University Hospital, Japanese Red Cross Fukuoka Hospital, Jikei University Hospital, Jikei University Katsushika Medical Center (Formally Jikei University Aoto Hospital), Jikei University Daisan Hospital, Jikei University Kashiwa Hospital, Juntendo University Hospital, Kanazawa Medical Center, Keio University Hospital, Nagasaki University Hospital, Saitama Medical Center, Showa University Hospital, St. Marianna University Hospital, Tokai University Hospital, Tokyo Women’s Medical University Hospital (Internal Medicine), Tokyo Women’s Medical University Hospital (Pediatrics).