Differences of Histological Classification Between the Japanese Histological Grade Classification and the Oxford Classification

An international committee of pathologists and nephrologists from four continents were first convened in 2004 for the purpose of developing a new, evidence-based, international consensus histologic classification for IgAN. The 265 cases were assembled including biopsies from 206 adults and 59 children and were from 17 different centers based in eight countries and four continents.

The following rigorous procedure was taken to develop the evidence-based classification (Fig. 5.1). First, the histological parameters which are necessary to take in the lesions of IgAN were discussed and determined. Using these selected lesions, a score sheet was produced to quantify these selected histological parameters consisting of glomerular, tubulointerstitial, and vascular lesions. Second, on the basis of data-using score sheets, reproducibility was tested by the Intraclass Correlation Coefficient (ICC), and the parameters with poor reproducibility were excluded for further analysis. Third, the histological parameters with reasonable reproducibility were assessed by linear regression analysis and Cox regression analysis to determine if they were independent predictors for the renal functional outcome for a minimum of 3 years and/or until an end point of end-stage renal disease (ESRD) or ≥50 % decline in estimated glomerular filtration rate (eGFR).

As a consequence, three histologic parameters were selected as independent predictors within this classification (M: mesangial hypercellularity, S: segmental sclerosis, and T: tubular atrophy/interstitial fibrosis (TA/IF)). One additional histologic parameter—endocapillary hypercellularity (E) in >= 1 glomerulus—was not significantly correlated with the above outcomes by multivariate analysis but was strongly correlated with response to immunosuppressive therapy and hence this additional parameter was included in the classification. Finally, in order to dichotomize each of the selected parameters to produce a split classification system, cutoff points were determined by ROC (Receiver Operating Characteristic) analysis. Thus, the recommendation of the classification with IgAN includes four independently reported histologic parameters (M, E, S, and T): M0 or M1, indicating mesangial hypercellularity in ≤50 % versus >50 % of glomeruli; E0 or E1, indicating endocapillary hypercellularity in 0 versus ≥1 glomeruli; S0 or S1, indicating segmental sclerosis in 0 versus ≥1 glomeruli; and T0, T1, or T2, indicating TA/IF in ≤25 %, 26–50 %, or >50 % of renal cortex, respectively. They produced a four-parameter dichotomous scoring system to describe IgAN lesions.

The Oxford Histologic Classification has gained a significant level of worldwide acceptance and has been the subject of several single-center or multicenter validation studies. Validating the classification in a diverse range of cohorts treated in different ways is important to confirm that the classification can be widely applied. Among validation studies, the selected independent predictors for renal functional outcome by multivariate analysis were M, S, and T [8] in one, M and S in one, 2 [9], S and T in two [10–12], M and T in two [13, 14], E and T in one, [15], only T in three, [16–18], only CT in one [11], and none in one study [19], respectively (Fig. 5.2).

As mentioned in the introduction, within Japan, an alternate classification system has been developed. This came from the work of the IgAN Study Group of the Progressive Renal Diseases Study Committee under the auspices of the Ministry of Health, Labor and Welfare. A multicenter case-control study on IgAN was conducted to develop an evidence-based clinicopathological classification for predicting long-term renal outcome.

This working group consisted of 16 centers. The cohort was drawn from patients seen in Japanese hospitals. Lesions were assessed independently by two pathologists, and if they did not agree, lesions were reviewed by both pathologists until a consensus was reached. The initial panel of histological parameters examined was very similar to that of the Oxford classification. During a median follow-up of 9.3 years after biopsy, 49 out of 287 patients (19 %) progressed to ESRD. The associations between pathological variables and the need for chronic dialysis were examined by multivariate logistic regression analysis separately in patients who required dialysis earlier than 5 years (early progressors) and those who required dialysis within 5–10 years (late progressors) after biopsy. Independent pathological variables predicting progression to ESRD were global sclerosis, segmental sclerosis, and fibrous crescents for early progressors and global sclerosis and cellular/fibrocellular crescents for late progressors (Fig. 5.3). Four histological grades (HGs), such as HG 1, HG 2, HG 3, and HG 4, were established corresponding to <25 %, 25–49 %, 50–74 %, and ≥75 % of glomeruli, exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis, or fibrous crescents. Eleven (7 %) patients in HG 1, 12 (16 %) in HG 2, 13 (31 %) in HG 3, and 13 (68 %) in HG 4 progressed to ESRD. Multivariate logistic analysis revealed that the risk of progression to ESRD was significantly higher in HG 2, 3, and 4 than in HG 1 (odds ratio, 2.4, 5.7, and 27.6 vs. 1.0). Age, mean arterial pressure, and urinary protein excretion were higher, while eGFR was lower in higher grades, suggesting that our histological grading agrees with the prognostic clinical features of IgAN at the time of diagnosis. The risk of progression to ESRD and the rate of GFR decline were significantly greater in higher grades, indicating that the grading can identify the magnitude of the risk of progression to ESRD as well as the deterioration rate of renal function [7]. In addition to the grading system, this classification allowed for active (A) chronic lesions (C) and mixed (A/C) to be produced as a subgroup of each grade which allows identification of a balance between activity and chronicity.

Compared to the Oxford classification scheme, a limited number of validation studies have been conducted, and these have been confined to Japanese cohorts. Sato et al. validated the JHGC in a Japanese single-center cohort [20]. This was a retrospective study in 198 Japanese adult patients with IgAN. Clinical parameters including blood pressure, urinary protein, eGFR, and outcomes were evaluated in these patients. The glomerular lesion percentage score (GLPS) [number of glomeruli with cellular crescents, fibrocellular crescents, global sclerosis, segmental sclerosis, or fibrous crescents per number of total obtained glomeruli] was assessed in each patient and categorized into histologic grades of HG1 (<25 %), HG2 (25–49 %), and HG3/4 (≥50 %). Associations of GLPS (or HG) with disease progression (50 % eGFR decline or ESRD-requiring dialysis) within 10 years after biopsy and the rate of annual eGFR decline were examined. During a median follow-up period of 12.0 years after biopsy, disease progression occurred in 12.8 % (12/94) of HG1 patients, 32.3 % (21/65) of HG2 patients, and 46.2 % (18/39) of HG3/4 patients. The risk of disease progression was significantly higher in the HG2 and HG3/4 groups than in the HG1 group (odds ratios: 3.3 and 5.9 vs.1). A higher GLPS was significantly associated with a higher risk of disease progression and a greater annual eGFR decline. JHGC based on GLPS (or HG) was well correlated with long-term prognosis in the cohort of Japanese adult patients with IgAN [20].