Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort

Abstract

Background The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Extracapillary proliferation scoring correlates with renal outcome and contributes to stratification in adult patients with immunoglobulin A nephropathy

“…These findings from the Spanish population are in agreement with the last paper from the VALIGA study [ 21 ], which stated that extracapillary lesion was associated with worse renal function during follow-up, finding a worse prognosis in the group of patients without immunosuppressive treatment. The presence of mild-and-moderate IFTA (T1 and T2) was also an independent factor of loss of renal function at 5 years of follow-up.…”

“…The presence of mild-and-moderate IFTA (T1 and T2) was also an independent factor of loss of renal function at 5 years of follow-up. However, this is a rather severe cohort of IgAN patients given that 43% presented crescents compared with 10.5% in the VALIGA cohort [ 21 ].…”

“…The evaluation of the presence of cellular crescents in the renal biopsy is a procedure very dependent on the quality of the histological preparation and the experience of the renal pathologist. According to the study by Bellur et al [ 21 ], there is disagreement when classifying the histological lesions of the MEST terms among pathologists from different centres, especially with regard to the parameters of glomerular sclerosis and active extracapillary lesion. On the contrary, the presence of lesions M1, E1, C1 and S1 was associated with the decision to treat with steroids, resulting in better outcomes for the group of treated patients.…”

Clinical importance of the updated Oxford classification in allograft IgA nephropathy

“…Notably the E score, which is typically not a significant prognostic factor in native IgAN, was also associated with graft prognosis for the recurred patients. When applying the Oxford classification to allograft biopsies, clinical attention may be necessary regarding the E component, which was reported to be one of the parameters that respond to additional immunosuppression . Nonetheless, as a glomerular endocapillary lesion is a shared finding between the E score and antibody‐mediated rejection, careful interpretation would be required …”

Digital pathology and computational image analysis in nephropathology

“…As outlined below, standardization of pathology analytics requires consideration of three major components (Fig. 1 ): a pre-analytical phase, which includes the steps from tissue procurement to fixation, processing, cutting and drying time; an analytical phase, which includes a histology phase (involving stain selection, optimization and validation) and a digital phase (scanning, consideration of image and monitor resolution, number of colours, colour distribution, compression ratio and image format 63 ); and a post-analytical phase, which involves the analysis and interpretation of results, the recording and reporting of data, and pathologist and ML performance metrics 1 , 10 , 12 , 16 , 64 – 66 (Fig. 1 ).…”