Structural modeling for Oxford histological classifications of immunoglobulin A nephropathy

Abstract

In immunoglobulin A nephropathy (IgAN), Cox regression analysis can select independent prognostic variables for renal functional decline (RFD). However, the correlation of the selected histological variables with clinical and/or treatment variables is unknown, thereby making histology-based treatment decisions unreliable. We prospectively followed 946 Japanese patients with IgAN for a median of 66 mo. and applied structural equation modeling (SEM) to identify direct and indirect effects of histological variables on RFD as a regression line of estimated glomerular filtration rate (eGFR) via clinical variables including amount of proteinuria(UPE), eGFR, mean arterial pressure(MAP) at biopsy, and treatment variables such as steroid therapy with/without tonsillectomy(ST) and renin-angiotensin system blocker (RASB). Multi-layered correlations between the variables and RFD were identified by multivariate linear regression analysis and the model’s goodness of fit was confirmed. Only tubular atrophy/interstitial fibrosis (T) had an accelerative direct effect on RFD, while endocapillary hypercellularity (E) and active crescent (C) had an attenuating indirect effect via ST. S had an attenuating indirect effect via eGFR. M had accelerative indirect effect for RFD via UPE. Moreover, M and C had accelerative indirect effect via UPE, which can be controlled by ST. However, both T and S had additional indirect accelerative effects via eGFR0c or MAP, which cannot be controlled by ST. SEM identified a systemic path links between histological variables and RFD via dependent clinical and/or treatment variables. These findings lead to clinically applicable novel methodologies that can contribute to predict treatment outcomes using the Oxford classifications.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was supported in part by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan. This research was supported by AMED under Grant Number JP19ek0109261.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Not Applicable

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This clinical research project was produced by the ethical committee of The Research Group on Progressive Renal Diseases organized by the Ministry of Health, Labour and Welfare in Japan. The study protocol was in accordance with the standards of the ethics committee at each center, and each patient consented to participate after being informed of the purpose and procedure of the study. Patients with IgAN registered between April 2005 and August 2015 in the Japan IgA Nephropathy Prospective Cohort Study (JIGACS), which is a prospective observational study conducted at facilities throughout Japan, were included in the study. The protocol was approved by the Jikei University School of Medicine’s Institutional Review Board on Human Research, which acted as the main ethics committee for this study (No. 16-174 [4402])

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Data Availability

All relevant data are within the manuscript and its Supporting Information files.

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