Clinicopathological prognostic stratification for proteinuria and kidney survival in IgA nephropathy: a Japanese prospective cohort study

Abstract

Background: We require a clinicopathological risk stratification method for immunoglobulin A nephropathy (IgAN) to predict kidney outcomes. We examined a renal failure risk group (RF-RG) classification system created following a prior multicentre, retrospective study to determine if RF-RG could predict kidney outcomes.

Methods: We collected data from Japanese patients with IgAN registered between 1 April 2005 and 31 August 2015. The primary outcome was a composite 50% increase in serum creatinine from baseline or dialysis induction. The secondary outcomes were times to proteinuria remission (ProR) and haematuria remission (HemR).

Results: The enrolled 991 patients from 44 facilities were followed for a median of 5.5 years (interquartile range 2.5-7.5), during which 87 composite events (8.8%) occurred. RF-RG was significantly associated with the primary outcome {hazard ratio [HR] II 2.78 [95% confidence interval (CI) 1.12-6.93], III 7.15 (2.90-17.6), IV 33.4 (14.1-79.0), I as a reference, P < .001}.The discrimination performance was good [C-statistic 0.81 (95% CI 0.76-0.86)] and the time-dependent C-statistics exceeded 0.8 over 10 years. Among the 764 patients with proteinuria and 879 patients with haematuria at baseline, 515 and 645 patients showed ProR and HemR, respectively. ProR was significantly less frequent in patients with advanced disease [subdistribution HR: II 0.79 (95% CI 0.67-0.94), III 0.53 (0.41-0.66), IV 0.15 (0.09-0.23), I as a reference, P < .001]. We also observed an association between HemR and RF-RG.

Conclusions: RF-RG demonstrated good predictive ability for kidney outcomes.

Keywords: IgA nephropathy; clinicopathological grading; haematuria; kidney prognosis; proteinuria.

Graphical Abstract

Figure 1:

Chart of the ESKD risk group produced by combining clinical and histological grades. This chart was modified from our previous studies [15, 16]. CG I, II and III consisted of those patients with proteinuria <0.5 g/day, those with proteinuria ≥0.5 g/day and eGFR ≥60 ml/min/1.73 m² and those with proteinuria ≥0.5 g/day and eGFR <60 ml/min/1.73 m², respectively. HG I, II, III and IV were established corresponding to <25%, 25–<50%, 50–<75% and 75–100% of glomeruli exhibiting cellular or fibrocellular crescents, global sclerosis, segmental sclerosis or fibrous crescents, respectively. Our previous retrospective study classifies the RF-RG into four levels according to the odds ratio of the individual compartments defined by combining CG and HG [15].

Figure 2:

Patient flow.

Figure 3:

The association between the primary outcome and RF-RG. (A) Kaplan–Meier survival curves showed significantly different kidney outcomes relative to the RF-RG level. (B) Univariate and multivariate Cox regression models (upper panel: univariate; lower panel: multivariate) revealed a significant association for the primary outcome by the RF-RG. The multivariate models were adjusted for age, sex, MAP, eGFR, UPER, URBC, UA and initial treatment with RASis, glucocorticoids and tonsillectomy. Both univariate and multivariate models show good discrimination, as indicated by high C-statistic values. The time-dependent AUC in univariate and multivariate analyses by the RF-RG revealed good discriminatory performance of the RF-RG for the primary outcome over 10 years in (C) univariate and (D) multivariate analyses.

Figure 4:

Association between proteinuria remission and the RF-RG. (A) The CIF curves and Gray's tests showed significantly different rates of proteinuria remission among RF-RG I–IV. (B) The subdistribution hazard ratio (sHR) among RF-RG I–IV for proteinuria remission using the Fine-Gray model (see Supplementary Table S5).

Figure 5:

Association between haematuria remission and RF-RG. (A) The CIF curve shows that as the RF-RG level increases, the remission rate of haematuria decreases. Gray's tests showed significantly different rates of haematuria remission among RF-RG I–IV. (B) The subdistribution hazard ratio (sHR) among RF-RG I–IV for haematuria remission according to the Fine–Gray model (see Supplementary Table S6).