Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy

Abstract

Background: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown.

Methods: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR).

Results: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups.

Conclusions: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

Keywords: IgA nephropathy; end stage kidney disease; epidemiology and outcomes; glomerular disease; proteinuria; renal function decline; renal pathology.

Graphical abstract

Figure 1.

Flowchart of case ascertainment.

Figure 2.

Histogram of the distribution of duration of first remission.

Figure 3.

Restricted cubic spline illustrating the functional form of the unadjusted association between duration of first remission and the primary outcome (ESKD or a 50% decline in eGFR). The y-axis represents the hazard ratio of the primary outcome on the logarithmic scale. The graph shows an initial steep reduction in risk associated with longer duration of remission up to approximately 4 years, followed by an attenuation in further risk reduction.

Figure 4.

Smoothed plot of the hazard ratio (gray line) and associated 95% confidence interval (shaded area) for the risk of the primary outcome associated with the cumulative duration of remission.

Figure 5.

Association between each additional 3 months in remission and the primary outcome in predefined subgroups. Continuous variables such as time to remission, peak proteinuria before remission, and proteinuria at remission were categorized on the basis of their median values. The results are presented for the effect of additional time in remission during shorter remissions of up to approximately 4 years. The multivariable model is adjusted for age, sex, race/ethnicity, MEST score, crescents, mean arterial pressure, eGFR (log-transformed), peak proteinuria before remission, proteinuria at remission, time from biopsy to remission, RAAS blockade at remission, and immunosuppression at or before remission.