Quantifying the benefits of remission duration in focal and segmental glomerulosclerosis

Abstract

Background: Although the clinical benefit of obtaining a remission in proteinuria in nephrotic patients with focal segmental glomerulosclerosis (FSGS) is recognized, the long-term value of maintaining it and the impact of relapses on outcome are not well described.

Methods: We examined the impact of remissions and relapses on either a 50% decline in kidney function or end-stage kidney disease (combined event) using time-dependent and landmark analyses in a retrospective study of all patients from the Toronto Glomerulonephritis Registry with biopsy-proven FSGS, established nephrotic-range proteinuria and at least one remission.

Results: In the 203 FSGS individuals with a remission, 89 never relapsed and 114 experienced at least one relapse. The first recurrence was often followed by a repeating pattern of remission and relapse. The 10-year survival from a combined event was 15% higher in those with no relapse versus those with any relapse. This smaller than anticipated difference was related to the favourable outcome in individuals whose relapses quickly remitted. Relapsers who ultimately ended in remission (n = 46) versus in relapse (n = 68) experienced a 91% and 32% 7-year event survival (P < .001), respectively. Using time-varying survival analyses that considered all periods of remission and relapse in every patient and adjusting for each period's initial estimated glomerular filtration rate, the state of relapse was associated with a 2.17 (95% confidence interval 1.32-3.58; P = .002) greater risk of experiencing a combined event even in this FSGS remission cohort.

Conclusion: In FSGS, unless remissions are maintained and relapses avoided, long-term renal survival remains poor. Treatment strategies addressing remission duration remain poorly defined and should be an essential question in future trials.

Keywords: FSGS; landmark analyses; relapse; remission; time-dependent survival analyses.

Graphical Abstract

Figure 1:

First, second, third and subsequent remissions and relapses. Flow diagram of remissions and relapses of the 203 individuals who obtained a remission in proteinuria and their status changes over time.

Figure 2:

Maximal proteinuria and its reduction during the first, second and third remission events. (A) Maximal proteinuria while nephrotic. (B) Maximal reduction in proteinuria with a remission (defined by the maximal proteinuria before remission minus the lowest value obtained after). These findings illustrate the magnitude of fluctuations in FSGS with (A) relapses and (B) remissions is similar, although the numbers (y-axis) are smaller with each event. Blue: first remission; red: second remission; green: third remission.

Figure 3:

Survival from a combined event following the remission status at different landmarks following first remission. The P-values were obtained with Cox regression adjusted for the initial eGFR. The patient's status at the time points of 1 and 2 years (remission or relapse at that point) were more predictive of outcomes compared with the outcome based on the status at 6 months.

Figure 4:

Survival from a combined event following the last remission obtained. The P-value was obtained with Cox regression using a time-dependent expression of the last relapse adjusted for the eGFR.