Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network

Abstract

Rationale & objective: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response.

Study design: Prospective, multicenter, observational study.

Study participants: CureGN participants with proven MCD on biopsy.

Exposure: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period.

Outcome: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure.

Analytical approach: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission.

Results: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002).

Limitations: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy.

Conclusions: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response.

Plain-language summary: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

Keywords: Adolescents; adults; age at disease onset; children; clinical phenotype; clinical trajectory; disease course; eGFR change; estimated glomerular filtration rate (eGFR); minimal change disease (MCD); nephrotic syndrome (NS); prognosis; proteinuria; relapse; remission; rituximab.

Figure 1.

Visual summary figure of study design and outcomes.

Figure 2:

Among CureGN participants, time from complete remission to first initial relapse and subsequent relapses (index date is first remission after enrollment): A) Time to first initial relapse comparing childhood, adolescent and adult-onset disease, B) Time to subsequent second relapse comparing childhood-onset, adolescent-onset, and adult onset disease. C) Time to third or more subsequent relapses. Gray horizontal line shows the number of years from remission when 50% of the population experienced relapse.

Figure 3:

Time from relapse to complete remission is faster in childhood-onset disease compared to adult-onset and adolescent-onset for initial and subsequent second remission and similar for all age groups for subsequent remissions (index date is first relapse after enrollment). A) Time to initial complete remission comparing childhood-, adolescent-, and adult-onset disease. B) Time to subseqent second remission comparing childhood-onset, adolescent-onset and adult-onset disease. C) Time to third or subsequent remissions. Gray horizontal line shows the number of years from relapse when 50% of the population achieved remission.

Figure 4:

The means and 95% confidence intervals of the eGFR predicted slopes over follow-up duration in childhood-onset, adolescent-onset and adult-onset MCD are shown (index date is date of disease onset). The intercepts differ substantially, but the slopes are not significantly different. Unadjusted slope (Std Err) - childhood-onset: −0.27 (0.23), adolescent-onset: 0.02 (0.73), adult-onset: −1.11 (0.34), adjusted slope (Std Err) - childhood-onset −0.20 (0.23), adolescent-onset: 0.06 (0.74), adult-onset: −1.13 (0.35). eGFR (mL/min/1.73 m²) was calculated using the Schwartz formula for Pediatric patients <18 years, the CKD-EPI formula for Adult patients >26 years, and the average of pediatric and adult formulas for Adolescent patients 18 to 26 years. Post-ESKD values were excluded.

Figure 5.

Time from rituximab initiation to complete remission is faster among those who were glucocorticoid-sensitive compared to those who were not glucocorticoid sensitive (index date is date of rituximab therapy).