Clinical significance of focal segmental glomerulosclerosis subclassification in IgA nephropathy

Background and Hypothesis Evidence from the VALIGA IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S). Our study aimed to validate and explore the clinical significance of S subclassification in an Asian population. Methods A total of 746 patients with IgAN were retrospectively included. The Chi-Squared Automatic Interaction Detection method was used to identify subgroups of S lesions associated with proteinuria, eGFR, and major adverse kidney events (MAKE). Kaplan-Meier analysis was performed to assess differences in MAKE. Hazard ratios for S1 lesions with respect to MAKE were estimated using Cox proportional hazards regression models. Propensity score analysis was used to evaluate whether immunosuppressive therapy was associated with a favorable outcome within subgroups. Results Among 746 patients, S1 lesions were present in 80% of individuals, with segmental capillary occlusion by matrix (NOS, 69%), simple capsular adhesion without capillary occlusion (Adh, 63%), and podocyte hypertrophy (PH, 16%) being the top 3 subtypes. All 3 lesion types were associated with proteinuria, and NOS was also correlated with eGFR. Patients in the S1 with NOS+Adh+ subgroup had the worst prognosis. Moreover, immunosuppressive therapy was associated with better outcomes in S1 patients with NOS+Adh+. Subgroup analysis showed that the effect of NOS+Adh+ lesions on MAKE was significantly influenced by systolic blood pressure (SBP). Patients with NOS+Adh+ lesions and SBP > 130 mmHg had a significantly increased risk of MAKE. Conclusion Our study validated the clinical value of S subclassification in IgAN in an Asian population. Patients with NOS+Adh+ lesions have more severe proteinuria and renal function damage. Their overall renal prognosis is significantly worse; however, they can benefit from a treatment strategy that combines renin-angiotensin system inhibitors with immunosuppressants. Additionally, controlling SBP to below 130 mmHg seems to be an appropriate range.