Association of histologic variants in FSGS clinical trial with presenting features and outcomes

Abstract

Background and objectives: FSGS histologic variants have correlated with outcomes in retrospective studies. The FSGS Clinical Trial provided a unique opportunity to study the clinical impact of histologic variants in a well defined prospective cohort with steroid-resistant primary FSGS.

Design, setting, participants, & measurements: Renal biopsies of 138 FSGS Clinical Trial participants aged 2-38 years enrolled from 2004 to 2008 were analyzed using the Columbia classification by core pathologists. This study assessed the distribution of histologic variants and examined their clinical and biopsy characteristics and relationships to patient outcomes.

Results: The distribution of histologic variants was 68% (n=94) FSGS not otherwise specified, 12% (n=16) collapsing, 10% (n=14) tip, 7% (n=10) perihilar, and 3% (n=4) cellular. Individuals with not otherwise specified FSGS were more likely to have subnephrotic proteinuria (P=0.01); 33% of teenagers and adults had tip or collapsing variants compared with 10% of children, and subjects with these variants had greater proteinuria and hypoalbuminemia than not otherwise specified patients. Tip variant had the strongest association with white race (86%) and the lowest pathologic injury scores, baseline creatinine, and rate of progression. Collapsing variant had the strongest association with black race (63%, P=0.03) and the highest pathologic injury scores (P=0.003), baseline serum creatinine (P=0.003), and rate of progression. At 3 years, 47% of collapsing, 20% of not otherwise specified, and 7% of tip variant patients reached ESRD (P=0.005).

Conclusions: This is the first prospective study with protocol-defined immunomodulating therapies confirming poor renal survival in collapsing variant and showing better renal survival in tip variant among steroid-resistant patients.

Figure 1.

Major histologic variants are illustrated. (A) Not otherwise specified (NOS) is the common generic form of FSGS, and it exhibits segmental solidification of the tuft by extracellular matrix (in this case, involving approximately half of the tuft with hyalinosis, loss of overlying podocytes, and adhesion to Bowman’s capsule [Jones methenamine silver, ×600]). (B) The tip variant displays a segmental lesion located at the tubular pole with adhesion to the tubular neck and confluence of podocytes and parietal epithelial cells (Periodic acid Schiff, ×400). (C) The collapsing variant has implosive wrinkling and retraction of glomerular basement membranes with hypertrophy and hyperplasia of the overlying glomerular epithelial cells, which contain abundant fuchsinophilic protein resorption droplets (Masson trichrome, ×400).

Figure 2.

The rate of progression to ESRD for the three major subgroups is illustrated using Kaplan–Meier curves and the log-rank test. Numbers in parentheses indicate patients remaining at risk. Error bars represent ±1 SD. A shows all subjects in the study, and B separates the subjects by randomized treatment allocation.