Histologic classification of FSGS: does form delineate function?

In this issue of CJASN, D’Agati and colleagues assess the association of the Columbia classification system of FSGS histologic variants with clinical characteristics and outcomes in patients enrolled in the FSGS Clinical Trial (FSGS-CT) (1). FSGS is the most common primary glomerular histology that results in ESRD (2). This is not a single disease, and it can have idiopathic, genetic, or secondary causes. FSGS patients present with diverse pathology and proceed with variable clinical courses. The Columbia classification attempts to categorize FSGS into five histologic variants (3). The collapsing variant is described as having at least one glomerulus with segmental or global glomerular capillary tuft collapse with hypertrophy and hyperplasia of overlying epithelial cells. The tip variant shows at least one glomerulus with a segmental lesion involving the outer 25% of the tuft next to the proximal tubule with adhesion of podocytes at the tubular lumen or neck, and without collapsing features. The not otherwise specified (NOS) variant is described by segmental capillary lumen obliteration by extracellular matrix, with no collapsing, tip, cellular (segmental endocapillary hypercellularity obliterating capillary lumens), or perihilar (vascular) lesions. This study compares the presentation and outcomes in 94 NOS, 16 collapsing, and 14 tip variant patients in the FSGS-CT. Unfortunately, the perihilar (n510) and cellular (n54) variants had too few patients for statistical analysis. The FSGS-CT was an open-label, multicenter, randomized controlled clinical trial comparing the efficacy of 12 months of cyclosporine versus combinationmycophenolate mofetil/oral pulse dexamethasone treatment in 138 biopsy-proven steroid-resistant FSGS patients (4,5). Both groups received low-dose prednisone for 6 months. Mean follow-up was 2.91 1.1 years. Patients were between 2 and 40 years of age, with estimated GFR (eGFR) values $40 ml/min per 1.73 m2 and first morning urine protein/creatinine (Up/c) ratios .1g/g despite .4 weeks of corticosteroid treatment before enrollment. Collapsing FSGS patientsweremore likely to be of black race (P50.03), and had the highest pathologic injury scores (total glomerular scarring and tubulointerstitial atrophy/fibrosis) (P50.003) and baseline serum creatinine (P50.003). The tip variant had the highest association with white race as well as the lowest pathologic scores and baseline creatinine. Features of the nephrotic syndrome were more pronounced in both the collapsing and tip variants compared with the NOS variant. Most importantly, 47% of collapsing patients reached ESRD at 3 years compared with 20% of NOS and 7% of tip variants. It was concluded that there was worse renal survival in the collapsing variant compared with the tip variant, despite therapy under the FSGS-CT protocol. After adjustment for baseline creatinine and Up/c, the collapsing FSGS variant was not a statistically significant predictor of ESRD. Limitations of this study include modest sample size, short follow-up, and generalizability to adults due to the trial’s age criteria with only one-third of the cohort aged .18 years. Patients with the most aggressive FSGS may not have been eligible for the study if eGFR decreased to ,40 ml/min per 1.73 m2 while on corticosteroid therapy. An obvious strength is that this is a randomized controlled trial. With the poor prognosis of the collapsing variant, prior case seriesmay be biased by undertreatment because immunosuppression may have been considered futile. In this trial, the specific variant could not influence the choice of therapy. These findings support the association between histologic variants and clinical outcome previously reported in retrospective series. Thomas and colleagues found that the collapsing and tip variants had higher proteinuria and lower serum albumin levels than the NOS and perihilar variants in a cohort of 197 FSGS patients (6). The collapsing variant had worse renal prognosis with only 33% renal survival (not doubling serum creatinine or requiring renal replacement therapy) at 3 years compared with 76%with the tip variant and 65% in the NOS variant. Stokes and colleagues found similar results for collapsing and tip variants in a retrospective cohort of 225 FSGS patients (7). The collapsing variant had 65.3% of patients reaching ESRD compared with only 5.7% with the tip variant and 34.5% in the NOS variant. One difference between these two cohorts is that only 34% received corticosteroids in the analysis by Thomas et al. versus 72.4% in the study by Stokes et al. It is noteworthy that these two series had authors who were the pathologists that devised the original classification system. In stark contrast, Chun and colleagues examined 87 FSGS patients and found their equivalent classification of Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland