In this study, we sought to delineate clinical features and outcomes according to the Columbia classification in 111 Korean adult patients with primary FSGS. We showed that cellular and collapsing variants were uncommon in our cohort and overall outcome was not affected by pathologic variants. However, nephrotic syndrome was the most common in tip variant, which exhibited favorable outcome in terms of achieving remission. The present study provided distinct clinical features of FSGS in the Korean population for the first time and reinforced the findings of previous studies indicating that pathologic variants of FSGS may have different prognostic implications.
As aforementioned, the Columbia classification has been used worldwide in patients with FSGS. However, many studies have clearly shown that the relative frequency of the five variants varies depending on race and ethnicity [4, 9, 11, 12, 14–17]. It is well known that collapsing and cellular variants are more common in African Americans than other populations, while whites are more likely to have tip variant [9, 14]. However, collapsing and cellular variants were not common in the present study. This finding is corroborated by other previous studies showing a low frequency of collapsing and cellular variants in non-African American populations [11, 12]. To date, there have been few studies to evaluate the prevalence of the five pathologic variants by the Columbia classification in Asian populations. In keeping with our findings, NOS variant was the most common and collapsing variant was uncommon in an Indian study and two Chinese studies [11, 18, 19]. However, four Asian studies were not in accordance with the frequency of cellular variant. Our cohort showed the lowest (2.7%) frequency, while it was the highest for the Chinese studies (14.4% and 25.5%) and intermediate between the two populations for the Indian study (8.0%). Interestingly, there was a substantial discrepancy in the frequency of cellular variant between Korean and Chinese populations. Moreover, the two Chinese studies reported a 10% difference in the frequency although they were the same population. Of note, there may be misclassification of cellular variant as tip variant because cellular lesions can exist within the tuft in tip variants and intracapillary expansile foam cells can be observed in both variants depending on location; either at the polar domain in tip variants or at any other location in the cellular variants. In fact, Stokes et al. emphasized the importance of adequate sampling and sectioning because about 30% of cellular variants were reclassified as tip variants by deeper sectioning of the biopsy. On the other hand, there has been controversy about whether tip and cellular variants may be two stages of a single entity identified at different points of time [11, 17]. Due to the retrospective nature of the study, it is unknown whether additional deeper tissue sectioning might result in more identification of tip variants in the Chinese studies. Nevertheless, our findings were consistent with most previous studies showing that cellular variant is uncommon. Further studies involving other Asian populations are warranted to elucidate whether cellular variant is as common in Asian populations as in African Americans.
In general, collapsing variant has the worst prognosis among the five variants, whereas tip variant has the best prognosis. Cellular variant shows an intermediate prognosis between the two variants. Unfortunately, the present study did not confirm these observations because of the limited number of collapsing and cellular variants. Two patients with cellular variant and one patient with collapsing variant had substantial amounts of proteinuria and kidney impairment at presentation. This finding suggests that clinical outcomes of these two variants may not be favorable, and rare frequency of these two variants may draw a favorable prognosis. However, long-term follow-up studies with a larger sample size are required to determine the prognosis.
A number of studies have reported that tip variant has clinical features similar to that of minimal change disease and its responsiveness to corticosteroids is favorable; thus, tip variant is considered to have good prognosis [10, 20]. In line with this, in the present study, tip variant was significantly associated with achieving CR or PR. In addition, only 1 (5.0%) patient with tip variant reached the composite outcome compared to 12 (17.1%) patients with NOS variant and 2 (11.8%) patients with perihilar variant. However, this difference was not statistically significant possibly because of the small number of patients. Of note, previous studies compared tip variant with collapsing or cellular variants [10, 14], which are known to be associated with poor outcome. As aforementioned, in our cohort, these two variants were very rare; thus, detailed analysis to prove prognostic superiority of tip variant to other variants was not feasible. Because NOS and perihilar variants generally present subnephrotic range proteinuria and less severe clinical features compared to collapsing variant, it is possible that tip variant may not confer an advantage in renal outcome over NOS or perihilar variants depending on the characteristics of the study subjects. In fact, two previous studies did not demonstrate that renal outcome of tip variant is better than that of NOS variant [10, 14]. Nevertheless, given the significant correlation between remission rate and renal survival, it can be expected that tip variant may have favorable long-term outcome.
Perihilar variant is generally considered secondary FSGS. In the present study, patients with this variant comprised 15.3% of all patients and had no evidence of reflux nephropathy, sickle cell anemia, surgical ablation, or renal agenesis. Eleven (64.7%) patients were diagnosed with hypertension before renal biopsy, and some of them showed histologic features of hypertensive nephrosclerosis, which might contribute to adaptive change in glomerular capillaries. In our cohort, obesity was unlikely to be associated with perihilar variant because mean BMI was 25.3 kg/m2, which was not different from patients with other variants. Nephrotic syndrome developed in 41.2% of patients with perihilar variant. In addition, the clinical outcome of these patients was favorable because 5-year renal survival rate was 66.7% (Figure 2B) and only two (11.8%) patients reached the composite outcome during follow-up. Our findings were consistent with the results of previous studies showing that the frequency of nephrotic syndrome in perihilar variant varies from 25% to 55% [9, 12] and 5-year renal survival rate was reported up to 55% .
Our study has some limitations. First, this is a retrospective study with a small sample size. In particular, a small number of patients with cellular and collapsing variants rendered statistical analysis unavailable. Thus, we could not analyze these patients to prove that collapsing or cellular variant exhibit the worst prognosis as previously reported. For the same reason, tip variant was not associated with a significantly decreased risk of reaching the composite outcome. Second, we confirmed foot process effacement on EM reviewed initial pathologic reports due to lack of available EM photography in some patients. Third, the retrospective nature of the study did not clearly suggest a therapeutic approach by histologic variants. In fact, in many cases, physicians usually decide whether or not to treat with immunosuppression depending on clinical indicators such as heavy proteinuria or rapid deterioration of kidney function. In addition, there has been a concern about the usefulness of pathologic findings in predicting future outcome. Several studies showed that response rate to treatment in collapsing FSGS was not as poor as expected, ranging as high as 40 to 64% [1, 12]. In addition, Chun et al., reported a 92% remission rate in patients with celluar lesions involving < 20% of glomeruli, compared to only 33% in patients with cellular lesions in ≥ 20% of glomeruli , suggesting that cellular lesions per se do not universally portend a bad prognosis. In line with this notion, in the present study, entering CR or PR was significantly associated with a decreased risk of reaching the composite outcome (HR, 0.03; 95% CI, 0.002-0.594; P = 0.021, data not shown), while pathologic variants were not. Finally, there was relatively small number of patients presenting with nephrotic syndrome in this study. This is partly attributed to a lack of patients with collapsing and cellular variants in our study. In general, these two variants show nephrotic syndrome. In contrast, subnephrotic proteinuria is more common in patients with NOS and perihilar variants, which comprised 78.4% of our cohort. Such characteristics of our cohort may explain the low prevalence of nephrotic syndrome in this study.