In this study, we found that prophylactic PP was associated with a lower risk of immediate post-transplant FSGS recurrence. Among the traditional risk factors for recurrence FSGS, only young age significantly increased the recurrence rate in multivariate analysis. Rituximab alone did not show a significant preventable effect in our study. Among the 21 cases of post-operative recurrence, only 3 (14.3%) cases did not respond to treatment and ultimately experienced graft failure. During the long-term follow-up period, only 2 cases showed biopsy-proven recurrent FSGS, suggesting that the early post-operative period was critical for improving graft survival in patients with FSGS.
The recurrence and remission rates of our study are similar or lower than those reported in previous studies.[2, 4, 6, 13, 18] These outcomes must be interpreted with caution because the recipients in each study had varying baseline characteristics and underwent operations using different protocols. Most studies included in the recent meta-analysis and European registry data showed recurrence rates of 21–40%, which are similar to our study.[18] Alasfar et al. observed a much higher recurrence rate of 59%,[13] and also reported a tendency of efficacy but did not observe a significant difference in the post-operative recurrence rate according to preventative treatment. Such difference between our study and Alasfar et al. may be due to the fact that Alasfar et al. only included patients with high-risk idiopathic FSGS and the sample size was too small to reach enough statistical significance. A recent multicenter cohort study reported a 32% recurrence rate,[2] but the rate of treatment response in recurred patients was relatively lower than that in our study, with only 57% of patients achieving partial or complete remission.[2] The authors explained that the low remission rate likely resulted from nonstandardized treatment intensity and duration.[2] The relatively lower recurrence and higher remission rate in our study may have stemmed from the fact that more than half of the recipients had received prophylactic treatment. Furthermore, our center has implemented a protocol for FSGS in which recipients are not discharged until two weeks after KT while undergoing daily exams for proteinuria and serum creatinine. This policy enabled us to apply PP immediately after suspected FSGS recurrence and to achieve a high remission rate of 87.5%. Based on our results, we suggest that FSGS patients may benefit from careful monitoring—especially within 2 months after KT—because the median time of recurrence was six days and most recipients recurred within 2 months after transplantation.
Our study is the first single-center study to report the preventable effects of prophylactic treatment against FSGS recurrence with statistical significance, which was possible due to the relatively large number of study patients, all of whom had histologically proven primary FSGS and had relatively homogeneously distributed study groups. Several studies have shown a tendency of a protective effect of pre-transplant treatment.[5–7] Ohta et al. reported that the prophylaxis group treated with 1 to 2 sessions of PP before KT appeared to have a lower recurrence rate (5 out of 15, 33.3%) than the non-prophylactic group (4 out of 6, 66.7%), although the small number of study patients limited the achievement of statistical significance.[7] Gohh et al. reported a recurrence rate of 30% with a course of 8 PP in the peri-operative period in high-risk patients with an expected recurrence rate of 60%.[5] Hickson et al. tried to find the evidence of prophylactic effects of preemptive PP followed by additional PP after KT;[6] although the study did not reach its goal, the authors observed that severe aspects of recurrent FSGS that do not respond to treatment such as primary non-function did not occur in patients who received preemptive treatment.[6]
A major obstacle to studying FSGS is its low prevalence. Several studies using registry and meta-analysis have been performed to overcome the low sample size.[2, 4, 18] However, registry data had issues regarding data quality, missing data, and heterogeneity of transplant protocols among centers. During the study period (2007–2018), our center performed 4263 cases of KT, including 728 ABOi and 217 FXCM-positive KT, which allowed us to gather a sufficient number of FSGS cases and 28 pre-treatment recipients to have statistical strength. In addition, one physician at our center routinely performed prophylactic PP in FSGS, which allowed our cohort to have 23 patients in the pre-treatment group. The study groups in this study were divided homogeneously with the same clinical protocol, even though they were not randomly selected.
There were concerns that ABO incompatibility and FXCM-positivity could affect the clinical outcomes, and proteinuria with azotemia in the rejection episode was similar to the clinical aspect of recurred FSGS. However, we previously reported that ABOi KT had comparable graft survival and rejection rates after modifying the desensitization method, and recipients with pre-transplant DSA values less than 5000 MFI showed similar rejection rates with DSA-negative KT. [14, 17] Our multivariate analysis also revealed that ABO incompatibility was not a significant factor related to FSGS recurrence. Nevertheless, there is a possibility that rejection was confused with recurred FSGS because we did not perform graft biopsy in all cases due to the risk of bleeding complications, especially within 2 weeks after transplant. We consider that this limitation would not have significantly affected the main conclusion of our study because a previous study in this cohort reported that the one-year rejection rate was less than 4%.[17] We performed a biopsy in cases that were challenging to distinguish between rejection and FSGS recurrence. As a result, one patient who had increased serum creatinine and proteinuria that did not fulfill the definition of recurred FSGS underwent graft biopsy at post-operative 13 days, which showed acute cellular and antibody-mediated rejection; the kidney function was restored after steroid pulse treatment and PP.
Patient selection is a critical factor in performing the study to determine the effect of pre-transplant treatment. The hypothesis is that a prophylactic treatment that removes a permeability factor decreases the risk of FSGS recurrence after KT and is utilized only when the study includes recipients with primary FSGS. We initially reviewed the records of every patient with FSGS and a native kidney biopsy report and discussed them with pathologists and nephrologists at our center. FSGS cases with possible secondary causes such as infection, hypertension, diabetes mellitus, and chronic renal failure due to other medical conditions were excluded. Rituximab may have different mechanisms from PP in affecting the course of FSGS by modulating podocyte function.[19] Although one case report suggested protective effects of rituximab in preventing FSGS recurrence, there is still no conclusive study that demonstrated the efficacy of rituximab.[20] Our study also showed that rituximab had no significant effect as a prophylactic treatment.
The traditional risk factors for FSGS recurrence include native kidney failure within three years of onset, mesangial proliferation on biopsy, younger age, nephrectomy status, non-white ethnicity, and living donor transplantation.[2, 5, 8] Among them, only younger age was a significant factor in univariate analysis. Deceased donor transplantation was a significant factor in univariate analysis but not in multivariate analysis, which could be due to the fact that the living donor transplantation group included more pre-transplant treatment cases. Along with younger age, pre-transplant treatment remained statistically significant in multivariate analysis.
Our study has several limitations. It has a retrospective design, and the treatment group was not selected in a randomized manner, thereby resulting in potential selection bias. Also, although we tried to exclusively include primary FSGS cases, there is a possibility that secondary FSGS cases were included in the analysis. Conversely, it is also possible that primary FSGS cases were excluded due to a lack of evidence. Second, we did not perform a protocol or indicational biopsy to evaluate the possible causes of azotemia and proteinuria in all cases with suspected FSGS recurrence. However, recent studies have enabled the diagnosis of recurrence and remission of FSGS without pathological confirmation when clinical aspects fulfill the criteria.[16, 21] Third, because desensitization in ABOi KT and FXCM-positive KT was not intended for prophylaxis for FSGS recurrence, the pre-transplant treatment included different protocols, including the number of PP and the use of rituximab and its dose.