It is widely known that treatment of SCR significantly affects graft survival, and that providing that treatment in the early period of KT is important to long-term prognosis [3, 4]. Therefore, detecting and treating SCR early after KT might diminish the advancement of persistent allograft nephropathy and enhance allograft survival [3, 17, 23]. Most of our initial PBs were accomplished about 2 weeks (median, 12 days), and a considerable cases of SCR were identified in patients who do not have clinical manifestation of acute rejection. There are only a scanty studies describing the outcomes of early PB to determine if it can recognize SCR when it is accomplished within 1 month after KT.[3, 23] PBs can be used to figure out the baseline condition of donor grafts and for initial disclosure of tubular atrophy, interstitial fibrosis, calcineurin inhibitor nephrotoxicity, and BKV nephropathy. We analyzed how SCR treatment at 2 weeks after KT affected histological changes at 1 year and found that it`s potential protective results. Therefore, SCR treatment made possible through routine PB early after KT could be deemed reasonable. Particularly, because SCR is asymptomatic, PB is important for early detection.
The SCR rate in this study was 101/624 (16.2%) at 2 weeks and 130/624 (20.8%) at 1 year. Although the difference was not statistically significant, patients diagnosed with rejection at 2 weeks had a higher rate of SCR at 1 year than did those deemed normal at 2 weeks [102/523, (19.5%) vs. 28/101 (27.7%)]. According to previous studies, the average prevalence of SCR in the first year after renal transplantation depends on variations in PB strategy between nephrology units, ranging from 29% at 1 month to 17% at 1 year [2, 3]. Thus, in our study, the prevalence of SCR in the first year after KT would have increased if SCR had not been treated at 2 weeks. Untreated SCR produces a decrease in graft survival that increases socioeconomic costs, so SCR should be treated early. Moreover, SCR has a high prevalence early after KT and falls to low levels one year later, and the graft function after the first year significantly affects long-term prognosis. Therefore, SCR treatment at 2 weeks after KT could be important for graft maintenance.
Our results show that SCR found in a 2-week PB should be managed with SPT. At the same time, because the frequency of SCR remains significant in the 1-year PB results, managing it through routine PB is reasonable. An as-yet unpublished analysis by other researchers shows that, from 2012 to 2019, SCR among 1436 KT recipients in Samsung Medical Center was 16.5% at the 2-week PB and 32.9% at the 1-year PB. Therefore, it is feasible to consider a more aggressive PB strategy to detect and treat SCR during this period. Although previous studies have shown that graft function at 1 year after transplantation significantly affects the long-term prognosis of the graft kidney, we found no significant difference between the nPB and rPB groups in graft survival or graft function during the short-term follow-up period in this study.
As shown above, we confirmed the changes in histological differences at 1 year in patients who underwent SPT or intravenous immunoglobulins and plasmapheresis at 2 weeks. The significant difference in scores for the inflammatory response (such as I, PTC, and T) at the initial stage of transplantation decreased through improvement in histological findings. That improvement probably is the result of detecting and treating SCR early, which was possible because of the PB. Although the difference in G score was not statistically significant, it was close to significant, and the OR decreased; therefore, it could be considered an improved histological result.
However, we found no difference in the chronicity of the pathological results between the two groups and two periods. It is difficult to compare chronic scores (Cg, Ci, and Ct scores) at 2 weeks. However, we found no significant difference in chronicity scores when we compared the PB results of the rPB group and nPB group at the 1-year PB. Therefore, treatment of SCR at 2 weeks after KT may have a protective effect on chronic nephropathy progression. If the SCR we found through PB at 2 weeks had not been treated, it maybe have produced a difference in chronicity scores after 1 year. However, our results cannot be used as proof of that. Therefore, a large-scale study on the relationship between early PB implementation and chronic nephropathy progression is needed.
Few studies have confirmed the therapeutic effects of SCR treatment by comparing histological findings from PB at about 2 weeks after transplantation. Although Yokoyama et al. conducted a study similar to ours, their enrolled patient group was small; other studies looked at the histological results of PB at 3 and 12 months, but they focused on ABO incompatibility [26–28]. We analyzed histological changes in individual patients at two time points, which could have reduced the bias in our study. We compared results over a relatively short time and used propensity score matching to control variables that might have affected histological differences. However, extensive additional research on histological changes according to the time points of PB is required.
PB is invasive and carries a small but real risk of complications, with the best estimates for major complications being 0.4–1.0% [11, 29]. From 2012 to 2019, the major complication rate from PB among 1,438 KT recipients at Samsung Medical Center was 0.45% (4/882) at the 2-week PB and 0.17% (1/556) at the 1-year PB.[30] In the population of this study, no complications requiring intervention occurred after biopsy. This is not different from previous studies, so complications should probably not cause hesitation in applying a PB strategy.
PB provides a definite diagnosis and surveillance for rejection, but SPT after PB can be a risk factor for viral infection, which could lead to worse results for the rPB group. According to the infection outcomes in this study, SPT had a nonsignificant effect on infection. However, it is clear that SPT is a risk factor for infection, and another study at our institution reported that rejection treatment is a risk factor for mortality caused by invasive pulmonary aspergillosis [31]. Nonetheless, the frequency of infection is very low, especially considering the protective effect of PB on the maintenance of graft histology, as shown in the results of this study. Therefore, the risk of infection seems to be small enough to continue treatment. In addition, the infections that did occur were manageable with medications such as ganciclovir and anidulafungin, and they did not affect graft survival in this study.
This study had some limitations. First, it was a retrospective, single-center analysis with a cohort composed of Koreans. Therefore, the results might not be generalizable to other countries. Second, other factors influencing the histological results at 1 year were not analyzed. Although it was possible to demonstrate relatively accurate histological results through propensity score matching, the possibility that other factors affected the histological results cannot be excluded. Third, optimal timing of early PB was not determined because the long-term outcomes of early PB was not established. Further investigation will be necessary how soon it will be performed. Last, we did not measure TCMR and ABMR separately because most rejections are TCMR. For reference, in our center, at 2 weeks after KT TCMR was 14.8%, and ABMR was 1.7%; at 1 year after KT TCMR was 30.8%, and ABMR was 1.8%. Proportion of ABMR is relatively very low, we have not analyzed it separately.
In conclusion, SCR treatment plays a protective role against pathologic progression in KT recipients. Significant histological improvements were found in the major Banff classification factors. Furthermore, rather than a single PB, it would be better to manage SCR through more active biopsy implementation within 1 year after transplantation because SCR has a high prevalence early after transplantation that decreases to low level by 1 year later. The results of this study indicate that SCR treatment, made possible by a thorough examination, can be an essential part of graft kidney protection. A large-scale, prospective, randomized study is needed to investigate further the long-term outcomes of SCR treatment.