We reported the case of a patient with early recurrence of FSGS after KT who developed anuria with combined acute CNI nephrotoxicity. Recurrent FSGS occurs in approximately 30% of patients after KT. However, in this case, the urine volume abruptly decreased to anuria, making it difficult to diagnose recurrence of FSGS. Although proteinuria is an important early finding in cases of FSGS relapse, the occurrence of anuria due to acute CNI nephrotoxicity, as in our case, can make the diagnosis of recurrent FSGS difficult. Thus, these concurrent factors need to be considered to minimize a delay in the diagnosis of recurrent FSGS.
In kidney transplant recipients who had primary FSGS in the native kidney, significant proteinuria of over 1–3 g/g creatinine without other causes of early de novo proteinuria, including acute humoral rejection, was the primary indicator of recurrent FSGS, which ultimately led to a diagnosis through the histological findings of a graft biopsy [7,8,9]. In the histopathological findings of early recurrence of FSGS, glomeruli usually appear normal on LM, and the diagnosis is confirmed by diffuse foot process effacement on EM [3]. Severe nephrotic range proteinuria in recurrent FSGS can cause graft dysfunction through tubular injury and interstitial edema. However, the incidence of anuria associated with FSGS recurrence is very low. This has been the first case report on the recurrence of FSGS with concurrent anuria, where early recurrence of FSGS combined with acute CNI nephrotoxicity occurred in the graft kidney that had not fully recovered from postoperative ischemic reperfusion injury, resulting in an acute decline in urine volume and long-term anuria.
Of the risk factor for recurrent FSGS, including kidney failure within 3 years of onset, mesangial hypercellularity on initial biopsy, young age at presentation, nephrectomy status, white race, low serum albumin level, and living donor transplantation, this patient had few risk factors [9]. The patient experienced abrupt elevation in creatinine levels, anuria, and hand tremors, which were side effects of increased serum tacrolimus trough levels. Moreover, renal biopsy showed no evidence of FSGS recurrence on LM, which caused a delay in the initial diagnosis of recurrent FSGS until it was eventually confirmed through EM. Although anuria is a common manifestation in CNI toxicity, no previous study has documented its occurrence in recurrent FSGS, leading our group to initially overlook recurrent FSGS as a potential cause of anuria. Therefore, despite the unusual presentation, suspicion of FSGS recurrence is necessary for an early diagnosis of FSGS after KT. Acute tubular necrosis (ATN) needs to be considered as a cause of anuria in the early period following KT. However, in this case, the patient received a kidney from a healthy brain-dead donor with no underlying medical conditions. Additionally, the donor’s renal function was normal, the ischemia time was short, no complications occurred during surgery, and no abnormalities were observed on graft doppler ultrasound. Therefore, based on the temporal relationship and overall clinical course, we initially suspected that the acute graft dysfunction was primarily caused by anuria due to CNI toxicity rather than ATN or postrenal causes.
There are no definite treatment guidelines for recurrent FSGS after KT. However, currently, plasmapheresis with or without rituximab is the most widely used treatment [2]. Plasmapheresis has especially been the mainstay treatment approach for recurrent FSGS. Considering the causal effect of circulating permeability factors for recurrence, it is reasonable to apply plasmapheresis to target circulating factors. In addition to plasmapheresis, rituximab, which is a monoclonal antibody targeting CD20 expressed in B lymphocytes, has been used to treat recurrent FSGS. Despite the beneficial effect of rituximab on FSGS, the pathophysiologic mechanisms of its action are not fully elucidated. The potential mechanism of action of rituximab involves a decrease in the production of circulating permeability factors through the depletion of B lymphocytes, and it also has a direct protective effect on podocytes through the stabilization of proteins expressed on podocytes [10].
Table 1 summarizes the results of studies that evaluated the course and treatment of recurrence of primary FSGS after KT. Uffing et al. reported the outcomes of recurrent FSGS after KT in an international cohort from Europe, Brazil, and the United States [11]. Among 176 patients with primary FSGS, 57 (32%) experienced recurrence of FSGS, with a median time to recurrence of 1.5 months. Patients with recurrent FSGS had a 5-fold higher risk of graft loss than those without recurrence. The authors also evaluated treatment responses according to the types of immunosuppressive treatments. Among patients who received plasmapheresis, the complete remission rate was 28% and the partial remission rate was 44%. When rituximab was added to plasmapheresis, the complete remission rate was 17% and the partial remission rate was 30%. In a French study conducted by Lanaret et al. [2], of 914 patients with primary FSGS who underwent KT, 165 (18%) experienced recurrence of FSGS, with a mean time to recurrence of 7 days. Among them, 148 patients were divided into two groups to evaluate the efficacy of rituximab for treating recurrent FSGS after KT. Group 1 received the standard of care (SOC; plasmapheresis, high dose corticosteroids and high dose CNIs), and some of the patients received rituximab because of the treatment failure of the SOC or the early discontinuation of plasmapheresis after the achievement of remission. Group 2 received the SOC along with early use of rituximab either for recurrence prevention on the day of transplantation or immediately (within 28 days) after recurrence. The remission rates in groups 1 and 2 were 82.6% and 71.8%, respectively, without a significant difference between the two groups. Among nonresponders to the SOC who received rituximab in group 1, 57.9% achieved remission. This finding suggests that rituximab may be beneficial when patients do not respond to conventional treatment. Recently, Kwon et al. reported a single-center retrospective study analyzing South Korean kidney transplant recipients with biopsy-proven primary FSGS [8]. Of 99 patients, 21 (21.2%) experienced recurrence of FSGS, with a median time to recurrence of 6 days. Among the 21 patients with recurrence, 18 (85.7%) were treated with plasmapheresis only and 3 (14.3%) were treated with plasmapheresis and rituximab. The complete remission rate was 39.1%, and the partial remission rate was 47.6%. A single-center retrospective study conducted in the United States reported long-term outcomes of transplant recipients who experienced recurrent FSGS [12]. The recurrence rate was 26% in 100 patients with primary FSGS, with the median time to recurrence being 4.5 days following KT. To treat recurrence, 24 (96%) patients received plasmapheresis, and 11 (46%) received plasmapheresis along with rituximab. Among these patients, 18 (72%) had complete or partial remission after treatment, and the overall graft loss rate following recurrence was 12% over a median period of 1.5 years.
Currently, no international guidelines have been established for the use of rituximab in the treatment of recurrent FSGS after KT. Studies conducted thus far have been limited to retrospective analysis. Most studies on the use of rituximab in recurrent FSGS have been conducted on patients who were unresponsive to initial plasmapheresis treatment, those who desired early plasmapheresis discontinuation, or those receiving plasmapheresis as prophylaxis for recurrent FSGS in high-risk populations. Therefore, large-scale prospective studies are needed to confirm the efficacy and safety of rituximab as a treatment for recurrent FSGS in KT recipients.
To date, numerous retrospective analyses have been conducted to understand and potentially prevent the recurrence of FSGS after KT and improve graft outcomes. Kwon et al. evaluated whether recurrent FSGS after KT was reduced by pretransplant plasmapheresis with or without rituximab [8]. It was found that the rate of postoperative recurrence was significantly lower in the pretreatment group than in the non-pretreatment group (9.4% vs. 34.8%; p = 0.002). On the other hand, Alasfar et al. assessed the efficacy of plasmapheresis with rituximab for the prevention of recurrence of FSGS [9]. In that study, 66 patients with FSGS from African American (n = 21, 32%), Asian (n = 5, 7%), and Hispanic (n = 3, 4%) backgrounds were enrolled. Among them, 37 patients (56.1%) with a high risk of recurrence received preventive therapy with plasmapheresis and rituximab. Recurrence was noted in 23 (62.2%) patients from the pretreatment group and 14 (48.3%) from the non-pretreatment group, and the rate did not differ between the groups. However, the authors emphasized that early diagnosis and treatment of recurrence may result in improved outcomes. These studies showed different results of the effectiveness of preventive treatment for recurrent FSGS after KT, which may be associated with the differences in racial characteristics. In addition, whether high-risk patients were selectively targeted for preventive treatment may have influenced the results. Therefore, large-scale studies are needed to provide definite guidelines for the prevention and treatment of recurrent FSGS.
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- Source: https://bmcnephrol.biomedcentral.com/articles/10.1186/s12882-024-03524-y