Recurrent FSGS Post–kidney Transplantations: Where Do We Stand?

This is the authors' abstract. We don't add key points for this paper.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion that develops due to different underlying mechanisms that lead to podocyte damage and loss. In most cases, FSGS lesion develops secondary to an identifiable cause, such as genetic mutations, infections, drugs, or adaptive changes, leading to increased demand on the kidney. In contrast, in the vast majority of the patients with primary FSGS, the cause is unknown. In 9% of the patients, podocyte injury is secondary to anti–nephrin autoantibodies.1 Patients with primary FSGS present with diffuse foot process effacement (>80%) and nephrotic syndrome (proteinuria >3.5 g/d and hypoalbuminemia <3.5 g/dL). Despite immunosuppression, patients can have a progressive course leading to dialysis2,3 with a high rate of recurrence post–kidney transplantation.4-6 The best treatment strategy for recurrent FSGS is unclear but has included the use of plasmapheresis with or without an anti-CD20 therapy such as rituximab with variable outcomes.7 The added immunosuppressive therapy can increase the risk of infection. As such, there continues to be a desperate need for therapies that can help prevent the recurrence of the disease in renal allografts. Finding an effective therapy in patients with recurrent FSGS posttransplantation is challenging. Part of the challenge is conducting a study with enough power to detect a meaningful difference between the treatment and the placebo arms, requiring collaboration between multiple centers to reach an adequate sample size. In addition, most transplant centers have protocols already in place for pretreating patients to prevent recurrence, which may interfere with enrollment. Another major challenge is inadvertently including patients with secondary FSGS forms. Diagnosing primary FSGS will require evaluation of the degree of foot process effacement and confirmation that nephrotic syndrome was present at the time of native biopsy. However, this information may no longer be available. Another question is how to add an immunosuppressive therapy to the standard of care (SOC). Does one just add the new drug or does one add the new drug and take away one of the drugs from the SOC arm to lower the risk of infection, and if so, would that increase the rate of antibody or cell-mediated rejection? Another difficulty is the lack of consensus on how to define recurrent FSGS. How much proteinuria is required to make the diagnosis? Proteinuria >1.0 or >3.0 g/g? Or perform a kidney biopsy in all patients to confirm the presence of foot process effacement? In this issue of Transplantation, Shoji et al8 conducted a multicenter phase 2a, randomized, open-label clinical trial evaluating the role of bleselumab in “preventing” recurrent FSGS as a proof-of-concept study. Bleselumab is a humanized monoclonal CD40 antibody that interferes with CD40 and CD40 ligand (CD40L) interaction, leading to podocyte injury and the development of FSGS lesions.9,10 Based on these data, Shoji et al hypothesized that adding bleselumab to tacrolimus and prednisone was superior in preventing recurrent FSGS compared with SOC (tacrolimus, mycophenolate mofetil [MMF] and prednisone). Bleselumab was provided as an infusion of 200 mg dose at the time of transplantation, followed by weekly, biweekly, and monthly infusions. Overall, 67 patients were recruited, but for the final analysis, there were 33 patients in the SOC arm and 27 patients in the bleselumab arm. The primary endpoint was the recurrence of FSGS at 3 mo post–kidney transplantation. Recurrence was defined as protein-creatinine ratio ≥3.0 g/g with death, graft loss, or loss to follow-up imputed as recurrent FSGS. At 3 mo, there were 5 of 27 patients (18.5%) in the bleselumab arm versus 10 of 32 patients (31.3%) in the SOC arm who had recurrent FSGS (P = 0.37). There was a higher rate of using rituximab or plasmapheresis in the SOC arm compared with the bleselumab arm although not statistically significant. Overall, the study failed to reach its endpoint. Knowing the hurdles of conducting a trial in recurrent FSGS, the authors of this study should be commended for their attempt and ability to include multiple centers and see this trial to its completion. This was no easy task. Unfortunately, despite their herculean efforts, several issues remain with the study. One is the lack of power. Despite a 12.8% higher rate of recurrence in the SOC arm, there were no statistically significant differences. The other was how well patients with primary FSGS were included. It is likely that patients with genetic or secondary FSGS were enrolled, given the absence of clinical and native renal biopsy data. This could make the use of bleselumab less effective. Another major limitation was the definition of recurrent FSGS. This was defined as urinary protein to creatinine of ≥3.0 g/g within 3 mo posttransplantation. However, new onset proteinuria in a patient known to have primary FSGS should raise concerns regarding recurrence, and as such, some cases of early recurrence may have been missed. Similarly, other causes of proteinuria (such as antibody or cell-mediated rejection) should have been ruled out by performing a kidney biopsy, especially if progressive and associated with a decline in estimated glomerular filtration rate. A closer look at the data shows that when limiting the definition of recurrent FSGS to those with allograft biopsy, the difference in recurrence rate was even less in 10 of 28 patients (35.7%) in the SOC group and 7 of 22 patients (31.8%) in the bleselumab group. In addition, in 8 patients, the recurrent FSGS was diagnosed on the basis of the protocol biopsy alone. In addition, the increase in the rate of recurrent FSGS in the bleselumab group when evaluating the kidney biopsy (31.8%) versus relying on proteinuria criteria (18.5%) raises the possibility that bleselumab may potentially have off-target effects on the podocytes, which may be independent of its immunological effect. Such an off-target effect should be considered when conducting a trial that relies on proteinuria as an endpoint. Another factor to consider was the replacement of MMF with bleselumab in the treatment arm. Intuitively, this would make sense. However, bleselumab may be inferior to MMF in preventing rejections. Indeed, when evaluating the rate of biopsy-proven rejections in the study, there were 26.9% of rejections in the bleselumab group versus 20% in the SOC group. Although this did not reach statistical significance, it remains a concern. The number of patients in each group was small and the follow-up duration was short. Longer-term use in the absence of MMF in a larger number of patients may pose a real risk. This is the first successful randomized clinical trial evaluating the role of a novel therapy in patients with primary FSGS at risk of recurrence. Other attempts at conducting a trial have failed spectacularly. Despite the failure of this trial, there is useful information gained from the study, including importance of a unified definition of recurrence, need for allograft biopsy to confirm the diagnosis, collaboration between centers to enroll patients, and confirming enrollment of patients with high likelihood of primary FSGS. To date, there are no good therapeutic approaches available for these patients to prevent or treat the disease posttransplantation, and it will be only through collaboration between centers and the nephrology community coming together that tackling such a hurdle would be possible.