How to treat recurrent focal segmental glomerulosclerosis after kidney transplantation in children
Article information
Abstract
Focal segmental glomerulosclerosis (FSGS), a significant cause of kidney failure in children, is a common pathological diagnosis in cases of idiopathic nephrotic syndrome, especially steroid-resistant ones. FSGS has the potential to recur after kidney transplantation, often leading to graft loss. However, not all children with FSGS experience recurrence posttransplantation, such as those with genetic or secondary forms, which have minimal risk. Moreover, advancements in management, including intensive plasmapheresis and immunosuppressive therapies like rituximab, have increased remission rates in cases of recurrence. Identifying patients at high risk of recurrence, such as those with an initial treatment response or previous failed transplantation, is crucial. These children require close monitoring of proteinuria and prompt, intensive treatment upon recurrence to improve outcomes.
Introduction
Focal segmental glomerulosclerosis (FSGS) is a common cause of kidney failure affecting both adults and children. In children, although congenital abnormalities of the kidney and urinary tract are the primary causes of kidney failure, FSGS is the most prevalent acquired glomerulopathy, leading to kidney failure worldwide, including in Korea [1,2]. Additionally, it is the second most common pathological finding in childhood idiopathic nephrotic syndrome (NS), only surpassed by minimal change disease [3,4]. While most children with NS respond well to steroid therapy, some of them remain steroid-resistant and frequently progress to kidney failure [5]. In these cases, kidney biopsy often identifies FSGS.
FSGS presents a major challenge in kidney transplantation due to its tendency to recur in the transplanted kidney, with recurrence rates reported to be as high as 60% [6-9]. Recurrence threatens the graft function and affects the overall mortality and quality of life. Nevertheless, not every patient with FSGS will experience recurrence after transplantation, and the risk differs based on multiple factors. For instance, the genetic and secondary forms of FSGS have minimal risk of recurrence. Moreover, recent progress in managing recurrence, including intensive plasmapheresis and immunosuppressive treatments like rituximab, has enhanced remission rates [6,10,11]. Consequently, it is crucial to identify patients at high risk of recurrence and to implement timely management strategies to optimize outcomes.
This mini-review aims to summarize the current understanding of the risk factors for FSGS recurrence following kidney transplantation in children and explore recurrence prevention and treatment strategies (Fig. 1).
Management strategy for recurrent focal segmental glomerulosclerosis (FSGS). KT, kidney transplantation; KF, kidney failure; IS, immunosuppression.
Risk factors for the posttransplantation FSGS recurrence
Identifying children at high risk of recurrence is essential for effective counseling and management planning. Notably, the risk of recurrence of FSGS depends largely on its underlying cause. Genetic forms of FSGS, which arise from mutations regarding podocyte function or the cytoskeleton, exhibit a low risk of recurrence. For instance, Pelletier et al. [12] found no cases of recurrence among 22 patients with genetic steroid-resistant NS, compared with a 47% recurrence rate in those without a known genetic cause. Therefore, determining the presence of a genetic defect is crucial before proceeding with kidney transplantation in children with FSGS. Conversely, idiopathic NS with FSGS pathology is thought to be driven by circulating permeability factors, increasing the likelihood of recurrence. Secondary FSGS (recently termed adaptive FSGS, a condition resulting from other causes like reflux nephropathy) typically does not recur after transplantation if the underlying cause is resolved. However, the relationship between genotype and phenotype regarding the recurrence risk is not always straightforward, particularly when the identified variants have uncertain significance. Additionally, having a known genetic mutation does not eliminate the possibility of recurrence, as some patients with genetic mutations still experience recurrence posttransplantation [13].
Furthermore, the clinical progression of FSGS before reaching kidney failure can offer insights into the risk of recurrence. For example, children who initially respond to steroids but later develop secondary steroid resistance seem to have a higher recurrence risk compared with those with primary steroid resistance, likely because the latter group is more likely to have a genetic form of FSGS [9,14]. Other suggested risk factors for recurrence include rapid progression to kidney failure within 3 years of diagnosis, younger age at NS onset, and mesangial hypercellularity or minimal change histology on biopsy [12,15,16]. However, these findings are not entirely consistent. For example, a recent Italian cohort study excluding genetic FSGS age through genetic testing identified age >9 years as a risk factor for recurrence [17].
Historically, living-donor kidneys, compared with deceased-donor kidneys, were reported to be associated with a higher risk of disease recurrence [15,18]. However, recent research indicates that although recipients of living-donor kidneys may face a greater recurrence risk, they also benefit from better graft survival than deceased-donor kidney recipients [19]. The TANGO study of 176 adults with biopsy-proven idiopathic FSGS found no significant difference in recurrence risk based on donor type [20].
Finally, patients who have experienced recurrence in a previous allograft have a significantly higher risk of recurrence in subsequent transplants. In some studies, the recurrence risk in a second allograft has been reported to be as high as 100%, suggesting that further transplantation after graft loss due to recurrence should be cautiously approached.
Biomarkers predicting recurrence
Reliable biomarkers to predict FSGS recurrence and identify circulating permeability factors have been ongoing for decades. The soluble urokinase receptor was proposed as a candidate; however, subsequent studies have yielded conflicting results regarding its predictive value. More recently, the anti-nephrin antibody has emerged as a promising candidate. Shirai et al. [21] discovered that in children with posttransplant recurrent FSGS, anti-nephrin antibodies were significantly elevated before transplantation or during recurrence compared with periods of remission. However, since not all patients exhibit these antibodies, it cannot serve as a universal biomarker [22], and further research should be conducted since the findings so far have been encouraging. Additionally, Delville et al. [23] identified a panel of seven antibodies, including anti-CD40, that could accurately predict recurrence.
Management of recurrence
Recurrent FSGS significantly threatens graft survival; however, advancements in management have led to improved outcomes. The primary treatment involves plasmapheresis or immunoadsorption to eliminate circulating permeability factors. Initiating early therapy is crucial to averting irreversible glomerular damage. Nonetheless, to the best of our knowledge, there are no definitive guidelines due to the absence of randomized controlled trials, and most recommendations stem from retrospective studies. The CERTAIN group suggested that the initial approaches should include plasmapheresis or immunoadsorption, rituximab, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) therapy. If these are ineffective, apheresis should be considered if the patient becomes dependent on plasmapheresis, high-dose cyclosporin, rituximab, and low-density lipoprotein apheresis [24].
Extracorporeal therapy, namely plasmapheresis and immunoadsorption, aims to remove the circulating factors responsible for recurrent FSGS. Plasmapheresis typically involves removing 1.5 plasma volumes and replacing them with 5% albumin, while immunoadsorption employs columns to selectively eliminate immunoglobulins from the plasma. Numerous retrospective studies have demonstrated the effectiveness of these methods [25,26]. Various plasmapheresis protocols are employed, with plasmapheresis typically initiated within 7 days of the onset of proteinuria. During the initial treatment phase, sessions are usually administered every 2–3 days and continue until proteinuria is reduced to below 1 g per day or until sustained remission is achieved. Typically, the treatment comprises 5–13 sessions, although some reports have described extended treatment periods lasting several years [27,28]. Generally, kidney function normalization or a reduction in proteinuria occurs within 5–27 days. Immunoadsorption has also been utilized in many reports, with case series data suggesting that immunoadsorption has comparable efficacy to plasmapheresis, although no direct comparisons have been conducted, and the precise mechanism of immunoadsorption remains unclear [29].
Additionally, apoproteins play a role in lipid transport and possibly in maintaining the glomerular filtration barrier, which is why low-density lipoprotein apheresis can be considered [30]. This therapy is typically administered in 12 sessions over 9 weeks alongside pulse methylprednisolone, although it is not commonly performed in Korea.
Rituximab, a monoclonal antibody targeting CD20-positive B cells, has shown promise, with remission rates of up to 79% in recurrent FSGS [10,31]. Although the optimal dosing regimen is yet to be determined, both high-dose and low-dose protocols have proven effective, with 1–6 doses reported. Recently, lexatumumab, a fully humanized anti-CD20 antibody with a similar mechanism, has also been employed [32].
In addition to the aforementioned treatments, adjunctive immunosuppressive therapies are frequently used. For example, renin-angiotensin-aldosterone system blockage is employed to reduce protein excretion. In a pediatric study, ACEI were shown to decrease proteinuria by a median of 77% in children with posttransplant proteinuria of various etiologies [33]. In addition, high-dose corticosteroids, calcineurin inhibitors, and cyclophosphamide have been used with varying levels of success [5,34].
Other therapies under investigation include cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin fusion protein (abatacept), which targets B7-1 (CD80) on podocytes [35], anti-tumor necrosis factor-alpha agents [36], and adrenocorticotrophic hormone gel [37]. These treatments are primarily based on case reports or small-cohort studies, necessitating further research to establish their efficacy and safety.
An important consideration is that treatment failure in the native kidneys does not necessarily predict posttransplantation treatment failure. Early intervention after transplantation can prevent sclerosis formation, emphasizing the importance of prompt treatment upon recurrence.
Prevention strategies
Preventing recurrence remains a challenge because it is impossible to know the patients who will experience it beforehand. However, for high-risk patients, such as children with a history of recurrence in a previous allograft, preemptive strategies are considered. These include pretransplant plasmapheresis (3–5 pre-transplantation sessions followed by 3–5 immediate posttransplant sessions) or immunoadsorption sessions, sometimes combined with immunosuppression [6,38]. A single pre-transplantation dose of rituximab has also been used alongside standard immunosuppression protocols [39]. However, a recent TANGO study found no association between recurrence and induction immunosuppression [20]. Additionally, without reliable biomarkers, it is not feasible to administer preventive therapies to all at-risk patients. The potential benefits must be balanced against risks, such as infection.
Conclusion
FSGS continues to be a significant challenge in pediatric kidney transplantation. Although the risk of recurrence is considerable in certain patient groups, advancements in understanding the disease's pathogenesis and management strategies have led to better outcomes. Identifying reliable biomarkers for predicting recurrence would greatly enhance the ability to personalize care and implement preventive measures. Until such biomarkers are available, close monitoring and prompt, intensive treatment of recurrence is essential. Importantly, a diagnosis of FSGS should not be considered a contraindication to kidney transplantation, as many patients can achieve remission and enjoy long-term graft survival.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author contributions
All the work was done by PGP.