We report here the largest series to date of pediatric patients with C3G or IC-MPGN who had received a KTx, because their native kidney function had failed. We observed a high risk of recurrence (55%) within the first 5 years after KTx, which was comparable to the risk of recurrence observed in previously published adult cohorts [9]. A recent study from the GLOSEN group reporting outcomes in adult C3G and IC-MPGN patients following KTx showed that 81 patients (37%) reached kidney failure at a median follow-up of 79 months. Disease recurrence was a key driver of this, occurring in 62% of patients with C3G and 15% of patients with idiopathic IC-MPGN [21]. Zand et al. investigated recurrence of C3GN after KTx specifically in adolescents and adult patients with protocol biopsies performed at month 4 and years 1, 2, 3, and 10 after transplantation. The disease recurred in 66.7% of all cases, resulting in a graft-loss rate of 50% [22]. An earlier pediatric study on MPGN in general found an increased rate of graft loss (32.4%) in children within 5 years after KTx. Recurrence was not specifically investigated [23]. In our cohort, the respective recurrence rate did not significantly differ among C3GN, DDD, and IC-MPGN patients, but the numbers were rather small for a valid statistical comparison. A variety of therapies were used either for prophylaxis or treatment of recurrent C3G or IC-MPGN. Eight patients received eculizumab prophylactically; however, in 5 of these 8 patients (62.5%), C3G recurred nevertheless. These data confirm the previous observation that inhibition of the terminal complement pathway with a C5-targeting antibody is not sufficient for the treatment of C3G or IC-MPGN either in native disease [24] or in case of recurrence in the transplanted kidney [9], and underscores the urgent medical need for more effective therapies for these diseases.

One unique feature of the present study is the comparison of post-transplant outcome data of C3G or IC-MPGN patients with a well-matched control group of patients with non-glomerular (and hence non-recurring) primary kidney diseases. We observed that patients with C3G or IC-MPGN had a significantly lower 5-year graft survival than matched controls with other primary kidney diseases, and this lower graft survival was mainly due to recurrence and not due to rejection, because the rate of BPAR was comparable between C3G or IC-MPGN patients and matched controls. Hence, children and adolescents with C3G or IC-MPGN have a significantly shorter kidney transplant survival rate, due to the recurrence of their respective underlying disease, than patients of the same age with other primary kidney diseases, and therefore cannot benefit equally from KTx. This disadvantage is even more severe in children and adolescents than in adults, because pediatric patients are particularly dependent on the longest possible kidney transplant survival rate due to their significantly higher life expectancy.

There is no targeted therapy addressing the underlying pathophysiology of either C3G or IC-MPGN. Both diseases have recently been discussed in a KDIGO Controversies Conference [25]. Due to the current lack of randomized controlled trials for the treatment of C3G and IC-MPGN, KDIGO has published practice points for treatment, which are based on expert opinion, a limited number of retrospective studies, and extrapolation from other proliferative glomerulonephritides. These practice points focus on the management of primary disease but the level of evidence supporting the use of recommended therapies, including RAAS inhibition, corticosteroids, and MMF/MPS, is low [24]. Our data show that C3G in pediatric KTx recipients did recur despite immunosuppressive treatment with MMF and/or corticosteroids. Furthermore, KDIGO made no specific recommendations regarding the management of recurrent disease [24]. There is therefore great need for a specific therapy, which directly targets the underlying disease mechanism. After the recent successful approval of the C3 inhibitor pegcetacoplan for the treatment of paroxysmal nocturnal hemoglobinuria [26], iptacopan, a novel, low molecular weight, orally active, reversible, and selective inhibitor of Factor B (FB) of the complement AP, is currently developed. Inhibition of Factor B selectively inhibits the catalytic activity of C3 and C5 convertases [27]. Further, the C5a-Receptor antagonist avacopan has been successfully applied to a child with C3GN who was enrolled in the ACCOLADE study (NCT03301467) [28]. Targeted inhibition of complement pathways is expected to be therapeutically beneficial across a range of diseases in which complement AP dysregulation plays an important role in pathogenesis, including C3G and IC-MPGN [29].

The strengths of our study are the multicenter design, the largest number of pediatric patients with C3G or IC-MPGN patients post-transplant analyzed to date, and the review of all kidney transplant biopsy reports by a single histopathologist. Our study has several limitations, the most important of which is the retrospective study design, which is common to registry analyses in general. Another limitation is the lack of centralized laboratory assessment, and the missing data on autoantibodies against complement factors and on mutations in genes encoding complement-regulating proteins in some patients. Also, quantitative data on proteinuria, which is an important risk factor for KTx outcome, were not reported by many centers. In addition, it was not possible to retrospectively assess patient adherence to immunosuppressive medications, which could affect outcome in both the control and C3G/IC-MPGN groups. However, registries reflecting the real-world scenario with heterogeneous immunosuppressive regimens and treatment protocols are potentially suitable to provide a broader view of outcomes and complications, especially in small cohorts such as pediatric kidney allograft recipients.

In conclusion, this multicenter registry study provides an estimate of the incidence of recurrence of C3G or IC-MPGN in the largest series to date of pediatric kidney transplant recipients. Our data show a high risk of recurrence (55%) within 5 years after KTx. This rate is comparable to the risk of recurrence reported in adults. Due to recurrence, pediatric patients with C3G or IC-MPGN had a significantly lower 5-year graft survival than matched controls with other primary kidney diseases. These data underscore the medical need for effective and specific medications both for the prophylaxis and treatment of these progressive and post-transplant recurring kidney diseases to improve the outcome of KTx in this vulnerable patient population.