The current long-term single-center study found that 54% of young adults with childhood-onset SD/SRNS treated with CsA continued to have active disease. Young age at NS onset and a history of relapse during initial CsA treatment were identified as independent predictive factors for active disease into adulthood. Furthermore, renal complications developed in 20% of adult survivors. AKI at NS onset, histological evidence of FSGS, and histological evidence of irreversible CsA nephrotoxicity were identified as risk factors for the development of CKD during adulthood. In addition, the proportion of renal complications increased with age at last follow-up, irrespective of disease activity during adulthood. However, adult nephrologists would not likely follow young adults without renal complications unless they continue to have active disease [21]. The lack of knowledge about late-onset renal complications that can be attributed to prior disease and CsA treatment may prevent the suitable transition of patients to adult health care providers. Our data suggest that this cohort needs long-term follow-up to identify the development of late-onset renal complications, even in those achieving long-term remission.
In a follow-up French study of 102 young adults (median age, 25.9 years) with childhood-onset NS, Fakhouri et al. reported that 43 patients (42.2%) experienced at least one relapse in adulthood [5]. The authors also found that young age at NS onset, severe disease activity (i.e., greater number of relapses) during childhood, and more frequent use of CsA could predict the occurrence of relapse in adulthood. In a follow-up German study of 42 adults (median, 28.0 years) with childhood-onset NS, Rüth et al. reported that 14 patients (33%) experienced relapse in adulthood [6]. They also showed that severe disease activity (i.e., number of relapses and use of IS) during childhood was significantly associated with the occurrence of relapse in adulthood. In particular, linear regression model analysis identified only use of CsA as a significant predictor of adulthood relapses. In a follow-up Danish study of 39 adult patients (mean, 22.8 years) with childhood-onset NS from an unselected population, Korsgaard et al. reported that 12 patients (31%) continued to experience relapse or have ongoing IS in adulthood [7]. They also found that patients with childhood FR/SDNS were at higher risk for developing active disease in adulthood. Taken together, all recent follow-up studies, including ours, demonstrated that the incidence of relapses in adulthood was higher than that reported by previous studies in the 1980s, particular in those requiring CsA treatment. Notably, Ishikura et al. reported that 36 of 46 children (78.3%) with FRNS after initial CsA treatment continued to experience relapses of NS or receive IS approximately 10 years later, beyond adolescence and into adulthood [22]. The same authors found that a history of relapse during the initial CsA treatment could be a risk factor for relapse at the last observation, although no significant findings were observed (p = 0.09). Our study identified that young age at NS onset and a history of relapse during initial CsA treatment were independent predictive factors for active disease into adulthood. Early identification of factors that could predict active disease into adulthood during initial CsA treatment may allow optimal counselling for young children and their caregivers. This would ensure suitable timing of MMF and RTX administration in this cohort may be initiated, thereby reducing morbidity associated with long-term CsA treatment such as irreversible nephrotoxicity and renal complications.
Recently, transition from AKI to CKD has become an established concern in children with NS. In fact, a prospective short-term study of 119 children suffering from AKI associated with NS in Pakistan by Yaseen et al. demonstrated that 41.2% of the patients progressed to CKD at 3 months [23]. Moreover, they demonstrated that SRNS, histological evidence of FSGS, and use of CsA were factors significantly associated with the development of CKD. In a nationwide survey of 999 children with newly diagnosed NS in Japan, Sato et al. reported that 6.6% of the patients developed CKD at a median follow-up period of 4.1 years [24]. The same authors found that AKI at NS onset was significantly associated with the development of mild CKD. The current study also identified episode of AKI at NS onset, histological evidence of FSGS, and histological evidence of irreversible CsA nephropathy as risk factors for the development of CKD during adulthood. Indeed, our data showed that 6 of the 9 patients with both AKI at NS onset and irreversible CsA nephropathy (67%) progressed to CKD in adulthood. Thus, we recommend that long-term CsA use be avoided in patients with a history of AKI at NS onset.
Interestingly, we found that the proportion of patients with CKD and hypertension increased significantly with age at last follow-up, even among those achieving long-term remission in adulthood. However, no correlation was observed between active disease into adulthood and the development of renal complications. Similarly, in a long-term German study of 43 adult patients (mean age, 33.6 years) with childhood NS, Aydin et al. reported no correlation between the development of hypertension and severity of the disease course [25]. Moreover, a population-based large cohort study in Israel showed that childhood history of resolved glomerular disease, such as NS and acute glomerulonephritis, was significantly associated with an increased risk of kidney failure and hypertension during adulthood, even when no overt compromise of renal function existed during childhood [26–28]. This finding is consistent with the established notion that nephron loss due to critical events during childhood (i.e., AKI and CsA nephrotoxicity) can increase susceptibility to CKD and hypertension later in adulthood due to hyperfiltration of residual nephrons, despite having already resolved the prior disease.
Our study has several limitations worth noting. First, given the uncontrolled retrospective design of the current study, inherent selection and reporting biases could not be avoided. Second, the sample size was too small to draw robust conclusions. However, the therapeutic protocol was relatively homogeneous in this single-center study. Furthermore, to the best of our knowledge, this has been the longest follow-up study in children with SD/SRNS treated with CsA.
In conclusion, the present study demonstrated that childhood SD/SRNS requiring CsA treatment is not entirely confined to childhood but can persist into adulthood. Furthermore, later effects associated with prior disease and CsA treatment may continue to impact adult survivors, irrespective of the disease activity during adulthood. Therefore, we believe that adult patients with a history of childhood SD/SRNS treated with CsA require periodic and long-term urinalysis, renal function tests, and blood pressure measurements, regardless of whether treatment-free remission was achieved during adulthood. Further long-term follow-up studies are needed to improve the monitoring and management of patients with childhood SD/SRNS after the initiation of CsA treatment.