DOI: https://doi.org/10.21203/rs.3.rs-2965758/v1
Background
Although evidence has confirmed that cyclosporine A (CsA) is efficacious against childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome (SD/SRNS), some patients may continue to relapse during adulthood. However, predictive factors for active disease into adulthood and renal complications in this cohort remain unknown.
Methods
We conducted a retrospective study on the long-term outcomes of 81 young adults with childhood-onset SD/SRNS treated with CsA. The primary endpoint was the probability of active disease into adulthood, defined as disease relapse or ongoing immunosuppressive treatment throughout the 2 years preceding the last follow-up.
Results
At last follow-up (median age, 23.2 years; median disease duration, 15.8 years), 44 adult patients (54%) continued to have active disease, whereas 16 (20%) and 16 (20%) patients developed mild chronic kidney disease (CKD) and hypertension, respectively. Young age at NS onset and history of relapse during initial CsA treatment were independent predictive factors for active disease into adulthood. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CsA nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of renal complications. No correlation was observed between active disease into adulthood and the development of renal complications.
Conclusions
After CsA initiation for SD/SRNS, more than half of adult survivors continued to have active disease. Long-term follow-up is necessary to identify the development of renal complications later in adulthood that can be attributed to prior disease and CsA treatment in childhood, irrespective of disease activity.
Idiopathic nephrotic syndrome (NS) is the most common chronic glomerular disease in children. Although most patients with NS respond to corticosteroids with complete remission, 30–50% of them develop steroid-dependent nephrotic syndrome (SDNS). Furthermore, some patients with steroid-resistant nephrotic syndrome (SRNS) also develop SDNS after complete remission with second-line immunosuppressive agents (IS). Of particular interest to children with SD/SRNS and their caregivers is the likelihood of persistent relapses and renal complications in adult survivors [1]. Prior studies, particularly those in the 1980s when corticosteroids and cytotoxic agents were the only treatment choice available, had shown that long-term renal outcomes of childhood-onset NS were excellent when complete remission was achieved, with no relapse in > 80% of patients after puberty and no evidence of deteriorating renal function or hypertension in adulthood [2–4].
During the past three decades, the advent of cyclosporine A (CsA) has relieved children with SD/SRNS from corticosteroid toxicity, such as growth failure, obesity, ocular complications, and osteoporosis. However, recent studies in the post-CsA era have shown a higher incidence of relapse in adulthood than have studies from the 1980s prior to the introduction of CsA [5–7]. At present, a significant clinical concern regarding the later effects of irreversible CsA nephrotoxicity has emerged, especially in young children with a longer life expectancy. In this regard, we previously demonstrated that histologic evidence of CsA nephrotoxicity was significantly associated with the risk for the development of mild chronic kidney disease (CKD) and hypertension in adulthood [8]. Thus, the early initiation of CsA may not be necessarily associated with improved long-term outcomes among young children but rather with persistent active disease and development of renal complications in some adult survivors. However, studies reporting on long-term experiences with childhood-onset NS patients treated with CsA have been scarce.
The current retrospective study therefore aimed to investigate the long-term outcome of children with SD/SRNS after CsA initiation and identify the predictive factors associated with active disease and renal complications in adulthood.
We retrospectively reviewed the clinical course of 81 adult patients (> 18 years) who had initiated CsA treatment for childhood-onset SD/SRNS (1–15 years) between February 1996 and September 2018. The results for the short-term clinical courses of 43 patients have been previously reported [9]. Patients with SRNS who were unable to achieve complete remission with CsA treatment, those who had disease-causing variants, and those who were followed for < 3 years were excluded from the study.
The definitions and criteria for NS, remission, relapse, frequent relapse, steroid dependency, and steroid resistance were adopted from the Clinical Practice Guideline for Pediatric Idiopathic Nephrotic Syndrome in Japan [10]. Acute kidney injury (AKI) was defined as elevated serum creatinine levels ≥ 1.5 times the baseline level. Complicated SDNS was defined continues relapse after the initiation of IS such as CsA and mycophenolate mofetil (MMF). This study was approved by the ethics committee of Saitama Children’s Medical Center (approval no.: 2022-05-004).
For patients with SDNS, CsA (Sandimmun or Neoral, oral formulation, Novartis Pharma Co., Tokyo, Japan) was commenced at a daily dose of 2.5–5 mg/kg given in two divided doses when patients achieved complete remission with prednisolone (PSL). The CsA dosage was adjusted to maintain trough levels of 50–100 ng/mL. Since 2005, CsA has been converted to be initiated at a single daily dose of 1.5–2 mg/kg given before breakfast and adjusted to maintain 2-h post-dose (C2) levels of 600–800 ng/mL [11]. For patients with SRNS, CsA was commenced at a daily dose of 4–7 mg/kg given in two divided doses, increasing the dosage to maintain trough levels of 100–150 ng/mL or C2 levels of 600–800 ng/mL [12]. After achieving complete remission in patients with SRNS, the dosage was decreased to maintain trough levels of 50–100 ng/mL or C2 levels of 400–600 ng/mL. After approximately 2 years of CsA treatment, the dosage was gradually tapered off within 6 months. MMF (30–40 mg/kg/day given in two divided doses; maximum, 2000 mg/day) was offered as a treatment option for patients who developed complicated SDNS after CsA treatment [13]. For patients who achieved > 12 months of PSL-free remission, MMF was gradually tapered off within 6 months. Among the patients who developed relapses after MMF discontinuation, those with CsA nephrotoxicity were re-treated with MMF, whereas those without CsA nephrotoxicity were re-treated with CsA. Since 2007, a single dose (375 mg/m2; maximum, 500 mg) of rituximab (RTX; Rituxan, injection, Zenyaku Co., Tokyo, Japan) has been administered for patients with complicated SDNS after CsA or MMF treatment [14]. For young children with SDNS aged < 10 years and before puberty, cyclophosphamide (Endoxan, oral formulation, Shionogi Co., Osaka, Japan) was administered at a single daily dose of 2–2.5 mg/kg/day for 12 weeks (cumulative dosage, 200 mg/kg) [15]. For young children with low-dose steroid dependency, a single, daily, high dose of mizoribine (10 mg/kg/day maximum, 300 mg/day; Bredinine, oral formulation, Asahikasei, Tokyo, Japan) was offered as a treatment option [16]. Relapses were treated with PSL at 2 mg/kg/day (maximum, 60 mg/day) until proteinuria was undetectable for at least three consecutive days. PSL was administered on alternate days thereafter, and the dosage was tapered off within 6 months at a rate of 5–10 mg every 2–4 weeks.
To assess treatment outcomes and detect potential drug toxicity, clinical and laboratory parameters were measured every 1–3 months. Laboratory assessments included measurement of complete blood count, serum urea, creatinine, electrolyte, total protein, albumin, cholesterol, transaminase, bilirubin, amylase, uric acid, C-reactive protein, and immunoglobulin levels, as well as blood levels of drugs, including CsA and mycophenolic acid.
First, renal biopsy was performed at the time of initial CsA treatment in patients with SD/SRNS. After approximately 2 years of CsA treatment, serial biopsies were also performed to confirm the presence of CsA nephrotoxicity [17]. Kidney specimens were examined using light, immunofluorescence, and electron microscopies. Based on the Banff classification, CsA nephrotoxicity was classified according to the presence of arteriolar hyalinosis with accompanying interstitial fibrosis (grade ±, < 5%; grade 1, 5–25%; grade 2, 26–50%; grade 4, > 50%) [18]. Kidney specimens were evaluated by a single pathologist (HM) blinded to the patients’ clinical courses.
The primary endpoint was the probability of active disease into adulthood, defined as disease relapse or ongoing immunosuppressive treatment, including PSL, IS, and RTX throughout the 2 years preceding the last follow-up. In contrast, long-term remission was defined as > 2 years of remission without any treatment. To evaluate renal function, the estimated glomerular filtration rate (eGFR) was calculated using the equation for Japanese adult patients [19]. For children aged 2–18 years, the GFR was also calculated using a creatinine-based equation for Japanese children and adolescents [20]. The secondary endpoints were the probability of developing renal complications in adulthood: progression to CKD stage ≥ 2 (eGFR < 90 mL/min/1.73 m2) and hypertension (> 140/90 mmHg or ongoing antihypertensive treatment).
Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate and were reported as frequencies and percentages. Unless otherwise indicated, continuous variables were expressed as median (interquartile range). The parametric two-sample t-test or non-parametric Mann–Whitney U test was used as appropriate for comparing continuous variables. Logistic regression was used to identify independent predictive factors for active disease into adulthood. Quadratic regression was used to model the relationship between the cumulative proportion of renal complications and age at last follow-up. Statistical analyses were performed using R version 4.0.3, EZR version 1.54 (Saitama Medical Center, Jichi Medical University), and STATA 16.1 (Stata Corp, College Station, TX), with p values of < 0.05 indicating statistical significance.
Patients with SDNS (n = 59) or SRNS (n = 22) received initial CsA treatment at a median age of 10.0 years. Prior to initial CsA treatment, CPM and MZR were used in 14 and 6 patients, respectively. Among the 22 patients with SRNS, 21 were initial non-responder and 1 was a late non-responder. Although all patients maintained complete remission during initial CsA treatment (median duration, 31 months), 54 of the 81 patients (66%) experienced at least one relapse. Serial renal biopsies were performed in 79 patients, 36 of whom had CsA-induced nephrotoxicity (grade ±, n = 19; grade 1, n = 16; grade 2, n = 1). After the initial CsA treatment, MMF, CPM, MZR, and RTX were administered in 66, 9, 30, and 42 patients, respectively. After the CsA treatment interruption, 33 patients underwent re-treatment with CsA. At the last follow-up (median disease duration, 15.8 years; median age, 23.2 years), all patients maintained complete remission of NS. Among the included patients, 37 (46%) achieved long-term remission (long-term remission group), whereas the remaining 44 (54%) had received IS and/or RTX (MMF, 30 patients; CsA, 7 patients; RTX, 22 patients) within 2 years at last follow-up (active disease group). Although CKD 16 (20%) and 16 (20%) patients developed stage 2 and hypertension, respectively, none developed severe CKD (stage ≥ 3). Meanwhile, 14 and 8 patients developed obesity and short stature, respectively.
As shown in Table 1, no significant differences in sex, episode of AKI at NS onset, type of IS before initial CsA treatment, history of SRNS, histological evidence of focal segmental glomerulosclerosis (FSGS), age at last follow-up, disease duration, and development of CKD or hypertension were observed between the active disease and long-term remission groups. However, compared to the long-term remission group, the active disease group had a younger median age at NS onset (5.6 vs. 11.0 years; p < 0.05) and initial CsA treatment (8.7 vs. 11.7 years; p < 0.05) and more patients with a history of relapse during initial CsA treatment (86% vs. 46%; p < 0.001). Multivariate analysis showed that a younger age at NS onset (odds ratio, 0.88; 95% CI, 0.78–0.99) and a history of relapse during initial CsA treatment (odds ratio, 5.17; 95% CI, 1.78–15.0) were independent predictive factors for active disease in adulthood (Table 2). Furthermore, univariate analysis to compare the clinical characteristics between the CKD and non-CKD groups showed that former was significantly more likely to have an episode of AKI at NS onset, histological evidence of FSGS and irreversible CsA nephrotoxicity, hypertension, and older age at last follow-up (Table 3). Univariate analysis to compare the clinical characteristics between the hypertension and normotension groups also showed that the risk of hypertension in adulthood was positively associated with development of CKD and older age at last follow-up (Table 4). Taken together, older age at last follow-up was associated with a higher proportion of CKD or hypertension, irrespective of disease activity (Fig. 1). An analysis of the correlation between age at last follow-up and the cumulative proportion of renal complications revealed a quadratic regression curve with a higher rate of renal complications with increasing age (Y= -0.8918 + 0.06186X – 0.0008X2, P < 0.001, R2 = 0.96, Fig. 2).
| Overall | Active disease group | Long-term remission group | p-value | |
|---|---|---|---|---|
| (n = 81) | (n = 44) | (n = 37) | ||
| Male, n (%) | 57 (70.4) | 33 (75.0) | 24 (64.9) | 0.34 |
| Age at nephrotic syndrome onset (years) | 7.7 (3.8–12.0) | 5.62 (3.5–10.3) | 11.1 (6.3–12.4) | 0.014 |
| Acute kidney injury at nephrotic syndrome onset, n (%) | 18 (22.2) | 7 (15.9) | 11 (29.7) | 0.18 |
| Indication of initial cyclosporine: steroid resistance/dependence | 22/59 | 10/34 | 12/25 | 0.45 |
| History of initial steroid-resistant nephrotic syndrome, n (%) | 21 (26.0) | 9 (20.5) | 12 (32.4) | 0.31 |
| Renal histology of focal segmental glomerulosclerosis, n/N (%) | 8/79 (10.1) | 3/42 (7.1) | 5/37 (13.5) | 0.46 |
| Use of immunosuppressive agents before initial cyclosporine, n (%) | 18 (22.2) | 12 (27.3) | 6 (16.2) | 0.29 |
| Mizoribine | 6 (7.4) | 4 (9.1) | 2 (5.4) | 0.68 |
| Cyclophosphamide | 14 (17.3) | 10 (22.7) | 4 (10.8) | 0.24 |
| Age at initial cyclosporine (years) | 10.0 (5.85–12.4) | 8.59 (4.37–11.2) | 11.7 (7.95–12.9) | 0.023 |
| Duration of initial cyclosporine treatment (months) | 31.0 (26.7–40.0) | 29.0 (26.8–36.3) | 34.0 (29.0–40.0) | 0.23 |
| History of relapse during initial cyclosporine treatment, n (%) | 54 (66.7) | 37 (84.1) | 17 (45.9) | < 0.001 |
| Irreversible cyclosporine nephrotoxicity, n/N (%) | 17/79 (21.5) | 11/43 (25.6) | 6/36 (16.7) | 0.42 |
| Use of immunosuppressive agents after initial cyclosporine, n (%) | 75 (92.6) | 44 (100.0) | 31 (83.8) | 0.0072 |
| Mycophenolate mofetil | 66 (81.5) | 42 (95.5) | 24 (64.9) | < 0.001 |
| Rituximab | 43 (53.1) | 33 (75.0) | 10 (27.0) | < 0.001 |
| Mizoribine | 30 (37.0) | 18 (40.9) | 12 (32.4) | 0.49 |
| Cyclophosphamide | 9 (11.1) | 6 (13.6) | 3 (8.1) | 0.50 |
| Cyclosporine | 36 (40.7) | 25 (56.8) | 11 (29.7) | 0.024 |
| Age at last follow-up (years) | 23.2 (20.8–26.0) | 23.0 (20.0-25.7) | 23.6 (21.5–27.4) | 0.26 |
| Duration until last follow-up from nephrotic syndrome onset (years) | 15.8 (11.5–20.3) | 16.6 (11.5–21.0) | 14.7 (11.5–18.2) | 0.18 |
| estimated glomerular filtration rate (mL/min/1.73 m2) | 104.8 (94.3-118.9) | 106.3 (94.3-121.9) | 103.4 (94.3-117.4) | 0.45 |
| estimated glomerular filtration rate < 90 mL/min/1.73 m2, n (%) | 16 (19.8) | 8 (18.2) | 8 (21.6) | 0.78 |
| Hypertension | 16 (19.8) | 8 (18.2) | 8 (21.6) | 0.78 |
| Data are shown as median (interquartile range) or as n (%). | ||||
| Odd ratio | 95% CI | p-value | |
|---|---|---|---|
| Younger age at nephrotic syndrome onset | 0.88 | 0.78–0.99 | 0.030 |
| Sex (male) | 0.73 | 0.24–2.19 | 0.57 |
| History of relapse during initial cyclosporine treatment | 5.17 | 1.78-15.0 | 0.002 |
| Overall | CKD group | Non-CKD group | p-value | |
|---|---|---|---|---|
| (n = 81) | (n = 16) | (n = 65) | ||
| Male, n (%) | 57 (70.4) | 14 (87.5) | 43 (66.2) | 0.13 |
| Age at nephrotic syndrome onset (years) | 7.7 (3.8–12.0) | 10.1 (4.3–12.4) | 7.61 (3.7–11.3) | 0.31 |
| Acute kidney injury at nephrotic syndrome onset, n (%) | 18 (22.2) | 8 (50.0) | 10 (15.4) | 0.006 |
| Indication of initial cyclosporine: steroid resistance/dependence | 22/59 | 6/10 | 16/49 | 0.35 |
| History of initial steroid-resistant nephrotic syndrome, n (%) | 21 (26.0) | 6 (37.5) | 15 (23.1) | 0.34 |
| Renal histology of focal segmental glomerulosclerosis, n/N (%) | 8/79 (10.1) | 5/16 (31.3) | 3/63 (4.8) | 0.007 |
| Use of immunosuppressive agents before initial cyclosporine, n (%) | 18 (22.2) | 4 (25.0) | 14 (21.5) | 0.75 |
| Mizoribine | 6 (7.4) | 1 (6.3) | 5 (7.7) | 1.0 |
| Cyclophosphamide | 14 (17.3) | 4 (25.0) | 10 (15.4) | 0.46 |
| Age at initial cyclosporine (years) | 10.0 (5.85–12.4) | 11.2 (9.09-13.0) | 9.78 (4.61–12.3) | 0.27 |
| Duration of initial cyclosporine treatment (months) | 31.0 (26.7–40.0) | 30.5 (28.8–55.3) | 31.0 (26.0–37.0) | 0.15 |
| History of relapse during initial cyclosporine treatment, n (%) | 54 (66.7) | 12 (75.0) | 42 (64.6) | 0.56 |
| Irreversible cyclosporine nephrotoxicity, n/N (%) | 17/79 (21.5) | 9/16 (56.3) | 8/63 (12.7) | 0.001 |
| Immunosuppressive agents after initial cyclosporine, n (%) | 75 (92.6) | 15 (93.8) | 60 (92.3) | 1.0 |
| Mycophenolate mofetil | 66 (81.5) | 13 (81.3) | 53 (81.5) | 1.0 |
| Rituximab | 43 (53.1) | 11 (68.8) | 32 (49.2) | 0.26 |
| Mizoribine | 30 (37.0) | 8 (50.0) | 22 (33.8) | 0.26 |
| Cyclophosphamide | 9 (11.1) | 0 (0.0) | 9 (13.8) | 0.19 |
| Cyclosporine | 36 (40.7) | 6 (37.5) | 30 (46.2) | 0.59 |
| Age at last follow-up (years) | 23.2 (20.8–26.0) | 28.4 (25.2–29.8) | 22.8 (19.9–24.6) | < 0.001 |
| Duration until last follow-up from nephrotic syndrome onset (years) | 15.8 (11.5–20.3) | 19.1 (15.4–21.7) | 15.2 (11.3–18.7) | 0.049 |
| estimated glomerular filtration rate (mL/min/1.73 m2) | 104.8 (94.3-118.9) | 86.3 (78.4–88.7) | 111.3 (100.0-121.1) | < 0.001 |
| Active disease, n (%) | 44 (54.3) | 8 (50.0) | 36 (55.4) | 0.78 |
| Hypertension, n (%) | 16 (19.8) | 9 (56.3) | 7 (10.8) | < 0.001 |
| CKD chronic kidney disease. Data are shown as median (interquartile range) or as n (%). | ||||
| Overall | Hypertension group | Normotension group | p-value | |
|---|---|---|---|---|
| (n = 81) | (n = 16) | (n = 65) | ||
| Male, n (%) | 57 (70.4) | 14 (87.5) | 43 (66.2) | 0.13 |
| Age at nephrotic syndrome onset (years) | 7.7 (3.8–12.0) | 6.7 (3.4–11.6) | 8.4 (4.0-11.8) | 0.77 |
| Acute kidney injury at nephrotic syndrome onset, n (%) | 18 (22.2) | 5 (31.3) | 13 (20.0) | 0.33 |
| Indication of initial cyclosporine: SRNS/SDNS | 22/59 | 4/12 | 18/47 | 1.0 |
| History of initial steroid-resistant nephrotic syndrome, n (%) | 21 (26.0) | 5 (31.3) | 16 (24.6) | 0.75 |
| Renal histology of focal segmental glomerulosclerosis, n/N (%) | 8/79 (10.1) | 3/16 (18.8) | 5/63 (7.9) | 0.35 |
| Immunosuppressive agents before initial cyclosporine, n (%) | 18 (22.2) | 4 (25.0) | 14 (21.5) | 0.75 |
| Mizoribine | 6 (7.4) | 1 (6.3) | 5 (7.7) | 1.0 |
| Cyclophosphamide | 14 (17.3) | 4 (25.0) | 10 (15.4) | 0.46 |
| Age at initial cyclosporine (years) | 10.0 (5.85–12.4) | 10.6 (8.2–12.2) | 9.8 (4.6–12.4) | 0.66 |
| Duration of initial cyclosporine treatment (months) | 31.0 (26.7–40.0) | 35.5 (26.8–49.5) | 31.0 (27.0–37.0) | 0.32 |
| History of relapse during initial cyclosporine treatment, n (%) | 54 (66.7) | 10 (62.5) | 44 (67.7) | 0.77 |
| Irreversible cyclosporine nephrotoxicity, n/N (%) | 17/79 (21.5) | 5/16 (31.3) | 12/63 (19.0) | 0.32 |
| Use of immunosuppressive agents after initial cyclosporine, n (%) | 75 (92.6) | 15 (93.8) | 60 (92.3) | 1.0 |
| Mycophenolate mofetil | 66 (81.5) | 14 (87.5) | 52 (80.0) | 0.72 |
| Rituximab | 43 (53.1) | 9 (56.3) | 34 (52.3) | 1.0 |
| Mizoribine | 30 (37.0) | 8 (50.0) | 22 (33.8) | 0.26 |
| Cyclophosphamide | 9 (11.1) | 2 (12.5) | 7 (10.8) | 1.0 |
| Cyclosporine | 36 (40.7) | 7 (43.8) | 29 (44.6) | 1.0 |
| Age at last follow-up (years) | 23.2 (20.8–26.0) | 28.2 (24.4–29.8) | 22.7 (19.9–24.8) | < 0.001 |
| Duration until last follow-up from nephrotic syndrome onset (years) | 15.8 (11.5–20.3) | 18.8 (16.8–22.7) | 14.8 (11.1–18.7) | 0.004 |
| estimated glomerular filtration rate (mL/min/1.73 m2) | 104.8 (94.3-118.9) | 88.8 (86.7-106.4) | 109.5 (96.7–121.0) | 0.004 |
| Active disease, n (%) | 44 (54.3) | 8 (50.0) | 36 (55.4) | 0.78 |
| Chronic kidney disease, n (%) | 16 (19.8) | 9 (56.3) | 7 (10.8) | < 0.001 |
| Data are shown as median (interquartile range) or as n (%). | ||||
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.
Acknowledgements
The authors would like to thank MARUZEN-YUSHODO Co., Ltd. for the English language editing.
Author contributions
YT and SF designed the study, drafted the manuscript, were responsible for the data integrity and analysis results. DH provided statistical support. All authors critically reviewed and approved the final manuscript.
Funding
SF has received Grants-in-Aid for research of Saitama Children's Medical Center.
Data availability
The datasets of the current study are available from the corresponding author on reasonable request.
Conflict of interest
The authors declare no competing interests
Ethical approval
All procedures performed in this study involving human participants were in accordance with the ethical standards set by the ethics committee of Saitama Children’s Medical Center in which the study was conducted and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards
Informed consent
The Institutional Review Board waived the requirement for informed consent due to the retrospective nature of this study.