Adult survivors of childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome treated with cyclosporine: a long-term single-center experience.

BACKGROUND: Although evidence has confirmed that cyclosporine (CS) 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 adult active disease and kidney complications, such as chronic kidney disease (CKD) and hypertension, 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 CS. The primary endpoint was the probability of active disease into adulthood. The secondary endpoint was the probability of developing kidney complications. RESULTS: At the 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 patients developed CKD or hypertension, respectively. The proportion of patients developing kidney complications was similar between the active disease and long-term remission groups. Young age at NS onset and history of relapse during the initial CS (median, 31 months) were independent predictive factors for active disease. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CS nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of CKD and hypertension. CONCLUSIONS: More than 50% of adult survivors treated with CS continued to have active disease, and each 20% developed CKD or hypertension. A long-term follow-up is necessary for patients with SD/SRNS to identify the development of kidney complications later in adulthood that can be attributed to prior disease and CS treatment in childhood, irrespective of disease activity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants.

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Predictive factors of long-term disease remission after rituximab administration in patients with childhood-onset complicated steroid-dependent nephrotic syndrome: a single-center retrospective study.

BACKGROUND: Despite the fact that rituximab (RTX)-associated adverse events may be relatively frequent in younger patients, recent studies have reported RTX as a suitable first-line steroid-sparing agent for maintaining remission in children with steroid-dependent nephrotic syndrome (SDNS). However, the impact of age at RTX initiation on the long-term outcome remains unknown in this cohort. METHODS: We retrospectively reviewed the clinical course of 61 patients with complicated SDNS who received a single dose of RTX (375 mg/m2) followed by maintenance immunosuppressive agents (IS) from January 2008 to March 2021. In patients who achieved > 12 months of prednisolone-free remission, IS tapering within 6 months was tried to achieve. The primary endpoint was the probability of achieving long-term treatment-free remission at the last follow-up. RESULTS: After RTX initiation, 52 patients (85.2%) relapsed after a median of 665 days, and 44 patients (72.1%) received additional RTX doses (total, 226 infusions). At the last follow-up (median observation period, 8.3 years; median age, 18.3 years), 16 patients (26.2%) achieved long-term remission. Multivariate analysis showed that older age at RTX initiation was the independent predictive factor for achieving long-term remission (odds ratio, 1.25; p < 0.05). The proportion of those who achieved long-term remission was significantly higher in patients aged ≥ 13.5 years than in those aged < 13.5 years at RTX initiation (52.6 vs 14.3%, p < 0.05). Persistent severe hypogammaglobulinemia did not develop in older children (≥ 13.5 years) at RTX initiation. CONCLUSION: For older children with complicated SDNS, RTX appeared to be a suitable disease-modifying therapy without persistent adverse events.

Medical and psychosocial outcomes in adolescents and young adults with childhood-onset end-stage kidney disease: a multicenter study in Japan.

BACKGROUND: Adolescents and young adults face various socio-emotional and behavioral challenges that can affect their medical and psychosocial outcomes. Pediatric patients with end-stage kidney disease (ESKD) often have extra-renal manifestations, including intellectual disability. However, limited data are available regarding the impact of extra-renal manifestations on medical and psychosocial outcomes among adolescents and young adults with childhood-onset ESKD. METHODS: Patients born between January 1982 and December 2006 that had developed ESKD in 2000 and later at age < 20 years were enrolled in this multicenter study in Japan. Data for patients' medical and psychosocial outcomes were retrospectively collected. Associations between extra-renal manifestations and these outcomes were analyzed. RESULTS: In total, 196 patients were analyzed. The mean age at ESKD was 10.8 years, and at last follow-up was 23.5 years. The first modality of kidney replacement therapy was kidney transplantation, peritoneal dialysis, and hemodialysis in 42, 55 and 3% of patients, respectively. Extra-renal manifestations were documented in 63% of patients and 27% had intellectual disability. Baseline height at kidney transplantation and intellectual disability significantly impacted final height. Six (3.1%) patients died, of which five (83%) had extra-renal manifestations. Patients' employment rate was lower than that in the general population, especially among those with extra-renal manifestations. Patients with intellectual disability were less likely to be transferred to adult care. CONCLUSIONS: Extra-renal manifestations and intellectual disability in adolescents and young adults with ESKD had considerable impacts on linear growth, mortality, employment, and transfer to adult care.

Hydrogen-rich water reduced oxidative stress and renal fibrosis in rats with unilateral ureteral obstruction.

BACKGROUND: Congenital obstructive nephropathy (CKD) is commonly implicated in the pathophysiology of chronic kidney disease occurring in the pediatric and adolescent age groups and the release of reactive oxygen species contribute to the worsening of renal fibrosis. Molecular hydrogen (H2) protects against tissue injury by reducing oxidative stress. We evaluated the efficacy of oral H2-rich water (HW) intake in preventing unilateral ureteral obstruction (UUO)-induced renal injury in rats. METHODS: Male Sprague-Dawley UUO or control rats were administered with distilled water (DW) or HW for 2 weeks post-surgery. Histopathological and immunohistochemical analyses of kidney samples were performed. RESULTS: Histological changes were not apparent in the sham-operated kidneys. However, UUO kidneys were found to have widened interstitial spaces and tubular dilatation. Compared with the UUO + DW group, HW administration attenuated tubulointerstitial injury and reduced interstitial fibrotic area, causing a substantial decline in the frequency of α-SMA-, ED-1-, and TGF-ß1-positive cells in the UUO + HW group. The decrease in the klotho mRNA expression in the UUO + HW group was less pronounced than that in the UUO + DW group. CONCLUSION: Oral HW intake reduced oxidative stress and prevented interstitial fibrosis in UUO kidneys, potentially involving klotho in the underlying mechanism. IMPACT: Oral intake of hydrogen-rich water (HW) can reduce oxidative stress and suppress interstitial fibrosis in unilateral ureteral obstruction-induced renal injury in rats. This mechanism possibly involves klotho, which is known for its antiaging roles. The association between molecular hydrogen and klotho in renal fibrosis is well known; this is the first report on the association in a unilateral ureteral obstruction model. Drinking HW is a safe and convenient treatment for oxidative stress-induced pathologies, without side effects. As a prospect for future research, oral HW intake to treat oxidative stress may improve renal fibrosis in congenital obstructive nephropathy.

Clinical, pathological, and genetic characteristics of cases with asymptomatic proteinuria not manifesting nephrotic syndrome at onset: a single-center retrospective study.

BACKGROUND: Cases with asymptomatic proteinuria (ASP) not manifesting nephrotic syndrome often pathologically show focal segmental glomerulosclerosis (FSGS). However, characteristics of those cases had not been intensively studied so far. METHODS: We retrospectively reviewed clinical, pathological, and genetic characteristics of 37 children (median age, 9.3 years) who underwent renal biopsy for persistent isolated proteinuria (urine protein-to-creatinine ratio: UP/C, > 0.2 g/g) between 2003 and 2019. Targeted next-generation sequencing (NGS) was utilized for all patients with FSGS, excluding those with secondary FSGS. RESULTS: At biopsy, all patients with FSGS (N = 14) had UP/C ≥ 0.5 g/g and the median UP/C was significantly higher in those with FSGS than those with minor glomerular abnormalities (MGA) (N = 23) (1.49 vs. 0.53 g/g, P < 0.001). Causative variants were found in seven patients with FSGS (TRPC6, WT1, ACTN4, and INF2 in 3, 2, 1, and 1 patient, respectively): all gene variants were in genes manifesting autosomal dominant inheritance mode. The proportion of the perihilar variant was significantly higher in the genetic FSGS patients than in the non-genetic FSGS patients (4/7 vs. 0/7, P < 0.05). Kaplan-Meier analysis showed that the renal survival rate after ASP diagnosis was significantly lower in the genetic FSGS patients than in the non-genetic FSGS and the MGA patients (P < 0.001). CONCLUSIONS: UP/C was a simple and useful predictive parameter for the diagnosis of FSGS. APS without nephrotic syndrome at onset may be associated with autosomal dominant causes of FSGS, especially in those with the perihilar variant.

Predictors of Treatment Response and Long-Term Outcomes in Young Children with Steroid-Dependent Nephrotic Syndrome Treated with High-Dose Mizoribine as First-Line Steroid-Sparing Agent.

Mizoribine may be a safe and effective treatment for children with steroid-dependent nephrotic syndrome (SDNS). However, predictors of treatment response and long-term outcomes after mizoribine discontinuation remain unknown. We retrospectively reviewed the clinical course of 22 children aged ≤ 10 years (median age, 5.3 years) with SDNS who received high-dose mizoribine as the initial steroid-sparing agent (SSA). Mizoribine was administered at a single daily dose of 10 mg/kg (maximum, 300 mg/day) after breakfast. The dose was adjusted to maintain 2-h post-dose mizoribine levels of > 3 µg/mL and was tapered off after 12 months of steroid-free remission. Patients who regressed to SDNS were switched from mizoribine to other SSAs. The primary endpoint was probability of survival without regression to SDNS after mizoribine initiation. Ten patients were able to discontinue SDNS (response group), whereas twelve were switched from mizoribine to other SSAs (non-response group) during a median observation period of 6.0 years after mizoribine. The steroid-dependent dose prior to mizoribine was significantly lower in the response group than in the non-response group (p < 0.05). The Kaplan-Meier analysis revealed that the probability of regression-free survival was significant higher in patients with steroid-dependent dose of < 0.25 mg/kg/day than in those with steroid-dependent dose of ≥ 0.25 mg/kg/day (p < 0.05). During a median follow-up of 5.5 years after mizoribine discontinuation, all but one patient did not develop SDNS. High-dose mizoribine may be an attractive treatment option as initial SSA in young children with low steroid-dependent dose for improved long-term outcomes.

Reference serum creatinine levels according to sex, age, and height in children with Down syndrome.

Standard serum creatinine (S-Cr) levels in healthy children fluctuate with age and sex. However, it is unclear if this fluctuation in S-Cr levels is present for children with Down syndrome (DS) who show atypical growth rate. Therefore, we aimed to establish specific reference S-Cr levels for DS and compare them with the prevailing standard levels. We retrospectively reviewed 984 children with DS aged 3 months to 18 years who visited our medical center. Patients with diseases affecting S-Cr levels were excluded. We calculated the reference S-Cr levels according to sex, age, and length/height using medical records. A total of 3765 examinations of 568 children with DS were registered for this study. Ages and S-Cr levels were examined for boys (y = 0.032x + 0.20; r = 0.868, P < 0.0001), and girls (y = 0.024x + 0.23; r = 0.835, P < 0.0001). S-Cr levels in children aged >9 years were significantly higher in boys than in girls. The 430 children with DS aged 2-8 years were examined 1867 times. Height and S-Cr levels showed a significantly strong positive correlation (r = 0.670, P < 0.001) with regression equation y = 0.37x. The quintic equations calculated with S-Cr levels and length/height for boys (336 children, 2043 tests, r = 0.887) and girls (232 children, 1722 tests, r = 0.805) werey = - 6.132x5 + 32.78x4 - 67.86x3 + 68.31x2 - 33.14x + 6.41, and y = 0.09542x5 + 1.295x4 - 6.401x3 + 10.35x2 - 6.746x + 1.772. All calculated results varied from the standard levels for healthy children.Conclusion: This study established reference S-Cr levels and quintic equations specific for children with DS. These reference levels would be potentially useful in evaluating S-Cr levels and renal function in this population. What is Known: •Standard serum creatinine levels vary with age and sex to reflect muscle mass. •Reference serum creatinine levels specific to children with Down syndrome who show growth rates different from those of healthy children have not been established. What is New: •Serum creatinine levels in children with Down syndrome showed different trajectories for sex, age, and length/height when compared with the standard levels for healthy children. •This report on specific reference serum creatinine levels for children with Down syndrome is useful in the assessment of renal function in these children.

Is the estimated glomerular filtration rate formula useful for evaluating the renal function of Down syndrome?

BACKGROUND: Children with Down syndrome (DS) have different growth rates compared with normal children. The present study examined the reliability of a general formula, Uemura's formula, utilized in normal Japanese children to estimate renal function (estimated glomerular filtration rate - eGFR) in children with DS. METHODS: This study included 758 children aged 2-18 years with DS who visited our medical center. Patients with congenital heart disease, or congenital anomalies of the kidney or urinary tract detected via abdominal ultrasonography, chronic glomerulonephritis, and vesicoureteral reflux, etc., were excluded. Height and serum creatinine data gathered from 2421 examinations of 379 children with DS (224 boys and 155 girls) were used to evaluate Uemura's formula. RESULTS: The mean eGFR was lower in children with DS than in children without DS. Stage II chronic kidney disease was indicated in 44.6% of examinations and stage III in 0.8%. The association of eGFR with age differed between sexes. Boys with DS showed a significant but weak negative correlation between eGFR and age (r = -0.273, P < 0.001), whereas girls with DS showed a significant but very weak negative correlation (r = -0.111, P < 0.001). CONCLUSIONS: A new eGFR formula that takes into account specific growth rates and puberty is needed for children with DS because general renal function evaluation formulas are inappropriate for these patients.

Baseline characteristics and long-term outcomes of steroid-resistant nephrotic syndrome in children: impact of initial kidney histology.

BACKGROUND: Although many pediatric nephrologists consider focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) as separate clinical entities, whether the initial histology could affect clinical courses in children with steroid-resistant nephrotic syndrome (SRNS) suspected of having an immune-based etiology remains unknown, especially for long-term outcomes. METHODS: We retrospectively reviewed long-term outcomes (> 3 years; median follow-up, 9.1 years) of 21 children with initial SRNS (FSGS, N = 9; MCD, N = 12) who achieved complete remission with immunosuppressive agents, including cyclosporine. RESULTS: At NS onset, incidence of acute kidney injury (67% vs. 8%, P < 0.05) and proportion of patients with non-selective proteinuria (56% vs. 0%, P < 0.01) were significantly higher in the FSGS group than the MCD group. Furthermore, median days until complete remission after treatment was significantly longer in the FSGS group than the MCD group (116 days vs. 45 days, P < 0.001). Although subsequent biopsy histology of the 12 patients in the MCD group was still identical in all MCD, three of nine patients in the FSGS group were reclassified from FSGS to MCD at second biopsy. At last visit, all patients maintained complete remission, and none developed chronic kidney disease. CONCLUSIONS: Initial presentation in the FSGS group was characterized by more severe clinical manifestations than the MCD group. If complete remission is achieved, FSGS and MCD in children with immune-mediated SRNS may constitute a single disease spectrum because the long-term outcomes are favorable, irrespective of initial histology.

Unfavorable impact of anti-rituximab antibodies on clinical outcomes in children with complicated steroid-dependent nephrotic syndrome.

BACKGROUND: Anti-rituximab antibodies (ARA) are associated not only with adverse events, such as infusion reactions (IR) and serum sickness, but also with rituximab efficacy. However, the clinical relevance of ARA in children with steroid-dependent nephrotic syndrome (SDNS) remains unknown. METHODS: We retrospectively reviewed clinical outcomes of 13 children with complicated SDNS receiving repeated single-dose rituximab treatments at 375 mg/m2 to assess whether ARA formation could impact toxicity and efficacy of additional rituximab. Pre-rituximab 22 samples collected from patients who developed IR during the second or subsequent rituximab doses were measured by electrochemiluminescence analysis. RESULTS: ARA were identified in 5 of 13 patients (9 of 22 samples). Median time to recovery of CD19+ B cells to > 1% of total lymphocytes and median relapse-free time after rituximab treatment were significantly shorter in the 9 ARA-positive samples than the 13 ARA-negative samples (41 vs. 100 days, p < 0.01 and 119 vs. 308 days, p < 0.05, respectively). Kaplan-Meier analysis showed that time to CD19+ B cell recovery after rituximab was significantly shorter in ARA-positive samples than in ARA-negative samples (p < 0.005). Severe IR developed in two ARA-positive patients and serum sickness in one ARA-positive patient. CONCLUSIONS: The incidence of ARA formation was high in the pre-rituximab samples of patients with complicated SDNS who developed IR during the second or subsequent rituximab doses, suggesting that ARA formation might have an unfavorable impact on the toxicity and efficacy of additional rituximab doses in these patients.

Preventive Effect of Tonsillectomy on Recurrence of Henoch-Schönlein Purpura Nephritis after Intravenous Methylprednisolone Pulse Therapy.

Henoch-Schönlein purpura (HSP) is regarded as a benign and self-limiting vasculitis characterized by purpura, arthritis, and gastrointestinal symptoms; however, about one third of the patients develop HSP nephritis (HSPN), the most serious long-term complication. Since 2013, we have proposed that tonsillectomy in addition to intravenous methylprednisolone pulse therapy (IVMP) be performed in all patients with HSPN, similar to immunoglobulin A nephropathy (IgAN) patients because both diseases are considered to a share common pathogenesis. Herein, we retrospectively reviewed the clinical courses of 71 Japanese children with HSPN (34 boys; median age at diagnosis, 6.7 years; median follow-up period, 5.6 years) who had received initial treatment with IVMP (15-20 mg/kg; on 3 consecutive days/week for 3 weeks) followed by oral prednisolone (initially 1 mg/kg; tapered off within 12 months) and achieved clinical remission (i.e., disappearance of both proteinuria and hematuria). The patients were divided into two groups: 31 patients receiving tonsillectomy after IVMP between 2013 and 2017 (tonsillectomy group) and 40 patients receiving IVMP monotherapy between 2003 and 2012 (IVMP group). For the 2 years after IVMP therapy, the rate of HSPN recurrence (i.e., persistent proteinuria combined with hematuria requiring additional treatments) after clinical remission was significantly lower in the tonsillectomy group than the IVMP group (0% vs. 19%, P < 0.05). Despite the short follow-up period in the tonsillectomy group, this study provides the evidence that tonsillectomy may be beneficial for preventing recurrence of HSPN from clinical remission with IVMP therapy in Japanese children.

Long-term outcome of Japanese children with complicated minimal change nephrotic syndrome treated with mycophenolate mofetil after cyclosporine.

BACKGROUND: Although recent studies have shown that more than half of children with steroid-dependent nephrotic syndrome (SDNS) may continue to have active disease beyond childhood, the long-term outcome in this cohort treated with mycophenolate mofetil (MMF) after cyclosporine remains unknown, particularly in adulthood. METHODS: We conducted a retrospective study of 44 adult patients (median age, 22.3 years) who received MMF for complicated SDNS (median age at MMF initiation, 13.3 years) at a single center. Complicated SDNS was defined as the case continuing to relapse after cyclosporine (CsA) treatment. When patients experienced relapses despite MMF initiation, they additionally received a rituximab infusion. The primary endpoint was the probability of achieving treatment-free remission for > 2 years. RESULTS: Prior to MMF initiation, all patients received CsA for a median of 46 months and 19 received the 12-week cyclophosphamide. After switching from CsA to MMF, only four patients did not relapse during a median follow-up period of 9.6 years. At the last visit, only 15 of the 44 patients achieved treatment-free sustained remission. Multivariate analysis revealed that young age (< 6 years) at onset of nephrotic syndrome (odds ratio, 11.3) and the experience of steroid dependency during initial CsA treatment (odds ratio, 29.8) were the independent risk factors of active disease into adulthood after MMF initiation. CONCLUSIONS: Although none developed renal insufficiency and severe adverse effects of therapy, the introduction of MMF after CsA treatment may not be necessarily associated with improved long-term outcome of children with complicated SDNS.

Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome.

BACKGROUND: Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear. CASE-DIAGNOSIS/TREATMENT: We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with ≥ 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow-up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency. CONCLUSIONS: Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term.