Long-Term Outcomes, Including Fetal and Neonatal Prognosis, of Renal Oligohydramnios: A Retrospective Study over 22 Years.

OBJECTIVE: To assess the long-term outcome of renal oligohydramnios and risk factors for fetal, neonatal, and postneonatal death. STUDY DESIGN: This retrospective cohort study included fetuses with prenatally detected renal oligohydramnios between 2002 and 2023. Patients who were lost to follow-up were excluded. Fetal, neonatal, and long-term outcomes were evaluated, and their risk factors were analyzed. RESULTS: Of 131 fetuses with renal oligohydramnios, 46 (35%) underwent a termination of pregnancy, 11 (8%) had an intrauterine fetal death, 26 (20%) had a neonatal death, nine (7%) had a postneonatal death, and 39 (30%) survived. Logistic regression analyses showed that an earlier gestational age at onset (OR 1.16, 95% CI 1.01-1.37) was significantly associated with intrauterine fetal death; anhydramnios (OR 12.7, 95% CI 1.52-106.7) was significantly associated with neonatal death as a prenatal factor. Although neonatal survival rates for bilateral renal agenesis, bilateral multicystic dysplastic kidney (MCDK), and unilateral MCDK with contralateral renal agenesis were lower than for other kidney diseases, 1 case of bilateral renal agenesis and two of bilateral MCDK survived with fetal intervention. Kaplan-Meier overall survival rates were 57%, 55%, and 51% for 1, 3, and 5 years, respectively. In the Cox proportional hazards model, birth weight <2000 g (hazard ratio 7.33, 95% CI 1.48-36.1) and gastrointestinal comorbidity (hazard ratio 4.37, 95% CI 1.03-18.5) were significant risk factors for postneonatal death. CONCLUSION: Long-term survival following renal oligohydramnios is a feasible goal and its appropriate risk assessment is important.

Two siblings with acute necrotizing encephalopathy associated with variants of LARS1.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl-tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17-month-old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high-intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1-related disorder.

Sodium removal per ultrafiltration volume in automated peritoneal dialysis in pediatric patients.

BACKGROUND: The standard rate of sodium removal in adult anuric patients on continuous ambulatory peritoneal dialysis (CAPD) is 7.5 g/L of ultrafiltration volume (UFV). Although automated PD (APD) is widely used in pediatric patients, no attempt has yet been made to estimate sodium removal in APD. METHODS: The present, retrospective cohort study included pediatric patients with APD who were managed at Tokyo Metropolitan Children's Medical Center between July 2010 and November 2017. The patients underwent a peritoneal equilibrium test (PET) at our hospital. Sodium removal per UFV was calculated by peritoneal function and dwell time using samples from patients on APD with 1- and 2-h dwell effluent within three months of PET and 4- and 10-h dwell effluent at PET. RESULTS: In total, 217 samples from 18 patients were included, with 63, 81, and 73 of the samples corresponding to the High [H], High-average [HA], and Low-average [LA] PET category, respectively. Sodium removal per UFV (g/L in salt equivalent) for dwell times of one, two, four, and ten hours was 5.2, 8.8, 8.0, and 11.5 for PET [H], 5.3, 5.8, 5.6, and 8.1 for PET [HA], and 4.6, 5.1, 5.1, and 7.1 for PET [LA], respectively. CONCLUSIONS: Sodium removal per UFV in pediatric APD was less than the standard adult CAPD and tended to be lower with shorter dwell times, leading to sodium accumulation. Therefore, salt intake should be restricted in combination with one or more long daytime dwells, especially in anuric patients.

Feasibility of discontinuing immunosuppression in children with idiopathic nephrotic syndrome.

BACKGROUND: Despite adverse events associated with the long-term use of immunosuppressants, their long-term discontinuation remains challenging in children with idiopathic nephrotic syndrome. Relapse and resumption of immunosuppressants after discontinuation and associated risk factors were analyzed. METHODS: This single-center retrospective cohort study included children with frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS) or steroid-resistant nephrotic syndrome (SRNS) who initiated immunosuppressant treatment between 2010 and 2020. Patients treated with immunosuppressants for less than two years, those with genetic SRNS, and those with continuation of immunosuppressants were excluded. RESULTS: Sixty-eight patients with FRNS/SDNS or SRNS discontinued immunosuppressants. Discontinuation of immunosuppressants was more frequently tried in patients with less relapse on initial immunosuppressants and less rituximab administration. Of 68 patients who discontinued immunosuppressants, 45 (66%) relapsed and 31 (46%) resumed immunosuppressants with a median follow-up of 39.8 months (IQR 24.6-71.2 months) after discontinuation. The relapse-free survival rates were 40.0%, 35.3%, and 35.3% in 1, 2, and 3 years from discontinuation of immunosuppressants, respectively. Relapse on initial immunosuppressants (HR 2.038, 95%CI 1.006-4.128, P = 0.048) and the relapse-free interval before discontinuation of immunosuppressants (HR 0.971, 95%CI 0.944-0.998, P = 0.037) were significant risk factors associated with relapse after the discontinuation of immunosuppressants, adjusting for sex, age at immunosuppressant treatment initiation, SRNS, and rituximab use. CONCLUSIONS: Long-term discontinuation of immunosuppressants can be feasible in patients without a relapse on initial immunosuppressants, those with longer relapse-free interval before discontinuation of immunosuppressants, and those without a relapse for one year after discontinuation of immunosuppressants. TRIAL REGISTRATION: Not applicable.

A nationwide survey of MYH9-related disease in Japan.

BACKGROUND: MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, Döhle body-like granulocyte inclusions, and nephropathy, which may progress to end-stage kidney disease (ESKD). However, information on the effects of renin-angiotensin system (RAS) inhibitors on kidney survival is currently lacking and the outcomes of kidney replacement therapy (KRT) in MYH9-RD are largely unknown. METHODS: We conducted a cross-sectional nationwide survey by sending questionnaires to 145 institutions in Japan and analyzed data for 49 patients. RESULTS: The median patient age was 27 years. Genetic analysis was performed in 37 (76%) patients. Twenty-four patients (65%) had MYH9 variants affecting the motor domain of non-muscle myosin heavy chain-IIA, and these patients had poorer kidney survival than those with variants affecting the tail domain (P = 0.02). There was no significant difference in kidney survival between patients treated with and without RAS inhibitors. Hemodialysis and peritoneal dialysis were performed in 16 and 7 patients, respectively. There were no major bleeding complications during the perioperative period or during follow-up, except for one patient. Most of the 11 patients who underwent kidney transplantation required perioperative red cell concentrate transfusions, but there was no graft loss during the median posttransplant observational period of 2.0 (interquartile range, 1.3-6.8) years. CONCLUSION: Our study demonstrated no beneficial effect of RAS inhibitors on kidney function in patients with MYH9-RD, indicating the need for further studies with more patients. All modalities of KRT are feasible options for MYH9-RD patients who progress to ESKD, with adequate attention to bleeding complications.

Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial).

BACKGROUND: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety. METHODS: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m2 doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated. RESULTS: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection. CONCLUSIONS: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

Quantitative Evaluation of Right Ventricular Workload Based on the Stroke Work Index in Patients after Right Ventricular Outflow Tract Reconstruction.

The evaluation of right ventricular workload is sometimes complicated in patients after right ventricular outflow tract reconstruction (RVOTR) because both stenotic and regurgitation lesions are involved. In this study, we modified the right ventricular stroke work index (RVSWI) and evaluated the relationship between the modified RVSWI (mRVSWI) and patient prognosis after RVOTR.We enrolled 69 patients who underwent RVOTR (the RVOTR group), including those who needed early reoperation (early reoperation subgroup) and those who did not (follow-up subgroup), and 13 age-matched control participants (control group). Based on the catheterization results 1 year after RVOTR, we compared the mRVSWI between these groups. Additionally, we evaluated the influence of the mRVSWI on the reoperation avoidance rate and survival.The mRVSWI in the RVOTR group was significantly greater than that in the control group (17.7 ± 8.6 vs. 11.0 ± 2.7 g·m/m2, p = 0.008). The mRVSWI in the early reoperation subgroup was significantly greater than that in the follow-up subgroup (32.5 ± 11.1 vs. 15.8 ± 6.0 g·m/m2, p < 0.0001). In the follow-up subgroup, patients with an mRVSWI higher than the upper limit of normal (16.4 g·m/m2) had a greater rate of reoperation than did the other patients (p = 0.0013). One patient died suddenly, and her mRVSWI was consistently high throughout her life.We established the mRVSWI as an index that integrates the pressure and volume load on the right ventricle. Our results indicate the utility of the mRVSWI for predicting patient prognosis after RVOTR.

Changes in Patterns of Infection Associated with Pediatric Idiopathic Nephrotic Syndrome: A Single-Center Experience in Japan.

OBJECTIVE: We studied infection rates and risk factors for infection in current patients with idiopathic nephrotic syndrome (INS). STUDY DESIGN: This retrospective cohort study included the clinical data for children with diagnosed INS in our center between January 2010 and December 2020. The infection rates and risk factors were analyzed. RESULTS: We enrolled 187 patients, including 85 cases with steroid-dependent/frequently relapsing nephrotic syndrome and 45 with steroid-resistant nephrotic syndrome. Infection was observed a total of 84 times in 55 patients (95.5 per 1000 person-years). Pneumonia was the most common infection (21 cases, 23.9 per 1000 person-years), followed by febrile neutropenia (12 cases, 13.7 per 1000 person-years), whereas peritonitis and bacteremia were observed in only 3 and 2 cases, respectively. The multivariate analyses by logistic regression showed that rituximab treatment was significantly associated with infections in pediatric INS (P = .001). The infection rate during the B-cell-depleted state with immunosuppressants (318 per 1000 person-years) was greater than that with normal B-cell count with immunosuppressants (109 per 1000 person-years) or without immunosuppressants (76 per 1000 person-years). CONCLUSION: Common infections, such as peritonitis and bacteremia, decreased, whereas infections associated with medication (eg, rituximab) increased. The rate of infection increases during B-cell depletion after treatments with rituximab and other immunosuppressants.

Factors related to ultrafiltration volume with icodextrin dialysate use in children.

BACKGROUND: Icodextrin has a lower absorption rate, and icodextrin peritoneal dialysate contributes to more water removal than glucose dialysate in patients with high peritoneal permeability. There are limited data on icodextrin dialysate use in children. METHODS: This study included all pediatric patients who received peritoneal equilibration tests and peritoneal dialysis with icodextrin dialysate at the study center. The factors related to ultrafiltration volume with icodextrin dialysate with long dwell time were statistically analyzed. Then the ultrafiltration volume with icodextrin and medium-concentration glucose dialysate was compared in individual cycles in the same patients. RESULTS: Thirty-six samples were included in the icodextrin group, and nine samples were used to compare the ultrafiltration volume with icodextrin and glucose dialysate. Dwell time, D/P-creatinine, D/D0-glucose, age, height, and weight correlated significantly with the ultrafiltration volume of icodextrin dialysate (p < 0.05). A dwell volume equal to or more than 550 mL/m2 was associated with a significantly higher ultrafiltration volume than a lower dwell volume (p = 0.039). Multiple regression analysis revealed that dwell time (p = 0.038) and height (p < 0.01) correlated with ultrafiltration volume significantly. In addition, the ultrafiltration volume was superior (p < 0.01), and dwell time was longer (p = 0.02), with icodextrin dialysate than with medium-concentration glucose dialysate. CONCLUSIONS: The ultrafiltration volume with icodextrin dialysate decreases in patients with small stature. Providing sufficient dwell time and volume is important for maximal water removal even in children. Ultrafiltration volume is superior with icodextrin than medium-concentration glucose dialysate for long dwell times. A higher resolution version of the Graphical abstract is available as Supplementary information.

Urine alpha 1-microglobulin-to-creatinine ratio and beta 2-microglobulin-to-creatinine ratio for detecting CAKUT with kidney dysfunction in children.

BACKGROUND: The leading cause of advanced chronic kidney disease (CKD) in children is congenital anomalies of the kidney and urinary tract (CAKUT). However, the most appropriate parameters of biochemical urine analysis for detecting CAKUT with kidney dysfunction are not known. METHODS: The present observational study analyzed data on children with CAKUT (stage 2-4 CKD) and the general pediatric population obtained from school urine screenings. The sensitivity and specificity of urine alpha 1-microglobulin-, beta 2-microglobulin-, protein-, and the albumin-to-creatinine ratios (AMCR, BMCR, PCR, ACR, respectively) in detecting CAKUT with kidney dysfunction were compared with those of the conventional urine dipstick, and the most appropriate of these four parameters were evaluated. RESULTS: In total, 77 children with CAKUT and 1712 subjects in the general pediatric population fulfilled the eligibility criteria. Conventional dipstick urinalysis was insufficient due to its low sensitivity; even when the threshold of proteinuria was +/-, its sensitivity was only 29.7% for stage 2 and 44.1% for stage 3 CKD. Among the four parameters assessed, the AMCR and BMCR were adequate for detecting CAKUT in children with stage 3-4 CKD (the respective sensitivity and specificity of the AMCR for detecting CAKUT in stage 3 CKD was 79.4% and 97.5% while that of BMCR was 82.4% and 97.5%). These data were validated using national cohort data. CONCLUSION: AMCR and BMCR are superior to dipstick urinalysis, PCR, and ACR in detecting CAKUT with kidney dysfunction, particularly stage 3 CKD. However, for AMCR, external validation is required. A higher resolution version of the Graphical abstract is available as Supplementary information.

Is influenza vaccination associated with nephrotic syndrome relapse in children? A multicenter prospective study.

BACKGROUND: Prospective research of children receiving heterogeneous vaccines has shown that immunization is not associated with pediatric idiopathic nephrotic syndrome (NS) relapses. However, prospective data concentrating only on influenza (flu) virus vaccines are not available. METHODS: This multicenter prospective study was conducted in children with NS who received inactivated flu vaccines from June 2017 to July 2018. The day of flu vaccination was defined as day 0, and the period between prevaccination and postvaccination days was defined as - X to + Y (period from day - 180 to 0 as the precontrolled period). The primary outcome was the NS relapse rate from day 0 to + 30 as a direct association with vaccination compared with those in the precontrolled period. Exacerbation was defined as children experiencing more NS relapses after vaccination compared with those in the precontrolled period, or children starting any new immunosuppressants due to NS relapse after vaccination. RESULTS: Sixty-three children were included. Relapse rates were not significantly different between the precontrolled period and 0 to + 30 periods (0.38 vs. 0.19 times/person-year, p = 0.95). Although the exacerbation rate during the 0 to + 180 period in children without NS relapse in the precontrolled period was very low (4/54 [7.4 %]), children with at least one NS relapse in the precontrolled period showed a remarkable increase in the rate (4/9 [44.4%]; p = 0.01). CONCLUSIONS: Flu vaccination did not significantly precipitate the direct relapse of NS in children. However, it might increase the disease activity in children with at least one NS relapse within a half year before vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.

Early predictive factors for progression to kidney failure in infants with severe congenital anomalies of the kidney and urinary tract.

BACKGROUND: Severe congenital anomalies of the kidney and urinary tract (CAKUT) progress to infantile kidney failure with replacement therapy (KFRT). Although prompt and precise prediction of kidney outcomes is important, early predictive factors for its progression remain incompletely defined. METHODS: This retrospective cohort study included patients with CAKUT treated at 12 centers between 2009 and 2020. Patients with a maximum serum creatinine level ≤ 1.0 mg/dL during the first 3 days, patients who died of respiratory failure during the neonatal period, patients who progressed to KFRT within the first 3 days, and patients lacking sufficient data were excluded. RESULTS: Of 2187 patients with CAKUT, 92 were finally analyzed. Twenty-five patients (27%) progressed to KFRT and 24 (26%) had stage 3-5 chronic kidney disease without replacement therapy during the median observation period of 52.0 (interquartile range, 22.0-87.8) months. Among these, 22 (24%) progressed to infantile KFRT. The kidney survival rate during the infantile period was significantly lower in patients with a maximum serum creatinine level during the first 3 days (Cr-day3-max) ≥ 2.5 mg/dL (21.8%) compared with those with a Cr-day3-max < 2.5 mg/dL (95.2%) (log-rank, P < 0.001). Multivariate analysis demonstrated Cr-day3-max (P < 0.001) and oligohydramnios (P = 0.025) were associated with higher risk of infantile KFRT. Eighty-two patients (89%) were alive at the last follow-up. CONCLUSIONS: Neonatal kidney function, including Cr-day3-max, was associated with kidney outcomes in patients with severe CAKUT. Aggressive therapy for severe CAKUT may have good long-term life outcomes through infantile dialysis and kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

CD4 + and CD8 + T-lymphocyte number as predictive marker of relapse after rituximab treatment in childhood-onset refractory nephrotic syndrome.

BACKGROUND: Rituximab is a promising option for refractory idiopathic nephrotic syndrome. However, no simple predictive markers for relapse after rituximab have been established. To determine such markers, we investigated the relationship between CD4 + and CD8 + cell counts and relapse after rituximab administration. METHODS: We retrospectively investigated patients with refractory nephrotic syndrome who received rituximab followed by immunosuppressive as maintenance therapy. Patients were divided into no relapse in 2 years after rituximab treatment or relapse group. After rituximab treatment, CD4 + /CD8 + cell counts were measured monthly, at prednisolone discontinuation, and at B-lymphocyte recovery. To predict relapse, these cell counts were analyzed using receiver operating characteristic (ROC). Additionally, relapse-free survival was reevaluated based on the result of ROC analysis for 2 years. RESULTS: Forty-eight patients (18 in the relapse group) were enrolled. At prednisolone discontinuation (52 days after rituximab treatment), the relapse-free group showed significantly lower cell counts than the relapse group (median CD4 + cell count: 686 vs. 942 cells/µL, p = 0.006; CD8 + : 613 vs. 812 cells/µL, p = 0.005). In the ROC analysis, CD4 + cell count > 938 cell/µL and CD8 + cell count > 660 cells/µL could predict relapse in 2 years (sensitivity, 56% and 83%; specificity, 87% and 70%). The patient group with both lower CD4 + and CD8 + cell counts showed significantly longer 50% relapse-free survival (1379 vs. 615 days, p < 0.001 and 1379 vs. 640 days, p < 0.001). CONCLUSIONS: Lower CD4 + and CD8 + cell counts in the early phase after rituximab administration may predict a lower risk of relapse.

Reference blood pressure values obtained using the auscultation method for 2-year-old Japanese children: from the Japan Environment and Children's Study.

BACKGROUND: Reference blood pressure (BP) values for Japanese children based on a large number of measurements by auscultation have not yet been established. METHODS: This was a cross-sectional analysis of data from a birth-cohort study. The data from the sub-cohort study conducted for children at the age of 2 years in the Japan Environment and Children's Study from April 2015 to January 2017 were analyzed. BP was measured via auscultation using an aneroid sphygmomanometer. Each participant was measured in triplicate, and the average value of two consecutive measurements with a difference of less than 5 mmHg was recorded. The reference BP values were estimated using the lambda-mu-sigma (LMS) method and compared with those obtained via the polynomial regression model. RESULTS: Data from 3361 participants were analyzed. Although the difference between the estimated BP values by the LMS and the polynomial regression model was small, the LMS model was more valid based on the results of the fit curve of the observed values and regression models for each model. For 2-year-old children with heights in the 50th percentile, the 50th, 90th, 95th, and 99th percentile reference values of systolic BP (mmHg) for boys were 91, 102, 106, and 112, and that for girls were 90, 101, 103, and 109, respectively, and those of diastolic BP for boys were 52, 62, 65, and 71, and that for girls were 52, 62, 65, and 71, respectively. CONCLUSION: The reference BP values for 2-year-old Japanese children were determined based on auscultation and were made available.

Chapter 4: CKD treatment in cancer survivors, from Clinical Practice Guidelines for the Management of Kidney Injury During Anticancer Drug Therapy 2022.

Chronic kidney disease (CKD) is one of the most disabling disorders with significant comorbidity and mortality. Incidence and prevalence of CKD in cancer survivors are remarkably high in both adults and pediatric patients. The reasons for this high incidence/prevalence are multifold but kidney damage by cancer itself and cancer treatment (pharmacotherapy/surgery/radiation) are the main reasons. Since cancer survivors commonly have significant comorbidities, risk of cancer recurrence, limited physical function or life expectancy, special attentions should be paid when considering the treatment of CKD and its complications. Especially, shared decision-making should be considered when selecting the renal replacement therapies with as much information/facts/evidence as possible.

Mycophenolate Mofetil after Rituximab for Childhood-Onset Complicated Frequently-Relapsing or Steroid-Dependent Nephrotic Syndrome.

BACKGROUND: Rituximab is the standard therapy for childhood-onset complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS). However, most patients redevelop FRNS/SDNS after peripheral B cell recovery. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to examine whether mycophenolate mofetil (MMF) administration after rituximab can prevent treatment failure (FRNS, SDNS, steroid resistance, or use of immunosuppressive agents or rituximab). In total, 39 patients (per group) were treated with rituximab, followed by either MMF or placebo until day 505 (treatment period). The primary outcome was time to treatment failure (TTF) throughout the treatment and follow-up periods (until day 505 for the last enrolled patient). RESULTS: TTFs were clinically but not statistically significantly longer among patients given MMF after rituximab than among patients receiving rituximab monotherapy (median, 784.0 versus 472.5 days, hazard ratio [HR], 0.59; 95% confidence interval [95% CI], 0.34 to 1.05, log-rank test: P=0.07). Because most patients in the MMF group presented with treatment failure after MMF discontinuation, we performed a post-hoc analysis limited to the treatment period and found that MMF after rituximab prolonged the TTF and decreased the risk of treatment failure by 80% (HR, 0.20; 95% CI, 0.08 to 0.50). Moreover, MMF after rituximab reduced the relapse rate and daily steroid dose during the treatment period by 74% and 57%, respectively. The frequency and severity of adverse events were similar in both groups. CONCLUSIONS: Administration of MMF after rituximab may sufficiently prevent the development of treatment failure and is well tolerated, although the relapse-preventing effect disappears after MMF discontinuation.

Long-Term Efficacy and Safety of Repeated Rituximab to Maintain Remission in Idiopathic Childhood Nephrotic Syndrome: An International Study.

BACKGROUND: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. METHODS: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events. RESULTS: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P<0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01 to 0.18; P<0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P=0.05), age at first rituximab treatment (8.0 versus 10.0 years; P=0.01), and history of steroid resistance (28% versus 18%; P=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. CONCLUSIONS: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

Epidemiology of pediatric chronic kidney disease/kidney failure: learning from registries and cohort studies.

Although the concept of chronic kidney disease (CKD) in children is similar to that in adults, pediatric CKD has some peculiarities, and there is less evidence and many factors that are not clearly understood. The past decade has witnessed several additional registry and cohort studies of pediatric CKD and kidney failure. The most common underlying disease in pediatric CKD and kidney failure is congenital anomalies of the kidney and urinary tract (CAKUT), which is one of the major characteristics of CKD in children. The incidence/prevalence of CKD in children varies worldwide. Hypertension and proteinuria are independent risk factors for CKD progression; other factors that may affect CKD progression are primary disease, age, sex, racial/genetic factors, urological problems, low birth weight, and social background. Many studies based on registry data revealed that the risk factors for mortality among children with kidney failure who are receiving kidney replacement therapy are younger age, female sex, non-White race, non-CAKUT etiologies, anemia, hypoalbuminemia, and high estimated glomerular filtration rate at dialysis initiation. The evidence has contributed to clinical practice. The results of these registry-based studies are expected to lead to new improvements in pediatric CKD care.

Glucocorticoid discontinuation in pediatric-onset systemic lupus erythematosus: a single-center experience.

BACKGROUND: Glucocorticoid discontinuation, a challenge in systemic lupus erythematosus (SLE), might be achievable with the advent of new therapeutic options. METHODS: This single-center study included 31 children with newly diagnosed pediatric SLE between 2002 and 2021, after the exclusion of patients who were followed for less than 1 year after treatment initiation and those lost to follow-up. Patient characteristics, clinical course including flares, treatment, glucocorticoid discontinuation, and outcomes were retrospectively analyzed. RESULTS: Glucocorticoids could be discontinued in 19 (61%) patients during a median observation period of 105.5 (range, 17-221) months. Of these, 5 (26%), 12 (63%), and 18 (95%) patients could discontinue glucocorticoids in 3, 5, and 10 years from treatment initiation, respectively. Additionally, 18 of the 19 patients did not experience flares after glucocorticoid discontinuation during a median duration of 37.2 (7.2-106.8) months. Three of the nineteen patients achieved drug-free remission. At last follow-up, all patients achieved low disease activity with or without glucocorticoids and 19, 8, and 1 patient were receiving mycophenolate mofetil (MMF), MMF plus tacrolimus, and MMF plus ciclosporin A, respectively. Flares were observed in 15 patients during the observation period. MMF as initial immunosuppressant (P = 0.01) and shorter interval between therapy initiation and achieving maintenance prednisolone dose of 0.1-0.15 mg/kg/day (P = 0.001) were associated with significantly reduced flare risk. Femoral head necrosis was observed in two patients. CONCLUSION: Despite the small sample size, these results support glucocorticoid discontinuation as a therapeutic target in pediatric SLE.

Validation of the estimated glomerular filtration rate equation for Japanese children younger than 2 years.

BACKGROUND: We have developed a simple and easy method of estimating the glomerular filtration rate (eGFR) of serum creatinine in Japanese children (eGFRUemura). The eGFR equation is for children aged 2-18 years. Therefore Uemura et al. developed an equation for children younger than 2 years (eGFRunder 2). The aim of the present study was to validate this new equation. METHODS: We collected the data of 13 patients from previous studies and compared the results of eGFRunder 2, eGFRUemura, and updated eGFR developed by Schwartz (eGFRSchwartz) with measured GFR using mean error (ME), root mean square error (RMSE), P30 and Bland-Altman analysis. RESULTS: The ME of eGFRunder 2, eGFRUemura and eGFRSchwartz were 2.3 ± 15.9, 7.7 ± 14.5, and 16.0 ± 18.2 ml/min/1.73m2, respectively. The RMSEs were 15.5, 15.9, and 49.6, respectively. The P30 values were 76.9%, 76.9%, and 53.8%, respectively. The graph of Bland-Altman bias analysis showed fan-shape. The eGFRunder 2 equation was the most accurate in the three equations. CONCLUSION: The eGFRunder 2 equation was useful for Japanese children younger than 2 years.