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.

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.

Risks and renal outcomes of severe acute kidney injury in children with steroid-resistant nephrotic syndrome.

BACKGROUND: Risks and renal outcomes of severe acute kidney injury (AKI) in children with steroid-resistant nephrotic syndrome (SRNS), particularly those who require dialysis, have not been fully explored. METHODS: This retrospective cohort study enrolled children who had been diagnosed with idiopathic nephrotic syndrome at the National Center for Child Health and Development between March 2002 and December 2018. Children with steroid-sensitive nephrotic syndrome or SRNS-related gene mutations were excluded. RESULTS: Sixty-two children with SRNS (37 boys; median age, 3.6 years [interquartile range (IQR) 2.0-10.3]) were enrolled. Sixteen patients (25.8%) had severe AKI, including nine patients (14.5%) who received dialysis. The period from nephrotic syndrome (NS) onset to partial remission (median [IQR]) was not significantly influenced by dialysis status, but tended to be longer in the dialysis group (125 days [74-225] vs. 40 days [28-113]; p = 0.09); notably, no patient developed chronic kidney disease during the follow-up period. Infection and posterior reversible encephalopathy (PRES) were significantly associated with AKI. Patients with AKI tended to require dialysis in the presence of infection, undergo treatment with cyclosporine A, and have PRES. The period from onset of NS to AKI was significantly longer in the dialysis group (26 days [15.5-46.0] vs. 4 days [0.0-14.0]; p = 0.01). CONCLUSION: Dialysis was commonly required among children with SRNS who exhibited severe AKI. The period from onset of NS to partial remission tended to be longer in patients receiving dialysis, whereas renal prognosis was satisfactory during subsequent follow-up.

Prophylactic rituximab administration in children with complicated nephrotic syndrome.

BACKGROUND: Rituximab is effective for maintaining remission in patients with complicated nephrotic syndrome, although a history of steroid-resistant nephrotic syndrome (SRNS) is a risk factor for early relapse. We investigated the efficacy of prophylactic rituximab treatment for maintaining remission after B cell recovery. METHODS: Patients with complicated steroid-dependent or frequently relapsing nephrotic syndrome with history of SRNS who received a single dose of rituximab (375 mg/m2) and continued immunosuppressive agents were enrolled in this retrospective study. Patients were divided into two groups: a prophylaxis group, which received additional rituximab treatment at B cell recovery and a non-prophylaxis group. The relapse-free period from the last rituximab infusion (the second treatment in prophylaxis group and the first treatment in non-prophylaxis group) was compared between two groups using the Kaplan-Meier method, and risk factors for early relapse were calculated using multivariate analysis by Cox proportional hazards model. RESULTS: Sixteen patients in the prophylaxis group and 45 in the non-prophylaxis group were enrolled. Fifty-percent relapse-free survival after the last rituximab treatment was 667 days in the former and 335 days in the latter (p = 0.001). Multivariate analysis showed that additional rituximab treatment was the only significant negative factor for early relapse, with a hazard ratio of 0.40 (p = 0.02). Fifty-percent relapse-free survival after B cell recovery was much longer in the prophylaxis group (954 vs. 205.5 days, p = 0.003). CONCLUSIONS: Additional rituximab treatment at B cell recovery can maintain prolonged remission even after B cell recovery in patients with complicated nephrotic syndrome with history of SRNS.

Two cases of idiopathic steroid-resistant nephrotic syndrome complicated with thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is a histopathological entity associated with microangiopathic hemolytic anemia, thrombocytopenia, and end-organ ischemic damage. Although TMA is caused by various diseases, there have been few reports regarding children with idiopathic nephrotic syndrome (NS) and TMA. Here we report two 1-year-old infants with steroid-resistant NS (SRNS) who presented with severe hypertension, acute kidney injury (AKI), and TMA. CASE PRESENTATION: The diagnosis of NS was complicated with anemia, AKI, and hypertension. Maximum blood pressure was 150/70 mmHg in Case 1 and 136/86 mmHg in Case 2. There was no thrombocytopenia during their clinical course in both cases. Renal biopsy showed the features of TMA, including endothelial cell swelling, capillarectasia or marked mesangiolysis, along with mesangial proliferation in Case 1 and TMA with minor glomerular abnormalities in Case 2. Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and secondary TMA other than that caused by hypertension were excluded. Oral prednisolone therapy, frequent infusion of albumin and diuretics, and multiple anti-hypertensive drugs were initiated. Blood pressure was controlled after 6 and 7 days from initiation of multiple anti-hypertensive drugs and lisinopril was added due to persistent mild proteinuria and mild hypertension after improvement of renal function in both cases. Proteinuria resolved completely 4 months after admission with daily oral prednisolone for 4 weeks followed by alternative daily oral prednisolone for 4 weeks in Case 1. Proteinuria resolved completely 10 months after admission with initial prednisolone treatment for 4 weeks followed by cyclosporine A and intravenous methylprednisolone pulse therapy in Case 2. The follow-up biopsy showed no TMA findings in both patients. Because the patient in Case 1 subsequently developed frequent relapsing NS, cyclosporine A was commenced after the second biopsy and he did not have any flares for 2 years. Renal function was normal in Case 1 and mildly decreased in Case 2 at last follow-up (creatinine-eGFR of 136.2 mL/min/cm2 in Case 1 and 79.5 mL/min/cm2 in Case 2). CONCLUSION: Severe hypertension and AKI can be signs of TMA in patients with SRNS. Strict anti-hypertensive therapy might improve renal outcomes.

Association between the clinical presentation of congenital anomalies of the kidney and urinary tract (CAKUT) and gene mutations: an analysis of 66 patients at a single institution.

BACKGROUND: The association between the clinical presentation of congenital anomalies of the kidney and urinary tract (CAKUT) and gene mutations has yet to be fully explored. METHODS: In this retrospective cohort study, we examined patients with CAKUT who underwent gene analysis. The analysis was performed in patients with bilateral renal lesions, extrarenal complications, or a family history of renal disease. The data from the diagnosis, gene mutations, and other complications were analyzed. RESULTS: In total, 66 patients with CAKUT were included. Of these, gene mutations were detected in 14 patients. Bilateral renal lesions were significantly related to the identification of gene mutations (p = 0.02), and no gene mutations were observed in patients with lower urinary tract obstruction (six patients). There was no significant difference in the rate of gene mutations between those with or without extrarenal complications (p = 0.76). The HNF1ß gene mutation was identified in most of the patients with hypodysplastic kidney with multicystic dysplastic kidney (six of seven patients). There was no significant difference in the presence or absence of gene mutations with respect to the renal survival rate (log-rank test p = 0.53). The renal prognosis varied, but the differences were not statistically significant for any of the gene mutations. CONCLUSIONS: CAKUT with bilateral renal lesions were significantly related to gene mutations. We recommend that CAKUT-related gene analysis be considered in cases of bilateral renal lesions. No gene mutations were observed in patients with lower urinary tract obstruction. The renal prognosis varied for each gene mutation.

Association between Immunoglobulin M and Steroid Resistance in Children with Nephrotic Syndrome: A Retrospective Multicenter Study in Japan.

Background: The prognosis of steroid-resistant nephrotic syndrome (SRNS) in children is poorer than steroid-sensitive cases. Diagnosis of SRNS is made after observing the response to the initial 4-week corticosteroid therapy, which might be accompanied by side effects. However, predictive indicators at initial diagnosis remain unknown. We aimed to investigate whether selectivity index (SI) and other indicators at initial diagnosis-for example, serum IgM and total serum protein-albumin ratio (TA ratio, total serum protein level over albumin level)-can predict SRNS. Methods: A total of 80 children were enrolled from seven hospitals in Japan between January 2008 and December 2019 (mean age, 4.7 years; 65% male). Of the children enrolled, 13 (16%, M/F=5:8) had been diagnosed as steroid resistant after initial treatment with steroids. The association between serum IgM (tertile categories: low, 24-133; middle, 134-169; and high, 169.1-510 mg/dl), SI (<0.2 or ≥0.2), and TA ratio (tertile categories: low, 1.8-2.6; middle, 2.62-3.75; and high, 3.8-15.3) at initial diagnosis and steroid resistance was evaluated with logistic regression, adjusting for age and sex. Results: Low levels of serum IgM were significantly associated with steroid resistance (adjusted odds ratio, 6.94; 95% CI, 1.12 to 43.11). TA ratio and SI were not significantly associated with steroid resistance. Conclusions: Low levels of serum IgM at initial diagnosis might predict steroid resistance among Japanese children with idiopathic nephrotic syndrome.