Combination therapy of rituximab and mycophenolate mofetil in childhood lupus nephritis.

BACKGROUND: In clinical trials, the addition of rituximab (RTX) to the combination therapeutic regimen of mycophenolate mofetil (MMF) and corticosteroids failed to improve outcome in lupus nephritis (LN). However, recent data suggest that RTX may have steroid-sparing beneficial effects with an efficacy similar to that of conventional regimens. We report our experience with RTX in the treatment of children with LN. METHODS: Patients treated with RTX for first occurrence of LN class III to V were enrolled in the study. Treatment consisted of methylprednisolone pulse (500 mg/m2) followed by RTX (1000 mg/1.73 m2) at days 1 and 15, and MMF (1200 mg/m2/day). Prednisolone tapering and withdrawal was left to the physician's discretion. Complete remission (CR) was defined as a urine protein-to-creatinine ratio (U Pr/Cr) of <5 mg/mg and normal serum creatinine, and partial remission (PR) as a U Pr/Cr of <30 mg/mg and a <15% rise in serum creatinine over baseline. RESULTS: Twelve patients were included in the study, with median follow-up of 23.7 [interquartile range (IQR) 12.8-33.5] months. Median age of the patients was 13.6 [12.3-15.1] years, median proteinuria was 32 [19-67] mg/mg and median estimated glomerular filtration rate was 76.1 [59.3-97.7] mL/min/1.73 m2. Median CD20 depletion duration was 10 [6.8-11.0] months. Prednisolone was rapidly tapered, with median dose of 0.3 [0.15-0.41], 0.10 [0.09-0.16] and 0.0 [0.0-0.04] mg/kg/day at 3, 6 and 12 months respectively. At 3 months, three and seven patients achieved CR and PR, respectively; at 6 and 12 months all patients achieved remission (9 CR, 3 PR) and none relapsed during follow-up. Five infectious complications were observed, including three varicella-zoster virus (VZV) infections. CONCLUSIONS: In our pediatric patients with LN, therapy with RTX + MMF combined with a rapid decrease in steroid appears to have been an efficacious treatment for severe LN but was associated with high rate of VZV infection. The potential of RTX to allow complete steroid avoidance warrants further investigation in children.

Prediction of steroid-sparing agent use in childhood idiopathic nephrotic syndrome.

BACKGROUND: About half of children with steroid-sensitive idiopathic nephrotic syndrome (INS) will develop steroid dependency or a frequently relapsing course requiring steroid-sparing agents (SSA). Because of the adverse effects of prolonged steroid treatment, the early identification of children at high risk of requiring SSA may be a useful diagnostic tool to tailor the therapeutic strategy. The aim of this study was to identify predictors of the need for SSA and derive a predictive model. METHODS: This was a retrospective hospital-based cohort study which included all children with steroid-responsive INS followed for at least 4.5 months. Cox regression modeling and decision curve analysis were performed. RESULTS: A total of 120 children (81 boys) with INS were included and followed up for a median time of 6.7 (range 0.4-24.1) years. Median age at diagnosis was 3.4 years. Seventy-two (60 %) children required a SSA after a median time of 10 months following initial diagnosis. Male children, age at disease onset, methylprednisolone pulse use, and time to achieve first remission were significantly associated with the outcome. Time to achieve remission only remained significant after adjustment: hazard ratio (HR) =1.9 [95 % confidence interval (CI) 1.5-2.5] if considered as a continuous variable, and HR=4.1 (95 % CI 1.9-8.6) when dichotomized using the 9-day threshold. The area under the receiver operating curve of the related predictive model was 0.81 (95 % CI 0.74-0.89), and the decision curve analysis demonstrated that this model performed better than any other strategy. CONCLUSIONS: Time to first remission is a strong predictor of the need for SSA in pediatric INS. Further prospective and impact studies are warranted to confirm the accuracy and benefit of our prediction model.

Hemolytic uremic syndrome complicating Mycoplasma pneumoniae infection.

BACKGROUND: Mycoplasma pneumoniae can cause various extrapulmonary manifestations but, to our knowledge, no case of Mycoplasma pneumoniae associated with hemolytic uremic syndrome (HUS) has been reported. CASE-DIAGNOSIS/TREATMENT: We describe a 1-year-old boy with M. pneumoniae respiratory tract infection and associated microangiopathic hemolytic anemia, slightly decreased platelet count and mild renal impairment, suggesting a diagnosis of HUS. Assuming M. pneumoniae infection was the cause of HUS in this case, the different possible mechanisms, including an atypical HUS due to preexisting complement dysregulation, an alternative complement pathway activation induced by M. pneumoniae infection at the acute phase, an autoimmune disorder, and a direct role of the bacteria in inducing endothelial injury, are discussed. The signs of HUS resolved with treatment of the M. pneumoniae infection. CONCLUSIONS: Hemolytic uremic syndrome may be an unusual complication of M. pneumoniae infection.

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

Mycophenolic Acid Pharmacokinetics and Relapse in Children with Steroid-Dependent Idiopathic Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring of mycophenolic acid can improve clinical outcome in organ transplantation and lupus, but data are scarce in idiopathic nephrotic syndrome. The aim of our study was to investigate whether mycophenolic acid pharmacokinetics are associated with disease control in children receiving mycophenolate mofetil for the treatment of steroid-dependent nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective multicenter study including 95 children with steroid-dependent nephrotic syndrome treated with mycophenolate mofetil with or without steroids. Area under the concentration-time curve of mycophenolic acid was determined in all children on the basis of sampling times at 20, 60, and 180 minutes postdose, using Bayesian estimation. The association between a threshold value of the area under the concentration-time curve of mycophenolic acid and the relapse rate was assessed using a negative binomial model. RESULTS: In total, 140 areas under the concentration-time curve of mycophenolic acid were analyzed. The findings indicate individual dose adaptation in 53 patients (38%) to achieve an area under the concentration-time curve target of 30-60 mg·h/L. In a multivariable negative binomial model including sex, age at disease onset, time to start of mycophenolate mofetil, previous immunomodulatory treatment, and concomitant prednisone dose, a level of area under the concentration-time curve of mycophenolic acid >45 mg·h/L was significantly associated with a lower relapse rate (rate ratio, 0.65; 95% confidence interval, 0.46 to 0.89; P=0.01). CONCLUSIONS: Therapeutic drug monitoring leading to individualized dosing may improve the efficacy of mycophenolate mofetil in steroid-dependent nephrotic syndrome. Additional prospective studies are warranted to determine the optimal target for area under the concentration-time curve of mycophenolic acid in this population.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations.

BACKGROUND AND OBJECTIVES: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS: Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS: Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.