A case of rapid avacopan-induced liver injury in pediatric granulomatosis with polyangiitis.

Children with anti-neutrophil cytoplasmic antibody-associated vasculitis benefit immensely from avacopan as it reduces the requirement for steroids. However, descriptions of adverse drug reactions in children are lacking, and the dosage and follow-up intervals are unclear. A 10-year-old boy with initial granulomatosis and polyangiitis presented with diffuse pulmonary hemorrhage. Rituximab and 30 mg avacopan were administered twice daily as induction therapy following methylprednisolone pulse therapy. However, sudden liver function test abnormalities were observed on day 31 of avacopan treatment, despite liver enzyme levels being within the normal range 5 days earlier. A drug-induced lymphocyte stimulation and various infectious disease tests yielded negative results. Discontinuation of rituximab and avacopan resulted in improved liver function; no change in the Birmingham Vasculitis Activity Score during liver function test abnormalities was observed. Avacopan-associated abnormalities in liver function tests suggest that drug-induced liver injury may occur rapidly in children, and appropriate dosing strategies should be reconsidered.

Glomeruli Count and Arterial Injury in Real-Time Ultrasound-Guided Needle Kidney Biopsy Specimens: Adequacy of Three Approaches for Pig Kidneys.

INTRODUCTION: Real-time ultrasound-guided percutaneous kidney biopsy is essential for diagnosis and treatment planning; nonetheless, the optimal puncture approach has yet to be established. In vivo, performing different approaches on the same patient at once is not possible. This study aimed to determine the impact of different approaches on the number of obtained glomeruli and their potential to cause arterial injury using pig kidneys, which are similar to humans. METHODS: A total of 120 pig kidneys (60 right-sided kidneys and 60 left-sided kidneys) for research were obtained from a slaughterhouse. The specimens were collected from the lower pole on the sagittal plane of the kidney using three different approaches on the same kidney: caudocranial approach, caudal to cranial; craniocaudal approach, cranial to caudal; and vertical approach, through the surface cortex. Five blinded pediatric nephrologists assessed the number of glomeruli and arterial injuries. RESULTS: Overall, 360 specimens were collected from the kidneys through biopsy using a 16-gauge needle (mean vertical kidney length, 11.2 ± 0.7 cm; mean depth, 3.47 ± 0.23 cm). No significant difference in the incidence of arterial injury was observed between the three approaches (caudocranial vs. craniocaudal vs. vertical approaches: 78% vs. 87% vs. 87%, p = 0.14). In contrast, the vertical approach retrieved significantly more glomeruli than the caudocranial and craniocaudal approaches (caudocranial approach: 7.5 ± 2.8, craniocaudal approach: 7.8 ± 2.7, and vertical approach: 8.9 ± 3.3, p < 0.001). CONCLUSIONS: Considering its efficacy and safety profile, the vertical approach may be preferred, as more glomeruli can be obtained without increasing the incidence of arterial injury. Although the results cannot be directly extrapolated to humans due to the differences between species, they still offer important insights into the characteristics of each approach.

A Case of Shear Wave Velocity Reflecting the Disease Activity in Glomerulonephritis.

Ultrasound elastography can measure tissue elasticity using the shear wave velocity (SWV). Evaluating disease activity with elastography instead of renal biopsy may be less invasive. However, to the best of our knowledge, although there are studies comparing different glomerular diseases using SWV, there are no reports that have measured glomerulonephritis longitudinally from the acute phase of the disease. This study aimed to assess whether SWV reflects disease activity in glomerulonephritis, and we continued to observe children with post-streptococcal acute glomerulonephritis (PSAGN) from the acute phase to over a year later. In this case, a 6-year-old boy diagnosed with PSAGN had impaired renal function, and was admitted and tested. He was placed in a prone resting position and measurements were taken from the back. SWV was measured ≥50 times at each examination, and the mean was calculated when the net amount of effective SWV was ≥50%. The tests were performed once in the acute phase and thrice during the recovery phase for 13 months. SWV was found to be significantly lower in the recovery period than during the disease onset, and continued to stay lower at each test during the recovery period (P < 0.02). In conclusion, this indicated that SWV fluctuated similarly to the disease activity of glomerulonephritis; therefore, we suggest using SWV measurement to estimate the disease activity in glomerulonephritis in children. Although more clinical cases are needed, SWV measurement is a noninvasive and reproducible imaging modality to estimate the disease activity in glomerulonephritis.

Cyclosporine A C1.5 monitoring reflects the area under the curve in children with nephrotic syndrome: a single-center experience.

BACKGROUND: The currently used single-monitoring method for drug-blood-level evaluation in cyclosporine A (CsA) treatment for nephrotic syndrome (NS) was established through hourly measurements based on adult organ transplantation. However, the pharmacokinetics may differ due to different concomitant medications, age, and conditions. This study was conducted to determine the measurement timing that best reflects the CsA area under the curve (AUC) in pediatric NS. METHODS: This retrospective study included children aged 2-14 years who were started on CsA treatment for idiopathic NS during 2013-2020. AUC0-4 was calculated from 7 points, before and 0.5, 1, 1.5, 2, 3, and 4 h after administration. Mean values at each timing were compared with age-dependent different drug forms. Correlation between AUC0-4 and measurement timing was analyzed. RESULTS: There were 13 patients (11 boys) whose median age during testing was 7.3 years, and the total number of measurements was 94. The highest timing of CsA concentrations was found in C1 59.6%. The content liquid used at younger ages had a faster absorption time to peak value and lower blood concentration than those of capsules. Among the significant correlations observed, AUC0-4 and C1.5 showed the strongest significant correlation coefficient (r = 0.93, P < 0.001). CONCLUSION: In pediatric NS, CsA metabolism may be faster than that in previous organ transplantation. Compared with C2, C1.5 monitoring may result in better disease control as it can best reflect the AUC0-4 and peak values associated with side effects, which are indicators of therapeutic efficacy.

Effects of diurnal variation of bile acids by meal on cyclosporine A absorption.

BACKGROUND: Stabilizing blood levels with microemulsified cyclosporine A (CsA), administered in many pediatric kidney diseases, is important for effective immunosuppression and reduced nephrotoxicity. CsA is affected by total bile acids (TBAs); however, no reports have simultaneously measured both. We aimed to elucidate the hypothesized relationship between TBA levels and diurnal variation in CsA in children. METHODS: We retrospectively reviewed the medical records of children who were taking oral CsA for the treatment of kidney diseases between January 2016 and July 2021. They consumed four balanced meals and snacks during the day. CsA and TBA were measured twice, in pairs, before and at 0.5, 1, 1.5, 2, 3, and 4 h after oral administration in the morning and evening, and the four-h area under curve (AUC)0-4 of CsA and trough-to-peak ratio (TPR) of TBA were compared. RESULTS: Fifty-eight pairs were measured in total; 12 children had idiopathic nephrotic syndrome and 4 children had immunoglobulin A vasculitis with nephritis. The median age at measurement was 7.5 years and the dose of CsA was 3.8 mg/kg/day. The AUC0-4 (ng·h/mL) was significantly lower in the evening than in the morning (1,669 vs. 1,451, P < 0.001). The TPR of TBA was significantly higher in the evening than in the morning (0.14 vs. 0.25, P < 0.001). CONCLUSIONS: The low AUC0-4 and slow TBA secretion observed in the evening may be due to pediatric-specific dietary rhythms; thus, snack timing should be considered in children for stabilizing CsA levels.

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.

Effects of low-dose oxygen administration on renal blood oxygenation level-dependent MRI in children with glomerulonephritis.

OBJECTIVE: Children are often sedated for renal blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) and may require low-dose oxygen administration. It is unclear whether low-dose oxygen administration affects results of BOLD MRI. We investigated the effect of low-dose oxygen administration on renal BOLD MRI and its variation by the presence or absence of renal disease. MATERIALS AND METHODS: We retrospectively examined children undergoing MRI for renal disease between 2013 and 2020. Patients were divided into glomerulonephritis and non-glomerulonephritis groups; spin relaxation time (T2*) was determined using a 3.0 T MRI system. RESULTS: The study included 10 children (5 patients in each group); patient characteristics between the groups did not differ significantly. In the entire cohort, oxygen administration reduced mean spin relaxation rate (R2*) value in the medulla (p < 0.04). The mean R2* value decreased with oxygen administration in the non-glomerulonephritis group, whereas this was not observed in the glomerulonephritis group. The responses to oxygen administration of the two groups differed significantly in the cortex (p < 0.05) and medulla (p < 0.02). DISCUSSION: Low-dose oxygen administration affects the results of BOLD MRI. We suggest that understanding the fluctuations due to oxygen administration is useful in monitoring the disease activity of glomerulonephritis.

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.

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.

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.

Transposon-mediated random gene disruption with moderate halophilic bacteria and its application for halophilic bacterial siderophore analysis.

Analytical conditions using chromo azurol S was validated for quantification of siderophore in aqueous samples, followed by the characterization of siderophore derived from newly isolated moderately halophilic bacteria. Conditions with good linearity between the absorbance and the siderophore concentration were obtained at a siderophore concentration less than 20 µM, in the wavelength range between 630 and 660 nm with developing time for at least 2 h. Of the halophilic bacteria isolated from Tunisian soil, Halomonas sp., namely strain 21a was selected as siderophore producing halophiles. The strain produced siderophore significantly in the absence of iron in minimal medium. Siderophore-deficient mutant, namely IIa10, of the strain 21a was obtained from gene disruptant library constructed using transposon complex by electroporation. Genomic sequence analysis of the mutant IIa10 revealed that the transposon-inserted gene was TonB-dependent receptor.

Pathological Factors Affecting the R2* Values of the Kidney in Blood Oxygenation Level-dependent MR Imaging: A Retrospective Study.

PURPOSE: Despite the usefulness of blood oxygenation level-dependent (BOLD) MRI in assessing glomerulonephritis activity, its relationship with histological findings remains unclear. Because glomerulonephritis presents multiple complex injury patterns, analysis of each pattern is essential. We aimed to elucidate the relationship between the histological findings of the kidney and BOLD MRI findings in mesangial proliferative glomerulonephritis. METHODS: Children under 16 years of age diagnosed with mesangial proliferative glomerulonephritis by kidney biopsy at our university hospital between January 2013 and September 2022 were included in this study. Cortical and medullary spin relaxation rate (R2*) values were measured using BOLD MRI at 3T within two weeks before and after the kidney biopsy. The R2* values, including the fluctuations with low-dose oxygen administration, were retrospectively examined in relation to the cortical (mesangial proliferation, endothelial cell proliferation, crescent, sclerosis, and fibrosis) and medullary findings (fibrosis). RESULTS: Sixteen times kidney biopsies were performed for glomerulonephritis during the study period, and one patient was excluded because of comorbidities; the remaining 14 patients included six boys with a mean age of 11.9 ± 3.5 years at the BOLD examination. None of the patients had medullary fibrosis. Among the kidney tissue parameters, only sclerosis showed a significant correlation with R2* values: medulla with R2* values under atmospheric pressure (r = 0.53, P < 0.05) and cortex with the rate of change in R2* values with low-dose oxygen administration (r = -0.57, P < 0.03). In the multiple regression analysis, only sclerosis was an independent contributor to the change in R2* values with oxygen administration in the cortex (regression coefficient -0.109, P < 0.05). CONCLUSION: Since the R2* values reflect histological changes in the kidney, BOLD MRI may facilitate the evaluation of mesangial proliferative glomerulonephritis, potentially reducing the patient burden.

Effect of proteinuria at relapse on shear wave velocity assessed using ultrasound elastography in children with idiopathic nephrotic syndrome.

PURPOSE: Shear wave velocity (SWV) is an ultrasound elastography technique that provides much information for kidney disease assessment. However, the factors that alter SWV are not fully understood; it is unclear whether the variation in SWV seen in proteinuria associated with disease progression is due to tissue or proteinuria. This study investigated the effect of proteinuria on SWV. METHODS: This prospective observational study compared SWV at remission with SWV at relapse in children treated for idiopathic nephrotic syndrome (INS) between April 2020 and December 2023. All relapses without oral steroids during the observation period were measured. SWV at remission was defined as the date closest to relapse during which repeated measurements were taken approximately every 3 months after steroid discontinuation. RESULTS: Eight patients were treated for INS with a median observation period of 21.9 months (11.8-27.1). Of the 15 relapses, five that met the definition were considered for the study. The median interval between the measurement at relapse and remission was 40 days (11-55). SWV was significantly lower at relapse than remission (2.40 ± 0.20 m/s vs. 2.14 ± 0.15 m/s, P < 0.01). CONCLUSIONS: SWV decreased in the presence of severe proteinuria at relapse compared to the remission measurements. Although more cases need to be studied, the decrease in SWV may reflect the mechanism by which protein leaks into the urine, not just a direct change caused by the presence of proteinuria.