Yo Han Ahn

Development of antirituximab antibodies in children with nephrotic syndrome

BackgroundRituximab is actively used as a rescue therapy for nephrotic syndrome (NS). The development of antidrug antibodies, including antirituximab antibodies (ARA) and human antichimeric antibodies (HACA), is reported with rituximab treatment in various diseases. Here we report two pediatric patients with NS who developed ARA.Case diagnosis and treatmentRituximab was given as a rescue therapy for two patients with steroid-dependent NS. Both patients had been treated orally with glucocorticosteroid, methylprednisolone, and calcineurin inhibitors but experienced frequent relapses. With rituximab treatment, the patients remained in remission for several months. After the B-cell count recovered, the patients received a second course of rituximab administration and experienced a hypersensitivity reaction during drug infusion. CD19 cell counts rose despite treatment with rituximab. ARA titers were monitored before and after rituximab treatment, and the development of ARA after the second course of rituximab administration was confirmed.ConclusionsWe report the development of HACA in two patients with NS who did not achieve B-cell depletion after repeated administration of rituximab. This report suggests that additional studies are needed to determine the incidence of ARA in patients with NS, and its clinical significance.

COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss

The phenotypic combination of steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) and sensorineural hearing loss has been mainly reported in patients with mitochondrial cytopathies, including primary coenzyme Q10 (CoQ10) deficiency. In this report of 10 children with SR-FSGS and sensorineural hearing loss, we found 6 patients with biallelic COQ6 mutations. Median age at the onset of nephrotic syndrome was 29 (range, 15-47) months. All patients progressed to end-stage renal disease within a median of 13 (range, 1-27) months after the onset. Kidney biopsy revealed abnormal mitochondrial proliferation in podocytes in all 6 patients. None of the 5 patients who underwent kidney transplantation developed recurrence of FSGS. Primary CoQ10 deficiency due to COQ6 mutations should be considered in children presenting with both SR-FSGS and sensorineural hearing loss. An early diagnosis of COQ6 mutations is essential because the condition is treatable when CoQ10 supplementation is started at the early stage. We recommend early kidney biopsy because detection of abnormal mitochondrial proliferation in podocytes might provide an earlier diagnostic clue.

Tumour lysis syndrome in children: experience of last decade.

The strategy against tumour lysis syndrome (TLS) had been hyperhydration, urine alkalinization, and allopurinol. Recently, rasburicase was added to the armament against this life‐threatening condition. In Korea, rasburicase is used as a rescue therapy for cases with allopurinol‐resistant hyperuricemia, because of the restriction by the National Health Insurance. We reviewed our experiences to re‐assess the risk factors of TLS and the efficacy of rasburicase. Medical records were retrospectively reviewed for 396 children who were diagnosed as positive with acute leukemia and non‐Hodgkin lymphoma between the years 2000 and 2009. The risk factors for TLS were analyzed statistically, and those before and after the availability of rasburicase were compared. Sixty eight patients (17.2%) had TLS. Multivariate analysis showed that pre‐chemotherapy hypophosphatemia was a risk factor for TLS, in addition to the known risk factors of hyperuricemia and high lactate dehydrogenase concentration. The availability of rasburicase as a rescue therapy did not negate the importance of uric acid as a risk factor of TLS. Rasburicase as a second line treatment for intractable hyperuricemia was not effective in reducing the incidence of TLS. Pre‐chemotherapy hypophosphatemia was a significant independent risk factor for TLS. Copyright

Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior–Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC.

NUP107 mutations in children with steroid-resistant nephrotic syndrome.

Background NUP107 is a novel gene associated with autosomal recessive steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) in children. The frequency of NUP107 mutations in children with SR-FSGS remains unknown. Methods Nine families with two siblings affected by childhood-onset SRNS or proteinuria were recruited. FSGS was confirmed by a kidney biopsy in at least one affected sibling in all families. Additionally, 69 sporadic pediatric cases with biopsy-proven SR-FSGS who had not responded to any treatment were included. All coding exons with flanking introns of the NUP107 gene were amplified using polymerase chain reaction and directly sequenced. Results Biallelic NUP107 mutations were detected in four pairs (44.4%) of siblings from the familial cases and three (4.3%) sporadic cases. All affected patients harbored the p.Asp831Ala mutation in one allele and a truncating or abnormal splicing mutation in the other allele. NUP107 mutation-positive patients showed an earlier onset age (39.4 ± 13.1 versus 76.8 ± 50.0 months, P= 0.027) and more rapid progression to end-stage renal disease (at the ages of 58.9 ± 23.4 versus 123.1 ± 62.7 months, P < 0.001) compared with mutation-negative patients. None of the eight mutation-positive cases, who underwent kidney transplantation, showed recurrence of FSGS in the graft kidney, while 35.3% of mutation-negative cases showed recurrence of FSGS. Conclusions An unexpectedly high incidence of NUP107 mutations was observed in Korean children with SR-FSGS. Initial genetic screening of children with SR-FSGS should include the NUP107 gene, at least in Korea. Further studies are necessary to determine the incidences of NUP107 mutations in other countries.

Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort

Background Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Acute Raoultella planticola cystitis in a child with rhabdomyosarcoma of the bladder neck.

Raoultella planticola is a Gram‐negative, non‐motile, aerobic bacillus. It is an environmental bacteria found in soil and water, and a very rare cause of local or systemic infection in humans. Although some adult cases of R. planticola infection have been reported, childhood local or systemic infection caused by R. planticola is very rare. Reported herein is a rare case of acute cystitis due to R. planticola in a 16‐month‐old boy with rhabdomyosarcoma of the bladder neck, and a review of the literature.

Long-term repeated rituximab treatment for childhood steroid-dependent nephrotic syndrome

Background Rituximab (RTX) can be used as a rescue therapy for steroid-dependent nephrotic syndrome (SDNS). However, the efficacy and safety of long-term, repeated use of RTX are not established. This study was conducted to assess the efficacy and safety of long-term, repeated RTX treatment in children. Methods Eighteen consecutive child patients with SDNS who were treated with three or more cycles of RTX for one year or longer were recruited, and their medical records were retrospectively reviewed. Results The patients were followed for 4.7 ± 1.9 years and received 5.2 ± 2.3 cycles of RTX over 2.8 ± 1.1 years. Approximately 70% of the additional RTX cycles were administered due to recovery of B-cells without relapse. The relapse rate decreased from 3.4 ± 2.0 per year initially to 0.4 ± 0.8 per year at the third year after RTX treatment. Approximately 10% of the RTX infusions were accompanied by mild infusion reactions. Eight patients showed sustained remission without any oral medication after the last cycle of RTX, while 10 patients had one or more episodes of relapse after the last cycle of RTX. The relapse rate in the latter group decreased from 2.8 ± 1.5 per year before RTX treatment to 1.3 ± 0.8 per year after cessation of RTX treatment. No significant differences in clinical parameters were found between the two groups. Conclusion This retrospective study showed that pre-emptive and long-term, repeated RTX treatment is relatively effective and safe in children with SDNS. However, well-designed prospective studies are needed to confirm these findings.

Three cases of Gordon syndrome with dominant KLHL3 mutations

Abstract Background: Gordon syndrome (GS) is a rare form of monogenic hypertension characterized by low renin hypertension, hyperkalemia, hyperchloremic metabolic acidosis, and normal glomerular filtration rate. To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. Case presentation: We report three cases of GS in two families. All patients presented with typical clinical features of GS and had a known dominant KLHL3 mutation. Oral thiazide treatment with low salt diet resulted in normalization of blood pressure and serum electrolytes in all three cases. Conclusions: GS should be considered in patients with low renin hypertension and hyperkalemia. Although it is a rare disease, the correct diagnosis of GS is clinically important, as it can easily be treated with a low sodium diet or thiazides. In addition, family studies can identify individuals with undiagnosed GS as all mutations causing this disease, except for some recessive KLHL3 mutations, are dominant mutations.

A familial case of Blau syndrome caused by a novel NOD2 genetic mutation

Blau syndrome (BS) is a rare autosomal dominant, inflammatory syndrome that is characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis. Mutations in the nucleotide oligomerization domain 2 (NOD2) gene are responsible for causing BS. To date, up to 30 Blau-associated genetic mutations have been identified within this gene. We report a novel NOD2 genetic mutation that causes BS. A girl, aged 8 years, and her brother, aged 10 years, developed erythematous skin rashes and uveitis. The computed tomography angiogram of the younger sister showed features of midaortic dysplastic syndrome. The brother had more prominent joint involvement than the sister. Their father (38 years) was also affected by uveitis; however, only minimal skin involvement was observed in his case. The paternal aunt (39 years) and her daughter (13 years) were previously diagnosed with sarcoidosis. Mutational analysis revealed a novel c.1439 A>G mutation in the NOD2 gene in both siblings. The novel c.1439 A>G mutation in the NOD2 gene was found in a familial case of BS. Although BS is rare, it should always be considered in patients presenting with sarcoidosis-like features at a young age. Early diagnosis of BS and prompt multisystem workup including the eyes and joints can improve the patients outcome.