Hee Gyung Kang

Atypical Hemolytic Uremic Syndrome Associated With Complement Factor H Autoantibodies and CFHR1/CFHR3 Deficiency

Although genetic defect of complement factor H (CFH) is a common cause of atypical hemolytic uremic syndrome (aHUS), development of autoantibodies to CFH (CFH-Ab) is also known to be an acquired cause of aHUS. Recently, a correlation between the development of CFH-Ab and the deficiency of the CFH-related proteins, CFHR1 and CFHR3, was identified. In this study, plasma complement profiles were measured and genetic analysis of the CFH, CFI, MCP, CFHR1, and CFHR3 genes were performed in three female patients diagnosed with aHUS with positive CFH-Ab. Acute stage plasmas of all the three patients revealed low C3, low or low-normal CFH antigenic levels, and high titers of CFH-Ab. All the patients also showed complete plasma CFHR1 deficiency and homozygous genomic deletion of CFHR1/CFHR3, but none had CFH, CFI, or MCP mutations. All the patients were treated with plasmapheresis, and two patients required additional immunosuppressive therapy. These patients had a novel subgroup of aHUS characterized by a combination of genetic (a homozygous deletion of CFHR1/CFHR3) and acquired (development of CFH-Ab) factors. Patients with this disease may need intensive immunosuppressive therapy in addition to plasmapheresis. Screening for CFH-Ab and the CFHR1/CFHR3 deficiency should be included in the diagnostic tests for patients with aHUS.

Quality of life in children with end-stage renal disease based on a PedsQL ESRD module.

BackgroundHealth-related quality of life (HRQOL) is an essential subject for children with end-stage renal disease (ESRD) and their families.MethodsWe performed a cross-sectional investigation of HRQOL in children undergoing renal replacement therapies, such as dialysis and renal transplantation, using the 34-item Pediatric Quality of Life Inventory 3.0 End-Stage Renal Disease (PedsQL 3.0 ESRD) module. We assessed 92 ESRD patients aged 2–18 from four Korean university hospitals.ResultsThe male:female ratio was 44:48, and the most common cause of ESRD was chronic glomerulonephritis. Fifty-five children were treated by dialysis, and 37 received renal transplantation. Transplant patients had better HRQOL than dialysis patients in two domains in parent proxy reports: “About my kidney disease” and “Worry.” In child self-reports, transplant patients had better HRQOL than dialysis patients in one domain: Treatment problems. However, there were no significant differences in total QOL scores between peritoneal dialysis (PD) and transplant patients in child self-reports. In addition, there were differences in the ESRD module scores between child self- and parent proxy reports. Children usually reported better QOL than their parents. Child self-reports showed significantly higher QOL scores than parent proxy reports in the domains of General fatigue, Family & peer interaction, and Worry. Children on PD self-reported a significantly higher QOL than children on hemodialysis (HD).ConclusionsThe PedsQL 3.0 ESRD module may be useful as an ESRD-specific instrument to evaluate HRQOL in children; however, a larger, longitudinal prospective study is warranted.

Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome

Oral steroid treatment is the first line of therapy for childhood nephrotic syndrome (NS). Nonetheless, some patients are resistant to this treatment. Many efforts have been made to explain the differences in the response to steroid treatment in patients with NS based on the genetic background. We have investigated single nucleotide polymorphisms of the MDR1 [C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642)] and MIF (G-173C, rs755622) genes in 170 children with NS. Of these children, 69 (40.6%) were initial steroid non-responders, and 23 (13.5% of total) developed chronic kidney disease. Renal biopsy findings, which were available for 101 patients, showed that 35 patients had minimal change lesion and 66 had focal segmental glomerulosclerosis. The frequencies of the MDR1 1236 CC (18.8 vs 7.2%) or TC (53.5 vs 43.5%) genotype and C allele (45.5 vs 29.0%) were significantly higher in the initial steroid responders than in the non-responders. Analysis of MDR1 three-marker haplotypes revealed that the frequency of the TGC haplotype was significantly lower in the initial steroid responders than in the non-responders (15.8 vs 29.0%). There was no association between the MIF G-173C polymorphism and clinical parameters, renal histological findings, and steroid responsiveness. These data suggest that the initial steroid response in children with NS may be influenced by genetic variations in the MDR1 gene.

Renal manifestations of patients with MYH9-related disorders

MYH9-related disorders are a group of autosomal, dominantly inherited disorders caused by mutations of the MYH9 gene, which encodes the non-muscle myosin heavy chain IIA (NMMHC-IIA). May–Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes belong to this group. Macrothrombocytopenia is a common characteristic associated with MYH9-related disorders, and basophilic cytoplasmic inclusion bodies in leukocytes (Döhle-like bodies), deafness, cataracts, and glomerulopathy are also found in some patients. In this study, renal manifestations of 7 unrelated Korean patients with MYH9-related disorders were analyzed. Of a total of 7 patients, 4 had disease-related family histories. One familial case had a mutation in the tail domain of NMMHC-IIA and showed milder renal involvement with preserved renal function by his 30s. Among the 3 familial cases without renal involvement, 2 had mutations in the tail domain of NMMHC-IIA and 1 had a mutation in the motor domain. The remaining 3 sporadic cases had severe renal involvement with rapid progression to end-stage renal disease and mutations located in the motor domain. In summary, mutations in the motor domain of NMMHC-IIA and negative family history were associated with severe renal involvement in patients with MYH9-related disorders. These results are in agreement with those of previous reports.

Outcome of antimicrobial therapy of pediatric urinary tract infections caused by extended-spectrum β-lactamase-producing Enterobacteriaceae.

Background The purpose of this study was to compare the outcome of carbapenem versus non-carbapenem antimicrobial therapy for pediatric urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae. Materials and Methods From 2006 to 2011, 42 episodes of UTI caused by ESBL-producing Enterobacteriaceae were diagnosed at Seoul National University Childrens Hospital. Patients were grouped according to the antimicrobials they received into a carbapenem group and a non-carbapenem group. Medical records were retrospectively reviewed to assess treatment outcome, time to defervescence after initiation of treatment, and relapse rate. Results There were 36 children with 42 episodes of UTI caused by ESBL-producing Enterobacteriaceae. Twenty-seven cases (64%) had an underlying urologic disease, 28 (67%) cases were caused by Escherichia coli, and 14 (33%) cases were caused by Klebsiella pneumoniae. Four (10%) cases were treated with carbapenem, 23 cases (55%) were treated with non-carbapenem, and 15 (36%) cases were treated by switching from a carbapenem to a non-carbapenem and vice versa. There was no treatment failure at the time of antimicrobial discontinuation. Between the carbapenem and the non-carbapenem treatment groups, there were no significant differences in bacterial etiology (P = 0.59), time to defervescence after the initiation of antimicrobials (P = 0.28), and relapse rate (P = 0.50). In vitro susceptibility to non-carbapenem antimicrobials did not affect the time to defervescence after the initiation of antimicrobial treatment, and the relapse rate in the non-carbapenem group. Conclusions This study found no significant difference in the treatment outcome between pediatric patients treated with carbapenem and those treated with non-carbapenem antimicrobials for UTI caused by ESBL-producing Enterobacteriaceae. Therefore, the initially administered non-carbapenem can be maintained in UTI patients showing clinical improvement.

Urinary exosomal WT1 in childhood nephrotic syndrome

BackgroundRecently, urinary exosomal WT1 has been proposed as a novel biomarker for simple podocyte injury. We investigated urinary exosomal WT1 to confirm its role as a non-invasive biomarker for predicting steroid responsiveness or renal pathological conditions in patients with idiopathic nephrotic syndrome (NS).Case DiagnosisForty children with active NS were recruited. Twenty-eight (70%) were steroid-sensitive, including 3 with minimal change NS (MCNS) and 1 with focal segmental glomerulosclerosis (FSGS). The remaining 12 (30%) were steroid-resistant, including 8 with FSGS and 4 with MCNS. Urinary exosomes were isolated by a differential centrifugation method, and WT1 was measured by Western blot analysis.ResultsWT1 was detected in 25 patients (62.5%). There was no significant difference in the proportion of the patients with a detectable amount of WT1 according to steroid responsiveness or renal pathological condition, the amount of WT1 showed no significant difference according to steroid responsiveness or renal pathological condition, and there was no significant difference in the amount of proteinuria between patients with or without detectable WT1.ConclusionsUrinary exosomal WT1 was detected in some patients with NS. However, its role as an appropriate biomarker in childhood NS was not verified in this study.

Idiopathic membranous nephropathy in children

Idiopathic membranous nephropathy (MN) is a rare cause of asymptomatic proteinuria (AP) or nephrotic syndrome (NS) in childhood. To improve our understanding of its clinical course, we retrospectively reviewed 19 cases of idiopathic MN seen in our hospital over a period of 28.5 years, i.e., from January 1977 to July 2005. Eight patients (39%) had AP and 11 (61%) presented with NS. All eight AP patients achieved remission, regardless of treatment modality. Oral corticosteroid was given to all 11 NS patients, but only three of them responded to corticosteroid. Of the eight steroid non-responders, three achieved remissions with the addition of cyclosporine, and the five who were not administered additional immunosuppressive drugs had persistent NS. At the latest evaluation, all six NS patients that achieved remission remained free of proteinuria and had a normal renal function. Moreover, two of the 5 steroid non-responders showed persistent nephrotic-range proteinuria but a stable renal function. The remaining three steroid non-responders progressed into chronic renal insufficiency, and this progression was preceded by renal vein thrombosis (RVT) in two of the three patients. Presentation with NS (P=0.045) and the development of RVT (P=0.010) were identified as poor prognostic factors.

Decreased renal uptake of 99mTc-DMSA in patients with tubular proteinuria

Although technetium-99m-dimercaptosuccinic acid (99mTc-DMSA) renal scans are widely used to evaluate renal tubular mass function, the mechanism by which renal uptake of DMSA occurs is still the subject of debate. Patients with various proximal tubular disorders show markedly decreased renal DMSA uptake, even when there is normal creatinine clearance. We measured the renal uptake of 99mTc-DMSA 3 h after its injection in 13 patients with Dent disease or Lowe syndrome, both of which are typical proximal tubular disorders with defective megalin and cubilin-mediated endocytosis. Serial images of three patients were also obtained at 0.5, 1, 2 and 3 h post-injection. The correlations between renal uptake of 99mTc-DMSA and creatinine clearance and the degrees of acidemia and tubular proteinuria were then evaluated. The renal uptake of 99mTc-DMSA was markedly decreased in all patients, and the decreased uptake was detected in all serial images. In contrast, bladder radioactivity was higher than normal in all of the serial images when compared to renal radioactivity. Additionally, the uptake of 99mTc-DMSA was inversely proportional to the amount of urine β2-microglobulin. These results strongly suggest that DMSA is filtered in the glomeruli and subsequently undergoes megalin- and cubilin-mediated endocytosis in the proximal tubules.

Atypical hemolytic uremic syndrome: Korean pediatric series.

Atypical hemolytic uremic syndrome (aHUS) is a rare disease with a genetic predisposition. Few studies have evaluated the disease in the Asian population. We studied a Korean pediatric cohort to delineate the clinical characteristics and genotypes.

Genetic basis of Bartter syndrome in Korea

BACKGROUND Bartter syndrome (BS) is clinically classified into antenatal or neonatal BS (aBS) and classic BS (cBS) as well as five subtypes based on the underlying mutant gene; SLC12A1 (BS I), KCNJ1 (BS II), CLCNKB (BS III), BSND (BS IV) and CASR (BS V). METHODS Clinico-genetic features of a nationwide cohort of 26 Korean children with BS were investigated. RESULTS The clinical diagnosis was aBS in 8 (30.8%), cBS in 15 (57.7%) and mixed Bartter-Gitelman phenotype in 3 cases (11.5%). Five of eight patients with aBS and all 18 patients with either cBS or mixed Bartter-Gitelman phenotype had CLCNKB mutations. Among the 23 patients (46 alleles) with CLCNKB mutations, p.W610X and large deletions were detected in 25 (54.3%) and 10 (21.7%) alleles, respectively. There was no genotype-phenotype correlation in patients with CLCNKB mutations. CONCLUSIONS Twenty-three (88.5%) of the 26 BS patients involved in this study had CLCNKB mutations. The p.W610X mutation and large deletion were two common types of mutations in CLCNKB. The clinical manifestations of BS III were heterogeneous without a genotype-phenotype correlation, typically manifesting cBS phenotype but also aBS or mixed Bartter-Gitelman phenotypes. The molecular diagnostic steps for patients with BS in our population should be designed taking these peculiar genotype distributions into consideration, and a new more clinically relevant classification including BS and Gitelman syndrome is required.