Earlier, better prediction of severe AKI has the potential to improve AKI associated patient outcomes. Compared to isolated, context-free changes in SCr, renal angina risk assessment improved accuracy for prediction of severe AKI in critically ill children and young adults.
X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment.No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s HR is defined as a group of rachitic bone diseases associated with chronic hypophosphatemia, which results from defects in the renal tubular reabsorption of filtered phosphate (1-8). Clinically, XLH, ADHR, HHRH, and TIO can be categorized as HR (1-8).XLH is the most common form of hereditary HR (2-6) and is caused by loss-of-function mutations in the PHEX gene (phosphate regulating gene with homologies to endopeptidases on the X chromosome). On the other hand, ADHR is far less common than XLH (2-6), and is associated with a gain-offunction mutation in the FGF23 gene encoding FGF23. The mutant FGF23 molecule is resistant inactivation by proteolytic cleavage (2,(5)(6)(7)(8)(9)(10)(11)(12). Moreover, TIO is an acquired form of HR, which is caused by a variety of benign primitive mesenchymal tumors that secrete FGF23 (2,7,13). HHRH is a rare hereditary disease and its underlying pathogenesis remains to be elucidated.Several studies of the molecular defects in XLH, ADHR, and TIO support a model of a common pathogenetic mechanism in these three diseases (2,6,14). In this model, FGF23 has been suggested to be the main circulating phosphaturic factor (2,6,14), and the circulating level of FGF23 is determined in part by the rate of its proteolytic cleavage by PHEX protease (9,13,15). The common abnormality shared by loss-of-function mutation...
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. (Pediatr Res 66: 336-340, 2009)
To date, two responsible genes for the development of Dent disease have been identified: CLCN5 and OCRL1. In this study, genotype-phenotype correlations were studied in patients with Dent disease and those with Lowe syndrome. Among the 12 boys with a phenotype typical of Dent disease, nine had a mutation in CLCN5 (Dent disease 1), two had a mutation in OCRL1 (Dent disease 2), and one had no mutations in either gene. All seven boys with a clinical diagnosis of Lowe syndrome had a mutation in OCRL1. Patients with Lowe syndrome showed more frequent hypophosphatemia/rickets and more prominent tubular proteinuria than patients with Dent disease 1, and patients with Dent disease 2 had higher degree of tubular proteinuria and hypercalciuria than patients with Dent disease 1. Additionally, one patient with Dent disease 2 showed a mild degree of developmental delay, elevated serum muscle enzyme levels, and cryptorchidism. In this study, the genetic heterogeneity in Dent disease and the phenotypic heterogeneity in Lowe syndrome were confirmed. In patients with Dent disease, the presence of the above-mentioned extrarenal manifestations indicates that it is more likely that the patient is affected by Dent disease 2 than by Dent disease 1.
Idiopathic renal hypouricemia is a hereditary disease characterized by abnormally high renal uric acid clearance. Most patients are clinically silent, but acute renal failure (ARF), urolithiasis, or hematuria may develop. A defect in the SLC22A12 gene, which encodes the renal uric acid transporter, URAT1, is the known major cause of this disorder. We performed a mutational analysis of the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia in this study. Two patients presented with microscopic hematuria, one with uric acid urolithiasis, and one with exercise-induced ARF. One patient was asymptomatic. Three different mutations, W258X, R90H and R477H, were detected in four of the patients. However, no mutation was found in the fifth ARF patient. This is the first study of SLC22A12 mutations in a country other than Japan. W258X was found to be the predominant SLC22A12 mutation in Korean renal hypouricemia patients, as has been reported in Japan.
Kabuki syndrome (KS) (OMIM#147920) is a multiple congenital anomaly/mental retardation syndrome. Recently, pathogenic variants in KMT2D and KDM6A were identified as the causes of KS in 55.8-80.0% of patients. To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A. Whole-exome sequencing and direct sequencing for validation were performed in 12 patients with a clinical suspicion of KS. KMT2D and KDM6A mutations were identified in 11 (91.7%) patients. No recurrent mutation was observed, and 10 out of the 11 mutations found were novel. KMT2D mutations were detected in 10 patients, including four small deletions or insertions and four nonsense and two missense mutations. One girl had a novel splice-site mutation in KDM6A. Each patient had a unique individual mutation. This is the first report of mutational analysis via exome sequencing in Korean patients with KS. Because the mutation-detection rate was high in this study, rigorous mutation analysis of KMT2D and KDM6A may be an important tool for the early diagnosis and genetic counseling of Korean patients with KS.
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.
This study retrospectively reviewed the medical records of children with lupus nephritis (LN) who were treated at Seoul National University Children's Hospital from 1986 to 2005 (mean duration 8.3+/-4.4 years). The records of 77 children (22 male and 55 female) were examined. The mean age at diagnosis was 11.9+/-3.0 years. The initial biopsy results revealed a WHO class IV classification for 60 (88.2%) of 68 biopsy proven cases. Of 77 patients, 67 (87.0%) responded initially to the high-dose corticosteroids with or without additional immunosuppressive therapy. Of the initial responders (67), 30 (44.8%) experienced at least one episode of proteinuric (24) or nephritic (6) flare. Thirteen patients (16.9%) progressed to either chronic renal failure (CRF) or end-stage renal disease (ESRD). Six (7.8%) patients died. A Kaplan-Meier estimate of patient survival and CRF-free survival rate was 95.4% and 88.7% at 5 years and 91.8% and 74.7% at 10 years, respectively. Multivariate analysis for class IV LN revealed male gender (P=0.029), initial hypertension (P=0.001) and absence of remission (P=0.002) to be prognostic factors predicting CRF. Glomerulosclerosis of 10% or more (P=0.005), nephritic flare (P=0.011), and presence of anti-phospholipid antibody (P=0.017) or syndrome (P=0.004) were also found to be independent risk factors for CRF. Cyclophosphamide pulse therapy failed to demonstrate superiority over other combined immunosuppressants used for the treatment of diffuse proliferative LN.
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