Faysal Gok

ADCK4 mutations promote steroid-Resistant nephrotic syndrome through CoQ10 biosynthesis disruption

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) has furthered the understanding of the pathogenesis of this disease. Here, using a combination of homozygosity mapping and whole human exome resequencing, we identified mutations in the aarF domain containing kinase 4 (ADCK4) gene in 15 individuals with SRNS from 8 unrelated families. ADCK4 was highly similar to ADCK3, which has been shown to participate in coenzyme Q10 (CoQ10) biosynthesis. Mutations in ADCK4 resulted in reduced CoQ10 levels and reduced mitochondrial respiratory enzyme activity in cells isolated from individuals with SRNS and transformed lymphoblasts. Knockdown of adck4 in zebrafish and Drosophila recapitulated nephrotic syndrome-associated phenotypes. Furthermore, ADCK4 was expressed in glomerular podocytes and partially localized to podocyte mitochondria and foot processes in rat kidneys and cultured human podocytes. In human podocytes, ADCK4 interacted with members of the CoQ10 biosynthesis pathway, including COQ6, which has been linked with SRNS and COQ7. Knockdown of ADCK4 in podocytes resulted in decreased migration, which was reversed by CoQ10 addition. Interestingly, a patient with SRNS with a homozygous ADCK4 frameshift mutation had partial remission following CoQ10 treatment. These data indicate that individuals with SRNS with mutations in ADCK4 or other genes that participate in CoQ10 biosynthesis may be treatable with CoQ10.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Reversible nephrotoxicity after overdose of colloidal bismuth subcitrate.

Abstract Although toxicity due to acute and chronic use of bismuth salts is well known, nephrotoxicity after ingestion of colloidal bismuth has been reported in few cases so far. Here we report the first case of acute renal failure (ARF) due to colloidal bismuth subcitrate overdosage in childhood. A 2-year-old boy was admitted to the hospital 6 h after ingestion of 28 De-Nol tablets (colloidal bismuth subcitrate 8.4 g). On admission, physical examination was unremarkable and he showed no signs of encephalopathy. Initially gastric lavage was performed then appropriate fluid therapy was started. ARF associated with uremia and oliguria developed on day 2 and peritoneal dialysis therapy was prescribed on day 4 for 10 days. Blood and urine bismuth levels were 739 µg/l and 693 µg/l, respectively, 10 days after the pills had been taken. His urine volume gradually increased and plasma BUN and creatinine levels decreased during peritoneal dialysis. On day 20 post-admission, plasma BUN and creatinine were 14 mg/dl and 0.7 mg/dl, respectively. Blood bismuth levels were 96 µg/l on day 60 and 12 µg/l on day 105. Now the patient is well and has no problem. This case suggests that ARF may develop in children following colloidal bismuth subcitrate overdosage; the prognosis is good, and peritoneal dialysis may be useful in these cases.

Oral-ibuprofen-induced acute renal failure in a preterm infant.

The side effects of indomethacin for ductal closure in preterm neonates (e.g. increased incidence of necrotizing enterocolitis, decreased cerebral blood volume and transient renal failure) have led clinicians to seek a safer alternative. Intravenous indomethacin and ibuprofen appear to be equally effective for patent ductus arteriosus closure, but oral ibuprofen remains an experimental option with theoretical advantages yet with potential side effects. We herein report a case of transient but severe acute renal failure developing in a preterm infant in whom oral ibuprofen was used and discuss the safety of this drug in relation to its pharmacokinetics.

A very frequent mutation and remarkable association of R761H with M694V mutations in Turkish familial Mediterranean fever patients

Familial Mediterranean fever (FMF) is an autosomal-recessive disease. It is characterized by recurring fever, abdominal pain, and serositis. The Mediterranean fever (MEFV) gene is localized on 16p13.3 and more than 35 mutations have been described to date. There are some differences in the gene mutations of FMF in the various ethnic groups. The aim of this study is to determine the frequency of the mutations which has been reported comparatively rare, to define the most effective mutation set, and to select the most suitable DNA analysis system for Turkish FMF patients. Mutations in 330 Turkish FMF patients with typical phenotypes from various regions of Turkey were evaluated for the research purposes. These patients were analyzed for six MEFV gene mutations by the NanoChip® Molecular Genetics Workstation. The most frequent mutation was M694V, identified in 50.00% of the alleles examined; M680I followed with 14.10% and V726A—9.70%. Consequently, we determined that R761H (n = 23; 3.48%) was the most frequent rare mutations in Turkish FMF patients. Frequency of the rare mutations were R761H (3.48%), E148Q (1.36%), and M694I (1.21%). All of these mutations were in the compound heterozygote state. Our study showed that R761H mutations were higher than it has been reported in literature until now and were mainly associated with M694V. We suggest that mutation R761H should be included in the mutation scanning analysis researches or considered if the patient has M694V/? mutation especially in Turkish FMF patients. Larger serial studies need to be done to investigate the rate and coexistence of these mutations.

Endothelin levels in Henoch-Schonlein purpura

Abstract. Henoch-Schonlein purpura (HSP) is one of the most common types of vasculitis disorders seen in childhood and is characterized by a rash, arthritis, abdominal pain, and renal involvement. Although HSP is an immunoglobulin A (IgA) related immune complex disease, the pathogenesis has not been fully elucidated. Cytokines have been implicated in the pathogenesis, but endothelins (ET) – vasoconstrictor hormones produced by endothelial cells – have not been studied in patients with HSP. In a controlled study, we measured ET-1 levels in children with HSP during the acute and remission phases. ET-1 levels were significantly higher in the HSP patients during the acute phase compared with the control group and the HSP patients in the remission phase. There was no correlation between ET-1 levels and disease severity, acute phase reactant response, or morbidity. The role of endothelins and other cytokines in the pathogenesis of HSP needs to be further explored.

Management of Abnormal Postvoid Residual Urine in Children With Dysfunctional Voiding

OBJECTIVES To evaluate the effect of biofeedback therapy on the residual urine volume in children with dysfunctional voiding. METHODS This prospective study was conducted in children with dysfunctional voiding associated with abnormal postvoid residual urine (PVR) from June 2002 to 2007. The children were divided randomly into 2 groups. Group 1 was treated with standard urotherapy combined with biofeedback therapy and group 2 was treated with only standard urotherapy. The outcomes of uroflow-electromyography pattern, urinary tract infection (UTI), and PVR were recorded before and at the end of sixth month of treatment. RESULTS A total of 94 patients were enrolled in this study. Groups 1 and 2 consisted of 62 and 32 patients, respectively. The voiding pattern became normal in 80.6% (50/62) and 56.2% (18/32) of patients in groups 1 and 2, respectively. The PVR resolved in 40 of 62 (64.5%) patients in group 1 and in 11 of 32 (34.4%) children in group 2. Before the treatment, UTI was noted in 22.5% of patients (14/62) in group 1 and 21.8% of patients (7/32) in group 2. After the treatment, UTI was observed in 3.2% of patients (2/62) and in 9.3% (3/32) of patients in groups 1 and 2, respectively. Although both treatment modalities changed the voiding pattern, rate of febrile UTI, and PVR positively, these outcomes were better in a combination group. CONCLUSIONS The combination of standard urotherapy with the biofeedback therapy improved the results significantly.

Henoch–Schönlein purpura associated with hepatitis A infection

common vasculitis conditions of childhood, and is characterized by nonthrombocytopenic purpura, arthritis and/or arthralgia, abdominal pain, gastrointestinal hemorrhage and renal involvement. Although the etiology of HSP is still unknown, it is considered to be an immune-mediated vasculitic disorder resulting from an immune complex reaction to various antigenic stimuli. Many bacterial and viral organisms such as streptococci, adenovirus, parvovirus, hepatitis B virus (HBV), Epstein–Barr virus, varicella and mycoplasma have been reported as predisposing factors for HSP.1 So far, HSP associated with hepatitis A virus (HAV) infection has only been reported in one other patient, as a letter to the editor.2 In the present report we describe two patients with HSP associated with acute hepatitis A.

Clinical and radiographic findings in two brothers affected with a novel mutation in matrix metalloproteinase 2 gene.

The two well-described osteolysis syndromes associated with matrix metalloproteinase-2 deficiency and mutations in the metalloproteinase-2 gene are Torg–Winchester syndrome and nodulosis–arthropathy–osteolysis variant. They are characterized by carpal–tarsal destruction, subcutaneous nodules, and generalized osteoporosis and show autosomal recessive inheritance. Herein, we report two siblings affected with a novel mutation in matrix metalloproteinase 2 gene and discuss their clinical and radiographic findings.

Henoch-Schonlein purpura and pulmonary tuberculosis

Henoch–Schonlein purpura (HSP) is one of the most common vasculitic disorders of childhood and is characterized by non-thrombocytopenic purpura, arthritis and/or arthralgia, abdominal pain, gastrointestinal hemorrhage and renal involvement. The cause of the disease still remains obscure, although there is often an antecedent respiratory infection. Many bacterial and viral organisms including streptococci, adenovirus, parvovirus, Epstein–Barr virus (EBV), varicella and mycoplasma have been reported as preceding factors for HSP.1,2 A review of published reports found that HSP associated with tuberculosis has been rarely reported.3–9 Here we present an unusual child patient with HSP associated with pulmonary tuberculosis. Such an association in childhood has not been reported so far.