Takahisa Kimata

A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3

BackgroundPseudohypoaldosteronism type II (PHA II), also referred to as Gordon syndrome, is a rare renal tubular disease that is inherited in an autosomal manner. Though mutations in WNK1 and WNK4 partially account for this disorder, in 2012, 2 research groups showed that KLHL3 and CUL3 were the causative genes for PHA II. Here, we firstly report on the Japanese child of PHA II caused by a mutation of CUL 3.Case presentationThe patient was a 3-year-old Japanese girl having healthy unrelated parents. She was initially observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension. A close investigation led to the diagnosis of PHA II, upon which abnormal findings of laboratory examinations and hypertension were immediately normalized by administering thiazides. Genetic analysis of WNK1 and WNK4 revealed no mutations. However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9. The patient is currently 17 years old and does not exhibit hypertension or any abnormal findings on laboratory examination.ConclusionsIn this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid–base balance.

Novel Use of Rituximab for Steroid-Dependent Nephrotic Syndrome in Children

Background: Though rituximab (RTX) is effective for childhood steroid-dependent nephrotic syndrome (SDNS), an established regimen does not exist. The relapses tend to occur when the peripheral blood B-cell count re-arises at 3 months upon single RTX infusion. This study was conducted to clarify whether the long-term remission of SDNS can be obtained by repeated RTX administrations. Methods: RTX was administered 4 times at 3-month intervals at 375 mg/m2/time to 5 children with SDNS. The changes in the clinical indicators were analyzed. Results: The median (range) observation period was 6.3 (0.9-8.4) years before RTX and 3.2 (1.9-3.8) years following the commencement of RTX. The changes in the clinical indicators were as follows (median and range): (1) annual number of relapses: before administration 1.4 (1.1-3.5) times/year, after administration 0.0 (0.0-0.0) times/year, and (2) median steroid dosage: before administration 0.80 (0.23-0.96) mg/kg/day, after administration 0.00 (0.00-0.00) mg/kg/day. All changes were significant at p < 0.05. Relapse occurred 3 times following the start of RTX (the period to relapse was 2.2, 1.9, and 2.3 years, respectively). No serious side effects were seen. Conclusions: Repeated RTX against SDNS in children may be a useful therapeutic option.

Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes

BackgroundNephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome.Data sourcesThis article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words “pathogenesis”, “minimal change nephrotic syndrome” or “idiopathic nephrotic syndrome”.ResultsUnknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4.ConclusionsRecent evidence suggests that minimalchange disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease.

A Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin, Ameliorates Puromycin Aminonucleoside-Induced Nephrosis in Mice

Background/Aims: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS. Methods/Results: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus. Conclusions: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS.

Urinary Biomarkers for Screening for Renal Scarring in Children with Febrile Urinary Tract Infection: Pilot Study

PURPOSE Recurrent febrile urinary tract infections during infancy cause renal scarring, which is characterized by progressive focal interstitial fibrosis and may lead to renal failure. Renal scarring can be diagnosed through scintigraphy, although it seems impractical to perform renal scintigraphy for all infants with febrile urinary tract infections. Therefore, it is important to search for a biomarker to identify the presence of renal scarring. We hypothesized that urinary biomarkers of nephropathy may increase in infants with renal scarring following febrile urinary tract infections. MATERIALS AND METHODS A total of 49 infants who underwent renal scintigraphy for febrile urinary tract infections were enrolled in the study. Several measurements were performed using urine samples, including total proteins, beta2-microglobulins, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase associated lipocalin, liver-type fatty acid binding protein and angiotensinogen. Values were corrected by creatinine and compared between patients with and without renal scarring. RESULTS Among urinary biomarkers only angiotensinogen in patients with scarring (median 14.6 μg/gm creatinine) demonstrated significantly higher levels than in patients without scarring (3.6 μg/gm creatinine, p <0.001). CONCLUSIONS Urinary angiotensinogen may be useful for diagnosing the presence of renal scarring.

Close association between proteinuria and regulatory T cells in patients with idiopathic nephrotic syndrome

BackgroundIdiopathic nephrotic syndrome (INS) has been considered to be a T cell disorder. Supporting this hypothesis is the reported occurrence of remission following measles infection, which suppresses T cell function. In contrast, there has been no case report suggesting an association between influenza B virus infection and the remission of INS.Case-Diagnosis/TreatmentWe report the case of a 5-year-old boy with INS who achieved remission without steroid treatment in response to influenza B virus infection. Although he relapsed soon after remission, he was successfully treated with prednisolone. Both the induction of remission and the response to prednisolone were associated with an increase in the number of circulating regulatory T cells (Tregs), assessed as CD4+CD25+Foxp3+ cells. These results suggest that both influenza B virus infection and steroid administration increased the number of circulating Tregs, thus leading to the remission of INS.ConclusionsIn summary, our case indicates an important role for Tregs in the development of the proteinuria associated with INS and sheds light on its pathogenesis. Further studies are warranted.

Different phenotypes of HNF1ß deletion mutants in familial multicystic dysplastic kidneys.

Multicystic dysplastic kidney (MCDK) is one of the most common congenital abnormalities of the kidney and urinary tract (CAKUT), although its pathophysiology remains unknown. Familial occurrence of MCDK suggests that mutations in genes associated with nephrogenesis are involved in the pathogenesis in at least some cases. Hepatocyte nuclear factor 1β (HNF1β) is a member of the homeodomain-containing super family of transcription factors, and is known to regulate tissue-specific gene expression in a number of organs including the kidneys, pancreas and liver. It has been recently postulated to be associated with CAKUT, including MCDK. We recently encountered a family with a deletion mutant of HNF1β, of which the 2nd son, the proband, developed bilateral MCDK resulting in renal loss of function in infancy while the 1st son developed unilateral MCDK. Their father has two normal kidneys. This family confirmed that mutations in the HNF1β gene are strongly associated with the development of MCDK. Furthermore, the fact that no clear phenotype-genotype correlation exists suggests that gene(s) other than HNF1β are also involved in nephrogenesis and the development of MCDK.

Change in urinary 8-hydroxydeoxyguanosine in idiopathic nephrotic syndrome

Sirs, We read with great interest the article entitled “Antioxidant status of children with idiopathic nephrotic syndrome” by Mishra et al. which was recently published in Pediatric Nephrology [1]. Oxidative stress (OS), defined as a disturbance in the reactive oxygen species (ROS) and antioxidant balance, can result either from low levels of antioxidants and/or from an increased production of ROS. It has been postulated that childhood idiopathic nephrotic syndrome (INS) is associated with OS due to increased levels of ROS and decreased levels of antioxidants [2], although results to the contradictory have been published [3]. Mishra et al. [1] report evidence of OS and impaired antioxidant defense during acute INS. 8-Hydroxydeoxyguanosine (8-OHdG), which originates from damaged DNA repaired by non-specific endonucleases and specific glycosylases and is eliminated into the urine, is currently accepted as a sensitive biomarker for oxidative DNA damage, as OS leads to the damage of not only lipids and proteins, but also nucleic acids [4]. In order to investigate oxidative cellular damage in INS, we are currently performing serial measurements of urinary 8-OHdG using a novel analyzer (model No. ICR001; Techno-Medica, Yokohama, Japan). Here, we report changes in urinary 8-OHdG during five nephrotic relapses in four patients with INS (ages 3, 4, 15, and 20 years, respectively) and three patients with poststreptococcal acute glomerulonephritis (PSAGN; ages 4, 7, and 16 years, respectively). As shown in Fig. 1, the urinary levels of 8-OHdG (ng/mL) corrected by creatinine (ng/mg Cr) in patients with INS were significantly higher in patients with nephrotic relapse (active phase) than in those in remission (convalescent phase; p=0.04, Wilcoxon signed-rank test); in contrast, there was no significant change between the active and convalescent phase in those patients with PSAGN (p=0.59). Thus, our finding of oxidative DNA damage assessed by urinary 8-OHdG is in agreement with the observation by Mishra et al. [1] that OS in INS is characterized by increased levels of ROS with decreased levels of antioxidant in the active phase and by normalized ROS in the

Methicillin-resistant Staphylococcus aureus-related glomerulonephritis in a child

BackgroundMethicillin-resistant Staphylococcus aureus-associated glomerulonephritis (MRSA-GN), a syndrome in which superantigens play an important role in the pathogenesis of the infection, has been well described in adult patients but not previously recognized in children.Case Diagnosis/TreatmentWe report the case of a 6-year-old girl with MRSA-GN. She presented multiple malformations, including tracheal stenosis necessitating tracheotomy. She was admitted to our hospital because of acute pneumonia caused by a MRSA infection and was found to have proteinuria and abnormal renal function. MRSA was detected in her sputum, and this MRSA isolate produced toxic shock syndrome toxin-1, which acts as a superantigen and stimulates Vβ2+ T cells. A blood test revealed that the number of circulating Vβ2+ T cells expressing CD45RO, a marker of activation, was increased along with a concomitant elevation in the levels of serum immunoglobulins. Both are hallmarks of MRSA-GN. The eradication of MRSA using appropriate antibiotics resulted in the disappearance of the proteinuria; in contrast, corticosteroid treatment failed. To the best of our knowledge, this is the youngest patient to be diagnosed with MRSA-GN.ConclusionsIn summary, there should be a high index of suspicion for MRSA-GN, even in the very young, in order to avoid the unnecessary use of immune suppressants in this context.

A child with Epstein-Barr Virus-associated hemophagocytic lymphohistiocytosis complicated by coronary artery lesion mimicking Kawasaki disease.

There is considerable overlap between hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) in terms of aberrant immune response though the etiology of KD remains unknown. We present a case fulfilling the criteria of both HLH and KD complicated by coronary artery dilatation: HLH was confirmed to be triggered by Epstein-Barr virus. This case alarms us the possibility that even patients with HLH may be complicated by coronary artery lesion, which is one of the hallmarks of KD. We would like to draw attention that if features of KD become apparent in patients with HLH, echocardiographic examinations should be performed not to miss coronary artery lesion.