Pre-operative colour Doppler ultrasound for the prevention of bleeding complications after renal biopsy: A rare case of left renal lower pole vein.

Albeit rare, renal vein abnormalities on autopsy and in cases of abdominal surgery complications have been reported and should be kept in mind when performing invasive procedures, such as renal biopsy. We detected a rare renal vein abnormality on colour Doppler ultrasound before renal biopsy, thereby, avoiding a haemorrhagic complication. A 10-year-old boy presented to our department for the first time because of incidental findings of haematuria and proteinuria. We suspected chronic glomerulonephritis and scheduled an ultrasound-guided percutaneous renal biopsy. A simple screening ultrasound at the initial visit revealed no renal or vascular abnormalities. The day before the renal biopsy, we confirmed the biopsy site by performing a colour Doppler ultrasound, which showed abnormal blood flow from the lower pole of the left kidney, which was the planned puncture site; therefore, we changed the biopsy site to the right and completed the examination. Subsequent computed tomography angiography depicted two renal veins; one was the usual left renal vein draining from the kidney hilum, and the second was an accessory vein draining from the inferior pole of the left kidney and entering the inferior vena cava through the dorsal side of the aorta. Although rare, abnormalities in the renal vessels on the inferior pole of the kidney, which is the usual site of renal biopsy, are essential to rule out preoperatively by colour Doppler ultrasound, because these can cause significant bleeding during renal biopsy if not recognized.

Congenital chloride diarrhea needs to be distinguished from Bartter and Gitelman syndrome.

Pseudo-Bartter/Gitelman syndrome (p-BS/GS) encompasses a clinically heterogeneous group of inherited or acquired disorders similar to Bartter syndrome (BS) or Gitelman syndrome (GS), both renal salt-losing tubulopathies. Phenotypic overlap frequently occurs between p-BS/GS and BS/GS, which are difficult to diagnose based on their clinical presentation and require genetic tests for accurate diagnosis. In addition, p-BS/GS can occur as a result of other inherited diseases such as cystic fibrosis, autosomal dominant hypocalcemia, Dent disease, or congenital chloride diarrhea (CCD). However, the detection of the variants in genes other than known BS/GS-causing genes by conventional Sanger sequencing requires substantial time and resources. We studied 27 cases clinically diagnosed with BS/GS, but with negative genetic tests for known BS/GS genes. We conducted targeted sequencing for 22 genes including genes responsible for tubulopathies and other inherited diseases manifesting with p-BS/GS symptoms. We detected the SLC26A3 gene variants responsible for CCD in two patients. In Patient 1, we found the SLC26A3 compound heterozygous variants: c.354delC and c.1008insT. In Patient 2, we identified the compound heterozygous variants: c.877G > A, p.(Glu293Lys), and c.1008insT. Our results suggest that a comprehensive genetic screening system using targeted sequencing is useful for the diagnosis of patients with p-BS/GS with alternative genetic origins.

Inhibition of autophagy by chloroquine induces apoptosis in primary effusion lymphoma in vitro and in vivo through induction of endoplasmic reticulum stress.

Autophagy plays a crucial role in cancer cell survival and the inhibition of autophagy is attracting attention as an emerging strategy for the treatment of cancer. Chloroquine (CQ) is an anti-malarial drug, and is also known as an inhibitor of autophagy. Recently, it has been found that CQ induces cancer cell death through the inhibition of autophagy; however, the underlying mechanism is not entirely understood. In this study, we identified the role of CQ-induced cancer cell death using Primary Effusion Lymphoma (PEL) cells. We found that a CQ treatment induced caspase-dependent apoptosis in vitro. CQ also suppressed PEL cell growth in a PEL xenograft mouse model. We showed that CQ activated endoplasmic reticulum (ER) stress signal pathways and induced CHOP, which is an inducer of apoptosis. CQ-induced cell death was significantly decreased by salbrinal, an ER stress inhibitor, indicating that CQ-induced apoptosis in PEL cells depended on ER stress. We show here for the first time that the inhibition of autophagy induces ER stress-mediated apoptosis in PEL cells. Thus, the inhibition of autophagy is a novel strategy for cancer chemotherapy.

Role of Iron in Children With Immunoglobulin A Nephropathy and Macrohematuria-Induced Acute Kidney Injury.

Introduction: The role of iron in, and the prognosis of, pediatric Immunoglobulin A nephropathy (IgAN) with macrohematuria (MH)-induced acute kidney injury (AKI) (MH-AKI) have not been evaluated. Thirty percent of adults with MH-AKI, and especially those who are older, show progression to chronic kidney disease. Methods: We evaluated the immunohistopathologic characteristics of renal biopsy samples from pediatric patients with MH-AKI IgAN and controls, using Berlin Blue to identify iron, CD163 (a hemoglobin-scavenging receptor), and CD68 (a total macrophage marker), then compared the findings against the clinical characteristics of the patients. Results: We enrolled 44 children as follows: 19 with IgAN but no MH or AKI; 5 with IgAN and MH but no AKI (MH(+)AKI(-) IgAN); 11 with MH-AKI IgAN; and 9 with no IgAN, MH, or AKI, according to a renal biopsy. Berlin Blue staining was detected predominantly at the injured tubulointerstitium, and the areas of staining in children with MH(+)AKI(-) and MH-AKI IgAN were significantly more extensive. The areas of Berlin Blue and CD163 staining did not perfectly match; however, areas of Berlin Blue were surrounded by immunopositivity for CD163. No children with MH-AKI IgAN showed decreased renal function at their last visit. Conclusion: Children with IgAN and MH, with or without AKI, showed considerable iron deposition in their renal tubules. CD163-positive cells might scavenge hemoglobin in patients with MH-AKI IgAN, but not their roles as macrophages. The renal prognosis of pediatric MH-AKI IgAN is good.

N-terminal pro-brain natriuretic Peptide as a useful diagnostic marker of acute Kawasaki disease in children.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NTproBNP) is often elevated in patients with acute Kawasaki disease (KD), but the NTproBNP level in normal children is higher than in adults. Thus, characterization of the normal levels and cut-off values of NTproBNP according to age is warranted for proper diagnosis of acute KD in children. METHODS AND RESULTS: Six hundred and fifty-five patients aged 1 month-15 years (median, 2.9 years) were included. Patients were admitted to the NTT East Japan Sapporo Hospital between October 2007 and October 2011. Serum NTproBNP level was examined in 149 patients with KD (median, 2.1 years) and 506 control patients with acute infectious disease (median, 3.2 years). In the control group, a Z-score curve of NTproBNP was generated for each age group using least mean square-based methods. The Z-score distribution of KD patients was then compared with that of the control group. The specificity and sensitivity of NTproBNP for diagnosing acute KD were 97.8% and 47.0%, respectively, at Z-score >2.0. Additionally, simple cut-offs every 100 pg/ml according to age were established for more convenient use at the bedside. CONCLUSIONS: The Z-score curve for NTproBNP in children was characterized. A Z-score >2.0 or the cut-off for children may be used to diagnose acute KD.

Clinical features and treatment strategies of febrile urinary tract infection caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: a multicenter retrospective observational study in Japan.

OBJECTIVES: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. METHODS: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL-producing bacteria were compared. RESULTS: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). CONCLUSION: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic.

Induction of apoptosis by Shikonin through ROS-mediated intrinsic and extrinsic apoptotic pathways in primary effusion lymphoma.

Primary effusion lymphoma (PEL) is an incurable non-Hodgkin's lymphoma and novel biology-based treatments are urgently needed in clinical settings. Shikonin (SHK), a napthoquinone derivative, has been used for the treatment of solid tumors. Here, we report that SHK is an effective agent for the treatment of PEL. Treatment with SHK results in significant reduction of proliferation in PEL cells and their rapid apoptosis in vitro. SHK-induced apoptosis of PEL cells is accompanied by the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Δψm), an activation of c-Jun-N-terminal kinase (JNK), p38, as well as caspase-3, -8, and -9. Scavenging of ROS in the presence of N-acetylcysteine (NAC) almost blocks the loss of mitochondrial membrane Δψm, activation of JNK, cleavage of caspase-3, -9, and an induction of apoptosis in SHK treated PEL cells. SP600125, a specific inhibitor of JNK, also rescues a proportion of cells from the apoptotic effect of SHK. In addition, inhibition of caspase activation in the presence of pan-caspase inhibitor, Q-VD-OPh, blocks the SHK-inducing apoptosis, but doesn't completely inhibit SHK-mediated JNK activation. Therefore, ROS is an upstream trigger of SHK-induced caspase dependent apoptosis of PEL cells through disruption of mitochondrial membrane Δψm in an intrinsic pathway and an activation of JNK in an extrinsic pathway. In a PEL xenografted mouse model, SHK treatment suppresses PEL-mediated ascites formation without showing any significant adverse toxicity. These results suggested that SHK could be a potent anti-tumor agent for the treatment of PEL.

Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.

X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology. We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis. Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels. Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.

Poststreptococcal acute glomerulonephritis can be a risk factor for accelerating kidney dysfunction in Alport syndrome: a case experience.

Alport syndrome (AS) is a progressive kidney disease. Male cases with X-linked AS (XLAS) are reported to develop end-stage kidney disease (ESKD) at the age of around 20-30 years. One risk factor for developing ESKD at a young age is a genotype of having truncating variants in the COL4A5 gene. However, to date, other such factors have remained unclear. Here, we describe a 15-year-old Japanese boy with XLAS who had a missense variant in the COL4A5 gene. He presented with gross hematuria, severe proteinuria, oliguria, systemic edema, body weight gain, and hypertension after pharyngitis. Blood examination showed kidney dysfunction, hypocomplementemia, and elevated antistreptolysin-O level. We diagnosed him with poststreptococcal acute glomerulonephritis (PSAGN) and he was stopped treatment by lisinopril, and received supportive treatment. However, he showed an unusual clinical course for PSAGN and, consequently, developed ESKD 15 months after the onset of PSAGN without recovery from the kidney dysfunction. This case showed that the onset of PSAGN can be a risk factor for AS patients to develop ESKD at a young age.

Solute Clearance and Fluid Removal: Large-Dose Cyclic Tidal Peritoneal Dialysis.

Large-dose cyclic tidal peritoneal dialysis (TPD) is an original prescription of TPD involving frequent infusion and drainage of the dialysate to increase weekly urea clearance normalized to total body water (Kt/Vurea ) and fluid removal. This study aimed to evaluate the efficiency of solute clearance and fluid removal achieved with large-dose cyclic TPD compared to that achieved with nightly peritoneal dialysis (NPD). Seventeen patients with end-stage renal disease, for whom maintenance PD was changed from NPD to large-dose cyclic TPD, were enrolled. Their median age at administration of PD was 4.9 years. Kt/Vurea and fluid removal were compared between large-dose cyclic TPD and NPD. The median peritoneal Kt/Vurea achieved with NPD and large-dose cyclic TPD was 1.5 and 2.7, respectively. The median peritoneal Kt/Vurea per hour with large-dose cyclic TPD was significantly higher than that with NPD (P = 0.0003). Among nine patients who used dialysates with the same glucose concentration for both NPD and large-dose cyclic TPD, nightly fluid removal amount per hour with large-dose cyclic TPD was significantly higher than that with NPD (P = 0.0039). Large-dose cyclic TPD is a useful prescription of PD for increasing Kt/Vurea and fluid removal.

Efficacy of Honeydew Honey and Blossom Honey on Full-thickness Wound Healing in Mice.

INTRODUCTION: The wound healing properties of honey, including blossom honey, are well known; however, the effects of honeydew honey during the wound healing process have not yet been investigated and thus remain unclear. OBJECTIVE: This study compares the effects of honeydew honey with those of blossom honey. MATERIALS AND METHODS: A total of 140 mice were divided into 2 control groups, which received either a hydrocolloid dressing (HCD; n = 22) or gauze (n = 22), and 4 experimental groups: honeydew honey (n = 23), Acacia honey (n = 23), Manuka honey (n = 22), and Japanese Pharmacopoeia honey (n = 28). Two circular full-thickness wounds were made and measured for 14 days. Each wound in the experimental groups was treated with 0.1 mL of honey and covered with gauze. Dressings in the control and experimental groups were changed daily. RESULTS: The wounds in all of the honey groups and the HCD group were moist by day 14, while those in the gauze group were dry. The ratio of wound area to initial wound area and the number of inflammatory cells decreased during the inflammatory phase in all honey groups. However, the honey groups exhibited reepithelialization rates of < 40%, numerous neutrophils, weak wound contraction, and impaired collagen deposition in wounds after day 11. CONCLUSIONS: These results suggest honeydew honey and blossom honey both exert anti-inflammatory effects during the inflammatory phase. However, all of the honeys examined were less effective at promoting full-thickness wound healing than the controls. Further studies are warranted.