Exploring the genetic diversity of the Japanese population: Insights from a large-scale whole genome sequencing analysis.

The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.

Urine oxygenation predicts COVID-19 risk.

Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government's basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed.

Urinary liver-type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone-induced acute kidney injury.

AIM: Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study. METHODS: Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram. RESULTS: The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased. CONCLUSION: Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

HMGB1 Is a Prognostic Factor for Mortality in Acute Kidney Injury Requiring Renal Replacement Therapy.

INSTRUCTION: High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that reportedly causes kidney injury and other organ damage in rodent acute kidney injury (AKI) models. However, it remains unclear whether HMGB1 is associated with clinical AKI and related outcomes. This study aimed to evaluate the association with HMGB1 and prognosis of AKI requiring continuous renal replacement therapy (CRRT). METHODS: AKI patients treated with CRRT in our intensive care unit were enrolled consecutively during 2013-2016. Plasma HMGB1 was measured on initiation. Classic initiation was defined as presenting at least one of the following conventional indications: hyperkalemia (K ≥6.5 mEq/L), severe acidosis (pH <7.15), uremia (UN >100 mg/dL), and diuretics-resistant pulmonary edema. Early initiation was defined as presenting no conventional indications. The primary outcome was defined as 90-day mortality. RESULTS: A total of 177 AKI patients were enrolled in this study. HMGB1 was significantly associated with the primary outcome (hazard ratio, 1.06; 95% CI, 1.04-1.08). When the patients were divided into two-by-two groups by the timing of CRRT initiation and the HMBG1 cutoff value obtained by receiver operating curve (ROC) analysis, the high HMGB1 group (>10 ng/mL) with classic initiation was significantly associated with the primary outcome compared with the others, even after adjusting for other factors including the nonrenal serial organ failure assessment (SOFA) score. CONCLUSION: HMGB1 was associated with 90-day mortality in AKI patients requiring CRRT. Notably, the highest mortality was observed in the high HMGB1 group with classic initiation. These findings suggest that CRRT should be considered for AKI patients with high HMGB1, regardless of the conventional indications.

Different Roles of Functional and Structural Renal Markers Measured at Discontinuation of Renal Replacement Therapy for Acute Kidney Injury.

INTRODUCTION: Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) has been associated with an unacceptably high mortality of 50% or more. Successful discontinuation of RRT is thought to be linked to better outcomes. Although functional and structural renal markers have been evaluated in AKI, little is known about their roles in predicting outcomes at the time of RRT discontinuation. METHODS: In this prospective single-center cohort study, we analyzed patients who received continuous RRT (CRRT) for AKI between August 2016 and March 2018 in the intensive care unit of the University of Tokyo Hospital (Tokyo, Japan). Clinical parameters and urine samples were obtained at CRRT discontinuation. Successful CRRT discontinuation was defined as neither resuming CRRT for 48 h nor receiving intermittent hemodialysis for 7 days from the CRRT termination. Major adverse kidney events (MAKEs) were defined as death, requirement for dialysis, or a decrease in the estimated glomerular filtration rate (eGFR) of more than 25% from the baseline at day 90. RESULTS: Of 73 patients, who received CRRT for AKI, 59 successfully discontinued CRRT and 14 could not. Kinetic eGFR, urine volume, urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary L-type fatty acid binding protein were predictive for CRRT discontinuation. Of these factors, urine volume had the highest area under the curve (AUC) 0.91 with 95% confidence interval [0.80-0.96] for successful CRRT discontinuation. For predicting MAKEs at day 90, the urinary NGAL showed the highest AUC 0.76 [0.62-0.86], whereas kinetic eGFR and urine volume failed to show statistical significance (AUC 0.49 [0.35-0.63] and AUC 0.59 [0.44-0.73], respectively). CONCLUSIONS: Our prospective study confirmed that urine volume, a functional renal marker, predicted successful discontinuation of RRT and that urinary NGAL, a structural renal marker, predicted long-term renal outcomes. These observations suggest that the functional and structural renal makers play different roles in predicting the outcomes of severe AKI requiring RRT.

Urinary liver-type fatty acid binding protein is increased in the early stages of the disease with a risk of acute kidney injury induced by histone.

AIM: Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases. METHODS: Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava. RESULTS: After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP. CONCLUSIONS: Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.

Direct hemoperfusion using a polymyxin B-immobilized polystyrene column for COVID-19.

OBJECTIVE: To evaluate the efficacy and safety of direct hemoperfusion using a polymyxin B-immobilized polystyrene column (PMX-DHP) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive pneumonia patients. METHODS: This study was a case series conducted at a designated infectious diseases hospital. Twelve SARS-CoV-2-positive patients with partial pressure of arterial oxygen/percentage of inspired oxygen (P/F) ratio < 300 were treated with PMX-DHP on two consecutive days each during hospitalization. We defined day 1 as the first day when PMX-DHP was performed. PMX-DHP efficacy was assessed on days 7 and 14 after the first treatment based on eight categories. Subsequently, improvement in P/F ratio and urinary biomarkers on days 4 and 8, malfunctions, and ventilator and extracorporeal membrane oxygenation avoidance rates were also evaluated. RESULTS: On day 14 after the first treatment, disease severity decreased in 58.3% of the patients. P/F ratio increased while urine ß2-microglobulin decreased on days 4 and 8. Cytokine measurement pre- and post-PMX-DHP revealed decreased levels of interleukin-6 and the factors involved in vascular endothelial injury, including vascular endothelial growth factor. Twenty-two PMX-DHPs were performed, of which seven and five PMX-DHPs led to increased inlet pressure and membrane coagulation, respectively. When the membranes coagulated, the circuitry needed to be reconfigured. Circuit problems were usually observed when D-dimer and fibrin degradation product levels were high before PMX-DHP. CONCLUSIONS: Future studies are expected to determine the therapeutic effect of PMX-DHP on COVID-19. Because of the relatively high risk of circuit coagulation, coagulation capacity should be assessed beforehand.

First detection of voltage-gated sodium channel mutations in Phlebotomus argentipes collected from Bangladesh.

BACKGROUND & OBJECTIVES: Phlebotomus argentipes is the main vector of visceral leishmaniasis in Bangladesh and is controlled using deltamethrin, a synthetic pyrethroid, through indoor residual spraying (IRS). A mutation at L1014 (leucine at codon 1014) of the voltage-gated sodium channel (VGSC), known as a knockdown resistance (kdr) gene, is thought to be an important pyrethroid resistance mechanism. This study detected mutations at codon 1014, and at codons 1011, 1016, and 1020, which are kdr sites in other insects. The kdr relationship with deltamethrin resistance in P. argentipes from an IRS-targeted site in Bangladesh was also evaluated. METHODS: Sand flies were collected from Magurjora village, Mymensingh district, Bangladesh in November 2012. A WHO cone bioassay test using deltamethrin was conducted and specimens were grouped as 'live' or 'dead'. After morphological identification, genomic DNA was used to genotype a partial VGSC gene from P. argentipes. The kdr/ pyrethroid resistance relationship was evaluated using Fisher's exact test. RESULTS: Targeted codons were genotyped from 8 'live' and 63 'dead' P. argentipes. All 'live' specimens had mutant alleles (L1014F and L1014S) at codon 1014. The mutant allele rate was 94% for 'live' specimens and 55% for 'dead' specimens. The mutant allele survival odds were higher for the wild-type L1014L allele, and L1014F odds were lower for L1014S. There were no mutations at codons 1011, 1016, and 1020. INTERPRETATION & CONCLUSION: The L1014 mutations suggested that pyrethroid resistance had appeared in Bangladesh. Further research on kdr mutations in P. argentipes is important for the appropriate IRS.

Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

Recombinant Thrombomodulin on Neutrophil Extracellular Traps in Murine Intestinal Ischemia-Reperfusion.

BACKGROUND: In multiple-organ dysfunction, an injury affecting one organ remotely impacts others, and the injured organs synergistically worsen outcomes. Recently, several mediators, including extracellular histones and neutrophil extracellular traps, were identified as contributors to distant organ damage. This study aimed to elucidate whether these mediators play a crucial role in remote organ damage induced by intestinal ischemia-reperfusion. This study also aimed to evaluate the protective effects of recombinant thrombomodulin, which has been reported to neutralize extracellular histones, on multiple-organ dysfunction after intestinal ischemia-reperfusion. METHODS: Intestinal ischemia was induced in male C57BL/6J mice via clamping of the superior mesenteric artery. Recombinant thrombomodulin (10 mg/kg) was administered intraperitoneally with the initiation of reperfusion. The mice were subjected to a survival analysis, histologic injury scoring, quantitative polymerase chain reaction analysis of tumor necrosis factor-α and keratinocyte-derived chemokine expression, Evans blue dye vascular permeability assay, and enzyme-linked immunosorbent assay analysis of histones in the jejunum, liver, lung, and kidney after 30- or 45-min ischemia. Neutrophil extracellular trap formation was evaluated by immunofluorescence staining. RESULTS: Recombinant thrombomodulin yielded statistically significant improvements in survival after 45-min ischemia (ischemia-reperfusion without vs. with 10 mg/kg recombinant thrombomodulin: 0% vs. 33%, n = 21 per group, P = 0.001). Recombinant thrombomodulin reduced the histologic injury score, expression of tumor necrosis factor-α and keratinocyte-derived chemokine, and extravasation of Evans blue dye, which were augmented by 30-min ischemia-reperfusion, in the liver, but not in the intestine. Accumulated histones and neutrophil extracellular traps were found in the livers and intestines of 30-min ischemia-reperfusion-injured mice. Recombinant thrombomodulin reduced these accumulations only in the liver. CONCLUSIONS: Recombinant thrombomodulin improved the survival of male mice with intestinal ischemia-reperfusion injury. These findings suggest that histone and neutrophil extracellular trap accumulation exacerbate remote liver injury after intestinal ischemia-reperfusion. Recombinant thrombomodulin may suppress these accumulations and attenuate liver injury.

Kinetic estimated glomerular filtration rate as a predictor of successful continuous renal replacement therapy discontinuation.

AIM: No standardized criteria for continuous renal replacement therapy (CRRT) discontinuation have been established. Kinetic estimated glomerular filtration rate (eGFR) is a newly developed estimation method based on dynamic changes of serum creatinine expected to reflect the true GFR. This study aimed to evaluate the predictive role of kinetic eGFR for CRRT discontinuation. METHODS: A retrospective single-centre cohort study was conducted. Acute kidney injury (AKI) patients who received CRRT between May 2015 and April 2016 were enrolled. Successful CRRT discontinuation was defined as neither resuming CRRT for the next 48 h nor receiving intermittent haemodialysis 7 days from the CRRT discontinuation. Clinical factors associated with CRRT discontinuation were evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Of 52 AKI patients treated with CRRT, 38 could discontinue CRRT while 14 could not. Urine volume, regular and kinetic eGFR of days 0 (day of CRRT discontinuation) and 1 were all good predictive parameters (area under the ROC curve (AUC) > 0.7). Kinetic eGFR of day 1 showed the AUC of 0.87 [95% confidence interval 0.73-0.94]). Combining kinetic eGFR of day 1 and urine volume of day 0 gave a high AUC of 0.93 [95% confidence interval 0.82-0.97]. The combination was significantly greater than urine volume of day 0 (P = 0.008). CONCLUSION: Kinetic eGFR combined with urine volume was a better predictor for CRRT discontinuation. Evaluation of kinetic eGFR utility in other clinical settings will be necessary.

IFN-ß Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality.

IFN-ß is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-ß for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-ß 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-α or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., "incomplete alveolar neutrophil recruitment"), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-ß reversed the TNF-α/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis → pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-ß improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Seasonality of acute kidney injury incidence and mortality among hospitalized patients.

Background: Understanding disease seasonality is important for improving clinical practice, hospital resource utilization and community-based preventive care. However, no studies have investigated the seasonality of acute kidney injury (AKI). Methods: In the Tokushukai Medical Database, which includes 38 Japanese community hospitals, we identified hospitalized patients with AKI based on the Kidney Disease: Improving Global Outcomes serum creatinine criteria from January 2012 to December 2014. We plotted the number and proportion of patients with AKI among hospitalized patients by month of hospital admission. Subgroup analyses were conducted by the admission diagnosis category, timing of AKI diagnosis and age. We also examined the association between month of hospital admission and AKI, adjusting for patient characteristics and AKI risk factors. Finally, we assessed seasonal variations in disease severity and 30-day mortality of patients with AKI. Results: We identified 81 279 (14.6%) patients with AKI among 555 940 hospitalized patients. The proportion of patients with AKI was highest in January (16.7%) and lowest in June (13.4%). Subgroup analyses suggested that the seasonality of AKI incidence was driven by community-acquired AKI associated with the admission diagnosis of cardiovascular and pulmonary diseases among older patients. The adjusted odds ratio for AKI (January versus June) was 1.24 (95% confidence interval, 1.17-1.31). Patients with AKI showed a larger number of failing organs in winter, and their 30-day mortality was 16.4% in spring, 14.5% in summer, 15.6% in autumn and 18.4% in winter. Conclusion: AKI is more common among hospitalized patients and patients with AKI are more severely ill in winter.

The Japanese clinical practice guideline for acute kidney injury 2016.

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention is necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search.

Prediction of immunoglobulin M reduction via therapeutic dose of simple plasma exchange and double filtration plasmapheresis using membrane separation in patients with hyperviscosity syndrome caused by Waldenstrom macroglobulinemia.

BACKGROUND: Plasma exchange (PE) and double filtration plasmapheresis (DFPP) are known as effective treatment options for hyperviscosity syndrome (HVS) caused by Waldenstrom macroglobulinemia. Nonetheless, few data are available for the relation between the prescribed dose of apheresis and the reduction rate of target molecule immunoglobulin M (IgM), especially in the modality using membrane separation. OBJECTIVES: This study was conducted to establish a model to predict the IgM reduction rate by the dose of simple PE and DFPP using membrane separation in patients with HVS and to compare the consumption of albumin between PE and DFPP. METHODS: We retrospectively analyzed data of total 17 sessions of PE and DFPP with various therapeutic doses performed for five patients at our institution. We used linear regression analysis to examine the relation between the ratio of processed plasma volume to estimated circulating plasma volume (X) and the reduction rate of IgM (Y). RESULTS: Regression analysis revealed that Y is expressed by X as the following equation: Y = 0.35X + 0.095. The total usage of albumin for replacement fluid was lower in DFPP than in PE (21.5 g vs 150 g per session), although the treatment efficacies of both modalities are similar. CONCLUSION: The dose of PE and DFPP using membrane separation can predict IgM reduction rate in the HVS patients. Predicted IgM reduction rates based on our model are lower than those calculated using a known theoretical model. In terms of the amount of use of albumin, DFPP is preferred to PE.

Impact of end-stage renal disease on hospital outcomes among patients admitted to intensive care units: A retrospective matched-pair cohort study.

AIM: We aimed to estimate the burden of end-stage renal disease (ESRD) among patients admitted to intensive care units (ICUs), by comparing hospital outcomes between patients with and without ESRD. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified patients aged 20 years or older who were admitted to ICUs for ≥3 days (2 nights) in 2011. We created a matched cohort of patients with and without ESRD for hospital, age, sex, main diagnosis category, and ICU admission type (medical or surgical) at a maximum ratio of 1:3. For these matched patients, we compared patient characteristics, treatment regimens at ICU admission, and hospital outcomes. We also performed a multivariable logistic regression analysis for the associations between ESRD and 28-day (counting from ICU admission) and in-hospital mortality. RESULTS: Among the 164 423 eligible patients, 7998 (4.9%) had ESRD, from which 5228 ESRD and 12 274 non-ESRD patients were matched for the aforementioned factors. Compared to non-ESRD patients, ESRD patients were on more intensive treatment regimens, including mechanical ventilation, vasoactive drugs, and blood transfusion. Patients with ESRD showed significantly higher ICU, 28-day, and in-hospital mortality and longer lengths of stay in the ICU and hospital (28-day mortality: 11.7% vs. 8.3%; P < 0.001, in-hospital mortality: 21.1% vs. 12.0%; P < 0.001). After adjusting for confounding factors, ESRD was independently associated with 28-day mortality (adjusted odds ratio: 1.36, 95% confidence interval [CI]: 1.22-1.52) and in-hospital mortality (adjusted odds ratio: 1.85, 95% CI: 1.69-2.02). CONCLUSION: This study involving the Japanese national inpatient database, with a matched-pair cohort design, suggested that ESRD is an important burden in the critical care setting.

Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.

Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.

Glypican-5 Increases Susceptibility to Nephrotic Damage in Diabetic Kidney.

Type 2 diabetes mellitus is a leading health issue worldwide. Among cases of diabetes mellitus nephropathy (DN), the major complication of type 2 diabetes mellitus, the nephrotic phenotype is often intractable to clinical intervention and demonstrates the rapid decline of renal function to end-stage renal disease. We recently identified the gene for glypican-5 (GPC5), a cell-surface heparan sulfate proteoglycan, as conferring susceptibility for acquired nephrotic syndrome and additionally identified an association through a genome-wide association study between a variant in GPC5 and DN of type 2 diabetes mellitus. In vivo and in vitro data showed a progressive increase of GPC5 in type 2 DN along with severity; the excess was derived from glomerular mesangial cells. In this study, diabetic kidney showed that accumulation of fibroblast growth factor (Fgf)2 strikingly induced progressive proteinuria that was avoided in Gpc5 knockdown mice. The efficacy of Gpc5 inhibition was exerted through expression of the Fgf receptors 3 and 4 provoked in the diabetic kidney attributively. Extraglomerular Fgf2 was pathogenic in DN, and the deterrence of Gpc5 effectively inhibited the glomerular accumulation of Fgf2, the subsequent increase of mesangial extracellular matrix, and the podocytes' small GTPase activity. These findings elucidate the pivotal role of GPC5, identified as a susceptible gene in the genome-wide association study, in hyperglycemia-induced glomerulopathy.

Potential Survival Benefit of Polymyxin B Hemoperfusion in Septic Shock Patients on Continuous Renal Replacement Therapy: A Propensity-Matched Analysis.

BACKGROUND/AIMS: We assessed the survival benefit of polymyxin B hemoperfusion (PMX) in septic shock patients starting continuous renal replacement therapy (CRRT), who are known to have an increased rate of mortality. METHODS: Adult patients in the Japanese diagnosis procedure combination database satisfying the following criteria were enrolled: hospitalized in 2007-2012; diagnosed as having sepsis; required noradrenaline and/or dopamine; and started CRRT in intensive care unit. Propensity scores for receiving PMX were created from patient and hospital characteristics. RESULTS: Of 3,759 eligible patients, 1,068 received PMX. Propensity-score matching produced a matched cohort of 978 pairs. The 28-day mortality was 40.2% (393/978) in the PMX group and 46.8% (458/978) in the control group (p = 0.003). Logistic regression analysis revealed a significant association between the use of PMX and decreased 28-day mortality (adjusted OR 0.75; 95% CI 0.62-0.91). CONCLUSION: This large retrospective study suggests that septic shock patients starting CRRT may benefit from PMX.

Erythropoietin concentration in acute kidney injury is associated with insulin-like growth factor-binding protein-1.

AIM: Erythropoietin (EPO) production is stimulated by hypoxia in the kidney. Ischaemic injury plays a crucial role in the pathogenesis of acute kidney injury (AKI). However, EPO concentrations in critically ill patients complicated with AKI have not been evaluated sufficiently. This study was conducted to clarify the factors associated with plasma EPO concentrations in AKI. METHODS: This study prospectively enrolled 98 critically ill adult patients treated at the adult mixed ICU. Plasma EPO, insulin-like growth factor-binding protein-1 (IGFBP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and urinary N-acetyl-ß-D-glucosaminidase (NAG) were measured on ICU admission. RESULTS: Acute kidney injury occurred in 42 (42.9%) patients. Significantly higher plasma EPO in the AKI group was detected than in the non-AKI group (16.13 (9.87-28.47) mIU/mL versus 27.81 (10.16-106.02) mIU/mL, P < 0.05). Plasma IGFBP-1 in the AKI group was also significantly higher than in the non-AKI group (19 208 (8820-50 780) pg/mL versus 63 199 (25 289-147 489) pg/mL, P < 0.05). Plasma EPO concentration was negatively correlated with haemoglobin in the non-AKI group with statistical significance, but not in the AKI group. Multiple logistic regression analysis revealed that plasma EPO in the AKI group was associated significantly with plasma IGFBP-1 and complication of diabetes mellitus, but not the haemoglobin concentration, partial pressure of arterial oxygen (PaO2 ), and IL-6. CONCLUSIONS: Not low arterial oxygen tension, haemoglobin concentration, and inflammation evaluated by IL-6 but plasma IGFBP-1 was significantly associated with plasma EPO concentration in AKI, suggesting an unknown mechanism related to systemic stress conditions for EPO regulation in AKI.