Blood perfusion with polymyxin B immobilized columns in patients with COVID-19 requiring oxygen therapy.

Extracorporeal blood purification with polymyxin B immobilized fiber column direct hemoperfusion (PMX-DHP), is reported to be effective in treating COVID-19 pneumonitis with oxygen demand. This multicenter prospective study evaluated the efficacy and safety of PMX-DHP in oxygen-requiring patients with COVID-19 admitted between September 28, 2020, and March 31, 2022. The primary endpoint was the percentage of clinical improvement 15 days after treatment. The secondary endpoint was the percentage of worsened disease status. Data from the COVID-19 patient registry were used for the synthetic control group. The improvement rate on Day 15 did not differ between PMX-treated patients and controls; however, the deterioration rate was 0.38 times lower in the PMX-treated group, and the death rates on Day 29 were 0 and 11.1% in the PMX-treated and control groups, respectively. The PMX group showed a 0.73 times higher likelihood for reduced intensive care demand, as 16.7% of PMX-treated patients and 22.8% of controls worsened. After treatment blood oxygenation improved, urinary ß2-microglobulin and liver-type fatty acid-binding protein showed significant decreases, and IL-6 decreased once during treatment but did not persist. In this study, PMX treatment effectively prevented the worsening of COVID-19 pathology, accompanied by improved oxygenation. PMX treatment to remove activated cells may effectively improve patient outcomes.

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.

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.

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.

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.

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.

Urinary L-Type Fatty Acid-Binding Protein Predicts Oxygen Demand of COVID-19 in Initially Mild Cases.

Early detection of illness trajectory in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients is crucial for patients and healthcare workers. An effective, noninvasive approach, with simple measurement for decision-making, is necessary in a pandemic to discriminate between high- and low-risk patients, even though both groups may exhibit mild symptoms in the beginning. OBJECTIVES: To predict COVID-19 disease severity within 10 days, distinguishing cases that will progress to moderate or severe versus mild, patient urinary L-type fatty acid-binding protein (L-FABP) was assayed within 4 days of receiving a diagnosis. The study also examined whether L-FABP point of care (POC) test is helpful in risk screening. DESIGN: Symptomatic subjects who tested positive for SARS-CoV-2 and were hospitalized were prospectively enrolled at the National Center for Global Health and Medicine (NCGM), Yamanashi Prefectural Central Hospital (YPCH), and Sinai Hospital in Maryland. The outcome of each case was evaluated 7 days after admission and the diagnostic performance of L-FABP was assessed. SETTING AND PARTICIPANTS: Subjects were treated for COVID-19 at public healthcare centers in Japan from January 31, 2020, to January 31, 2021, to NCGM, YPCH, and at Sinai Hospital in Baltimore, MD, during the same period. MAIN OUTCOMES AND MEASURES: The primary outcome was to determine whether urinary L-FABP within 48 hours of admission can predict the patient's severity of COVID-19 1 week later. We obtained demographic data, information on clinical symptoms, radiographic images, and laboratory data. RESULTS: Diagnostic performance was assessed using receiver operating characteristic analysis. Of the 224 participants in the study, 173 initially had a mild form of COVID-19. The area under the curve (AUC) for a severe outcome was 93.5%. L-FABP POC risk prediction of a severe outcome had an AUC of 88.9%. CONCLUSIONS AND RELEVANCE: Urinary L-FABP can predict patient risk of COVID-19 illness severity. L-FABP POC is implementable for patient management. (ClinicalTrials.gov number, NCT04681040).

Outcomes associated with acute kidney disease: A systematic review and meta-analysis.

Background: Acute kidney disease (AKD) defines the period after kidney damage and it is a critical period of both repair and fibrotic pathways. However, the outcomes of patients with AKD have not been well-defined. Methods: In this meta-analysis, PubMed, Embase, Cochrane and China National Knowledge Infrastructure were searched on July 31,2022. We excluded studies including patients undergoing kidney replacement therapy at enrollment. The data was used to conduct a random-effects model for pool outcomes between patients with AKD and non-AKD (NKD). This study is registered with PROSPERO, CRD 42021271773. Findings: The search generated 739 studies of which 21 studies were included involving 1,114,012 patients. The incidence rate of community-acquired AKD was 4.60%, 2.11% in hospital-acquired AKD without a prior AKI episode, and 26.11% in hospital-acquired AKD with a prior AKI episode. The all-cause mortality rate was higher in the AKD group (26.54%) than in the NKD group (7.78%) (odds ratio [OR]: 3.62, 95% confidence interval [CI]: 2.64 to 4.95, p < 0.001, I2 = 99.11%). The rate of progression to end-stage kidney disease (ESKD) was higher in the AKD group (1.3%) than in the NKD group (0.14%) (OR: 6.58, p < 0.001, I2 = 94.95%). The incident rate of CKD and progressive CKD was higher in the AKD group (37.2%) than in the NKD group (7.45%) (OR:4.22, p < 0.001, I2 = 96.67%). Compared to the NKD group, patients with AKD without prior AKI had a higher mortality rate (OR: 3.00, p < 0.001, I2 = 99.31%) and new-onset ESKD (OR:4.96, 95% CI, p = 0.002, I2 = 97.37%). Interpretation: AKD is common in community and hospitalized patients who suffer from AKI and also occurs in patients without prior AKI. The patients with AKD, also in those without prior AKI had a higher risk of mortality, and new-onset ESKD than the NKD group. Funding: This study was supported by Ministry of Science and Technology (MOST) of the Republic of China (Taiwan) [grant number, MOST 107-2314-B-002-026-MY3, 108-2314-B-002-058, 110-2314-B-002-241, 110-2314-B-002-239], National Science and Technology Council (NSTC) [grant number, NSTC 109-2314-B-002-174-MY3, 110-2314-B-002-124-MY3, 111-2314-B-002-046, 111-2314-B-002-058], National Health Research Institutes [PH-102-SP-09], National Taiwan University Hospital [109-S4634, PC-1246, PC-1309, VN109-09, UN109-041, UN110-030, 111-FTN0011] Grant MOHW110-TDU-B-212-124005, Mrs. Hsiu-Chin Lee Kidney Research Fund and Chi-mei medical center CMFHR11136. JAN is supported, in part, by grants from the National Institute of Health, NIDDK (R01 DK128208 and P30 DK079337) and NHLBI (R01 HL148448-01).

Clinical Utility of a Biomarker to Detect Contrast-Induced Acute Kidney Injury during Percutaneous Cardiovascular Procedures.

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a major clinical complication of percutaneous cardiovascular procedures requiring iodinated contrast. Despite its relative frequency, practicing physicians are unlikely to identify or treat this condition. METHODS: In a 2-round clinical trial of simulated patients, we examined the clinical utility of a urine-based assay that measures liver-type fatty acid-binding protein (L-FABP), a novel marker of CI-AKI. We sought to determine if interventional cardiologists' ability to diagnose and treat potential CI-AKI improved using the biomarker assay for 3 different patient types: pre-procedure, peri-procedure, and post-procedure patients. RESULTS: 154 participating cardiologists were randomly divided into either control or intervention. At baseline, we found no difference in the demographics or how they identified and treated potential complications of AKI, with both groups providing less than half the necessary care to their patients (46.4% for control vs. 47.6% for intervention, p = 0.250). The introduction of L-FABP into patient care resulted in a statistically significant improvement of 4.6% (p = 0.001). Compared to controls, physicians receiving L-FABP results were 2.9 times more likely to correctly identify their patients' risk for AKI (95% CI 2.1-4.0) and were more than twice as likely to treat for AKI by providing volume expansion and withholding nephrotoxic medications. We found the greatest clinical utility in the pre-procedure and peri-procedure settings but limited value in the post-procedure setting. CONCLUSION: This study suggests L-FABP as a clinical marker for assessing the risk of potential CI-AKI, has clinical utility, and can lead to more accurate diagnosis and treatment.

PpSP32-like protein as a marker of human exposure to Phlebotomus argentipes in Leishmania donovani foci in Bangladesh.

Phlebotomus argentipes is a predominant vector of Leishmania donovani, the protozoan parasite causing visceral leishmaniasis in the Indian subcontinent. In hosts bitten by P. argentipes, sand fly saliva elicits the production of specific anti-salivary protein antibodies. Here, we have utilised these antibodies as markers of human exposure to P. argentipes in a visceral leishmaniasis endemic area in Pabna district, Bangladesh. The use of whole salivary gland homogenate as an antigen to detect these antibodies has several limitations, therefore it is being superseded by the use of specific recombinant salivary proteins. We have identified three major P. argentipes salivary antigenic proteins recognised by sera of bitten humans, expressed them in a recombinant form (rPagSP04, rPagSP05 and rPagSP06) and tested their applicability in ELISA and immunoblot. One of them, PpSP32-like protein rPagSP06, was identified as the most promising antigen, showing highest resemblance and correlation with the IgG response to P. argentipes salivary gland homogenate. Furthermore, we have validated the applicability of rPagSP06 in a large cohort of 585 individuals and obtained a high correlation coefficient for anti-rPagSP06 and anti-P. argentipes saliva IgG responses. The anti-rPagSP06 and anti-P. argentipes salivary gland homogenate IgG responses followed a similar right-skewed distribution. This is the first report of screening human sera for anti-P. argentipes saliva antibodies using recombinant salivary protein. The rPagSP06 was proven to be a valid antigen for screening human sera for exposure to P. argentipes bites in a visceral leishmaniasis endemic area.

Preexisting heart failure with reduced ejection fraction attenuates renal fibrosis after ischemia reperfusion via sympathetic activation.

Although chronic heart failure is clinically associated with acute kidney injury (AKI), the precise mechanism that connects kidney and heart remains unknown. Here, we elucidate the effect of pre-existing heart failure with reduced ejection fraction (HFrEF) on kidney via sympathetic activity, using the combining models of transverse aortic constriction (TAC) and unilateral renal ischemia reperfusion (IR). The evaluation of acute (24 h) and chronic (2 weeks) phases of renal injury following IR 8 weeks after TAC in C57BL/6 mice revealed that the development of renal fibrosis in chronic phase was significantly attenuated in TAC mice, but not in non-TAC mice, whereas no impact of pre-existing heart failure was observed in acute phase of renal IR. Expression of transforming growth factor-ß, monocyte chemoattractant protein-1, and macrophage infiltration were significantly reduced in TAC mice. Lastly, to investigate the effect of sympathetic nerve activity, we performed renal sympathetic denervation two days prior to renal IR, which abrogated attenuation of renal fibrosis in TAC mice. Collectively, we demonstrate the protective effect of pre-existing HFrEF on long-term renal ischemic injury. Renal sympathetic nerve may contribute to this protection; however, further studies are needed to fully clarify the comprehensive mechanisms associated with attenuated renal fibrosis and pre-existing HFrEF.

Measuring the Variation in the Prevention and Treatment of CI-AKI Among Interventional Cardiologists.

Contrast-induced acute kidney injury (CI-AKI) occurs in up to 10% of cardiac catheterizations and coronary interventions, resulting in increased morbidity, mortality, and cost. One main reason for these complications and costs is under-recognition of CI-AKI risk and under-treatment of patients with impaired renal status. 157 interventional cardiologists each cared for three simulated patients with common conditions requiring intravascular contrast media in three typical settings: pre-procedurally, during the procedure, and post-procedure. We evaluated their ability to assess the risk of developing CI-AKI, make the diagnosis, and treat CI-AKI, including proper volume expansion and withholding nephrotoxic medications. Overall, the quality-of-care scores averaged 46.0% ± 10.5, varying between 18% to 78%. The diagnostic scores for accurately assessing risk of CI-AKI were low at 57.1% ± 21.2% and the accuracy of diagnosis pre-existing chronic kidney disease was 50.2%. Poor diagnostic accuracy led to poor treatment: proper volume expansion done in only 30.7% of cases, in-hospital repeat creatinine evaluation performed in 32.1%, and avoiding nephrotoxic medications occurred in 14.2%. While volume expansion was relatively similar across the three settings (P = 0.287), the cardiologists were less likely to discontinue nephrotoxic medications in pre-procedurally (9.7%) compared to the other settings (27.0%), and to order in-hospital creatinine testing in peri-procedurally (18.8%) compared to post-procedure (57.8%) (P < 0.05 for both). The overall care of patients at risk for contrast-induced acute kidney injury varied widely and showed room for improvement. Improving care for this condition will require greater awareness by cardiologists and better diagnostic tools to guide them.

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.

SHROOM3, the gene associated with chronic kidney disease, affects the podocyte structure.

Chronic kidney disease is a public health burden and it remains unknown which genetic loci are associated with kidney function in the Japanese population, our genome-wide association study using the Biobank Japan dataset (excluding secondary kidney diseases, such as diabetes mellitus) clearly revealed that almost half of the top 50 single nucleotide polymorphisms associated with estimated glomerular filtration rate are located in the SHROOM3 gene, suggesting that SHROOM3 will be responsible for kidney function. Thus, to confirm this finding, supportive functional analyses were performed on Shroom3 in mice using fullerene-based siRNA delivery, which demonstrated that Shroom3 knockdown led to albuminuria and podocyte foot process effacement. The in vitro experiment shows that knockdown of Shroom3 caused defective formation of lamellipodia in podocyte, which would lead to the disruption of slit diaphragm. These results from the GWAS, in vivo and in vitro experiment were consistent with recent studies reporting that albuminuria leads to impairment of kidney function.

Evaluation of Coronavirus Disease 2019 Severity Using Urine Biomarkers.

SUBJECTS: Early detection of coronavirus disease 2019 in patients likely to develop severe manifestations enables appropriate interventions, including rapid ICU admission. This study was conducted to determine whether noninvasive urine biomarkers can predict the clinical severity of coronavirus disease 2019. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: This is single-center study, national center hospital designated for infectious disease. Fifty-eight patients who tested positive for severe acute respiratory syndrome coronavirus 2 in respiratory specimens through real-time reverse transcription-polymerase chain reaction were retrospectively studied. Urinary ß2-microglobulin, liver-type fatty acid-binding protein were serially measured. Serum interferon-γ and monocyte chemotactic protein-1 were also evaluated. The 58 patients were assigned into three groups. Patients requiring intensive care were assigned to the severe group (n = 12). Patients treated with oxygen were assigned to the moderate group (n = 13). Other patients were assigned to the mild group (n = 33). Urine tests revealed that low ß2-microglobulin and liver-type fatty acid-binding protein levels were associated with mild disease, whereas high levels were associated with severe disease. In severe cases, liver-type fatty acid-binding protein tended to be persistently high. The resulting cutoff values were ß2-microglobulin; severe versus moderate + mild: 2,457 µg/dL (specificity 76.9% and sensitivity 90.0%, area under the receiver operating characteristic curve 85.9%), liver-type fatty acid-binding protein; severe versus moderate + mild: 22.0 µg/gCre (specificity 84.6% and sensitivity 90%, area under the receiver operating characteristic curve 91.8%). Urinary ß2-microglobulin and serum interferon-γ/monocyte chemotactic protein-1 showed a similar trend. CONCLUSIONS: Evaluating urinary biomarkers such as ß2-microglobulin and liver-type fatty acid-binding protein may allow determination of coronavirus disease 2019 patients with active cytokines and recognition of patients likely to become critically ill and requiring careful observation and early intervention.

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).

The Clinical Course of Acute Kidney Disease after Cardiac Surgery: A Retrospective Observational Study.

Acute kidney disease (AKD), or renal dysfunction persisting >7 days after an initiating event of acute kidney injury, is a rising concern. This study aimed to elucidate the clinical course of AKD after cardiac surgery with data on post-cardiac surgery patients admitted to intensive care units (ICU) at 18 Japanese hospitals during 2012-2014. Using multivariable logistic models, we evaluated the association of AKD with 90-day mortality and the 50% eGFR decline during 2-year follow-up compared to eGFR at 90 days. AKD was defined as an elevation in serum creatinine to at least 1.5-fold from baseline in >7 days after ICU admission. Of the 3,605 eligible patients undergoing cardiac surgery, 403 patients (11.2%) had AKD. Multivariable analysis revealed that the adjusted odds ratio (OR) of AKD for 90-day mortality was 63.0 (95% confidence interval [CI], 27.9-180.6). In addition, the adjusted OR of AKD for 50% eGFR decline was 3.56 (95% CI, 2.24-5.57) among hospital survivors. In conclusion, AKD after cardiac surgery was associated with higher 90-day mortality and renal function decline after hospital discharge.

A Simple Scoring Method for Predicting the Low Risk of Persistent Acute Kidney Injury in Critically Ill Adult Patients.

The renal angina index has been proposed to identify patients at high risk of persistent AKI, based on slight changes in serum creatinine and patient conditions. However, a concise scoring method has only been proposed for pediatric patients, and not for adult patients yet. Here, we developed and validated a concise scoring method using data on patients admitted to ICUs in 21 Japanese hospitals from 2012 to 2014. We randomly assigned to either discovery or validation cohorts, identified the factors significantly associated with persistent AKI using a multivariable logistic regression model in the discovery cohort to establish a scoring system, and assessed the validity of the scoring in the validation cohort using receiver operating characteristic analysis and the calibration slope. Among 8,320 patients admitted to the ICUs, persistent AKI was present in 1,064 (12.8%) patients. In the discovery cohort (n = 4,151), 'hyperbilirubinemia', 'sepsis' and 'ventilator and/or vasoactive' with small changes in serum creatinine were selected to establish the scoring. In the validation cohort (n = 4,169), the predicting model based on this scoring had a c-statistic of 0.79 (95%CI, 0.77-0.81) and was well calibrated. In conclusion, we established a concise scoring method to identify potential patients with persistent AKI, which performed well in the validation cohort.