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Background: Early trials of dihydropyridine calcium channel blockers (DCCBs) suggest a detrimental effect on intraglomerular pressure and an association with albuminuria., Objective: We sought to evaluate the associations of DCCB initiation with albuminuria and kidney failure with replacement therapy (KFRT) and to determine whether renin-angiotensin system (RAS) blockade modified these associations., Design: We conducted a target trial emulation study using a new user, active comparator design and electronic health record data from Geisinger Health., Participants: We included patients without severe albuminuria or KFRT who were initiated on a DCCB or thiazide (active comparator) between January 1, 2004, and December 31, 2019., Main Measures: Using inverse probability of treatment weighting, we performed doubly robust Cox proportional hazards regression to estimate the association of DCCB initiation with incident severe albuminuria (urine albumin to creatinine ratio > 300 mg/g) and KFRT, overall and stratified by RAS blocker use., Key Results: There were 11,747 and 26,758 eligible patients initiating a DCCB and thiazide, respectively, with a weighted baseline mean age of 60 years, systolic blood pressure of 143 mm Hg, and eGFR of 86 mL/min/1.73 m 2 , and with a mean follow-up of 8 years. Compared with thiazides, DCCBs were significantly associated with the development of severe albuminuria (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.16-1.43), with attenuation of risk in the presence of RAS blockade (P for interaction < 0.001). The risk of KFRT was increased among patients without RAS blockade (HR, 1.66; 95% CI, 1.19-2.31), but not with RAS blockade (P for interaction = 0.005)., Conclusions: DCCBs were associated with increased risk of albuminuria and, in the absence of RAS blockade, KFRT. These findings suggest coupling DCCB therapy with RAS blockade may mitigate adverse kidney outcomes., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Communication between tumors and lymph nodes carries substantial significance for antitumor immunotherapy. Remodeling the immune microenvironment of tumor-draining lymph nodes (TdLN) plays a key role in enhancing the anti-tumor ability of immunotherapy. In this study, we constructed a biomimetic artificial lymph node structure composed of F127 hydrogel loading effector memory T (T EM ) cells and PD-1 inhibitors (aPD-1). The biomimetic lymph nodes facilitate the delivery of T EM cells and aPD-1 to the TdLN and the tumor immune microenvironment, thus realizing effective and sustained anti-tumor immunotherapy. Exploiting their unique gel-forming and degradation properties, the cold tumors were speedily transformed into hot tumors via T EM cell supplementation. Meanwhile, the efficacy of aPD-1 was markedly elevated compared with conventional drug delivery methods. Our finding suggested that the development of F127@T EM @aPD-1 holds promising potential as a future novel clinical drug delivery technique. STATEMENT OF SIGNIFICANCE: F127@T EM @aPD-1 show unique advantages in cancer treatment. When injected subcutaneously, F127@T EM @aPD-1 can continuously supplement T EM cells and aPD-1 to tumor draining lymph nodes (TdLN) and the tumor microenvironment, not only improving the efficacy of ICB therapy through slow release, but also exhibiting dual regulatory effects on the tumor and TdLN., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

This paper presents a remote sensing-based method to efficiently generate multi-temporal landslide inventories and identify recurrent and persistent landslides. We used free data from Landsat, nighttime lights, digital elevation models, and a convolutional neural network model to develop the first multi-decadal inventory of landslides across the Himalaya, spanning from 1992 to 2021. The model successfully delineated >265,000 landslides, accurately identifying 83 % of manually mapped landslide areas and 94 % of reported landslide events in the region. Surprisingly, only 14 % of landslide areas each year were first occurrences, 55-83 % of landslide areas were persistent and 3-24 % had reactivated. On average, a landslide-affected pixel persisted for 4.7 years before recovery, a duration shorter than findings from small-scale studies following a major earthquake event. Among the recovered areas, 50 % of them experienced recurrent landslides after an average of five years. In fact, 22 % of landslide areas in the Himalaya experienced at least three episodes of landslides within 30 years. Disparities in landslide persistence across the Himalaya were pronounced, with an average recovery time of 6 years for Western India and Nepal, compared to 3 years for Bhutan and Eastern India. Slope and elevation emerged as significant controls of persistent and recurrent landslides. Road construction, afforestation policies, and seismic and monsoon activities were related to changes in landslide patterns in the Himalaya., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Karen C. Seto reports financial support was provided by NASA. Nick J. Rosser reports financial support was provided by UK Research and Innovation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Rationale & Objective: Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at lower levels. We evaluated whether serum UMOD levels were associated with the risks of incident kidney failure with replacement therapy (KFRT) and mortality., Study Design: Prospective cohort., Setting & Participants: Participants in AASK (the African American Study of Kidney Disease and Hypertension) with available stored serum samples from the 0-, 12-, and 24-month visits for biomarker measurement., Predictors: Baseline log-transformed UMOD and change in UMOD over 2 years., Outcomes: KFRT and mortality., Analytical Approach: Cox proportional hazards and mixed-effects models., Results: Among 500 participants with baseline serum UMOD levels (mean age, 54y; 37% female), 161 KFRT events occurred during a median of 8.5 years. After adjusting for baseline demographic factors, clinical factors, glomerular filtration rate, log-transformed urine protein-creatinine ratio, and randomized treatment groups, a 50% lower baseline UMOD level was independently associated with a 35% higher risk of KFRT (adjusted HR, 1.35; 95% CI, 1.07-1.70). For annual UMOD change, each 1-standard deviation lower change was associated with a 67% higher risk of KFRT (adjusted HR, 1.67; 95% CI, 1.41-1.99). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply for metoprolol versus ramipril (P<0.001) as well as for intensive versus standard blood pressure goals (P = 0.002)., Limitations: Small sample size and limited generalizability., Conclusions: Lower UMOD levels at baseline and steeper declines in UMOD over time were associated with a higher risk of subsequent KFRT in a cohort of African American adults with chronic kidney disease and hypertension., Plain-Language Summary: Prior studies of uromodulin (UMOD), the most abundant protein in urine, and kidney disease have focused primarily on urinary UMOD levels. The present study evaluated associations of serum UMOD levels with the risks of kidney failure with replacement therapy (KFRT) and mortality in a cohort of African American adults with hypertension and chronic kidney disease. It found that participants with lower levels of UMOD at baseline were more likely to experience KFRT even after accounting for baseline kidney measures. Similarly, participants who experienced steeper annual declines in UMOD also had a heightened risk of kidney failure. Neither baseline nor annual change in UMOD was associated with mortality. Serum UMOD is a promising biomarker of kidney health., (Published by Elsevier Inc.)

Concrete cracks and local damage can affect the bond performance between concrete and steel bars, thereby reducing the durability of reinforced concrete structures. Compared with general concrete crack repair methods, biomineralization repair not only has effective bonding capabilities but is also particularly environmentally friendly. Therefore, this study aimed to apply biomineralization technology to repair damaged fiber-reinforced lightweight aggregate concrete (LWAC). Two groups of LWAC specimens were prepared. The experimental group used lightweight aggregates (LWAs) containing bacterial spores and nutrient sources, while the control group used LWAs without bacterial spores and nutrient sources. These specimens were first subjected to compression tests and pull-out tests, respectively, and thus were damaged. After the damaged specimen healed itself in different ways for 28 days, secondary compression and pull-out tests were conducted. The self-healing method of the control group involved placing the specimens in an incubator. The experimental group was divided into experimental group I and experimental group II according to the self-healing method. The self-healing method of experimental group I was the same as that of the control group. The self-healing method of experimental group II involved soaking the specimen in a mixed solution of urea and calcium acetate for two days, and then taking it out and placing it in an incubator for two days, with a cycle of four days. The test results show that in terms of the relative bond strength ratio, the experimental group II increased by 17.9% compared with the control group. Moreover, the precipitate formed at the cracks in the sample was confirmed to be calcium carbonate with the EDS and XRD analysis results, which improved the compressive strength and bond strength after self-healing. This indicates that the biomineralization self-healing method used in experimental group II is more effective.

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure., Competing Interests: Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: TKC and MEG received an honorarium from the American Society of Nephrology (nephSAP)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Rationale & Objective: Proteomics could provide pathophysiologic insight into the increased risk of mortality in patients with chronic kidney disease (CKD). This study aimed to investigate associations between the circulating proteome and all-cause mortality among patients with CKD., Study Design: Observational cohort study., Setting & Participants: Primary analysis in 703 participants in the African American Study of Kidney Disease and Hypertension (AASK) and validation in 1,628 participants with CKD in the Atherosclerosis Risk in Communities (ARIC) study who attended visit 5., Exposure: Circulating proteins., Outcome: All-cause mortality., Analytical Approach: Among AASK participants, we evaluated the associations of 6,790 circulating proteins with all-cause mortality using multivariable Cox proportional hazards models. Proteins with significant associations were further studied in ARIC Visit 5 participants with CKD., Results: In the AASK cohort, the mean age was 54.5 years, 271 (38.5%) were women, and the mean measured glomerular filtration rate (GFR) was 46 mL/min/1.73 m 2 . The median follow-up was 9.6 years, and 7 distinct proteins were associated with all-cause mortality at the Bonferroni-level threshold ( P  < 0.05 of the 6,790) after adjustment for demographics and clinical factors, including baseline measured estimated GFR and proteinuria. In the ARIC visit 5 cohort, the mean age was 77.2 years, 903 (55.5%) were women, the mean estimated GFR was 54 mL/min/1.73 m 2 and median follow-up was 6.9 years. Of the 7 proteins found in AASK, 3 (β 2 -microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide) were available in the ARIC data, with all 3 significantly associated with death in ARIC., Limitations: Possibility of unmeasured confounding. Cause of death was not known., Conclusions: Using large-scale proteomic analysis, proteins were reproducibly associated with mortality in 2 cohorts of participants with CKD., Plain-Language Summary: Patients with chronic kidney disease (CKD) have a high risk of premature death, with various pathophysiological processes contributing to this increased risk of mortality. This observational cohort study aimed to investigate the associations between circulating proteins and all-cause mortality in patients with CKD using large-scale proteomic analysis. The study analyzed data from the African American Study of Kidney Disease and Hypertension (AASK) study and validated the findings in the Atherosclerosis Risk in Communities (ARIC) Study. A total of 6,790 circulating proteins were evaluated in AASK, and 7 proteins were significantly associated with all-cause mortality. Three of these proteins (β 2 -microglobulin, spondin-1, and N-terminal pro-brain natriuretic peptide (BNP)) were also measured in ARIC and were significantly associated with death. Additional studies assessing biomarkers associated with mortality among patients with CKD are needed to evaluate their use in clinical practice., (© 2023 The Authors.)

Urban areas are associated with higher depression risks than rural areas. However, less is known about how different types of urban environments relate to depression risk. Here, we use satellite imagery and machine learning to quantify three-dimensional (3D) urban form (i.e., building density and height) over time. Combining satellite-derived urban form data and individual-level residential addresses, health, and socioeconomic registers, we conduct a case-control study ( n = 75,650 cases and 756,500 controls) to examine the association between 3D urban form and depression in the Danish population. We find that living in dense inner-city areas did not carry the highest depression risks. Rather, after adjusting for socioeconomic factors, the highest risk was among sprawling suburbs, and the lowest was among multistory buildings with open space in the vicinity. The finding suggests that spatial land-use planning should prioritize securing access to open space in densely built areas to mitigate depression risks.

Background: We carried out a study of the aptamer proteomic assay, SomaScan V4, to evaluate the analytical and biological variability of the assay in plasma samples of patients with moderate to severe chronic kidney disease (CKD)., Methods: Plasma samples were selected from 2 sources: (a) 24 participants from the Chronic Renal Insufficiency Cohort (CRIC) and (b) 49 patients from the Brigham and Women's Hospital-Kidney/Renal Clinic. We calculated intra-assay variability from both sources and examined short-term biological variability in samples from the Brigham clinic. We also measured correlations of aptamer measurements with traditional biomarker assays., Results: A total of 4656 unique proteins (4849 total aptamer measures) were analyzed in all samples. Median (interquartile range [IQR] intra-assay CV) was 3.7% (2.8-5.3) in CRIC and 5.0% (3.8-7.0) in Brigham samples. Median (IQR) biological CV among Brigham samples drawn from one individual on 2 occasions separated by median (IQR) 7 (4-14) days was 8.7% (6.2-14). CVs were independent of CKD stage, diabetes, or albuminuria but were higher in patients with systemic lupus erythematosus. Rho correlations between aptamer and traditional assays for biomarkers of interest were cystatin C = 0.942, kidney injury model-1 = 0.905, fibroblast growth factor-23 = 0.541, tumor necrosis factor receptors 1 = 0.781 and 2 = 0.843, P < 10-100 for all., Conclusions: Intra-assay and within-subject variability for SomaScan in the CKD setting was low and similar to assay variability reported from individuals without CKD. Intra-assay precision was excellent whether samples were collected in an optimal research protocol, as were CRIC samples, or in the clinical setting, as were the Brigham samples., (© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alluvial fans are large-scale depositional structures commonly found at the base of mountain ranges. They are relatively soil-rich compared to the rocky terrains, or catchment areas, from which their material originates. When frequented by debris flows (massive, muddy, rocky flows) they contribute significantly to local hazards as they carry focused, collisional, fast-moving materials across alluvial fans, unpredictable in size, speed, and direction. We research how fine particle content in debris flows correlates with directional changes, i.e., debris flow avulsions. Toward this, we analyzed field data from two neighboring alluvial fans in the White Mountains (California, USA) that exhibit dramatically different topographies despite their proximity and associated similar long-term climates. Informed by these measurements, we performed long-term and incremental alluvial fan experiments built by debris flows with systematically-varied fine particle content. We found that (1) decreasing fine particle content increases the variability of fan slopes and associated channelization dynamics, and (2) for all mixtures longer-term continuous alluvial fan experiments form more complex surface channelizations than repeated flows for the same total time, indicating the importance of both particle sizes and timescales on alluvial fan surface morphology., (© 2022. The Author(s).)

Rationale & Objective: Few studies have investigated racial disparities in acute kidney injury (AKI), in contrast to the extensive literature on racial differences in the risk of kidney failure. We sought to study potential differences in risk in the setting of chronic kidney disease (CKD)., Study Design: Prospective cohort study., Setting & Participants: We studied 2,720 self-identified Black or White participants with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study from July 1, 2013, to December 31, 2017., Exposure: Self-reported race (Black vs White)., Outcome: Hospitalized AKI (≥50% increase from nadir to peak serum creatinine)., Analytical Approach: Cox regression models adjusting for demographics (age and sex), prehospitalization clinical risk factors (diabetes, blood pressure, cardiovascular disease, estimated glomerular filtration rate, proteinuria, receipt of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers), and socioeconomic status (insurance status and education level). In a subset of participants with genotype data, we adjusted for apolipoprotein L1 gene (APOL1) high-risk status and sickle cell trait., Results: Black participants (n = 1,266) were younger but had a higher burden of prehospitalization clinical risk factors. The incidence rate of first AKI hospitalization among Black participants was 6.3 (95% CI, 5.5-7.2) per 100 person-years versus 5.3 (95% CI, 4.6-6.1) per 100 person-years among White participants. In an unadjusted Cox regression model, Black participants were at a modestly increased risk of incident AKI (HR, 1.22 [95% CI, 1.01-1.48]) compared with White participants. However, this risk was attenuated and no longer significant after adjusting for prehospitalization clinical risk factors (adjusted HR, 1.02 [95% CI, 0.83-1.25]). There were only 11 AKI hospitalizations among individuals with high-risk APOL1 risk status and 14 AKI hospitalizations among individuals with sickle cell trait., Limitations: Participants were limited to research volunteers and potentially not fully representative of all CKD patients., Conclusions: In this multicenter prospective cohort of CKD patients, racial disparities in AKI incidence were modest and were explained by differences in prehospitalization clinical risk factors., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs)., Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted., Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds ( Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response)., Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs., Competing Interests: Potential conflicts of interest. C.R. and L.L. are employees of and hold stock options for Partner Therapeutics, Inc. T.W. has received grants for experimental and clinical antimicrobial pharmacology, therapeutics, and diagnostics to his institutions from Allergan, Amplyx, Astellas, Lediant, Medicines Company, Merck, Scynexis, Shionogi, T2 Biosystems, Tetraphase, and Viosera. He has served as consultant to Amplyx, Astellas, Allergan, ContraFect, Gilead, Karyopharm Therapeutics, Leadiant, Medicines Company, Merck, Methylgene, Partner Therapeutics, Inc., Pfizer, Scynexis, Shionogi, and T2 Biosystems. C.B.S. has received grant support from GlaxoSmithKline, ViiV, Abbott, Merck, Gilead, Chimerix, Shire/Takeda, Schering-Plough, Ablynx, Janssen, Ansun Biopharma, and Karyopharm Therapeutics. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rationale and Objective: Chronic kidney disease is a risk enhancing factor for cardiovascular disease (CVD) and mortality, and the role of aspirin use is unclear in this population. We investigated the risk and benefits of aspirin use in primary and secondary prevention of CVD in the Chronic Renal Insufficiency Cohort Study., Study Design: Prospective observational cohort., Setting & Participants: 3,664 Chronic Renal Insufficiency Cohort participants., Exposure: Aspirin use in patients with and without preexisting CVD., Outcomes: Mortality, composite and individual CVD events (myocardial infarction, stroke, and peripheral arterial disease), kidney failure (dialysis and transplant), and major bleeding., Analytical Approach: Intention-to-treat analysis and multivariable Cox proportional hazards model to examine associations of time varying aspirin use., Results: The primary prevention group was composed of 2,578 (70.3%) individuals. Mean age was 57 ± 11 years, 46% women, 42% Black, and 47% had diabetes. The mean estimated glomerular filtration rate was 45 mL/min/1.73 m 2 . Median follow-up was 11.5 (IQR, 7.4-13) years. Aspirin was not associated with all-cause mortality in those without preexisting cardiovascular disease (CVD) (HR, 0.84; 95% CI, 0.7-1.01; P  = 0.06) or those with CVD (HR, 0.88; 95% CI, 0.77-1.02, P  = 0.08). Aspirin was not associated with a reduction of the CVD composite in primary prevention (HR, 0.97; 95% CI, 0.77-1.23; P  = 0.79) and in secondary prevention because the original study design was not meant to study the effects of aspirin., Limitations: This is not a randomized controlled trial, and therefore, causality cannot be determined., Conclusions: Aspirin use in chronic kidney disease patients was not associated with reduction in primary or secondary CVD events, progression to kidney failure, or major bleeding., (© 2022 The Authors.)

Background: Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied., Methods: We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m 2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m 2 , respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function., Results: There were 129 ESKD events over a median of 7.0 years in AASK ( n =418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D ( n =754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively., Conclusions: Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: The APOL1 risk variants (G1 and G2) are associated with kidney disease among Black adults, but the clinical presentation is heterogeneous. In mouse models and cell systems, increased gene expression of G1 and G2 confers cytotoxicity. How APOL1 risk variants relate to the circulating proteome warrants further investigation., Design, Setting, Participants, & Measurements: Among 461 African American Study of Kidney Disease and Hypertension (AASK) participants (mean age: 54 years; 41% women; mean GFR: 46 ml/min per 1.73 m 2 ), we evaluated associations of APOL1 risk variants with 6790 serum proteins (measured via SOMAscan) using linear regression models. Covariates included age, sex, percentage of European ancestry, and protein principal components 1-5. Associated proteins were then evaluated as mediators of APOL1 -associated risk for kidney failure. Findings were replicated among 875 Atherosclerosis Risk in Communities (ARIC) study Black participants (mean age: 75 years; 66% women; mean eGFR: 67 ml/min per 1.73 m 2 )., Results: In the AASK study, having two (versus zero or one) APOL1 risk alleles was associated with lower serum levels of APOL1 ( P =3.11E-13; P =3.12E-06 [two aptamers]), APOL2 ( P= 1.45E-10), CLSTN2 ( P =2.66E-06), MMP-2 ( P =2.96E-06), SPOCK2 ( P =2.57E-05), and TIMP-2 ( P =2.98E-05) proteins. In the ARIC study, APOL1 risk alleles were associated with APOL1 ( P =1.28E-11); MMP-2 ( P =0.004) and TIMP-2 ( P =0.007) were associated only in an additive model, and APOL2 was not available. APOL1 high-risk status was associated with a 1.6-fold greater risk of kidney failure in the AASK study; none of the identified proteins mediated this association. APOL1 protein levels were not associated with kidney failure in either cohort., Conclusions: APOL1 risk variants were strongly associated with lower circulating levels of APOL1 and other proteins, but none mediated the APOL1 -associated risk for kidney failure. APOL1 protein level was also not associated with kidney failure., (Copyright © 2022 by the American Society of Nephrology.)

We demonstrate the use of water-soluble C 60 -β-cyclodextrin conjugates to encapsulate and deliver doxorubicin to the cell nucleus. The behaviour of the fullerene aggregates inside cells is dictated by the functionalization of the C 60 cage. While both the C 60 conjugates are taken up by lysosomes upon cellular entry, only the one with a hydroxylated cage rapidly escaped the lysosome. The drug delivery system (DDS) with a hydroxylated C 60 cage showed significantly enhanced doxorubicin delivery to the cell nucleus, whereas the DDS with a hydrophobic C 60 cage was trapped in the lysosome for a longer time and showed significantly reduced doxorubicin delivery to the nucleus. This study opens new paths towards advanced fullerene-based DDSs for small molecule drugs.

Background and Objectives: Novel aptamer-based technologies can identify >7000 analytes per sample, offering a high-throughput alternative to traditional immunoassays in biomarker discovery. However, the specificity for distinct proteins has not been thoroughly studied in the context of CKD., Design, Setting, Participants, & Measurements: We assessed the use of SOMAscan, an aptamer-based technology, for the quantification of eight immune activation biomarkers and cystatin C among 498 African American Study of Kidney Disease and Hypertension (AASK) participants using immunoassays as the gold standard. We evaluated correlations of serum proteins as measured by SOMAscan versus immunoassays with each other and with iothalamate-measured GFR. We then compared associations between proteins measurement with risks of incident kidney failure and all-cause mortality., Results: Six biomarkers (IL-8, soluble TNF receptor superfamily member 1B [TNFRSF1B], cystatin C, soluble TNF receptor superfamily member 1A [TNFRSF1A], IL-6, and soluble urokinase-type plasminogen activator receptor [suPAR]) had non-negligible correlations ( r =0.94, 0.93, 0.89, 0.85, 0.46, and 0.23, respectively) between SOMAscan and immunoassay measurements, and three (IL-10, IFN- γ , and TNF- α ) were uncorrelated ( r =0.08, 0.07, and 0.02, respectively). Of the six biomarkers with non-negligible correlations, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were negatively correlated with measured GFR and associated with higher risk of kidney failure. IL-8, TNFRSF1B, cystatin C, TNFRSF1A, and suPAR were associated with a higher risk of mortality via both methods. On average, immunoassay measurements were more strongly associated with adverse outcomes than their SOMAscan counterparts., Conclusions: SOMAscan is an efficient and relatively reliable technique for quantifying IL-8, TNFRSF1B, cystatin C, and TNFRSF1A in CKD and detecting their potential associations with clinical outcomes., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;02&#95;23&#95;CJN11700921.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Mountainous regions are highly hazardous, and these hazards often lead to loss of human life. The Hindu Kush Himalaya (HKH), like many mountainous regions, is the site of multiple and overlapping natural hazards, but the distribution of multi-hazard risk and the populations exposed to it are poorly understood. Here, we present high-resolution transboundary models describing susceptibility to floods, landslides, and wildfires to understand population exposure to multi-hazard risk across the HKH. These models are created from historical remotely sensed data and hazard catalogs by the maximum entropy (Maxent) machine learning technique. Our results show that human settlements in the HKH are disproportionately concentrated in areas of high multi-hazard risk. In contrast, low-hazard areas are disproportionately unpopulated. Nearly half of the population in the region lives in areas that are highly susceptible to more than one hazard. Warm low-altitude foothill areas with perennially moist soils were identified as highly susceptible to multiple hazards. This area comprises only 31% of the study region, but is home to 49% of its population. The results also show that areas susceptible to multiple hazards are also major corridors of current migration and urban expansion, suggesting that current rates and patterns of urbanization will continue to put more people at risk. This study establishes that the population in the HKH is concentrated in areas susceptible to multiple hazards and suggests that current patterns of human movement will continue to increase exposure to multi-hazards in the HKH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Diabetes is a leading cause of end-stage kidney disease (ESKD). Biomarkers of tubular health may prognosticate chronic kidney disease (CKD) progression beyond estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR)., Methods: We examined associations of five urinary biomarkers of tubular injury and repair (NGAL, KIM-1, IL-18, MCP-1, YKL-40) with kidney function decline (first occurrence of a decrease in eGFR ≥30 mL/min/1.73 m2 if randomization eGFR ≥60 or ≥50% if randomization eGFR <60; ESKD) and all-cause mortality among 1,135 VA NEPHRON-D trial participants with baseline UACR ≥300 mg/g and available urine samples. Covariates included age, sex, race, BMI, systolic BP, HbA1c, treatment arm, eGFR, and UACR. In a subset of participants with 12-month samples (n = 712), we evaluated associations of KIM-1, MCP-1, and YKL-40 change (from baseline to 12 months) with eGFR decline (from 12 months onward)., Results: At baseline, mean age was 65 years, mean eGFR was 56 mL/min/1.73 m2, and median UACR was 840 mg/g. Over a median of 2.2 years, 13% experienced kidney function decline and 9% died. In fully adjusted models, the highest versus lowest quartiles of MCP-1 and YKL-40 were associated with 2.18- and 1.76-fold higher risks of kidney function decline, respectively. One-year changes in KIM-1, MCP-1, and YKL-40 were not associated with subsequent eGFR decline. Higher baseline levels of NGAL, IL-18, MCP-1, and YKL-40 levels (per 2-fold higher) were independently associated with 10-40% higher risk of mortality., Conclusion: Among Veterans with diabetes and CKD, urinary biomarkers of tubular health were associated with kidney function decline and mortality., (© 2023 S. Karger AG, Basel.)

Background: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed., Methods: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels., Results: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m 2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P 10 ], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m 2 ; 95% CI, -0.29 to 2.54; P 10 , 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m 2 ; 95% CI, -0.12 to 2.33; P 10 , 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m 2 ; 95% CI, -1.43 to 1.92) and accurate (P 10 , 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C., Conclusions: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)., (Copyright © 2021 Massachusetts Medical Society.)

Purpose: To clarify and investigate the prevalence and clinical impact of hepatitis D virus (HDV) infection in Taiwan's communities., Methods: HDV infection in patients with chronic hepatitis B viral (HBV) infection was examined using an anti-HDV antibody in Yonghe Cardinal Tien Hospital (YCTH), a district hospital in Taiwan. Clinical characteristics of anti-HDV-positive and anti-HDV-negative patients were collected and compared. These characteristics were also compared with the data collected from a medical center. Continuous variables and confounding factor adjustments were compared using the analysis of covariance method, whereas categorical variables were compared using the logistic regression method., Results: A total of 346 patients with chronic HBV infection were assessed from 2018 to 2019. Among them, 4 (1.15%) were positive for anti-HDV. The clinical, virological, and biochemical characteristics were similar between anti-HDV-positive and anti-HDV-negative groups. None of the four patients was positive for serum HDV RNA. Another 18 anti-HDV-positive patients were identified from National Taiwan University Hospital (NTUH). The clinical, virological, and biochemical characteristics of anti-HDV-positive patients from YCTH and NTUH were also similar., Conclusion: The prevalence of HDV and the serum HDV RNA-positive rate were low in district hospitals in Taiwan. Coexisting HDV infection did not influence the clinical manifestation of patients with chronic HBV infection in Taiwan. However, because the number of HDV RNA cases was very small, our findings may not be conclusive. Besides, since the sensitivity of current anti-HDV kit is not 100%, more sensitive methods are needed to achieve reliable prevalence data., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

Background: Proteomic profiling may allow identification of plasma proteins that associate with subsequent changesin kidney function, elucidating biologic processes underlying the development and progression of CKD., Methods: We quantified the association between 4877 plasma proteins and a composite outcome of ESKD or decline in eGFR by ≥50% among 9406 participants in the Atherosclerosis Risk in Communities (ARIC) Study (visit 3; mean age, 60 years) who were followed for a median of 14.4 years. We performed separate analyses for these proteins in a subset of 4378 participants (visit 5), who were followed at a later time point, for a median of 4.4 years. For validation, we evaluated proteins with significant associations (false discovery rate <5%) in both time periods in 3249 participants in the Chronic Renal Insufficiency Cohort (CRIC) and 703 participants in the African American Study of Kidney Disease and Hypertension (AASK). We also compared the genetic determinants of protein levels with those from a meta-analysis genome-wide association study of eGFR., Results: In models adjusted for multiple covariates, including baseline eGFR and albuminuria, we identified 13 distinct proteins that were significantly associated with the composite end point in both time periods, including TNF receptor superfamily members 1A and 1B, trefoil factor 3, and β -trace protein. Of these proteins, 12 were also significantly associated in CRIC, and nine were significantly associated in AASK. Higher levels of each protein associated with higher risk of 50% eGFR decline or ESKD. We found genetic evidence for a causal role for one protein, lectin mannose-binding 2 protein (LMAN2)., Conclusions: Large-scale proteomic analysis identified both known and novel proteomic risk factors for eGFR decline., (Copyright © 2021 by the American Society of Nephrology.)

We present here an evidence-based review of the utility, timing, and indications for laboratory test use in the domains of inflammation, cardiology, hematology, nephrology and co-infection for clinicians managing the care of hospitalized COVID-19 patients. Levels of IL-6, CRP, absolute lymphocyte count, neutrophils and neutrophil-to-lymphocyte ratio obtained upon admission may help predict the severity of COVID-19. Elevated LDH, ferritin, AST, and d-dimer are associated with severe illness and mortality. Elevated cardiac troponin at hospital admission can alert clinicians to patients at risk for cardiac complications. Elevated proBNP may help distinguish a cardiac complication from noncardiac etiologies. Evaluation for co-infection is typically unnecessary in nonsevere cases but is essential in severe COVID-19, intensive care unit patients, and immunocompromised patients., Competing Interests: Financial & competing interests disclosure KA Marr is a consultant and/or advisor for Amplyx, Cidara, Merck and Sfunga and receives equity and/or licensing revenue from MycoMed Technologies. MB Streiff reports research funding from The Patient-Centered Outcomes Research Institute, the Agency for Healthcare Research and Quality, Boehringer-Ingelheim, Janssen, Portola and Roche. MB Streiff has also consulted for Bristol Myers Squibb, Dispersol, Janssen, Pfizer and Portola and has given expert witness testimony in various medical malpractice cases. AAR Antar receives research funding from NIAID-NIH (K08 award) that was not specifically given for the writing of this review article. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2021 Future Medicine Ltd.)

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUC SS ) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUC SS range, 60 to 233 μg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).

Rationale & Objective: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear., Study Design: Prospective cohort., Setting & Participants: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement., Predictors: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ)., Outcomes: Incident KFRT, all-cause mortality., Analytical Approach: Cox proportional hazards models., Results: Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m 2 , and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction)., Limitations: Limited generalizability to other ethnic groups or causes of CKD., Conclusions: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality., (Copyright © 2021 National Kidney Foundation, Inc. All rights reserved.)

GIBBERELLIN MYB GENE (GAMYB), UNDEVELOPED TAPETUM1 (UDT1), TDR INTERACTING PROTEIN2 (TIP2/bHLH142), TAPETUM DEGENERATION RETARDATION (TDR), and ETERNAL TAPETUM 1/DELAYED TAPETUM DEGENERATION (EAT1/DTD) are important transcription factors that play a crucial role during pollen development in rice. This study demonstrates that bHLH142 acts downstream of UDT1 and GAMYB and works as a 'hub' in these two pollen pathways. We show that GAMYB modulates bHLH142 expression through specific binding to the MYB motif of the bHLH142 promoter during the early stage of pollen development, while TDR acts as a transcriptional repressor of the GAMYB modulation of bHLH142 by binding to the E-box close to the MYB motif on the promoter. Altered expression of these transcription factors highlights that a tight, precise, and coordinated regulation among them is essential for normal pollen development. Most notably, we show that the regulatory pathways of GAMYB and UDT1 rely on bHLH142 in a direct and indirect manner, respectively, and function in different tissues with distinct biological roles during pollen development. This study advances our understanding of the molecular mechanisms of rice pollen development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

An estimated 8% to 16% of the world's population has chronic kidney disease, defined by low glomerular filtration rate or albuminuria. Progression of chronic kidney disease is associated with adverse outcomes, including incident kidney failure with replacement therapy, accelerated cardiovascular disease, disability, and mortality. Therefore, slowing kidney function decline is paramount in the management of a patient with chronic kidney disease. Ascertaining the cause of kidney disease is an important first step and may compel specific therapies. Effective approaches that apply to the vast majority of patients with chronic kidney disease include the optimization of blood pressure and blockade of the renin-angiotensin-aldosterone system, particularly if albuminuria is present. Recent studies suggest that sodium/glucose cotransporter 2 inhibitors are highly effective treatments in patients with diabetes and/or albuminuria. For patients with type 2 diabetes, glycemic control is important in preventing the development of microvascular complications, and glucagon-like peptide 1 receptor agonists may help reduce albuminuria levels. Other strategies include correcting metabolic acidosis, maintaining ideal body weight, following diets that are low in sodium and animal protein, and avoiding potential nephrotoxins such as nonsteroidal anti-inflammatories, proton-pump inhibitors, and iodinated contrast., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objectives: Preeclampsia, which disproportionately affects Black women, is a leading cause of preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Apolipoprotein L1 (APOL1) kidney risk alleles, common among Black individuals, contribute substantially to CKD disparities. Given the strong link between preeclampsia and CKD, we investigated whether maternal and fetal APOL1 risk alleles can jointly influence preeclampsia risk, and explored potential modifiers of the association between APOL1 and preeclampsia., Study Design: Nested case-control study., Setting & Participants: 426 Black mother-infant pairs (275 African Americans and 151 Haitians) from the Boston Birth Cohort., Exposure: Maternal and fetal APOL1 risk alleles., Outcomes: Preeclampsia., Analytical Approach: Logistic regression models with adjustment for demographic characteristics were applied to analyze associations between fetal and maternal APOL1 risk alleles and risk of preeclampsia and to investigate the effects of modification by maternal country of origin., Results: Fetal APOL1 risk alleles tended to be associated with an increased risk of preeclampsia, which was not statistically significant in the total genotyped population. However, this association was modified by maternal country of origin (P<0.05 for interaction tests): fetal APOL1 risk alleles were significantly associated with an increased risk of preeclampsia among African Americans under recessive (odds ratio [OR], 3.6 [95% CI, 1.3-9.7]; P=0.01) and additive (OR, 1.7 [95% CI, 1.1-2.6]; P=0.01) genetic models but not in Haitian Americans. Also, maternal-fetal genotype discordance at the APOL1 locus was associated with a 2.6-fold higher risk of preeclampsia (P<0.001) in African Americans., Limitations: Limited sample size in stratified analyses; self-reported maternal country of origin; pre-pregnancy estimated glomerular filtration rate (eGFR) and proteinuria data in mothers were not collected; unmeasured confounding social and/or environmental factors; no replication study., Conclusions: This study supports the hypothesis that fetal APOL1 kidney risk alleles are associated with increased risk for preeclampsia in a recessive mode of inheritance in African Americans and suggests that maternal-fetal genotype discordance is also associated with this risk. These conclusions underscore the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic kidney disease (CKD) is an important cause of disability and death, but its pathogenesis is poorly understood. Plasma metabolites can provide insights into underlying processes associated with CKD., Objectives: To clarify the relationship of plasma metabolites with CKD and renal function in human., Methods: We used a targeted metabolomics approach to characterize the relationship of 450 plasma metabolites with CKD and estimated glomerular filtration rate (eGFR) in 616 adults, aged 38-94 years, who participated in the Baltimore Longitudinal Study of Aging., Results: There were 74 (12.0%) adults with CKD. Carnitine, acetylcarnitine, propionylcarnitine, butyrylcarnitine, trigonelline, trimethylamine N-oxide (TMAO), 1-methylhistidine, citrulline, homoarginine, homocysteine, sarcosine, symmetric dimethylarginine, aspartate, phenylalanine, taurodeoxycholic acid, 3-indolepropionic acid, phosphatidylcholines (PC).aa.C40:2, PC.aa.C40:3, PC.ae.C40:6, triglycerides (TG) 20:4/36:3, TG 20:4/36:4, and choline were associated with higher odds of CKD in multivariable analyses adjusting for potential confounders and using a false discovery rate (FDR) to address multiple testing. Six acylcarnitines, trigonelline, TMAO, 18 amino acids and biogenic amines, taurodeoxycholic acid, hexoses, cholesteryl esters 22:6, dehydroepiandrosterone sulfate, 3-indolepropionic acid, 2 PCs, 17 TGs, and choline were negatively associated with eGFR, and hippuric acid was positively associated with eGFR in multivariable analyses adjusting for potential confounders and using a FDR approach., Conclusion: The metabolites associated with CKD and reduced eGFR suggest that several pathways, such as the urea cycle, the arginine-nitric oxide pathway, the polyamine pathway, and short chain acylcarnitine metabolism are altered in adults with CKD and impaired renal function.

Background/objectives: APOL1 high-risk genotypes confer an increased risk for kidney disease, but their clinical significance among older adults remains unclear. We aimed to determine whether APOL1 genotype status (high risk = 2 risk alleles; low risk = 0-1 risk alleles) and self-reported race (Black; White) are associated with number of hospitalizations, incident chronic kidney disease (CKD), end-stage renal disease (ESRD), and mortality among older adults participating in a community-based cohort study., Design: Observational longitudinal cohort study., Setting: The Atherosclerosis Risk in Communities (ARIC) study., Participants: Community-dwelling older adults (mean age = 75.8 years; range = 66-90 years)., Results: Among 5,564 ARIC participants (78.2% White, 19.1% APOL1 low-risk Black, and 2.7% APOL1 high-risk Black), the proportion with creatinine and cystatin C-based estimated glomerular filtration rate (eGFR CrCys ) below 60 mL/min/1.73 m 2 at baseline was 40.6%, 34.8%, and 43.2%, respectively. Over a mean follow-up of 5.1 years, APOL1 high-risk Blacks had a 2.67-fold higher risk for ESRD compared with low-risk Blacks (95% confidence interval [CI] = 1.05-6.79) in models adjusted for age and sex. This association was no longer significant upon further adjustment for baseline eGFR CrCys and albuminuria (hazard ratio [HR] = 1.08; 95% CI = .39-2.96). Rate of hospitalizations and risks of mortality and incident CKD did not differ significantly by APOL1 genotype status. Compared with Whites, Blacks had 1.85-fold and 3.45-fold higher risks for incident CKD and ESRD, respectively, in models adjusted for age, sex, eGFR CrCys , and albuminuria. These associations persisted after additional adjustments for clinical/socioeconomic factors and APOL1 genotype (incident CKD: HR = 1.38; 95% CI = 1.06-1.81; ESRD: HR = 3.20; 95% CI = 1.16-8.86)., Conclusion: Among older Black adults, APOL1 high-risk genotypes were associated with lower kidney function and therefore higher risk of ESRD. Racial disparities in incident kidney disease persisted in older age and were not fully explained by APOL1., (© 2020 The American Geriatrics Society.)

Multiple clinical guidelines recommend an ACE (angiotensin-converting enzyme) inhibitor or angiotensin II receptor blocker (ARB) in patients with elevated albuminuria, which can be measured through urine albumin-to-creatinine ratio (ACR), protein-to-creatinine ratio, or dipstick. However, how albuminuria test results relate to the prescription of ACE inhibitor/ARB is uncertain. We identified individuals with an ACR measurement between January 1, 2004, and June 30, 2018, and no contraindications or allergy to ACE inhibitor/ARB. We performed multivariable logistic regression analyses to evaluate the association between ACR level and prescription of ACE inhibitor/ARB within 6 months after the test. We applied similar methods to investigate the association of protein-to-creatinine ratio and dipstick measurement results with the prescription of ACE inhibitor/ARB. Among 67 237 individuals with an ACR measurement, 47.7% were already taking an ACE inhibitor or ARB at the time of first ACR measurement. Among the 35 138 individuals who were not on ACE inhibitor/ARB, those with higher ACR levels were more likely to be prescribed ACE inhibitor/ARB in the following 6 months, with steep increases in prescriptions until ACR 300 mg/g, after which the association plateaued. The majority (80.9%) of ACE inhibitor/ARB prescriptions were made by family medicine and internal medicine. A similar pattern held in the cohorts tested by protein-to-creatinine ratio and dipstick measurement. Our study provides evidence that albuminuria test results change patient care, suggesting that adherence to albuminuria testing is a key step in optimal medical management.

Introduction: To better understand the impact of APOL1 risk variants in end-stage renal disease (ESRD) we evaluated associations of APOL1 risk variants with subclinical cardiovascular disease (CVD) and mortality among African Americans initiating hemodialysis and enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD cohort study., Methods: We modeled associations of APOL1 risk status (high = 2; low = 0/1 risk alleles) with baseline subclinical CVD (left ventricular [LV] hypertrophy; LV mass; ejection fraction; coronary artery calcification [CAC]; pulse wave velocity [PWV]) using logistic and linear regression and all-cause or cardiovascular mortality using Cox models, adjusting for age, sex, and ancestry. In sensitivity analyses, we further adjusted for systolic blood pressure and Charlson Comorbidity Index., Results: Of 267 African American participants successfully genotyped for APOL1 , 27% were high-risk carriers, 41% were women, and mean age was 53 years. At baseline, APOL1 high- versus low-risk status was independently associated with 50% and 53% lower odds of LV hypertrophy and CAC, respectively, and 10.7% lower LV mass. These associations were robust to further adjustment for comorbidities but not systolic blood pressure. APOL1 risk status was not associated with all-cause or cardiovascular mortality (mean follow-up 2.5 years)., Conclusion: Among African American patients with incident hemodialysis, APOL1 high-risk status was associated with better subclinical measures of CVD but not mortality., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background APOL1 high-risk genotypes are associated with increased risk for hypertension-attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by APOL1 status; less is known about the variants' associations with systemic vascular and endothelial function. Whether APOL1 risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross-sectional associations of APOL1 risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow-mediated dilation, n=777). Using linear mixed-effects models, we studied longitudinal associations of APOL1 risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% APOL1 high-risk) Black participants in MESA (Multi-Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000-2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow-mediated dilation in participants with APOL1 high- versus low-risk genotypes ( P >0.05 for all). Over a mean follow-up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by APOL1 risk status (between-group differences of -0.20, -0.14, and -0.25, respectively; P >0.05 for all). Conclusions Among Black participants in MESA, APOL1 high-risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of APOL1 with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.

Background: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population., Methods: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding., Results: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF- α , high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases)., Conclusions: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection., (Copyright © 2020 by the American Society of Nephrology.)

Background: Chronic kidney disease (CKD) progression can be a cause and potentially a consequence of anemia. Previous studies suggesting that anemia is associated with CKD progression have not utilized methodologic approaches to address time-dependent confounding., Methods: We evaluated the association of anemia (defined using World Health Organization criteria of hemoglobin <12 g/dL in women and <13 g/dL in men) with incident ESRD and all-cause death in individuals with CKD using data from the Chronic Renal Insufficiency Cohort Study. Marginal structural models were used to account for time-dependent confounding., Results: Among 3919 participants, 1859 (47.4%) had anemia at baseline. Over median follow up of 7.8 years, we observed 1,010 ESRD events and 994 deaths. In multivariable analyses, individuals with anemia had higher risk for ESRD compared to those without (HR 1.62, 95% CI 1.24-2.11). In stratified analyses, the increased risk for incident ESRD with anemia was observed in males (HR 2.15, 95% CI: 1.53-3.02) but not females (HR 1.20, 95% CI 0.82-1.78. The association between anemia and ESRD was significant among all racial/ethnic groups except non-Hispanic blacks (non-Hispanic white, HR 2.16, 95% CI 1.53-3.06; Hispanic, HR 1.92, 1.04-3.51; others, HR 2.94; 95% CI 1.16-7.44; non-Hispanic black, HR 1.39; 95% CI 0.95-2.02). There was no association between anemia and all-cause death., Conclusions: In this cohort, anemia was independently associated with increased risk for incident ESRD. Future work is needed to evaluate the mechanisms by which anemia leads to CKD progression as well as the impact of novel therapeutic agents to treat anemia., Competing Interests: Disclosure of Financial Interests: There are no relevant conflicts of interest to disclose.

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR)., Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD)., Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019., Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2., Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD., Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65)., Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Human settlement extent (HSE) information is a valuable indicator of world-wide urbanization as well as the resulting human pressure on the natural environment. Therefore, mapping HSE is critical for various environmental issues at local, regional, and even global scales. This paper presents a deep-learning-based framework to automatically map HSE from multi-spectral Sentinel-2 data using regionally available geo-products as training labels. A straightforward, simple, yet effective fully convolutional network-based architecture, Sen2HSE, is implemented as an example for semantic segmentation within the framework. The framework is validated against both manually labelled checking points distributed evenly over the test areas, and the OpenStreetMap building layer. The HSE mapping results were extensively compared to several baseline products in order to thoroughly evaluate the effectiveness of the proposed HSE mapping framework. The HSE mapping power is consistently demonstrated over 10 representative areas across the world. We also present one regional-scale and one country-wide HSE mapping example from our framework to show the potential for upscaling. The results of this study contribute to the generalization of the applicability of CNN-based approaches for large-scale urban mapping to cases where no up-to-date and accurate ground truth is available, as well as the subsequent monitor of global urbanization., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Background: Recent studies have demonstrated that intensive blood pressure control is associated with improved cardiovascular outcomes. Acute kidney injury (AKI), however, was more common in the intensive treatment group prompting concern in the nephrology community., Summary: Clinical trials on hypertension control have traditionally defined AKI by changes in serum creatinine. However, serum creatinine has several inherent limitations as a marker of kidney injury, with various factors influencing its production, secretion, and elimination. Urinary biomarkers of kidney injury and repair have the potential to provide insight on the presence and phenotype of kidney injury. In both the Systolic Blood Pressure Intervention Trial and the Action to Control Cardiovascular Risk in Diabetes study, urinary biomarkers have suggested that the increased risk of AKI associated with intensive treatment was due to hemodynamic changes rather than structural kidney injury. As such, clinicians who encounter rises in serum creatinine during intensification of hypertension therapy should "stay calm and carry on." Alternative explanations for serum creatinine elevation should be considered and addressed if appropriate. When the rise in serum creatinine is limited, particularly if albuminuria is stable or improving, intensive blood pressure control should be continued for its potential long-term benefits. Key Messages: Increases in serum creatinine during intensification of blood pressure control may not necessarily reflect kidney injury. Clinicians should evaluate for other contributing factors before stopping therapy. Urinary biomarkers may address limitations of serum creatinine as a marker of kidney injury., (© 2020 S. Karger AG, Basel.)

Double-spikes Phalaenopsis orchids have greater market value than those with single-spike. In this study, a gene designated as Spike Activator 1 ( SPK1 ), which encodes a basic helix-loop-helix (bHLH) transcription factor, was isolated and characterized from Phalaenopsis aphrodite (moth orchid). SPK1 was highly expressed in the meristematic tissues. In the axillary bud, SPK1 was highly upregulated by a moderately low temperature of 20 °C but downregulated by a spike inhibition temperature of 30 °C. SPK1 protein is localized in the nucleus. Another bHLH, bHLH35 , which is also highly expressed in young tissues in the same way as SPK1 was also identified. In contrast to SPK1 , bHLH35 transcripts are downregulated at 20 °C but upregulated at 30 °C. Bimolecular florescence complementation assay and yeast two-hybrid assays indicated that SPK1 interacts with bHLH35 and forms a heterodimer. Virus-induced gene silencing (VIGS) showed that 7 out of 15 vector control plants produced double spikes but that only 1 out of 15 VIGS- spk1 plants produced double spikes. RT-qPCR results indicated that VIGS- spk1 downregulated gene expression levels of SPK1 , FT , CYCB , and EXPA8 . Overall, we propose that SPK1 plays an essential role in early axillary bud development and spike initiation of P. aphrodite .