Association of serum soluble urokinase receptor levels with progression of kidney disease in children

PubMedID: 28873129IMPORTANCE: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C–derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults. OBJECTIVE: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD. DESIGN, SETTING, AND PARTICIPANTS: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016. EXPOSURES: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy. MAIN OUTCOMES AND MEASURES: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2. RESULTS: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point–free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007). CONCLUSIONS AND RELEVANCE: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD. © 2017 American Medical Association. All rights reserved.Fifth Framework Programme: QLRT-2001-00908 Boehringer Ingelheim National Institute of Diabetes and Digestive and Kidney Diseases: R01DK100307 Baxter International Seventh Framework Programme 01EO0802, R01DK101350Accepted for Publication: July 6, 2017. Correction: This article was corrected on October 9, 2017, to fix an error in the presentation of data in Table 1. Published Online: September 5, 2017. doi:10.1001/jamapediatrics.2017.2914 Author Affiliations: Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg,Germany(Schaefer,Wühl);Departmentof Pediatrics, Division of Nephrology, New York University Langone Medical Center, New York (Trachtman); Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany (Kirchner); Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia (Hayek);DepartmentofPediatricNephrology,Faculty of Medicine, Cukurova University, Adana, Turkey (Anarat);PediatricNephrology,HacettepeUniversity Faculty of Medicine, Ankara, Turkey (Duzova); Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey (Mir); University Children’s Hospital Belgrade, Belgrade, Serbia (Paripovic); DepartmentofPediatricNephrology,IstanbulMedical Faculty,Istanbul,Turkey(Yilmaz);PediatricNephrology, Giannina Gasline Institute, Genova, Italy (Lugani); Pediatric Nephrology, Vienna University Children’s Hospital, Vienna, Austria (Arbeiter); Nephrology, KidneyTransplantationandHypertension,Children’s Memorial Health Institute, Warzaw, Poland (Litwin); Pediatric Nephrology, Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (Oh); Division of Pediatric Nephrology, Bambino Gesù Children’s Hospital and Research Institute,Rome,Italy(Matteucci);PediatricNephrology, Charité Children’s Hospital, Berlin, Germany (Gellermann); Children’s Dialysis Center, Hospital St Georg, Leipzig, Germany (Wygoda); Vilnius University, Pediatric Center, Vilnius, Lithuania (Jankauskiene); KfH Kidney Center for Children, Marburg, Germany (Klaus); Pediatrics, University Hospital Motol, Prague, Czech Republic (Dusek); Pediatric Nephrology and Dialysis, Fondazione OSP MaggiorePoliclinico,Milano,Italy(Testa);Department of Pediatric and Adolescent Nephrology, Medical University Gdansk, Gdansk, Poland (Zurowska); Pediatrics,HospitalSãoJoão,Porto,Portugal(Caldas Afonso); Department of Medicine, Rush University Medical Center, Chicago, Illinois (Tracy, Wei, Reiser); Harvard Medical School and Division of Nephrology, MassachusettsGeneralHospital,Charlestown(Sever); The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus (Smoyer). Author Contributions: Drs Schaefer and Kirchner had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Schaefer, Trachtman, Wühl, and Reiser contributed equally to the preparation of this article. Study concept and design: Schaefer, Trachtman, Wühl, Hayek, Anarat, Yilmaz, Lugani, Caldas Afonso, Sever, Smoyer. Acquisition, analysis, or interpretation of data: Schaefer, Trachtman, Wühl, Kirchner, Hayek, Duzova, Mir, Paripovic, Lugani, Arbeiter, Litwin, Oh, Matteucci, Gellermann, Jankauskiene, Klaus, Dusek, Testa, Zurowska, Tracy, Wei, Reiser. Draftingofthemanuscript:Schaefer,Trachtman,Wühl, Kirchner, Hayek, Anarat, Yilmaz, Matteucci, Dusek, Zurowska, Tracy, Wei. Critical revision of the manuscript for important intellectualcontent:Trachtman,Wühl,Kirchner,Hayek, Duzova,Mir,Paripovic,Yilmaz,Lugani,Arbeiter,Litwin, Oh, Gellermann, Jankauskiene, Klaus, Testa, Caldas Afonso, Wei, Sever, Smoyer, Reiser. Statistical analysis: Wühl, Kirchner, Hayek, Matteucci. Obtained funding: Schaefer, Mir, Gellermann. Administrative, technical, or material support: Schaefer, Duzova, Paripovic, Yilmaz, Lugani, Arbeiter, Oh, Klaus, Dusek, Zurowska, Caldas Afonso, Wei, Smoyer, Reiser. Supervision: Schaefer, Lugani, Sever. Conflict of Interest Disclosures: Drs Sever and Reiser are inventors on pending and issued patents related to antiproteinuric therapies. They stand to gain royalties from present and future commercialization. They also are cofounders and advisors to TRISAQ, a biotechnology company. Dr Wei has a pending patent on suPAR in diabetes. He stands to gain royalties from future commercialization products concerning this application. No other conflicts were disclosed. Funding/Support: Dr Schaefer received support for this study from grant agreement 2012-305608 (EURenOmics) from the European Community Seventh Framework Programme (FP7/2007-2013). The ESCAPE Trial was supported by grants from the Boehringer Ingelheim Stiftung, the European Commission Fifth Framework Programme (grant QLRT-2001-00908), the Kuratorium für Dialyse und Nierentransplantation Neu-Isenburg (KfH), and the Baxter Extramural Grant Program. Support for the 4C Study was received from the European Renal Association–European Dialysis and Transplant Association Research Programme, the KfH Foundation for Preventive Medicine, and the German Federal Ministry of Education and Research (grant 01EO0802). Drs Wei, Sever, and Reiser were supported by grant R01DK101350 from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr Trachtman was supported by grant R01DK100307 from the National Institute of Diabetes and Digestive and Kidney Diseases. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Group Information: The principal investigators of the ESCAPE Trial included the following: Cukurova University School of Medicine, Adana, Turkey: Ali Anarat, MD; Hacettepe University Faculty of Medicine, Ankara, Turkey: Aysin Bakkaloglu, MD, and Fatih Ozaltin, MD; University Children’s Hospital, Belgrade, Serbia: Amira Peco-Antic, MD; Charité Children’s Hospital, Berlin, Germany: Uwe Querfeld, MD, and Jutta Gellermann, MD; First Department o

The manufacture of hope : religion, eschatology and the culture of optimism

This article builds on earlier research, which concludes that societies cannot sustain themselves without cultures of optimism. These cultures are reproduced by a complex of ‘optimism promoters’, all of which can be seen to be engaged in a kind of unstated or ‘implicit’ cultural policy, with the production of optimism as one of its goals. The institution of religion is part of this complex. Its role in the production of optimism is the focus of this article, with particular reference to soteriology (theories of salvation) and eschatology. From a ‘detached’ and ‘functionalist’ perspective, it analyses how religions manufacture hope through (1) the production of meaning; (2) through their models of divine justice; and (3) through theories of ultimate destiny. These matters are discussed in relation to Hinduism, Buddhism, Christianity and Islam. The article concludes that the optimisms of religion are of a quite different order from those promoted by other institutions

Gene expression profiling and heterogeneity of nonspecific orbital inflammation affecting the lacrimal gland

Abstract not available.James T. Rosenbaum, Dongseok Choi, Christina A. Harrington, David J. Wilson, Hans E. Grossniklaus, Cailin H. Sibley, Sherveen S. Salek, John D. Ng, Roger A. Dailey, Eric A. Steele, Brent Hayek, Caroline M. Craven, Deepak P. Edward, Azza M. Y. Maktabi, Hailah Al Hussain, Valerie A. White, Peter J. Dolman, Craig N. Czyz, Jill A. Foster, Gerald J. Harris, Youn-Shen Bee, David T. Tse, Chrisfouad R. Alabiad, Sander R. Dubovy, Michael Kazim, Dinesh Selva, R. Patrick Yeatts, Bobby S. Korn, Don O. Kikkawa, Rona Z. Silkiss, Jennifer A. Sivak-Callcott, Patrick Stauffer, Stephen R. Planc

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36– 0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. REGISTRATION: URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT04818866. © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley

Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease

Sequence variants affecting blood lipids and coronary artery disease (CAD) may enhance understanding of the atherogenicity of lipid fractions. Using a large resource of whole-genome sequence data, we examined rare and low-frequency variants for association with non-HDL cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in up to 119,146 Icelanders. We discovered 13 variants with large effects (within ANGPTL3, APOB, ABCA1, NR1H3, APOA1, LIPC, CETP, LDLR, and APOC1) and replicated 14 variants. Five variants within PCSK9, APOA1, ANGPTL4, and LDLR associate with CAD (33,090 cases and 236,254 controls). We used genetic risk scores for the lipid fractions to examine their causal relationship with CAD. The non-HDL cholesterol genetic risk score associates most strongly with CAD (P = 2.7 x 10(-28)), and no other genetic risk score associates with CAD after accounting for non-HDL cholesterol. The genetic risk score for non-HDL cholesterol confers CAD risk beyond that of LDL cholesterol (P = 5.5 x 10(-8)), suggesting that targeting atherogenic remnant cholesterol may reduce cardiovascular risk

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19

OBJECTIVE Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicen-ter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospi-tal death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plas-minogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation. © 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license

Soluble urokinase receptor (SuPAR) in COVID-19-Related AKI

Background AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. Methods In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. Results Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR,4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels.6.86 ng/ml (third tertile). None of the patients with suPAR,4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. Conclusions Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19. Copyright © 2020 by the American Society of Nephrolog