Advertisement
Research Article| Volume 13, ISSUE 1, P69-87, March 1993

Serologic Evaluation of Renal Status

  • Richard A. McPherson
    Correspondence
    Address reprint requests to: Richard A. McPherson, MD, Scripps Immunology Reference Laboratory, 11107 Roselle Street, Suite A, San Diego, CA 92121.
    Affiliations
    From The Scripps Research Institute; and Department of Pathology, Scripps Clinic and Research Foundation, La Jolla, California
    Search for articles by this author
DOI:https://doi.org/10.1016/S0272-2712(18)30461-X
Serologic Evaluation of Renal Status
Previous ArticleQuantitation of Renal Function Using Radioisotopic Techniques
Next ArticleDiagnosis of Acute and Chronic Renal Failure
      This paper is only available as a PDF. To read, Please Download here.
      Mechanisms of immunologic injury causing glomerulonephritis are based on immune complex or autoantibody deposition with activation of complement. Circulating immune complex disease can be diagnosed and monitored with improved assays for immune complexes, DNA antibodies, complement levels, and complement activation products. Etiologic autoantibodies for the Goodpasture antigen, neutrophil enzymes, and ones directly promoting complement activation are now quantitated for more accurate serologic diagnosis. The spectrum of postinfectious glomerulonephritis also presents several new measurements for assessing clinical status. Diagnosis and monitoring of glomerulonephritis now entails panel testing for these humoral abnormalities that are useful to establish the etiology and treatment regimens.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribers receive full online access to your subscription and archive of back issues up to and including 2002.

      Content published before 2002 is available via pay-per-view purchase only.

      Subscribe:

      Subscribe to Clinics in Laboratory Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Aarden L.A.
        • de Groot E.R.
        • Feltkamp T.E.W.
        Immunology of DNA III. Crithidium luciliae, a simple substrate for the determination of anti-dsDNA with the im-munofluorescent technique.
        Ann NY Acad Sei. 1975; 254: 505-515
        • Abrass C.
        • Nies K.
        • Louis J.
        • et al.
        Correlation and predictive accuracy of circulating immune complexes with disease activity in patients with systemic lupus erythematosus.
        Arthritis Rheum. 1980; 23: 273-282
        • Anderson C.L.
        • Stillman W.S.
        Evidence for detection of Raji-directed immunoglobulin G antibody in sera from patients with systemic lupus erythematosus.
        J Clin Invest. 1980; 66: 353-360
        • André-Schwartz J.
        • Datta S.K.
        • Shoenfeld T.
        • et al.
        Binding of cytoskeletal proteins by monoclonal anti-DNA lupus autoantibodies.
        Clin Immunol Immunopathol. 1984; 31: 261-271
        • Aotsuka S.
        • Okawa M.
        • Ikebe K.
        • et al.
        Measurement of anti-double-stranded DNA antibodies in major immunoglobulin classes.
        J Immunol Methods. 1979; 28: 149-162
        • Atkinson J.P.
        Complement deficiency. Predisposing factor to autoimmune syndromes.
        Am J Med. 1988; 85: 45-47
        • Bell D.D.
        • Moffatt S.L.
        • Singer M.
        • et al.
        Antibasement membrane antibody disease without clinical evidence of renal disease.
        Am Rev Respir Dis. 1990; 142: 234-237
        • Bergrem H.
        • Jervell J.
        • Brodwall E.K.
        • et al.
        Goodpasture’s syndrome: a report of seven patients including long-term follow-up of three who received a kidney transplant.
        Am J Med. 1980; 68: 54-58
        • Bisno A.L.
        The coexistence of acute rheumatic fever and acute glomerulonephritis.
        Arthritis Rheum. 1989; 32: 230-232
        • Bisno A.L.
        Group A streptococcal infections and acute rheumatic fever.
        N Engl J Med. 1991; 325: 783-793
        • Bisno A.L.
        • Pearce I.A.
        • Wall H.P.
        • et al.
        Contrasting epidemiology of acute rheumatic fever and acute glomerulonephritis: nature of the antecedent streptococcal infection.
        N Engl J Med. 1970; 283: 561-565
        • Boscata L.M.
        • Stuart M.C.
        Incidence and specificity of interference in two site immunoassays.
        Clin Chem. 1986; 32: 199-200
        • Brinkman K.
        • Termaat R.
        • Berden J.H.M.
        • et al.
        Anti-DNA antibodies and lupus nephritis: the complexity of crossreactivity.
        Immunol Today. 1990; 11: 232-234
        • Brzosko W.J.
        • Krawczynski K.
        • Nazarewicz T.
        • et al.
        Glomerulonephritis associated with hepatitis-B surface antigen immune complexes in children.
        Lancet. 1974; 2: 478-482
        • Butkowski R.J.
        • Langeveld J.P.M.
        • Wieslander J.
        • et al.
        Localization of the Goodpasture epitope to a novel chain of basement membrane collagen.
        J Biol Chem. 1987; 262: 7874-7877
        • Clough J.D.
        • Chang R.K.
        Effectiveness of testing for anti-DNA and the complement components iC3b, Bb, and C4 in the assessment of activity of systemic lupus erythematosus.
        J Clin Lab Anal. 1990; 4: 268-273
        • Colaco C.B.
        • Elkon K.B.
        The lupus anticoagulant—a disease marker in antinuclear antibody negative lupus that is cross-reactive with autoantibodies to double-stranded DNA.
        Arthritis Rheum. 1985; 28: 67-73
        • Combes B.
        • Shorey J.
        • Barrera A.
        • et al.
        Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane.
        Lancet. 1971; 2: 234-237
        • Crowe W.
        • Kushner I.
        An immunofluorescent method using Crithidium luciliae to detect antibodies to double-stranded DNA.
        Arthritis Rheum. 1977; 20: 811-814
        • Csernok E.
        • Lüdemann J.
        • Gross W.L.
        • et al.
        Ultrastructural localization of proteinase 3, the target antigen of anti-cytoplasmic antibodies circulating in Wegener’s granulomatosis.
        Am J Pathol. 1990; 137: 1113-1120
        • Deng J.-S.
        • Rubin R.L.
        • Lipscomb M.F.
        • et al.
        Reappraisal of the specificity of the Crithidia luciliae assay for nDNA antibodies: evidence for histone antibody kinetoplast binding.
        Am J Clin Pathol. 1984; 82: 448-452
        • Dillon Jr, H.C.
        Post-streptococcal glomerulonephritis following pyoderma.
        Rev Infect Dis. 1979; 1: 935-943
        • Donaghy M.
        • Rees A.J.
        Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane.
        Lancet. 1983; 2: 1390-1393
        • Eilat D.
        Cross reactions of anti-DNA antibodies and the central dogma of lupus nephritis.
        Immunol Today. 1986; 6: 123-127
        • Eilat D.
        • Zlotnick A.Y.
        • Fischei R.
        Evaluation of the cross-reaction between anti-DNA and anti-cardiolipin antibodies in SLE and experimental animals.
        Clin Exp Immunol. 1986; 65: 269-278
        • Eisenberg R.A.
        • Theofilopoulos A.N.
        • Dixon F.J.
        Use of bovin conglutinin for the assay of immune complexes.
        J Immunol. 1977; 188: 1428-1433
        • Faaber P.
        • Capel P.J.A.
        • Rijke G.P.M.
        • et al.
        Cross-reactivity of anti-DNA antibodies with proteoglycans.
        Clin Exp Immunol. 1984; 55: 502-510
        • Faaber P.
        • Rijke G.P.M.
        • Van de Putte L.B.A.
        • et al.
        Cross-reactivity of human and murine anti-DNA antibodies with heparan sulfate. The major glycosaminoglycan in glomerular basement membranes.
        J Clin Invest. 1986; 77: 1824-4830
        • Falk R.J.
        • Jennette J.C.
        Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis.
        N Engl J Med. 1988; 318: 1651-1657
        • Feldkamp C.S.
        • Levinson S.S.
        • Perry M.
        • et al.
        Anti-IgG combined with rate nephelometry for measuring polyethylene glycol-precipitated circulating immune complexes.
        Clin Chem. 1985; 31: 2024-2027
        • Feldman M.D.
        • Huston D.P.
        • Karsh J.
        • et al.
        Correlation of serum IgG, IgM and anti-native DNA antibodies with renal and clinical indexes of activity in systemic lupus erythematosus.
        J Rheumatol. 1982; 9: 52-58
        • Fillit H.
        • Damle S.P.
        • Gregory J.D.
        • et al.
        Sera from patients with post-streptococcal glomerulonephritis contain antibodies to glomerular heparan sulfate proteoglycan.
        J Exp Med. 1985; 161: 277-289
        • Gerger M.A.
        Comparison of throat cultures and rapid strep tests for diagnosis of streptococcal pharyngitis.
        Pediatr Infect Dis J. 1989; 8: 820-824
        • Gripenberg M.
        • Helve T.
        Anti-DNA antibodies of IgA class in patients with systemic lupus erythematosus.
        Rheumatol Int. 1986; 6: 53-63
        • Hay F.C.
        • Nineham L.J.
        • Roitt I.M.
        Routine assay for the detection of immune complexes of known immunoglobulin class using solid phase Clq.
        Clin Exp Immunol. 1976; 24: 396-400
        • Hebert L.A.
        • Costo F.G.
        • Neff J.C.
        Diagnostic significance of hypocomplementemia.
        Kidney Int. 1991; 39: 811-821
        • Horsefall C.A.
        • Venables P.J.W.
        • Mumford P.A.
        Interpretation of the Raji cell assay in sera containing antinuclear antibodies and immune complexes.
        Clin Exp Immunol. 1981; 44: 405-415
        • Hsu H.C.
        • Ling G.H.
        • Chang M.H.
        • et al.
        Association of hepatitis B surface (HBs) anti-genemia and membranous nephropathy in children in Taiwan.
        Clin Nephrol. 1983; 20: 121-129
        • Izui S.
        • Lambert P.H.
        • Miescher P.A.
        Failure to detect circulating DNA-anti-DNA complexes by four radioimmunological methods in patients with systemic lupus erythematosus.
        Clin Exp Immunol. 1977; 30: 384-392
        • Jacob L.
        • Lety M.-A.
        • Bach J.-F.
        • et al.
        Human systemic lupus erythematosus sera contain antibodies against cell-surface protein(s) that share(s) epitope(s) with DNA.
        Proc Natl Acad Sei USA. 1986; 83: 6970-6974
        • Jacob L.
        • Tron F.
        • Bach J.-F.
        • et al.
        A monoclonal antiDNA antibody also binds to cell-surface proteins.
        Proc Natl Acad Sei USA. 1984; 81: 3843-3845
        • Kallenberg C.G.M.
        • Tervaert J.W.C.
        • van det Woude F.J.
        • et al.
        Autoimmunity to lysosomal enzymes: new clues to vasculitis and glomerulonephritis?.
        Immunol Today. 1991; 12: 61-64
        • Kanai Y.
        • Yaoita Y.
        • Imaoka K.
        • et al.
        A unique monoclonal antibody derived from a lupus-prone mouse with multiple bindings to autoantigens associated with rheumatic disease.
        Immunol Lett. 1988; 19: 15-20
        • Karsh J.
        • Halbert S.P.
        • Anken M.
        • et al.
        Anti-DNA, anti-deoxyribonucleoprotein and rheumatoid factor measured by ELISA in patients with systemic lupus erythematosus, Sjogren’s syndrome and rheumatoid arthritis.
        Int Arch Allergy Appl Immun. 1982; 68: 60-69
        • Kefalides N.A.
        • Pegg M.T.
        • Ohno N.
        • et al.
        Antibodies to basement membrane collagen and to laminin are present in sera from patients with poststreptococcal glomerulonephritis.
        J Exp Med. 1986; 163: 588-602
        • Keogh A.M.
        • Ibels L.S.
        • Allen D.H.
        • et al.
        Exacerbation of Goodpasture’s syndrome after inadvertent exposure to hydrocarbon fumes.
        Br Med J. 1984; 288: 188
        • Khanna A.K.
        • Buskirk D.R.
        • Williams Jr, R.C.
        • et al.
        Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody.
        J Clin Invest. 1989; 83: 1710-1716
        • Kleinknecht C.
        • Levy M.
        • Peix A.
        • et al.
        Membranous glomerulonephritis and hepatitis B surface antigen in children.
        J Pediatr. 1979; 95: 946-952
        • Koffler D.
        • Agnello V.
        • Thoburn R.
        • et al.
        Systemic lupus erythematosus: prototype of immune complex nephritis in man.
        J Exp Med. 1971; 134: 169s-179s
        • Lafer E.M.
        • Rauch J.
        • Andrzejewski Jr, C.
        • et al.
        Polyspecific monoclonal lupus autoantibodies reactive with both polynucleotides and phospholipids.
        J Exp Med. 1981; 153: 897-909
        • Lai K.N.
        • Lai F.M.
        • Chan K.W.
        • et al.
        The clinico-pathologic features of hepatitis B virus-associated glomerulonephritis.
        Q J Med. 1987; 240: 323-333
        • Lai K.N.
        • Lai E.M.
        • Lo S.T.
        • et al.
        IgA nephropathy and membranous nephropathy associated with hepatitis B surface antigenemia.
        Human Pathol. 1987; 18: 411-414
        • Levinson S.S.
        Assays for circulating immune complexes.
        Am Clin Lab. 1991; 10: 16-19
        • Levinson S.S.
        • Goldman J.
        Absorbance nephelometry of immune complexes by reaction with anti-IgG after treatment with polyethylene glycol.
        Clin Chem. 1983; 29: 2036-2039
        • Levinson S.S.
        • Goldman J.
        Anomalous Raji cell activity related to DNA binding in some patients with autoimmune disease.
        Clin Physiol Biochem. 1989; 7: 18-26
        • Levinson S.S.
        • Keren D.F.
        Immunoglobulins from the sera of immunologically activated persons with pairs of electrophoretic restricted bands show a greater tendency to aggregate than normal.
        Clin Chim Acta. 1989; 182: 21-30
        • Lisker-Melman M.
        • Webb D.
        • Di Bisceglie A.M.
        • et al.
        Glomerulonephritis caused by chronic hepatitis B virus infection: treatment with recombinant human alpha-interferon.
        Ann Intern Med. 1989; 111: 479-483
        • Nölle B.
        • Specks U.
        • Lüdemann J.
        • et al.
        Anticytoplasmic autoantibodies: their im-munodiagnostic value in Wegener granulomatosis.
        Ann Intern Med. 1989; 111: 28-40
        • Pennebaker J.B.
        • Gilliam J.N.
        • Ziff M.
        Immunoglobulin classes of DNA binding activity in serum and skin in systemic lupus erythematosus.
        J Clin Invest. 1977; 60: 1331-1338
        • Pereira A.B.
        • Theofilopoulos A.N.
        • Dixon F.J.
        Detection and partial characterization of circulating immune complexes with solid-phase anti-C3.
        J Immunol. 1980; 125: 763-770
        • Potter E.V.
        • Svartman M.
        • Mohammed I.
        • et al.
        Tropical acute rheumatic fever and associated streptococcal infections compared with concurrent acute glomerulonephritis.
        J Pediatr. 1978; 92: 325-333
        • Preudhomme J.L.
        • Rochard E.
        • Gouet D.
        • et al.
        Isotypic distribution of anti-double-stranded DNA antibodies: a diagnostic evaluation by enzyme-linked immunosorbent assay.
        Diagn Clin Immunol. 1988; 5: 256-261
        • Price R.G.
        • Wong M.
        Heterogeneity of Goodpasture’s antigen (editorial).
        J Pathol. 1988; 156: 97-99
        • Regelmann W.E.
        • Talbot Cairns
        • et al.
        Distribution of cells bearing “rheumatic” antigens in peripheral blood of patients with rheumatic fever/rheumatic heart disease.
        J Rheumatol. 1989; 16: 931-935
        • Ritzmann S.E.
        • Daniels J.C.
        Immune complexes: characteristics, clinical correlations, and interpretive approaches in the clinical laboratory.
        Clin Chem. 1982; 28: 1259-1271
        • Roberts D.E.
        • Peebles C.
        • Curd J.G.
        • et al.
        Autoantibodies to native myeloperoxidase in patients with pulmonary hemorrhage and acute renal failure.
        J Clin Immunol. 1991; 11: 389-397
        • Roberts D.E.
        • Peebles C.
        • Daggett R.
        Simplified method of preparing neutrophil slides to examine antibodies to cytoplasmic antigens.
        J Clin Pathol. 1990; 43: 83-84
        • Saus J.
        • Wieslander J.
        • Langeveld J.P.M.
        • et al.
        Identification of the Goodpasture antigen as the α3(IV) chain of collagen IV.
        J Biol Chem. 1988; 263: 13374-43380
        • Savage C.O.S.
        • Pusey C.D.
        • Bowman C.
        • et al.
        Antiglomerular basement membrane antibody mediated disease in the British Isles 1980-4.
        Br Med J. 1986; 292: 301-304
        • Saxena R.
        • Isaksson B.
        • Bygren P.
        • et al.
        A rapid assay for circulating anti-glomerular basement membrane antibodies in Goodpasture syndrome.
        J Immunol Methods. 1989; 118: 73-78
        • Schoenfeld Y.
        • Rauch J.
        • Massicotte M.
        • et al.
        Polyspecificity of monoclonal lupus autoantibodies produced by human-human hybridomas.
        N Engl J Med. 1983; 308: 414-420
        • Slusarczyk J.
        • Michalak T.
        • Nazarewicz-de Mezer T.
        • et al.
        Membranous glomerulopathy associated with hepatitis B core antigen immune complexes in children.
        Am J Pathol. 1980; 98: 29-43
        • Smeenk R.J.T.
        • Brinkman K.
        • Van den Brink H.G.
        • et al.
        Reaction patterns of monoclonal antibodies to DNA.
        J Immunol. 1988; 140: 3786-3792
        • Smeenk R.J.T.
        • Lucassen W.A.M.
        • Swaak A.J.G.
        Is cardiolipin activity a cross-reaction of anti-DNA or a separate entity?.
        Arthritis Rheum. 1987; 30: 607-617
        • Smeenk R.
        • Van Rooyen A.
        • Swaak A.J.G.
        Dissociation studies of DNA/anti-DNA complexes in relation to anti-DNA avidity.
        J Immunol Methods. 1988; 109: 27-35
        • Steinman C.R.
        Circulating DNA in systemic lupus erythematosus. Isolation and characterization.
        J Clin Invest. 1984; 73: 832-838
        • Stollar B.D.
        Antibodies to DNA.
        Crit Rev Biochem. 1986; 20: 1-36
        • Strife C.F.
        • Prada A.L.
        • Clardy C.W.
        • et al.
        Autoantibody to complement neoantigens in membranoproliferative glomerulonephritis.
        J Pediatr. 1990; 116: S98-S102
        • Swaak A.J.G.
        • Aarden L.A.
        • Statius van Eps L.W.
        • et al.
        Anti-dsDNA and complement profiles as prognostic guides in systemic lupus erythematosus.
        Arthritis Rheum. 1979; 22: 226-235
        • Takekoshi Y.
        • Tanaka M.
        • Miyakawa Y.
        • et al.
        Free “small” and IgG associated “large” hepatitis B e antigen in the serum and glomerular capillary walls of two patients with membranous glomerulonephritis.
        N Engl J Med. 1979; 300: 814-819
        • Theofilopoulos A.N.
        The Raji, conglutinin, and anti-C3 assays for the detection of complement-fixing immune complexes.
        Methods in Enzymology. 1981; 74: 511-530
        • Theofilopoulos A.N.
        • Aguado M.T.
        Assays for detection of complement-fixing immune complexes: Raji cell, conglutinin, and anti-C3 assays.
        in: Rose N.R. Friedman H. Fahey J.L. Manual of Clinical Laboratory Immunology, 3 ed. American Society for Microbiology, Washington, DC1986: 197-203
        • Theofilopoulos A.N.
        • Wilson C.B.
        • Dixon F.J.
        The Raji cell radioimmune assay for detecting immune complexes in human sera.
        J Clin Invest. 1976; 57: 169-182
        • Thompson R.J.
        • Jackson A.P.
        • Langlois N.
        Circulating antibodies to mouse monoclonal immunoglobulins in normal subjects. Incidence, species specificity, and effect on a two site assay for creatine kinase-MB isoenzyme.
        Clin Chem. 1986; 32: 476-481
        • Toth C.A.
        • Pohl D.
        • Agnello V.
        Methods for detection of immune complexes by utilizing Clq or rheumatoid factors.
        in: Rose N.R. Friedman H. Fahey J.L. Manual of Clinical Laboratory Immunology. ed 3. American Society for Microbiology, Washington, DC1986: 204-210
        • Tung K.S.K.
        • De Hortatius R.J.
        • Williams Jr, R.C.
        Study of circulating immune complex size in systemic lupus erythematosus.
        Clin Exp Immunol. 1981; 43: 615-625
        • Uko G.
        • Christiansen F.T.
        • Dawkins R.L.
        Serum C4 concentration in the monitoring of systemic lupus erythematosus: requirement for C4 allotyping.
        Rheumatol Int. 1986; 6: 111-114
        • West C.D.
        The complement profile in clinical medicine. Inherited and acquired conditions lowering the serum concentrations of complement component and control proteins.
        Complement and Inflammation. 1989; 6: 49-64
        • Wieslander J.
        • Barr J.F.
        • Butkowski R.J.
        • et al.
        Goodpasture antigen of the glomerular basement membrane: localization to noncollagenous regions of type IV collagen.
        Proc Natl Acad Sei USA. 1984; 81: 3838-3842
        • Wieslander J.
        • Bygren P.G.
        • Heinegárd D.
        Anti-basement membrane antibody: im-munoenzymatic assay and specificity of antibodies.
        Scand J Clin Lab Invest. 1981; 41: 763-772
        • Wieslander J.
        • Bygren P.
        • Heinegárd D.
        Antiglomerular basement membrane antibody: antibody specificity in different forms of glomerulonephritis.
        Kidney Int. 1983; 23: 855-861
        • Wieslander J.
        • Bygren P.
        • Heinegárd D.
        Isolation of the specific glomerular basement membrane antigen involved in Goodpasture syndrome.
        Proc Natl Acad Sei USA. 1984; 81: 1544-1548
        • Wieslander J.
        • Kataja M.
        • Hudson B.G.
        Characterization of the human Goodpasture antigen.
        Clin Exp Immunol. 1987; 69: 332-340
        • Wieslander J.
        • Langeveld J.
        • Butkowski R.
        • et al.
        Physical and immunochemical studies of the globular domain of type IV collagen, cryptic properties of the Goodpasture antigen.
        J Biol Chem. 1985; 260: 8564-8570
        • Wilson C.B.
        • Dixon F.J.
        Anti-glomerular basement membrane antibody-induced glomerulonephritis.
        Kidney Int. 1973; 3: 74r-89
        • Winfield J.B.
        • Faiferman I.
        • Koffler D.
        Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus.
        J Clin Invest. 1977; 59: 90-96
        • Ziola B.
        • Salmi A.
        • Penttinen K.
        Porcine Clq and the solid phase immunoassay of human immune complexes.
        J Immunol Methods. 1982; 49: 247-260
        • Zweig M.H.
        • Csako G.
        • Benson C.C.
        • et al.
        Interference by antiimmunoglobulin G antibodies in immunoradiometric assays for thyrotropin involving mouse monoclonal antibodies.
        Clin Chem. 1987; 33: 840-844

      Article info

      Identification

      DOI: https://doi.org/10.1016/S0272-2712(18)30461-X

      Copyright

      © 1993 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX