Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: 'Shrunken pore syndrome'

Anders Grubb, Veronica Lindström, Magnus Jonsson, Sten-Erik Bäck, Tomas Åhlund, Bengt Rippe, Anders Christensson, Anders Grubb, Veronica Lindström, Magnus Jonsson, Sten-Erik Bäck, Tomas Åhlund, Bengt Rippe, Anders Christensson

Abstract

The plasma levels of cystatin C, β2-microglobulin, beta-trace protein, retinol binding protein (RBP) and creatinine were determined in plasma samples from 111 randomly selected patients with eGFRcystatin C ≤ 60% of eGFRcreatinine and from 55 control patients with 0.9eGFRcreatinine ≤ eGFRcystatin C ≤ 1.1eGFRcreatinine (eGFRcystatin C ≈ eGFRcreatinine). The concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, beta-trace protein/creatinine and RBP/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine. When the patients were divided into three groups with different estimated GFR intervals (≤ 40, 40-60 and ≥ 60 mL/min/1.73m(2)) the concentration ratios of cystatin C/creatinine, β2-microglobulin/creatinine, and beta-trace protein/creatinine were significantly higher in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine than in patients with eGFRcystatin C ≈ eGFRcreatinine for all GFR intervals. Similar results were obtained when the population without pregnant women was studied as well as the subpopulations of men or of non-pregnant women. Populations of pre-eclamptic women and pregnant women in the third trimester display similar results. Since the production of these four proteins with sizes similar to that of cystatin C is not co-regulated, the most likely explanation for the simultaneous increase of their creatinine-ratios in patients with eGFRcystatin C ≤ 60% of eGFRcreatinine is that their elimination by glomerular filtration is decreased. We suggest that this is due to a reduction in pore diameter of the glomerular membrane and propose the designation 'Shrunken pore syndrome' for this pathophysiological state.

Keywords: Beta-trace protein; beta 2-microglobulin; creatinine; cystatin C; glomerular filtration rate; kidney diseases; retinol-binding proteins.

References

    1. Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, Sterner G, Bäck SE, SBU GFR Review Group Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64:411–24.
    1. Norden AG, Lapsley M, Lee PJ, Pusey CD, Scheinman SJ, Tam FW, Thakker RV, Unwin RJ, Wrong O. Glomerular protein sieving and implications for renal failure in Fanconi syndrome. Kidney Int. 2001;60:1885–92.
    1. Lund U, Rippe A, Venturoli D, Tenstad O, Grubb A, Rippe B. Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys. Am J Physiol. 2003;284:F1226–34.
    1. Gagliardini E, Conti S, Benigni A, Remuzzi G, Remuzzi A. Imaging of the porous ultrastructure of the glomerular epithelial filtration slit. J Am Soc Nephrol. 2010;21:2081–9.
    1. Löfberg H, Grubb A. Quantitation of γ-trace in human biological fluids: indications for production in the central nervous system. Scand J Clin Lab Invest. 1979;39:619–26.
    1. Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H. Serum concentration of cystatin C, factor D and β2-microglobulin as a measure of glomerular filtration rate. Acta Med Scand. 1985;218:499–503.
    1. Simonsen O, Grubb A, Thysell H. The blood serum concentration of cystatin C (γ-trace) as a measure of the glomerular filtration rate. Scand J Clin Lab Invest. 1985;45:97–101.
    1. Strevens H, Wide-Swensson D, Torffvit O, Grubb A. Serum cystatin C for assessment of glomerular filtration rate in pregnant and non-pregnant women. Indications of altered filtration process in pregnancy. Scand J Clin Lab Invest. 2002;62:141–7.
    1. Kristensen K, Lindström V, Schmidt C, Blirup-Jensen S, Grubb A, Wide-Swensson D, Strevens H. Temporal changes of the plasma levels of cystatin C, beta-trace protein, β2-microglobulin, urate and creatinine during pregnancy indicate continuous alterations in the renal filtration process. Scand J Clin Lab Invest. 2007;67:612–8.
    1. Grubb A, Lindström V, Kristensen K, Christensson A, Wide-Swensson D, Strevens H, Schmidt C, Blirup-Jensen S. Filtration quality: a new measure of renal disease. Clin Chem Lab Med. 2007;45(Suppl):S273–4.
    1. Strevens H, Wide-Swensson D, Grubb A. Serum cystatin C is a better marker for preeclampsia than serum creatinine or serum urate. Scand J Clin Lab Invest. 2001;61:575–80.
    1. Kristensen K, Wide-Swensson D, Schmidt C, Blirup-Jensen S, Lindström V, Strevens H, Grubb A. Cystatin C, beta-2- microglobulin and beta-trace protein in pre-eclampsia. Acta Obstet Gynecol Scand. 2007;86:921–6.
    1. Grubb A, Horio M, Hansson LO, Björk J, Nyman U, Flodin M, Larssson A, Bökenkamp A, Yasuda Y, Blufpand H, Lindström V, Zegers I, Althaus H, Blirup-Jensen S, Itoh Y, Sjöström P, Nordin G, Christensson A, Klima H, Sunde K, Hjort-Christensen P, Armbruster D, Ferrrero C. Generation of a new cystatin C-based estimating equation for glomerular filtration rate using seven assays standardized to the international calibrator. Clin Chem. 2014;60:974–86.
    1. Nyman U, Grubb A, Larsson A, Hansson L-O, Flodin M, Nordin G, Lindström V, Björk J. The revised Lund-Malmö GFR estimating equation outperforms MDRD and CKD-EPI across GFR, age and BMI intervals in a large Swedish population. Clin Chem Lab Med. 2014;52:815–24.
    1. Mátrai Z, Németh J, Miklós K, Szabó Z, Masszi T. Serum beta2-microglobulin measured by immunonephelometry: expression patterns and reference intervals in healthy adults. Clin Chem Lab Med. 2009;47:585–9.
    1. Arrer E, Meco C, Oberascher G, Piotrowski W, Albegger K, Patsch W. beta-Trace protein as a marker for cerebrospinal fluid rhinorrhea. Clin Chem. 2002;48:939–41.
    1. Malvy DJ, Povéda JD, Debruyne M, Burtschy B, Dostalova L, Amédée-Manesme O. Immunonephelometry and radial immunodiffusion compared for measuring serum retinol-binding protein. Eur J Clin Chem Clin Biochem. 1993;31:47–8.
    1. Nyman U, Grubb A, Sterner G, Björk J. Different equations to combine creatinine and cystatin C to predict GFR. Arithmetic mean of existing equations performs as well as complex combinations. Scand J Clin Lab Invest. 2009;69:619–27.
    1. Grubb A. Non-invasive estimation of glomerular filtration rate (GFR). The Lund model: simultaneous use of cystatin C- and creatinine-based GFR prediction equations, clinical data and an internal quality check. Scand J Clin Lab Invest. 2010;70:65–70.
    1. Grubb A, Nyman U, Björk J. Improved estimation of glomerular filtration rate (GFR) by comparison of eGFRcystatin C and eGFRcreatinine . Scand J Clin Lab Invest. 2012;72:73–7.
    1. Björk J, Grubb A, Larsson A, Hansson LO, Flodin M, Sterner G, Lindström V, Nyman U. Accuracy of GFR estimating equations combining standardized cystatin C and creatinine assays: a cross-sectional study in Sweden. Clin Chem Lab Med. 2015;53:403–14.
    1. Deen WM, Lazzara MJ, Myers BD. Structural determinants of glomerular permeability. Am J Physiol. 2001;281:F579–96.
    1. Rippe B, Haraldsson B. Transport of macromolecules across microvascular walls: the two-pore theory. Physiol Rev. 1994; 74:163–219.
    1. Jeansson M, Haraldsson B. Glomerular size and charge selectivity in the mouse after exposure to glucosaminoglycan-degrading enzymes. J Am Soc Nephrol. 2003;14:1756–65.
    1. Venturoli D, Rippe B. Ficoll and dextran vs. globular proteins as probes for testing glomerular permselectivity: effects of molecular size, shape, charge, and deformability. Am J Physiol. 2005;288:F605–13.
    1. Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88:451–87.
    1. Axelsson J, Mahmutovic I, Rippe A, Rippe B. Loss of size selectivity of the glomerular filtration barrier in rats following laparotomy and muscle trauma. Am J Physiol. 2009;297:F577–82.
    1. Axelsson J, Rippe A, Venturoli D, Swärd P, Rippe B. Effects of early endotoxemia and dextran-induced anaphylaxis on the size selectivity of the glomerular filtration barrier in rats. Am J Physiol. 2009;296:F242–8.
    1. Axelsson J, Rippe A, Rippe B. Acute hyperglycemia induces rapid, reversible increases in glomerular permeability in nondiabetic rats. Am J Physiol. 2010;298:F1306–12.
    1. Sverrisson K, Axelsson J, Rippe A, Gram M, Åkerström B, Hansson SR, Rippe B. Extracellular fetal hemoglobin induces increases in glomerular permeability: inhibition with α1-microglobulin and tempol. Am J Physiol. 2014;306:F442–8.
    1. Abrahamson M, Islam MQ, Szpirer J, Szpirer C, Levan G. The human cystatin C gene (CST3), mutated in hereditary cystatin C amyloid angiopathy, is located on chromosome 20. Hum Genet. 1989;82:223–6.
    1. Rocchi M, Covone A, Romeo G, Faraonio R, Colantuoni V. Regional mapping of RBP4 to 10q23-q24 and RBP1 to 3q21-q22 in man. Somat Cell Molec Genet. 1989;15:185–90.
    1. Goodfellow PN, Jones EA, Van Heyningen V, Solomon E, Bobrow M. The beta-2-microglobulin gene is on chromosome 15 and not in the HL-A region. Nature. 1975;254:267–9.
    1. White DM, Mikol DD, Espinosa R, Weimer B, Le Beau MM, Stefansson K. Structure and chromosomal localization of the human gene for a brain form of prostaglandin D-2 synthase. J Biol Chem. 1992;267:23202–8.
    1. Abbink FC, Laarman CA, Braam KI, van Wijk JA, Kors WA, Bouman AA, Spreeuwenberg MD, Stoffel-Wagner B, Bökenkamp A. Beta-trace protein is not superior to cystatin C for the estimation of GFR in patients receiving corticosteroids. Clin Biochem. 2008;41:299–305.
    1. Gobin SJ, Biesta P, Van den Elsen PJ. Regulation of human beta 2-microglobulin transactivation in hematopoietic cells. Blood. 2003;101:3058–64.
    1. Hokland M, Larsen B, Heron I, Plesner T. Corticosteroids decrease the expression of beta 2-microglobulin and histocompatibility antigens on humanperipheral blood lymphocytes in vitro. Clin Exp Immunol. 1981;44:239–46.
    1. Kotnik P, Fischer-Posovszky P, Wabitsch M. RBP4: a controversial adipokine. Eur J Endocrinol. 2011;165:703–11.
    1. Juraschek SP, Coresh J, Inker LA, Levey AS, Köttgen A, Foster MC, Astor BC, Eckfeldt JH, Selvin E. Comparison of serum concentrations of β-trace protein, β2-microglobulin, cystatin C, and creatinine in the US population. Clin J Am Soc Nephrol. 2013;8:584–92.
    1. National Cancer Institute at the National Institutes of Health
    1. Ibn Sina (Avicenna, 980–1037), in the original Arabic version of “The Canon of Medicine “ (1999), p. 110 and 158, DAR al-KOTOB al-ILMIYAH Beirut-Lebanon, ISBN 2-7451-2617-2
    1. Dorland's Illustrated Medical Dictionary. (32 ed) USA: Elsevier Saunders; p. 1819.
    1. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakal NA, Safford MM, Zhan X, Muntner P. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA. 2011;305:1545–52.
    1. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352:2049–60.
    1. Knight EL, Verhave JC, Spiegelman D, Hillege HL, deZeeuw D, Curhan GC, deJong PE. Factors influencing cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int. 2004;65:1416–21.
    1. Grubb A, Björk J, Nyman U, Pollak J, Bengzon J, Östner G, Lindström V. Cystatin C, a marker for successful aging and glomerular filtration rate, is not influenced by inflammation. Scand J Clin Lab Invest. 2011;71:145–19.
    1. Bjarnadottir M, Grubb A, Olafsson I. Promoter-mediated, dexamethasone-induced increase in cystatin C production by HeLa cells. Scand J Clin Lab Invest. 1995;55:617–23.
    1. Risch L, Herklotz R, Blumberg A, Huber AR. Effects of glucocorticoid immunosuppression on serum cystatin C concentrations in renal transplant patients. Clin Chem. 2001;47:2055–9.
    1. Bökenkamp A, Laarman CA, Braam KI, van Wijk JA, Kors WA, Kool M, de Valk J, Bouman AA, Spreeuwenberg D, Stoffel-Wagner B. Effect of corticosteroid therapy on low-molecular weight protein markers of kidney function. Clin Chem. 2007;53:2219–21.
    1. Abbink FC, Laarman CA, Braam KI, van Wijk JA, Kors WA, Bouman AA, Spreeuwenberg MD, Stoffel-Wagner B, Bökenkamp A. Beta-trace protein is not superior to cystatin C for the estimation of GFR in patients receiving corticosteroids. Clin Biochem. 2008;41:299–305.
    1. Roberts M, Lindheimer MD, Davison JM. Altered glomerular permselectivity to neutral dextrans and heteroporous membrane modeling in human pregnancy. Am J Physiol. 1996;270:F338–43.

Source: PubMed

3
購読する