Esclerosis focal y segmentaria glomerular primaria: ubi sumus et quo eamus?
Resumen
La esclerosis focal y segmentaria glomerular primaria es una causa frecuente de sindrome nefrótico con alta morbilidad que con frecuencia lleva a la insuficiencia renal terminal debido a que sus esquemas terapeúticos no son exitosos, ya que sus mecanismos fisiopatológicos a la actualidad han sido parcialmente descifrados. Éstos son heterogéneos, complejos de integrar, y además el término agrupa bajo la misma denominación, la cual evoca una descripción histológica a un variado número de causas moleculares con distinta fisiopatogenia. En esta revisión se describen los últimos adelantos respecto a la fisiopatología de esta compleja entidad y los últimos adelantos en su terapéutica.
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Benchimol C. Focal segmental glomerulosclerosis: pathogenesis and treatment. Curr Opin Pediatr. 2003;15(2):171-80.
Korbet SM. Treatment of primary focal segmental glomerulosclerosis. Kidney Int. 2002;62(6):2301-10.
Boyer O, Moulder JK, Somers MJ. Focal and segmental glomerulosclerosis in children: a longitudinal assessment. Pediatr Nephrol. 2007;22(8):1159-66.
Barisoni L, Schnaper HW, Kopp JB. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy. Arch Pathol Lab Med. 2009;133(2):201-16.
Santín S, Bullich G, Tazón-Vega B, García-Maset R, Giménez I, Silva I, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011;6(5):1139-48.
Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, et al. Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol. 2012;23(12):2051-9.
Maas RJ, Deegens JK, Wetzels JF. Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol. 2013;28(7):1041-8.
Naesens M, Meijers B, Sprangers B. suPAR and FSGS: the gap between bench and bedside. Transplantation. 2013;96(4):368-9.
Palacios CRF, Lieske JC, Wadei HM, Rule AD, Fervenza FC, Voskoboev N, et al. Urine But Not Serum Soluble Urokinase Receptor (suPAR) May Identify Cases of Recurrent FSGS in Kidney Transplant Candidates. Transplantation. 2013;96(4):394–9.
Wei Y, Waltz DA, Rao N, Drummond RJ, Rosenberg S, Chapman HA. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem. 1994;269(51):32380-8.
Ploug M, Rønne E, Behrendt N, Jensen AL, Blasi F, Danø K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991;266(3):1926-33.
De Bock CE, Wang Y. Clinical significance of urokinase-type plasminogen activator receptor (uPAR) expression in cancer. Med Res Rev. 2004;24(1):13-39.
Estreicher A, Mühlhauser J, Carpentier JL, Orci L, Vassalli JD. The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol. 1990;111(2):783-92.
Florquin S, Van den Berg JG, Olszyna DP, Claessen N, Opal SM, Weening JJ, et al. Release of urokinase plasminogen activator receptor during urosepsis and endotoxemia. Kidney Int. 2001;59(6):2054-61.
Grøndahl-Hansen J, Lund LR, Ralfkiaer E, Ottevanger V, Danø K. Urokinase- and tissue-type plasminogen activators in keratinocytes during wound reepithelialization in vivo. J Invest Dermatol. 1988;90(6):790-5.
Wei C, Möller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, et al. Modification of kidney barrier function by the urokinase receptor. Nat Med. 2008;14(1):55-63.
Svenningsen P, Bistrup C, Friis UG, Bertog M, Haerteis S, Krueger B, et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol. 2009;20(2):299-310.
Thunø M, Macho B, Eugen-Olsen J. suPAR: the molecular crystal ball. Dis Markers. 2009;27(3-4):157-72.
Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, et al. Structure of human urokinase plasminogen activator in complex with its receptor. Science. 2006;311(5761):656-9.
Sier CF, Sidenius N, Mariani A, Aletti G, Agape V, Ferrari A, et al. Presence of urokinase-type plasminogen activator receptor in urine of cancer patients and its possible clinical relevance. Lab Invest. 1999;79(6):717-22.
Stephens RW, Pedersen AN, Nielsen HJ, Hamers MJ, Høyer-Hansen G, Rønne E, et al. ELISA determination of soluble urokinase receptor in blood from healthy donors and cancer patients. Clin Chem. 1997;43(10):1868-76.
Østergaard C, Benfield T, Lundgren JD, Eugen-Olsen J. Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome. Scand J Infect Dis. 2004;36(1):14-9.
Sidenius N, Sier CF, Blasi F. Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett. 2000;475(1):52-6.
Andersen O, Eugen-Olsen J, Kofoed K, Iversen J, Haugaard SB. Soluble urokinase plasminogen activator receptor is a marker of dysmetabolism in HIV-infected patients receiving highly active antiretroviral therapy. J Med Virol. 2008;80(2):209-16.
Cunningham O, Andolfo A, Santovito ML, Iuzzolino L, Blasi F, Sidenius N. Dimerization controls the lipid raft partitioning of uPAR/CD87 and regulates its biological functions. EMBO J. 2003;22(22):5994-6003.
Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F. A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J. 1997;16(24):7279-86.
Høyer-Hansen G, Ploug M, Behrendt N, Rønne E, Danø K. Cell-surface acceleration of urokinase-catalyzed receptor cleavage. Eur J Biochem. 1997;243(1-2):21-6.
Beaufort N, Leduc D, Rousselle JC, Magdolen V, Luther T, Namane A, et al. Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G. J Immunol. 2004;172(1):540-9.
Ossowski L, Aguirre-Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol. 2000;12(5):613-20.
Chapman HA. Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol. 1997;9(5):714-24.
Blasi F. uPA, uPAR, PAI-1: key intersection of proteolytic, adhesive and chemotactic highways? Immunol Today. 1997;18(9):415-7.
Waltz DA, Natkin LR, Fujita RM, Wei Y, Chapman HA. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest. 1997;100(1):58-67.
Behrendt N, Ploug M, Patthy L, Houen G, Blasi F, Danø K. The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem. 1991;266(12):7842-7.
Vaziri ND, Gonzales EC, Shayestehfar B, Barton CH. Plasma levels and urinary excretion of fibrinolytic and protease inhibitory proteins in nephrotic syndrome. J Lab Clin Med. 1994;124(1):118-24.
Tudpor K, Laínez S, Kwakernaak AJ, Kovalevskaya NV, Verkaart S, Van Genesen S, et al. Urinary plasmin inhibits TRPV5 in nephrotic-range proteinuria. J Am Soc Nephrol. 2012;23(11):1824-34.
Svenningsen P, Bistrup C, Friis UG, Bertog M, Haerteis S, Krueger B, et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J Am Soc Nephrol. 2009;20(2):299-310.
May AE, Kanse SM, Lund LR, Gisler RH, Imhof BA, Preissner KT. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo. J Exp Med. 1998;188(6):1029-37.
Wei Y, Yang X, Liu Q, Wilkins JA, Chapman HA. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol. 1999;144(6):1285-94.
Wei Y, Eble JA, Wang Z, Kreidberg JA, Chapman HA. Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. Mol Biol Cell. 2001;12(10):2975-86.
Welsh GI, Saleem MA. The podocyte cytoskeleton--key to a functioning glomerulus in health and disease. Nat Rev Nephrol. 2011;8(1):14-21.
Resnati M, Guttinger M, Valcamonica S, Sidenius N, Blasi F, Fazioli F. Proteolytic cleavage of the urokinase receptor substitutes for the agonist-induced chemotactic effect. EMBO J. 1996;15(7):1572-82.
Resnati M, Pallavicini I, Wang JM, Oppenheim J, Serhan CN, Romano M, et al. The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R. Proc Natl Acad Sci U S A. 2002;99(3):1359-64.
Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nat Med. 2011;17(8):926-7.
Sison K, Eremina V, Baelde H, Min W, Hirashima M, Fantus IG, et al. Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J Am Soc Nephrol. 2010;21(10):1691-701.
Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. 2011;17(1):117-22.
Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, et al. Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol. 2009;20(2):260-6.
Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, et al. Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int. 2010;78(3):296-302.
McCarthy ET, Sharma M, Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5(11):2115-21.
Ghiggeri GM, Aucella F, Caridi G, Bisceglia L, Ghio L, Gigante M, et al. Posttransplant recurrence of proteinuria in a case of focal segmental glomerulosclerosis associated with WT1 mutation. Am J Transplant. 2006;6(9):2208-11.
Srivastava T, Garola RE, Kestila M, Tryggvason K, Ruotsalainen V, Sharma M, et al. Recurrence of proteinuria following renal transplantation in congenital nephrotic syndrome of the Finnish type. Pediatr Nephrol. 2006;21(5):711-8.
Lennon R, Singh A, Welsh GI, Coward RJ, Satchell S, Ni L, et al. Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes. J Am Soc Nephrol. 2008;19(11):2140-9.
Bakker WW, Borghuis T, Harmsen MC, Van den Berg A, Kema IP, Niezen KE, et al. Protease activity of plasma hemopexin. Kidney Int. 2005;68(2):603-10.
Lagrue G, Xheneumont S, Branellec A, Hirbec G, Weil B. A vascular permeability factor elaborated from lymphocytes. I. Demonstration in patients with nephrotic syndrome. Biomedicine. 1975;23(1):37-40.
Matsumoto K, Kanmatsuse K. Transforming growth factor-beta1 inhibits vascular permeability factor release by T cells in normal subjects and in patients with minimal-change nephrotic syndrome. Nephron. 2001;87(2):111-7.
Tune BM, Mendoza SA. Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J Am Soc Nephrol. 1997;8(5):824-32.
Fine RN. Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children. Pediatr Nephrol. 2007;22(4):496–502.
Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, et al. Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations. Kidney Int. 2007;72(12):1429-47.
Moudgil A, Bagga A, Jordan SC. Mycophenolate mofetil therapy in frequently relapsing steroid-dependent and steroid-resistant nephrotic syndrome of childhood: current status and future directions. Pediatr Nephrol. 2005;20(10):1376-81.
Nozu K, Iijima K, Fujisawa M, Nakagawa A, Yoshikawa N, Matsuo M. Rituximab treatment for posttransplant lymphoproliferative disorder (PTLD) induces complete remission of recurrent nephrotic syndrome. Pediatr Nephrol. 2005;20(11):1660-3.
Guigonis V, Dallocchio A, Baudouin V, Dehennault M, Hachon-Le Camus C, Afanetti M, et al. Rituximab treatment for severe steroid- or cyclosporine-dependent nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol. 2008;23(8):1269-79.
Keith DS. Therapeutic apheresis rescue mission: recurrent focal segmental glomerulosclerosis in renal allografts. Semin Dial. 2012;25(2):190-2.
Ponticelli C. Recurrence of focal segmental glomerular sclerosis (FSGS) after renal transplantation. Nephrol Dial Transplant. 2010;25(1):25-31.
Gipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol. 2006;21(3):344-9.
Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC; Toronto Glomerulonephritis Registry Group. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol. 2005;16(4):1061-8.
Gao W, Wang Z, Bai X, Xi X, Ruan C. Detection of soluble urokinase receptor by immunoradiometric assay and its application in tumor patients. Thromb Res. 2001;102(1):25-31.
Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008;14(9):931-8.
Salomon R, Gagnadoux MF, Niaudet P. Intravenous cyclosporine therapy in recurrent nephrotic syndrome after renal transplantation in children. Transplantation. 2003;75(6):810-4.
Raafat RH, Kalia A, Travis LB, Diven SC. High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children. Am J
Kidney Dis. 2004;44(1):50-6.
Ingulli E, Tejani A, Butt KM, Rajpoot D, Gonzalez R, Pomrantz A, et al. High-dose cyclosporine therapy in recurrent nephrotic syndrome following renal transplantation. Transplantation. 1990;49(1):219-21.
Schwarz A, Krause PH, Offermann G, Keller F. Recurrent and de novo renal disease after kidney transplantation with or without cyclosporine A. Am J Kidney Dis. 1991;17(5):524-31.
Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med. 2011;3(85):85ra46.
Zhang B, Xie S, Shi W, Yang Y. Amiloride off-target effect inhibits podocyte urokinase receptor expression and reduces proteinuria. Nephrol Dial Transplant. 2012;27(5):1746-55.
Wei C, El Hindi S, Li J, Fornoni A, Goes N, Sageshima J, et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med. 2011;17(8):952-60.
Passero CJ, Mueller GM, Rondon-Berrios H, Tofovic SP, Hughey RP, Kleyman TR. Plasmin activates epithelial Na+ channels by cleaving the gamma subunit. J Biol Chem. 2008;283(52):36586-91.
