Abstract
Minimal change disease (MCD) is the most common type of nephrotic syndrome in children and adolescents. The pathogenesis of proteinuria in this condition is currently being reassessed. Following the Shalhoub hypothesis, most efforts have been placed on identifying the putative circulating factor, but recent advancement in podocyte biology has focused attention on the molecular changes at the glomerular capillary wall, which could explain the mechanism of proteinuria in MCD. This report critically reviews current knowledge on the different postulated mechanisms at the glomerular capillary wall level for increased permeability to plasma proteins in MCD. The report helps describe the rationale behind novel therapies and suggests future targeted therapies for MCD.
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Churg J, Habib R, White HR (1970) Pathology of the nephrotic syndrome in children: A report for the International Study of Kidney Disease in Children. Lancet 760:1299–1302
Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, Egbrink o (2000) The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454:345–359
Kanwar YS, Farquhar MG (1979) Presence of heparan sulfate in the glomerular basement membrane. Proc Natl Acad Sci U S A 76:1300–1307
Nielsen JS, McNagny KM (2009) The role of podocalyxin in health and disease. J Am Soc Nephrol 20:1669–1676
Welsh GI, Saleem MA (2011) The podocyte cytoskeleton--key to a functioning glomerulus in health and disease. Nat Rev Nephrol 8:14–21
Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582
Li X, Chuang PY, D’Agati VD, Dai Y, Yacoub R, Fu J, Xu J, Taku O, Premsrirut PK, Holzman LB, He JC (2015) Nephrin Preserves Podocyte Viability and Glomerular Structure and Function in Adult Kidneys. J Am Soc Nephrol 26:2361–2377
Jones N, New LA, Fortino MA, Eremina V, Ruston J, Blasutig IM, Aoudjit L, Zou Y, Liu X, Yu GL, Takano T, Quaggin SE, Pawson T (2009) Nck proteins maintain the adult glomerular filtration barrier. J Am Soc Nephrol 20:1533–1543
New LA, Keyvani Chahi A, Jones N (2013) Direct regulation of nephrin tyrosine phosphorylation by Nck adaptor proteins. J Biol Chem 288:1500–1510
George B, Verma R, Soofi AA, Garg P, Zhang J, Park TJ, Giardino L, Ryzhova L, Johnstone DB, Wong H, Nihalani D, Salant DJ, Hanks SK, Curran T, Rastaldi MP, Holzman LB (2012) Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest 122:674–692
Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938
Ibraghimov-Beskrovnaya O, Milatovich A, Ozcelik T, Yang B, Koepnick K, Francke U, Campbell KP (1993) Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization. Hum Mol Genet 2:1651–1657
Raats CJ, Van Den Born J, Bakker MA, Oppers-Walgreen B, Pisa BJ, Dijkman HB, Assmann KJ, Berden JH (2000) Expression of agrin, dystroglycan, and utrophin in normal renal tissue and in experimental glomerulopathies. Am J Pathol 156:1749–1765
Ishimoto T, Shimada M, Gabriela G, Kosugi T, Sato W, Lee PY, Lanaspa MA, Rivard C, Maruyama S, Garin EH, Johnson RJ (2013) Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80 in mice. Nephrol Dial Transplant 28:1439–1446
Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, Li J, Mattiazzi A, Ciancio G, Chen L, Zilleruelo G, Abitbol C, Chandar J, Seeherunvong W, Ricordi C, Ikehata M, Rastaldi MP, Reiser J, Burke GW 3rd (2011) Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med 3:85ra46
Xing CY, Saleem MA, Coward RJ, Ni L, Witherden IR, Mathieson PW (2006) Direct effects of dexamethasone on human podocytes. Kidney Int 70:1038–1045
Ohashi T, Uchida K, Uchida S, Sasaki S, Nitta K (2011) Dexamethasone increases the phosphorylation of nephrin in cultured podocytes. Clin Exp Nephrol 15:688–693
Carrie BJ, Salyer WR, Myers BD (1981) Minimal change nephropathy: an electrochemical disorder of the glomerular membrane. Am J Med 70:262–268
Ryan GB, Karnosvsky MJ (1975) An ultrastructural study of the mechanisms of proteinuria in aminonucleoside nephrosis. Kidney Int 8:219–232
Washizawa K, Kasai S, Mori T, Komiyama A, Shigematsu H (1993) Ultrastructural alteration of glomerular anionic sites in nephrotic patients. Pediatr Nephrol 7:1–5
van der Born J, van der Heuval PWJ, Bakker MAH, Veerkamp JH, Assmann KJ, Weening JJ, Berden JH (1993) Distribution of GBM heparan sulfate proteoglycan core protein and side changes in human glomerular diseases. Kidney Int 43:454–463
Mitsuhashi H, Tsukada Y, Ono K, Yano S, Naruse T (1993) Urine glycosaminoglycans and heparan sulfate excretions in adult patients with glomerular diseases. Clin Nephrol 39:231–238
Goldberg S, Harvey JS, Cunningham J, Tryggvason K, Miner JH (2009) Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane. Nephrol Dial Transplant 24:2044–2051
Chen S, Wassenhove-McCarthy DJ, Yamaguchi Y, Holzman LB, van Kuppevelt TH, Jenniskens GJ, Wijnhoven TJ, Woods AC, McCarthy KJ (2008) Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria. Kidney Int 74:289–299
Van Den Hoven MJ, Wijnhoven TJ, Li JP, Zcharia E, Dijkman HB, Wismans RG, Rops AL, Lensen JF, van den Heuvel LP, van Kuppevelt TH, Vlodavsky I, Berden JH, van der Vlag J (2008) Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria. Kidney Int 73:278–287
Clement LC, Avila-Casado C, Macé C, Soria E, Bakker WW, Kersten S, Chugh SS (2011) Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med 17:117–122
Clement LC, Macé C, Avila-Casado C, Joles JA, Kersten S, Chugh SS (2014) Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med 20:37–46
Cara-Fuentes G, Segarra A, Garin EH (2015) CD80 and angiopoietin-like 4 in glomerulopathies (abstract). J Am Soc Nephrol 26:451A
Garin EH, Blanchard DK, Matsushima K, Djeu JY (1994) IL-8 production by peripheral blood mononuclear cells in nephrotic patients. Kidney Int 45:1311–1317
Cho MH, Lee HS, Choe BH, Kwon SH, Chung KY, Koo JH, Ko CW (2003) Interleukin-8 and tumor necrosis factor-alpha are increased in minimal change disease but do not alter albumin permeability. Am J Nephrol 23:260–266
Garin EH, Laflam P, Chandler L (1998) Anti-interleukin 8 antibody abolishes effects of lipoid nephrosis cytokine. Pediatr Nephrol 12:381–385
Garin EH, West L, Zheng W (1997) Effect of interleukin-8 on glomerular sulfated compounds and albuminuria. Pediatr Nephrol 11:274–279
Hvidberg V, Maniecki MB, Jacobsen C, Højrup P, Møller HJ, Moestrup SK (2005) Identification of the receptor scavenging hemopexin-heme complexes. Blood 1:2572–2579
Bakker WW, Baller JF, van Luijk WH (1988) A kallikrein-like molecule and plasma vasoactivity in minimal change disease. Increased turnover in relapse versus remission. Contrib Nephrol 67:31–36
Cheung PK, Klok PA, Bakker WW (1996) Minimal change-like glomerular alterations induced by a human plasma factor. Nephron 74:586–593
Cheung PK, Klok PA, Baller JF, Bakker WW (2000) Induction of experimental proteinuria in vivo following infusion of human plasma hemopexin. Kidney Int 57:1512–1520
Bakker WW, van Dael CM, Pierik LJ, van Wijk JA, Nauta J, Borghuis T, Kapojos JJ (2005) Altered activity of plasma hemopexin in patients with minimal change disease in relapse. Pediatr Nephrol 20:1410–1415
Cheung PK, Stulp B, Immenschuh S, Borghuis T, Baller JF, Bakker WW (1999) Is 100KF an isoform of hemopexin? Immunochemical characterization of the vasoactive plasma factor 100KF. J Am Soc Nephrol 10:1700–1708
Hrkal Z, Kuzelová K, Muller-Eberhard U, Stern R (1996) Hyaluronan-binding properties of human serum hemopexin. FEBS Lett 383:72–74
Bakker WW, Borghuis T, Harmsen MC, van den Berg A, Kema IP, Niezen KE, Kapojos JJ (2005) Protease activity of plasma hemopexin. Kidney Int 68:603–610
Lennon R, Singh A, Welsh GI, Coward RJ, Satchell S, Ni L, Mathieson PW, Bakker WW, Saleem MA (2008) Hemopexin induces nephrin-dependent reorganization of the actin cytoskeleton in podocytes. J Am Soc Nephrol 19:2140–2149
Cheung PK, Baller JF, Bakker WW (1998) Oxygen-dependent injury by a human plasma factor associated with minimal change disease. Pediatr Nephrol 12:452–458
Cheung PK (1996) Plasma factor associated with Minimal Disease. Interactions of 100KF with the glomerular filtration barrier. An experimental study. s.n., 1996. 140 p (Doctorial Thesis).
Kavoura E, Gakiopoulou H, Paraskevakou H, Marinaki S, Agrogiannis G, Stofas A, Boletis I, Patsouris E, Lazaris AC (2011) Immunohistochemical evaluation of podocalyxin expression in glomerulopathies associated with nephrotic syndrome. Hum Pathol 42:227–235
Hara M, Yanagihara T, Takada T, Itoh M, Adachi Y, Yoshizumi A, Kawasaki K, Yamamoto T, Kihara I (1994) Podocalyxin on the glomerular epithelial cells is preserved well in various glomerular diseases. Nephron 67:123–124
Wernerson A, Dunér F, Pettersson E, Widholm SM, Berg U, Ruotsalainen V, Tryggvason K, Hultenby K, Söderberg M (2003) Altered ultrastructural distribution of nephrin in minimal change nephrotic syndrome. Nephrol Dial Transplant 18:70–76
Patrakka J, Ruotsalainen V, Ketola I, Holmberg C, Heikinheimo M, Tryggvason K, Jalanko H (2001) Expression of nephrin in pediatric kidney diseases. J Am Soc Nephrol 12:289–296
Furness PN, Hall LL, Shaw JA, Pringle JH (1999) Glomerular expression of nephrin is decreased in acquired human nephrotic syndrome. Nephrol Dial Transplant 14:1234–1237
Doublier S, Ruotsalainen V, Salvidio G, Lupia E, Biancone L, Conaldi PG, Reponen P, Tryggvason K, Camussi G (2001) Nephrin redistribution on podocytes is a potential mechanism for proteinuria in patients with primary acquired nephrotic syndrome. Am J Pathol 158:1723–1731
Uchida K, Suzuki K, Iwamoto M, Kawachi H, Ohno M, Horita S, Nitta K (2008) Decreased tyrosine phosphorylation of nephrin in rat and human nephrosis. Kidney Int 73:926–932
Cara-Fuentes G, Garin EH (2014) Nephrin phosphorylation in MCD (abstract). J Am Soc Nephrol 25:738A
Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, Rastaldi MP, Calvaresi N, Watanabe H, Schwarz K, Faul C, Kretzler M, Davidson A, Sugimoto H, Kalluri R, Sharpe AH, Kreidberg JA, Mundel P (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113:1390–1397
Garin EH, Diaz LN, Mu W, Wasserfall C, Araya C, Segal M, Johnson RJ (2009) Urinary CD80 excretion increases in idiopathic minimal-change disease. J Am Soc Nephrol 20:260–266
Garin EH, Mu W, Arthur JM, Rivard CJ, Araya CE, Shimada M, Johnson RJ (2010) Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis. Kidney Int 78:296–302
Lai KW, Wei CL, Tan LK, Tan PH, Chiang GS, Lee CG, Jordan SC, Yap HK (2007) Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J Am Soc Nephrol 18:1476–1485
Ishimoto T, Cara-Fuentes G, Wang H, Shimada M, Wasserfall CH, Winter WE, Rivard CJ, Araya CE, Saleem MA, Mathieson PW, Johnson RJ, Garin EH (2013) Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes. Pediatr Nephrol 28:1803–1812
Kanai T, Shiraishi H, Yamagata T, Ito T, Odaka J, Saito T, Aoyagi J, Momoi MY (2010) Th2 cells predominate in idiopathic steroid-sensitive nephrotic syndrome. Clin Exp Nephrol 14:578–583
Shimada M, Ishimoto T, Lee PY, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Wymer DT, Yamabe H, Mathieson PW, Saleem MA, Garin EH, Johnson RJ (2012) Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway. Nephrol Dial Transplant 27:81–89
Srivastava T, Sharma M, Yew KH, Sharma R, Duncan RS, Saleem MA, McCarthy ET, Kats A, Cudmore PA, Alon US, Harrison CJ (2013) LPS and PAN-induced podocyte injury in an in vitro model of minimal change disease: changes in TLR profile. J Cell Commun Signal 7:49–60
MacDonald NE, Wolfish N, McLaine P, Phipps P, Rossier E (1986) Role of respiratory viruses in exacerbations of primary nephrotic syndrome. J Pediatr 108:378–382
Zhang SY, Kamal M, Dahan K, Pawlak A, Ory V, Desvaux D, Audard V, Candelier M, BenMohamed F, Matignon M, Christov C, Decrouy X, Bernard V, Mangiapan G, Lang P, Guellaën G, Ronco P, Sahali D (2010) c-mip impairs podocyte proximal signaling and induces heavy proteinuria. Sci Signal 3:ra39
Audard V, Zhang SY, Copie-Bergman C, Rucker-Martin C, Ory V, Candelier M, Baia M, Lang P, Pawlak A, Sahali D (2010) Occurrence of minimal change nephrotic syndrome in classical Hodgkin lymphoma is closely related to the induction of c-mip in Hodgkin-Reed Sternberg cells and podocytes. Blood 115:3756–3762
Denhez B, Lizotte F, Guimond MO, Jones N, Takano T, Geraldes P (2015) Increased SHP-1 protein expression by high glucose levels reduces nephrin phosphorylation in podocytes. J Biol Chem 290:350–358
Camby I, Le Mercier M, Lefranc F, Kiss R (2006) Galectin-1: a small protein with major functions. Glycobiology 16:137R–157R
Shimizu M, Khoshnoodi J, Akimoto Y, Kawakami H, Hirano H, Higashihara E, Hosoyamada M, Sekine Y, Kurayama R, Kurayama H, Joh K, Hirabayashi J, Kasai K, Tryggvason K, Ito N, Yan K (2009) Expression of galectin-1, a new component of slit diaphragm, is altered in minimal change nephrotic syndrome. Lab Invest 89:178–195
Ostalska-Nowicka D, Zachwieja J, Nowicki M, Kaczmarek E, Siwińska A, Witt M (2007) Immunohistochemical detection of galectin-1 in renal biopsy specimens of children and its possible role in proteinuric glomerulopathies. Histopathology 51:468–476
Srivastava T, Garola RE, Whiting JM, Alon US (2001) Synaptopodin expression in idiopathic nephrotic syndrome of childhood. Kidney Int 59:118–125
Barisoni L, Kriz W, Mundel P, D’Agati V (1999) The dysregulated podocyte A novel concept in the pathogenesis of collapsing idiopathic focal segmental glomerulosclerosis and HIV-associated nephropathy. J Am Soc Nephrol 10:51–61
Horinouchi I, Nakazato H, Kawano T, Iyama K, Furuse A, Arizono K, Machida J, Sakamoto T, Endo F, Hattori S (2003) In situ evaluation of podocin in normal and glomerular diseases. Kidney Int 64:2092–2099
Guan N, Ding J, Zhang J, Yang J (2003) Expression of nephrin, podocin, alpha-actinin, and WT1 in children with nephrotic syndrome. Pediatr Nephrol 18:1122–1127
Vogtländer NP, van der Vlag J, Bakker MA, Dijkman HB, Wevers RA, Campbell KP, Wetzels JF, Berden JH (2010) Expression of sialidase and dystroglycan in human glomerular diseases. Nephrol Dial Transplant 25:478–484
Regele HM, Fillipovic E, Langer B, Poczewki H, Kraxberger I, Bittner RE, Kerjaschki D (2000) Glomerular expression of dystroglycans is reduced in minimal change nephrosis but not in focal segmental glomerulosclerosis. J Am Soc Nephrol 11:403–412
Kojima K, Nosaka H, Kishimoto NY, Fukuda S, Shimada M, Kodaka K, Saito F, Matsumura K, Shimizu T, Toda T, Takeda S, Kawachi H, Uchida S (2011) Defective glycosylation of α-dystroglycan contributes to podocyte flattening. Kidney Int 79:311–316
Bains R, Furness PN, Critchley DR (1997) A quantitative immunofluorescence study of glomerular cell adhesion proteins in proteinuric states. J Pathol 183:272–280
Baraldi A, Furci L, Zambruno G, Rubbiani E, Annessi G, Lusvarghi E (1992) Very late activation-3 integrin is the dominant beta 1-integrin on the glomerular capillary wall: an immunofluorescence study in nephrotic syndrome. Nephron 62:382–388
Lahdenkari AT, Lounatmaa K, Patrakka J, Holmberg C, Wartiovaara J, Kestilä M, Koskimies O, Jalanko H (2004) Podocytes are firmly attached to glomerular basement membrane in kidneys with heavy proteinuria. J Am Soc Nephrol 15:2611–2618
Tejani AT, Butt K, Trachtman H, Suthanthiran M, Rosenthal CJ, Khawar MR (1988) Cyclosporine A induced remission of relapsing nephrotic syndrome in children. Kidney Int 33:729–734
Hauser PV, Pippin JW, Kaiser C, Krofft RD, Brinkkoetter PT, Hudkins KL, Kerjaschki D, Reiser J, Alpers CE, Shankland SJ (2010) Novel siRNA delivery system to target podocytes in vivo. PLoS One 5:e9463
Cara-Fuentes G, Wasserfall CH, Wang H, Johnson RJ, Garin EH (2014) Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? Pediatr Nephrol 29:2333–2340
Garin EH, Reiser J, Cara-Fuentes G, Wei C, Matar D, Wang H, Alachkar N, Johnson RJ (2015) Case series: CTLA4-IgG1 therapy in minimal change disease and focal segmental glomerulosclerosis. Pediatr Nephrol 30:469–477
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Cara-Fuentes, G., Clapp, W.L., Johnson, R.J. et al. Pathogenesis of proteinuria in idiopathic minimal change disease: molecular mechanisms. Pediatr Nephrol 31, 2179–2189 (2016). https://doi.org/10.1007/s00467-016-3379-4
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DOI: https://doi.org/10.1007/s00467-016-3379-4