Fig. 13.1
Signalling pathways targeted by different drugs in podocytes. The glomerular capillary wall comprises of three components: glomerular endothelial cells, GBM (glomerular basement membrane) and podocytes. With its unique properties and importance for maintaining the function of the glomerular filtration barrier, the podocyte has been suggested as a promising target for future specific therapies for proteinuric disease. Drugs that are currently used in the treatment of idiopathic nephrotic syndrome have been shown to exert direct effects on podocytes via different mechanisms: (1) Induction of CD80 results in disruption of SD complex. Blocking of this pathway may be involved in the protective effects of glucocorticoids (GCs), abatacept and levamisole on podocytes. By binding to CD80, abatacept reduces proteinuria likely by stabilising β1-integrin activation in podocytes. GCs act through binding to GR (glucocorticoid receptor). This receptor is also suggested to be involved in the actions of levamisole on podocytes. (2) Phosphorylation of Akt is decreased in podocyte injury. GCs and levamisole can restore Akt phosphorylation to promote podocyte survival. (3) ROS is another factor causing podocyte injury and apoptosis. GCs prevent podocyte apoptosis by reducing ROS, decreasing p53 expression and increasing Bcl-xL expression. Expression and translocation of AIF (apoptosis-inducing factor) can be blocked by both GCs and levamisole. (4) GTPase RhoA is a key regulator of actin cytoskeleton. This pathway has been shown to be targeted by GCs and by mTOR inhibitor everolimus and to be involved in their effects of stabilising podocyte actin cytoskeleton. (5) Expression and phosphorylation of nephrin is critical for maintaining the integrity and function of SD complex. GCs can increase nephrin expression. They also increase phosphorylation of nephrin via regulation of Nck and Fyn pathway. (6) Synaptopodin is an actin-associated podocyte protein and can be dephosphorylated by calcineurin activation resulting in cleavage and degradation mediated by Cat L (cathepsin L), which can be blocked by calcineurin inhibitor cyclosporin. When calcineurin is blocked, phosphorylated synaptopodin binds to 14-3-3 protein and is subsequently protected from degradation. Calcineurin activation could be caused by TRPC6 (transient potential cation channel 6)-mediated calcium influx. (7) Changes in distribution or expression of tight junction protein ZO-1 (zonula occludens-1) in podocytes are associated with proteinuria. Cyclosporin shows a stabilising effect on ZO-1 expression which is thought to be likely an indirect effect from stabilisation of synaptopodin. (8) Rituximab has been shown to be able to preserve the podocyte actin cytoskeleton and prevent apoptosis by binding and stabilising SMPDL-3b (sphingomyelin phosphodiesterase acid-like 3b) protein in podocytes. (9) Mizoribine promotes podocyte survival by inhibiting activation of ILK (integrin-linked kinase) and phosphorylation of GSK3β (glycogen synthase kinase-3β). The signalling pathways or molecules shown above may represent targets for future podocyte-specific therapies
References
1.
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;17:117–22.PubMedCentralPubMed
2.
Yu-Shengyou, Li Y. Dexamethasone inhibits podocyte apoptosis by stabilizing the PI3K/Akt signal pathway. Biomed Res Int. 2013;2013:326986.PubMedCentralPubMed
3.
Reiser J, Von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, et al. Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. 2004;113:1390–7.PubMedCentralPubMed
4.
Túri S, Németh I, Torkos A, Sághy L, Varga I, Matkovics B, et al. Oxidative stress and antioxidant defense mechanism in glomerular diseases. Free Radic Biol Med. 1997;22:161–8.PubMed
5.
Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74:299–323.PubMedCentralPubMed
6.
Somlo S, Mundel P. Getting a foothold in nephrotic syndrome. Nat Genet. 2000;24:333–5.PubMed
7.
Wada T, Pippin JW, Marshall CB, Griffin SV, Shankland SJ. Dexamethasone prevents podocyte apoptosis induced by puromycin aminonucleoside: role of p53 and Bcl-2-related family proteins. J Am Soc Nephrol. 2005;16:2615–25.PubMed
8.
Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Sekizuka K, et al. Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy. Am J Nephrol. 2000;20:373–9.PubMed
9.
Hara M, Yanagihara T, Kihara I. Urinary podocytes in primary focal segmental glomerulosclerosis. Nephron. 2001;89:342–7.PubMed
10.
Shankland SJ, Floege J, Thomas SE, Nangaku M, Hugo C, Pippin J, et al. Cyclin kinase inhibitors are increased during experimental membranous nephropathy: potential role in limiting glomerular epithelial cell proliferation in vivo. Kidney Int. 1997;52:404–13.PubMed
11.
Kestilä M, Lenkkeri U, Männikkö M, Lamerdin J, McCready P, Putaala H, et al. Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell. 1998;1:575–82.PubMed
12.
Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet. 2000;24:349–54.PubMed
13.
Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, et al. Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science. 1999;286:312–5.PubMed
14.
Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. 2000;24:251–6.PubMed
15.
Fiorina P, Vergani A, Bassi R, Niewczas MA, Altintas MM, Pezzolesi MG, et al. Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol. 2014;25:1415–29.PubMedCentralPubMed
16.
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;78:296–302.PubMed
17.
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;20:260–6.PubMedCentralPubMed
18.
Cara-Fuentes G, Wasserfall CH, Wang H, Johnson RJ, Garin EH. Minimal change disease: a dysregulation of the podocyte CD80-CTLA-4 axis? Pediatr Nephrol. 2014;29:2333–40.PubMed
19.
Kinra S, Rath B, Kabi BC. Indirect quantification of lipid peroxidation in steroid responsive nephrotic syndrome. Arch Dis Child. 2000;82:76–8.PubMedCentralPubMed
20.
Walker PD, Shah SV. Evidence suggesting a role for hydroxyl radical in gentamicin-induced acute renal failure in rats. J Clin Invest. 1988;81:334–41.PubMedCentralPubMed
21.
Raats CJI, Bakker MAH, Van Den Born J, Berden JHM. Hydroxyl radicals depolymerize glomerular heparan sulfate in vitro and in experimental nephrotic syndrome. J Biol Chem. 1997;272:26734–41.PubMed
22.
Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. J Am Soc Nephrol. 2007;18:16–28.PubMed
23.
Ichikawa I, Fogo A. Reactive oxygen metabolites cause massive, reversible proteinuria and glomerular sieving defect without apparent ultrastructural abnormality. J Am Soc Nephrol. 1991;2:902–12.PubMed
24.
Chen S, Meng XF, Zhang C. Role of NADPH oxidase-mediated reactive oxygen species in podocyte injury. Biomed Res Int. 2013;2013:839761.PubMedCentralPubMed
25.
Ricardo D, Bertram F, Ryan B, Bertram JF. Antioxidants protect podocyte foot processes in puromycin aminonucleoside-treated rats. J Am Soc Nephrol. 1994;4:1974–86.PubMed
26.
Kojima K, Matsui K, Nagase M. Protection of α3 integrin-mediated podocyte shape by superoxide dismutase in the puromycin aminonucleoside nephrosis rat. Am J Kidney Dis. 2015;35:1175–85.
27.
Kawamura T, Yoshioka T, Bills T, Fogo A, Ichikawa I. Glucocorticoid activates glomerular antioxidant enzymes and protects glomeruli from oxidant injuries. Kidney Int. 1991;40:291–301.PubMed
28.
Yamaguchi H, Wang HG. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene. 2001;20:7779–86.PubMed
29.
Jiang L, Dasgupta I, Hurcombe JA, Colyer HF, Mathieson PW, Welsh GI. Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte. Clin Sci. 2015;128:883–93.PubMed
30.
Xiao H, Shi W, Liu S, Wang W, Zhang B, Zhang Y, et al. 1,25-dihydroxyvitamin D3 prevents puromycin aminonucleoside-induced apoptosis of glomerular podocytes by activating the phosphatidylinositol 3-kinase/Akt-signaling pathway. Am J Nephrol. 2009;30:34–43.PubMed
31.
Xing C, Saleem MA, Coward RJ, Ni L, Witherden IR, Mathieson PW. Direct effects of dexamethasone on human podocytes. Kidney Int. 2006;70:1038–45.PubMed
32.
Ransom RF, Lam NG, Hallett MA, Atkinson SJ, Smoyer WE. Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilization. Kidney Int. 2005;68:2473–83.PubMed
33.
Guess A, Agrawal S, Wei C-C, Ransom RF, Benndorf R, Smoyer WE. Dose- and time-dependent glucocorticoid receptor signaling in podocytes. Am J Physiol Renal Physiol. 2010;299:F845–53.PubMedCentralPubMed
34.
Liu H, Gao XIA, Xu H, Feng C, Kuang X, Li Z, et al. α -actinin-4 is involved in the process by which dexamethasone protects actin cytoskeleton stabilization from adriamycin-induced podocyte injury. Nephrology. 2012;17:669–75.PubMed
35.
Mathieson PW. The podocyte as a target for therapies – new and old. Nat Rev Nephrol. 2011;8:52–6.PubMed
36.
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;14:931–8.PubMedCentralPubMed
37.
Chan AC. Rituximab’s new therapeutic target: the podocyte actin cytoskeleton. Sci Transl Med. 2011;3:85ps21.PubMed
38.
Hlatky M. Is renal biopsy necessary in adults with nephrotic syndrome? Lancet. 1982;320:1264–8.
39.
Gupta BBP, Lalchhandama K. Molecular mechanisms of glucocorticoid action. Curr Sci. 2002;83:1103–11.
40.
Yan K, Kudo A, Hirano H, Watanabe T, Tasaka T, Kataoka S, et al. Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus. Kidney Int. 1999;56:65–73.PubMed
41.
Ransom RF, Vega-Warner V, Smoyer WE, Klein J. Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes. Kidney Int. 2005;67:1275–85.PubMed
42.
Agrawal S, Guess AJ, Chanley MA, Smoyer WE. Albumin-induced podocyte injury and protection are associated with regulation of COX-2. Kidney Int. 2014;86:1153–63.
43.
Agrawal S, Guess AJ, Benndorf R, Smoyer WE. Comparison of direct action of thiazolidinediones and glucocorticoids on renal podocytes: protection from injury and molecular effects. Mol Pharmacol. 2011;80:389–99.PubMedCentralPubMed
44.
Bertram JF, Messina A, Ryan GB. In vitro effects of puromycin aminonucleoside on the ultrastructure of rat glomerular podocytes. Cell Tissue Res. 1990;260:555–63.PubMed
45.
Messina A, Davies DJ, Dillane PC, Ryan GB. Glomerular epithelial abnormalities associated with the onset of proteinuria in aminonucleoside nephrosis. Am J Pathol. 1987;126:220–9.PubMedCentralPubMed
46.
Whiteside CI, Cameron R, Munk S, Levy J. Podocytic cytoskeletal disaggregation and basement-membrane detachment in puromycin aminonucleoside nephrosis. Am J Pathol. 1993;142:1641–53.PubMedCentralPubMed
47.
Löwenborg EK, Jaremko G, Berg UB. Glomerular function and morphology in puromycin aminonucleoside nephropathy in rats. Nephrol Dial Transplant. 2000;15:1547–55.PubMed
48.
Wada T, Pippin JW, Nangaku M, Shankland SJ. Dexamethasone’s prosurvival benefits in podocytes require extracellular signal-regulated kinase phosphorylation. Nephron Exp Nephrol. 2008;109:e8–19.PubMed
49.
Björnson Granqvist A, Ebefors K, Saleem MA, Mathieson PW, Haraldsson B, Nyström JS. Podocyte proteoglycan synthesis is involved in the development of nephrotic syndrome. Am J Physiol Renal Physiol. 2006;291:F722–30.PubMed
50.
Shimada M, Ishimoto T, Lee PY, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, et al. Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF-κB-dependent pathway. Nephrol Dial Transplant. 2012;27:81–9.PubMed
51.
Xing Y, Ding J, Fan Q, Guan N. Diversities of podocyte molecular changes induced by different antiproteinuria drugs. Exp Biol Med. 2006;231:585–93.
52.
Li X, Yuan H, Zhang X. Adriamycin increases podocyte permeability: evidence and molecular mechanism. Chin Med J (Engl). 2003;116:1831–5.
53.
Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, et al. Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest. 2001;108:1621–9.PubMedCentralPubMed
54.
Liu G, Kaw B, Kurfis J, Rahmanuddin S, Kanwar YS, Chugh SS. Neph1 and nephrin interaction in the slit diaphragm is an important determinant of glomerular permeability. J Clin Invest. 2003;112:209–21.PubMedCentralPubMed
55.
Yamauchi K, Takano Y, Kasai A, Hayakawa K, Hiramatsu N, Enomoto N, et al. Screening and identification of substances that regulate nephrin gene expression using engineered reporter podocytes. Kidney Int. 2006;70:892–900.PubMed
56.
Lehtonen S. Connecting the interpodocyte slit diaphragm and actin dynamics: emerging role for the nephrin signaling complex. Kidney Int. 2008;73:903–5.PubMed
57.
Zhang Y, Yoshida Y, Nameta M, Xu B, Taguchi I, Ikeda T, et al. Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphorylated in the normal rat kidney. Nephrol Dial Transplant. 2010;25:1785–95.PubMed
58.
Uchida K, Suzuki K, Iwamoto M, Kawachi H, Ohno M, Horita S, et al. Decreased tyrosine phosphorylation of nephrin in rat and human nephrosis. Kidney Int. 2008;73:926–32.PubMed
59.
Ohashi T, Uchida K, Uchida S, Sasaki S, Nitta K. Dexamethasone increases the phosphorylation of nephrin in cultured podocytes. Clin Exp Nephrol. 2011;15:688–93.PubMed
60.
Yu M, Ren Q, Yu SY. Role of nephrin phosphorylation inducted by dexamethasone and angiotensin II in podocytes. Mol Biol Rep. 2014;41:3591–5.PubMed
61.
Fujii Y, Khoshnoodi J, Takenaka H, Hosoyamada M, Nakajo A, Bessho F, et al. The effect of dexamethasone on defective nephrin transport caused by ER stress: a potential mechanism for the therapeutic action of glucocorticoids in the acquired glomerular diseases. Kidney Int. 2006;69:1350–9.PubMed
62.
Zhang J, Pippin JW, Krofft RD, Naito S, Liu Z-H, Shankland SJ. Podocyte repopulation by renal progenitor cells following glucocorticoids treatment in experimental FSGS. Am J Physiol Renal Physiol. 2013;304:F1375–89.PubMedCentralPubMed
63.
Aramburu J, Heitman J, Crabtree GR. Calcineurin: a central controller of signalling in eukaryotes. EMBO Rep. 2004;5:343–8.PubMedCentralPubMed
64.
Fornoni A, Li H, Foschi A, Striker GE, Striker LJ. Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis. Am J Pathol. 2001;158:275–80.PubMedCentralPubMed
65.
Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37:739–44.PubMedCentralPubMed
66.
Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308:1801–4.PubMed
67.
Möller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. 2007;18:29–36.PubMed
68.
Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nürnberg G, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38:1397–405.PubMed
69.
Mukerji N, Damodaran TV, Winn MP. TRPC6 and FSGS: the latest TRP channelopathy. Biochim Biophys Acta. 2007;1772:859–68.PubMed
70.
Vassiliadis J, Bracken C, Matthews D, O’Brien S, Schiavi S, Wawersik S. Calcium mediates glomerular filtration through calcineurin and mTORC2/Akt signaling. J Am Soc Nephrol. 2011;22:1453–61.PubMedCentralPubMed
71.
Kurihara H, Anderson JM, Kerjaschki D, Farquhar MG. The altered glomerular filtration slits seen in puromycin aminonucleoside nephrosis and protamine sulfate-treated rats contain the tight junction protein ZO-1. Am J Pathol. 1992;141:805–16.PubMedCentralPubMed
72.
Kawachi H, Kurihara H, Topham PS, Brown D, Shia MA, Orikasa M, et al. Slit diaphragm-reactive nephritogenic MAb 5-1-6 alters expression of ZO-1 in rat podocytes. Am J Physiol. 1997;273:F984–93.PubMed
73.
Kim BS, Park HC, Kang SW, Choi KH, Ha SK, Han DS, et al. Impact of cyclosporin on podocyte ZO-1 expression in puromycin aminonucleoside nephrosis rats. Yonsei Med J. 2005;46:141–8.PubMedCentralPubMed
74.
Stefanidis CJ, Querfeld U. The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations. Eur J Pediatr. 2011;170:1377–83.PubMed
75.
Bensman A, Niaudet P. Non-immunologic mechanisms of calcineurin inhibitors explain its antiproteinuric effects in genetic glomerulopathies. Pediatr Nephrol. 2010;25:1197–9.PubMed
76.
Charbit M, Gubler MC, Dechaux M, Gagnadoux MF, Grünfeld JP, Niaudet P. Cyclosporin therapy in patients with Alport syndrome. Pediatr Nephrol. 2007;22:57–63.PubMed
77.
Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, et al. Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model. J Am Soc Nephrol. 2003;14:690–8.PubMed
78.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–101.PubMed
79.
Senior PA, Paty BW, Cockfield SM, Ryan EA, Shapiro AM. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant. 2005;5:2318–23.PubMed
80.
Aliabadi AZ, Pohanka E, Seebacher G, Dunkler D, Kammerstätter D, Wolner E, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant. 2008;8:854–61.PubMed
81.
Hochegger K, Wurz E, Nachbaur D, Rosenkranz AR, Clausen J. Rapamycin-induced proteinuria following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2009;44:63–5.PubMed
82.
Torras J, Herrero-Fresneda I, Gulias O, Flaquer M, Vidal A, Cruzado JM, et al. Rapamycin has dual opposing effects on proteinuric experimental nephropathies: is it a matter of podocyte damage. Nephrol Dial Transplant. 2009;24:3632–40.PubMed
83.
Biancone L, Bussolati B, Mazzucco G, Barreca A, Gallo E, Rossetti M, et al. Loss of nephrin expression in glomeruli of kidney-transplanted patients under m-TOR inhibitor therapy. Am J Transplant. 2010;10:2270–8.PubMed
84.
Müller-Krebs S, Weber L, Tsobaneli J, Kihm LP, Reiser J, Zeier M, et al. Cellular effects of everolimus and sirolimus on podocytes. PLoS One. 2013;8:1–13.
85.
Vollenbröker B, George B, Wolfgart M, Wolfgart M, Saleem MA, Pavenstädt H, Weide T. mTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes. Am J Physiol Renal Physiol. 2009;296:F418–26.PubMed
86.
Letavernier E, Bruneval P, Vandermeersch S, Perez J, Mandet C, Belair MF, et al. Sirolimus interacts with pathways essential for podocyte integrity. Nephrol Dial Transplant. 2009;24:630–8.PubMed
87.
Hartleben B, Gödel M, Meyer-Schwesinger C, Liu S, Ulrich T, Köbler S, et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120:1084–96.PubMedCentralPubMed
88.
Cina DP, Onay T, Paltoo A, Li C, Maezawa Y, De Arteaga J, et al. Inhibition of MTOR disrupts autophagic flux in podocytes. J Am Soc Nephrol. 2012;23:412–20.PubMedCentralPubMed
89.
Wu L, Feng Z, Cui S, Hou K, Tang L, Zhou J, et al. Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway resulting in reduced podocyte injury. PLoS One. 2013;8:e63799.PubMedCentralPubMed
90.
Baas MC, Kers J, Florquin S, De Fijter JW, van der Heide JJ, van den Bergh Weerman MA, et al. Cyclosporine versus everolimus: effects on the glomerulus. Clin Transplant. 2013;27:535–40.PubMed
91.
Jeruschke S, Büscher AK, Oh J, Saleem MA, Hoyer PF, Weber S, et al. Protective effects of the mTOR inhibitor everolimus on cytoskeletal injury in human podocytes are mediated by RhoA signaling. PLoS One. 2013;8:e55980.PubMedCentralPubMed
92.
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;20:1660–3.PubMed
93.
Gilbert RD, Hulse E, Rigden S. Rituximab therapy for steroid-dependent minimal change nephrotic syndrome. Pediatr Nephrol. 2006;21:1698–700.PubMed
94.
Munyentwali H, Bouachi K, Audard V, Remy P, Lang P, Mojaat R, et al. Rituximab is an efficient and safe treatment in adults with steroid-dependent minimal change disease. Kidney Int. 2013;83:511–6.PubMed
95.
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;3:85ra46.PubMedCentralPubMed
96.
Yu C-C, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, et al. Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. 2013;369:2416–23.PubMedCentralPubMed
97.
Moertel CG, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990;322:352–8.PubMed
98.
Elmas AT, Tabel Y, Elmas ÖN. Short- and long-term efficacy of levamisole in children with steroid-sensitive nephrotic syndrome. Int Urol Nephrol. 2013;45:1047–55.PubMed
99.
Hodson EM, Willis NS, Craig JC. Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev. 2008;1, CD002290.PubMed
100.
Hodson EM, Craig JC, Willis NS. Evidence-based management of steroid-sensitive nephrotic syndrome. Pediatr Nephrol. 2005;20:1523–30.PubMed
101.
Levamisole for childhood nephrotic syndrome. Lancet. 1991;337:1574.
102.
Davin JC, Merkus MP. Levamisole in steroid-sensitive nephrotic syndrome of childhood: the lost paradise? Pediatr Nephrol. 2005;20:10–4.PubMed
103.
Yoshioka K, Ohashi Y, Sakai T, Ito H, Yoshikawa N, Nakamura H, et al. A multicenter trial of mizoribine compared with placebo in children with frequently relapsing nephrotic syndrome. Kidney Int. 2000;58:317–24.PubMed
104.
Tanaka H, Aizawa T, Watanabe S, Oki E, Tsuruga K, Imaizumi T. Efficacy of mizoribine-tacrolimus-based induction therapy for pediatric lupus nephritis. Lupus. 2014;23:813–8.PubMed
105.
Ichinose K, Origuchi T, Kawashiri S, Iwamoto N, Fujikawa K, Aramaki T, et al. Efficacy and safety of mizoribine by one single dose administration for patients with rheumatoid arthritis. Intern Med. 2010;49:2211–8.PubMed
106.
Rokutanda R, Kishimoto M, Ohde S, Shimizu H, Nomura A, Suyama Y, et al. Safety and efficacy of mizoribine in patients with connective tissue diseases other than rheumatoid arthritis. Rheumatol Int. 2014;34:59–62.PubMed
107.
Mitchell BS, Dayton JS, Turka LA, Thompson CB. IMP dehydrogenase inhibitors as immunomodulators. Ann N Y Acad Sci. 1993;685:217–24.PubMed
108.
Nakajo A, Khoshnoodi J, Takenaka H, Hagiwara E, Watanabe T, Kawakami H, et al. Mizoribine corrects defective nephrin biogenesis by restoring intracellular energy balance. J Am Soc Nephrol. 2007;18:2554–64.PubMed
109.
Takeuchi S, Hiromura K, Tomioka M, Takahashi S, Sakairi T, Maeshima A, et al. The immunosuppressive drug mizoribine directly prevents podocyte injury in puromycin aminonucleoside nephrosis. Nephron Exp Nephrol. 2010;116:e3–10.PubMed