Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.
The introduction of biologics that are safer and less toxic than conventional immunosuppressive therapies has markedly improved patient outcomes for many common autoimmune diseases
Good evidence suggests that many biologics will be effective in autoimmune renal diseases, but their development and introduction into clinical practice has been remarkably slow
Clinical and basic research is required to define the dominant disease-promoting molecules that underlie autoimmune renal diseases and could be targeted by current and evolving biologics
An increase in the size of patient cohorts and the assembly of clinician networks will facilitate the design and execution of multicentre, multinational, randomized controlled trials for new biologics
A strategic approach must be adopted to define the appropriate patient subgroups that will help prioritize which biologics should be tested, based on the available evidence of likely efficacy
AbstractBiological therapeutics (biologics) that target autoimmune responses and inflammatory injury pathways have a marked beneficial impact on the management of many chronic diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease, and ankylosing spondylitis. Accumulating data suggest that a growing number of renal diseases result from autoimmune injury 鈥?including lupus nephritis, IgA nephropathy, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, autoimmune (formerly idiopathic) membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and C3 nephropathy 鈥?and one can speculate that biologics might also be applicable to these diseases. As many autoimmune renal diseases are relatively uncommon, with long natural histories and diverse outcomes, clinical trials that aim to validate potentially useful biologics are difficult to design and/or perform. Some excellent consortia are undertaking cohort studies and clinical trials, but more multicentre international collaborations are needed to advance the introduction of new biologics to patients with autoimmune renal disorders. This Review discusses the key molecules that direct injurious inflammation and the biologics that are available to modulate them. The opportunities and challenges for the introduction of relevant biologics into treatment protocols for autoimmune renal diseases are also discussed.
Subscription info for Chinese customers
We have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.
Go to naturechina.comRent or Buy article
Get time limited or full article access on ReadCube.
from$8.99
Rent or BuyAll prices are NET prices.
References1Furst, D. E. et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann. Rheum. Dis. 72 (Suppl. 2), ii2鈥搃i34 (2013).
CASPubMed Google Scholar2Couser, W. G. Basic and translational concepts of immune-mediated glomerular diseases. J. Am. Soc. Nephrol. 23, 381鈥?99 (2012).
CASPubMed Google Scholar3McInnes, I. B. Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205鈥?219 (2011).
CASPubMed Google Scholar4Couser, W. G. Johnson, R. J. The etiology of glomerulonephritis: roles of infection and autoimmunity. Kidney Int. 86, 905鈥?14 (2014).
CASPubMed Google Scholar5Yeo, S. C. Liew, A. Biologic agents in the treatment of glomerulonephritides. Nephrology (Carlton) 20, 767鈥?87 (2015).
Google Scholar6Naik, A. et al. Complement regulation in renal disease models. Semin.. Nephrol. 33, 575鈥?85 (2013).
CASPubMedPubMed Central Google Scholar7Emancipator, S. N. Animal models of IgA nephropathy. Curr. Protoc. Immunol. 15, 15.11 (2001).
Google Scholar8Du, Y., Sanam, S., Kate, K. Mohan, C. Animal models of lupus and lupus nephritis. Curr. Pharm. Des. 21, 2320鈥?349 (2015).
CASPubMed Google Scholar9Borza, D. B. et al. Mouse models of membranous nephropathy: the road less travelled by. Am. J. Clin. Exp. Immunol. 2, 135鈥?45 (2013).
PubMedPubMed Central Google Scholar10Ooi, J. D., Gan, P. Y., Odobasic, D., Holdsworth, S. R. Kitching, A. R. T cell mediated autoimmune glomerular disease in mice. Curr. Protoc. Immunol. 107, 15.27.1鈥?5.27.19 (2014).
Google Scholar11Odobasic, D., Ghali, J. R., O\'Sullivan, K. M., Holdsworth, S. R. Kitching, A. R. Glomerulonephritis induced by heterologous anti-GBM globulin as a planted foreign antigen. Curr. Protoc. Immunol. 106, 15.26.1鈥?5.26.20 (2014).
Google Scholar12Gutcher, I. Becher, B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest. 117, 1119鈥?127 (2007).
CASPubMedPubMed Central Google Scholar13Holdsworth, S. R., Kitching, A. R. Tipping, P. G. Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis. Kidney Int. 55, 1198鈥?216 (1999).
CASPubMed Google Scholar14Kitching, A. R. Holdsworth, S. R. The emergence of Th17 cells as effectors of renal injury. J. Am. Soc. Nephrol. 22, 235鈥?38 (2011).
CASPubMed Google Scholar15Browning, J. L. B cells move to centre stage: novel opportunities for autoimmune disease treatment. Nat. Rev. Drug Discov. 5, 564鈥?76 (2006).
CASPubMed Google Scholar16Dorner, T. et al. Current status on B-cell depletion therapy in autoimmune diseases other than rheumatoid arthritis. Autoimmun. Rev. 9, 82鈥?9 (2009).
PubMed Google Scholar17Iwata, Y. et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 117, 530鈥?41 (2011).
CASPubMedPubMed Central Google Scholar18Janeway, C. A., Travers, P., Walport, M. Schlomchick, M. J. Immunobiology: The immune System in Health and Disease 5th edn (Garland Science, 2001).
Google Scholar19Tipping, P. G. Holdsworth, S. R. Cytokines in glomerulonephritis. Semin. Nephrol. 27, 275鈥?85 (2007).
CASPubMed Google Scholar20Polman, C. H. et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899鈥?10 (2006).
CASPubMed Google Scholar21Rudick, R. A. et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N. Engl. J. Med. 354, 911鈥?23 (2006).
CASPubMed Google Scholar22Deshmane, S. L., Kremlev, S., Amini, S. Sawaya, B. E. Monocyte chemoattractant protein-1 (MCP-1): an overview. J. Interferon Cytokine Res. 29, 313鈥?26 (2009).
CASPubMedPubMed Central Google Scholar23Kalinowska, A. Losy, J. Investigational C-C chemokine receptor 2 antagonists for the treatment of autoimmune diseases. Expert Opin. Investig. Drugs 17, 1267鈥?279 (2008).
CASPubMed Google Scholar24Brodmerkel, C. M. et al. Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344. J. Immunol. 175, 5370鈥?378 (2005).
CASPubMed Google Scholar25Kulkarni, O. et al. Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J. Am. Soc. Nephrol. 18, 2350鈥?358 (2007).
CASPubMed Google Scholar26Gong, J. H., Ratkay, L. G., Waterfield, J. D. Clark-Lewis, I. An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model. J. Exp. Med. 186, 131鈥?37 (1997).
CASPubMedPubMed Central Google Scholar27Legendre, C. M. et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 368, 2169鈥?181 (2013).
CASPubMed Google Scholar28Rathbone, J. et al. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 3, e003573 (2013).
PubMedPubMed Central Google Scholar29Tillmanns, S. et al. SM101, a novel recombinant, soluble, human Fc纬IIB receptor, in the treatment of systemic lupus erythematosus: results of a double-blline, placebo-controlled multicenter study. Am. Coll. Rheumatol. 66, S1238 (2014).
Google Scholar30van de Wiel, B. A. et al. Interference of Wegener\'s granulomatosis autoantibodies with neutrophil proteinase 3 activity. Clin. Exp. Immunol. 90, 409鈥?14 (1992).
CASPubMedPubMed Central Google Scholar31Jennette, J. C. Falk, R. J. Small-vessel vasculitis. N. Engl. J. Med. 337, 1512鈥?523 (1997).
CASPubMed Google Scholar32Lyons, P. A. et al. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214鈥?23 (2012).
CASPubMedPubMed Central Google Scholar33Xiao, H. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J. Clin. Invest. 110, 955鈥?63 (2002).
CASPubMedPubMed Central Google Scholar34Huugen, D. et al. Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-伪. Am. J. Pathol. 167, 47鈥?8 (2005).
CASPubMedPubMed Central Google Scholar35Stone, J. H. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221鈥?32 (2010).
CASPubMedPubMed Central Google Scholar36Jones, R. B. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211鈥?20 (2010).
CASPubMed Google Scholar37Guillevin, L. et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N. Engl. J. Med. 371, 1771鈥?780 (2014).
PubMed Google Scholar38US National Libary of Science. ClinicalTrials.gov[online], (2015).
39Oflazoglu, E. Audoly, L. P. Evolution of anti-CD20 monoclonal antibody therapeutics in oncology. MAbs 2, 14鈥?9 (2010).
PubMedPubMed Central Google Scholar40US National Libary of Science. ClinicalTrials.gov[online], (2015).
41Schneeweis, C. et al. Increased levels of BLyS and sVCAM-1 in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitides (AAV). Clin. Exp. Rheumatol. 28, 62鈥?6 (2010).
PubMed Google Scholar42Krumbholz, M. et al. BAFF is elevated in serum of patients with Wegener\'s granulomatosis. J. Autoimmun. 25, 298鈥?02 (2005).
CASPubMed Google Scholar43Bader, L., Koldingsnes, W. Nossent, J. B-lymphocyte activating factor levels are increased in patients with Wegener\'s granulomatosis and inversely correlated with ANCA titer. Clin. Rheumatol. 29, 1031鈥?035 (2010).
PubMed Google Scholar44US National Libary of Science. ClinicalTrials.gov[online], (2015).
45Stilmant, M. M., Bolton, W. K., Sturgill, B. C., Schmitt, G. W. Couser, W. G. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 15, 184鈥?95 (1979).
CASPubMed Google Scholar46Huugen, D. et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int. 71, 646鈥?54 (2007).
CASPubMed Google Scholar47Xiao, H. et al. C5a receptor (CD88) blockade protects against MPO鈥揂NCA GN. J. Am. Soc. Nephrol. 25, 225鈥?31 (2014).
CASPubMed Google Scholar48Schreiber, A. et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J. Am. Soc. Nephrol. 20, 289鈥?98 (2009).
CASPubMedPubMed Central Google Scholar49US National Libary of Science. ClinicalTrials.gov[online], (2015).
50US National Libary of Science. ClinicalTrials.gov[online], (2015).
51Romo-Tena, J., Gomez-Martin, D. Alcocer-Varela, J. CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun. Rev. 12, 1171鈥?176 (2013).
CASPubMed Google Scholar52Abrams, J. R. et al. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J. Exp. Med. 192, 681鈥?94 (2000).
CASPubMedPubMed Central Google Scholar53Langford, C. A. et al. An open-label trial of abatacept (CTLA4-IG) in non-severe relapsing granulomatosis with polyangiitis (Wegener\'s). Ann. Rheum. Dis. 73, 1376鈥?379 (2014).
CASPubMed Google Scholar54US National Libary of Science. ClinicalTrials.gov[online], (2015).
55Moreland, L. W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337, 141鈥?47 (1997).
CASPubMed Google Scholar56Moelants, E. A., Mortier, A., Van Damme, J. Proost, P. Regulation of TNF-伪 with a focus on rheumatoid arthritis. Immunol. Cell Biol. 91, 393鈥?01 (2013).
CASPubMed Google Scholar57Little, M. A. et al. Therapeutic effect of anti-TNF-伪 antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis. J. Am. Soc. Nephrol. 17, 160鈥?69 (2006).
CASPubMed Google Scholar58Stone, J. H. et al. Etanercept combined with conventional treatment in Wegener\'s granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum. 44, 1149鈥?154 (2001).
CASPubMed Google Scholar59The Wegener\'s Granulomatosis Etanercept Tiral (WGET) Research Group. Etanercept plus standard therapy for Wegener\'s granulomatosis. N. Engl. J. Med. 352, 351鈥?61 (2005).
60Stone, J. H. et al. Solid malignancies among patients in the Wegener\'s Granulomatosis Etanercept Trial. Arthritis Rheum. 54, 1608鈥?618 (2006).
CASPubMed Google Scholar61Mukhtyar, C. Luqmani, R. Current state of tumour necrosis factor 伪 blockade in Wegener\'s granulomatosis. Ann. Rheum. Dis. 64, iv31鈥搃v36 (2005).
CASPubMedPubMed Central Google Scholar62Lamprecht, P. et al. Effectiveness of TNF-伪 blockade with infliximab in refractory Wegener\'s granulomatosis. Rheumatol. (Oxford) 41, 1303鈥?307 (2002).
CAS Google Scholar63Booth, A. D., Jefferson, H. J., Ayliffe, W., Andrews, P. A. Jayne, D. R. Safety and efficacy of TNF伪 blockade in relapsing vasculitis. Ann. Rheum. Dis. 61, 559 (2002).
CASPubMedPubMed Central Google Scholar64Bartolucci, P. et al. Efficacy of the anti-TNF-伪 antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatol. (Oxford) 41, 1126鈥?132 (2002).
CAS Google Scholar65Booth, A. et al. Prospective study of TNF伪 blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J. Am. Soc. Nephrol. 15, 717鈥?21 (2004).
CASPubMed Google Scholar66US National Libary of Science. ClinicalTrials.gov[online], (2008).
67Morgan, M. D., Drayson, M. T., Savage, C. O. Harper, L. Addition of infliximab to standard therapy for ANCA-associated vasculitis. Nephron Clin. Pract. 117, c89鈥揷97 (2011).
CASPubMed Google Scholar68Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987鈥?97 (2008).
CASPubMed Google Scholar69Arimura, Y. et al. Serum myeloperoxidase and serum cytokines in anti-myeloperoxidase antibody-associated glomerulonephritis. Clin. Nephrol. 40, 256鈥?64 (1993).
CASPubMed Google Scholar70Ohlsson, S., Wieslander, J. Segelmark, M. Circulating cytokine profile in anti-neutrophilic cytoplasmatic autoantibody-associated vasculitis: prediction of outcome? Mediators Inflamm. 13, 275鈥?83 (2004).
CASPubMedPubMed Central Google Scholar71Berti, A. et al. Interleukin-6 in ANCA-associated vasculitis: rationale for successful treatment with tocilizumab. Semin. Arthritis Rheum. 45, 48鈥?4 (2015).
CASPubMed Google Scholar72Vaglio, A., Moosig, F. Zwerina, J. Churg鈥揝trauss syndrome: update on pathophysiology and treatment. Curr. Opin. Rheumatol. 24, 24鈥?0 (2012).
CASPubMed Google Scholar73Kahn, J. E. et al. Sustained response to mepolizumab in refractory Churg鈥揝trauss syndrome. J. Allergy Clin. Immunol. 125, 267鈥?70 (2010).
CASPubMed Google Scholar74Kim, S., Marigowda, G., Oren, E., Israel, E. Wechsler, M. E. Mepolizumab as a steroid-sparing treatment option in patients with Churg鈥揝trauss syndrome. J. Allergy Clin. Immunol. 125, 1336鈥?343 (2010).
CASPubMed Google Scholar75Herrmann, K., Gross, W. L. Moosig, F. Extended follow-up after stopping mepolizumab in relapsing/refractory Churg鈥揝trauss syndrome. Clin. Exp. Rheumatol. 30, S62鈥揝65 (2012).
PubMed Google Scholar76US National Libary of Science. ClinicalTrials.gov[online], (2009).
77US National Libary of Science. ClinicalTrials.gov[online], (2012).
78Giavina-Bianchi, P., Giavina-Bianchi, M., Agondi, R. Kalil, J. Omalizumab and Churg鈥揝trauss syndrome. J. Allergy Clin. Immunol. 122, 217; author reply 217鈥?18 (2008).
CASPubMed Google Scholar79Iglesias, E. et al. Successful management of Churg鈥揝trauss syndrome using omalizumab as adjuvant immunomodulatory therapy: first documented pediatric case. Pediatr. Pulmonol. 49, E78鈥揈81 (2014).
CASPubMed Google Scholar80Pabst, S., Tiyerili, V. Grohe, C. Apparent response to anti-IgE therapy in two patients with refractory \'forme fruste\' of Churg鈥揝trauss syndrome. Thorax 63, 747鈥?48 (2008).
CASPubMed Google Scholar81Mellors, R. C., Ortega, L. G. Holman, H. R. Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction. J. Exp. Med. 106, 191鈥?02 (1957).
CASPubMedPubMed Central Google Scholar82Beck, L. H. Jr. et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N. Engl. J. Med. 361, 11鈥?1 (2009).
CASPubMedPubMed Central Google Scholar83Tomas, N. M. et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N. Engl. J. Med. 371, 2277鈥?287 (2014).
PubMedPubMed Central Google Scholar84Beck, L. H. Jr Salant, D. J. Membranous nephropathy: from models to man. J. Clin. Invest. 124, 2307鈥?314 (2014).
CASPubMedPubMed Central Google Scholar85Beck, L. H. Jr. et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J. Am. Soc. Nephrol. 22, 1543鈥?550 (2011).
CASPubMedPubMed Central Google Scholar86Howman, A. et al. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial. Lancet 381, 744鈥?51 (2013).
CASPubMedPubMed Central Google Scholar87Jha, V. et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. J. Am. Soc. Nephrol. 18, 1899鈥?904 (2007).
CASPubMed Google Scholar88Heymann, W., Hackel, D. B., Harwood, S., Wilson, S. G. Hunter, J. L. Production of nephrotic syndrome in rats by Freund\'s adjuvants and rat kidney suspensions. Proc. Soc. Exp. Biol. Med. 100, 660鈥?64 (1959).
CASPubMed Google Scholar89Baker, P. J. et al. Depletion of C6 prevents development of proteinuria in experimental membranous nephropathy in rats. Am. J. Pathol. 135, 185鈥?94 (1989).
CASPubMedPubMed Central Google Scholar90Cunningham, P. N. Quigg, R. J. Contrasting roles of complement activation and its regulation in membranous nephropathy. J. Am. Soc. Nephrol. 16, 1214鈥?222 (2005).
CASPubMed Google Scholar91Noris, M., Mele, C. Remuzzi, G. Podocyte dysfunction in atypical haemolytic uraemic syndrome. Nat. Rev. Nephrol. 11, 245鈥?52 (2015).
CASPubMed Google Scholar92Neale, T. J. et al. Tumor necrosis factor-伪 is expressed by glomerular visceral epithelial cells in human membranous nephropathy. Am. J. Pathol. 146, 1444鈥?454 (1995).
CASPubMedPubMed Central Google Scholar93Ruggenenti, P. et al. Rituximab for idiopathic membranous nephropathy: who can benefit? Clin. J. Am. Soc. Nephrol. 1, 738鈥?48 (2006).
CASPubMed Google Scholar94Fervenza, F. C. et al. Rituximab treatment of idiopathic membranous nephropathy. Kidney Int. 73, 117鈥?25 (2008).
CASPubMed Google Scholar95Fervenza, F. C. et al. Rituximab therapy in idiopathic membranous nephropathy: a 2-year study. Clin. J. Am. Soc. Nephrol. 5, 2188鈥?198 (2010).
CASPubMedPubMed Central Google Scholar96Cravedi, P., Ruggenenti, P., Sghirlanzoni, M. C. Remuzzi, G. Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin. J. Am. Soc. Nephrol. 2, 932鈥?37 (2007).
CASPubMed Google Scholar97Segarra, A. et al. Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients. Clin. J. Am. Soc. Nephrol. 4, 1083鈥?088 (2009).
CASPubMedPubMed Central Google Scholar98US National Libary of Science. ClinicalTrials.gov[online], (2015).
99US National Libary of Science. ClinicalTrials.gov[online], (2015).
100US National Libary of Science. ClinicalTrials.gov[online], (2015).
101Fervenza, F. C. et al. A multicenter randomized controlled trial of rituximab versus cyclosporine in the treatment of idiopathic membranous nephropathy (MENTOR). Nephron 130, 159鈥?68 (2015).
CASPubMed Google Scholar102Sethi, S. Fervenza, F. C. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification. Semin. Nephrol. 31, 341鈥?48 (2011).
CASPubMed Google Scholar103Fakhouri, F., Fremeaux-Bacchi, V., Noel, L. H., Cook, H. T. Pickering, M. C. C3 glomerulopathy: a new classification. Nat. Rev. Nephrol. 6, 494鈥?99 (2010).
CASPubMed Google Scholar104Sethi, S. Fervenza, F. C. Membranoproliferative glomerulonephritis 鈥?a new look at an old entity. N. Engl. J. Med. 366, 1119鈥?131 (2012).
CASPubMed Google Scholar105Zipfel, P. F. et al. The role of complement in C3 glomerulopathy. Mol. Immunol. 67, 21鈥?0 (2015).
CASPubMed Google Scholar106Pickering, M. C. et al. C3 glomerulopathy: consensus report. Kidney Int. 84, 1079鈥?089 (2013).
PubMedPubMed Central Google Scholar107Sethi, S. et al. Mayo clinic/renal pathology society consensus report on pathologic classification, diagnosis, and reporting of GN. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2015060612 (2015).
108Servais, A. et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 82, 454鈥?64 (2012).
CASPubMed Google Scholar109Pickering, M. C. et al. Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice. Proc. Natl Acad. Sci. USA 103, 9649鈥?654 (2006).
CASPubMed Google Scholar110Sethi, S. et al. C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int. 82, 465鈥?73 (2012).
CASPubMedPubMed Central Google Scholar111Bomback, A. S. Eculizumab in the treatment of membranoproliferative glomerulonephritis. Nephron Clin. Pract. 128, 270鈥?76 (2014).
CASPubMed Google Scholar112Bomback, A. S. et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin. J. Am. Soc. Nephrol. 7, 748鈥?56 (2012).
CASPubMedPubMed Central Google Scholar113Herlitz, L. C. et al. Pathology after eculizumab in dense deposit disease and C3 GN. J. Am. Soc. Nephrol. 23, 1229鈥?237 (2012).
CASPubMedPubMed Central Google Scholar114Radhakrishnan, S. et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N. Engl. J. Med. 366, 1165鈥?166 (2012).
CASPubMed Google Scholar115Vivarelli, M., Pasini, A. Emma, F. Eculizumab for the treatment of dense-deposit disease. N. Engl. J. Med. 366, 1163鈥?165 (2012).
CASPubMed Google Scholar116Daina, E., Noris, M. Remuzzi, G. Eculizumab in a patient with dense-deposit disease. N. Engl. J. Med. 366, 1161鈥?163 (2012).
CASPubMed Google Scholar117McCaughan, J. A., O\'Rourke, D. M. Courtney, A. E. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am. J. Transplant. 12, 1046鈥?051 (2012).
CASPubMed Google Scholar118Gurkan, S. et al. Eculizumab and recurrent C3 glomerulonephritis. Pediatr. Nephrol. 28, 1975鈥?981 (2013).
PubMedPubMed Central Google Scholar119Rousset-Rouviere, C. et al. Rituximab fails where eculizumab restores renal function in C3nef-related DDD. Pediatr. Nephrol. 29, 1107鈥?111 (2014).
PubMed Google Scholar120Ozkaya, O. et al. Eculizumab therapy in a patient with dense-deposit disease associated with partial lipodystropy. Pediatr. Nephrol. 29, 1283鈥?287 (2014).
PubMed Google Scholar121Kerns, E., Rozansky, D. Troxell, M. L. Evolution of immunoglobulin deposition in C3-dominant membranoproliferative glomerulopathy. Pediatr. Nephrol. 28, 2227鈥?231 (2013).
PubMed Google Scholar122Nester, C. M. Smith, R. J. Treatment options for C3 glomerulopathy. Curr. Opin. Nephrol. Hypertens. 22, 231鈥?37 (2013).
PubMedPubMed Central Google Scholar123US National Libary of Science. ClinicalTrials.gov[online], (2014).
124Melis, J. P. et al. Complement in therapy and disease: regulating the complement system with antibody-based therapeutics. Mol. Immunol. 67, 117鈥?30 (2015).
CASPubMed Google Scholar125Ricklin, D. Lambris, J. D. Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190, 3839鈥?847 (2013).
CASPubMedPubMed Central Google Scholar126Ruseva, M. M. et al. Efficacy of targeted complement inhibition in experimental C3 glomerulopathy. J. Am. Soc. Nephrol. 27, 405鈥?16 (2015).
PubMedPubMed Central Google Scholar127US National Libary of Science. ClinicalTrials.gov[online], (2015).
128US National Libary of Science. ClinicalTrials.gov[online], (2014).
129Zhang, Y. et al. Soluble CR1 therapy improves complement regulation in C3 glomerulopathy. J. Am. Soc. Nephrol. 24, 1820鈥?829 (2013).
CASPubMedPubMed Central Google Scholar130Schmidt, C. Q. et al. Rational engineering of a minimized immune inhibitor with unique triple-targeting properties. J. Immunol. 190, 5712鈥?721 (2013).
CASPubMed Google Scholar131Hebecker, M. et al. An engineered construct combining complement regulatory and surface-recognition domains represents a minimal-size functional factor H. J. Immunol. 191, 912鈥?21 (2013).
CASPubMed Google Scholar132Angioi, A. et al. Diagnosis of complement alternative pathway disorders. Kidney Int. 89, 278鈥?88 (2016).
CASPubMed Google Scholar133Barratt, J. Feehally, J. Primary IgA nephropathy: new insights into pathogenesis. Semin. Nephrol. 31, 349鈥?60 (2011).
CASPubMed Google Scholar134Mestecky, J. et al. Defective galactosylation and clearance of IgA1 molecules as a possible etiopathogenic factor in IgA nephropathy. Contrib. Nephrol. 104, 172鈥?82 (1993).
CASPubMed Google Scholar135Gharavi, A. G. et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J. Am. Soc. Nephrol. 19, 1008鈥?014 (2008).
PubMedPubMed Central Google Scholar136Suzuki, H. et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J. Clin. Invest. 119, 1668鈥?677 (2009).
CASPubMedPubMed Central Google Scholar137Moura, I. C. et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)a1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J. Exp. Med. 194, 417鈥?25 (2001).
CASPubMedPubMed Central Google Scholar138Dohi, K. et al. The prognostic significance of urinary interleukin 6 in IgA nephropathy. Clin. Nephrol. 35, 1鈥? (1991).
CASPubMed Google Scholar139Lee, T. W., Ahn, J. H., Park, J. K., Ihm, C. G. Kim, M. J. Tumor necrosis factor 伪 from peripheral blood mononuclear cells of IgA nephropathy and mesangial cell proliferation. Kor. J. Intern. Med. 9, 1鈥? (1994).
CAS Google Scholar140Xin, G. et al. Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features. J. Nephrol. 26, 683鈥?90 (2013).
CASPubMed Google Scholar141Lin, F. J. et al. Imbalance of regulatory T cells to Th17 cells in IgA nephropathy. Scand. J. Clin. Lab. Invest. 72, 221鈥?29 (2012).
CASPubMed Google Scholar142Ohsawa, I. et al. Extraglomerular C3 deposition and metabolic impacts in patients with IgA nephropathy. Nephrol. Dial. Transplant. 28, 1856鈥?864 (2013).
CASPubMed Google Scholar143Suzuki, H. et al. Fluctuation of serum C3 levels reflects disease activity and metabolic background in patients with IgA nephropathy. J. Nephrol. 26, 708鈥?15 (2013).
CASPubMed Google Scholar144Sugiura, H. et al. Effect of single-dose rituximab on primary glomerular diseases. Nephron Clin. Pract. 117, c98鈥揷105 (2011).
CASPubMed Google Scholar145US National Libary of Science. ClinicalTrials.gov[online], (2015).
146US National Libary of Science. ClinicalTrials.gov[online], (2015).
147US National Libary of Science. ClinicalTrials.gov[online], (2015).
148Lamm, M. E. et al. Microbial IgA protease removes IgA immune complexes from mouse glomeruli in vivo: potential therapy for IgA nephropathy. Am. J. Pathol. 172, 31鈥?6 (2008).
CASPubMedPubMed Central Google Scholar149Cairns, L. S. et al. The fine specificity and cytokine profile of T-helper cells responsive to the 伪3 chain of type IV collagen in Goodpasture\'s disease. J. Am. Soc. Nephrol. 14, 2801鈥?812 (2003).
CASPubMed Google Scholar150Ooi, J. D. et al. The HLA-DRB1*15:01-restricted Goodpasture\'s T cell epitope induces GN. J. Am. Soc. Nephrol. 24, 419鈥?31 (2013).
CASPubMedPubMed Central Google Scholar151Pedchenko, V. et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N. Engl. J. Med. 363, 343鈥?54 (2010).
CASPubMedPubMed Central Google Scholar152Chen, J. L. et al. Association of epitope spreading of antiglomerular basement membrane antibodies and kidney injury. Clin. J. Am. Soc. Nephrol. 8, 51鈥?8 (2013).
PubMed Google Scholar153Phelps, R. G. Rees, A. J. The HLA complex in Goodpasture\'s disease: a model for analyzing susceptibility to autoimmunity. Kidney Int. 56, 1638鈥?653 (1999).
CASPubMed Google Scholar154Wu, J. et al. CD4+ T cells specific to a glomerular basement membrane antigen mediate glomerulonephritis. J. Clin. Invest. 109, 517鈥?24 (2002).
CASPubMedPubMed Central Google Scholar155Ooi, J. D., Phoon, R. K., Holdsworth, S. R. Kitching, A. R. IL-23, not IL-12, directs autoimmunity to the Goodpasture antigen. J. Am. Soc. Nephrol. 20, 980鈥?89 (2009).
CASPubMedPubMed Central Google Scholar156Hunemorder, S. et al. TH1 and TH17 cells promote crescent formation in experimental autoimmune glomerulonephritis. J. Pathol. 237, 62鈥?1 (2015).
PubMed Google Scholar157Salama, A. D. et al. Regulation by CD25+ lymphocytes of autoantigen-specific T-cell responses in Goodpasture\'s (anti-GBM) disease. Kidney Int. 64, 1685鈥?694 (2003).
CASPubMed Google Scholar158Kidney Disease Improving Global Outcomes. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int. 2, (Suppl. 2) 233鈥?39 (2012).
159Henderson, L. et al. Treatment for lupus nephritis. Cochrane Database Syst. Rev. 12, CD002922 (2012).
PubMed Google Scholar160Finck, B. K., Linsley, P. S. Wofsy, D. Treatment of murine lupus with CTLA4Ig. Science 265, 1225鈥?227 (1994).
CASPubMed Google Scholar161Reap, E. A., Sobel, E. S., Cohen, P. L. Eisenberg, R. A. Conventional B cells, not B-1 cells, are responsible for producing autoantibodies in lpr mice. J. Exp. Med. 177, 69鈥?8 (1993).
CASPubMed Google Scholar162Mackay, F. et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190, 1697鈥?710 (1999).
CASPubMedPubMed Central Google Scholar163Santiago-Raber, M. L. et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J. Exp. Med. 197, 777鈥?88 (2003).
CASPubMedPubMed Central Google Scholar164Kiberd, B. A. Interleukin-6 receptor blockage ameliorates murine lupus nephritis. J. Am. Soc. Nephrol. 4, 58鈥?1 (1993).
CASPubMed Google Scholar165Merrill, J. et al. Assessment of flares in lupus patients enrolled in a Phase II/III study of rituximab (EXPLORER). Lupus 20, 709鈥?16 (2011).
CASPubMed Google Scholar166Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64, 1215鈥?226 (2012).
CASPubMed Google Scholar167Lightstone, L. The landscape after LUNAR: rituximab\'s crater-filled path. Arthritis Rheum. 64, 962鈥?65 (2012).
PubMed Google Scholar168Rovin, B. H. Targeting B-cells in lupus nephritis: should cautious optimism remain? Nephrol. Dial. Transplant. 28, 7鈥? (2013).
PubMed Google Scholar169US National Libary of Science. ClinicalTrials.gov[online], (2015).
170US National Libary of Science. ClinicalTrials.gov[online], (2015).
171US National Libary of Science. ClinicalTrials.gov[online], (2015).
172Mysler, E. F. et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, Phase III study. Arthritis Rheum. 65, 2368鈥?379 (2013).
CASPubMed Google Scholar173Gregersen, J. W. Jayne, D. R. B-cell depletion in the treatment of lupus nephritis. Nat. Rev. Nephrol. 8, 505鈥?14 (2012).
CASPubMed Google Scholar174Al Rayes, H. Touma, Z. Profile of epratuzumab and its potential in the treatment of systemic lupus erythematosus. Drug Des. Devel. Ther. 8, 2303鈥?310 (2014).
CASPubMedPubMed Central Google Scholar175Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, Phase 3 trial. Lancet 377, 721鈥?31 (2011).
CASPubMed Google Scholar176US National Libary of Science. ClinicalTrials.gov[online], (2015).
177US National Libary of Science. ClinicalTrials.gov[online], (2015).
178Vincent, F. B. et al. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 24, 203鈥?15 (2013).
CASPubMed Google Scholar179US National Libary of Science. ClinicalTrials.gov[online], (2014).
180Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).
CASPubMedPubMed Central Google Scholar181Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study. Arthritis Rheumatol. 66, 379鈥?89 (2014).
CASPubMed Google Scholar182Askanase, A. D. et al. Treatment of lupus nephritis with abatacept: the Abatacept and Cyclophosphamide Combination Efficacy and Safety Study. Arthritis Rheumatol. 66, 3096鈥?104 (2014).
CASPubMed Central Google Scholar183Mohan, C., Shi, Y., Laman, J. D. Datta, S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J. Immunol. 154, 1470鈥?480 (1995).
CASPubMed Google Scholar184Ruth, A. J. et al. An IL-12-independent role for CD40鈥揅D154 in mediating effector responses: studies in cell-mediated glomerulonephritis and dermal delayed-type hypersensitivity. J. Immunol. 173, 136鈥?44 (2004).
CASPubMed Google Scholar185Ruth, A. J., Kitching, A. R., Semple, T. J., Tipping, P. G. Holdsworth, S. R. Intrinsic renal cell expression of CD40 directs Th1 effectors inducing experimental crescentic glomerulonephritis. J. Am. Soc. Nephrol. 14, 2813鈥?822 (2003).
CASPubMed Google Scholar186Sidiropoulos, P. I. Boumpas, D. T. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391鈥?97 (2004).
CASPubMed Google Scholar187Jacob, C. O. McDevitt, H. O. Tumour necrosis factor-伪 in murine autoimmune \'lupus\' nephritis. Nature 331, 356鈥?58 (1988).
CASPubMed Google Scholar188Aringer, M. Smolen, J. S. Therapeutic blockade of TNF in patients with SLE 鈥?promising or crazy? Autoimmun. Rev. 11, 321鈥?25 (2012).
CASPubMed Google Scholar189US National Libary of Science. ClinicalTrials.gov[online], (2013).
190US National Libary of Science. ClinicalTrials.gov[online], (2009).
191Michaelson, J. S., Wisniacki, N., Burkly, L. C. Putterman, C. Role of TWEAK in lupus nephritis: a bench-to-bedside review. J. Autoimmun. 39, 130鈥?42 (2012).
CASPubMedPubMed Central Google Scholar192US National Libary of Science. ClinicalTrials.gov[online], (2015).
193US National Libary of Science. ClinicalTrials.gov[online], (2015).
194Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711鈥?23 (2003).
CASPubMedPubMed Central Google Scholar195Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA 100, 2610鈥?615 (2003).
CASPubMed Google Scholar196Zheng, B., Yu, X. Q., Greth, W. Robbie, G. J. Population pharmacokinetic analysis of sifalimumab from a clinical Phase IIb trial in systemic lupus erythematosus patients. Br. J. Clin. Pharmacol. (2015).
197Kalunian, K. C. et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-伪) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196鈥?02 (2016).
PubMed Google Scholar198Fukatsu, A. et al. Distribution of interleukin-6 in normal and diseased human kidney. Lab. Invest. 65, 61鈥?6 (1991).
CASPubMed Google Scholar199Ryffel, B. et al. Interleukin-6 exacerbates glomerulonephritis in (NZB x NZW)F1 mice. Am. J. Pathol. 144, 927鈥?37 (1994).
CASPubMedPubMed Central Google Scholar200US National Libary of Science. ClinicalTrials.gov[online], (2014).
201van Vollenhoven, R. et al. A Phase 2, multicenter, randomized, double-blind, placebo-controlled, proof-of-concept study to evaluate the efficacy and safety of sirukumab in patients with active lupus nephritis. Ann. Rheum. Dis. 73 (Suppl. 2), 78 (2014).
Google Scholar202Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542鈥?52 (2010).
CASPubMedPubMed Central Google Scholar203Jacob, C. O., van der Meide, P. H. McDevitt, H. O. In vivo treatment of (NZB X NZW)F1 lupus-like nephritis with monoclonal antibody to 纬 interferon. J. Exp. Med. 166, 798鈥?03 (1987).
CASPubMed Google Scholar204Summers, S. A. et al. Endogenous interleukin (IL)-17A promotes pristane-induced systemic autoimmunity and lupus nephritis induced by pristane. Clin. Exp. Immunol. 176, 341鈥?50 (2014).
CASPubMedPubMed Central Google Scholar205US National Libary of Science. ClinicalTrials.gov[online], (2014).
206Martin, D. A. et al. A multiple dose study of AMG 811 (Anti-IFN-Gamma) in subjects with systemic lupus erythematosus and active nephritis. Ann. Rheum. Dis. 74 (Suppl. 2), 337 (2015).
Google Scholar207Hoi, A. Y. et al. Macrophage migration inhibitory factor deficiency attenuates macrophage recruitment, glomerulonephritis, and lethality in MRL/lpr mice. J. Immunol. 177, 5687鈥?696 (2006).
CASPubMed Google Scholar208US National Libary of Science. ClinicalTrials.gov[online], (2015).
209Leng, L. et al. MIF signal transduction initiated by binding to CD74. J. Exp. Med. 197, 1467鈥?476 (2003).
CASPubMedPubMed Central Google Scholar210Djudjaj, S. et al. Macrophage migration inhibitory factor mediates proliferative GN via CD74. J. Am. Soc. Nephrol. http://dx.doi.org/10.1681/ASN.2015020149 (2015).
211US National Libary of Science. ClinicalTrials.gov[online], (2015).
212Kidney Disease Improving Global Outcomes. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int. 2 (Suppl. 2), 240鈥?42 (2012).
213Falk, 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. 318, 1651鈥?657 (1988).
CASPubMed Google Scholar214Kain, R. et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat. Med. 14, 1088鈥?096 (2008).
CASPubMedPubMed Central Google Scholar215Netzer, K. O. et al. The goodpasture autoantigen. Mapping the major conformational epitope(s) of 伪3(IV) collagen to residues 17鈥?1 and 127鈥?41 of the NC1 domain. J. Biol. Chem. 274, 11267鈥?1274 (1999).
CASPubMed Google Scholar216Lech, M. Anders, H. J. The pathogenesis of lupus nephritis. J. Am. Soc. Nephrol. 24, 1357鈥?366 (2013).
CASPubMedPubMed Central Google Scholar217Lockwood, C. M. et al. Treatment of refractory Wegener\'s granulomatosis with humanized monoclonal antibodies. QJM 89, 903鈥?12 (1996).
CASPubMed Google Scholar218US National Libary of Science. ClinicalTrials.gov[online], (2012).
219US National Libary of Science. ClinicalTrials.gov[online], (2011).
220Laurino, S., Chaudhry, A., Booth, A., Conte, G. Jayne, D. Prospective study of TNF伪 blockade with adalimumab in ANCA-associated systemic vasculitis with renal involvement. Nephrol. Dial. Transplant. 25, 3307鈥?314 (2010).
CASPubMed Google ScholarDownload references
AcknowledgementsResearch in glomerular disease performed by S.R.H., P.Y.G., and A.R.K. is funded by project grants from the National Health and Medical Research Council of Australia (grant numbers 1048575, 1045065, 1046585, 1064112, and 1084869).
Author informationAffiliationsDepartment of Medicine, Centre for Inflammatory Diseases, Monash University, 3800, VIC, AustraliaStephen R. Holdsworth,聽Poh-Yi Gan聽 聽A. Richard KitchingDepartment of Nephrology, Monash Health, 246 Clayton Road, Clayton, Melbourne, 3168, VIC, AustraliaStephen R. Holdsworth聽 聽A. Richard KitchingAuthorsStephen R. HoldsworthView author publicationsYou can also search for this author in PubMed Google Scholar Poh-Yi GanView author publicationsYou can also search for this author in PubMed Google Scholar A. Richard KitchingView author publicationsYou can also search for this author in PubMed Google Scholar ContributionsA.R.K., P.Y.G., and S.R.H. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.
Corresponding authorCorrespondence to Stephen R. Holdsworth.
Ethics declarations Competing interestsA.R.K. has been a member of an advisory board for Roche Products, Australia. P.Y.G and S.R.H. declare no competing interests.
PowerPoint slides Stephen P. McAdoo, Maria Prendecki, Anisha Tanna, Tejal Bhatt, Gurjeet Bhangal, John McDaid, Esteban S. Masuda, H. Terence Cook, Frederick W.K. Tam Charles D. Pusey Kidney International (2020) Joana Eug茅nio Santos, David Fiel, Ricardo Santos, Rita Vicente, Rute Aguiar, Iolanda Santos, Manuel Amoedo Carlos Pires Brazilian Journal of Nephrology (2020) Lili Song, Qingsheng Yin, Mingqin Kang, Ningning Ma, Xin Li, Zhen Yang, Hua Jin, Mengya Lin, Pengwei Zhuang Yanjun Zhang Journal of Pharmaceutical and Biomedical Analysis (2020) Julia Hagenstein, Simon Melderis, Anna Nosko, Matthias T. Warkotsch, Johannes V. Richter, Torben Ramcke, Georg R. Herrnstadt, J眉rgen Scheller, Isabell Yan, Hans-Willi Mittr眉cker, Malte A. Kluger Oliver M. Steinmetz Journal of the American Society of Nephrology (2019)本文链接: http://immune.immuno-online.com/view-1502850618.html