Maurizio Salvadori*Professor of Nephrology, Director of Transplant Department, Careggi University Hospital, Florence, Italy
*Corresponding author: Maurizio Salvadori, Professor of Nephrology, Director of Transplant Department, Careggi University Hospital, Florence, Viale Pieraccini 18 50139, Italy, Tel: 0039 055 597151; E-mail: firstname.lastname@example.org
In the past, glomerular diseases and renal transplantation have always been considered as independent fields of nephrology. This concept has been supported by the prevalent rate of antibody production and immune complexes formation in glomerulonephritis versus the direct action of immune cell in renal transplantation . Recent findings have shown that the pathogenetic mechanisms operating in both conditions share common pathways that offer identical new therapeutic approaches identical for both conditions. In this review, after having described which these common pathogenetic pathways are, we will review in details which are to date the principal biologic medicines adopted in both conditions.
Glomerulonephritis; Renal transplantation; Innate immune system; B cell network; T cell network; Systemic inflammation
Common Pathogenetic Pathways
a) Innate immune system
The innate immunity acts through the recognition of pathogen associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) by macrophages, dendritic cells (DCs), leukocytes [2,3]. Innate immunity acts on antigen processing, so representing a link to adaptive immunity, favoring the antigen presentation, the T and B cell responses and the specific adaptive immune response . The activation of the innate immunity has been documented in several glomerulonephritis (GN) among which IgA-GN [5-7], crescentic GN, anti-neutrophil cytoplasmic autoantibody-GN [ANCA-GN [8,9]] and lupus GN [10,11].
The complement is another essential component of the innate immune system. Complement involvement has been clearly identified in several renal diseases as lupus GN, membranoproliferative GN (MPGN) and C3 glomerulonephritis (C3GN), and hemolytic uremic syndrome (HUS) [12,13]. Its role has recently been recognized in autoimmune GN and ANCA vasculitis [14,15].
Recent studies have documented a pivotal role of the innate immunity also in renal transplantation where it causes two step damage. Early after transplantation the innate immunity contributes, principally via the complement activation, to the ischemia-reperfusion injury (IRI) [16,17]. Later on, IRI represents a link with the adaptive immunity and may cause cell mediated rejection (CMR), antibody mediated rejection (ABMR) and progressive graft injury [18-20].
b) B cells and antibody network
Circulating antibodies are deeply involved in the development of GN as well as in the renal transplantation damage. Circulating antibodies are involved in the pathogenesis of membranous nephropathy (MN) where they are directed against neutral endopeptidase , as well as against other podocyte enzymes as M-type phospholipase-2-receptor , aldosereductase and manganese superoxide dismutase [23-25]. Circulating nephrotoxic auto antibodies have also been recognized in ANCA vasculitis , in hepatitis C-related cryoglobulinemia , in lupus GN , and in the anti glomerular basement GN .
In renal transplantation a relevant proportion of rejection episodes is mediated by circulating antibodies that, after binding to the antigens of the graft donor cells, cause the ABMR. In addition, the activation of the complement cascade recruits macrophages and neutrophils and cause additional graft injury . Moreover, recent data document the antibody involvement also in antibody mediated chronic rejection where the “bad” activity of antibodies may also be involved in previously considered “chronic” lesions (i.e. transplant glomerulopathy) [31,32].
c) T cells network
Several lines of evidence support a role for T cells in the pathogenesis of several GN. T cells are clearly involved in the pathogenesis of ANCA vasculitis [33,34]. In ANCA GN CD4 and CD8 T cells are present within the disease lesions in relationship with antigen presenting cells (APCs) and B cells .
Similarly, abnormalities in T cells and in T cell activation have been reported in lupus GN [36,37], in anti GBM GN  and in IgA GN . Clearly T cells are deeply involved in renal transplantation and the regulation of all reactive T cells ultimately determines whether the graft is rejected or accepted .
d) Systemic inflammation
An inflammatory “milieu” and its related cytokines are involved in the pathogenesis of several GN.
Up-regulation of pro-inflammatory cytokines and the efficacy of blocking agents have been documented in focal segmental glomerular sclerosis (FSGS) . Similarly, cytokine network up-regulation has been documented in ANCA GN [42,43] and in lupus GN. In the latter disease newer cytokines have been identified in the pathogenesis . Finally, macrophage up-regulation is also involved in the pathogenesis of the inflammation and its block is under investigation in a safety study for IgA-GN .
In renal transplantation the cytokine up-regulation and the increased network of inflammatory factors contributes to cause renal damage [46,47]. A study from Wu et al.  allowed identifying the role of several inflammatory proteins in the disease progress. Trials with antiinflammatory agents are ongoing, but to date their usefulness seems to be related only to the islet transplantation.
- Ponticelli C, Coppo R, Salvadori M (2011) Glomerular diseases and transplantation: similarities in pathogenetic mechanisms and treatment options. Nephrol Dial Transplant 26: 35-41. [Ref.]
- Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22: 240-273. [Ref.]
- Anders HJ, Schlondorff DO (2010) Innate immune receptors and autophagy: implications for autoimmune kidney injury. Kidney Int 78: 29-37. [Ref.]
- Rasmussen SB, Reinert LS, Paludan SR (2009) Innate recognition of intracellular pathogens: detection and activation of the first line of defense. APMIS 117: 323-337. [Ref.]
- Suzuki Y, Tomino Y (2007) The mucosa-bone-marrow axis in IgA nephropathy. Contrib Nephrol 157: 70-79. [Ref.]
- Suzuki H, Suzuki Y, Narita I, Aizawa M, Kihara M, et al. (2008) Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol 19: 2384-2395. [Ref.]
- Coppo R, Camilla R, Amore A, Peruzzi L, Daprà V, et al. (2010) Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin Exp Immunol 159: 73-81. [Ref.]
- Fujinaka H, Nameta M, Kovalenko P, Matsuki A, Kato N, et al. (2007) Periglomerular accumulation of dendritic cells in rat crescentic glomerulonephritis. J Nephrol 20: 357-363. [Ref.]
- Saiga K, Tokunaka K, Ichimura E, Toyoda E, Abe F, et al. (2006) NK026680, a novel suppressant of dendritic cell function, prevents the development of rapidly progressive glomerulonephritis and perinuclear antineutrophil cytoplasmic antibody in SCG/Kj mice. Arthritis Rheum 54: 3707-3715. [Ref.]
- Fiore N, Castellano G, Blasi A, Capobianco C, Loverre A, et al. (2008) Immature myeloid and plasmacytoid dendritic cells infiltrate renal tubulointerstitium in patients with lupus nephritis. Mol Immunol 45: 259-265. [Ref.]
- Tucci M, Calvani N, Richards HB, Quatraro C, Silvestris F (2005) The interplay of chemokines and dendritic cells in the pathogenesis of lupus nephritis. Ann N Y Acad Sci 1051: 421-432. [Ref.]
- Barbour TD, Pickering MC, Cook HT (2013) Recent insights into C3 glomerulopathy. Nephrol Dial Transplant 28: 1685-1693. [Ref.]
- Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs-Mecarelli L, Sautes-Fridman C, et al. (2011) Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods 365: 8-26. [Ref.]
- Allam R, Anders HJ (2008) The role of innate immunity in autoimmune tissue injury. Curr Opin Rheumatol 20: 538-544. [Ref.]
- Chen M, Daha MR, Kallenberg CG (2010) The complement system in systemic autoimmune disease. J Autoimmun 34: J276-J286. [Ref.]
- Land W (2007) Innate alloimmunity: history and current knowledge. Exp Clin Transplant 5: 575-584. [Ref.]
- Castellano G, Melchiorre R, Loverre A, Ditonno P, Montinaro V, et al. (2010) Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. Am J Pathol 176: 1648-1659. [Ref.]
- Fuquay R, Renner B, Kulik L, McCullough JW, Amura C, et al. (2013) Renal ischemia-reperfusion injury amplifies the humoral immune response. J Am Soc Nephrol 24: 1063-1072. [Ref.]
- Pratt JR, Basheer SA, Sacks SH (2002) Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 8: 582-587. [Ref.]
- Curci C, Castellano G, Stasi A, Divella C, Loverre A, et al. (2014) Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/ reperfusion injury are mediated by complement anaphylatoxins and Akt pathway. Nephrol Dial Transplant 29: 799-808. [Ref.]
- Debiec H, Guigonis V, Mougenot B, Haymann JP, Bensman A, et al. (2003) Antenatal membranous glomerulonephritis with vascular injury induced by anti-neutral endopeptidase antibodies: toward new concepts in the pathogenesis of glomerular diseases. J Am Soc Nephrol 14: S27-S32. [Ref.]
- Ronco P, Debiec H (2014) Anti-Phospholipase A2 Receptor Antibodies and the Pathogenesis of Membranous Nephropathy. Nephron Clin Pract 128: 232-237. [Ref.]
- Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, et al. (2009) M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 361: 11-21. [Ref.]
- Prunotto M, Carnevali ML, Candiano G, Murtas C, Bruschi M, et al. (2010) Autoimmunity in membranous nephropathy targets aldose reductase and SOD2. J Am Soc Nephrol 21: 507-519.[Ref.]
- Debiec H, Ronco P (2014) Immunopathogenesis of membranous nephropathy: an update. Semin Immunopathol 36: 381-397. [Ref.]
- Finkielman JD, Lee AS, Hummel AM, Viss MA, Jacob GL, et al. (2007) ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med 120: 643. [Ref.]
- Saadoun D, Resche Rigon M, Sene D, Terrier B, Karras A, et al. (2010) Rituximab plus Peg-interferon-alpha/ribavirin compared with Peginterferon-alpha/ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 116: 326-334. [Ref.]
- Condon MB, Ashby D, Pepper RJ, Cook HT, Levy JB, et al. (2013) Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 72: 1280-1286. [Ref.]
- Syeda UA, Singer NG, Magrey M (2013) Anti-glomerular basement membrane antibody disease treated with rituximab: A case-based review. Semin Arthritis Rheum 42: 567-572. [Ref.]
- Colvin RB, Smith RN (2005) Antibody-mediated organ-allograft rejection. Nat Rev Immunol 5: 807-817. [Ref.]
- Einecke G, Sis B, Reeve J, Mengel M, Campbell PM, et al. (2009) Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant 9: 2520-2531. [Ref.]
- Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, et al. (2010) Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 10: 464-471. [Ref.]
- Sanders JS, Abdulahad WH, Stegeman CA, Kallenberg CG (2014) Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment. Nephron Clin Pract 128: 216-223. [Ref.]
- Abdulahad WH, Lamprecht P, Kallenberg CG (2011) T-helper cells as new players in ANCA-associated vasculitides. Arthritis Res Ther 13: 236. [Ref.]
- McKinney EF, Willcocks LC, Broecker V, Smith KG (2014) The immunopathology of ANCA-associated vasculitis. Semin Immunopathol 36: 461-478. [Ref.]
- Liu Y, Anders HJ (2014) Lupus Nephritis: From Pathogenesis to Targets for Biologic Treatment. Nephron Clin Pract 128: 224-231. [Ref.]
- Mak A, Kow NY (2014) The pathology of T cells in systemic lupus erythematosus. J Immunol Res 2014: 419029. [Ref.]
- Zhang Q, Luan H, Wang L, He F, Zhou H, et al. (2014) Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice. Am J Physiol Renal Physiol 306: F822-F832 . [Ref.]
- Inoshita H, Kim BG, Yamashita M, Choi SH, Tomino Y, et al. (2013) Disruption of Smad4 expression in T cells leads to IgA nephropathylike manifestations. PLoS One 8: e78736. [Ref.]
- van der Touw W, Bromberg JS (2010) Natural killer cells and the immune response in solid organ transplantation. Am J Transplant 10: 1354-1358. [Ref.]
- Joy MS, Gipson DS, Powell L, MacHardy J, Jennette JC, et al. (2010) Phase 1 trial of adalimumab in Focal Segmental Glomerulosclerosis (FSGS): II. Report of the FONT (Novel Therapies for Resistant FSGS) study group. Am J Kidney Dis 55: 50-60. [Ref.]
- Booth A, Harper L, Hammad T, Bacon P, Griffith M, et al. (2004) Prospective study of TNFalpha blockade with infliximab in antineutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 15: 717-721. [Ref.]
- Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352: 351-361. [Ref.]
- Michaelson JS, Wisniacki N, Burkly LC, Putterman C (2012) Role of TWEAK in lupus nephritis: a bench-to-bedside review. J Autoimmun 39: 130-142. [Ref.]
- McIntosh LM, Barnes JL, Barnes VL, McDonald JR (2009) Selective CCR2-targeted macrophage depletion ameliorates experimental mesangioproliferative glomerulonephritis. Clin Exp Immunol 155: 295- 303. [Ref.]
- Cherukuri A, Rothstein DM, Clark B, Carter CR, Davison A, et al. (2014) Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells. J Am Soc Nephrol 25: 1575-1585. [Ref.]
- Wu D, Liu X, Liu C, Liu Z, Xu M, et al. (2014) Network analysis reveals roles of inflammatory factors in different phenotypes of kidney transplant patients. J Theor Biol 362: 62-68. [Ref.]
Download Provisional PDF Here
Article Type: Editorial
Citation: Salvadori M (2015) The Damage of Glomerulonephritis and Kidney Transplantation Shares Common Pathogenetic Pathways. Int J Nephrol Kidney Failure 1 (1): doi http://dx.doi.org/10.16966/ijnkf.e101
Copyright: © 2015 Salvadori M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.