glomerular capillary wall Pathogenic Mechanisms of Glomerular Diseases General Outline General Trend General Concepts

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1 General Outline Pathogenic Mechanisms of Glomerular Diseases Patrick H. Nachman, MD Professor University of North Carolina UNC Kidney Center Chapel Hill, NC USA Overview of Pathogenetic Mechanisms For each general mechanism :» Description» Specific examples of diseases» Specific pathogenetic pathway» Therapeutic implications More than one mechanism usually apply» Will focus on initiating events Will NOT discuss details of molecular pathways Will NOT discuss common pathways of progressive fibrosis Will NOT discuss details of therapy General Concepts Glomerular diseases are classified based on different conceptual approaches: Clinical phenotype» E.g. nephrotic vs. nephritic sdm;» renal-limited vs. systemic illness Histologic appearance» Different underlying pathogeneses may result in similar histologic appearance» Similar pathogeneses may result in different histologic lesions Underlying etiology: primary vs. secondary glomerular diseases. General Trend With better understanding of pathophysiology:» Disease classification is evolving from a descriptive (histologic) to mechanistic basis.» Diseases that were traditionally grouped together, may be categorized separately in the future (and in this lecture). General Pathogenetic Mechanisms Structural abnormalities of GBM Immune complexmediated diseases Primary complement dysregulation Endothelial injury and thrombosis Antibody-mediated disease Primary podocyte injury or dysregulation Structural abnormalities of glomerular capillary wall Direct antibody attack Pauci-immune ANCA Dysproteinemias

2 Type IV collagen Hudson BG et al. N Eng J Med 2003(348)2543 Hudson BG et al. N Eng J Med 2003(348)2543 Thin Basement Membrane Disease Normal Alport s Syndrome Thin Basement Membrane Persistent hematuria Minimal proteinuria Normal GFR and benign course No extra-renal manifestations TBMN may represent the carrier state for Alport s S. Clinical Features Alport s Syndrome Persistent hematuria Proteinuria (< 1-2 g/d) Progressive renal failure ± sensorineural deafness ± lenticonus ± leiomyomatosis ± mental retardation Retinopathy Wide clinical variability among kindreds Alport s Sdm: Transplantation Development of alloantibodies to GBM is common. Abs are directed against multiple epitopes on the α3, α4 or α5 chain. Actual nephritis is uncommon. Alport s Sdm transplant recipients do worse than recipients from other renal diseases. Adapted from Hudson BG et al. N Eng J Med 2003(348)2543

3 Endothelial Injury and thrombosis Drug association Pregnancy TTP Malignant HTN Systemic Sclerosis HUS Stem Cell Transplant Autoimmune (severe SLE) Verotoxins biology Diarrheal (D + ) HUS (Verotoxin) Hemolytic Uremic Syndrome D - -HUS Atypical (ahus) Ribosome-inactivating protein Direct injury to microvascular endothelial cells; depends on surface expression of globotriaosylceramide (Gb3) receptor. Host cell dysregulation occurs at [VT] that do not inhibit protein synthesis Sub-inhibitory [VT] cause increased expression of:» pro-adhesive» pro-thrombotic» inflammatory genes» endothelin 1. Petruzziello TN et al. Kidney Int 2009:75:S17-S19 D+ HUS: Management Supportive, including dialysis Some antibiotics may increase VT expression in vitro, and increase the risk of HUS.» Fosfomycin may protect against HUS if given before 3rd day of diarrhea» The effect of antibiotics depends on: The strain of E. coli (O157:H7 vs O104:H4) The class of antibiotics» Early analysis of the strain of STEC and response to antibiotics will affect management of an epidemic Future: Gb3 receptor blockers; VT neutralizing monoclonal antibody. Congenital TTP ADAMTS13 deficiency Thrombotic Thrombocytopenic Purpura Idiopathic TTP Ab to ADAMTS13 Nonidiopathic Direct endothelial injury

4 Von Willebrand Factor normal capillary Pathogenesis of TTP type TMA TTP capillary thrombus Endothelial cell vwf Tsai Hematol Oncol Clin N Am Abnormally long vwf on endothelial cells initiate thrombosis Antibodies to ADAMTS13* Autoantibody inhibitors are reported in 30-95% of patients with idiopathic TTP. IgG antibodies detected in almost all patients. IgM Ab also detected in 11% of patients. Non-inhibitory IgG autoantibodies found in rare patients with non-idiopathic TTP. TTP Therapy Plasma infusion vs. plasma exchange Failure of remission at < 2 weeks All cause mortality *A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif, member 13 Michael M et al. Am J Kidney Dis Feb;53(2): Immune-complex mediated diseases Immune Complex In Situ Formation» Intrinsic or planted target antigen» Sub-epithelial deposition» E.g. Primary membranous nephropathy Deposition of Circulating Complexes» Sub-epithelial + sub-endothelial deposition» Sub-endothelial deposition» E.g. Lupus nephritis, Cryoglobulinemia

5 Immune Complex Formation MEMBRANOUS NEPHROPATHY 25 Phospholipase A2 Receptor (PLA2R) as the Target Antigen Sera of 70-80% of patients with primary (idiopathic) MN detect the glomerular antigen, PLA2R, by western blot Anti-PLA2R absent from normal or disease-control sera. The majority of the anti-pla2r is IgG4, the predominant Ig seen in primary MN. PLA2R is present in podocytes as detected by IF of normal human kidney The Presence of Anti-PLA2R Antibodies in MN Sera Parallels Clinical Course of Disease CYC/PRED Beck LH Jr. et al. N Engl J Med 2009; Beck 361(1):11-21 et al. ASN 2008, FC-458 Beck LH Jr. et al. N Engl J Med 2009; 361(1):11-21 Pathogenesis: from IC to NS IC activate the complement pathway formation of the C5b-C9 membrane attack complex complementmediated injury to the epithelial cells and GBM. Secondary Membranous Nephropathy Associated with:» autoimmune diseases (e.g., SLE, autoimmune thyroiditis),» infection (e.g., HBV, HCV),» drugs (e.g., penicillamine, gold, NSAIDs)» malignancies (e.g., colon cancer, lung cancer). Cybulsky AV et al. Am J Physiol Renal Physiol 289: , 2005.

6 Class I Class II Class III Class IV Class V LUPUS NEPHRITIS Pathogenesis of Lupus Glomerulonephritis Pathogenic Event Pathologic Result Genesis of autoimmunity with epitope spreading Biologic Therapy for Lupus Nephritis Multiple circulating autoantibodies mesangial immune complexes Mesangial matrix expansion and mesangial cell proliferation subendothelial immune complexes Wire loop thickening of capillary walls Activated Fc regions, activation of complement, and up-regulation of adhesion molecules Recruitment and activation of leukocytes Influx of monocytes, macrophages and neutrophils. Inflammatory amplification by complement fragments and cytokines leukocyte influx, endothelial cell proliferation, apoptosis, thrombosis, necrosis, GBM rupture, crescent formation Innate immune response to injury Chronic progression with increase in extracellular matrix (sclerosis), adhesions, and fibrosis of crescent (macrophages + T cells cytokine release) Tubular atrophy, interstitial fibrosis and chronic inflammation Concurrent tubular injury End stage kidney disease Abbreviations: FcR = Fc receptor, CR = complement receptor IgA Nephropathy IgA Nephropathy mesangial immune complex deposits

7 - In IgA nephropathy and Henoch-Schönlein purpura nephritis, serum IgA1 has reduced terminal glycosylation in the hinge region (Gd-IgA1) Patients with IgA nephropathy have increased serum galactose-deficient IgA1 (Gd-IgA1) levels. VL CL VH Hinge Region CH 2 CH 3 CH 1 IgA1 Ser/Thr-O-GalNAc Reduced in IgAN and HSP Ser/Thr-O-GalNAc--Galactose Ser/Thr-O-GalNAc--Galactose-Sialic Acid Ser/Thr-O-GalNAc----Galactose-Sialic Acid Sialic Acid A lectin that recognizes N-acetylgalactosamine was used in an ELISA to measure serum galactose-deficient IgA1. Moldoveanu Z, Wyatt RJ, et al. Kidney Int. 2007;71: Glycan-specific IgG antibodies present in IgA nephropathy patients Galactose-deficient IgA1 (Gd-IgA1) or IgG-Gd-IgA1 immune complexes may cause IgA nephropathy Abnormally glycosylated IgA1 molecules ( ) aggregate and localize in the glomerular mesangium. Immune complexes of Gd-IgA1 molecules ( ) and IgG directed against then ( ) localize in the glomerular mesangium. Gd-IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. Suzuki H, et al. J Clin Invest. 2009;119: Antibody-mediated diseases Direct Antibody Attack: Anti-GBM Disease

8 Pathophysiology Cryptic target epitopes J Exp Med November 30; 126(6): The present studies were designed to look for anti-gbm antibodies in human nephritis both in the circulation and in the kidneys and, if found, to determine their nephritogenic properties. Anti-GBM antibodies were found in the serum and/or kidneys of six nephritic patients. These antibodies would react with GBM antigens in vitro and in vivo. On passive transfer, they induced an immediate glomerulonephritis in recipient monkeys. Pedchenko V et al. N Engl J Med 2010;363: Anti-GBM antibodies Primary target is NC1domain of α3 chain of Type IV collagen Cellular immunity» autoantibody class switch (IgG1 & IgG4) implies T cell-mediated help.» CD4+ and CD8+ T cells are found within affected glomeruli.» Autoreactive T cells directed against the a3(iv)nc1 antigen demonstrated in patients. ANCA-MALL VESSEL VASCULITIS Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA) C-ANCA Cytoplasmic Pattern Anti-Proteinase 3 PR3-ANCA P-ANCA Perinuclear Pattern Anti-myeloperoxidase MPO-ANCA

9 ANCA-small vessel vasculitis Necrotizing vasculitis affecting capillaries, arterioles and venules, with few or no immune deposits Frequency of PR3-ANCA and MPO-ANCA by a variety of clinical phenotypes Microscopic Polyangiitis (MPA) Granulomatosis with Polyangiitis (GPA) Eosinophilic Granulomatosis with Polyangiitis (EGPA) Pauci-immune necrotizing & crescentic GN - May also affect small and medium size arteries. - GN and pulmonary capillaritis are common - Granulomatous inflammation involving the respiratory tract. - GN is common - Eosinophil-rich granulomatous inflammation involving the respiratory tract. - Asthma and eosinophilia. - MPO-ANCA in ~40% of patients. No extra-renal manifestations Lionaki S et al. Arthritis Rheum.2012; 64: Disease classification based on ANCA specificity (MPO- vs PR3-ANCA) is supported by differences in:» Genetics» Pathogenesis (?)» Disease phenotype (with overlap)» Risk of Relapse» Possibly response to specific therapy (?) Adapted from Falk RJ et al J Am Soc Nephrol 21: , Anti-GBM Corticosteroids.» Prednisone 1 mg/kg/day x 4 weeks then taper over 6-9 months. Oral cyclophosphamide x 3 months Plasmapheresis:» 14 days or until anti-gbm Ab are undetectable. Treatment ANCA Vasculitis Corticosteroids.» Pulse methylprednisolone then oral prednisone 1 mg/kg/day x 4 weeks then taper over 6 months. Cyclophosphamide x 3-6 months OR Rituximab Plasmapheresis:» Pulmonary hemorrhage» Severe renal failure Maintenance therapy:» Azathioprine > mycophenolate Complement Dysregulation: Atypical HUS DDD & C3 Glomerulopathy 6/27/

10 Hemolytic Uremic Syndrome Diarrheal (D + ) HUS (Verotoxin) D - -HUS Atypical (ahus) Infectious (e.g. S. pneumoniae) Genetic Complement deficiency Factor Frequency in D- HUS Prognosis Factor H 15-30% Poor Factor I ~5% Poor Membrane Cofactor Protein 10-13% Good (CD46) CFHR1/CFHR3 with Ab ~10% C3b Single case/family* Factor B Single case/family* Total Account for 45-60% Dense Deposit Disease and C3 Glomerulopathy *frequencies have not been analyzed in large cohorts. Dense Deposit Disease (DDD) (Type II Membranoproliferative GN) Acquired and Genetic Abnormalities Associated with Complement-Mediated MPGN Sethi S, Fervenza FC, N Engl J Med 2012; 366:

11 MPGN with Neg Ig, Positive C3 C3 Glomerulonephritis Light Microscopy Immunofluorescence Microscopy Criteria: C3 glomerulonephritis MPGN (most common) Mesangial proliferative GN Diffuse proliferative (exudative) GN Crescentic GN Sclerosing GN Bright C3 in mesangium and along capillary walls Rarely, C3 along tubular basement membranes No significant staining for Ig, C1q or light chains 61 Electron Microscopy Subendothelial and mesangial deposits, often large and confluent Intramembranous and subepithelial deposits, often present Immunoglobulin and C3 deposits by IF MPGN by LM C3 deposits but no immunoglobulin deposits by IF Complement Dysregulation Disease C3 GN MPGN Immune Complex Disease Infection Monoclonal gammopathy Autoimmunity Alternative pathway dysregulation with complement or complement-regulating protein mutations or antibodies DDD MPGN I Based on Sethi, Fervenza. N Engl J Med 2012;366: C3GN EM DDD CFH, CFHR, CFB; or anti-cfh, anti- CFB, C3 NeF MPGN III Infection Autoimmunity Neoplasia Possible Therapies for Complement-Mediated MPGN Podocyte dysregulation or injury Smith et al, JASN, 2007

12 Adapted from D Agati VD, Kaskel FJ, Falk RJ, N Engl J Med 2011; 365(25): Type of Disease Primary (idiopathic) form Secondary forms Familial or genetic Virus-associated Causes of FSGS Cause Specific cause unknown; mediated by circulating permeability factor(s) Mutations in specific podocyte genes HIV, parvovirus B19, simian virus 40, CMV, EBV Molecular Anatomy of the Foot Process Drug-induced Adaptive Heroin; interferon; lithium; pamidronate; sirolimus; calcineurin inhibitors; anabolic steroids Conditions with reduced renal mass: (e.g.; very low birth weight, unilateral agenesis or ablation, reflux nephropathy, renal allograft, aging ) Conditions with initially normal renal mass: (e.g.; HTN, vaso-occlusive processes, elevated BMI, cyanotic congenital heart disease, sickle cell disease Kerjaschki, D. J. Clin. Invest 2001(108)1583 Population Risk allele MyH9 ApoL1 Genetics of Nephrotic Syndrome and FSGS Familial Causative NPHS1 NPHS2 TRPC6 ACTN4 INF2 PLCE other genes Sporadic Causative? Disease Modifying? NPHS2 NPHS1 6/27/ Prognostic and therapeutic implications: Compared to patients with 2 pathogenic mutations, NPHS2 heterozygous patients develop SRNS at a significantly older age (Santin S et al. Clin J Am Soc Nephrol 6: , 2011.) NPHS2 mutation is associated with a lower likelihood of recurrent FSGS after transplantation The impact of genetic mutations on response to therapy is not yet elucidated. Jungraithmayr TC et al. J Am Soc 6/27/ Nephrol 22: , FSGS NOS FSGS VARIANTS Perihilar Tip Lesion Collapsing supar (Soluble Urokinase-type Plasminogen Activator Receptor) Most common Primary or secondary Variable severity cellular Common in adaptive FSGS +/- glomerulomegaly Subnephrotic Primary Abrupt onset Severe NS More common in Caucasians Best prognosis & response to glucocorticoids Primary or Secondary to viral infections, meds. Severe NS More common in African Americans Poor prognosis Least common Endocapillary hypercellularity Primary or secondary Severe NS Wei C et al Nature Med. 2011;17:

13 Is supar the FSGS permeability factor? Angiopoeitin-like Protein 4 Patients with FSGS r=0.53, P=0.003 Bock ME et al. Clin J Am Soc Nephrol 8: ccc ccc, Clement LC et al. Nature Med 2011;17: Chugh SS et al. Am J Kidney Dis 2012;59: CD80 Ishimoto T et al. Semin Nephrol 2011;31: Ishimoto T et al. Nephrol Dial Transplant 2013;28: Summary Glomerular injury mediated through a variety of pathogenetic mechanisms May be primary or secondary to underlying causes (infectious, autoimmune, paraneoplastic, genetic, toxic) Similar pathogenetic mechanisms may be associated with different clinical and histologic phenotypes Understanding of the pathogenetic mechanism determines approach to therapy 76