Anti-GBM Diseases

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Overview of renal disease with anti-GBM involvement

Overview of renal disease with anti-GBM involvement

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  • 1. Anti-GBM Diseases Amanda Valliant, MD Nephrology Fellow 11.28.12
  • 2. Objectives: Epidemiology Pathogenesis Clinical Presentation Laboratory and Pathology Findings Treatment Prognosis
  • 3. Epidemiology Acute GN due to anti-GBM antibody disease is rare, estimated in <1 per million <20% of RPGN cases Bimodal distribution young males (3rd decade) and older females (6th decade) most typical Disease limited to the kidney more common in older patients Less common in blacks, likely due to HLA antigen differences
  • 4. Nomenclature Goodpasture’s Syndrome • Used to describe clinical findings of GN and pulmonary hemorrhage Goodpasture’s Disease • Triad of proliferative GN (usually crescentic), pulmonary hemorrhage, anti-GBM antibodies Anti-GBM Disease • Anti-GBM antibodies + GN
  • 5. Chelsea Naval Hospital Circa 1918Dr. Ernest Goodpasture 1955 Vanderbilt Laboratory1919—looking at pathologicfeatures of influenza in the lungpatient with systemic diseaseand pulmonary + renal involvement
  • 6. A lesson in history… 1919: Goodpasture described the case of an 18-yo man who died with lung hemorrhage and acute GN 1958: Clinical picture of pulmonary renal syndrome described by Stanton and Tage and named after Dr. Goodpasture Anti-GBM antibodies discovered in 1967 • Lerner, et al. conducted famous studies with antibodies eluted from the serum of Goodpasture’s patients transferred to monkeys who developed proliferative GN
  • 7. Table 1 Differential Diagnosis in Patients Presenting Clinically with Pulmonary-Renal Syndrome- NECROTIZING SMALL-VESSEL VASCULITIS* PR3- and MPO-ANCA associated (MPA, WG, CSS)* Anti-GBM disease* Other vasculitides (Henoch-Schönlein purpura, SLE, cryoglobulinemia, drug induced)- CATASTROPHIC ANTI-PHOSPHOLIPID SYNDROME- RENAL FAILURE WITH VOLUME OVERLOAD / CARDIAC FAILURE* Chronic/acute glomerulonephritis, diabetes* Atherosclerosis/hypertensive nephrosclerosis* Microangiopathic renal failure/hemolytic uremic syndrome- RENAL FAILURE ASSOCIATED WITH PULMONARY INFECTION* Legionella, mycoplasma, streptococcus* Hemorrhagic fever with renal syndrome (eg, Hantavirus)- ENDOCARDITIS- SIRS/SEPSIS WITH MULTIORGAN FAILURE- CARDIOVASCULAR (eg, renal artery stenosis) Sanders, et al. 2011
  • 8. Pathogenesis Antibodies directed against an antigen intrinsic to the GBM • Antibodies may precede clinical signs by weeks or months • Typically IgG1 or IgG3 antibodies • Principal target is the NC1 domain of the alpha-3 chain of type IV collagen
  • 9. Varied Presentations of Anti-GBM Disease In anti-GBM disease the pulmonary hemorrhage may precede, occur concurrently with, or follow the glomerular involvement Some patients with anti-GBM antibodies and GN and hence “anti-GBM” disease never experience pulmonary involvement and thus do not have true “Goodpasture’s syndrome.” (perhaps 60%) Typical presentation is relatively acute renal failure with urinalysis showing proteinuria and a nephritic sediment • Typically not nephrotic range proteinuria • Dysmorphic RBCs, WBCs, red cell and granular casts
  • 10. Clinical Presentation Systemic complaints typically absent • Malaise, weight loss, fever, arthralgia • May suggest concurrent vasculitis Relatively mild degree of renal involvement may be more common than previously thought • Retrospective analysis in Australia found 36% (5/14) had previous findings of hematuria and/or proteinuria with normal creatinine
  • 11. Antibodies bind tightly and rapidly to the GBM, which has been demonstrated in passive transfer experiments in which antibody obtained from the plasma of patients with the disorder are infused into animals.Titers of antibodies directed againstthe N-terminus of the NC1 domaincorrelate directly with renal survival.Hellmark, et al. Kidney International, 1999.
  • 12. Subendothelial deposits of circulating immune complexes mostcommon, with subepithelial deposits rarely seen.
  • 13.  Anti-GBM autoantibodies react with epitopes on the noncollagenous domain of the α-3 and -5 chains of type IV collagen. The antigenic epitope has been localized between amino acids 198 and 237 of the terminal region of the α-3 chain. The α-3 chain of type IV collagen is found predominantly in the GBM and alveolar capillary basement membranes, which correlates with the limited distribution of disease involvement in Goodpasture’s syndrome Cryptic epitope??
  • 14. Pathogenesis: Antigen Structure The alpha-3 chain forms a triple helix with alpha 4/5 chains, combining with another triple helix to form a hexamer The antibodies DO NOT BIND the intact hexamer, binding only when it dissociates In vivo studies indicate that the alpha 3 epitopes are sequestered under normal circumstances (hidden) and become exposed due to some disruption of the GBM
  • 15. Pathogenesis: Autoreactive T Cells T cell infiltrates typically found on biopsy T cell proliferative response found with exposure to α-3 IV NC1 domain (serum from patients with anti-GBM) Regulatory T cells (CD4/25+) that counter the effects of autoreactive cells reduce the severity of lesions in murine anti-GBM GN Correlation found between number of autoreactive T cells and disease activity
  • 16. Role of epidermal growth factor? constitutively expressed in the kidney, activation linked with RPGNIn RPGN there is an accumulation of CD4 T cells and macrophages in the tuft, proliferation of endogenousglomerular cells, development of cellularcrescents that result from capillary damage and leakage of plasmaproteins into Bowman’s space. Crescents consist of fibrous material and proliferatingcells arising from the parietal epithelium and podocytes as well as infilatrating macrophages and fibroblasts.
  • 17. Antigenic Triggers Smoking Exposure to hydrocarbons Lithotripsy Pulmonary Infections Secondary GN process Degradation by reactive oxygen species Damage to the GBM revealing the epitope? Damage to alveolar capillaries allowing circulating antibody to interact?
  • 18. Genetic Susceptibility Patients with HLA-DR15 and DR4 appear to be at increased risk • Association with DR15 confirmed in Chinese and Japanese studies • Molecular analysis has revealed a particular 6 amino acid motif common to both that may confer susceptibility DR1 and DR7 appear to be at lesser risk
  • 19. Diagnosis Pulmonary hemorrhage can be seen with other acute nephritides • SLE, ANCA+ vasculitis, patients with pulmonary edema Diagnosis requires demonstration of anti-GBM antibodies in serum or kidney Renal biopsy should be done unless there is a contraindication
  • 20. Renal Biopsy Light microscopy typically shows crescentic glomerulonephritis Immunofluorescence demonstrates pathognomonic findings of linear IgG deposition along the capillaries and occasionally distal tubules (occasionally IgA or IgM) Linear IgG staining can be seen in 2 other disorders: • Diabetic Nephropathy • Fibrillary Glomerulonephritis **staining typically not as strong as with anti-GBM
  • 21. Pathology Findings
  • 22. FIGURE 32-21 Anti–glomerular basement membrane disease  (Goodpasture’s syndrome). There is diffuse crescentic  glomerulonephritis with large circumferential cellular crescents and severe compression of the glomerular tuft (periodic acid–Schiff, ×80).  Brenner and Rector’s The Kidney
  • 23. FIGURE 32-22 Anti–glomerular basement membrane disease  (Goodpasture’s syndrome). Immunofluorescence photomicrograph  showing linear glomerular basement membrane deposits of immunoglobulin G. Some of the glomerular basement membranes are  discontinuous, indicating sites of rupture (×800).   Brenner and Rector’s The Kidney
  • 24. Serologic Testing Indirect Immunofluorescence  • Requires an experienced renal pathologist • Fluorescein-labeled anti-human IgG added to  incubation of the patient’s serum with normal renal  tissue ELISA serum assay for anti-GBM antibodies • Specificity can be confirmed by Western blot • Sensitivity varies by kit (63% to almost 100%) • False negatives in Alport syndrome patients
  • 25. Antineutrophil Cytoplasm Antibodies Should be tested in any patient with acute GN with  or without pulmonary findings • 10-38% of patients with anti-GBM also ANCA+ (usually  MPO) Low levels of ANCA may be detectable years before  production of anti-GBM antibody and onset of  symptoms Clinically relevant because patients with ANCA may  have more treatable disease than anti-GBM + only • Tailor long-term management to vasculitis treatment • These patients may have relapses of systemic vasculitis
  • 26. Retrospective military analysis of 30 patients who  ultimately developed anti-GBM disease:Looked back 30 years at stored serum samples obtained at the time   of enlistment and every other year afterPatients diagnosed with anti-GBM and healthy controls were identified   from the military databaseCompared with matched controls, a greater number of patients with     anti-GBM disease had PR3-ANCA and MPO-ANCA levels detected in     multiple serum samples obtained in the years prior to clinical disease82% versus 14% control for PR3-ANCA72% versus 27% control for MPO-ANCAIn all cases, ANCA were detected in earlier samples than anti-GBM antibodies that were detected months prior to onset of symptoms (but not years).  Mechanism of ANCA in disease pathogenesis not clear.   Olson, et al.  J Am Soc Nephrol, 2011.
  • 27. Treatment Plasmapheresis + Prednisone  + Cyclophosphamide • Plasmapheresis removes  circulating anti-GBM  antibodies and complement • Immunosuppression  minimizes new antibody  formation 40-45% will benefit by not  progressing to ESRD or death  when treated with this  combination • Recovery more likely in non- oliguric patients  • Patients on dialysis or with  100% crescents on renal  biopsy unlikely to respond to  treatment
  • 28. To pherese or not to pherese? 1 randomized trial evaluated outcomes among 17 patients  prednisone and cyclophosphamide alone or with plasmapheresis • 2/8 patients with plasmapheresis progressed to ESRD compared  with 6/9 in the immunosuppression group • % crescents on initial renal biopsy and entry plasma creatinine  correlated better with outcomes • Patients with creatinine <3 and <30% crescents did well • Creatinine >4 and severe crescentic involvement did not Typically recommended based on 2 factors:   • improved morbidity and mortality in the era of plasmapheresis  when compared to historic rates • The “common sense” argument of greater reduction of disease  consequences with rapid removal of anti-GBM antibody Johnson, et al. Medicine, 1985.
  • 29. Plasmapheresis Typically daily or alternate day 4-liter exchanges for 2-3 weeks Albumin given as replacement fluid 1-2 units of FFP at the end of the procedure should be  substituted for albumin if recent hemorrhage or biopsy to  reverse depletion of coagulation factors by pheresis Monitor for metabolic alkalosis with FFP administration  Recheck antibody titers after regimen, may need to continue  for another 2-3 weeks
  • 30. Immunosuppressants Methylprednisolone 15-30 mg/kg to  a max of 1000 mg IV for 3 doses • Followed by daily oral prednisone (max  60-80 mg per day) Oral cyclophosphamide 2 mg/kg per  day initial dosing • Not to exceed 100 mg/day in those  patients > 60 years due to toxicity
  • 31. Treatment Duration Optimal timing unknown, may take 6-9 months for cessation of antibody formation Maintenance therapy with prednsione and azathioprine typically given after remission induced • Some use 3 months of prednisone and cyclophosphamide therapy if titers negative • Anti-GBM antibody levels should be monitored every 1-2 weeks Patients presenting with dialysis-dependant renal failure  must weigh risks of treatment
  • 32. Treatment: Patient Selection Retrospective review of 71 Plasma Patient Renal patients treated with the Creatinine Survival Survival typical triad @ 1 year @ 1 year Among 42 patients with <5.7mg/dL 100% 95% pulmonary hemorrhage, bleeding resolved in 90% >5.7mg/dL No urgent 83% 82% Dialysis All patients with crescents Requiring urgent 65% 8% in all glomeruli on biopsy dialysis required long-term dialysis Levy, et al. Ann Intern Med, 2001
  • 33. Treatment: Patient Selection Recommendations are to treat with pheresis + immunosuppression in the following situations: • Pulmonary hemorrhage, regardless of renal involvement • Patients with renal involvement NOT requiring immediate RRT • Most patients with less severe disease (30-50% crescents) although they may do well with methylprednisolone followed by oral prednisone **Some consider a short trial of combination therapy in patients with very acute disease, younger patients, patients with ANCA+ and clinical signs of vasculitis (purpura, arthralgias) as they may recover function. Levy, et al. Ann Intern Med, 2001
  • 34. Complications of Therapy Infection • May be exacerbated by plasmapheresis and require IVIG infusion • High dose steroids  multiple adverse effects Cyclophosphamide-related • Increased risk of PJP • Amenorrhea • Bladder toxicity (cystitis, bladder CA)
  • 35. Novel Therapy Suppression of T Cell involvement via blockade of CD28-B7 (co-stimlatory pathyway for T cell activation) • Fusion protein CTLA41g evaluated in rat model of anti- GBM • Development of crescentic GN completely prevented • No human studies done yet
  • 36. Prognosis In general, patients who survive the first year with intact renal function do well Survival (patient and renal) closely correlates with degree of renal impairment at diagnosis Few requiring immediate dialysis recover renal function Relapses uncommon  2% in a single center study, clinically more common with ANCA+ patients Higher rate of recurrence in smokers
  • 37. Post-Transplantation Disease Occurs in 5-10% of renal transplants in patients with underlying hereditary nephritis (Alport Syndrome) Commonly have abnormality in the alpha-5 type IV collagen chain • May also have alpha-3 or alpha-4 mutation • Defective organization of alpha 3,4,5 chains in the GBM leads to altered Goodpasture antigen in the alpha 3 chain • Altered antigen not recognized by the GBM antibody • Donor kidney has normal antigen, which elicits an immune response against the “new” antigen in the transplanted kidney • Alloantibody produced recognizes a different epitope than the autoantibody in Goodpasture’s disease
  • 38. References: Levy JB, Turner AN, Rees AJ, et al. Long term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppressants. Ann Intern Med. 2001;134(11):1033. Taal: Brenner and Rector’s The Kidney, 9th Ed. Chapter 32: Secondary Glomerular Diseases. 2012:1224-1226 www.unckidneycenter.org www.uptodate.com *Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture’s) disease *Treatment of anti-GBM antibody (Goodpasture’s) disease