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
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
Chelsea Naval Hospital Circa 1918Dr. Ernest Goodpasture 1955 Vanderbilt Laboratory1919—looking at pathologicfeatures of influenza in the lungpatient with systemic diseaseand pulmonary + renal involvement
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
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
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
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
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
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.
Subendothelial deposits of circulating immune complexes mostcommon, with subepithelial deposits rarely seen.
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??
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
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
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.
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?
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
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
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
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
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
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
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
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 afterPatients diagnosed with anti-GBM and healthy controls were identified from the military databaseCompared 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.
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
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.
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
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
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
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
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
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)
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
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
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
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