Anti-GBM DiseasesAnti-GBM Diseases

Amanda Valliant, MDAmanda Valliant, MD

Nephrology FellowNephrology Fellow

11.28.1211.28.12

Objectives: Objectives:

EpidemiologyEpidemiology PathogenesisPathogenesis Clinical PresentationClinical Presentation Laboratory and Pathology FindingsLaboratory and Pathology Findings Treatment Treatment PrognosisPrognosis

EpidemiologyEpidemiology Acute GN due to anti-GBM antibody disease is Acute GN due to anti-GBM antibody disease is

rare, estimated in <1 per millionrare, estimated in <1 per million

<20% of RPGN cases<20% of RPGN cases

Bimodal distributionBimodal distribution young males (3 young males (3rdrd decade) decade) and older females (6and older females (6thth decade) most typical decade) most typical

Disease limited to the kidney more common in Disease limited to the kidney more common in older patientsolder patients

Less common in blacks, likely due to HLA antigen Less common in blacks, likely due to HLA antigen differencesdifferences

NomenclatureNomenclature Goodpasture’s SyndromeGoodpasture’s Syndrome

• Used to describe clinical findings of GN and Used to describe clinical findings of GN and pulmonary hemorrhagepulmonary hemorrhage

Goodpasture’s DiseaseGoodpasture’s Disease• Triad of proliferative GN (usually crescentic), Triad of proliferative GN (usually crescentic),

pulmonary hemorrhage, anti-GBM antibodiespulmonary hemorrhage, anti-GBM antibodies

Anti-GBM DiseaseAnti-GBM Disease• Anti-GBM antibodies + GNAnti-GBM antibodies + GN

Dr. Ernest Goodpasture1955

Vanderbilt Laboratory

Chelsea Naval HospitalCirca 1918

1919—looking at pathologic features of influenza in the lung

patient with systemic disease and 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

PathogenesisPathogenesis Antibodies directed against an antigen Antibodies directed against an antigen

intrinsic to the GBMintrinsic to the GBM

• Antibodies may precede clinical signs by Antibodies may precede clinical signs by weeks or monthsweeks or months

• Typically IgG1 or IgG3 antibodiesTypically IgG1 or IgG3 antibodies

• Principal target is the NC1 domain of Principal target is the NC1 domain of the alpha-3 chain of type IV collagenthe 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 andrapidly to the GBM, whichhas been demonstrated in passive transfer experimentsin which antibody obtained from the plasma of patientswith the disorder are infusedinto animals.

Titers of antibodies directed againstthe N-terminus of the NC1 domain correlate directly with renal survival.

Hellmark, et al. Kidney International, 1999.

Subendothelial deposits of circulating immune complexes most common, 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

In RPGN there is an accumulation of CD4 T cells and macrophages in the tuft, proliferation of endogenous glomerular cells, development of cellularcrescents that result from capillary damage and leakage of plasma proteins 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.

Role of epidermal growth factor?

constitutively expressed in the kidney, activation

linked with RPGN

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

Pathology Findings

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 disease

82% versus 14% control for PR3-ANCA72% versus 27% control for MPO-ANCA

In 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.

PlasmapheresisPlasmapheresis Typically daily or alternate day 4-liter exchanges for 2-3 weeksTypically daily or alternate day 4-liter exchanges for 2-3 weeks

Albumin given as replacement fluidAlbumin given as replacement fluid

1-2 units of FFP at the end of the procedure should be 1-2 units of FFP at the end of the procedure should be substituted for albumin if recent hemorrhage or biopsy to substituted for albumin if recent hemorrhage or biopsy to reverse depletion of coagulation factors by pheresisreverse depletion of coagulation factors by pheresis

Monitor for metabolic alkalosis with FFP administration Monitor for metabolic alkalosis with FFP administration

Recheck antibody titers after regimen, may need to continue Recheck antibody titers after regimen, may need to continue for another 2-3 weeksfor another 2-3 weeks

ImmunosuppressantsImmunosuppressants

Methylprednisolone 15-30 mg/kg to a Methylprednisolone 15-30 mg/kg to a max of 1000 mg IV for 3 dosesmax of 1000 mg IV for 3 doses• Followed by daily oral prednisone (max Followed by daily oral prednisone (max

60-80 mg per day)60-80 mg per day)

Oral cyclophosphamide 2 mg/kg per Oral cyclophosphamide 2 mg/kg per day initial dosingday initial dosing• Not to exceed 100 mg/day in those Not to exceed 100 mg/day in those

patients > 60 years due to toxicitypatients > 60 years due to toxicity

Treatment DurationTreatment 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

patients treated with the typical triad

Among 42 patients with pulmonary hemorrhage, bleeding resolved in 90%

All patients with crescents in all glomeruli on biopsy required long-term dialysis

Levy, et al. Ann Intern Med, 2001

Plasma Creatinine

Patient Survival @ 1 year

Renal Survival @ 1 year

<5.7mg/dL 100% 95%>5.7mg/dLNo urgentDialysis

83% 82%

Requiring urgent dialysis

65% 8%

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: References:

Levy JB, Turner AN, Rees AJ, et al. Long term outcome of Levy JB, Turner AN, Rees AJ, et al. Long term outcome of anti-glomerular basement membrane antibody disease anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppressants. treated with plasma exchange and immunosuppressants. Ann Intern MedAnn Intern Med. 2001;134(11):1033.. 2001;134(11):1033.

Taal: Brenner and Rector’s The Kidney, 9Taal: Brenner and Rector’s The Kidney, 9thth Ed. Chapter 32: Ed. Chapter 32: Secondary Glomerular Diseases. 2012:1224-1226Secondary Glomerular Diseases. 2012:1224-1226

www.unckidneycenter.org www.uptodate.com

*Pathogenesis and diagnosis of anti-GBM antibody *Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture’s) disease(Goodpasture’s) disease

*Treatment of anti-GBM antibody (Goodpasture’s) disease*Treatment of anti-GBM antibody (Goodpasture’s) disease