Anti GBM Disease

Anti-Glomerular Basement Membrane Disease

Dr.

Overview Anti-Glomerular Basement Membrane

(Anti-GBM) Disease Introduction Epidemiology Etio-Pathogenesis Clinical presentation Diagnosis Treatment Prognosis

RPGN

Rapidly progressive (crescenteric) GN Increase in Cr over days to weeks >50% loss of kidney function Extensive (>50%) crescent formation Proliferative or necrotizing injury to

glomerular capillary wall (rents) letting plasma and fibrinogen into Bowman’s space, forming fibrin, bringing in macrophages, T cells, releasing cytokines

GN- Glomerulonephritis

RPGN (Contd)

Type 1: Anti-GMB Type 2: Immune Complex

IgA, postinfectious, lupus, mixed cryoglobulinemia

Type 3: Pauci-immune Most are P-ANCA, some ANCA neg

Type 4: Double-antibody positive Features of type 1 and 3

RPGN: Histopathology

RPGN: Clinical Summary

Acute macroscopic hematuria, decreased urine output, edema

Insidious fatigue and edema

Renal insufficiency, dysmorphic hematuria, red cell casts, other casts, proteinuria

Pulmonary hemorrhage and hemoptysis

RPGN: Clinical Summary (Contd)

Tests:

ANCA, anti-GBM antibodies, complement, ANA, and renal biopsy

Treatment:

Pulse steroids, Cyclophosphamide

Anti GBM disease: Introduction In 1919, E.W. Goodpasture described a 19-

year-old man with fatal lung hemorrhage and glomerulonephritis

In 1958, Stanton and Tange introduced the term Goodpasture syndrome to describe patients with these conditions The syndrome was subsequently shown to be

caused by an antibody response against antigens present in the glomerular basement membrane (GBM)

Anti GBM disease: Introduction (Contd)

Anti-GBM disease (also k/as Goodpasture’s disease/syndrome) Rare autoimmune disorder characterized

by Circulating autoantibodies directed to

specific antigenic targets within the glomerular and/or pulmonary basement membrane

Am J Nephrol 2010;32:482–90


Circulating antibodies against antigen in the GBM causing RPGN +/- pulmonary hemorrhage

Goodpasture’s syndrome if pulm. Hemorrhage

Anti GBM disease: Introduction(Contd)

Untreated anti-GBM disease has an almost universally poor outcome with death from renal failure or lung hemorrhage Even with extensive treatment, kidney

damage is irreversible Patients with severe renal involvement

are often left with permanent renal failure and face a life of renal replacement therapy

Am J Nephrol 2010;32:482–90


Due to its Acute onset, rapid progression,

irreversibility and high mortality, Anti-GBM disease represents a great

challenge in the field of nephrology

Am J Nephrol 2010;32:482–90

Anti GBM disease: Epidemiology

< 1 case per million population Although rare, anti-GBM disease is often

lethal, As most of the patients present with rapidly

progressive GN that accounts for up to 20% of acute renal failure

Anti GBM disease: Epidemiology (Contd)

Young men and elderly women are more prone to anti-GBM disease

More pulm involvement if < 30 yo, M>F Isolated RPGN if > 50 yo, F>M

Anti GBM disease: Epidemiology (Contd)

AgeThe incidence of anti-GBM nephritis is

bimodalThe first, and larger, peak occurs in the 2nd

and 3rd decade of life. Men in this age group are more susceptible than women in this age group

The second, and smaller, peak occurs in the 6th and 7th decades of life, and women in this age group have a higher preponderance of the disease than men in this age group

Anti-GBM Antibody Disease: Etio-pathogenesis Causes The disease is caused by autoantibodies directed

against the NC1 domain of the alpha-3 chain of type IV collagen

Genetic susceptibility Anti-GBM disease shows a strong association with HLA-

DR2 Further molecular genetics studies of HLA-DR2 reveal

that the association of anti-GBM nephritis is with HLA-DRB1 alleles (HLA-DRB1 1501 and 1502 alleles), HLA-DQA1 01 alleles, and HLA-DQB1 06 alleles

Anti-GBM nephritis is major histocompatibility complex–restricted HLA-DRB1*1501 and 1502 alleles increase the

susceptibility, while HLA-DR1 and HLA-DR7 are protective

Anti-GBM Antibody Disease: Etio-pathogenesis (Contd)

Causes Environmental factors

A number of studies suggest a strong association between pulmonary hemorrhage and smoking

Pulmonary hemorrhage may also be associated with exposure to hydrocarbons or other agents (eg, respiratory pathogens)


A large body of evidence indicates that genetics might play an important role in anti-GBM disease

Over the past few years, the nature of the autoantigen and its epitopes has been defined, as well as the possible pathogenic role played by environmental factors, and by cellular and humoral immunity However, the majority of data on anti-GBM

disease comes from studies conducted on animal models, since human studies are relatively scarce

Am J Nephrol 2010;32:482–90


Genetic studies have highlighted strong positive associations of anti-GBM disease with the HLA-DRB1 * 1501 allele

In addition, the disease has been associated with genes of the FCGR and KLK families

Important as they are, these findings have to be considered preliminary, if not contentious.

Am J Nephrol 2010;32:482–90


IgG against the NC1 domain of the alpha-3 chain of type IV collagen [alpha-3(IV)] on 2q35-37 The epitope is about 9 amino acids long Can rarely be IgA or IgM

Alpha-3(IV) is concentrated in glomeruli and alveoli

Prior lung disease is RF for pulm involvement

Anti-GBM Antibody Disease: Clinical presentation

Like other RPGN: ARF, nephritic sediment (look at the urine!), non-nephrotic proteinuria

Alveolar hemorrhage: 60-70% of pts SOB, cough, hemoptysis, infiltrates, high

DLCO Iron deficiency anemia if prolonged Smokers, lung infections, cocaine,

hydrocarbon

Anti-GBM Antibody Disease: Clinical presentation (Contd)

Systemic symptoms suggest ANCA vasculitisMalaise, weight-loss, fevers, arthralgias


History Patients with anti-GBM nephritis can present

with GN alone or with accompanying pulmonary hemorrhage

Although pulmonary hemorrhage may be minor, it is often severe and life threatening

Pulmonary hemorrhage occurs more frequently in young adult males, whereas anti-GBM nephritis without lung involvement tends to occur more frequently in women in their seventh decade of life


The disease may begin with either renal or pulmonary manifestations Usually, both organs are involved more

or less simultaneously However, in several cases, the interval to

the second organ's involvement may be prolonged up to a year


Prodromal period In 25-30% of patients, a prodromal

period of flulike illness occurs In approximately 5% of patients,

arthralgia, myalgia, and arthritis are prominent features


Pulmonary manifestations The onset of pulmonary hemorrhage may be

insidious, with symptoms such as anemia, pallor, weakness, lethargy, dyspnea upon exertion, and, sometimes, dry cough

In some cases, onset is acute and includes fever, massive hemoptysis, acute respiratory failure, asphyxia, and death; however, in many cases, the symptoms,

including hemoptysis, dyspnea, cough, fever, tachycardia, and fatigue, may be present intermittently for weeks to months before the diagnosis is established


Renal manifestations The patient usually presents with an

abrupt onset of oliguria or anuria Hematuria or the passage of tea-colored

urine is usually observed Rarely, the patient's renal involvement is

more insidious in onset and he or she remains asymptomatic, progressing slowly until the development of uremic symptoms


Physical Physical examination in the acute stage of the

disease reveals respiratory distress, tachycardia, and cyanosis

The patient usually appears pale because of anemia

In severe cases, the patient may be in hemorrhagic shock and in respiratory failure, thus requiring volume resuscitation and ventilatory support, respectively.

Chest examination may reveal fine rales and dullness to percussion over the affected lung areas

Anti-GBM Antibody Disease: Differential diagnosis

Acute Renal Failure Hemolytic-Uremic Syndrome Churg-Strauss Syndrome Microscopic Polyangiitis Glomerulonephritis, Crescentic Thrombotic Thrombocytopenic Purpura Glomerulonephritis, Rapidly Progressive Wegener Granulomatosis

Anti-GBM Antibody Disease: Workup Laboratory Studies Urinalysis: A urinary dipstick test and a 24-hour urine

collection to test for protein and creatinine should be performed for detection of hematuria and proteinuri Urinary sediment should be analyzed using microscopy to detect dysmorphic red blood cells and cellular casts Hematuria: Urinary sediment frequently reveals

dysmorphic red blood cells and red blood cell casts Proteinuria: This is usually absent in the early years

of life Proteinuria usually progresses with age and may be in

the nephrotic range in up to 30% of patients

Anti-GBM Antibody Disease: Workup (Contd)

Blood chemistry and CBC count Blood chemistry: Patients usually have elevated

blood urea nitrogen and serum creatinine levels Serum bicarbonate levels are usually low, and serum

phosphate levels may be elevated because of renal failure

CBC count: This may show low hemoglobin and hematocrit levels, reflecting blood loss from pulmonary hemorrhage Serial analysis may be helpful for monitoring blood loss Low hemoglobin levels can also be due to advanced

renal failure The platelet count is usually within reference ranges A mild leukocytosis is often observed


Complement levels and serology Complement: levels are usually within reference

ranges Antineutrophil cytoplasmic antibodies (ANCA)

These test findings are usually negative However, approximately 25-30% patients with

anti-GBM disease have circulating ANCA Of these patients, approximately 75% have

perinuclear ANCA; the remaining 25% have cytoplasmic ANCA


Serology: Circulating anti-GBM antibodies: More than 95% of patients with anti-GBM

nephritis have circulating anti-GBM antibodies The antibodies are usually of the

immunoglobulin G (IgG) class, although Ig A or Ig M anti-GBM antibodies are occasionally observed They can be detected using

Indirect immunofluorescence assays, usually using monkey kidneys as the substrate, or by

Radioimmunoassay or enzyme-linked immunosorbent assay (ELIZA), which use human recombinant GBM antigens


Serology: Circulating anti-GBM antibodies: Radioimmunoassay and ELISA are more sensitive

and specific than indirect immunofluorescence assays

Currently, ELISA is most commonly used to help detect circulating anti-GBM antibodies Highly sensitive However, their specificity varies depending

upon the antigen used for the assay


Imaging Studies Renal ultrasound: In the early stages, renal ultrasound

shows normal-sized kidneys However, with advancing renal failure, the

kidneys shrink and become echogenic


Procedures Unless contraindicated, a renal biopsy

should be promptly performed in every case

Rapid diagnosis is necessary to assess the degree of crescentic involvement and the extent of fibrosis and to exclude other disease processes Furthermore, prompt diagnosis is essential

in order to start specific treatment as early as possible to preserve renal function


Renal Biopsy: Necrotizing and crescenteric GN on light microscopy Light microscopy reveals the presence of

crescents in > 95% of patients and approx. 80% of patients show crescents involving > 50% glomeruli)

In early stages, the crescents are cellular and associated with necrotizing glomerular lesions They gradually evolve into fibrotic crescents

and glomerular sclerosis Focal rupture of the GBM and fibrinoid necrosis

of glomeruli are usually observed


Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the collapse of glomerular tuft.


Renal Biopsy: Necrotizing and crescenteric GN on light

microscopyLight microscopy

In severe cases, rupture of the Bowman capsule ensues

Tubulointerstitial changes, including interstitial edema and inflammation and tubular damage, are usually observed along with glomerular injury

If necrotizing inflammation is observed in arteries or arterioles, the possibility of concurrent ANCA-associated glomerulonephritis should be considered


Renal Biopsy: Immunoflourescence- linear IgG deposition along

glomerular capillariesCharacteristic linear deposition of IgG

(rarely Ig A or Ig M) antibodies along the GBM

Linear staining for IgG may also occur along the tubular BM

Weak linear staining of the GBM is frequently observed in persons with diabetic nephropathy, but Clinical data and light microscopic features

can easily distinguish the 2 conditions

Immunofluorescent examination of a kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.



Electron microscopy findings reflect those observed with light microscopy and include The presence of crescents, disruption of

the GBM, and cellular infiltration at the sites of necrosis


ANCA: can have both (Type 4): Wegener’s or MPA 10-38% of anti-GBMs are + ANCA, usually MPO Repeat if negative but disease recurs

Anti-GBM Antibody Disease: Treatment

Medical Care Anti-GBM nephritis is a rapidly

progressive disease with a high mortality rate if not treated Therefore, a prompt diagnosis and early

treatment are of paramount importance in preventing death and preserving renal function

Anti-GBM Antibody Disease: Treatment (Contd)

The usual treatment for anti-GBM nephritis uses plasmapheresis in combination with intense immunosuppression consisting of corticosteroids and cyclophosphamide or azathioprine Other therapeutic options include

immunoadsorption using protein A affinity columns or treatment with cyclosporine


Plasmapheresis Since the first successful treatment by Lockwood

and colleagues in 1976, plasmapheresis has become the standard treatment of anti-GBM nephritis The therapy effectively removes circulating

anti-GBM antibodies and consists of removal of 1 volume of plasma (usually 4 L) and replacement with an equal volume of 5% albumin

Plasmapheresis is continued daily until anti-GBM antibodies are undetectable in the blood Usually, 10-14 treatments are required


Plasmapheresis In patients with pulmonary hemorrhage, replace

clotting factors by administering fresh frozen plasma at the end of treatment

An early series of studies suggested that oliguric patients and those on dialysis before treatment rarely improve with plasmapheresis However, more recent reports suggest that

patients with advanced renal disease occasionally do respond, particularly if they are not anuric or if the biopsy specimen reveals a low proportion of sclerosed glomeruli


Protein A immunoadsorption Several investigators have reported the successful

use of immunoadsorption with protein A in patients with anti-GBM nephritis who do not respond to plasmapheresis

Protein A, isolated from the cell wall of the Staphylococcus aureus Cowan I strain, binds to the Fc portions of IgG Thus, separated plasma from the patient is pumped

through a protein A-Sepharose column to enable anti-GBM antibodies to bind, and the plasma is then returned to the patient

This prevents depletion of coagulation factors and other essential plasma proteins and obviates the need for large-volume replacement of fluids


Immunosuppression Immunosuppression usually includes high doses of

steroids and cyclophosphamide Cyclophosphamide is administered at a dose of 2-2.5

mg/kg/d Adjust the dose of cyclophosphamide according to the

degree of renal impairment Administer cyclophosphamide for at least 1 year after

remission, and then taper in 25-mg decrements every 2-3 months until discontinuation or disease recurrence

Monitor the total leukocyte count frequently, and maintain it between 3000-5000/µL

High-dose steroids are also administered along with cyclophosphamide.

Anti-GBM Antibody Disease: Treatment

Steroids Methylprednisolone 15-30 mg/kg up to 1 g over

20 minutes IV qd x 3 days Then oral prednisone 1 mg/kg qd up to 60-80, 9

moCyclophosphamide (Cytoxan)

2 mg/kg/day PO x 3 months IV if can’t take PO, unreliable, severe renal

failure and oliguria


Immunosuppression The role of pulse steroids is not clear in persons

with anti-GBM nephritis, but some centers usually administer pulse steroids in patients with fulminant disease

Typically, methylprednisolone is given in dosages of 7-17 mg/kg/d for 3 consecutive days

Thereafter, oral prednisolone is started at a dosage of 1 mg/kg/d for 4 weeks and tapered slowly to 20 mg on alternate days by week 52 and withdrawn, as tolerated, thereafter

Anti-GBM Antibody Disease: Consultations

Consultation with pulmonary and critical care specialists is needed in patients presenting with hypoxia due to severe pulmonary hemorrhage These patients may require intubation

and mechanical ventilation Furthermore, they may present with

hemorrhagic shock and require hemodynamic monitoring in an intensive care unit


Diet Place patients with renal failure on a diet

restricted to 2 g of sodium per day, 60 mEq of potassium per day, and 0.85 g/kg of protein per day

Activity Patients may engage in activities as

tolerated


Follow up: Further Inpatient Care Patients presenting with respiratory failure may

require intubation and mechanical ventilation Furthermore, patients may present with

hemorrhagic shock and require blood transfusion and hemodynamic monitoring

Patients presenting with advanced renal failure may require short- or long-term dialysis.

While in the hospital, patients should also receive supportive care (eg, adequate nutrition, prophylaxis for deep vein thrombosis and stress ulcers, good blood pressure control)


Follow up:Further Outpatient Care After discharge from the hospital, patients need a detailed

follow-up visit with a nephrologist Renal function should be closely monitored for progression of

renal disease or recurrence of anti-GBM nephritis Patients should also have their blood cell counts checked

frequently while they are taking cyclophosphamide because they are at high risk for hemorrhagic cystitis or transitional cell carcinoma of the urinary bladder Therefore, their urine should be screened for nonglomerular

hematuria; all patients with nonglomerular hematuria should undergo a further urological evaluation

Patients with anti-GBM nephritis who are taking high doses of steroids are at a high risk of developing osteoporosis Therefore, they should receive calcium and vitamin D

supplements (1000 mg/d elemental calcium for men and 1500 mg/d for women). Bone densitometry may also be performed to check for osteoporosis


Follow up:Further Outpatient Care Patients receiving immunosuppression in high doses

are also at risk for opportunistic infections They should be placed on a single-strength tablet of

trimethoprim-sulfamethoxazole per day for prophylaxis of Pneumocystis carinii infection

In addition, patients should rinse their mouths several times a day to prevent oral thrush and, if necessary, be given nystatin swish and swallows

Patients who take high doses of steroids are prone to develop diabetes and hypertension Thus, they should be screened for diabetes and have

their blood pressure checked frequently

Anti-GBM Antibody Disease: Complications

Respiratory failure

Hemorrhagic shock

Renal failure

Anti-GBM Antibody Disease: Prognosis

Survival correlates with renal impairment at presentation Creatinine > 5 = > 75% crescents If untreated, death or HD in >90% of pts If need immediate HD or has 100%

crescents, unlikely to recover renal function

Anti-GBM Antibody Disease: Prognosis (Contd)

After treatment, relapse is rare. Higher in smokers, hydrocarbon exposure, and +ANCA

Those w/ Cr < 3, < 30% crescents do well


In the early years, the mortality rate was extremely high (approximately 90-95%) With the introduction of

immunosuppression and plasmapheresis, patient and renal survival rates are approximately 85% and 60%, respectively


Both renal survival and patient survival depend on the severity of the disease at the time of presentation

Importance of rapid diagnosis and prompt institution of aggressive immunosuppression therapy for patients with Goodpasture syndrome and severe renal failure Patients who present with a serum creatinine level of

< 500 µmol/L (5.7 mg/dL) have 1-year patient and renal survival rates of 100% and 95%, respectively

Patients who present with a serum creatinine level of > 500 µmol/L (5.7 mg/dL) but do not require dialysis have 1-year patient and renal survival rates of 83% and 82%, respectively

Patients who present with dialysis-dependent renal failure have 1-year patient and renal survival rates of 65% and 8%, respectively


Importantly, patients with advanced renal disease at the time of presentation (ie, oliguric or dialysis dependent) do not usually respond to plasmapheresis, methylprednisolone, or other immunosuppressive therapy Other poor prognostic factors include

Extensive crescent formation (>50%), The presence of significant tubular atrophy, Interstitial fibrosis or glomerulosclerosis, Oliguria or anuria, and Serum creatinine level of > 6 mg/dL Patients with HLA-DR W2 and HLA-B7 appear to have a

more malignant course

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Anti GBM Disease

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