1. Anti-Glomerular Basement Membrane Disease
Dr.

2. Overview Anti-Glomerular Basement Membrane (Anti-GBM) Disease
Introduction
Epidemiology
Etio-Pathogenesis
Clinical presentation
Diagnosis
Treatment
Prognosis

3. 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 3

4. 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

5. RPGN: Histopathology

6. 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 6

7. RPGN: Clinical Summary (Contd)
Tests:
ANCA, anti-GBM antibodies, complement, ANA, and renal biopsy
Treatment:
Pulse steroids, Cyclophosphamide 7

8. 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)

9. 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

10. Anti GBM disease: Introduction (Contd)
Circulating antibodies against antigen in the GBM causing RPGN +/- pulmonary hemorrhage
Goodpasture’s syndrome if pulm. Hemorrhage 10

11. 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

12. Anti GBM disease: Introduction (Contd)
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

14. 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 14

15. 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 15

16. Anti GBM disease: Epidemiology (Contd)
Age
The incidence of anti-GBM nephritis is bimodal
The 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 16

17. 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-DRB 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

18. 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)

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

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

21. Anti-GBM Antibody Disease: Etio-pathogenesis (Contd)
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 21

22. 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 22

23. Anti-GBM Antibody Disease: Clinical presentation (Contd)
Systemic symptoms suggest ANCA vasculitis
Malaise, weight-loss, fevers, arthralgias 23

24. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

25. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

26. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

27. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

28. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

29. Anti-GBM Antibody Disease: Clinical presentation (Contd)
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

30. 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

31. 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

32. 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

33. Anti-GBM Antibody Disease: Workup (Contd)
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

34. Anti-GBM Antibody Disease: Workup (Contd)
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

35. Anti-GBM Antibody Disease: Workup (Contd)
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

36. Anti-GBM Antibody Disease: Workup (Contd)
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

37. Anti-GBM Antibody Disease: Workup (Contd)
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

38. Anti-GBM Antibody Disease: Workup (Contd)
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 38

39. Anti-GBM Antibody Disease: Workup (Contd)
Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the collapse of glomerular tuft.

40. Anti-GBM Antibody Disease: Workup (Contd)
Renal Biopsy:
Necrotizing and crescenteric GN on light microscopy
Light 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 40

41. Anti-GBM Antibody Disease: Workup (Contd)
Renal Biopsy:
Immunoflourescence- linear IgG deposition along glomerular capillaries
Characteristic 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 41

42. Anti-GBM Antibody Disease: Workup
(Contd)
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.

43. Anti-GBM Antibody Disease: Workup (Contd)
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

44. Anti-GBM Antibody Disease: Workup (Contd)
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 44

45. 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

46. 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

47. Anti-GBM Antibody Disease: Treatment (Contd)
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, treatments are required

48. Anti-GBM Antibody Disease: Treatment (Contd)
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

49. Anti-GBM Antibody Disease: Treatment (Contd)
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

50. Anti-GBM Antibody Disease: Treatment (Contd)
Immunosuppression
Immunosuppression usually includes high doses of steroids and cyclophosphamide
Cyclophosphamide is administered at a dose of 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 /µL
High-dose steroids are also administered along with cyclophosphamide.

51. Anti-GBM Antibody Disease: Treatment
Steroids
Methylprednisolone 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 mo
Cyclophosphamide (Cytoxan)
2 mg/kg/day PO x 3 months
IV if can’t take PO, unreliable, severe renal failure and oliguria 51

52. Anti-GBM Antibody Disease: Treatment (Contd)
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

53. 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

54. Anti-GBM Antibody Disease: Treatment (Contd)
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

55. Anti-GBM Antibody Disease: Treatment (Contd)
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)

56. Anti-GBM Antibody Disease: Treatment (Contd)
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

57. Anti-GBM Antibody Disease: Treatment (Contd)
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

58. Anti-GBM Antibody Disease: Complications
Respiratory failure
Hemorrhagic shock
Renal failure

59. 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

60. 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

61. Anti-GBM Antibody Disease: Prognosis (Contd)
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

62. Anti-GBM Antibody Disease: Prognosis (Contd)
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

63. Anti-GBM Antibody Disease: Prognosis (Contd)
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

64. Thank You!
Thank You!