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

Anti GBM disease: Introduction

(Contd)

 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

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

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)



Age

 The incidence of anti-GBM nephritis is bimodal  The first, and larger, peak occurs in the 2 nd and 3 rd are more susceptible than women in this age group decade of life. Men in this age group  The second, and smaller, peak occurs in the 6 th and 7 th 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)

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

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

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

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 vasculitis  Malaise, weight-loss, fevers, arthralgias

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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.

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

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

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

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, 10-14 treatments are required

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

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

Anti-GBM Antibody Disease: Treatment

(Contd)

 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 mo  Cyclophosphamide (Cytoxan)   2 mg/kg/day PO x 3 months IV if can’t take PO, unreliable, severe renal failure and oliguria

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

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

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

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)

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

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

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

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

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

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

 Thank You!