Potentially life-threatening disorder,
Diffuse alveolar hemorrhage
Rapidly progressive glomerulonephritis
AGN/RPGN +/- lung hemorrhage is and
emergency requires early diagnosis and
Diffuse Alveolar Hemorrhage
Presentation of patients with DAH can range
from cough with or without hemoptysis to
severe respiratory distress.
Onset is usually abrupt.
Hemoptysis (Absent in 1/3 of patients)
Radiographic Abnormalities (Alveolar opacities,
Interstitial opacities, Fibrosis)
Unexplained drop in Hematocrit
Capillaritis: neutrophile infiltrates
Acute onset (days to weeks)
Acute renal failure and oliguria (400mL/day)
Renal Blood flow and GFR fall
Obstruction of the glomerular capillary lumen
By infiltrating inflammatory cells
Proliferating resident glomerular cells.
Intrarenal vasoconstricion and mesangial cell contraction
Local imbalances of vasoconstrictors (leukotrienes, endothelins,
thromboxanes, platelet-activating factor) and vasodilators (NO,
prostacyclin) in the microcirculation of the kidney.
vasculitides account 60%
Other causes 20%
Work-up for GN
Complement levels (C3,C4)
Depending on history/clinical suspicion:
Consider GN mimics: thrombotic microantiopathy, cholesterol emboli, AIN,
For Pulmonary-Renal Syndrome you will also want to bx other tissues.
Autoantibodies directed against type IV collagen
RPGN and crecentic glomerulonephritis.
50-80% have lung hemorrhage.
Typically young males (5-40years) Male:Female ratio = 6:1
Presentation in second peak, 6th decade, generally do not
have lung hemorrhage and have almost equal sex
Nephritic urinary sediment (dysmorphic RBC &/or RBC casts)
Subnephrotic proteinuria (<3.5 g/24 hours)
Rapidly progressive renal failure over weeks
With or without pulmonary hemorrhage
Pulmonary hemorrhage, when it does occur, usually predates
nephritis by weeks or months.
Lung involvement can vary from fluffy pulmonary infiltrates on
CXR with mild dyspnea on exertion to potentially fatal
Usually not hypertensive.
Diagnostic serologic marker is anti-GBM antibodies
with a specificity for NCI domain of the alpha3 chain of
type IV collagen.
These antibodies are detected in >90% of patients with
RENAL BIOPSY is the GOLD STANDARD for
diagnosis of anti-GBM nephritis.
Light microscopy: diffuse proliferative GN with focal necrotizing
lesions and crescents in >50% of glomeruli.
Immunofluorescence: linear ribbon-like deposits of IgG
Electron Microscopy: inflammatory change without immune
Normal Glomerulus RPGN/Crescentic GN
“Linear ribbon like”
deposition of IgG along GBM
Emergency plasmapheresis is done daily or on
alternate days until anti-GBM antibodies are
not detected in circulation
Prednisone (1mg/kg per day) is started
simultaneously along with cyclophosphamide
(2 to 3 mg/kg per day) or azathioprine (1 to 2
mg/kg per day) to suppress new synthesis of
Without treatment, 80% get ESRD within 1 year
If treatment is started early, before creatinine is over
5mg/dL, then 1 year survival is over 90%. It is 80% if
renal failure is more advanced.
If patients require dialysis at time of
presentation, they rarely recover renal function.
If crescents exist in >50% of glomeruli, then
usually survival <2 yrs
Better response to treatment if ANCA +
ANCA Vasculitis (pauci-immune)
ANCA + Vasculitis (pauci-immune)
Disease Granulomas Renal Pulmonary Asthma ANCA type ANCA
+ 80% 90% - C-ANCA
- 90% 50% - P-ANCA
+ 45% 70% + P-ANCA
PR3 = Proteinase 3
MPO = Myeloperoxidase
(found in granules of neutrophils/monocytes)
ANCA-associated small vessel
More common in Caucasian and elderly (mean age is
Usual presentation: nonspecific constitutional symptoms
Granulomatous vasculitis of the upper and
lower respiratory tracts together with
Prevalence is 3/100,000, very rare in blacks.
Mean age of onset = 40 (but age of onset can
Necrotizing vasculitis of small arteries and veins with
granuloma formation (either intra- or extravascular).
Lung involvement typically appears as multiple
bilateral, nodular cavitary infiltrates. On biopsy they
reveal typical necrotizing granulomatous vasculitis.
Upper airway lesions (especially sinuses and
nasopharynx) reveal inflammation, necrosis and
Renal involvement can be focal and segmental
glomerulitis early in the disease but typically
progresses to RPGN. RARELY are granulomas seen
on renal biopsy.
95% have upper airway involvement
Paranasal sinus pain
Purulent or bloody nasal discharge with or without nasal
Nasal septal perforation can occur leading to saddle nose
Serous otitis media can occur as a result of blockage of
16% will have subglottic tracheal stenosis (from active
disease or scarring) which can cause airway obstruction.
Pulmonary involvement in 85-90%
Cough, hemoptysis, dyspnea, chest discomfort.
Endo-bronchial disease (from active disease or
scarring) can leads to obstruction with atelectasis
Renal involvement dominates the clinical
If left untreated, it accounts directly or indirectly for
most mortality of the disease.
Demonstration of necrotizing granulomatous
vasculitis on tissue biopsy in a patient with compatible
Pulmonary tissue biopsy offers the highest diagnostic yield.
Renal biopsy can confirm pauci-immune glomerulonephritis.
Upper airway tissue biopsy usually shows granulomatous
inflammation with necrosis but may or may not show
Glucocorticoids (predisone 1mg/kg/day) should be
started for symptomatic improvement and then
tapered over 6 months.
Monitor leukocyte count to adjust dose to maintain count
above 3000/microL (neutrophile count of 1500). Gives you
clinical remission without severe leukopenia and associated
Relapse occurs in about 25% of patients.
Treatment for relapse is the same (goal is to
achieve remission again).
Methotrexate or azathioprine can be given after
remission is achieved and cyclophosphamide is
stopped to maintain remission in patients that do
AKA allergic angiitis and granulomatosis.
Peripheral and tissue eosinophilia
Extravascular granuloma formation
Vasculitis of multiple organ systems.
Incidence is estimated at 1 in 3 million.
Can occur at any age (not documented in
Mean age is 48yrs.
M:F ratio= 1:1.2
Granulomatous reaction and eosinophil
infiltration can occur in any organ in the body,
but the lungs predominate. Other areas
Peripheral nervous system
Pulmonary findings clearly dominate clinical
Severe asthma attacks and presence of pulmonary
Allergic rhinitis and sinusitis
Heart disease (14%) = Most frequent cause of
Skin involvement 51%
Include purpura in addition to cutaneous and
Renal involvement 45%
Less common than seen in Wegener’s and MPA
Biopsy of affected tissue (lung).
Microgranulomas, fibrinoid necrosis and throbosis of small
arteries and veins (necrotizing vasculitis) with eosinophilic
Classification criteria (4 of 6 criteria is 85% Sensitive and
Mono- or polyneuropathy
Migratory or transitory pulm infiltrates
Paranasal sinus abnormality
Extravascular eosinophils on biopsy
Glucocorticoids; high dose.
Attempt to taper. Asthma makes tapering difficult, patients
may need to be maintained on low-dose prednisone for years
after clinical recovery from vasculitis to control asthma.
Patients who do not respond to glucocorticoids alone,
can be treated with cyclophosphamide and
prednisone (similar to Wegener’s treatment).
Necrotizing vasculitis with few or no immune complexes
affecting small vessels (capillaries, venules, or arterioles).
Glomerulonephritis and pulmonary capillaritis are
common in Microscopic Polyangiitis. (NO pulmonary
capillaritis in PAN).
Not associated with HBV like PAN
ABSENCE of granulomatous inflammation differentiates
this disease from Wegener’s granulomatosis.
Incidence not really established because it
use to be included in PAN.
Age of onset is about 57 years.
Slightly more occurrence in males than
Vascular lesion is a necrotizing inflammation
of capillaries, venules, as well as small and
Rare immunoglobulin deposition seen in the
Renal lesion is identical to that of Wegener’s
Renal involvement 90%
Glomerulonephritis, often rapidly progressive.
Can quickly lead to renal failure
Lung involvement 50%
Alveolar hemorrhage (12%)= hemoptysis
Gastrointestinal tract vasculitis
(upper airway disease and pulmonary nodules are not
typically found - if found: suggests Wegener’s)
Biopsy of affected tissue.
Necrotizing pauci-immune inflammation of
arterioles, capillaries and venules WITHOUT
granulomas or eosinophilic infiltrates.
Similar approach to that of Wegener’s.
Relapse occurs in up to 34% of patients.
Differential Diagnosis for
Connective Tissue Disease
Progressive Systemic Sclerosis
Primary Glomerular Disease
Pneumonitis + SLE GN
+ ASO titer, can continue
to have pulmonary
symptoms by the time
renal symptoms manifest.
Harrison et. al, (2005), Principles of Internal Medicine, 16th Edition,
Jennette J. (1997), Small Vessel Vasculitis. New England Journal of
Medicine; 21: 1512-1523.
PubMed: Renal-Pulmonary Syndrome. Retrieved on (9/1/09) from:
Sabatine, Marc S,(2008) Pocket Medicine, 3rd Edition, Lippincott Williams
Toy, et.al. (2007), Case Files: Internal Medicine, Second Edition, McGraw-