síndrome riñón pulmón
TRANSCRIPT
Pulmonary-Renal
Syndrome
Pulmonary-Renal Syndrome
Potentially life-threatening disorder,
Diffuse alveolar hemorrhage
pulmonary capillaritis
Rapidly progressive glomerulonephritis
AGN/RPGN +/- lung hemorrhage is and
emergency requires early diagnosis and
treatment.
Diffuse Alveolar Hemorrhage
Presentation of patients with DAH can range from cough with or without hemoptysis to severe respiratory distress.
Onset is usually abrupt.
Suspect DAH: Hemoptysis (Absent in 1/3 of patients)
Radiographic Abnormalities (Alveolar opacities, Interstitial opacities, Fibrosis)
Unexplained drop in Hematocrit
Capillaritis: neutrophile infiltrates
and hemorrhage
Rapidly Progressive
Glomerulonephritis
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.
Pulmonary-Renal Syndromes
ANCA-associated vasculitides account 60%
Goodpasture's Syndrome 20%.
Other causes 20%
ANCA
GP-GN
Other
Work-up for GN
ANCA
Anti-GBM
Complement levels (C3,C4)
Depending on history/clinical suspicion: ANA
ASLO
BCx
Cryocrit
Hepatitis serologies
Renal Biopsy Immunofluorescence
Electron microscopy
(Light microscopy)
Consider GN mimics: thrombotic microantiopathy, cholesterol emboli, AIN, myeloma
For Pulmonary-Renal Syndrome you will also want to bx other tissues.
Goodpasture´s Syndrome
Autoimmune
Autoantibodies directed against type IV collagen
RPGN and crecentic glomerulonephritis.
50-80% have lung hemorrhage.
Bimodal distribution:
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
distribution.
Goodpasture’s Syndrome
Common presentation: Hematuria
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 pulmonary hemorrhage
Usually not hypertensive.
GP Diagnosis
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 anti-GBM nephritis.
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 deposits
Normal Glomerulus RPGN/Crescentic GN
Immunofluoresence Microscopy:
“Linear ribbon like”
deposition of IgG along GBM
GP Treatment
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
anti-GBM antibodies.
GP Prognosis
Without treatment, 80% get ESRD within 1 year
Early Treatment 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)
Wegener’s
Granulomatosis
Microscopic
Polyangiitis
Churg-Strauss
Arteritis
ANCA + Vasculitis (pauci-immune)
Disease Granulomas Renal Pulmonary Asthma ANCA type ANCA
positive
Wegener’s
granulo-
matosis
+ 80% 90% - C-ANCA
(anti-PR3)
90%
Microscopic
polyantiitis
- 90% 50% - P-ANCA
(anti-MPO)
70%
Churg-
Strauss
Syndrome
+ 45% 70% + P-ANCA
(anti-MPO)
50%
PR3 = Proteinase 3
MPO = Myeloperoxidase
(found in granules of neutrophils/monocytes)
ANCA-associated small vessel
vasculitis
More common in Caucasian and elderly (mean age is 57 years)
Usual presentation: nonspecific constitutional symptoms and signs Lethargy
Mailaise
Anorexia
Weight loss
Fever
Arthralgia
Myalgias
ANCA-associated small vessel
vasculitis
Nonspecific lab abnormalities
Rapid sedimentation rate
Elevated C-reactive protein
Leukocytosis
Thrombocytosis
Normochromic/normocytic anemia
Normal complement levels (usually)
C-ANCA PR3
Wegener’s
Granulomatous vasculitis of the upper and
lower respiratory tracts together with
glomerulonephritis.
Prevalence is 3/100,000, very rare in blacks.
M:F=1:1
Mean age of onset = 40 (but age of onset can
vary widely)
Wegener’s Pathogenesis:
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 granuloma formation.
Renal involvement can be focal and segmental glomerulitis early in the disease but typically progresses to RPGN. RARELY are granulomas seen on renal biopsy.
Wegener’s
Presentation 95% have upper airway involvement
Paranasal sinus pain
Purulent or bloody nasal discharge with or without nasal mucosal ulceration.
Nasal septal perforation can occur leading to saddle nose deformity.
Serous otitis media can occur as a result of blockage of eustachian tube.
16% will have subglottic tracheal stenosis (from active disease or scarring) which can cause airway obstruction.
Wegener’s
Presentation
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 picture If left untreated, it accounts directly or indirectly for
most mortality of the disease.
Wegener’s
Diagnosis
Demonstration of necrotizing granulomatous
vasculitis on tissue biopsy in a patient with compatible
clinical features.
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
vasculitis.
Wegener’s
Treatment
Glucocorticoids (predisone 1mg/kg/day) should be
started for symptomatic improvement and then
tapered over 6 months.
Cyclophosphamide (2mg/kg/day)
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
infectious risk.
Wegener’s
Treatment
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
relapse.
P-ANCA MPO
Churg-Strauss
AKA allergic angiitis and granulomatosis.
Asthma
Peripheral and tissue eosinophilia
Extravascular granuloma formation
Vasculitis of multiple organ systems.
Churg-Strauss
Incidence is estimated at 1 in 3 million.
Can occur at any age (not documented in
infants).
Mean age is 48yrs.
M:F ratio= 1:1.2
Churg-Strauss
Granulomatous reaction and eosinophil infiltration can occur in any organ in the body, but the lungs predominate. Other areas involved include: Skin
Cardiovascular system
Kidney
Peripheral nervous system
Gastrointestinal tract
Churg-Strauss
Presentation
Pulmonary findings clearly dominate clinical picture Severe asthma attacks and presence of pulmonary
infiltrates.
Mononeuritis multiplex
Allergic rhinitis and sinusitis
Heart disease (14%) = Most frequent cause of death.
Churg-Strauss
Presentation
Skin involvement 51%
Include purpura in addition to cutaneous and
subcutaneous nodules.
Renal involvement 45%
Less common than seen in Wegener’s and MPA
Severe glomerulonephritis
Churg-Strauss Biopsy of affected tissue (lung).
Microgranulomas, fibrinoid necrosis and throbosis of small arteries and veins (necrotizing vasculitis) with eosinophilic infiltrates.
Classification criteria (4 of 6 criteria is 85% Sensitive and 99.7% specific) Asthma
Eosinophilia >10%
Mono- or polyneuropathy
Migratory or transitory pulm infiltrates
Paranasal sinus abnormality
Extravascular eosinophils on biopsy
Churg-Strauss
Treatment
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).
P-ANCA MPO
Microscopic Polyangiitis. 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.
Microscopic Polyangiitis
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
females.
Microscopic Polyangiitis
Presentation
Vascular lesion is a necrotizing inflammation
of capillaries, venules, as well as small and
medium-sized arteries.
Rare immunoglobulin deposition seen in the
vascular lesions.
Renal lesion is identical to that of Wegener’s
granulomatosis lesion.
Microscopic Polyangiitis
Renal involvement 90% Glomerulonephritis, often rapidly progressive.
Can quickly lead to renal failure
Lung involvement 50% Alveolar hemorrhage (12%)= hemoptysis
Mononeuritis multiplex
Gastrointestinal tract vasculitis
Cutaneous vasculitis.
(upper airway disease and pulmonary nodules are not typically found - if found: suggests Wegener’s)
Microscopic Polyangiitis
Diagnosis
Biopsy of affected tissue.
Necrotizing pauci-immune inflammation of
arterioles, capillaries and venules WITHOUT
granulomas or eosinophilic infiltrates.
ANCA positive
Microscopic Polyangiitis
Treatment
Similar approach to that of Wegener’s.
Relapse occurs in up to 34% of patients.
Differential Diagnosis for
Pulmonary-Renal Syndrome Goodpasture’s Disease
Systemic Vasculitis Wegener’s Granulomatosis
Microscopic Polyangiitis
Churg-Strauss syndrome
Cryoglobulinemia
Henoch-Schonlein Purpura
Connective Tissue Disease Polymyositis/Dermatomyositis
Progressive Systemic Sclerosis
SLE
Primary Glomerular Disease IgA nephropathy
Post-Infectious GN
Membranoproliferative GN
Pleural effusions/Lupus
Pneumonitis + SLE GN
+ ASO titer, can continue
to have pulmonary
symptoms by the time
renal symptoms manifest.
References
Harrison et. al, (2005), Principles of Internal Medicine, 16th Edition, McGraw-Hill, NY
Jennette J. (1997), Small Vessel Vasculitis. New England Journal of Medicine; 21: 1512-1523.
PubMed: Renal-Pulmonary Syndrome. Retrieved on (9/1/09) from: http://www.ncbi.nlm.nih.gov/pubmed/15905974
Sabatine, Marc S,(2008) Pocket Medicine, 3rd Edition, Lippincott Williams &Wilkins, Philadelphia
Toy, et.al. (2007), Case Files: Internal Medicine, Second Edition, McGraw-Hill, NY