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