Pulmonary-Renal Syndrome

Alanna Beckman

MSIV

Pulmonary-Renal Syndrome

Potentially life-threatening disorder, Diffuse alveolar hemorrhage

pulmonary capillaritis

In conjunction with 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 for approximately 60%

Goodpasture's Syndrome for approximately 20% of the cases.

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.

Goodpastures

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 PolyangiitisChurg-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 3MPO = 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 rateElevated C-reactive proteinLeukocytosisThrombocytosisNormochromic/normocytic anemiaNormal 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

PresentationPulmonary involvement in 85-90%

Cough, hemoptysis, dyspnea, chest discomfort. Endo-bronchial disease (from active disease or

scarring) can leads to obstruction with atelectasisRenal 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

TreatmentRelapse 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

PresentationPulmonary 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

PresentationSkin 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

PresentationVascular 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

DiagnosisBiopsy of affected tissue.

Necrotizing pauci-immune inflammation of arterioles, capillaries and venules WITHOUT granulomas or eosinophilic infiltrates.

ANCA positive

Microscopic Polyangiitis

TreatmentSimilar approach to that of Wegener’s. Relapse occurs in up to 34% of patients.

Differential Diagnosis for Pulmonary-Renal SyndromeGoodpasture’s DiseaseSystemic Vasculitis

Wegener’s Granulomatosis Microscopic PolyangiitisChurg-Strauss syndromeCryoglobulinemiaHenoch-Schonlein Purpura

Connective Tissue DiseasePolymyositis/DermatomyositisProgressive Systemic SclerosisSLE

Primary Glomerular DiseaseIgA nephropathyPost-Infectious GNMembranoproliferative 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