Microscopic polyangiitis differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Ali Poyan Mehr, M.D. [2]Associate Editor(s)-in-Chief: Krzysztof Wierzbicki M.D. [3], Eiman Ghaffarpasand, M.D. [4], Mehrian Jafarizade, M.D [5]

Overview

Microscopic polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, fever, arthralgia, myalgia, necrotizing extra-capillary glomerulonephritis, such as Granulomatosis with polyangiitis and Eosinophilic granulomatosis with polynagiitis.

Differentiating Microscopic polyangiitis for other diseases

Microscopic polyangiitis must be differentiated from other diseases that cause purpura, alveolar hemorrhage, necrotizing extra-capillary glomerulonephritis, such as Eosinophilic granulomatosis with polyangiitis and Granulomatosis with polyangiitis.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis serological findings
Eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis Microscopic polyangiitis
Cytoplasmic ANCA (cANCA) 90% positive
Perinuclear ANCA (pANCA) 30 to 40% positive 60 to 80% positive
Myeloperoxidase antigen 40% sensitivity 10% sensitivity 30% sensitivity
Proteinase 3 antigen <5% sensitivity 70-80% sensitivity 60% sensitivity

Differentiating Microscopic polyangiitis from other Diseases:

Abbreviations: ABG= Arterial blood gas, ANA= Antinuclear antibody, ANP= Atrial natriuretic peptide, ASO= Antistreptolysin O antibody, BNP= Brain natriuretic peptide, CBC= Complete blood count, COPD= Chronic obstructive pulmonary disease, CRP= C-reactive protein, CT= Computed tomography, CXR= Chest X-ray, DVT= Deep vein thrombosis, ESR= Erythrocyte sedimentation rate, HRCT= High Resolution CT, IgE= Immunoglobulin E, LDH= Lactate dehydrogenase, PCWP= Pulmonary capillary wedge pressure, PCR= Polymerase chain reaction, PFT= Pulmonary function test.

Diseases Clinical manifestations Para-clinical findings Gold standard Additional findings
Symptoms Physical examination
Lab Findings Imaging Histopathology
Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other
Large-Vessel Vasculitis Takayasu arteritis[1] + +/- + - + + +/- +/- MMP-3 and MMP-9 Leukocytosis, Anemia ↑ ↑CRP Aneurysmal dilatation of the aorta Blood vessel stenosis Circumferential thickening of the arterial wall (Macaroni sign) PET-scan, Cardiac CT Granulomatous inflammation of arteries Arteriography Coronary aneurysm
Giant cell arteritis[2] + - + +/- - - - +/- Pentraxin 3 (PTX3) Normal ↑ ↑CRP Stenosis, Occlusion, Dilatation Aneurysm - Mural inflammation in MRA Granulomatous inflammation of arteries Biopsy  Jaw pain and claudication
Neurological disease Cerebral aneurysm[3] + - - - - - +/- + - Normal Normal - Well-defined round, slightly hyperattenuating lesion Bulging out of the main lumen - Heterogeneous signal intensity in MRA Layers of smooth muscle cells, Intact endothelium Digital subtraction angiography (DSA) Nausea, Vomiting
Neurofibromatosis type 1[4] +/- - +/- - - - + + NF1 mutated gene Normal Normal Neurofibromin gene Bone abnormalities  Optical coherence tomography angiography (OCTA) - Optic nerve gliomas in MRI Elongated spindle-shaped cells in neurofibromas NIH diagnostic criteria Cafe au Lait spot
Neurofibromatosis type 2[5] +/- - +/- - +/- - - + NF2 mutated gene Normal Normal Schwannomin Meningioma, Schwannoma, Ependymoma Fluorescein angiography showed retinal hamartoma Localized schwannomas in nerve ultrasound Schwannoma in MRI Encapsulated biphasic nerve sheath tumor NIH diagnostic criteria Hearing loss, Vision loss
Systemic disease Fibromuscular dysplasia[6] + - +/- + + + + +/- Transforming growth factor β (TGF-β) Normal ↑ ↑ Cr or BUN Alternating stenosis and dilatations in CT angiography Stenosis in the renal arteries Luminal narrowing alternating with dilatation (Beads sign) Focal concentric, long-segment tubular stenosis or outpouching in MRA Fibrodysplastic changes, Collagen deposition Digital subtraction angiography (DSA)  Spontaneous coronary artery dissection (SCAD)
Ehlers-Danlos syndrome[7] - - - + +/- +/- - +/- TGF-β Normal Normal Cultured skin fibroblasts Multiple vascular segments with aneurysms and dissections Dissection of the posterolateral branch of the left circumflex coronary artery (LCx) Visceral arteries abnormality Vascular abnormalities in MRA Thin and rare collagen bundles in the dermis History and physical examination Bleeding, Bruisability, Heart murmur
Polymyalgia rheumatica (PMR)[8] + - +/- + - - - - Plasma fibrinogen Normocytic, normochromic anemia ↑ CRP Periodontoid localization of calcification Vessel wall thickening, Increased mural contrast enhancement Subacromial or subdeltoid bursitis High F-FDG accumulation around the joints in FDG PET-CT Small angular fibers, Pyknotic nuclear clumps, or target-targetoid fibers - Joint stiffness, Fatigue
Amyloidosis[9] +/- - - +/- +/- - + + Immunoglobulin light chain(Amyloid) Anemia Normal ↑ Cr or BUN,

↑ ALT or AST

Diffusely hypoattenuating and enlarged liver Amyloid deposition in the media and adventitia of small arteries  Solid organs increased echogenicity Tc-DPD for cardiac amyloid deposits Extracellular deposition of fibrillar proteins Biopsy Cardiomegaly, Dyspnea
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Medium-Vessel Vasculitis Polyarteritis nodosa[10] + + + + + + +/- +/- LAMP-2 protein autoantibodies Leukocytosis, Normochromic anemia, Thrombocytosis ↑ ↑ Cr or BUN,

↑ ALT or AST, Proteinuria

Focal regions of infarction or hemorrhage Multiple microaneurysms, Hemorrhage due to focal rupture, Occlusion Aneurysms and renal arteriovenous fistula in color Doppler sonography - Necrotizing inflammatory lesions Angiography Sudden weight loss, Abdominal pain
Hepatitis B virus-associated polyarteritis nodosa[11] +/- +/- + + +/- +/- + - HBsAg Leukocytosis, Normochromic anemia, Thrombocytosis ↑ ↑ ALT or AST Focal regions of infarction or hemorrhage Microaneurysms in mesenteric artery Aneurysms and renal arteriovenous fistula in color Doppler sonography - Necrotizing inflammatory lesions Angiography Peripheral neuropathy, Livedo reticularis
Kawasaki disease[12] - + +/- + + - +/- - NT-proBNP, Meprin A, Filamin C Normochromic anemia, ↑WBC with a left shift, Thrombocytosis  ↑ Acute-phase reactants, ↓Cholesterol, ↓HDL, ↓ApolipoA Coronary artery calcifications Coronary artery aneurysms, stenosis or occlusion Coronary artery anomaly in echocardiography Electron beam CT (EBCT) Acute destruction of the media by neutrophils, with loss of elastic fibers History and physical examination Diarrhea, Vomiting
Infectious disease Parvovirus B19 infection[13] + + + + - - - +/- B19 DNA, ↓Reticulocyte count Anemia ↑ anti–parvovirus B19 IgM - - Hydrops in fetal ultrasonography - - B19 DNA Purpuric rash, Erythema multiforme
Scarlet fever[14] + + +/- + - - - - Antistreptolysin-O (ASO) titers Leukocytosis ↑ ↑CRP Thickened pulmonary markings if pneumonia - - - Sparse neutrophilic perivascular infiltrate History and physical examination Sand-paper rashes, Sore throat
Toxic shock syndrome[15] + + + + - - - +/- Procalcitonin Leukocytosis with left shift ↑ Myoglobinuria, Sterile pyuria Acute respiratory distress syndrome - - - Necrolysis of keratinocytes in epidermis, Perivascular lymphocytic infiltrate Clinical criteria Peeling or rashes, Organ dysfunction
Mononucleosis[16] + + + + - - - - EBV DNA Atypical lymphocyte ↑ Heterophile antibodies CNS involvement - Splenomegaly Encephalitis in MRI Lymphoproliferative response in oropharynx, Lymphocytic infiltration in spleen Heterophile antibody test Splenomegaly, Palatal petechiae
Leptospirosis[17] + + + + +/- - - - IL-6, IL-8 and IL-10 Anemia - ↑Cr or BUN,

↑ALT or AST, Proteinuria

 Diffuse alveolar hemorrhage - - - Toxin-mediated break down of endothelial cell membranes of capillaries Culture and the microscopic agglutination test Red eyes, Skin rash
Lyme Disease[18] +/- + +/- + +/- - - - CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B) Leukopenia, Thrombocytopenia - Microscopic hematuria, Proteinuria, ↑ALT or AST Punctate lesions in periventricular white matter in brain SPECT - - - Acrodermatitis chronica atrophicans Serologic tests Erythema migrans
Measles[19] +/- + +/- + - - - - Measles IgM Leukopenia, Lymphocytosis, Thrombocytopenia - ↑ALT or AST Pneumonia - - CXR Spongiosis and vesiculation in the epidermis with scattered dyskeratotic keratinocytes PCR Generalized rash, Cough, Coryza, or Conjunctivitis
Rocky Mountain Spotted Fever[20] + + + + - - - - R rickettsii serology Thrombocytopenia, Anemia  - ↑ALT or AST, Hyponatremia Infarction, edema, and meningeal enhancement - Myocardial or conduction abnormalities in echocardiography - Immunofluorescent or immunoperoxidase staining of R rickettsii Clinical criteria and tick exposure Rash on the palms and soles
Staphylococcal Scalded Skin Syndrome[21] + + + + - - +/- +/- Anti exfoliatin and anti alpha-toxin antibodies Leukocytosis with left shift ↑ Blood culture Pneumonia - - - Intraepidermal blister, dense superficial perivascular lymphohistiocytic infiltrate  Blood culture and clinical findings Widespread skin erythema, fluid-filled blisters
Toxic Epidermal Necrolysis[22] - + + - - - - +/- MicroRNA-124 Normochromic normocytic anemia, Eosinophilia ↑ Fluid loss and electrolyte abnormalities Tracheobronchial inflammation - - - Necrotic keratinocytes with full-thickness epithelial necrosis Histopathology and clinical findings Erythematous macular rash with purpuric centers
Cardiovascular disease Atrial Myxoma[23] - - +/- - - - - +/- Calretinin Mild anemia, Leukocytosis ↑ ↑IL-6 Atrial filling defect larger than a thrombus - Tumor location, size, attachment, and mobility in echocardiography Size, shape, and surface characteristics in MRI Lipidic cells embedded in a vascular myxoid stroma Echocardiography Dyspnea on exertion, Syncope
Cholesterol Embolism[24] +/- +/- - - + - - + IL-5 Eosinophilia, Leukocytosis   ↑ Eosinophiluria Thoracic and abdominal aortic sources of embolism Atheroembolism in abdominal aorta and the lower extremity arteries Excluding an intracardiac source of embolism with echocardiography  - Birefringent crystals or biconvex needle-shaped ghostly clefts within the arterial lumen Angiography  Livedo reticularis,

Ischemic patches

Segmental arterial mediolysis[25] + - - - + + + +/- - Leukocytosis - - Visceral artery aneurysm in CT angiography Alternating aneurysms and stenoses (beading) Retroperitoneal hematoma - Disruption of the smooth muscle in the media Angiography  Hematuria, Ischemic colitis
Systemic disease Antiphospholipid Syndrome[26] + + - - - - - +/- Antiphospholipid antibodies Thrombocytopenia, Hemolytic anemia - Lupus anticoagulant (LA) Stroke,

Pulmonary embolism, Budd-Chiari syndrome

Thrombus in major vessels Valve thickening, vegetations, or insufficiency in echocardiography - Noninflammatory bland thrombosis without perivascular inflammation Hx of thrombosis and antiphospholipid antibodies Miscarriage, Pulmonary hypertension
Juvenile Idiopathic Arthritis[27] - - - + +/- - - - Rheumatoid factor (RF), S100A12 Lymphocytosis, Thrombocytopenia ↑ Myeloid-related proteins 8/14 (MRP8/14) Synovial hypertrophy, Joint effusions Cerebral vasculitis Inflamed synovium Bone scanning Vascular congestion, RBC extravasation, Venular lumen occlusion Conventional radiography Evanescent rash, Dactylitis 
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Small-Vessel Vasculitis ANCA-associated vasculitis Microscopic polyangiitis[28] + - - +/- - - - + Anti-PR3 antibody (C-ANCA) (40%), Anti-MPO antibody (P-ANCA) (60%) Leukocytosis, Normocytic anemia ↑ Proteinuria, Erythrocyte casts Suspected pancreatitis Mesenteric angiography for differentiating from polyarteritis nodosa - Bilateral nodular, and patchy opacities in CXR Glomerulonephritis with focal necrosis, crescent formation, and lack or paucity of immunoglobulin deposits Histological confirmation Rash, Hemoptysis 
Granulomatosis with polyangiitis (Wegener’s)[29] + +/- +/- - - - - + Anti-PR3 antibody (C-ANCA) (90%), Anti-MPO antibody (P-ANCA) (10%) Leukocytosis, Normochromic normocytic anemia ↑ ↑Cr or BUN, Hypoalbuminemia Consolidation, Patchy or diffuse ground-glass opacities Occlusion or stenosis of LAD and RCA in coronary angiography - Single or multiple nodules and masses with cavitation in CXR Parenchymal necrosis, Granulomatous inflammation Histological confirmation Conjunctivitis,

Episcleritis,

Uveitis,

Optic nerve vasculitis

Eosinophilic granulomatosis with polyangiitis

(Churg-Strauss)[30]

+/- - - + - - - + Anti-MPO antibody (P-ANCA) (40%), Eotaxin-3 Eosinophilia, Anemia ↑ ↑Cr or BUN, Proteinuria, Erythrocyte casts, ↑IgE levels Significant enlargement of peripheral pulmonary arteries Myocardial ischemia and infarction in coronary angiography Congestive heart failure (CHF) in echocardiography Extensive air-space opacities in CXR Small necrotizing granulomas with eosinophilic core surrounded by macrophages and epithelioid giant cells Histological confirmation Allergic rhinitis, Asthma, Urticarial rash
Hydralazine-associated ANCA-associated vasculitis[31] - - - + - - - +/- Anti-MPO antibody (P-ANCA), Anti-histone antibodies Anemia - ↑Cr or BUN, Hypoalbuminemia Bilateral pulmonary infiltrates Aneurysms or occlusions of the visceral arteries - - Pauci-immune necrotizing and crescentic glomerulonephritis Histological confirmation Sinusitis, Hemoptysis
Immune complex small-vessel vasculitis Anti-glomerular basement membrane disease[32] + +/- - - - - + - Anti-GBM antibodies Hypochromic microcytic anemia, Thrombocytopenia - ↓C3 level Pulmonary hemorrhage - Normal kidneys Alveolar infiltrates spreading from the hilum in CXR Cellular crescents in the glomeruli, Intra-alveolar hemorrhages Anti-GBM antibodies Hemoptysis, Hematuria
Cryoglobulinemic vasculitis[33] +/- +/- - + +/- - - - C4 component Leukocytosis, Anemia ↑ ANA, hypocomplementemia R/O underlying malignancy Stenosis or occlusions of the visceral arteries Bacterial endocarditis in echocardiography Interstitial involvement or pleural effusions in CXR HCV-associated proteins in vasculitic skin, Intraluminal cryoglobulin deposits  Histological confirmation Acrocyanosis, Retinal hemorrhage, Purpura
Hepatitis C virus-associated cryoglobulinemic vasculitis[34] +/- +/- + + - - + +/- HCV RNA, Cryoglobulins Leukocytosis, Anemia ↑ ↓Serum C4, Positive RF Increased hepatic echogenicity - Hepatomegaly, Splenomegaly Increased hepatic echogenicity in MRI Vasculitic skin, Antigen infilteration in lesions HCV RNA, Histological confirmation Palpable purpura, Microscopic hematuria
IgA vasculitis (Henoch-Schönlein purpura)[35] - - + + - - - - IgA Normochromic anemia, Leukocytosis  ↑ Stool OB, ↓C3, ↓C4 - - Increased bowel wall thickness, hematomas, peritoneal fluid, and intussusception Dilated loops of bowel consistent in abdominal X-ray Leukocytoclastic vasculitis in postcapillary venules with IgA deposition History and physical examination Hematuria, Palpable purpura
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis)[36] - - +/- + - - - - C1q Mild anemia ↑ ANA, ↓C1q, ↓C3, ↓C4 - - Hepatomegaly, Splenomegaly - Deposits of immunoglobulins, complement, or fibrin around blood vessels Urticaria,

Histological confirmation

Urticaria, Hematuria
Gastrointestinal disease Acute mesenteric ischemia[37] - +/- - - - - - - I-FABP, Alpha-GST, Ischemia-modified albumin (IMA) Leukocytosis, ↑HCT -  ↑Amylase Bowel wall thickening, Intestinal pneumatosis, Portomesenteric thrombosis Mesenteric venous thrombosis  Arterial stenosis or occlusion of the celiac or superior mesenteric arteries in duplex ultrasound Ileus with distended loops of bowel, Bowel wall thickening in abdominal X-ray Superficial mucosal hemorrhage, edema and necrosis History and physical examination Abdominal pain, Distension, Absent bowel sounds
Cardiovascular disease Infective Endocarditis[38] + + + - - - - + NT-proBNP Normochromic-normocytic anemia ↑ Hyperglobulinemia, Cryoglobulinemia Metastatic infections, such as splenic infarct, renal infarcts, or psoas abscess - Vegetation, abscess, or new dehiscence of a prosthetic valvein echocardiography Vertebral osteomyelitis in MRI Vegetation or intracardiac abscess demonstrating active endocarditis Echocardiography (TTE) Janeway lesions, Osler nodes, Roth spots, Vertebral osteomyelitis
Leukocytoclastic Vasculitis[39] + - - + - - - + IgM, IgA, IgG Leukocytosis, Anemia ↑ Hypocomplementemia - Vascular stenosis and obstruction in visceral angiography - - Perivascular inflammatory infiltrate of neutrophils with leukocytoclasia (releasing nuclear debris) Histological confirmation Palpable purpura, Petechiae 
Pulmonary disease Langerhans Cell Histiocytosis[40] +/- - - + - - - - CD1a, CD207,BRAF-V600E Anemia ↑ Hypercalcemia Pulmonary cysts and nodules, Bone lytic lesions - Hepatomegaly, Splenomegaly Cerebellum and pons hyperintensity in MRI Birbeck granules by electron microscopy Histological confirmation Brown to purplish papules, Eczematous rash
Non-Small Cell Lung Cancer[41] - +/- + - - - - +/- EGFR, ROS1, EML4-ALK,  PD-L1 Leukocytosis, Anemia ↑ Hypercalcemia, Hyponatremia Pulmonary lesion or mass - Pulmonary marginal lesions Staging and response to treatment in PET-CT Adenocarcinoma, Squamous cell carcinoma High resolution CT-scan Cough, Hemoptysis
Small Cell Lung Cancer[42] - +/- + - - - - +/- p53, Thyroid transcription factor-1 (TTF1) Anemia ↑ Hyponatremia Large hilar mass with bulky mediastinal adenopathy - Endobronchial ultrasound (EBUS) Standard staging Spindled cells with dark nuclei, scant cytoplasm, and fine, granular nuclear chromatin High resolution CT-scan Cough, Hemoptysis
Pulmonary Infarction[43] +/- - - - - - + - D-dimer Mild leukocytosis, Mild anemia - Hypoxemia, Hypocarbia or Hypercarbia, Respiratory alkalosis Pulmonary embolism Low-density filling defect within the pulmonary artery Pericardial effusion in echocardiography Pulmonary infiltrates, atelectasis, and pleural effusions in CXR Infarct induced apoptosis Pulmonary artery angiography Cough, Hemoptysis
Renal disease Acute Poststreptococcal Glomerulonephritis[44] - - - + - - + +/- Antistreptolysin-O (ASO) titers Leukocytosis ↑ Hypocomplementemia - - Normal to slightly enlarged kidneys Central venous congestion in a hilar pattern in CXR Hypercellularity of endothelial and mesangial cells, Infiltration of the glomerular tuft with polymorphonuclear cells Histological confirmation Hematuria
Hematologic disease Hemolytic-Uremic Syndrome[45] + + - + - - + + C5b-9, ADAMTS13 Anemia, Thrombocytopenia, Reticulocytosis  ↑ ↑Lactate dehydrogenase (LDH), Hypercalcemia  Thalami, brainstem, or cerebellum abnormality Cerebral microangiopathy or hypertension Hypoechoic kidney  Abnormal hyperintensity in the brain cisterns in MRI Microthromboses include fibrin thrombi that may occlude the glomerular tuft Clinical findings coupled with laboratory abnormalities Hematuria, Proteinuria 
Chronic Lymphocytic Leukemia (CLL)[46] + + + + +/- - - +/- CD5, CD19, CD20, IgVH Absolute lymphocytosis, Smudge cells ↑ Flow cytometry Staging - - - Large atypical cells, cleaved cells, and prolymphocytes  Chromosomal and genetic testing Easy bruising
Multiple Myeloma[47] + - + + + + +/- +/- Ig light chain Anemia, Thrombocytopenia, Leukopenia ↑ Bone marrow aspiration and biopsy, ↑Cr Osseous involvement and lytic lesions Peripheral zone of increased vascularity in lesions - Punched-out lesion in skull X-ray Clonal proliferation of plasma cells Protein electrophoresis plus conventional X-rays Constipation
Hypereosinophilic Syndrome[48] +/- +/- - - - - - - IgE, CD117 with CD2 Eosinophilia - ↑Serum tryptase Lymphadenopathy and splenomegaly - Intracardiac thrombi in echocardiography - Reticulin stain for myelofibrosis and tryptase staining for mast cells Clinical findings coupled with laboratory abnormalities Splinter hemorrhages, Raynaud phenomenon
Non-Hodgkin Lymphoma[49] + + + + +/- +/- +/- +/- MYC, BCL2, BCL6, and TP53 Lymphocytosis, Anemia, Thrombocytopenia ↑ ↑Lactate dehydrogenase (LDH), Hypercalcemia  Enlarged lymph nodes, Hepatosplenomegaly, Filling defects in the liver and spleen - Hepatosplenomegaly Mediastinal lymphadenopathy Small cleaved or noncleaved, intermediate, or large cell with a follicular or diffuse pattern Surgically excised tissue biopsy Easy bruising, Testicular mass, Skin lesion
Serum Sickness[50] + + - +/- +/- - - +/- IL-1, IL-6, TNF Leukopenia  ↑ Polyclonal gammopathy, ↑Cr, Cryoglobulinemia - - - - Arteritic lesions are focal, necrotizing, and inflammatory involving all layers of the artery Clinical findings coupled with laboratory abnormalities Hematuria, Skin rash
Disseminated Intravascular Coagulation[51] +/- + - +/- - - + + Fibrin degradation product (FDP) Thrombocytopenia, Schistocytes ↑ ↑D-dimer, aPTT and PT Intracranial hemorrhage - - - Ischemia and necrosis due to fibrin deposition in small and medium-sized vessels Clinical findings coupled with laboratory abnormalities  Acral cyanosis, Hemorrhagic skin infarctions
Idiopathic Thrombocytopenic Purpura[52] + +/- - + - - - + FC gamma receptors (FCGR) IIb Anemia, Thrombocytopenia - HIV, ANA R/O other causes - R/O splenomegaly - Increased number of normal morphologic megakaryocytes Clinical findings coupled with thrombocytopenia Easy bruising, Purpura
Systemic disease Sarcoidosis[53] + + + + - - - +/-  IL-2 and IFN-γ Mild anemia ↑ ↑ACE, ↑1, 25-dihydroxyvitamin D Active alveolitis or fibrosis - Hepatosplenomegaly Bilateral hilar adenopathy Noncaseating granulomas (NCGs) Histological confirmation Heart block, Ocular lesion
Legionella Infection[54] + + + + - - - +/- Inflammatory cytokines Leukocytosis with left shift, Thrombocytosis ↑ ↑D-dimer, FDP, Hyponatremia Pleural effusion - - Nonspecific and indistinguishable CXR Intra-alveolar inflammation, Microabscesses in the parenchyma Sputum culture Cough, Diarrhea
Systemic lupus erythematosus[55] + + + + - - + + Anti dsDNA, ANA  Leukopenia, Lymphopenia, Anemia, Thrombocytopenia ↑ ↑Cr or BUN,

↑ALT or AST, Proteinuria

Interstitial lung disease, Pneumonitis, Pulmonary emboli, Alveolar hemorrhage Aneurysms Pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis in echocardiography Central nervous system (CNS) lupus white-matter changes in MRI Staging lupus nephritis Anti-dsDNA antibody test Skin rashes or photosensitivity
Rheumatoid arthritis[56] - - + + + + - - RF, Anti-CCP antibody Anemia ↑ ↑Cr or BUN,

↑ALT or AST, ANA

Microfractures Aneurysms Effusions in joints Basilar invagination with cranial migration of an eroded odontoid peg in MRI Influx of inflammatory cells into the synovial membrane, with angiogenesis, proliferation of chronic inflammatory cells Clinical findings coupled anti-CCP antibody Rheumatoid nodules
Relapsing polychondritis[57] - +/- +/- + + - - - - Leukocytosis, Anemia - Cryoglobulins, ANA, C-ANCA Calcification of cartilaginous structures Aortic root dilatation Aortic root dilatation and degree of aortic regurgitation in echocardiography Tracheal stenosis in CXR Chondrolysis, Chondritis, Perichondritis Clinical findings coupled with imaging Ear pain and redness, Polyarthritis
Diseases Headache Fever Weight loss Arthralgia Claudication Bruit HTN Focal neurological disorder Biomarker CBC ESR Other CT scan Angiography Ultrasound/ Echocardiography Other Histopathology Gold standard Additional findings
Variable-vessel vasculitis Behçet’s syndrome[58] - - - + - - +/- - CXCL1  Mild anemia, Neutrophilia ↑ Factor V Leiden Focal CNS lesions Aneurysm formation and thrombosis areas Valve vegetations and ventricular thrombi in echocardiography Meningoencephalitis  in MRI Lymphocytic and plasma cell invasion in the prickle cell layer of the epidermis Clinical criteria Genital ulcerations, Oral ulceration
Cogan's syndrome[59] +/- - - +/- - - - +  Anti-Hsp70 antibodies Anemia, Thrombocytosis ↑ RF, ANA Thickening and enhancement of both posterior sclera  Stenosis, thrombosis or more lesions in aortic root Aortic insufficiency in echocardiography Early interstitial keratitis by slit lamp Muscle necrosis and atrophy resembling myositis - Red eye, Hearing loss, Vertigo
Gastrointestinal disease Inflammatory Bowel Disease[60] +/- + + + + - - - Anti-Saccharomyces cerevisiae antibody (ASCA), P-ANCA Leukocytosis, Anemia ↑  Iron or vitamin deficiency, Stool OB Mesenteric fat stranding, bowel wall enhancement, increased vascularity (comb sign) - Fistulas, Abscesses, Stenosis Grossly denuded mucosa with active bleeding in colonoscopy Crypt abscesses and mucosal ulceration, Granulomas  Endoscopy  GI bleeding
Whipple's disease[61] + +/- + + + + + + CCR6, Gut-homing marker integrin β7-chain, T whippelii DNA Mild anemia, Neutrophilia ↑ 72-hour fecal fat determination Nonspecific malabsorption - Hepatosplenomegaly - Periodic acid-Schiff–positive macrophages infiltration in lamina propria of the small bowel Broad-spectrum PCR amplifications Cachexia,

Glossitis

Sjögren's syndrome[62] - - +/- + - - - - Anti-Ro and Anti-La, Anti-alpha-fodrin antibody Anemia,

Leukopenia,

Eosinophilia

↑ Hypergammaglobulinemia, Low bicarbonate level, Hypokalemia  Salt and pepper or honeycomb appearance in parotid glands - Multicystic or reticular pattern in atrophic salivary gland R/O obstructions or strictures with Sialography  Focal aggregates of lymphocytes Schirmer test Keratoconjunctivitis, Gingival inflammation
Single-organ vasculitis Primary central nervous system vasculitis[63] + + + - + - + + von Willebrand factor antigen (vWF) Normal - CSF pleocytosis, predominantly lymphocytes Cerebral infarcts or hemorrhages with mass effect, or hydrocephalus Aneurysm in circle of Willis - Progression of the disease or response to therapy in MRI Chronic granulomatous inflammation and giant cells Histological confirmation Skin rash, Purpura
Infectious disease Aspergillosis[64] + + + - - - - + Aspergillus nucleic acid in blood, Galactomannan Eosinophilia ↑ ↑Serum IgE Aspergilloma mass within a cavity Mass effect stenosis - Aspergilloma mass within the brain in MRI Septate hyphae, branching at acute angles, and tissue necrosis with granulomata and blood vessel invasion Histological confirmation Hemoptysis, Aspergilloma
Histoplasmosis[65] + + + + + - - + - Mild anemia ↑ ↑ALP, ↑LDH Cerebral histoplasmosis  - Valvular involvement in echocardiography PFT Presence of yeast forms in tissue through hematoxylin and eosin staining Sputum cultures Pneumonia, Mediastinitis
Herpes Simplex Encephalitis[66] + + - - - - - + HSV DNA Mild lymphocytosis ↑ CSF pleocytosis Low-density lesions in the temporal and/or frontal lobe - - Hemorrhagic lesion in white matter Multinuclear giant cells PCR or brain biopsy Seizures,

Vomiting

Systemic disease Eclampsia[67] + + - + - - + + VEGF, PlGF, Soluble FLT-1 Anemia, Thrombocytopenia, Schistocytes - ↑Bilirubin, ↓Haptoglobin, ↑LDH, ↑Cr Cortical hypodense areas in the occipital lobes, Diffuse cerebral edema - Poor fetal growth, Oligohydramnios, Abnormal umbilical artery  Increased signal at the gray-white matter junction in MRI - 24-hour urine study  Seizure, Edema
Fibromuscular dysplasia[6] + - +/- + + + + +/- Transforming growth factor β (TGF-β) Normal ↑ ↑ Cr or BUN Alternating stenosis and dilatations in CT angiography Stenosis in the renal arteries Luminal narrowing alternating with dilatation (Beads sign) Focal concentric, long-segment tubular stenosis or outpouching in MRA Fibrodysplastic changes, Collagen deposition Digital subtraction angiography (DSA)  Spontaneous coronary artery dissection (SCAD)

Differentiating renal disease in the microscopic polyangiitis from other Diseases:

The various types of glomerular diseases should be differentiated from each other based on associations, presence of pitting edema, hematuria, hypertension, hemoptysis, oliguria, peri-orbital edema, hyperlipidemia, type of antibodies, light and electron microscopic features. The following table differentiates between various types of glumerular diseases:

Glomerular diseases Disease History and Symtoms Laboratory Findings Pathology
History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
Acute Nephritic Syndromes Poststreptococcal Glomerulonephritis[68][69][70] +/- + +/- +/- +/- +/- +/- +/-
  • Immune complex GN
  • Granular deposit
Renal disease due to Subacute Bacterial Endocarditis, or cardiac shunt (Atrioventricular)[71][72] +/- + +/- +/- +/- +/- +/- +/-
  • Crescentic GN is the most common pathological features
  • Mesangial deposits,
  • Subendothelial deposits
  • Subepithelial "humps," in minority of cases
  • Pauci-immune GN
Lupus Nephritis[73]
  • History of SLE features
 +/- + +/- +/- +/- +/- +/- +/-
  • Differs based on the disease classification
  • Differs based on the disease classification
  • Differs based on the disease classification, mostly immune complex GN
  • Granular deposit
Antiglomerular Basement Membrane Disease (Goodpasture's syndrome)[74][75]
  • Young adults
 + + + + + + - - Diffuse thickening of the glomerular basement membrane with absence of sub-epithelial and sub-endothelial deposits 
  • Immune complex GN
  • Linear deposit
IgA Nephropathy[76][77] + +/- + +/- + - + -
  • Immune complex deposition
  • Crescent formation
  • Immune complex GN, granular deposite
Disease History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
ANCA Small-Vessel Vasculitis[78][79] Granulomatosis with Polyangiitis (Wegener's)[80][81][82]
  • Middle age male
 + + + +/- + - + -
  •  Pauci-immune GN
Microscopic Polyangiitis[28] +/- + + + + + + -
  •  Pauci-immune GN
Churg-Strauss Syndrome[83] +/- + + + + + + -
  •  Pauci-immune GN
Membranoproliferative Glomerulonephritis[84][85] + + + +/- + + - - -
  • Immune complex GN
  • Granular deposite
Henoch-Schönlein purpura [86] + + + +/- + + - - -
  • Diffuse mesangial IgA deposits often associated with mesangial hypercellularity
  • Diffuse mesangial IgA deposits often associated with mesangial hypercellularity
  • Immune complex GN, granular deposite
Disease History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
Cryoglobulinemia[87] Patients having cryoglobulinemia may have positive history of: Pulmonary symptoms:
  • Cough

Cutaneous symptoms:

Gastrointestinal symptoms:

  • Abdominal pain

General symptoms:

+/- + +/- + +/- +/- +/- +/- +/-
  • Prominent IgM and C3
Nephrotic Syndrome Minimal Change Disease[88][89] - + - + +/- + - +
  • Normal
 -
Focal Segmental Glomerulosclerosis[90][91][92] - + - + +/- + - + -
Membranous Glomerulonephritis[93][94] - + - + +/- + - + Immune complex deposition Immune complex GN, granular deposite
Diabetic Nephropathy[95][96][97][98][99][100][101][102][103][104] For more information on diabetes click here. - + - + +/- + - +
  • Diffuse mesangial matrix expansion (nodular glomerulosclerosis)
  • Increased mesangial hypercellularity
  • Prominent glomerular basement membranes
  • Thick basement membrane without any deposit
  • Nodular glomerulosclerosis
 -
Disease History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
 Glomerular Deposition Diseases  Light Chain Deposition Disease[105]
  • Occurs in the setting of high tumor burden
 - - + - + +/- + - + -
  • Light-chain deposits
  • Granular deposits on electron microscopy
  • Detection of light chain deposits using anti–light chain antibody
Renal Amyloidosis[9][106][107][108] - + - + +/- + - + -
  • Diffuse glomerular deposition of amorphous hyaline material (nodular pattern), in mesangium (weakly staining with periodic acid-Schiff (PAS)
  • Nodular deposit
  • AA amyloidosis type: negative for immunoglobulins and complement
  • AL amyloidosis type: Positive for lambda or kappa light chains
Fibrillary-Immunotactoid Glomerulopathy[109] - +/- + +/- +/- +/- + +/- +/- -
  • Diffuse sclerosing glomerulonephritis
  • Diffuse proliferative glomerulonephritis
  • Membranoproliferative glomerulonephritis
  • Mesangioproliferative/sclerosing disease
  • Membranous glomerulonephritis
  • Large fibrillar deposits in the mesangium randomly
  • Glomerular capillary walls different from amloidosis
  • No staining with Congo red or thioflavine-T or with antibodies to a specific type
  • Positive for immunoglobulin G (IgG), C3
  • Kappa and lambda (ie, polyclonal) light chains
Fabry's Disease[110][111][112] - + - + +/- + - + -
  • Vacuolization of visceral glomerular epithelial cells (podocytes) and distal tubular epithelial cells
  • Glycolipid accumulation
  • Myeloid or zebra bodies: Gb3 deposition within enlarged secondary lysosomes as lamellated membrane structures
  • Inclusions, composed of concentric layers (onion skin appearance)
 -
Basement Membrane Syndrome Alport's Syndrome[113][114][115][116][117][118]
  • Positive family history
 Auditary:

Occular problems:

  • Refractory Error
 - + - + +/- + - + -
  • Early stage: unremarkable
Disease History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
Thin Basement Membrane Disease[119][120] - - + -/+ - -/+ - -/+ - - - Diffuse thinning of the glomerular basement membranes (GBM) -
Nail-Patella Syndrome[121][122]
  • Positive family history
  • Poorly developed fingernails, toe nails, and patellae (kneecaps).
  • Elbow deformities
  • Abnormally shaped pelvis bone (hip bone)
  • Knee may be small, deformed or absent
 + + - - - - - - -
  • Mostly unremarkable changes
  • Secondary FSGS
  • Late stages:
    • Global glomerulosclerosis,
    • Tubulointerstitial fibrosis
  • Glomerular basement membranes (GBMs): Focal or diffuse irregular thickening with electron-lucent areas (moth-eaten appearance) containing type III collagen bundles.
  • Similar collagen fibrils can be seen in mesangial matrix.
  • Podocytes: Segmental effacement of foot processes.
  • Nonspecific IgM and C3 deposition may be seen in sclerotic glomeruli.
 Glomerular-Vascular Syndromes  Hypertensive Nephrosclerosis[123] Chronic hypertension +/- +/- + +/- +/- +/- - +/- -
  • Interstitial fibrosis and atrophy
  • Medial thickening and intimal fibrosis of medium-sized and larger vessels
  • Arteriolar thickening, and hyalinosis
  • Chronic stages:
Cholesterol Emboli[124]
  • Depends on the organ involved
 +/- +/- + +/- +/- +/- - +/- -
  • Atheroemboli are seen in interlobular and arcuate arteries, as lance-shaped clefts, due to dissolution of cholesterol crystals
  • Acute lesions:
    • Atheroemboli are surrounded by red blood cells, fibrin, and leukocytes, with multinucleated giant cell reactions
  • Chronic lesions:
    • Cholesterol clefts are surrounded by intimal fibrosis
    • Vessel recanalization of chronic lesions can occur.
  • Global and segmental sclerosis of glomeruli may be present.
  • Extensive foot process effacement can be seen
  • Not specific changes
Disease History Systemic symptoms Hemeturia Proteinuria Hypertension Pitting edema Oliguria Nephrotic features Nephritic features Hyperlipidemia and hypercholesterolemia Auto-antibodies,

Complements

Light microscope Electron microscope Immunoflourescence pattern
Sickle Cell Disease[125]
  • Positive family history
 +/- +/- +/- - - - - - -
  • Glomerular hypertrophy
  • Hemosiderin deposits
  • Focal areas of hemorrhage or necrosis
  • Chronic stage: interstitial inflammation, edema, fibrosis, tubular atrophy, and papillary infarcts
  • Glomerular enlargement and focal segmental glomerulosclerosis (FSGS)
Thrombotic Microangiopathies[126] Click for more information on Thrombotic Microangiopathies. + +/- + +/- +/- +/- - - -
  • Acute stage:
    • Inravasculr fibrin thrombi
  • Chronic stage:
    • Endocapillary hypercellularity.
    • Intimal proliferation of arterioles
  • Swollen glomerular endothelial cells with loss of fenestrations
  • Chronic stage: interposed cells with new GBM matrix material deposition.
Antiphospholipid Antibody Syndrome [127][128][129] + +/- + +/- +/- +/- - - -
  • Swollen glomerular endothelial cells with loss of fenestrations
  • Chronic stage: interposed cells with new GBM matrix material deposition.


Some infectious diseases such as HIV, HBV, HCV, syphilis, leprosy, malaria, and schistosomiasis may cause glomerular diseases.

References

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  120. ↑ Hou P, Chen Y, Ding J, Li G, Zhang H (2007). "A novel mutation of COL4A3 presents a different contribution to Alport syndrome and thin basement membrane nephropathy". Am. J. Nephrol. 27 (5): 538–44. doi:10.1159/000107666. PMID 17726307.
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