Case Presentation Staci Smith DO April 17th, 2009

Differential Diagnosis hematuria proteinuria glomerulonephritis red blood cell casts

Red Blood Cell Casts Glomerular hematuria Nephritic syndrome Dysmorphic rbc’s glomerular damage rule out urologic causes Nephritic syndrome HTN RBC casts Proteinuria Edema

Dysmorphic rbc dysmorphic red cells acanthocytes ring form

Fatty Cast fat droplets nephrotic syndrome

Differential Diagnosis: Glomerulonephritis Postinfectious GN IgA nephropathy Thin basement membrane Henoch-Schönlein purpura Mesangial proliferative GN SLE Goodpasture’s dz Vasculitis Wegener’s, Churg-Strauss Cryoglobulinemia HIV Membranoproliferative glomerulonephritis Rapidly progressive GN Fibrillary glomerulonephritis Focal glomerulosclerosis Membranous nephropathy Amyloidosis Multiple Myeloma DM HUS

Differential Diagnosis : Glomerulonephritis UA with C and S Cbc with differential Renal panel Urine Pr/Cr Renal US Renal Duplex Cystography Urine eosinophils SPEP / UPEP with IFE

Differential Diagnosis of Glomerulonephritis ANA, dsDNA SLE Cryoglobulins, RF Cryoglobulinemia, HCV Anti-GBM Anti-GBM dz ,Goodpasture’s ANCA’s c-ANCA: Wegener’s p-ANCA: PAN, Churg Strauss, MPA Complements C3, C4, CH50 ASO Post Strept GN Hepatitis profile MPGN HIV HIV, FSGS Renal Biopsy

Differential Diagnosis Low Complements SLE Endocarditis MPGN Post infectious GN Atheroembolic dz Urine eos

Pulmonary Renal Syndromes Wegener’s granulomatosis MPA Churg-Strauss Goodpasture’s syndrome SLE

Vasculitis

Wegener's Granulomatosis distinguished from other vasculitides by the pattern of organ involvement histologic features of granulomatosis and necrotizing inflammation primary involvement upper and lower respiratory tracts kidneys - glomerulonephritis

Wegener's Granulomatosis pathogenesis is unknown interplay of an initiating inflammatory event and a highly specific immune response response is directed against neutrophil granule proteins high titer autoantibodies known as anti-neutrophil cytoplasmic antibodies (ANCA)

Wegener’s Triad 1954- Goodman and Churg triad of pathological features systemic necrotizing angiitis necrotizing granulomatous inflammation of the respiratory tract necrotizing glomerulonephritis

ACR Criteria for WG : Two of four Were developed before ANCA testing was in widespread use Nasal or oral inflammation oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph findings nodules, fixed infiltrates, or cavities Urinary sediment microhematuria (>5 red blood cells per high-power field) red blood cell casts Granulomatous inflammation noted at biopsy

Wegener’s Granulomatosis Organs most frequently affected by Wegener’s Confirm with tissue bx

Homogenous Perinuclear Staining p-ANCA Microscopic polyangitis Churg-Strauss syndrome Polyarteritis nodosa

Granular Cytoplasmic Staining C-ANCA PR3 Wegener’s

ANCA Positive and ANCA Negative 90 to 95 % of patients ANCA-positive small subset of patients who do not have ANCA limited forms up to 40 % of patients may be ANCA-negative

Clinical History ELK classification broad spectrum of organ involvement ears, nose, and throat or upper respiratory tract (E); lungs (L); and kidneys (K)

ELK Classification: Ears, nose, and throat nasal obstruction with serosanguineous discharge chronic sinusitis deep central facial pain saddle nose deformity middle ear involvement -hearing loss subglottic stenosis-hoarseness and stridor

Wegener’s Granulomatosis Saddle nose deformity

ELK Classification Lungs asymptomatic or may present with cough and occasional hemoptysis progressive dyspnea and respiratory failure massive pulmonary hemorrhage

Wegener’s Granulomatosis nodules in the middle and lower lung fields bilaterally

ELK Classification Patients with kidney involvement generally are asymptomatic, but some patients may notice mild hematuria. Edema secondary to nephrotic syndrome may be present

Wegener’s Granulomatosis Neurologic involvement approximately one third of patients peripheral neuropathy with mononeuritis multiplex cranial neuropathy involving the second, sixth, and seventh cranial nerves

Wegener’s Granulomatosis Skin 14% of patients with a purpuric rash over the lower extremities

Wegener’s Granulomatosis Eye and orbit 29% of patients present with red or swollen eyes Joints arthralgias inflammatory joint involvement not erosive or deforming

Limited form of Wegener’s clinical findings isolated to the upper respiratory tract or the lungs one-fourth of cases up to 80 percent eventually develop glomerulonephritis incompletely understood phenotypic differences younger at disease onset more likely to be women

Renal Involvement : Wegener’s acute renal failure with red cells red cell and other casts proteinuria rapidly progressing renal biopsy segmental necrotizing glomerulonephritis with few or no immune deposits (pauci-immune) on immunofluorescence and electron microscopy

Wegener’s Granulomatosis light micrograph segmental necrotizing lesions bright red fibrin deposition

Renal Involvement : Wegener’s glomerular involvement often accompanied by mononuclear tubulointerstitial infiltrates small vessel involvement venules, capillaries, arterioles reoccurs in renal transplant

Renal Involvement : Wegener’s may be severe enough to require dialysis hypertension mediated by ischemia-induced activation of the renin-angiotensin system angiotensin converting enzyme inhibitors risk of worsening renal function removal of the angiotensin II effect on autoregulation and maintenance of the glomerular filtration rate

Treatment untreated systemic WG long-lasting remission poor prognosis 90% of patients dying within 2 years from respiratory or renal failure long-lasting remission cyclophosphamide in combination with corticosteroids 90% of patients respond to cyclophosphamide

Treatment : Induction Methylprednisolone 7mg/kg/day IV for 3 days followed by oral prednisone 1 mg/kg/day tapered to every other day and stopped in 3-4mo Cyclophosphamide 2 mg/kg/day oral or IV 0.5g/m2 per month adjust upward to 1 g/m2 follow cbc

Maintenance Therapy Reduce toxicity after three to six months Use for one year MTX mild–to–moderatedisease no pulmonary hemorrhage or fulminant renal failure If intolerable to Cytoxan Azathioprine Cellcept Infliximab, Etanercept

Predicting Relapse ANCA titers usually parallel the course of vasculitis, especially C-ANCA decreasing titers of ANCA predict a lower risk for clinical relapse

Plasma Exchange role is controversial no real added benefits may be beneficial if life threatening pulmonary hemorrhage especially if dialysis dependent

Key Points : Decreased Complements SLE Endocarditis MPGN Post infectious GN Atheroembolic dz Urine eos

Differential Diagnosis hematuria proteinuria glomerulonephritis red blood cell casts

Differential Diagnosis Low Complements SLE Endocarditis MPGN Post infectious GN Atheroembolic dz Urine eos

Red Blood Cell Casts Glomerular hematuria Nephritic syndrome Dysmorphic rbc’s glomerular damage rule out urologic causes Nephritic syndrome HTN RBC casts Proteinuria Edema

Differential Diagnosis: Glomerulonephritis Postinfectious GN IgA nephropathy Thin basement membrane Henoch-Schönlein purpura Mesangial proliferative GN SLE Goodpasture’s dz Vasculitis Wegener’s, Churg-Strauss Cryoglobulinemia HIV Membranoproliferative glomerulonephritis Rapidly progressive GN Fibrillary glomerulonephritis Focal glomerulosclerosis Membranous nephropathy Amyloidosis Multiple Myeloma DM HUS

Differential Diagnosis of Glomerulonephritis ANA, dsDNA SLE Cryoglobulins, RF Cryoglobulinemia, HCV Anti-GBM Anti-GBM dz ,Goodpasture’s ANCA’s c-ANCA: Wegener’s p-ANCA: PAN, Churg Strauss, MPA Complements C3, C4, CH50 ASO Post Strept GN Hepatitis profile MPGN HIV HIV, FSGS Renal Biopsy

ACR Criteria for WG : Two of four Were developed before ANCA testing was in widespread use Nasal or oral inflammation oral ulcers or purulent or bloody nasal discharge Abnormal chest radiograph findings nodules, fixed infiltrates, or cavities Urinary sediment microhematuria (>5 red blood cells per high-power field) red blood cell casts Granulomatous inflammation noted at biopsy

Renal Involvement : Wegener’s acute renal failure with red cells red cell and other casts proteinuria rapidly progressing renal biopsy segmental necrotizing glomerulonephritis with few or no immune deposits (pauci-immune) on immunofluorescence and electron microscopy

Renal Involvement : Wegener’s acute renal failure with red cells red cell and other casts proteinuria rapidly progressing renal biopsy segmental necrotizing glomerulonephritis with few or no immune deposits (pauci-immune) on immunofluorescence and electron microscopy

Wegener’s Granulomatosis light micrograph segmental necrotizing lesions bright red fibrin deposition

Thank You

Reference Duna, GF, Cotch, MF, Galperin, C, et al. Wegener's granulomatosis: Role of environmental exposures. Clin Exp Rheumatol 1998; 16:669. Hoffman, GS, Kerr, GS, Leavitt, RY, et al. Wegener's granulomatosis: An analysis of 158 patients. Ann Intern Med 1992; 116:488. Banerjee, A, McKane, W, Thiru, S, Farrington, K. Wegener's granulomatosis presenting as acute suppurative interstitial nephritis. J Clin Pathol 2001; 54:787. Wen, YK, Chen, ML. Transformation from tubulointerstitial nephritis to crescentic glomerulonephritis: an unusual presentation of ANCA-associated renal vasculitis. Ren Fail 2006; 28:189