Case 3 -

Microscopic Polyangiitis ("Micropolyarteristis") Franco Ferrario San Carlo Borromeo Hospital Milan, Italy

Case History: A 66 years old man reported since 1988 HTA and repeated episodes of bilateral renal colic with spontaneous stone expulsion. In a routine cardiologic examination, the first evidence of a systolic murmur was detected. July 1993 : after extraction of a tooth the patient presents fever (38.5° C), arthralgias, diffuse muscular pain. Exams : serum creatinine 1.2 mg/dl; WBC 11.400/mmc; Hb 12.6 g/dl; total serum proteins 6.8 g/dl; ESR 72; CRP 15; RA test negative; AST negative. Echocardiography: Detection of mitral valve vegetation, with diagnosis of bacterial endocarditis. Therapy : unspecified antibiotic therapies for one month. NSAD (arthralgias). September 1993: for the persistence of fever and arthralgias was admitted to Reumatology Department. Exames : Serum creatinine 3.4 mg/dl; WBC 15.800/mmc; Hb 10.4 g/dl; ESR 60; CRP 10.9; ANA negative; RA test positive; normocomplementemia; Proteinuria 0.3 g/24h, microscopic hematuria. Echocardiography : confirmation of bacterial endocarditis. He was referred to our Nephrology Department for renal biopsy. At admission: rapid decline of renal function (serum creatinine 5 → 9 mg/dl) with oligoanuria. Proteinuria 0.5 g/24 h, microscopic hematuria. Sonography : normal kidneys. A renal biopsy was performed. Renal Biopsy Results Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Slide 2 Click to view with ImageScope Click to view with a Web-Based Viewer Light Microscopy: The renal sample presented 20 glomeruli. No glomeruli showed global sclerotic lesions. 12 glomeruli were totally normal without mesangial expansion or mesangial cells proliferation. Few glomeruli showed a typical picture of tuft necrosis, with disruption of capillary walls and extracapillary proliferation. In the other glomeruli there were a granuloma-like reaction around recognizable glomeruli, characterized by total destruction of glomeruli with circumferential accumulation of T lymphocytes, monocytes and epithelioid cells. A very intense interstitial leukocyte infiltration was present. One medium size artery showed a massive necrosis of the arterial wall with intense perivascular infiltrates (arteritis). Immunofluorescence Microscopy: The immunofluorescence was characterized by few scattered glomerular deposits of C3 (pauci-immune pattern) with contemporaneous presence in some glomeruli of fibrinogen deposits in the site of intra-extracapillary proliferation. There was no significant staining for IgG, IgM or IgA. Differential Histological Diagnosis 1) Endocarditis associated glomerulonephritis: the renal lesion in endocarditis associated GN can be characterized by necrotizing-extracapillary lesions, but was never described the presence of granuloma-like reaction and usually immunofluorescence presents evident glomerular deposition of immunocomplexes 2) Acute interstitial nephritis (Antibodies or NSAD Toxicity): Acute interstitial nephritis is of course characterized by variable but usually diffuse interstitial infiltration of mononuclear cells. Glomeruli and vessels are usually within normal limit. In some cases renal granuloma related to drugs were described, but granuloma are found in the interstitium in association with destroyed tubules and NO in clear periglomerular location. 3) Diffuse Lupus Nephritis: DLN is usually characterized by diffuse and marked glomerular hypercellularity with intense massive parietal deposits (wire-loops). Crescent formation is frequently present but a clear necrotizing-extracapillary proliferation is very rare. Immunofluorescence is characterized by so called "full-house pattern" with massive deposits of immunoglobulins and complement fractions. 4) Anti-GBM antibody disease: the disease can present absolutely the same picture of necrotizing-extracapillary proliferation sometimes with periglomerular granuloma-like reaction. The Immunohistological pattern should be diagnostic with typical linear deposition of IgG along glomerular basement membrane. 5) Primary glomerulonephritis: all primary glomerulonephritis such as acute post-infectious GN, IgA GN, Membranoproliferative GN can present a rapidly progressive course with diffuse extracapillary proliferation. These diseases present quite always a "intra-extracapillary" form and necrotizing glomerular lesions are extremely rare. Moreover all primary glomerulonephritis show their typical Immunoistological pattern of different Immunocomplexes deposition. 6) ANCA-associated vasculitis: Pauci-immune necrotizing-extracapillary nephritis is quite suggestive of the diagnosis of ANCA-associated vasculitis. The presence of granuloma-like reaction is not diagnostic of Wegener's granulomatosis, but is also present in Micropolyarteritis and in Renal limited form. Subsequent Diagnostic Exames: ESR 80 CRP 11 RA test positive Normocomplementemia ANA and Anti-DNA negative (excluding SLE nephritis) Anti-GBM negative (excluding Anti-GBM antibody disease) P-ANCA positive with MPO > 1000 u/ml Echocardiography: mitral insufficiency of moderate degree due to incompetence of mitral posterior leaflet. Cordal rupture minicking a vegetation (no endocarditis) Conclusions: The presence of "pauci-immune necrotizing-extracapillary nephritis with P-ANCA (MPO) positivity is strongly diagnostic of ANCA-associated vasculitis. The absence of convincing clinical syntoms of systemic vasculitis (only artralgias and muscolar pain) is suggestive of "renal limited vasculitis". However five days after the onset of therapy the patient developed an hemorragic alveolitis. The final diagnosis at this point could be microscopic polyangiitis ("Micropolyarteristis"). References: Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases: anti-glomerular basement membrane antibody disease. J Nephrol. 2005 Jul-Aug;18(4):351-3. Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases: ANCA-associated vasculitis (Second part). J Nephrol. 2005 May-Jun;18(3):217-20. Ferrario F, Rastaldi MP. Histopathological atlas of renal diseases: ANCA-associated vasculitis (first part).J Nephrol. 2005 Mar-Apr;18(2):113-6. Hauer HA, Bajema IM, Van Houwelingen HC, Ferrario F, Noel LH, Waldherr R, Jayne DR, Rasmussen N, Bruijn JA, Hagen EC; European Vasculitis Study Group (EUVAS). Determinants of outcome in ANCA-associated glomerulonephritis: a prospective clinico-histopathological analysis of 96 patients. Kidney Int. 2002 Nov;62(5):1732-42. Hauer HA, Bajema IM, Hagen EC, Noel LH, Ferrario F, Waldherr R, van Houwelingen HC, Lesavre P, Sinico RA, van der Woude F, Gaskin G, Verburgh CA, de Heer E, Bruijn JA. Long-term renal injury in ANCA-associated vasculitis: an analysis of 31 patients with follow-up biopsies. Nephrol Dial Transplant. 2002 Apr;17(4):587-96. Ferrario F, Rastaldi MP. Necrotizing-crescentic glomerulonephritis in ANCA-associated vasculitis: the role of monocytes. Nephrol Dial Transplant. 1999 Jul;14(7):1627-31.