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Lupus Nephritis with Complications: Vascular Lesions

This patient presents with sob and headache, and a history of lupus nephritis. Findings include renal vascular lesions and non-inflammatory necrotizing vasculopathy. Differential diagnosis includes lupus vasculopathy, thrombotic microangiopathy, and malignant hypertension.

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Lupus Nephritis with Complications: Vascular Lesions

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  1. 18 AAF presented with sob, headache x 2 days. Pt was recently discharged 3days ago after treated for Lupus pneumonitis with steroids. Denies NSAIDs, jt pain, rashes, over the counter meds. Compliance of meds is an issue Pt had in all 14 admissions since Nov 2010 for headache, sob and treated for acc HTN and discharged home on lisinopril amlodepin, metoprolol, plaquinil and prednisone. PMH: HTN, Lupus V Kid Biopsy Jan 2011: Lupus V: w Scr 11.7, u Pr/Cr 0.36, ANA+ 196 (0-19), dsDna + 17 (0-9iu/ml), anti Sm +, low c3, antiRNP+, UA: rbc casts, ssa 3+ : started on Prednisone PSH: termination of pregnancy at 19 weeks, tonsillectomy Social history; lives with grandma, denies smoking, ETOH abuse, illicit drugs Family history: mom died at 40yrs heart attack. Ob/Gyn hist: no abortions, G1P1L0, not on OC pills,no DVT

  2. O/E BP 220/120 86/min, 20/min, 98.1F on cardene drip, Sitting comfortably, no resp distress Chest: b/l air entry good CVS: S1S2+, no G/M/R PA: soft, NT, BS+, No Organomegaly, ascitis+ EXT: edema 1-2+ CNS: aaox3, nonfocal 9.6 143 108 28 4.2>--------<527 INR 1.13, PTT 29.8 ESR 94 ------/--------/--------< 116 28.9 4.7 25 2.2→2.7 →3.2 →3.4 UA: 3+ Pr, rbc 30-35, wbc 5-7, glucose-ve, LE-ve. (Pr 3+,rbc 7-19,wbc0-4) Upr/cr : 0.4 →1.2 →13.4 CXR; B/L mild pl effusion with enlarged mediastinum, no pul edema USG abd : R kid 13.8x5.5x6.7cm , L kid 9.3x7.1x6.6cm, normal echogenicity, ascites+ TTE: LVEF 40-45%, Diastolic dysfunction ,Mod TR,MILD AR, Small P effusion ↓C3 27 (90-180), ↓ C4 <8(9-36), ↓ CH50<11 (22-60) ↑ANA:1:640, DsDna : ???, ↑ antiSm >8( 0-0.9) ANCA (C,P), Anti GBM ,HIV,HBV,HCV : Negative ↑ Anti Card ab IgG 23 (0-14), ↑ IgM 47 (0-12), IgA < 9 (0-11), B2GP < 9 (0-20) both IgG , IgA, Lupus ant icaog : neg, VDRL:NR ↑ Ant scl 70 : 3.81.1 (0-0.9), ↑ anti RNP >8 (0-0.9), anticentromere0.2(0-0.9)

  3. IgG

  4. C3

  5. D/D Lupus III, IV with V APS TMA a)Lupus b)APS c)scleroderma d) malignant HTN (Other causes radiation nephritis, Chr TX rejection) MCTD w predominant lupus +scleroderma sine scleroderma

  6. Renal Vascular Lesions in Systemic Lupus Erythematosus • Uncomplicated vascular immune deposits • Non-inflammatory necrotizing vasculopathy • Thrombotic microangiopathy (TMA) • Renal vasculitis

  7. Uncomplicated vascular immune deposits • LM : accumulation of eosinophilic material underneath the endothelium of arterioles and small arteries, no inflammatory cell infiltrate in the arterial wall. The arterial lumens are not compromised • Uncomplicated vascular immune deposits are more common in patients with active lupus nephritis (class III and IV) in which more immune complex is produced. • D/D : hypertension, diabetes. • Immuno-staining determines whether IgG, IgA, IgM and complement components are present, indicating deposition of immune complex. • EM : immune complex deposits beneath the endothelium and/or extending between medial myocytes. • Renal Outcome same as pts with or without deposits.

  8. Noninflammatory necrotizing vasculopathy • Also know as lupus vasculopathy More common in proliferative forms of lupus nephritis (class III, IV) • LM shows granular eosinophilic deposits in the intima and media of arterioles and interlobular arteries . No or few inflammatory cell infiltrates. • Immunostaining shows positive staining with IgG, IgA, IgM, complement components and fibrin-related antigen in varying degrees • Ultra structurally, there are immune complex deposits, sometimes with fibrin tactoids and platelets in the vessel wall. The endothelium may be denuded and the myocytes may show degenerative changes in areas adjacent to the immune complex. Thrombotic process is evident by the presence of fibrin-related products and injury to the vessel is more severe. Severe hypertension is frequently found, but it is not regarded as the cause of this lesion. There were a number of patients with this lesion without hypertension. Lupus vasculopathy is associated with elevated serum creatinine, hypertension and progression to end stage renal disease.

  9. Thrombotic microangiopathy (TMA) Acute phase; lesion is characterized by the presence of fibrin thrombi in glomerular capillaries, arterioles and sometimes interlobular arteries There are no or few inflammatory cell infiltrates Similar to lupus vasculopathy , lupus vasculopathy seldom shows thrombosis in glomeruli or vascular poles. With glomerular and arterial lumen occlusion, the renal parenchyma shows ischemic changes. Chronic phase show organization and recanalization (fibroblast proliferation and capillary formation within thrombus ),severe narrowing of the lumens and fibrointimal proliferation “onion skin” D/D accelerated or malignant hypertension. Immunostaining shows positive staining for fibrin-related antigen and may show positive IgM and C3. However, unlike lupus vasculopathy, IgG is negative and the immune complex is not seen by EM in the arterioles and arteries. Immunostaining and/or EM are crucial in differentiating TMA from lupus vasculopathy. There is widening of the lamina rara interna of the glomerular basement membrane with new basement membrane formation and subendothelial electron-lucent flocculent material Prevalence 8.4%* ( series of 285 lupus pts with Biopsy) In contrast 0.7%≠ (2/276 autopsied cases lupus) 1 in 14 SLE pt has TMA ¥ *Banfi G et al. Renal vascular lesions as a marker of poor prognosis in patients with lupus nephritis.Am J Kidney Dis. 1991 Aug;18(2):240-8. ≠Grishman,venkateshan :vascular lesions in lupus nephritis.Mod Pathol 1:235-241,1988 ¥Devinsky et al. Clinical andneuropathological findings in systemic lupus erythematosus:the role of vasculitis, heart emboli, and thrombotic thrombocytopenic purpura. Ann Neurol 1988;23:380–4.

  10. TMA is a pathological term characterized by the above description. Renal limited or systemic. The clinical syndromes associated with TMA include a) hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS/TTP) b) antiphospholipid antibody syndrome (APS) c) systemic sclerosis d) malignant hypertension TMA can occur in lupus nephritis without other associated conditions or systemic involvement Antiphospholipid antibody syndrome (APS): aPL ab: anticardiolipin (44%), anti-β2 microglobuin , lupus anticoagulant (34%)#, 1/3 of these patients developed APS. Intrarenal lesions are termed antiphospholipid syndrome nephropathy (APSN).The clinical manifestation is from a normal into a prothrombotic state. Biopsied lupus pts had 32% in western popln$ and 34% Thai patients@ Three hypotheses: 1) Ab can activate endothelium by binding to β2 microglobulin on the endothelial surface resulting in increased expression of adhesion molecules, secretion of cytokine and prostacyclin. These processes turn the endothelium from a normal into a prothrombotic state. 2) cross reaction of aPL with oxidized low-density lipoprotein (LDL) in macrophages, leading to macrophage activation and damage to the endothelium. 3) last hypothesis points to the interference of aPL with the normal coagulation process. The binding of β2 microglobulin, a natural anticoagulant, with aPL creates a prothrombotic environment aPL can be found in both normal persons & patients with APS but without SLE or other autoimmune diseases (primary APS)APSN has been associated with poor renal outcome regardless of the class of lupus nephritis. Detection of this lesion in a renal biopsy is not only providing clinicians with an important prognostic indicator, but also directs treatment towards anticoagulation. # Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med.1990 May 1;112(9):682-98. $ Daugas E et al Antiphospholipid syndrome nephropathy in systemic lupus erythematosus.J Am Soc Nephrol. 2002 Jan;13(1):42-52. @ Cheunsuchon et al. Prevalence and clinicopathologic findings of antiphospholipid syndrome nephropathy in Thai systemic lupus erythematosus patients who underwent renal biopsies. Nephrology (Carlton) 2007 Oct;12(5):474-80

  11. Renal vasculitis • The lesion is the rarest among the 4 types. • Common vessels involved are the small and medium-sized arteries. The interlobular arteries are the most common targets. This is true vasculitis. The arterial walls are destroyed by inflammatory cell infiltrate and fibrinoid necrosis • Immunostaining shows positivity with fibrin-related antigen, and with IgG, IgM and complement factor C3 in varying degrees. Immune complex deposits were observed in some, but not all cases. • Histologic findings are identical to PAN and pauci-immune glomerulonephritis. • SLE may have superimposed pauci-immune glomerulonephritis. ANCA has been found in 37% of patients with lupus nephritis • The glomeruli may show no or scant endocapillary proliferation and subendothelial immune complex deposits while crescents and fibrinoid necrosis are prominent • Renal vascultis can occur in any class of lupus nephritis though more common in proliferative class III and IV • The findings of this lesion in lupus nephritis not only indicates poor renal outcome and the need of more aggressive immunosuppressive treatment, it also prompts the clinician to look for other superimposed vasculitic diseases.

  12. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol. 1994 Feb;4(8):1499-15.

  13. Appel GB, Pirani CL, D’Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol. 1994 Feb;4(8):1499-15.

  14. I. Standard therapy, acceptable but not mandatory II. Available evidence tends to favor efficacy: conventional therapy usually tried first III. Inadequately tested at this time IV. No demonstrated value in controlled trials The American Society for Apheresis June 2007 The American Medical Association (AMA) Council on Scientific Affairs Systemic Lupus Erythematosus:TPE may still be useful in certain special situations: A. Pregnancy, when cytotoxic agents are undesirable B. Lupus-associated TTP C. Lupus anticoagulant (LA)/antiphospholipid antibody syndrome LA, Anticardiolipin Antibodies, and Antiphospholipid Antibody Syndrome Scleroderma: TPE may be useful in rare coexistence of scleroderma and ANCA-positive or antinuclear antibody (ANA)-positive renal disease. Therapeutic Plasma Exchange: Core Curriculum 2008 Andre A. Kaplan, MD American Journal of Kidney Diseases, Vol 52, No 6 (December), 2008: pp 1180-1196

  15. TMA with APS: manifested in 46pts (36 female) pubmed search 83-02 PAPS 61%, sec 39%.TMA first manifestation 57%TTP/HUS 33% catastrophic APS 23% AKI 15% Malignant HTN 13% HELLP 4% Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies.Espinosa G, Asherson RA et al Ann Rheum Dis. 2004;63(6):730-36.

  16. Treatment Steroids 29/42 (69%)Pl Ex 26/42 (62%)anti coag 20/42 (48%)Immuno Suppression 12/42 (29%)IV IG 5/42 (12%)Recovery steroids 10/29 (34%)Plex 19/27 (70%)Death 10/46 (22%) Thrombotic microangiopathic haemolytic anaemia and antiphospholipid antibodies. Espinosa G, Asherson RA et al Ann Rheum Dis. 2004;63(6):730-36.

  17. THANK YOU

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