and the kidney硬皮病肾课件

Scleroderma and the Kidney David Shure July 14, 2009 DD: Renal Failure ATN Renal Scleroderma Crisis Epidemiology Prevalence: 19-75 cases per 100,000 Susceptibility Age: peak occurrence 35-65 F:M 7-12:1 Environmental Factors: infection Occupational exposure: silica dust Usually occurs w/in 4-5 yrs of SSc onset Local vs Systemic Disease Classification dcSSC: diffuse cutaneous SSc lcSSc: limited cutaneous SSC SSc sine scleroderma internal organ involvement Environmentally induced scleroderma Overlap syndrome: ie MCTD Calcinosis cutis Raynaud Phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia Pathogenesis Complex and poorly understood Immune activation Inflammatory response Vascular damage Excessive synthesis EC matrix and collagen deposition Hypothesis: interplay between early immunological events and vascular changes leading to generation of a pop of activated fibrogenic fibroblasts believed to be effector cells in disease Vascular and Endothelial Changes Appear to precede other features of SSc Vasoconstriction ET-1: significantly elevated in SSc and assoc with pulm htn, may initiate fibrosis Superoxide anions: released from endothelium neutralize NO Defective vasculogenesis: fewer circulating endothelial ell precursors ie CD34+, CD133+ and VEGF type 2 Pts with SSc have incr in endothelial cell surface expression of adhesion molecules and elevation in circulating levels of their soluble forms. Cytokine induced upregulation of adhesion molecules ie ICAM-1, VCAM-1, ELAM-1 Autoantibodies 75% pts with SSc have circulating autoantibodies Topoisomerase I (anti-scl 70) anti-topoisomerase antibodies highly specific for SSc, and correlate with greater risk for ILD and more extensive skin involvement Centromere antigens (12-44%) Anticentromere antibodies assoc with limited cutaneous involvement Fibrosis Fibrosis gradually replaces vascular inflammatory phase and ultimately disrupts architecture of affected tissue 1.TGF-b 2.CTGF 3.PDGF TGF b Main Cell Source: macrophages, fibroblasts, T/B cells, platelets, endothelial cells Pathogenic relevance: Induces proliferation fibroblasts and production CTGF and endothirlin-1 Stimulates synthesis collagen, fibronectin Inhibits EC matrix degradation by reduced synthesis of MMP and induction of TIMP-1 Effect in SCL Increased levels in skin Elevated expression/ phosphorylation of smad2,3 effectors of TGF b signaling pathway Blobe G et al. N Engl J Med 2000;342:1350-1358 Mechanism of Signal Transduction Mediated by Transforming Growth Factor beta (TGF-beta) CTGF Cell source: fibroblasts, endothelial cells, smooth muscle cells Pathogenic relevance: induced by TGFb, IL-4, and VEGF Induces proliferation and chemotaxis of fibroblasts and stimulates production of EC matrix Effect in SCL Elevated levels in serum Incr gene expression in skin and in fibroblasts PDGF Cell source: platelets, macrophages, endothelial cells, fibroblasts Pathogenic Relevance: Mitogen and chemoattractant for fibroblasts Induces syntehsis of collagen, fibronectin, proteoglycans, Stimulates secretion of TGF b type I, MCP-1, IL-6 Effect in SCL Elevated expression PDGN in skin Incr levels in BAL Tan F. N Engl J Med 2006;354:2709-2711 Selective Up-Regulation of PDGFR by Fibroblasts in Scleroderma SRC: Diagnosis New/abrupt onset BP 150/85 Progressive/sudden rise in creat Additional findings MAHA and thrombocytopenia Acute retinal changes of malignant HTN New onset proteinuria/ hematuria Urine sediment is bland with limited but incr protein MAHA/TMA Characteristic changes on renal bx Renal Biopsy Subintimal Fibrin Deposition Interlobular artery Muscular Renal Artery Onion Skin thickening with complete obliteration of vascular lumen Fibrin Deposition Prevention/Treatment Prevention: avoidance glucocorticoids If left untreated, SRC can progress to ESRD over 1-2 months and death usually within 1 yr Treatment: Mainstay prompt control HTN, return to baseline bp in 72 hrs Optimal anti-HTN is ACE-I ie captopril Captopril? Advantage = rapid onset and short DOA allowing for more frequent titration Also follow: plt count, LDH, Hb, haptoglobin, LDH for resolution of intravascular hemolysis Indefinite continuation of ACE for bp control ACE Inhibitors Retrospective & case-control studies show no efficacy in prevention of SRC Prospective cohort study- treated vs. untreated: treated w/ recovery of renal fxn & survival at 1 yr (76% vs 15%) Long-term Outcomes of Scleroderma Reanl Crisis Steen V, et al, Annals of Int Med, 2000 Prospective observational cohort w5-10 yr f/u 145 pts with SRC who received continuous ACE-I, and 662 pts with SCL who did not have renal crisis Results: At time of renal crisis, 75% pts had SCL sxs for 1/2 of pts who began HD could dc it 3 to 18 mths later Survival of pts in good outcome group was similar to pts with diffuse SCL without renal crisis Autologous non-myeloablative hematopoietic stem cell transplantation in pts with systemic sclerosis Burt RK, et al 2007 Bone Marrow Transplantation Phase I non-myeloablative autologous HSCT 10 pts with SSc and poor prognostic features PBCS mobilized with CY and G-CSF PBSC graft re-infused after tx with non-myeloablative conditioning regimen statistically significant improvement of modified Rodnan skin score, however cardiac, pulmonary functi