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Description : This medical presentation titled "Scleroderma and the Kidney" provides us details on scleroderma, a long-lasting disease affecting skin, connective tissue, and internal organs including kidney.

Tags : Scleroderma, Kidney, Local, Systemic Disease, Renal Failure, Renal Scleroderma Crisis, Calcinosis cutis, Raynaud Phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia

Published on : Apr 27, 2021 | Views : 2639 | Downloads : 1

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Slide 1-

Scleroderma and the Kidney David Shure
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DD: Renal Failure ATN Renal Scleroderma Crisis
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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
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Local vs Systemic Disease
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Classification dcSSC: diffuse cutaneous SSc lcSSc: limited cutaneous SSC SSc sine scleroderma – internal organ involvement Environmentally induced scleroderma Overlap syndrome: ie MCTD
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Calcinosis cutis Raynaud Phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia
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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
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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
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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
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Fibrosis Fibrosis gradually replaces vascular inflammatory phase and ultimately disrupts architecture of affected tissue TGF-b CTGF PDGF
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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
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Blobe G et al. N Engl J Med 2000;342:1350-1358 Mechanism of Signal Transduction Mediated by Transforming Growth Factor {beta} (TGF-{beta})
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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
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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
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Tan F. N Engl J Med 2006;354:2709-2711 Selective Up-Regulation of PDGFR by Fibroblasts in Scleroderma
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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
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Renal Biopsy Subintimal Fibrin Deposition – Interlobular artery Muscular Renal Artery – Onion Skin thickening with complete obliteration of vascular lumen
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Fibrin Deposition
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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
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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%)
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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 <4 yrs 61 % pts with SRC had good outcomes (55 received no HD, 34 received temp HD). Only 4% of later group progressed to ESRD >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
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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 function, and creat remained unchanged F/U: 25 mths, overall and progression free survival rates are 90 and 70% Concl: Autologous HSCT with non-myeloablative conditioning regimen may lead to improved skin flexibility similar to a myeloablative TBI , but without the toxicity and risks