1. Scleroderma and the Kidney David Shure July 14, 2009

2. DD: Renal Failure ATN Renal Scleroderma Crisis

3. 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

4. Local vs Systemic Disease

5. Classification – dcSSC: diffuse cutaneous SSc – lcSSc: limited cutaneous SSC – SSc sine scleroderma – internal organ involvement – Environmentally induced scleroderma – Overlap syndrome: ie MCTD

6. Calcinosis cutis Raynaud Phenomenon Esophageal dysmotility Sclerodactyly Telangiectasia

7. 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

8. 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

9. 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

10. Fibrosis Fibrosis gradually replaces vascular inflammatory phase and ultimately disrupts architecture of affected tissue 1.TGF-b 2.CTGF 3.PDGF

11. 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

12. Blobe G et al. N Engl J Med 2000;342:1350-1358 Mechanism of Signal Transduction Mediated by Transforming Growth Factor {beta} (TGF-{beta})

13. 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

14. 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

16. Tan F. N Engl J Med 2006;354:2709-2711 Selective Up-Regulation of PDGFR by Fibroblasts in Scleroderma

17. 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

18. Renal Biopsy Subintimal Fibrin Deposition – Interlobular artery Muscular Renal Artery – Onion Skin thickening with complete obliteration of vascular lumen

19. Fibrin Deposition

20. 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

21. 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%)

22. 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

24. 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