Scleroderma and the Kidney

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

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

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