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
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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
Mechanism of Signal Transduction Mediated by Transforming Growth Factor {beta} (TGF-{beta})
Blobe G et al. N Engl J Med 2000;342:1350-1358
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
Selective Up-Regulation of PDGFR by Fibroblasts in Scleroderma
Tan F. N Engl J Med 2006;354:2709-2711
SRC: Diagnosis
• New/abrupt onset BP >150/85
• Progressive/sudden rise in creat
• Additional findings
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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 <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
Autologous non-myeloablative hematopoietic stem cell
transplantation in pts with systemic sclerosis
• Burt RK, et al 2007 Bone Marrow Transplantation
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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